protocole - Canadian Cancer Trials Group

Transcription

DATE DU PROTOCOLE: 2006-JAN-04
NCIC CTG TRIAL: MA.27 BONE
NCI US SUBMISSION: 2005-OCT-17
NCI US RE-SUBMISSION #1: 2005-NOV-24
NCI US RE-SUBMISSION #2: 2006-JAN-04
AMENDMENT #1: 2006-MAR-31
AMENDMENT #2: 2007-MAY22
NATIONAL CANCER INSTITUTE OF CANADA
CLINICAL TRIALS GROUP (NCIC CTG)
THE INFLUENCE OF FIVE YEARS OF ADJUVANT ANASTROZOLE OR EXEMESTANE
ON BONE MINERAL DENSITY IN POSTMENOPAUSAL WOMEN
WITH PRIMARY BREAST CANCER
A COMPANION STUDY TO NCIC CTG MA.27
NCIC CTG MA.27B
CTSU MA.27B
MA.27 STUDY CHAIR:
TRIAL COMMITTEE:
PHYSICIAN COORDINATOR:
BIOSTATISTICIAN:
STUDY COORDINATOR:
SUPPORTED BY:
PAUL GOSS
JAMES INGLE
DAWN HERSHMAN
JOSEPH PATER
JUDY-ANNE CHAPMAN
CATHERINE ELLIOTT
PFIZER INC.
U.S. Cooperative Group Members who are not aligned with NCIC CTG will enroll patients
and submit data via the Cancer Trials Support Unit (CTSU)
(for NCI CTEP Use ONLY: VERSION DATE: 2007-MAY-22; UPDATE DATE: 2007-MAY-22)
CONFIDENTIAL
CONFIDENTIAL
AMENDMENT #2: 2007-MAY-22
This study is supported by the NCI Cancer Trials Support Unit (CTSU).
Institutions not aligned with NCIC CTG will participate through the CTSU
mechanism as outlined below and detailed in the CTSU logistical appendix.
•
The study protocol and all related forms and documents must be downloaded from the
protocol-specific Web page of the CTSU Member Web site located at https://members.ctsu.org
•
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU
logistical appendix for specific instructions and documents to be submitted.
•
Patient enrollments will be conducted by the CTSU. Refer to the CTSU logistical appendix for
specific instructions and forms to be submitted.
•
Data management will be performed by the NCIC Clinical Trials Group. Case report forms (with
the exception of patient enrollment forms), clinical reports, and transmittals must be sent to the
NCIC Clinical Trials Group unless otherwise directed by the protocol. Do not send study data or
case report forms to the CTSU Data Operations.
•
Data query and delinquency reports will be sent directly to the enrolling site by the NCIC
Clinical Trials Group. Please send query responses and delinquent data to the NCIC Clinical Trials
Group and do not copy the CTSU Data Operations.
•
Each site should have a designated CTSU Administrator and Data Administrator and must keep
their CTEP AMS account contact information current. This will ensure timely communication
between the clinical site and the NCIC Clinical Trials Group.
CONFIDENTIAL
CONFIDENTIAL
TABLE OF CONTENTS
BONE MINERAL DENSITY STUDY CONTACTS: ................................................................................. 1
TREATMENT SCHEMA ............................................................................................................................. 2
1.0
OBJECTIVES .................................................................................................................................. 4
2.0
2.1
BACKGROUND AND RATIONALE ............................................................................................ 5
Introduction ...................................................................................................................................... 5
3.0
TRIAL DESIGN ............................................................................................................................ 11
4.0
4.1
4.2
STUDY POPULATION ................................................................................................................ 12
Eligibility Criteria........................................................................................................................... 12
Ineligibility Criteria ........................................................................................................................ 13
5.0
BASELINE EVALUATION (See also Appendix I) ...................................................................... 14
6.0
6.1
6.2
ENTRY/REGISTRATION PROCEDURES ................................................................................. 15
Entry Procedures ............................................................................................................................ 15
Documentation Requirements ........................................................................................................ 15
7.0
EVALUATION DURING AND AFTER PROTOCOL TREATMENT ....................................... 16
8.0
8.1
8.2
PROCEDURE DESCRIPTIONS ................................................................................................... 17
Dual Energy X-ray Absorptiometry................................................................................................ 17
Concomitant Therapy ..................................................................................................................... 17
9.0
SERIOUS ADVERSE EVENT REPORTING .............................................................................. 18
10.0
10.1
10.2
10.3
10.4
10.5
10.6
10.7
STATISTICAL CONSIDERATIONS ........................................................................................... 19
Population ...................................................................................................................................... 19
Background and Demographic Characteristics............................................................................... 19
Study Medication ........................................................................................................................... 19
Concomitant Therapy ..................................................................................................................... 19
Evaluations ..................................................................................................................................... 20
Interim Analyses............................................................................................................................. 21
Sample Size Considerations ........................................................................................................... 21
11.0
11.1
11.2
11.3
PUBLICATION POLICY .............................................................................................................. 22
Authorship of Papers, Meeting Abstracts, Etc................................................................................ 22
Responsibility for Publication ........................................................................................................ 22
Submission of Material for Presentation or Publication ................................................................. 22
CONFIDENTIAL
i
CONFIDENTIAL
12.0
12.1
12.2
12.3
12.4
12.5
12.6
12.7
12.8
12.9
12.10
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ............................................... 23
Institution Eligibility for Participation ............................................................................................ 23
Retention of Patient Records and Study Files ................................................................................ 23
REB/IRB (Research Ethics Board/Institutional Review Board) Approval for Protocols ............... 23
Informed Consent ........................................................................................................................... 24
Centre Performance Monitoring ..................................................................................................... 25
On-Site Monitoring/Auditing ......................................................................................................... 26
Case Report Forms ......................................................................................................................... 26
Protocol Adherence and Amendments ........................................................................................... 26
Trial Closure Considerations .......................................................................................................... 26
NCI Data Monitoring Mechanism .................................................................................................. 26
13.0
REFERENCES .............................................................................................................................. 27
APPENDIX I APPENDIX II APPENDIX III APPENDIX IV APPENDIX V APPENDIX VI APPENDIX VII -
PATIENT EVALUATION FLOW SHEET................................................................. 29
DOCUMENTATION FOR STUDY ............................................................................ 30
CTSU PARTICIPANT PROCEDURES ...................................................................... 31
BLOOD SAMPLING INSTRUCTIONS ..................................................................... 34
MA.27B – DRUG SUPPLY ........................................................................................ 35
CENTRAL REVIEW OF BONE MINERAL DENSITY SCANS .............................. 38
SAMPLE CONSENT FORMS .................................................................................... 40
English Sample Consent............................................................................................... 40
Exemple de formulaire de consentement en FRANÇAIS ............................................ 49
LIST OF CONTACTS ........................................................................................................................... Final Page
CONFIDENTIAL
ii
CONFIDENTIAL
BONE MINERAL DENSITY STUDY CONTACTS:
Dr. Paul Goss
Telephone:
Fax:
email:
Dr. James Ingle
Telephone:
Fax:
email:
Dr. Dawn Hershman
Telephone:
Fax:
E-mail:
Dr. Joseph Pater
Telephone:
Fax:
email:
CONFIDENTIAL
Study Chair
Director of Breast Cancer Research
Massachusetts General Hospital Cancer Center
55 Fruit Street, Cox Building, Suite 640
Boston, MA, USA 02114
(617) 724-3118
(617) 724-1079
[email protected]
NCCTG Co-Chair
NCCTG Mayo Clinic
200 First Street SW
Rochester, MN, USA
507-284-1887
507-284-1803
[email protected]
SWOG Co-Chair
Assistant Professor of Medicine
Herbert Irving Cancer Center
Columbia University
161 Fort Washington – 1068
New York, NY 10032
(212) 305-1945
(212) 305-0178
[email protected]
Physician Coordinator
NCIC Clinical Trials Group
10 Stuart Street
Queen’s University
Kingston, Ontario
K7L 3N6
(613) 533-6430
(613) 533-2814
[email protected]
1
CONFIDENTIAL
AMENDMENT #1: 2006-MAR-31; AMENDMENT #2: 2007-MAY-22
TREATMENT SCHEMA
MA.27 patients who have a Bone Mineral Density measurement (using DEXA: Dual Energy X-ray
Absorptiometry) done within 25 weeks prior to randomization to the MA.27 core protocol may participate in
the companion protocol. In order to be eligible patients must not have malabsorption syndrome, clinically
relevant vitamin D deficiency, active hyper- or hypoparathyroidism, Paget’s disease, uncontrolled thyroid
disease, Cushing’s disease, other pituitary diseases, or other bone diseases. Patients must not have received
previous treatment with anticonvulsants or anabolic steroids within the past 12 months, high doses of
corticosteroids or sodium fluoride for an extended time or be on long term treatment with coumarins.
Eligible MA.27B patients will be stratified according to their baseline bone mineral density measurement:
Group A: BMD T-score > -2.0 SD of the mean value of peak bone mass in young normal women
Group B: BMD T-score < -2.0 SD of the mean value of peak bone mass in young normal women
Patients in Group A must not have taken investigational drug therapy or any other drug including
bisphosphonates for the prevention of osteoporosis within the past six months. Patients in Group B may have
started bisphosphonate therapy up to a maximum of 25 weeks prior to the MA.27B registration and may
remain on the same bisphosphonate after registration. (No bisphosphonate therapy prior to 25 weeks before
registration is allowed, however). Specific bone biomarkers will be followed.
Patient consented for MA.27B
BMD assessed within 25 weeks prior to
randomization to core protocol and results obtained
Randomization to Core protocol
Registration in Bone Mineral Density Companion
Study (with stratification). Serum for baseline bone
biomarkers collected after registration & prior to
starting MA.27/MA.27B drugs
Group A
Group B
(no osteopenia or osteoporosis)
No Bisphosphonate Therapy;
Calcium (1000 mg/day) &
Vitamin D (800 IU/day)
supplementation mandatory
(osteopenia or osteoporosis)
Bisphosphonate Therapy;
(while on MA.27 aromatase inhibitors)
Bone Biomarkers
Baseline, 6, 12 months;
BMD
Baseline, then annually
CONFIDENTIAL
2
CONFIDENTIAL
Endpoints:
Group A:
Co-Primary:
 Percentage change in BMD, measured in gm/cm2, from baseline in 1) the L1-L4 postero-anterior (PA)
region of the spine, and 2) the hip* at 2 years from randomization to the core protocol.
Secondary:
region of the spine, and 2) the hip at 5 years from randomization to the core protocol;
 Mean percentage change from baseline in 1) the lumber spine, and 2) the hip BMD, measured in
gm/cm2 at 1, 3, and 5 years, whether patients received exemestane or anastrozole;
 Proportion of women in Group A who develop BMD below the absolute threshold for osteopenia
(< - 2.0 SD below the mean), suffer clinical osteoporotic fracture or have an asymptomatic fracture
revealed at 36 months;
 Pattern of changes in bone biomarkers from baseline;
 Clinical safety of study medications with respect to osteoporosis in the evaluation of fractures
(collected as part of the core protocol).
Group B:
Co-Primary:
 Percentage change in BMD from baseline, measured in gm/cm2, in 1) the L1-L4 postero-anterior (PA)
region of the spine, and 2) the hip* at 2 years from randomization to the core protocol.
Secondary:
region of the spine and 2) the hip at 5 years from randomization to the core protocol;
 Mean percentage change in BMD from baseline, measured in gm/cm2, in 1) the L1-L4 postero-anterior
(PA) region of the spine, and 2) the hip at 1, 3 and 5 years from randomization to the core protocol,
whether patients received exemestane or anastrozole;
 Percentage of patients in Group B who have a > 5% improvement of BMD from baseline to 2 years in
1) the L1-L4 postero-anterior (PA) region of the spine and 2) the hip;
 Pattern of changes in bone biomarkers from baseline;
 Incidence of clinically apparent osteoporosis related clinical fracture of long bones;
 Safety and tolerability of combination of AI with bisphosphonate.
Sample Size: 408 eligible** women
(includes expected 10% withdrawal [missing assessment or lost to follow-up] and a 5% drop-out rate [stopping
medication due to adverse events or developing conditions contraindicated in the study])
* “hip” refers to total hip
** See section 4 for eligibility criteria.
CONFIDENTIAL
3
CONFIDENTIAL
1.0
OBJECTIVES
This companion study aims to answer an important clinical question for women, diagnosed with early
stage breast cancer, who are being considered for treatment with an aromatase inhibitor.
The primary objective is to examine whether there is a clinically relevant difference in impact on
BMD between the steroidal (exemestane) and the non-steroidal (anastrozole) agents at 2 years, i.e.
whether there is a 5% difference in change of BMD between patients receiving the two aromatase
inhibitors: 1) in women without osteopenia or osteoporosis (Group A patients), and; 2) in women with
documented osteopenia or osteoporosis (Group B patients).
The percentage change in BMD from baseline between patients receiving exemestane and those
receiving anastrozole will be compared using the Mann-Whitney (Wilcoxon) rank-sum test. This test
procedure will be used to examine differences in BMD in 1) the L1-L4 (PA) region of the spine, and
2) the hip, for patient Group A and for patient Group B.
The analysis will be performed when all the patients registered have been followed for two years and
will include only those patients assessed at two years.
CONFIDENTIAL
4
CONFIDENTIAL
2.0
BACKGROUND AND RATIONALE
2.1
Introduction
This companion study has been designed as part of the NCIC CTG MA.27 trial in which
postmenopausal women with resected primary breast cancer are randomized to receive either
anastrozole or exemestane (for five years) given as adjuvant therapy for newly diagnosed breast
cancer. It will be conducted in selected centres to compare the effects of study drug treatment in a
subset of patients treated in the core MA.27 protocol.
The aromatase (estrogen synthetase) inhibitors are a new class of endocrine therapy for breast cancer.
Three agents in this class are approved for use in advanced breast cancer viz. the two non-steroidals
anastrozole and letrozole and one steroidal inhibitor exemestane. In this disease setting, these agents
appear more efficacious than tamoxifen. Toxicities and side effects from these agents have been
evaluated both in the metastatic and adjuvant setting. Non-significant differences have been reported
between the three inhibitors with respect to common toxicities such as nausea, vomiting, hot flashes,
musculoskeletal discomfort, fatigue and headaches. However, with their ability to almost completely
deplete estrogen levels in the circulation in postmenopausal women, the potential for significant
adverse end-organ effects exists with chronic aromatase inhibitor therapy. The most serious of these
are the potential to cause bone resorption and also to alter lipid metabolism with a potential
concomitant increase in adverse cardiovascular events. These effects are particularly relevant because
many women in the age group for whom these agents are suitable already have an age related risk of
cardiovascular and bone disease. Thus these potential side effects are extremely important if the agents
are going to be given for prolonged periods as adjuvant therapy in well women with newly diagnosed
breast cancer. The purpose of this study is to determine the effects on bone metabolism of the
aromatase inhibitors and whether there are differences between the non-steroidal anastrozole and the
steroidal inhibitor exemestane.
Bone loss in healthy postmenopausal women
The average annual rate of bone loss is 1% to 2% in postmenopausal women and 0.2%-0.5% in men
of the same age. While the rate of bone loss in women is higher in the early years after menopause, it
probably continues in many individuals for several years and may increase again after the age of 70.
Annual losses of 3% to 5% are not uncommon during the 5 to 8 years following menopause. An
annual loss of 8% or more is considered to be clinically significant, possibly leading to diagnosis of
osteoporosis.[Osteoporosis Int 1997]. Osteoporosis is diagnosed when bone mineral density is greater than
2.5 standard deviations (SD) below the mean value of peak bone mass in young normal women.
Established osteoporosis is defined when this bone loss is seen in the presence of fractures.[Osteoporosis
Int 1997].
Effects of Aromatase Inhibitors on Bone Metabolism
a) In-vivo in the Rat
The effects of exemestane on bone turnover were studied in 10-month-old Sprague-Dawley rats.[Goss,
2004] Experimental groups containing 12 to 16 animals each included baseline control (premenopausal
model), intact control (sham operated) plus vehicle, sham plus exemestane 100 mg/kg/week,
ovariectomized plus vehicle (postmenopausal model), and ovariectomized plus exemestane 100
mg/kg/week. Lumbar vertebral and femoral BMD were measured 16 weeks after initiating treatment
with exemestane or vehicle. Lumbar vertebral BMD and femoral BMD were 10.7% and 6.7% lower,
respectively, in ovariectomized control rats than in intact controls (P <.0001 and .001, respectively). In
contrast, the lumbar vertebral BMD in rats given exemestane was 99.7%
CONFIDENTIAL
5
CONFIDENTIAL
of BMD in intact controls and 11% higher than in ovariectomized controls (P < .0001). Femoral BMD
in rats given exemestane was 99.9% of the BMD in intact controls and 7.1% higher than in
ovariectomized controls (P < .001) (Table 2). Serum pyridinoline levels (a marker of bone resorption)
were 43% higher in ovariectomized controls versus intact controls (P < .0001), suggesting excessive
bone resorption with ovariectomy. Administration of exemestane to ovariectomized rats protected
against 96% of the ovariectomy-induced increase in pyridinoline (P < .0001 vs ovariectomized
controls). Serum osteocalcin levels (a marker of bone formation) increased 31% in ovariectomized
controls versus intact controls (P < .02). This increase was prevented by treatment with exemestane
[Goss, 2004].
Table 2. Effect of 16 weeks of treatment with exemestane on bone mineral density (BMD) in 10month-old Sprague-Dawley female rats [Goss, 2004]:
Experimental Group
Baseline Control (n = 12)
Intact Control (Sham operated) + Vehicle (n = 16)
Sham Operated + Exemestane 100 mg/kg/week (n = 13)
Ovariectomized + Vehicle (n = 14)
Ovariectomized + Exemestane 100 mg/kg/week (n = 16)
BMD (g/cm2)
Lumbar
Vertebral
Femoral
0.157
0.1721
0.1566
0.1765
0.1575
0.175
*
0.1398
0.1647†
‡
0.1552
0.1764§
* P < .0001 vs intact controls
† P < .001 vs intact controls
‡ P < .0001 vs ovariectomized controls
§ P < .001 vs ovariectomized controls
A subsequent study using the same design evaluated the bone effects of 16 weeks of treatment with
exemestane (20 to 100 mg/kg IM weekly), the principal exemestane metabolite 17-hydroexemestane
(20 mg/kg IM weekly), or letrozole (1 mg/kg orally daily) in rats [Goss, 2004] . This study was designed
to determine if the beneficial effects of exemestane observed in the previous study were a) actually due
to its 17-hydro metabolite and b) unique to steroidal anti-aromatase agents. Both exemestane and its
17-hydro metabolite increased lumbar spine BMD to a similar extent when compared with
ovariectomized controls (P <.05 for all) and both reduced the ovariectomy-induced increase in
pyridinoline (85%-97% and 95%, respectively; P <.05 for all), a marker of bone resorption (Table 3).
Similar results were noted in femoral BMD. The increase observed in the bone formation marker
osteocalcin in ovariectomized rats was completely blocked by both exemestane and 17hydroexemestane; osteocalcin levels in rats treated with exemestane or its metabolite were similar to
those observed in intact control animals. In contrast to these results, letrozole-treated rats had BMD
measurements and bone biomarker levels similar to those seen in ovariectomized control rats (Table 3)
[Goss, 2004].
Table 3. Effect of 16 weeks of treatment with exemestane, 17-hydroexemestane, or letrozole on bone
mineral density (BMD) and mechanical strength in 10-month-old Sprague-Dawley female rats. Data
are results compared with results in ovariectomized controls [Goss, 2004] .
CONFIDENTIAL
6
CONFIDENTIAL
Exemestane
20-100 mg/kg/week IM
17-Hydroexemestane
20 mg/kg/week IM
Letrozole
1 mg/kg/day orally
Lumbar vertebral BMD
↑ 7.4% - 14.8%*
↑ 14.0%*
↓3.0%
Femoral BMD
↑ 5.8% - 7.7%*
↑ 7.9%*
↑ 0.4%
↑ 20.8%*
↑ 0.2%
↑ 14.6%*
↑ 0.3%
3-Point bending strength of the ↑ 9.7% - 21.3%*
femur
Compressive strength of the 5th ↑ 6.8% - 14.7%*
lumbar vertebra
* P < .05 vs. ovariectomized control (postmenopausal controls)
This study also assessed mechanical properties of the vertebra and femora (Table 3). 3-point bending
strength of the femur and compressive strength of the 5th lumbar vertebra were measured after 16
weeks of treatment. Both parameters were higher in ovariectomized rats given exemestane or
hydroexemestane than in ovariectomized controls (P < 0.05 for all comparisons). There were no
statistically significant differences in the results of either parameter in ovariectomized rats receiving
letrozole versus ovariectomized controls [Goss, 2004] .
These data demonstrate that both exemestane and its 17-hydro metabolite prevent ovariectomyinduced changes in biochemical markers of bone turnover, significantly prevent bone loss, and
enhance bone mechanical strength in ovariectomized animals (a postmenopausal model). These
protective effects on bone are not achieved with the nonsteroidal imidazole-based anti-aromatase agent
letrozole [Goss, 2004].
b) In postmenopausal women
Early Breast Cancer
In the ATAC (Arimidex or Tamoxifen Alone or in Combination) Trial, adjuvant therapy with
anastrozole (1 mg daily), tamoxifen (20 mg daily), or the combination was compared in 9366
postmenopausal women. [ATAC Trialists’ Group, 2002] During a median follow-up of 33.3 months, a
statistically significantly higher incidence of musculoskeletal disorders (27.8% vs 21.3%) and
fractures (5.9% vs 3.7%) was recorded with anastrozole vs. tamoxifen (P <.0001 for both), with the
greatest increase in fractures seen in the spine. [ATAC Trialists’ Group, 2002] An updated analysis at a
median follow-up of 37 months continues to demonstrate a statistically significant difference
(musculoskeletal disorders: 30.3% vs. 23.7%; fractures: 7.1% vs. 4.4%) [Sainsbury, 2002], with the
absolute difference between anastrozole and tamoxifen widening for fracture risk. After a median 68
months follow-up, 11% of the patients receiving anastrozole had a fracture while only 7.7% of those
receiving tamoxifen had one (P < 0.0001).
The IES trial compared 5 years of tamoxifen to 2-3 years of tamoxifen followed by exemestane for
total of five years of adjuvant hormone therapy. Early results, at a median 30.6 months follow-up
indicated that therapy with exemestane did not lead to significantly more fractures than tamoxifen:
respectively, 3.1% versus 2.3% (p=0.08) [Coombes 2004]. The 3.1% fracture rate for exemestane is
comparable to the 11% fracture rate at median 68 months for anastrozole. The patients in both studies
were not stratified by baseline BMD nor was there prophylactic administration of bisphosphonates;
however, patients may have received bisphosphonates on trial, following a diagnosis of osteopenia or
osteoporosis.
CONFIDENTIAL
7
CONFIDENTIAL
Estimated percent change in BMD and biochemical markers of bone turnover at 1 year are available
from a non-randomized, non-matched subpopulation of women enrolled in the ATAC trial (80
anastrozole-treated women, 87 tamoxifen-treated women, and 82 women treated with the combination
of tamoxifen and anastrozole) and 39 control patients with breast cancer but not receiving hormone
therapy. [Eastell, 2002] Lumbar spine BMD decreased 2.6% and thoracic spine BMD decreased 1.7% in
women treated with anastrozole for 1 year, but increased 1% and 0.5%, respectively with tamoxifen.
Combination therapy resulted in 0.2% and 0.8% increases, respectively, while there were 0.4% and
0.1% decreases, respectively, in the control group. The biochemical marker urine NTx increased
12.2% with anastrozole, but decreased in all other groups. BAP increased 20.8% with anastrozole, but
decreased in the tamoxifen and combination groups. BAP increased 4.6% in the control group. Thus
anastrozole is associated with an increase in bone turnover and an accompanying decrease in BMD. In
contrast, tamoxifen and the combination of tamoxifen and anastrozole are associated with a decrease
in markers of bone turnover and a slight increase in BMD. [Eastell, 2002]
Postmenopausal women with breast cancer
The effects of exemestane 25 mg daily (n=24) vs. megestrol acetate 160 mg daily (n=29) on markers
of bone turnover were assessed at baseline and after 8 weeks of therapy in postmenopausal women
with metastatic breast cancer. [Zilembo, 2002] In women with bone metastases (about 75% of patients),
exemestane was associated with a statistically significant increase in ICTP and BAP, while megestrol
acetate was associated with a statistically significant increase only in ICTP. [Pfizer] (It is known that
women with bone metastases have increased bone turnover. [Kanis 1995; Martinetti 1997]) In 12 patients
without evidence of bone metastases, neither hormone had a statistically significant effect on ICTP
levels and only exemestane significantly increased BAP levels, suggesting an anabolic effect [Pfizer].
These data are contrasted with the results of a study assessing the effect of the nonsteroidal imidazolebased anti-aromatase inhibitor anastrozole on bone metabolism in postmenopausal women with
advanced breast cancer. [Bajetta 2002] In this study, increases in biochemical markers of bone formation
and resorption were noted after 12 weeks of treatment. In the subpopulation of patients without bone
metastases, the only biochemical marker of bone turnover altered by anastrozole was urine crosslinked N-telopeptides of type I collagen (NTx), which was increased, suggesting a catabolic effect
[Bajetta 2002].
Healthy postmenopausal women
Exemestane was evaluated in a 12-week, randomized, single-blind, placebo-controlled study
conducted in healthy women to investigate effects on bone turnover. A total of 60 postmenopausal
women (50 to 75 years old) without history of osteoporosis or other metabolic disorder of the bone
were randomized to exemestane 25 mg daily, letrozole 2.5 mg daily, or placebo. At 12 weeks, there
were similar baseline adjusted AUCs for BAP and urine CTx in the placebo and exemestane groups,
whereas changes in both markers were more substantial in women receiving letrozole (Figure 5).
These data show an early distinction in bone biomarker responses following short-term treatment with
steroidal and nonsteroidal imidazole-based anti-aromatase agents. [Subar 2003] Trials are ongoing to
confirm these findings in postmenopausal women with early breast cancer.
CONFIDENTIAL
8
CONFIDENTIAL
Baseline-adjusted area under the curve (AUC) values* for bone alkaline phosphatase (BAP) and urine
cross-linked C-telopeptides of type 1 collagen (u-CTx) in healthy postmenopausal women after 12
weeks of placebo, Exemestane 25 mg daily, or letrozole 2.5 mg daily [Pfizer] were assessed in a
double-blind, placebo-controlled, prospective, 6-month study conducted in 42 healthy 60 to 76-yearold (median 69 years) postmenopausal women to determine the effects on bone resorption (see figure
above) [Heshmati 2002]. Serum levels of estrogens, OC, BAP, and parathyroid hormone and urinary
levels of pyridinoline (Pyd) and deoxypyridinoline (Dpd) were measured at baseline and again after 6
months of treatment with letrozole or placebo. After 6 months of treatment with letrozole, there was a
reduction in serum estrogen concentrations to nearly undetectable levels and a compensatory decrease
in parathyroid hormone levels (Table 4). There were no significant changes in the bone formation
markers OC and BAP. The bone resorption markers urinary Pyd and Dpd increased significantly
(13.3% and 14.2%, respectively; P =.03 for both) in letrozole-treated patients. These data demonstrate
that the reduction in estrogen concentrations from low postmenopausal levels to nearly undetectable
levels achieved by administration of letrozole is associated with an increase in markers of bone
resorption, without affect on markers of bone formation.12 Thus, letrozole administration is associated
with an acceleration of the effect on bone remodeling seen with natural aging.
*A mathematical approach to depicting the net impact of treatment over time.
Table 4. Effect (median change from baseline) of letrozole 2.5 mg daily for 6 months vs. placebo on
estrogen levels and markers of bone resorption [Heshmati 2002].
Variable
Estrone (E1), pg/mL*
Estradiol (Es), pg/mL*
Parathyroid Hormone (PTH), pmol/L*
Osteocalcin (OC), ng/mL*
Bone-specific alkaline phosphatase (BAP), U/L*
Pyridinoline (Pyd), nM/mM/24 hr†
Deoxypyridinoline (Dpd), nM/mM/24 hr†
Letrozole
-19.0
-4.8
-0.7
1.8
0.6
6.3
2.1
Placebo
-2.5
0.1
0.1
1.4
0.8
0.8
0.4
P value
<.001
<.001
.002
.659
.588
.028
.029
* Measured in blood
† Measured in urine
CONFIDENTIAL
9
CONFIDENTIAL
A second study also reported increased bone resorption in healthy postmenopausal women treated with
letrozole. [Harper-Wynne 2002] Thirty-two healthy women were treated with letrozole 2.5 mg daily for 3
months. Plasma estradiol levels fell significantly during the study period (P <.001). Effects on bone
remodeling were assessed by serum cross-linked C-telopeptides of type I collagen (CTx), with samples
timed to reduce the affect of circadian variation. CTx increased from 1900 to 2370 pmol/L (P =.02) or
a mean of 25% over the 12-week study period in the 27 women who completed the study (95% CI, 549).
Bone Mass measurements
A number of techniques are available to evaluate bone density in peripheral, central or the entire
skeleton as well as the cancellous or cortical bone envelopes. These include radiographic
absorptiometry (RA), dual X-ray absorptiometry (DEXA), spinal and peripheral quantitative computed
tomography (QCT/pQCT) and quantitative ultrasound.
These techniques vary in both clinical and research utility, and in general availability but for proper
comparative assessments these techniques need to be accurate, precise and expose patients to minimal
radiation.
The most widely used methods for bone density measurement are SXA and DEXA for peripheral
(forearm, heel) or axial (hip, spine) measurement. DEXA is the more commonly used technique
providing accurate and precise measurements of bone density and has therefore been selected as the
standard in this protocol [Osteoporosis Int. 1997].
CONFIDENTIAL
10
CONFIDENTIAL
3.0
TRIAL DESIGN
The MA.27 core protocol is an open label multicentre, multinational randomized trial of the steroidal
aromatase inhibitor, exemestane (25 mg daily) versus the non-steroidal inhibitor anastrozole (1 mg
daily) given for five years. Canadian and American participants are involved in this trial. MA.27B will
evaluate a sub-set of MA.27 patients.
Only centres with approved and certified Hologic or Lunar instrumentation of pre-confirmed standards
can participate in this bone sub-study. Participating centres will approach all patients randomized in
their centre in order to maintain a balance between the two arms of the trial.
The investigator will inform the patient about the purpose of the companion study and obtain informed
consent for participation. Patients who agree to participate in this companion study will have had their
baseline BMD measurement within 25 weeks prior to randomization to the core MA.27 protocol.
Eligible MA.27B patients will be stratified according to their baseline bone mineral density
measurement (the lowest of the two T-scores: L1-L4 or total hip):
Group A: BMD T-score > -2.0 SD of the mean value of peak bone mass in young normal women
Group B: BMD T-score < -2.0 SD of the mean value of peak bone mass in young normal women
Serum for bone biomarkers (formation marker: serum amino-terminal procollagen 1 extension peptide
[P1NP]; resorption marker: serum N-telopeptide ) will be obtained at baseline, 6 and 12 months
Sample kits with specific instructions for specimen collection, tubes, labels and mailing instructions
will be provided. These specimens will be shipped to and stored in a central laboratory for future
assays of these markers. Please see Appendix IV for details.
BMD of the L1-L4 (PA) region of the spine and hip will be determined at baseline and repeated at
year 1, 2, 3, 4 and 5. If protocol treatment is discontinued before 5 years, a bone density measurement
should be obtained unless a measurement was performed within the past 6 months or unless the patient
discontinues trial treatment within the first year after randomization to the core protocol.
At the time of randomization to the MA.27 core protocol, the caller will confirm that the patient is
participating in the Bone Mineral Density Companion Study (MA.27B). All patients participating in
the Bone Mineral Density Companion Study will receive Calcium 1000 mg daily and Vitamin D
800 IU daily*. This cost of this medication will be covered centrally for the purposes of the companion
study. Please see Appendix V for details.
* The expectation is that MA.27B patients will take 500-1000 mg of calcium a day, dependent upon
tolerability.
MA.27B
Group A
Group B
Evaluations
Medications
Bone Biomarkers*
Baseline, 6,12 months
BMD Assessment*
Baseline & then annually
Calcium / Vitamin D*
(locally provided, but study funded)
Calcium / Vitamin D*
(locally provided, but study funded)
Bisphosphonate
(provided only for patients without insurance
coverage – to be determined by Investigator)
* while on MA.27 aromatase inhibitor therapy
CONFIDENTIAL
11
CONFIDENTIAL
4.0
STUDY POPULATION
MA.27 patients who have a Bone Mineral Density measurement done within 25 weeks prior to
randomization to the MA.27 core protocol may participate in this companion study (MA.27B) subject
to the eligibility and ineligibility criteria below.
Eligible MA.27B patients will be stratified according to their baseline bone mineral density
measurement (the lowest of the two T-scores: L1-L4 or total hip):
Group A: BMD > -2.0 SD of the mean value of peak bone mass in young normal women (no
osteopenia or osteoporosis)
Group B: BMD < -2.0 SD of the mean value of peak bone mass in young normal women.
4.1
Eligibility Criteria
There will be NO EXCEPTIONS to eligibility requirements at the time of registration. Questions
about eligibility criteria should be addressed PRIOR to calling for registration.
The eligibility criteria for this study have been carefully considered. Eligibility criteria are standards
used to assure that patients who enter this study are medically appropriate candidates. For the safety of
the patients, as well as to ensure that the results of this study can be useful for making treatment
decisions regarding other patients with similar diseases, it is important that no exceptions be made to
these criteria for admission to the study.
Patients must fulfill all of the following criteria to be eligible for admission to the study:
For all patients:
4.1.1
Patient is randomized to and eligible for the MA.27 core protocol.
4.1.2
Patient consent has been obtained according to local Institutional and/or University Human
Experimentation Committee requirements. It will be the responsibility of the local participating
investigators to obtain the necessary local clearance, and to indicate in writing to the NCIC CTG Study
Coordinator that such clearance has been obtained, before the trial can commence in that centre.
Because of differing requirements, a standard consent form for the trial will not be provided but a
sample form is given in Appendix III. A copy of the initial full board REB approval and approved
consent form must be sent to the central office. The patient must sign the consent form prior to
registration. Please note that the consent form for this study must contain a statement which gives
permission for the NCIC CTG and monitoring agencies to review patient records (see section 12.4 for
further details).
4.1.3
Acceptable quality DEXA of the L1-L4 postero-anterior (PA) spine and hip has been taken within 25
weeks prior to randomization to the MA.27 core protocol. Radiographs are retained at the site and
available for central review if requested. BMD determined in this fashion is > -2.0 SD (for Group A –
no osteopenia or osteoporosis) or < -2.0 SD (for Group B) of the mean value of peak bone mass in
young normal women.
CONFIDENTIAL
12
CONFIDENTIAL
4.1.4
Serum for bone biomarkers (serum N-telopeptide and serum amino-terminal procollagen 1 extension
peptide) will be collected after registration and prior to starting any study treatment. (These specimens
will be sent to a central laboratory.)
4.1.5
For Patients in Group A, no drugs, investigational or not, including bisphosphonates, for the
prevention of osteoporosis, have been taken within the past 6 months. Patients in Group B may have
started bisphosphonate therapy up to a maximum of 25 weeks prior to the MA.27B registration and
may remain on the same bisphosphonate after registration. (No bisphosphonate therapy prior to 25
weeks before registration is allowed, however).The following bisphosphonate regimens are provided
as examples of suitable therapy:
RISEDRONATE SODIUM – ACTONEL
35 mg orally once weekly
ALENDRONATE – FOSAMAX
70 mg once weekly
Bisphosphonate treatment, in Group B patients, may have started up to 25 weeks in advance of the
registration date but, if not yet begun, should be started at the same time as core protocol (MA.27)
aromatase inhibitor therapy.
4.1.6
Serum creatinine has been measured (in µmol/L or in mg/dl) and creatinine clearance calculated, using
the Cockcroft-Gault Formula, for all patients whose baseline bone mineral density assessment places
them in protocol group B (requiring a bisphosphonate). The “calculated creatinine clearance” is
calculated as follows.
If the serum creatinine is measured in µmol/L, please use the following Cockcroft-Gault Formula:
CrCl (ml/min) = [(140-age) X weight in Kg] X 1.23 X 0.85
(Cr in µmol/L)
If the serum creatinine is measured in mg/dl, please use the following formula:
CrCl (ml/min) = [(140-age) X weight in Kg] X 0.85
72 X (Cr in mg/dl)
The calculated creatinine clearance must be > 35 ml/min for eligibility.
4.2
Ineligibility Criteria
Patients who fulfill any of the following criteria are not eligible for admission to the study:
4.2.1
Malabsorption syndrome, or known vitamin D deficiency, active hyper- or hypoparathyroidism, or
Paget’s disease.
4.2.2
Uncontrolled thyroid disease, Cushing’s disease or other pituitary diseases.
4.2.3
Any other bone disease (including osteomalacia, osteogenesis imperfecta).
CONFIDENTIAL
13
CONFIDENTIAL
4.2.4
Any of the following previous treatments:
 Anticonvulsants within the past 12 months;
 Corticosteroids at doses greater than the equivalent of 5 mg/day prednisone for more than 2 weeks
within the past 6 months;
 Anabolic steroids within the past 12 months;
 For patients in Group A, any drug treatment, whether investigational or not, including
bisphosphonates, for the prevention of osteoporosis within the past 6 months. For patients in
Group B, more than 25 weeks of bisphosphonate therapy just prior to registration or any
bisphosphonate use before 25 weeks prior to registration;
 Long-term use of coumarins.
4.2.5
Concurrent treatment with sodium fluoride at doses of > 5mg/day.
CONFIDENTIAL
13a
CONFIDENTIAL
5.0
BASELINE EVALUATION (SEE ALSO APPENDIX I)
History & Physical
Exam
including:
Biochemistry
Investigations
Previous History
Concomitant medications
Height
Weight
Body Mass Index
Serum creatinine and calculated
creatinine clearance for Group B
patients (see section 4.1.6)
Timing
Within 4 weeks prior to
randomization to the MA.27
core protocol
Bone Mineral
Density
L1-L4 (PA) spine
hip
Within 25 weeks prior to randomization
to the core protocol
(BMD results must be known prior to
registration)
Bone biomarkers
Serum P1NP
Serum N-telopeptide
After registration and prior to starting
any study treatment
The cost of Bone Mineral Density DEXA scans, required by the protocol, will be covered by the
study.
The Bone Mineral Density (BMD) measurements must be done on Hologic or Lunar instrumentation
in approved, certified centres and subsequently repeated in follow-up on the same instruments so that
the results are comparable. Electronic versions of scans will be sent to UHN for analysis by a certified
(ISCD) densitometrist. Please see Appendix VI for details.
Hard copy reports of all BMD measurements will be sent to the NCIC CTG central office as
supporting documentation. Appropriate intervention, if necessary will be taken by the individual
investigators and communicated to NCIC CTG on the case report form.
Blood specimens will be shipped to and stored in a central laboratory for future assays of the bone
biomarkers. The blood specimens should be processed and frozen at -20oC or lower until shipped.
Please consult Appendix IV regarding sampling and shipping of blood specimens for bone
biomarkers.
CONFIDENTIAL
14
CONFIDENTIAL
6.0
ENTRY/REGISTRATION PROCEDURES
6.1
Entry Procedures
At the time of randomization to the MA.27 core protocol, the caller will confirm that the patient is
participating in the Bone Mineral Density Companion Study (MA.27B). All eligible patients enrolled
on the companion study by a participating centre will be entered into a patient registration log
provided by the NCIC CTG. The appropriate serial number for each patient, assigned at randomization
to the core protocol, should be used on all documentation and correspondence with NCIC CTG for the
companion study. Patients will be stratified according to baseline measurement:
Group A: BMD> -2.0 SD of the mean value of peak bone mass in young normal women (no
osteopenia or osteoporosis)
Group B: BMD< -2.0 SD of the mean value of peak bone mass in young normal women
in addition to the stratification factors in the core protocol.
All registrations will be done centrally by the NCIC CTG and will be obtained by calling the NCIC
CTG Clinical Trials Assistant at (613) 533-6430 or by faxing the Bone Mineral Density Eligibility
Checklist to (613) 533-2814. At the time of registration, a copy of the completed Bone Mineral
Density Eligibility Checklist must be available.
The following information will be required:






trial code (NCIC CTG MA.27 B)
treatment centre and investigator
date of full board REB/IRB approval for Bone Mineral Density Companion Study (MA.27B) at
participating centre
patient's initials, hospital number, NCIC CTG serial number for MA.27
confirmation of the requirements listed in Section 4.0, including dates of essential tests
completed Eligibility Checklist
Registration will be given by telephone and confirmed by mail.
6.2
Documentation Requirements
A specific Bone Mineral Density Companion Study (MA.27B) Eligibility Checklist and Form 1B will
be completed at the time of randomization to the MA.27 core protocol if the patient consents to and is
eligible for MA.27B. The Eligibility Checklist and Form 1B are available on the NCIC CTG website.
For each MA.27B protocol-mandated visit, the Form 1B (at baseline) or Form 5B (at follow-up)
should be completed and two photocopies made of the completed form. Please submit the original to
NCIC CTG, enclose one photocopy with the shipment of serum samples and retain the other copy for
your files.
CONFIDENTIAL
15
CONFIDENTIAL
7.0
EVALUATION DURING AND AFTER PROTOCOL TREATMENT
All patients registered in MA.27B must be evaluated according to the schedule outlined in Appendix I
with documentation submitted according to the schedule in Appendix II.
The following table describes required investigations for patients receiving protocol aromatase
inhibitor treatment (on the core protocol, MA.27) for a maximum of 5 years. The table also describes
required investigations after the patient discontinues protocol treatment (a maximum of 5 years after
beginning protocol treatment). The timing of each visit coincides with a core protocol (MA.27)
mandated visit so that no extra visits are required.
Timing from Registration to MA.27B
Investigations
At MA.27 core protocol
treatment discontinuation*
if more than 6 months
since last BMD
24, 36, 48
6 mths 12 mths & 60 mths
measurement
History &
Physical
Clinical Evaluation
X
X
including+
Bone Mineral Of L1-L4 (PA) spine &
X
Density
hip
Serum Bone
serum P1NP, serum
X
X
Biomarkers
N-telopeptide
* discontinuation of treatment on the main MA.27 study
+ as part of the main, MA.27 protocol
X
X
X
X
Only centres with approved and certified Hologic or Lunar instrumentation can participate in
MA.27B. The same instrument (Hologic or Lunar) that was used to measure bone mineral density at
baseline must be used to measure bone mineral density during and at the completion of protocol
treatment. Electronic versions of scans will be sent to UHN for analysis by a certified (ISCD)
densitometrist. Please see Appendix VI for details.
Blood specimens will be shipped to and stored in a central laboratory for future assays of the bone
biomarkers. See Appendix IV for details.
Patients who are registered to MA.27B and stop MA.27 protocol aromatase inhibitor treatment within
one year of randomization will continue to be followed for all core protocol (MA.27) endpoints but
will not require the evaluations of the companion study (MA.27B). Calcium / Vitamin D supply will
cease when aromatase inhibitor supply ceases. Bisphosphonate therapy after aromatase inhibitor
cessation will be at the discretion of the Investigator.
Patients registered in MA.27B and subsequently found to be ineligible will not require the evaluations
of the companion study (MA.27B) but follow-up for all core protocol (MA.27) endpoints will
continue.
CONFIDENTIAL
16
CONFIDENTIAL
8.0
PROCEDURE DESCRIPTIONS
8.1
Dual Energy X-ray Absorptiometry
BMD of L1-L4 (PA) region of the spine and hip will be done at baseline and at 12, 24, 36, 48, 60
months from registration to MA.27B. All measurements will be carried out by means of Hologic or
Lunar instruments in approved, certified centres. The same instrument must be used for all
measurements. Electronic versions of scans will be sent to UHN for analysis by a certified (ISCD)
densitometrist. Please see Appendix VI for details.
8.2
Concomitant Therapy
8.2.1
Permitted:
Concomitant calcium and Vitamin D supplements (1000 mg/day of calcium and 800 IU/day of
Vitamin D) are mandatory for all patients in the companion study and will be provided (locally
provided and study funded). The expectation is that MA.27B patients will take 500-1000 mg of
calcium a day, dependent upon tolerability. Bisphosphonates are required therapy (though not
provided for patients with insurance coverage) for patients in Group B (osteopenic or osteoporotic at
baseline). The following bisphosphonate regimens are provided as examples of suitable therapy:
70 mg once weekly
8.2.2
Not Permitted:
While on the MA.27B protocol:
 Anticonvulsants;
 Corticosteroids at doses greater than the equivalent of 5 mg/day prednisone for more than 2
weeks;
 Sodium fluoride at doses > 5 mg/day;
 Anabolic steroids;
 For patients in Group A, any drug, whether investigational or not, including bisphosphonates, for
the prevention of osteoporosis (new requirement for bisphosphonates represents an endpoint in
MA.27B);
 Long-term use of coumarins.
CONFIDENTIAL
17
CONFIDENTIAL
9.0
SERIOUS ADVERSE EVENT REPORTING
Since this companion study involves only investigation and not treatment, there are not expected to be
any adverse events related to this protocol specifically. However, information concerning fractures is
required to be documented for all patients entered in the MA.27 core protocol. This includes: the date
of the fracture, the site: weight-bearing bones (pelvis, femur, tibia) or vertebral compression (cervical,
thoracic, lumbar). In addition the main cause of the fracture should be recorded (metastasis,
osteoporosis, trauma) and a copy of the radiology or imaging report, identifying the fracture, should be
sent to NCIC CTG.
In the event that a clinically significant bone loss occurs, defined as one of the following:
a) 6% per year;
b) a cumulative reduction of 8% or more over any period of time;
c) in the group starting out with “normal” BMD values, a BMD worse than -2.5 SD below the
mean value of peak bone mass in young normal women.
This information should be communicated immediately to the NCIC CTG central office in Kingston,
Ontario, Canada. DEXA scans will also be reviewed centrally by a certified ISCD densitometrist (see
Appendix VI for details).
In any patient in Group A not already on bisphosphonate treatment, therapeutic intervention with
bisphosphonates should be undertaken in the event of any of these findings; this information will be
documented on the CRF (bone biomarker and BMD assessments will continue as scheduled in these
patients to assess the response to bisphosphonate). These findings will usually not necessitate patients
being removed from the core protocol. The following bisphosphonate regimens are provided as
examples of suitable therapy:
70 mg once weekly
Prior to starting bisphosphonates, Group A patients should have an assessment of renal function
(please see protocol section 4.1.6 for details of assessment).
Investigators should refer to the core protocol (MA.27 - section 11) for SAE reporting guidelines for
the core study investigational agents.
CONFIDENTIAL
18
CONFIDENTIAL
10.0
STATISTICAL CONSIDERATIONS
This companion study aims to answer the important clinical question for women diagnosed with breast
cancer, who are being considered for treatment with an aromatase inhibitor. The primary objective is
to examine whether there is a clinically relevant difference in impact on BMD between the steroidal
(exemestane) and non-steroidal (anastrozole) agents at 2 years, i.e. whether there is a 5% difference in
change of BMD between patients receiving the two aromatase inhibitors: 1) in women without
osteopenia or osteoporosis (Group A patients); 2) in women with documented osteopenia or
osteoporosis (Group B patients).
To answer this question, MA.27B will compare the effects on bone mineral density (BMD) in 1) the
L1-L4 (postero-anterior) region of the spine and 2) the hip, as well as changes in bone biomarkers, in a
sub-set of MA.27 patients treated with either anastrozole or exemestane (for five years), given as
adjuvant therapy for newly diagnosed breast cancer.
10.1
Population
All eligible patients enrolled in the core study (MA.27) are eligible for the bone mineral density
companion study (MA.27B) subject to the inclusion and exclusion criteria specified in this protocol.
10.2
Background and Demographic Characteristics
Data will be summarized with respect to demographic and baseline characteristics. The comparability
of the treatment groups will be assessed with respect to these variables.
10.3
Study Medication
Descriptive statistics will be used to summarize the duration of treatment.
10.4
Concomitant Therapy
All patients will receive calcium 1000 mg daily and vitamin D 800 IU daily. (The expectation is that
MA.27B patients will take 500-1000 mg of calcium a day, dependent upon tolerability.)
Group B patients, if not already on a bisphosphonate, will be required to take a bisphosphonate
selected by the Investigator (supplied only for those patients without insurance coverage). The
following bisphosphonate regimens are provided as examples of suitable therapy:
70 mg once weekly
The number of patients in Group A receiving drug for treatment of low bone mineral density will be
summarized by treatment received and duration on study medication.
CONFIDENTIAL
19
CONFIDENTIAL
10.5
Evaluations
Co-Primary variables:
BMD in 1) the L1-L4 (PA) region of spine and 2) the hip.
Secondary variables:
Bone biomarkers (formation marker serum amino-terminal procollagen 1 extension peptide (PINP);
resorption marker: serum N-telopeptide).
Primary endpoint:
The primary endpoint for analyses is the percentage change of BMD measured at two years from
baseline in 1) the L1-L4 (PA) region of spine and 2) the hip.
Secondary endpoints:
The percentage change in BMD at five years is a secondary endpoint. Other secondary endpoints
include: mean percentage change in BMD from baseline at 1, 3, and 5 years; the proportion of women
in Group A who develop BMD below the absolute threshold for osteopenia (<-2.0 SD below the
mean), suffer any osteoporotic fracture or have an asymptomatic fracture revealed at 36 months;
percentage of patients in Group B who have a > 5% improvement of BMD at 2 years post
randomization; patients in Group B who have clinically apparent osteoporosis related fracture of long
bones; pattern of change in bone biomarkers measured from baseline; clinical safety and tolerability of
study medications.
If patients in Group A receive treatment with bisphosphonate due to low BMD, the values measured
after initiation of bisphosphonate are treated as missing values and will be replaced by the worst value
that occurs in the specified time interval. Although these data will be censored from primary analysis,
they will be presented in descriptive analysis to assess response to delayed administration of
bisphosphonate. To be included in the primary analysis at two years, patients must be assessed at two
years. The same is true for the comparisons at the end of one, three, and five years.
Data analyses
Primary Objective:
The primary objective is to examine whether there is a clinically relevant difference in impact on
BMD between the steroidal (exemestane) and non-steroidal (anastrozole) agents at 2 years, i.e.
whether there is a 5% difference in change of BMD between patients receiving the two aromatase
inhibitors: 1) in women without osteopenia or osteoporosis (Group A patients); 2) in women with
documented osteopenia or osteoporosis (Group B patients). The analysis will be performed when all
the patients randomized are followed for two years.
The percentage change in BMD from baseline between patients receiving exemestane and those
receiving anastrozole will be compared using the Mann-Whitney (Wilcoxon) rank-sum test. This test
procedure will be used to examine differences in BMD in 1) the L1-L4 (PA) region of spine and 2) the
hip for patient Group A, and for patient Group B.
Secondary Objectives:
1. At two years, we will test for differences in BMD from baseline for patients who received
exemestane and for those who received anastrazole, for Group A patients and for Group B
patients.
CONFIDENTIAL
20
CONFIDENTIAL
2. The 95% confidence interval for the percentage changes in BMD at two years from baseline will
be presented for each group of patients by aromatase inhibitor, as well as for the betweenaromatase inhibitor differences.
3. Mean percentage change in BMD from baseline at 1, 3, and 5 years.
4. The proportion of patients with an individual clinically relevant change in BMD will be
summarized by whether they received exemestane or anatrozole and whether they were in Group
A or Group B; tests for these differences in response to aromatase inhibitor by Group will be with
an exact Fisher test. Clinically relevant changes in BMD are
a) BMD < -2.0 SD below the mean for women in Group A;
b) BMD > 5% positive change from baseline for women in Group B.
5. The analyses in points 1,2, and 4 will be repeated at 5 years.
6. Exploratory longitudinal analyses will be conducted to examine the pattern of changes in bone
biomarkers over time.
10.6
Interim Analyses
No formal interim analysis is planned. The data from this companion study will be reviewed by the
Data and Safety Monitoring Committee to review patient safety.
10.7
Sample Size Considerations
From a previous study conducted by NCIC CTG on women with early breast cancer, we estimate that
the standard deviation of the percentage change in BMD is around 0.10. To detect a 5% difference
between exemestane and anastrozole, each study arm should have 89 patients, based on a power of
0.80 and a two-sided alpha of 0.05, that incorporates adjustments for the 2 BMD assessments and 2
tests for aromatase inhibitor effect. However, we would expect a 10% withdrawal rate (missing
assessment or lost to follow-up) and a 5% drop out rate (stopping study medication due to adverse
events or developing conditions contraindicated in this study) during the first two year follow-up, so
we would need 102 patients per study arm and 408 patients overall.
CONFIDENTIAL
21
CONFIDENTIAL
11.0
PUBLICATION POLICY
11.1
Authorship of Papers, Meeting Abstracts, Etc
The trial will be published, with naming of individual authors, using the following rules:




The first author will be the chair of the companion study.
Co-authors will include the companion Study Co-chairs
A limited number of the members of the NCIC CTG Clinical Trials Group and Pfizer may be
credited as authors depending on their level of involvement in the study.
Additional authors, up to a maximum of 15, will be those who have made the most significant
contribution to the overall success of the study. This contribution will be assessed, in part but
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the
study chair.
11.1.2 In an appropriate footnote or at the end of the article the following statement will be made:
"A study coordinated by the Clinical Trials Group of the National Cancer Institute of
Canada. Participating investigators included: (a list of the individuals who have
contributed patients and their institutions)."
11.2
Responsibility for Publication
It will be the responsibility of the study chair to write up the results of the study within a reasonable
time of its completion. If after a period of six months following the analysis of study results the draft is
not substantially complete, the central office reserves the right to make other arrangements to ensure
timely publication.
11.3
Submission of Material for Presentation or Publication
Material may not be submitted for presentation or publication without prior review by Pfizer, the
NCIC CTG physician and study coordinator, and approval of the study chair. Individual participating
centres may not present outcome results from their own centres separately. Supporting groups and
agencies will be acknowledged.
CONFIDENTIAL
22
CONFIDENTIAL
12.0
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES
12.1
Institution Eligibility for Participation
All centres in Canada and the United States participating on the MA.27 core protocol must participate
in this companion study. (Please refer to the core MA.27 protocol for further information on
Investigator qualifications.) Please see Appendix III for CTSU procedures.
12.2
Retention of Patient Records and Study Files
ICH Good Clinical Practice guidelines apply to NCIC CTG studies. It is the responsibility of NCIC
CTG to inform the investigator/institution as to when trial related records no longer need to be
retained. The investigator/institution should take measures to prevent accidental or premature
destruction of these documents.
NCIC CTG will notify all the trial investigators/institutions and all the regulatory authorities if clinical
development of an investigational product discontinues or when trial related records no longer need to
be retained.
12.3
REB/IRB (Research Ethics Board/Institutional Review Board) Approval for Protocols
Each participating centre will have on file with the NCIC CTG central office, as part of its
membership/ agreement documents, a description of its ethics review process.
Initial Approval
Member centres wishing to participate in this companion study are required to obtain full board local
ethics approval of the protocol and consent form (see below) by the appropriate REB/IRB.
This trial will be locally activated only after full board approval of the protocol, informed consent
form, advertising materials for subject recruitment and subject compensation plans, if applicable, has
been obtained from the local REB/IRB. A copy of the local REB/IRB approval, and a completed
NCIC CTG Confirmation of Initial Ethics Approval Form as well as a copy of the approved informed
consent form to be used at the centre should be sent to the NCIC CTG central office.
Continuing Approval
This trial is NCI US affiliated and therefore U.S. regulations regarding the Protection of Human
Subjects apply (U.S. Code of Federal Regulations Title 45, Part 46). These regulations require that reapprovals of research be conducted at least once per year for as long as data are being submitted on
trial patients, even through the follow-up period. Furthermore, these regulations require that annual reapprovals must be full board as long as the study is open to accrual or patients are receiving protocol
treatment or undergoing protocol mandated interventions.
CONFIDENTIAL
23
CONFIDENTIAL
Amendments
An amendment to a protocol is a change significant enough to require review/approval by local
REB/IRBs (and, if applicable, by HPB). Protocol amendments will be circulated in standard format
with clear instructions regarding REB/IRB review. If full board approval of an amendment is required,
it will be specified. No centre may make amendments to the protocol without written permission from
NCIC CTG and Pfizer.
12.4
Informed Consent
Informed Consent Document
The REB/IRB of an institution must approve the consent form document that will be used at that
centre prior to its local activation; changes to the consent form in the course of the study will also
require REB/IRB notification/approval.
It is essential that the consent form contain a clear statement which gives permission for 1) information
to be sent to and 2) source medical records to be reviewed by the NCIC CTG and other agencies as
necessary. In addition, the consent form should include all ICH-GCP consent elements.
Because this study is NCI U.S. affiliated, U.S. regulations regarding consent form content also apply.
The OHRP lists the following elements which must be addressed in each institutions consent form:
I.
Required (by OHRP) Elements - Must be present in the informed consent document
1. a.
b.
c.
d.
Clearly state that the study involves research.
State which drug(s), treatment(s), or delivery technique(s) is experimental.
Clarify the study purpose(s) in layman's terms.
State the patient's expected duration of participation in study (e.g., the patient will be
treated until there is evidence that therapy is no longer effective).
e. Give a brief description of the procedure(s) to be performed to monitor the patient during
study (e.g., X-rays, lab evaluations, etc.). An exhaustive list is not necessary.
f. Give a description of the experimental aspect(s) or new delivery technique(s) of the study.
g. State in specific terms the route of administration of each drug (e.g., IV, oral, continuous
infusion, etc.).
h. State estimated time of delivery of each drug or time of procedure (e.g., 5 minutes, 30
minutes, 24 hours, etc.).
2. State which risks are attributed to specific drug(s) or procedure(s).
3. Clarify and describe expected benefit(s) to be derived from participation in this study (e.g.,
tumour shrinkage, quality of life, etc.).
4. In general terms, discuss alternative treatment(s) to participation in this study (e.g.,
conventional chemotherapy, irradiation, hormonal therapy, surgery, etc.).
5. a. State the extent to which confidentiality of records will be maintained.
b. State that a qualified representative of the FDA may inspect patient/study records.
c. State that a qualified representative of the NCI may inspect patient/study records.
6. a. State if compensation for study related injury will be provided by the institution or other
insurer.
b. State if emergency treatment of injury will or will not be provided by the institution.
7. a. Provide space in the form or list the name(s) and number(s) of contact person(s) for
research related questions.
b. Provide space in the form or list the name(s) and number(s) of contact person(s) (not
involved in the research) for research related injuries or patient rights related questions.
CONFIDENTIAL
24
CONFIDENTIAL
8. a.
b.
c.
Clearly state participation is voluntary.
State that refusal to participate will involve no loss of benefits or penalize the patient's
care.
State that discontinuation of participation in the study will involve no loss of benefits to
which the patient is entitled.
II. Additional Elements - May be appropriate for some studies
1. State that unforeseeable or unexpected risk(s) may be involved.
2. State the circumstances under which the patient's participation may be terminated by the
investigator without the patient's consent.
3. State that additional costs may be incurred by the patient's participation in the study.
4. State the consequences of the patient's decision to withdraw from the study.
5. State that significant new findings that relate to the patient's treatment will be discussed with
the patient.
6. State the approximate number of patients involved in the study.
III. Suggested Elements
1. State that a copy of the informed consent form shall be given to the patient.
2. The form should be written in layman's terms.
3. Reference to approval by the REB, NCI or Cooperative Group may be misleading to the
patient.
The sample consent form provided in the protocol includes all the required elements, as well as the
"additional" and "suggested" elements relevant to this study. REBs must consider the sample consent
as the basis for review, as this form has been approved by the U.S. National Institutes of Health.
Significant changes of wording or deletions of the adverse event or alternative therapy sections of the
sample consent must be justified by the REB in writing; note however that additions to these sections
are rarely a problem.
Consent Process/ Patient Eligibility
Patients who cannot give informed consent (i.e. mentally incompetent patients, or those physically
incapacitated such as comatose patients) are not to be recruited into the study. Patients competent but
physically unable to sign the consent form may have the document signed by their nearest relative or
legal guardian. Each patient will be provided with a full explanation of the study before consent is
requested.
Written informed consent must be obtained from each participant prior to any study-specific
assessments being performed. The participant will receive a copy of the signed consent and the
original will be retained by the investigator. A copy will be filed in the subject's hospital chart.
12.5
Centre Performance Monitoring
Ineligibility and timeliness are monitored for all centres and the results are reported in the Centre
Performance Index. This index is generated twice a year and there are minimum standards for
performance.
Centres are required to submit the MA.27 Bone Mineral Density Eligibility Checklist and Form 1B
within the time guidelines specified in Appendix II (Documentation for Study).
CONFIDENTIAL
25
CONFIDENTIAL
12.6
On-Site Monitoring/Auditing
In addition to the routine review of case report forms and supporting documents sent to the central
office, NCIC CTG site monitoring will be conducted at participating centres in the course of the study
as part of the overall quality assurance programme. The monitors/auditors will require access to patient
medical records to verify the data, as well as essential document binders, standard operating
procedures (including electronic information) and ethics documentation.
As this trial is conducted under a CTA with Health Canada, your site may be subject to an inspection
by the Health Canada Inspectorate.
12.7
Case Report Forms
A list of forms to be submitted as well as expectation dates are to be found in Appendix II.
CRFs are available on-line at www.ctg.queensu.ca. All forms must be filled in legibly in durable blue
or black ballpoint pen. Please send the original to NCIC CTG and keep a photocopy of each
completed CRF for your files.
All data relating to the trial must be recorded on the CRF and completed at the time of the subject's
visit, with the exception of results of tests performed outside the investigator's office, so that they
always reflect the latest observations on the subject's participation in the trial. Every effort should be
made to ensure that all efficacy evaluations are completed by the same individual who made the
baseline determinations. The investigator must verify that all data entries in the CRF are accurate and
correct.
12.8
Protocol Adherence and Amendments
The investigator is required to sign the approved protocol, and any subsequent amendments, or study
Letter of Agreement confirming full agreement with the terms and procedures. An investigator may
not amend the protocol in any manner without prior written approval of the study sponsors.
It is the investigator's responsibility to ensure that the study is conducted according to the protocol and
to supervise residents and research coordinators. The investigator will ensure that all centre personnel
are properly trained and qualified.
12.9
Trial Closure Considerations
The sponsors reserve the right to close an investigational site. Reasons for such action include:
 safety concerns
 sufficient data suggesting lack of efficacy
 inadequate recruitment of subjects by investigator
 failure of the investigator to comply with the protocol, or requirements of the sponsors
12.10
NCI Data Monitoring Mechanism
This study will be monitored by the Clinical Data Update System (CDUS) version 1.1. Cumulative
CDUS data will be submitted quarterly (by the NCIC CTG central office, as the lead group) to CTEP
by electronic means. Reports are due January 31, April 30, July 31, and October 31.
CONFIDENTIAL
26
CONFIDENTIAL
13.0
REFERENCES
The ATAC (Arimidex or Tamoxifen Alone or in Combination) Trialists’ Group. Anastrozole alone or
in combination with tamoxifen versus tamoxifen alone for adjuvant treatment or postmenopausal
women with early breast cancer: first results of the ATAC randomized trial. Lancet Jun 22 2002; 359
(9324), 2131-2139.
Bajetta E, Martinetti A, Zilembo N, et al. Biological activity of anastrozole in postmenopausal patients
with advanced breast cancer: effects on oestrogen and bone metabolism. Ann Oncol. 2002;13, 10591066.
Coombes RC, Hall E, Gibson LJ, et al. A Randomized Trial of Exemestane After Two to Three Years
of Tamoxifen Therapy on Postmenopausal Women with Primary Breast Cancer. N Engl J Med 2004;
350(11), 1081-1092.
Eastell R, Adams J. Results of the ‘Arimidex’ (anastrozole, A), tamoxifen (T), alone or in combination
(C) (ATAC) trial: Effects on bone mineral density (BMD) and bone turnover (ATAC Trialsists’
Group) (abstract 113OPD). Ann Oncol. 2002;13 (Suppl 5), 32.
Goss PE, Qi S, Cheung AM, Hu H, Mendes M, Pritzker KPH. Effects of the steroidal aromatase
inhibitor and the non-steroidal inhibitor letrozole on bone and lipid metabolism in ovariectomized rats.
Clin Cancer Res. 2004 Sep. 1 10(17): 5717-23.
Goss PE, Qi S, Josse RG, Pritzker KPH, Mendes M, Hu H, Waldman SD, Grynpas MD, The steroidal
aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone 34(3): 384-392, 2004.
Harper-Wynne C, Ross G, Sacks N, et al. Effects of the aromatase inhibitor letrozole on normal breast
epithelial cell proliferation and metabolic indices in postmenopausal women: a pilot study for breast
cancer prevention. Cancer Epidemiol Biomarkers Prev. 2002 (Jul); 11(7), 614-621.
Heshmati HM, Khosla S, Robins SP, O’Fallon WM, Melton LJ, Riggs BL. Role of low levels of
endogenous estrogen in regulation of bone resorption in late postmenopausal women J Bone Mineral
Metab. 2002; 17, 172-178.
Kanis JA. Bone and Cancer: pathophysiology and treatment of metastases. Bone 1995 (Aug); 17
(Suppl 2), 101s-105s.
Loning PE, Geisler J, Krag LE, Ottestad L, Bremnes Y, Hagen AI, Schlichting E, Polli A, Paolini J,
Massimini G. Effect of exemestane on bone: A randomized placebo controlled study in
postmenopausal women with early breast cancer at low risk. (Abstract 518) J Clin Oncolgy 2004
ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement,
2004: 518
Martinetti A, Bajetta E, Seregni E, et al. Serum markers of bone metastases in postmenopausal breast
cancer patients treated with formestane. Tumour Biol. 1997; 18(4), 197-205.
Osteoporosis Int. Who are the candidates for prevention and treatment of osteoporosis? 1997;7, 1-6.
Pfizer Corporation: Data on file. Peapack, NJ.
Sainsbury R, on behalf of the ATAC Trialists’ Group. Beneficial side effect profile of anastrozole
compared with tamoxifen confirmed by additional 7 months of exposure data: a safety update from the
‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) Trail (poster and abstract 633). Breast
Cancer Res Treat. 2002; 76 (Suppl 1), s156.
CONFIDENTIAL
27
CONFIDENTIAL
Subar M, Goss PE, Thomsen T, Banke-Bochita J, Effects of steroidal and nonsteroidal aromatase
inhibitors (AIs) on markers of bone turnover and lipid metabolism in healthy volunteers. Proc. Annu,
Meet Am Soc. Clin Oncol., 23:734, A8038, 2004
Zilembo N, Bajetta E, Martinetti A, et al. Markers of bone turnover in metastatic breast cancer (MBC)
patients having progressed on tamoxifen: short term effect of further treatment with either exemestane
(EXE) or megestrol acetate (MA) (abstract and poster 707). Eur J Cancer 2001;37 (Suppl 6), s193.
CONFIDENTIAL
28
CONFIDENTIAL
APPENDIX I - PATIENT EVALUATION FLOW SHEET
All MA.27B visits coincide with core protocol (MA.27) visits. For registered patients, confirmed subsequently
by NCIC CTG to be ineligible for MA.27B, no additional MA.27B investigations or follow-up are required.
Treatment and follow-up for the core protocol (MA.27) continues.
6
12
24
36
48
60
at MA.27 protocol
treatment discontinuation
if more than 6 months
since last BMD
measurement
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Months from Registration to MA.27B
Investigations
Previous
history♦
History and
Exam
including:
Biochemistry
Prestudy*
X
Concomitant♦
medication
X
Weight
X
Height
X
Body Mass
Index
X
Clinical
Evaluation
X
Calculated
Creatinine
Clearance
X
Group B Group A patients if bisphosphonate becomes necessary
patients (see section 9.0)
(see section
4.1.6)
L1-L4 (PA)
spine
X
X
X
X
X
X
X
hip
Serum P1NP
X
X
X
Bone
Biomarkers*** Serum
X
X
X
N-telopeptide
*
BMD assessment within 12 weeks prior to randomization to MA.27; the remainder of investigations, except
bone biomarkers, within 4 weeks prior to randomization (serum for bone biomarkers collected after
registration and prior to starting any study treatment)
** The same instrument that was used to measure bone mineral density at baseline must be used to measure bone
mineral density during and after protocol treatment (Hologic or Lunar instrumentation)
*** Please see Appendix IV for blood sampling and shipping.
♦
Information recorded on core study (MA.27) Form 1 Initial Evaluation at baseline and Form 5 at follow-up.
Bone Mineral
Density**
CONFIDENTIAL
29
CONFIDENTIAL
APPENDIX II - DOCUMENTATION FOR STUDY
Follow-up is required for patients from the time of registration and will apply to all eligible patients. For
registered patients, confirmed subsequently by NCIC CTG to be ineligible for MA.27B, no additional MA.27B
investigations or follow-up are required. Treatment and follow-up for the core protocol (MA.27) continues.
Form
Bone Mineral Density
Eligibility Checklist
To be Completed
prior to calling
NCIC CTG to
register the patient
Due in Central Office
within 6 weeks of
registration
within 6 weeks of
registration
Form 1B
At baseline
Form 5B
on each MA.27B
within 8 weeks of the
scheduled
date the patient was
follow-up visit to the
seen at clinic
clinic
CONFIDENTIAL
Supporting Documentation Required
30
attach copies of patient consent form
and bone mineral density report
attach bone mineral density report
(and radiology/imaging reports of
any fractures).
CONFIDENTIAL
APPENDIX III - CTSU PARTICIPANT PROCEDURES
Registration
Only sites that are active for NCIC CTG protocol MA.27 may participate in this companion study, MA.27B.
Prior to the recruitment of a patient for this study, investigators must be registered members of the CTSU. Each
CTSU investigator or group of investigators at a clinical site must obtain IRB approval for this companion
protocol and submit all IRB/regulatory documents to the CTSU before they can enroll patients. All forms and
documents associated with this study can be downloaded from the NCIC CTG MA.27B Web page on the
CTSU registered member Web site (http://members.ctsu.org). Patients can be registered only after pretreatment evaluation is complete, all eligibility criteria have been met, and all pertinent forms and documents
are approved and on file with the CTSU. As soon as NCIC CTG is notified that a MA.27 site is ready to
participate also in MA.27B, blood sampling/shipping kits for bone biomarkers will be shipped to the site.
Requirements for NCIC CTG MA.27B site registration:




CTSU IRB Certification
IRB/Regulatory Approval Transmittal Form
IRB-approved consent form
Form for ordering blood draw kits from Cirion. Complete form and fax it to NCIC CTG at 1-613-5332814 (NCIC CTG will confirm with CTSU that site is active.)
Requirements for patient enrollment on NCIC CTG MA.27B




Patient must meet all inclusion (eligibility) criteria and no exclusion (ineligibility) criteria should apply.
Patient signed and dated consent.
Baseline bone mineral density assessment completed and results known
Serum will be drawn for bone biomarkers ( after registration and prior to any study treatment)
Patients must be registered to MA.27B at the same time that they are randomized to the core protocol, MA.27.
In addition, all enrolling investigators must have an NCI investigator number and must maintain an “active”
investigator registration status through the annual submission of a complete investigator registration packet
(FDA Form 1572 with original signature, current CV, Supplemental Investigator Data Form with signature,
and Financial Disclosure Form with original signature) to the Pharmaceutical Management Branch, CTEP,
DCTD, NCI. These forms are available on the CTSU registered member website or by calling the PMB at 301496-5725 Monday through Friday between 8:30 am and 4:30 pm Eastern time.
CTSU Procedures for Patient Enrollment
Contact the CTSU Patient Registration Office by calling 1-888-462-3009 to alert the CTSU Patient Registrar
that an enrollment is forthcoming. Complete the following forms:


CTSU Patient Enrollment Transmittal Form
Eligibility Checklist: Prior to registering patient, CTSU investigators should complete the form with the
exception of “NCIC CTG Patient Serial No.”. Fax form to CTSU Patient Registrar along with CTSU
Patient Enrollment Transmittal Form. (Hold onto original Eligibility Checklist. Within 6 weeks of
randomization, complete the Form 1B and mail Form 1B with the original of the Eligibility Checklist and
Bone Mineral Density Report, to NCIC Clinical Trials Group.)
CONFIDENTIAL
31
CONFIDENTIAL
Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the hours of 8:00 am and 4:30 p.m.,
Mon-Fri, Eastern time. The CTSU registrar will check the investigator and site information provided to ensure
that all regulatory requirements have been met. The registrar will also check the forms for completeness and
follow-up with the site to resolve any discrepancies. Once investigator and patient eligibility are confirmed, the
CTSU registrar will perform the registration and assign a unique patient ID (the same patient ID# as for the
core protocol, MA.27 - to be used on all future forms and correspondence). The CTSU registrar will convey
this information to the enrolling site by phone followed by a confirmation of registration e-mail or fax.
Data Submission
All forms and documents associated with this study can be downloaded from the NCIC CTG MA.27B Web
page located on the CTSU registered member Web site (http://members.ctsu.org). CTSU investigators should
use the protocol-specific NCIC CTG forms and adhere to the NCIC CTG schedule for data submission.
Submit all completed CRFs (with the exception of patient enrollment forms), clinical reports, and
transmittals directly to the NCIC Clinical Trials Group. Original CRFs should be sent to the NCIC Clinical
Trials Group at the address listed in the Contacts Table.
The NCIC Clinical Trials Group will send query notices and delinquency reports directly to the site for
reconciliation. Please mail query responses and delinquent data to the NCIC Clinical Trials Group and do
not copy the CTSU Data Operations
Each site should have a designated CTSU Administrator and Data Administrator and must keep their
CTEP AMS account contact information current. This will ensure timely communication between the
clinical site and the NCIC Clinical Trials Group.
Serum Sampling and Shipping Kits
As soon as CTSU confirms for NCIC CTG that a site is ready to participate in MA.27B, and the supply request
form has been submitted, serum sampling/shipping kits for bone biomarkers will be sent to that site. These kits
will contain the necessary materials for drawing, labeling and shipping the serum samples to the central
laboratory for analysis. Shipping costs will be covered. Please see Appendix IV for details of analysis of bone
biomarkers.
Calcium and Vitamin D Procurement:
Calcium and Vitamin D will be supplied free of charge to study participants. Each institution’s pharmacy is
expected to supply Calcium and Vitamin D for their own MA.27B participants and will be reimbursed
accordingly. CTSU investigators should refer to Appendix V of the protocol for more detailed information and
for a copy of the Request for Reimbursement Form.
REGULATORY AND MONITORING
Study Audit
To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 312, 314 and HHS 45
CFR 46] and National Cancer Institute (NCI)/ Cancer Therapy Evaluation Program (CTEP) Clinical Trials
Monitoring Branch (CTMB) guidelines for the conduct of clinical trials and study data validity, all protocols
approved by NCI/CTEP that have patient enrollment through the CTSU are subject to audit.
CONFIDENTIAL
32
CONFIDENTIAL
Responsibility for assignment of the audit will be determined by the site’s primary affiliation with a
Cooperative Group or CTSU. For Group-aligned sites, the audit of a patient registered through CTSU will
become the responsibility of the Group receiving credit for the enrollment. For CTSU Independent Clinical
Research Sites (CICRS), the CTSU will coordinate the entire audit process.
For patients enrolled through the CTSU, you may request the accrual be credited to any Group for which you
have an affiliation provided that Group has an active clinical trials program for the primary disease type being
addressed by the protocol. Per capita reimbursement will be issued by the credited Group provided they have
endorsed the trial, or by the CTSU if the Group has not endorsed the trial.
Details on audit evaluation components, site selection, patient case selection, materials to be reviewed, site
preparation, on-site procedures for review and assessment, and results reporting and follow-up are available for
download from the CTSU Operations Manual located on the CTSU Member Web site.
Health Insurance Portability and Accountability Act of 1996 (HIPAA)
The HIPAA Privacy Rule establishes the conditions under which protected health information may be used or
disclosed by covered entities for research purposes. Research is defined in the Privacy Rule referenced in HHS
45 CFR 164.501. Templated language addressing NCI-U.S. HIPAA guidelines are provided in the HIPAA
Authorization Form located on the CTSU website.
The HIPAA Privacy Rule does not affect participants from outside the United States. Authorization to release
Protected Health Information is NOT required from patients enrolled in clinical trials at non-US sites.
Clinical Data Update System (CDUS) Monitoring
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. Cumulative CDUS
data will be submitted quarterly to CTEP by electronic means. The sponsoring Group fulfills this reporting
obligation by electronically transmitting to CTEP the CDUS data collected from the study-specific case report
forms.
CONFIDENTIAL
33
CONFIDENTIAL
APPENDIX IV - BLOOD SAMPLING INSTRUCTIONS
As soon as NCIC CTG is made aware that your site has been approved as a participant in this MA.27B
protocol, you will be receiving, directly from Cirion Clinical Trials Services Inc., sampling and shipping kits
complete with shipping documentation and an instruction manual. These materials are to assist you in drawing
and preparing serum samples (for bone biomarkers: serum P1NP and serum N-telopeptide) and for shipment of
the samples to the central lab.
NCIC CTG will require the following information:
Blood Sampling/Shipping Kits for MA.27B Bone Biomarkers
Site Code: ______________
Date of Site Approval for MA.27B: ________________________________________
Estimated # of patients to be enrolled per year on the MA.27B protocol: ___________
Name of contact person to whom kits should be sent: ___________________________
Title: _________________________________________________________________
Address of Contact Person:
________________________________________________
________________________________________________
________________________________________________
________________________________________________
Phone # of Contact Person:
________________________________________________
Fax # of Contact Person:
________________________________________________
e-mail address of contact person:
________________________________________________
When completed, fax this form to
613-533-2814
Thank you!
CONFIDENTIAL
34
CONFIDENTIAL
APPENDIX V - MA.27B – DRUG SUPPLY
The Pharmacy at each participating institution is asked to supply Calcium (1000 mg/day) and Vitamin D (800
IU/day) for their MA.27B patients. (The expectation is that MA.27B patients will take 500-1000 mg of
calcium a day, dependent upon tolerability.) MA.27B patients are to take this for as long as they are on MA.27
Aromatase Inhibitor - for a maximum of 5 years. Pharmacies will be reimbursed for all Calcium and Vitamin D
dispensed under these criteria.
Please complete the MA.27B Request for Reimbursement Form at regular intervals throughout your
participation in MA.27B.
Calcium and Vitamin D are supplied to provide a baseline prophylaxis against osteoporosis. MA.27B patients
should take 1000 mg of Calcium and 800 IU of Vitamin D each day for as long as they are on the MA.27B
protocol. Withdrawal of the patient from MA.27B and/or cessation of MA.27 study drug will trigger a
cessation of reimbursable Calcium and Vitamin D supply.
Some patients may already be taking calcium supplements. As long as they are taking the minimum amount of
supplementation prescribed by the protocol and the Investigator is aware of their daily doses of each
supplement, the patient’s own personal pattern of supplementation may continue. The amount supplied by the
study, however, remains unchanged.
Recommended Bisphosphonate therapy for MA.27B is as follows:
Actonel, 35mg, orally, once weekly OR
Fosamax, 70mg, orally, once weekly
Group A patients will not require bisphosphonates unless, while on MA.27 aromatase inhibitor, they
experience bone failure (see endpoints for Group A patients). Given that these drugs are widely available, it is
expected that the local Pharmacy will be able to dispense one or the other of these bisphosphonates from their
own stock. Patients who have insurance coverage will pay in that manner; for patients who do not have
insurance coverage, the cost of either of these bisphosphonates used while on MA.27 aromatase inhibitor will
be reimbursed to the MA.27 institution pharmacy that dispensed it.
Group B patients are required to use bisphosphonate therapy from the time they begin their MA.27 aromatase
inhibitor. Again, patients who have insurance coverage for bisphosphonates should pay in that manner; for
those who do not, the cost of the bisphosphonates used while on MA.27 aromatase inhibitor will be reimbursed
to the MA.27 institution pharmacy that dispensed it.
Reimbursements should be sought at regular intervals throughout participation in MA.27B by completing the
Request for Reimbursement Form-MA.27B (actonel and fosamax).
For questions about drug supply:
Phone 613-533-6430 (and ask for the MA.27 Team – drug supply)
Fax
613-533-2814
E-mail [email protected] or [email protected]
Please have ready, with your request:
 your centre identification (CTEP-assigned institution # or NCIC CTG centre code)
 your name and a telephone number/fax number/e-mail at which we can reach you
We will respond to your query as soon as possible.
CONFIDENTIAL
35
CONFIDENTIAL
REQUEST FOR REIMBURSEMENT FORM – MA.27B
(fax this form, when completed, to 613-533-2814)
MA.27B Participating Site # or code:
__ __ __ __ __
# MA.27B patients still on MA.27 supply
Aromatase Inhibitor: __ __
# of patients enrolled, at your site, in MA.27B as
of this date: __ __
Brand name, strength, bottle size and cost/bottle of Calcium Supplement being dispensed for your MA.27B
patients: ____________________________________________________________________________
____________________________________________________________________________________
Brand name, strength, bottle size and cost/bottle of Vitamin D being dispensed for your MA.27B patients:
____________________________________________________________________________________
____________________________________________________________________________________
MA.27B
Patient ID#
MA.27B
Registration Date
Patient still on
MA.27 Study
Treatment?
Approved by MA.27 SC:
____________
Initials
Seeking Reimbursement for
# bottles calcium
# bottles vitamin D
Approved by NCIC CTG Operations:
____________
Date
____________
Initials
____________
Date
Reimbursement Funds should be sent to: (CTSU sites only need complete this section)
Name:____________________________________
Title:_____________________________________
Department:_______________________________
Institution:________________________________
Complete Address:___________________________________________________________________
Person Completing this request:______________________
Signature:___________________
Date:_____________________
CONFIDENTIAL
36
CONFIDENTIAL
REQUEST FOR REIMBURSEMENT FORM – MA.27B
(fax this form, when completed, to 613-533-2814)
Please complete this form only if you are seeking reimbursement for MA.27B
bisphosphonate for patients who did not have insurance coverage for the cost.
MA.27B Participating Site # or code:
__ __ __ __ __
# MA.27B patients still on MA.27 supply
Aromatase Inhibitor: __ __
# of patients enrolled, at your site, in MA.27B as
of this date: __ __
Reimbursement is being sought for the following patients for whom the Investigator has confirmed
do not have insurance covering the cost of bisphosphonates for this study:
Patient ID#
Actonel or
# tablets per
Fosamax Strength
package
Approved by MA.27 SC:
____________
Initials
Cost per
package
# packages
Investigator
Signature
Approved by NCIC CTG Operations:
____________
Date
____________
Initials
____________
Date
Reimbursement Funds should be sent to: (CTSU sites only need complete this section)
Name:____________________________________
Title:_____________________________________
Department:_______________________________
Institution:________________________________
Complete Address:___________________________________________________________________
Person Completing this request:______________________
Signature:___________________
Date:_____________________
CONFIDENTIAL
37
CONFIDENTIAL
APPENDIX VI – CENTRAL REVIEW OF BONE MINERAL DENSITY SCANS
The cost of Bone Mineral Density DEXA scans, required by the protocol, will be covered by the study.
Bone Mineral Density Scans, for MA.27B will be done:
•
Within 25 weeks prior to registration
•
1 year after registration (if patient still on MA.27 aromatase inhibitor)
•
2 years after registration (if patient still on MA.27 aromatase inhibitor)
•
•
•
•
after aromatase inhibitor discontinuation if the most recent bone mineral density scan was more
than 6 months ago
Each time the bone mineral density scan is performed, the BMD image should be captured on a floppy diskette
or CD and mailed to UHN for central review. The diskette or CD should be addressed and mailed to:
Judy Scher
Osteoporosis and Postmenopausal Health Research Centre
University Health Network
7 Eaton North – 219A
200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4
Diskettes or CDs with copies of scans should be labeled with the centre number, (NCIC CTG Centre # or
CTEP Site #), patient Study ID number, and the visit number (baseline or # years since registration). Scans will
be logged into a database as they arrive. Any other relevant comments received with the images (e.g.
positioning not correct, need to repeat scan, patient has osteoporosis and requires intervention of some kind)
will also be logged. Hard copies of the scans will be stored at UHN, and will be transferred to NCIC CTG at
the end of the study. As soon as the images are received at UHN, they will be analyzed on the same or the next
day and a letter directly to the Investigator will be sent (by mail) indicating whether:
•
there has been no significant change
•
the patient showed signs of osteopenia or
•
the patient showed signs of osteoporosis
At baseline these central review results would confirm or refute eligibility. Data will be stored electronically
and sent to NCIC CTG at intervals.
Phantom Scans
MA.27B is designed to evaluate the difference in impact, if any, on bone mineral density, between the two
aromatase inhibitors. The evaluation period is relatively long (5 years) and the size of the difference in impact
between the two treatments cannot be predicted. The reproducibility of the measurement tool, therefore,
becomes very important. As a check on the calibration and drift of the densitometers in the study over time,
each centre will perform scans on a designated Hologic morphometric spine phantom which will be shipped to
participating sites at the start of the study and at 2 and 5 years. If there is evidence of “drift” in DEXA
calibration, a sensitivity analysis of the primary outcome will use BMD values corrected for the drift. This can
be done by performing a least squares fit of the true to the observed densities of the phantoms and using this
factor to correct the observed BMD values at that particular centre. These BMD values will be corrected
according to the calibration scan performed closest in time to the affected scans.
CONFIDENTIAL
38
CONFIDENTIAL
The details of how this will be done are as follows:
•
A standardized artificial “limb” of sorts is mailed, by UHN to each participating site, in turn.
•
The BMD image of the “limb” is taken (instructions are provided with the mailing), the image
captured on a diskette or a CD and mailed to UHN (same address as for central densitometry
review).
•
The “limb” is then mailed back to UHN.
•
It is expected that each site will do this calibration exercise at least 2 times in 5 years (preferably 3
times).
•
Evidence of “drift” (and the implications thereof) will be communicated to the Investigator by the
Central Review Team at UHN.
CONFIDENTIAL
39
CONFIDENTIAL
APPENDIX VII - SAMPLE CONSENT FORMS
English Sample Consent
THE INFLUENCE OF FIVE YEARS OF ADJUVANT ANASTROZOLE
OR EXEMESTANE ON BONE MINERAL DENSITY IN
POSTMENOPAUSAL WOMEN WITH PRIMARY BREAST CANCER
MA.27B
A Companion Study to NCIC CTG Trial MA.27
Consent to Allow the Evaluation of Bone Mineral Density
Le formulaire de consentement est disponible en français sur demande
Note to centre: If an REB approved French consent is not used at your institution you should remove the above statement.
This is a clinical trial (a type of research study). Clinical trials include only patients who choose
to take part. Please take your time to make your decision. Discuss it with your friends and family.
WHY IS THIS COMPANION STUDY BEING DONE?
You are being asked to participate because after menopause, the strength of the bones slowly
declines. One of the reasons it declines is because your body’s estrogen levels have also
declined. The purpose of this part of the MA.27 research study, called a ‘companion study’, is to
evaluate the possible additional effects of anastrozole or exemestane on the thinning of your
bones (osteoporosis). The study of bone mineral density to look at changes in the thickness of
bone is an important part of the MA.27 study in North America.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
About 408 women from Canada, the United States and other countries will take part in this
study.
Version date and/or REB approval date of this form: ________________
CONFIDENTIAL
40
NCIC CTG Pt. Serial #: _______
CONFIDENTIAL
WHAT IS INVOLVED IN THE COMPANION STUDY?
Patient consented for MA.27B
BMD assessed within 25 weeks prior to
randomization to core protocol and results obtained
Randomization to Core protocol
Registration in Bone Mineral Density Companion
Study (with stratification). Serum for baseline bone
biomarkers collected after registration & prior to
starting MA.27/MA.27B drugs
Group A
Group B
(no osteopenia or osteoporosis)
No Bisphosphonate Therapy;
(osteopenia or osteoporosis)
Bisphosphonate Therapy;
Bone Biomarkers
Baseline, 6, 12 months;
BMD
Baseline, then annually
Bone Mineral Density Measurement:
If you decide to participate, one measurement of bone mineral density of your spine and hip will
be done before you begin the MA.27 study. This measurement is called ‘dual x-ray
absorptiometry’, or DEXA. The procedure involves lying down for 10-20 minutes on a machine
that produces very small amounts of x-rays. The amount of radiation is about 2% of the dose
used for a routine chest x-ray.
While you are taking part in MA.27B, you will have one measurement of bone mineral density of
your hip and spine, each year, for five years. Your doctor and you will be informed of the results
of these measurements. If you are not already on a drug to prevent or treat osteoporosis and the
results indicate that you have a lot of bone loss, then you will receive treatment for this.
CONFIDENTIAL
41
CONFIDENTIAL
Images of each bone mineral density scan will be saved on a computer diskette or CD and
mailed to Toronto, Ontario, Canada for review by a an ISCD densitometrist. These images will
be identified only by:
•
the Institution in which you were enrolled and
•
your study ID# (the same ID# used in the main MA.27 study).
The results of this review will also be sent to your doctor and will be available to you through
him/her.
Blood Sample Collection:
If you agree to participate, one 10 ml blood sample (amounting to one blood tube in addition to
that already being drawn for MA.27 or about 2 teaspoons of blood) will be drawn with a needle
from a vein in your arm at the time of enrollment in the MA.27 study. The blood sample will be
sent to the Cirion Central Laboratory where measurements will be made of the amounts of
certain components, called bone biomarkers, that indicate bone building or bone breakdown
activity. The samples will be identified only by the study code (MA.27B) and your study ID# (the
same ID# used in the main MA.27 study). Participation will involve giving one additional 10 ml
blood sample at each of these times after enrollment: 6 months, one year. These times all
coincide with MA.27 (core study) visits. The 6 month and one year draws are performed at the
same times that blood is being drawn for the MA.27 study. Bone biomarkers will be measured on
all of these samples. The blood samples you provide will be used for this study’s research only
and will not be sold. The blood samples will be stored at Cirion Biopharma Research Inc, Clinical
Trial Services in Laval, Quebec, Canada and later be analyzed there. Blood samples for bone
biomarkers will be kept until the biomarker tests are all completed and NCIC CTG has received
and confirmed the results. The results of the blood tests will not be given to your study doctor or
become part of your medical record. If, at any time, you change your mind about participating in
this companion study, you may request, through your study doctor, that your blood samples be
destroyed. Tissue used for research is identified only by a special code to protect your identity
and privacy.
Calcium and Vitamin D:
If you agree to take part in this companion study and are a suitable candidate you will be given
daily calcium and Vitamin D in standard doses (to be taken by mouth) to help prevent
osteoporosis.
You understand that you will not be allowed to participate if you:
•
have malabsorption syndrome, known vitamin D deficiency, active hyper or
hypoparathyroidism (over or under active parathyroid gland), or Paget’s disease (a bone
disease of unknown cause resulting in faulty bone structure);
•
have uncontrolled thyroid disease, Cushing’s disease, or other pituitary disease;
•
have any other bone disease;
•
have received previous treatment with anticonvulsants or anabolic steroids within the past
year; high doses of corticosteroids or coumarins for an extended time;
•
•
have evidence of kidney problems;
are taking sodium fluoride therapy.
CONFIDENTIAL
42
CONFIDENTIAL
If you stop participating in the main MA.27 study, your study doctor may ask that you have one
more bone mineral density scan and then your participation in this study will also end.
Bisphosphonates:
If your first bone mineral density measurement shows a mild level of bone loss, known as
“osteopenia” or “osteoporosis” when you begin the study, you will be asked to take also a drug
called a “bisphosphonate” (by mouth) to help prevent osteoporosis. If your first bone mineral
density measurement does not show any evidence of bone loss, you will be prohibited from
taking a bisphosphonate drug but will be followed closely by your study doctor. If any of the
subsequent bone mineral density tests indicate a lot of bone loss, a bisphosphonate will be
provided.
HOW LONG WILL I BE IN THE STUDY?
Bone density measurements will take place over the 5 years you are participating in the MA.27
study. If you permanently stop taking MA.27 Exemestane or Anastrozole within the first year of
treatment, you will have no further MA.27B blood samples drawn or bone mineral density
assessments performed as part of this protocol. If you permanently stop taking MA.27
Exemestane or Anastrozole after one year of treatment, you will have one final bone mineral
density assessment if the most recent assessment was more than six months ago.
In addition, the researchers may stop you from taking part in this study at any time if it is in your
best interest, if you do not follow the study rules or if the study is stopped. If you decide not to
stay in the parent study, MA.27, you will not be able to stay in this study either.
You can refuse to participate in this companion study or stop participating at any time. However,
if you decide to stop participating in this companion study, you should talk to your study doctor
first.
WHAT ARE THE RISKS OF THE STUDY?
There are no known described risks or side effects to the measurement of bone mineral density
with DEXA.
The needles used to take blood might be uncomfortable. You might get a bruise, or rarely, an
infection at the site of the needle puncture.
Vitamin D and Calcium will be provided to all women on this companion study. Side effects from
calcium and Vitamin D are rarely seen but may include: stomach upset or constipation.
CONFIDENTIAL
43
CONFIDENTIAL
SIDE EFFECTS OF BISPHOSPHONATES:
Side effects of bisphosphonates are usually mild. The following side effects were reported in
clinical trials comparing risedronate sodium or alendronate to placebo. In almost all instances,
the side effects were only slightly more frequent in patients receiving active drug.
Risedronate Sodium (Actonel)
Very Likely (> 20% of patients)
•
None
Less likely (5-20% of patients)
•
Hypertension (high blood pressure)
•
Abdominal pain, nausea, heartburn
•
Joint, neck, bone pain
•
Dizziness, weakness
•
Sore throat, runny nose
•
Cataracts
Rarely (1-4% of patients)
•
Heart problems
•
Hernia, gastritis, rectal problems, constipation, diarrhea
•
Bruising, anemia
•
Bone or tendon problems
•
Muscle tension, leg cramps
•
Anxiety, numbness
•
Shortness of breath, pneumonia
•
Itching, skin carcinoma
•
Eye infection, urinary tract infection
Alendronate (Fosamax)
Very likely (>20% of patients)
•
None
Less Likely (5-20% of patients)
•
Abdominal pain
Rarely (1-4% of patients)
•
Nausea, heartburn, constipation, diarrhea, flatulence, acid reflux, esophageal ulcer, vomiting,
gastritis, difficulty swallowing, bloating
•
Bone, muscle or joint pain, headache
Osteonecrosis (death of bone tissue) of the jaw has been observed with long-term use of other
forms of bisphosphonate drugs when they have been given by vein. It is not known whether or
how often this problem occurs with Fosamax and Actonel given by mouth.
CONFIDENTIAL
44
CONFIDENTIAL
A Data Safety Monitoring Board, an independent group of experts, will be reviewing the data
from this research throughout the study.
ARE THERE BENEFITS TO TAKING PART IN THE COMPANION STUDY?
If you agree to take part in this companion study, there may or may not be direct medical benefit
to you. The information learned from this companion study may benefit other patients with breast
cancer in the future.
WHAT OTHER OPTIONS ARE THERE?
If you decide not to participate in this companion study, you will continue to be monitored by your
study doctor. You should talk to your study doctor about the possible use of Calcium, Vitamin D
and bisphosphonates in your treatment outside of participation in MA.27B.
Please talk to your study doctor about these and other options. As with any treatment, there are
possible benefits and risks. Your study doctor will be able to provide you with information about
any known benefits and risks of these other treatment options. Your study doctor can also
discuss with you what will happen if you decide not to undertake any treatment at this time.
WHAT ABOUT CONFIDENTIALITY?
Efforts will be made to keep your personal information confidential. We cannot guarantee
absolute confidentiality.
Qualified representatives of the following organizations may inspect and receive your
medical/study records for quality assurance and data analysis:
•
•
•
•
•
•
•
•
•
•
National Cancer Institute of Canada Clinical Trials Group (NCIC CTG), the research group
coordinating this companion study.
The Research Ethics Committees who oversees the ethical conduct of this study
Pfizer, the company which is supplying the main study drug as well as Vitamin D and
Calcium, and is supporting the companion study.
National Cancer Institute of the U.S., the organization that oversees U.S. participation in this
companion study
U.S. Food and Drug Administration (because it oversees the use of new drugs in the U.S.)
Health Canada (because it oversees the use of new drugs in Canada)
CTSU, a research group sponsored by the National Cancer Institute (NCI) to provide greater
access to cancer trials
Other regulatory agencies as necessary
Southwest Oncology Group (SWOG) since a Study Chair belongs to this organization
North Central Cancer Treatment Group (NCCTG) since a Study Chair belongs to this
organization
CONFIDENTIAL
45
CONFIDENTIAL
This may include information that could potentially identify you and includes:
• Serum bone biomarker test results
• DEXA scan results
The organizations listed above will keep the information they see or receive about you
confidential, to the extent permitted by applicable laws. Identifying information will be kept behind
locked doors. Identifying information will never be included in a publication of the research.
The information collected during this study will be used in analyses and will be
published/presented to the scientific community at meetings and in journals. This information
may also be used as part of a submission to regulatory authorities around the world to support
the approval of drugs used in this research. It is expected that the study results will be published
in a scientific journal after the required number of patients have been enrolled and all
measurements (bone biomarkers and bone mineral density scans) have been completed and
analyzed. Your study doctor will be informed of the results of the study once they are known.
WHAT ARE THE COSTS?
You will receive no compensation for taking part in this companion study. Taking part may result
in added costs to you. You may ask about any expected added costs.
In the case of research-related side effects or injury, medical care will be provided by your study
doctor or you will be referred for appropriate medical care. Although no funds have been set
aside to compensate you in the event of injury or illness related to the study treatment or
procedures, you do not waive any of your legal rights for compensation by signing this form.
Calcium and Vitamin D will be given to you free of charge as long as you receive anastrozole or
exemestane treatment on the MA.27 study. If bisphosphonates become a necessary part of your
treatment, your study doctor will select the best drug, dose and schedule. You understand that
the bisphosphonates will NOT be provided free of charge by the organizers of the study and
that, if they are required, you or your medical insurer will have to cover their costs (only if you
confirm for your study doctor that your medical insurer will not cover the cost of the
bisphosphonate will it be supplied).
WHAT ARE YOUR RIGHTS AS A PARTICIPANT?
Taking part in this companion study is voluntary. You may choose not to take part or may leave
the companion study at any time. Refusing to take part or leaving the study will not result in any
penalty or loss of benefits to which you are entitled. You cannot begin to participate in the main
MA.27 study unless you participate in this companion study. If you choose to stop participating in
this companion study, your participation in the main study may also end. If you decide to stop
participating in the study, you are encouraged to talk to your study doctor first. Your study doctor
will discuss further treatments with you and continue to treat your cancer with the best means
available.
CONFIDENTIAL
46
CONFIDENTIAL
You will be told about new information in a timely manner that may affect your health, welfare, or
willingness to stay in this companion study.
You will be given a copy of this signed consent form.
CONFLICT OF INTEREST
Note to centres: Please include details of any actual or potential conflict of interest concerning this study.
This centre is receiving funds from the NCIC Clinical Trials Group to help offset the costs of
conducting this research. NCIC CTG is a non-profit research group.
WHO DO YOU CALL IF YOU HAVE QUESTIONS OR PROBLEMS?
If you have questions about taking part in this companion study, or suffer a research-related
injury, you can talk to your study doctor. Or, you can meet with the doctor who is in charge of the
study at this institution. That person is:
________________________________
Name
_________________________
Telephone
If you would like advice regarding your rights as a patient or about ethical issues related to this
companion study, you can talk to someone who is not involved in the study at all. That person is:
________________________________
Name
_________________________
Telephone
CONFIDENTIAL
47
CONFIDENTIAL
SIGNATURES
Your signature on this consent form means the following:
•
•
•
•
The study has been explained to you and all of your questions have been answered
You understand the requirements and the risks of the study
You authorize access to your medical records as explained in this consent form and
You agree to take part in this study
_________________________________
Signature of Patient
________________
Date
____________________________
Signature of Investigator
_________________________
Date
Was the patient assisted during the consent process in one of the ways listed below?
 Yes  No
If yes, please check the box and complete the signature space below:
 The consent form was read to the patient, and the person signing below attests that the
study was accurately explained to, and apparently understood by, the patient.
______________________________
Signature of Person Assisting in
the Consent Discussion
________________________
Date
Please note: More information regarding the assistance provided during the consent process
should be noted in the medical record for the patient if applicable.
CONFIDENTIAL
48
CONFIDENTIAL
O
MODIFICATION N 1 : 2006-MAR-31
Exemple de consentement en français
EFFET DE CINQ ANS D’UNE THÉRAPIE D’APPOINT À L’ANASTROZOLE OU À
L’EXEMÉSTANE SUR LA TENEUR MINÉRALE DE L’OS CHEZ LES FEMMES
MÉNOPAUSÉES QUI ONT UN CANCER PRIMITIF DU SEIN
MA.27B
Étude d’accompagnement de l’essai GEC INCC MA.27
Consentement à permettre l’évaluation de la densité minérale de l’os
An English version of this consent form is available upon request.
Note au centre : Si votre établissement n’utilise PAS de formulaire de consentement en anglais approuvé par le CER, il faut
biffer cette phrase.
Cette étude est une étude clinique (type d’étude de recherche). Les études cliniques portent
seulement sur les patients qui choisissent d’y participer. Veuillez prendre le temps nécessaire
pour vous décider. Discutez-en avec vos amis et les membres de votre famille.
POURQUOI EFFECTUER CETTE ÉTUDE D’ACCOMPAGNEMENT?
Nous vous demandons de participer à cette étude parce qu’après la ménopause, les os perdent
lentement de leur force, notamment à cause de la baisse des concentrations d’œstrogène dans
le corps. Ce volet de l’étude de recherche MA.27, appelé « étude d’accompagnement », vise à
évaluer les effets supplémentaires possibles de l’anastrozole ou de l’exeméstane sur
l’amincissement de vos os (ostéoporose). L’étude de la teneur minérale de l’os qui vise à
analyser les changements de l’épaisseur des os constitue un volet important de l’étude MA.27
en Amérique du Nord.
COMBIEN DE PERSONNES PARTICIPERONT À L’ÉTUDE?
Quelque 408 femmes du Canada, des États-Unis et d’autres pays participeront à l’étude.
Date de la version de cette formule ou date d’approbation par le CER : ____________
CONFIDENTIEL
49
o
N série Pt GEC INCC :_____
CONFIDENTIEL
O
O
MODIFICATION N 1 : 2006-MAR-31; MODIFICATION N 2 : 2007-MAY-22
QU’EST-CE QUE COMPREND L’ÉTUDE?
Consentement de la patiente à l’étude MA.27B
TMO évaluée dans les 25 semaines précédant l’affectation par
randomisation au protocole de base et obtention des résultats
Affectation par randomisation au protocole de base
Inscription à l’étude d’accompagnement sur la teneur minérale de l’os (avec
stratification). Prélèvement de sérum pour la détermination de biomarqueurs
osseux de référence après l’inscription et avant que le sujet commence à prendre
les médicaments prévus aux études MA.27/MA.27B
Group A
(aucune ostéopénie ou ostéoporose)
Pas de traitement aux bisphosphonates;
Administration obligatoire de
suppléments de calcium (1 000 mg/jour)
et de vitamine D (800 UI/jour)
(pendant que le sujet prend des
inhibiteurs de l’aromatase MA.27)
Group B
(ostéopénie ou ostéoporose)
Traitement aux bisphosphonates;
Administration obligatoire de
suppléments de calcium (1 000 mg/jour)
et de vitamine D (800 UI/jour)
(pendant que le sujet prend des
inhibiteurs de l’aromatase MA.27)
Biomarqueurs osseux
Référence, 6, 12 mois;
TMO
Référence, ensuite une fois par année
(pendant que le sujet prend des inhibiteurs de l’aromatase MA.27)
Mesure de la teneur minérale de l’os :
Si vous décidez de participer, on mesurera votre teneur minérale de l’os à la colonne et à la
hanche avant le début de votre participation à l’étude MA.27. On appelle cette technique
« absorptiométrie à rayons-x en double énergie » ou DEXA. L’intervention consiste à vous
coucher de 10 à 20 minutes sur une machine qui produit de très faibles quantités de rayons-x.
L’irradiation représente environ 2 % de la dose utilisée pour une radiographie pulmonaire de
routine.
Pendant que vous participez à l’étude MA.27B, on mesurera votre teneur minérale de l’os à la
hanche et à la colonne une fois par année pendant cinq ans. On vous informera, votre médecin
et vous, des résultats de ces mesures. Si vous ne prenez pas déjà un médicament pour prévenir
ou traiter l’ostéoporose et si les résultats indiquent que vous avez perdu de la densité osseuse,
vous recevrez alors un traitement contre ce problème.
CONFIDENTIEL
50
o
CONFIDENTIEL
O
O
On sauvegardera des images de chaque mesure de la teneur minérale de l’os sur une disquette
ou un disque compact que l’on enverra par la poste à Toronto (Ontario) Canada pour étude par
un densitométriste de la SIDC. On identifiera ces images seulement par :
•
le numéro de l’établissement où vous êtes inscrite;
•
votre numéro d’ID de l’étude (le même que celui qu’on utilise dans le corps principal de
l’étude MA.27).
Votre médecin recevra aussi les résultats de cette analyse et vous y aurez accès par son
entremise.
Prélèvement d’un échantillon de sang :
Si vous consentez à participer, on prélèvera par ponction veineuse pratiquée dans le bras, au
moment de votre inscription à l’étude MA.27, un échantillon de 10 ml de sang (ce qui représente
un tube de sang en plus de ceux que l’on prélève déjà pour l’étude MA.27, soit environ deux
cuillérées à thé de sang). On enverra l’échantillon de sang au laboratoire central de Cirion, qui
mesurera la quantité de certains éléments constituants, appelés biomarqueurs osseux, qui
indiquent l’activité de formation ou de dissociation des os. On identifiera les échantillons
seulement par le code de l’étude (MA.27B) et votre ID de l’étude (le même qu’on utilise dans le
corps principal de l’étude MA.27). Votre participation consistera à donner un échantillon
supplémentaire de 10 ml de sang à chacune de ces étapes après l’inscription : six mois, un an.
Ces étapes coïncident toutes avec des visites à effectuer dans le cadre de l’étude MA.27 (étude
de base). On prélève les échantillons à six mois et un an en même temps que le sang prélevé
pour l’étude MA.27. On mesurera les biomarqueurs osseux dans tous ces échantillons. Les
échantillons de sang que vous fournirez serviront seulement aux recherches effectuées dans le
cadre de cette étude et ne seront pas vendus. On les conservera au Service des essais
cliniques de Cirion Biopharma Recherche Inc. à Laval (Québec), au Canada, où ils seront
analysés par la suite. On gardera les échantillons de sang servant à la détermination des
biomarqueurs osseux jusqu’à ce que tous les tests soient terminés et que le GEC INCC ait reçu
et confirmé les résultats. Les résultats des analyses ne seront pas communiqués à votre
médecin qui participe à l’étude, ni versés à votre dossier médical. Si vous changez d’idée
n’importe quand au sujet de la participation à cette étude d’accompagnement, vous pouvez
demander, par l’intermédiaire de votre médecin qui participe à l’étude, que l’on détruise vos
échantillons de sang. Les tissus servant à la recherche portent seulement un code spécial pour
protéger votre identité et votre vie privée.
Calcium et vitamine D :
Si vous consentez à participer à cette étude d’accompagnement et si vous êtes une candidate
convenable, vous recevrez des doses normales quotidiennes de calcium et de vitamine D (à
prendre par la bouche) afin d’aider à prévenir l’ostéoporose.
Vous comprenez que vous ne pourrez participer à l’étude si vous :
•
avez le syndrome de malabsorption, un déficit connu en vitamine D, une hyper ou
hypoparathyroïdie active (activité excessive ou insuffisante de la parathyroïde) ou la maladie
de Paget (maladie osseuse d’origine inconnue qui cause des défauts de la structure
osseuse);
CONFIDENTIEL
51
o
CONFIDENTIEL
O
MODIFICATION N 2 : 2007-MAY-22
•
avez une thyroïdie non contrôlée, la maladie de Cushing ou une autre affection de
l’hypophyse;
•
avez n’importe quelle autre ostéopathie;
•
avez pris des anticonvulsivants ou des stéroïdes anabolisants au cours de l’année écoulée,
des doses élevées de corticostéroïdes ou de coumarine pendant une période prolongée;
•
•
avez des signes de problèmes rénaux;
suivez une thérapie au fluorure de sodium.
Si vous cessez de participer au corps principal de l’étude MA.27, votre médecin qui participe à
l’étude pourra vous demander de vous soumettre à une autre analyse de teneur minérale de l’os
et votre participation à cette étude prendra fin aussi.
Bisphosphonates :
Si votre première mesure de teneur minérale de l’os révèle une perte osseuse légère, appelée
« ostéopénie », ou une « ostéoporose » au début de l’étude, on vous demandera de prendre
aussi un médicament appelé « bisphosphonate » (par la bouche) afin d’aider à prévenir
l’ostéoporose. Si votre première mesure de teneur minérale de l’os ne montre aucun signe de
perte osseuse, on vous interdira de prendre un bisphosphonate, mais votre médecin qui
participe à l’étude vous suivra de près. Si n’importe lequel des tests subséquents de mesure de
teneur minérale de l’os indique une perte osseuse importante, on vous fournira un
bisphosphonate.
PENDANT COMBIEN DE TEMPS PARTICIPERAI-JE À L’ÉTUDE?
On prendra des mesures de densité osseuse pendant les 5 ans au cours desquels vous
participerez à l’étude MA.27. Si vous cessez en permanence de prendre l’exeméstane ou
l’anastrozole prévus dans l’étude MA.27 au cours de la première année du traitement, on ne
prélèvera plus d’échantillon de sang dans le cadre de l’étude MA.27B et n’effectuera plus
d’analyse de teneur minérale de l’os dans le cadre de ce protocole. Si vous cessez
définitivement de prendre l’exeméstane ou l’anastrozole prévus dans l’étude MA.27 après un an
de traitement, on procèdera à une dernière évaluation de teneur minérale de l’os si l’évaluation
la plus récente remonte à plus de six mois.
Les chercheurs peuvent en outre mettre fin à votre participation à l’étude n’importe quand si
c’est dans votre meilleur intérêt, si vous ne suivez pas les règles de l’étude ou si l’on met fin à
celle-ci. Si vous décidez de ne pas continuer de participer à l’étude mère MA.27, vous ne
pourrez continuer de participer à celle-ci non plus.
Vous pouvez refuser de participer à l’étude d’accompagnement ou vous en retirer n’importe
quand. Si vous décidez de cesser d’y participer, nous vous encourageons toutefois à en parler
d’abord à votre médecin qui participe à l’étude.
CONFIDENTIEL
52
o
CONFIDENTIEL
QUELS SONT LES RISQUES?
La mesure de la teneur minérale de l’os par la méthode DEXA n’entraîne aucun risque ou effet
secondaire décrit connu.
Les aiguilles utilisées pour prélever le sang pourraient être inconfortables. Un hématome ou, ce
qui est rare, une infection peut faire son apparition au point de ponction à l’aiguille.
On fournira de la vitamine D et du calcium à toutes les femmes qui participent à cette étude
d’accompagnement. Le calcium et la vitamine D ont rarement des effets secondaires, mais
ceux-ci peuvent toutefois inclure des troubles d’estomac ou la constipation.
EFFETS SECONDAIRES DES BISPHOSPHONATES :
Les bisphosphonates ont habituellement des effets secondaires bénins. On a signalé les effets
secondaires suivants au cours d’essais cliniques de comparaison du risédronate sodique ou de
l’alendronate à un placebo. Dans presque tous les cas, les effets secondaires étaient à peine
légèrement plus fréquents chez les patientes qui prenaient le médicament actif.
Risédronate sodique (Actonel)
Très probables (plus de 20 % des patientes) :
•
aucun.
Moins probables (5 à 20 % des patients) :
•
hypertension artérielle;
•
douleurs abdominales, nausées, brûlements d’estomac;
•
douleurs articulaires, osseuses ou au cou;
•
étourdissements, faiblesse;
•
mal de gorge, nez qui coule;
•
cataractes.
Rares (1 à 4 % des patients) :
•
problèmes cardiaques;
•
hernie, gastrite, problèmes rectaux, constipation, diarrhée;
•
meurtrissures, anémie;
•
problèmes osseux ou tendineux;
•
tension musculaire, crampes aux jambes;
•
anxiété, engourdissement;
•
essoufflement, pneumonie;
•
démangeaisons, carcinome de la peau;
•
infection oculaire, infection urinaire.
CONFIDENTIEL
53
o
CONFIDENTIEL
Alendronate (Fosamax)
Très probables (plus de 20 % des patientes) :
•
aucun.
Moins probables (5 à 20 % des patients) :
•
douleurs abdominales.
Rares (1 à 4 % des patients) :
nausées, brûlements d’estomac, constipation, flatulence, reflux acide, ulcère
gastroduodénal, vomissements, gastrite, difficulté à avaler, ballonnement;
•
douleurs osseuses, musculaires ou articulaires, maux de tête.
•
On a observé une ostéonécrose (mort de tissu osseux) de la mâchoire causée par une
utilisation prolongée de bisphosphonates sous d’autres formes administrés par injection
veineuse. On ne sait pas si le Fosamax et l’Actonel administrés par la bouche causent ce
problème, ni à quelle fréquence il se manifeste.
Un conseil de surveillance de la sécurité des données, groupe indépendant d’experts,
examinera les données issues de cette recherche pendant toute l’étude.
Y A-T-IL DES AVANTAGES À PARTICIPER À L’ÉTUDE D’ACCOMPAGNEMENT?
Si vous consentez à participer à cette étude d’accompagnement, vous pourrez ou non en tirer
des avantages médicaux directs. L’information acquise à la suite de cette étude
d’accompagnement pourra bénéficier un jour à d’autres patientes qui ont un cancer du sein.
QUELLES SONT LES AUTRES OPTIONS?
Si vous décidez de ne pas participer à cette étude d’accompagnement, votre médecin qui
participe à l’étude continuera de vous suivre. Il faut lui parler de l’utilisation possible de calcium,
de vitamine D et de bisphosphonates dans votre traitement en dehors de la participation à
l’étude MA.27B.
Veuillez discuter de ces options et d’autres encore avec votre médecin qui participe à l’étude.
Comme dans le cas de tout traitement, il y a des avantages et des risques possibles. Votre
médecin qui participe à l’étude pourra vous informer de tout avantage et risque connu de ces
autres traitements possibles. Il pourra aussi discuter avec vous de ce qui se passera si vous
décidez de n’entreprendre aucun traitement pour le moment.
CONFIDENTIEL
54
o
CONFIDENTIEL
O
ET LE CARACTÈRE CONFIDENTIEL DES RENSEIGNEMENTS?
On fera tous les efforts possibles pour que vos renseignements personnels demeurent
confidentiels. Nous ne pouvons garantir la confidentialité absolue.
Des représentants qualifiés des organisations suivantes peuvent inspecter et recevoir vos
dossiers médicaux ou ceux de l’étude pour des fins d’assurance de la qualité et d’analyse des
données :
•
•
•
•
•
•
•
•
•
•
le Groupe des essais cliniques de l’Institut national du cancer du Canada (GEC INCC),
groupe de recherche qui coordonne l’étude d’accompagnement;
les comités d’éthique de la recherche qui surveillent la conduite éthique de la présente
étude;
Pfizer, l’entreprise qui fournit le médicament servant à l’étude principale, ainsi que la
vitamine D et le calcium, et qui appuie l’étude d’accompagnement;
l’Institut national du cancer des États-Unis, qui supervise la participation des États-Unis à
cette étude d’accompagnement;
la Food and Drug Administration américaine (parce qu’elle supervise l’utilisation des
nouveaux médicaments aux États-Unis);
Santé Canada (parce que le ministère supervise l’utilisation des nouveaux médicaments au
Canada);
la CTSU, groupe de recherche parrainé par l’Institut national du cancer (NCI) pour ouvrir
davantage l’accès aux études sur le cancer;
autres organismes de réglementation au besoin;
le Southwest Oncology Group (SWOG), puisqu’un directeur de l’étude appartient à cet
organisme;
le North Central Cancer Treatment Group (NCCTG), puisqu’un directeur de l’étude
appartient à cet organisme.
Ces renseignements peuvent en inclure qui pourraient permettre de vous identifier, comme les
suivants :
•
•
résultats de tests de détermination des biomarqueurs osseux dans le sérum;
résultats d’absorptiométrie à rayons-x à double énergie (DEXA).
Dans la mesure où les lois pertinentes le permettent, les organisations mentionnées ci-dessus
maintiendront le caractère confidentiel des renseignements qu’elles voient ou reçoivent à votre
sujet. On gardera sous clé les renseignements permettant de vous identifier. Aucune publication
sur la recherche ne contiendra de renseignements permettant de vous identifier.
Les renseignements recueillis au cours de cette étude serviront à des analyses et seront publiés
ou présentés aux milieux scientifiques au cours de réunions et dans des revues. Ces
renseignements pourront aussi servir dans le contexte d’une demande présentée à des
organismes de réglementation du monde entier pour appuyer l’approbation des médicaments
utilisés au cours de cette recherche. On s’attend à ce que les résultats de l’étude soient publiés
dans un journal scientifique après qu’on aura inscrit le nombre nécessaire de patientes et
terminé et analysé toutes les mesures (biomarqueurs osseux et teneur minérale de l’os). Votre
médecin qui participe à l’étude sera informé des résultats de celle-ci lorsqu’ils seront connus.
CONFIDENTIEL
55
o
CONFIDENTIEL
O
O
QU’EST-CE QU’IL EN COÛTE?
Vous ne toucherez aucun paiement pour participer à l’étude. La participation peut entraîner des
frais supplémentaires pour vous. Vous pouvez vous renseigner au sujet des coûts
supplémentaires prévus.
En cas d’effets secondaires ou de traumatisme reliés à la recherche, les soins médicaux vous
seront dispensés par votre médecin qui participe à l’étude, ou l’on vous enverra recevoir les
soins médicaux nécessaires. Même si l’on n'a pas réservé de fonds pour vous indemniser en
cas de traumatisme ou de maladie découlant des traitements à l’étude ou des interventions
connexes, vous ne renoncez à aucun de vos droits légaux à une indemnisation en signant le
présent formulaire de consentement.
On vous remettra gratuitement le calcium et la vitamine D aussi longtemps que vous suivrez le
traitement à l’anastrozole ou à l’exeméstane prévu à l’étude MA.27. S’il devient nécessaire de
prendre des bisphosphonates, votre médecin qui participe à l’étude choisira le médicament, la
dose et le calendrier les meilleurs. Vous comprenez que les organisateurs de l’étude ne vous
fourniront PAS gratuitement les bisphosphonates et que si vous en avez besoin, votre assureur
ou vous-même devrez en prendre les coûts en charge (on vous les fournira seulement si vous
confirmez pour votre médecin qui participe à l’étude que votre assureur ne les couvrira pas).
QUELS SONT VOS DROITS EN TANT QUE PARTICIPANTE?
La participation à cette étude d’accompagnement est volontaire. Vous pouvez décider de ne pas
y participer, ou cesser d’y participer n’importe quand. En décidant de ne pas y participer ou de
quitter l’étude par la suite, vous ne vous exposez à aucune pénalité et ne risquez nullement de
perdre des avantages auxquels vous avez droit. Vous ne pouvez commencer à participer à
l’étude principale MA.27 à moins de participer à cette étude d’accompagnement. Si vous
décidez de cesser de participer à l’étude d’accompagnement, votre participation à l’étude
principale pourra aussi prendre fin. Si vous décidez de cesser de participer à l’étude, nous vous
encourageons à en parler d’abord à votre médecin qui participe à l’étude. Celui-ci discutera plus
à fond des traitements avec vous et continuera de traiter votre cancer par les meilleurs moyens
disponibles.
On vous communiquera en temps et lieu les nouveaux renseignements qui peuvent avoir un
effet sur votre santé, votre mieux-être ou votre volonté de continuer de participer à l’étude
d’accompagnement.
Vous recevrez une copie de ce formulaire de consentement signé.
CONFLIT D’INTÉRÊTS
Note aux centres : Veuillez inclure les détails de tout conflit d’intérêts réel ou possible au sujet de cette étude.
Le centre reçoit du Groupe des essais cliniques de l’INCC des fonds qui aident à compenser les
coûts de la recherche. Le GEC INCC est un groupe de recherche sans but lucratif.
CONFIDENTIEL
56
o
CONFIDENTIEL
QUI APPELER SI VOUS AVEZ DES QUESTIONS OU DES PROBLÈMES?
Si vous avez des questions au sujet de votre participation à cette étude d’accompagnement ou
si vous subissez un traumatisme relié à la recherche, vous pouvez en parler avec votre
médecin. Vous pouvez aussi rencontrer le médecin responsable de l’étude ici. Il s’agit de :
________________________________
Nom
_________________________
Téléphone
Pour obtenir des conseils au sujet de vos droits de patiente ou de questions d’éthique qui ont
trait à l’étude, vous pouvez en parler à quelqu’un qui n’a aucun lien avec l’étude. Il s’agit de :
________________________________
Nom
_________________________
Téléphone
CONFIDENTIEL
57
o
CONFIDENTIEL
O
SIGNATURES
Votre signature apposée sur ce formulaire de consentement signifie ce qui suit :
•
•
•
•
L’étude vous a été expliquée et l’on a répondu à toutes vos questions.
Vous comprenez les exigences de l’étude et les risques qu’elle comporte.
Vous permettez que l’on consulte vos dossiers médicaux de la façon expliquée dans ce
formulaire de consentement.
Vous consentez à participer à cette étude.
_________________________________
Signature de la patiente
________________
Date
____________________________
Signature du chercheur
_________________________
Date
A-t-on aidé la patiente d’une des façons indiquées ci-dessous pendant le processus visant à
obtenir le consentement?
 Oui
 Non
Si oui, veuillez cocher la case et remplir l’espace réservé à la signature ci-dessous :
 On a lu le formulaire de consentement à la patiente et la personne qui appose sa signature
ci-dessous atteste qu’on a expliqué précisément l’étude à la patiente, qui semble l’avoir
comprise.
______________________________
Signature de la personne qui a participé
à la discussion sur le consentement
________________________
Date
Prière de noter : Il faut consigner dans le dossier médical de la patiente, le cas échéant, d’autres
renseignements sur l’aide fournie pendant le processus visant à obtenir le consentement.
CONFIDENTIEL
58
o
CONFIDENTIEL
LIST OF CONTACTS
Contact
ELIGIBILITY
CHECKLIST
Must be completed prior
to the telephone call to
request a registration
STUDY SUPPLIES
PRIMARY CONTACTS
FOR GENERAL
PROTOCOL-RELATED
INQUIRIES
(including eligibility
questions and protocol
management
STUDY CHAIR
SERIOUS ADVERSE
EVENT REPORTING
See section 9.0 for details
CALCIUM, VITAMIN D
& BISPHOSPHONATE
QUESTIONS
Telephone #
Fax #
Gina Howard or
Amy Hawkins
Clinical Trials Assistant(s), NCIC CTG
email:
[email protected]
[email protected]
Catherine Elliott, M.Sc.
Study Coordinator, NCIC CTG
email: [email protected]
or
Shari Leeson
Research Assoicate, NCIC CTG
or
Dr. Joseph Pater
Physician Coordinator, NCIC CTG
Dr. Paul Goss, Study Chair
email :
[email protected]
Dr. Joseph Pater,
Physician Coordinator
or
Catherine Elliott, M.Sc.
Study Coordinator
NCIC CTG
MA.27 Team (RE: MA.27B Drug Supply)
10 Stuart Street
Queen’s University
Kingston, Ontario, Canada K7L 3N6
(613)-533-2814
(613) 533-6430
(613) 533-2941
(617) 724-3118
(617) 724-1079
(613) 533-6430
(613) 533-2941
(613) 533-6430
(613) 533-2814
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION
To submit site registration
documents:
For patient enrollments:
CTSU Regulatory Office
1818 Market Street, Suite
1100
Philadelphia, PA 19103
Phone - 1-888-823-5923
Fax – 215-569-0206
CTSU Patient Registration
Voice Mail – 1-888-462-3009
Fax – 1-888-691-8039
Hours: 8:00 AM – 8:00 PM Eastern Time,
Monday – Friday (excluding holidays)
[For CTSU patient enrollments that must be
completed within approximately one hour, or
other extenuating circumstances, call 301-7042376. Please use the 1-888-462-3009 number
for ALL other CTSU patient enrollments.]
Submit study data directly to the Lead
Cooperative Group unless otherwise specified
in the protocol:
Original CRFs to be mailed to:
NCIC Clinical Trials Group
Queen’ s University
10 Stuart Street
Kingston, Ontario, Canada
K7L 3N6
Do not submit study data or forms to CTSU
Data Operations. Do not copy the CTSU on
data submissions.
For patient eligibility questions, contact the Study Coordinator at the NCIC Clinical Trials Group at 1-613-533-6430.
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help Desk by phone or e-mail:
CTSU General Information Line – 1-888-823-5923, or [email protected]. All calls and correspondence will be
triaged to the appropriate CTSU representative.
The CTSU Public Web site is located at: www.ctsu.org
The CTSU Registered Member Web site is located at https://members.ctsu.org
CONFIDENTIAL
Final Page
CONFIDENTIAL
CONFIDENTIAL
Final Page
CONFIDENTIAL

protocole - Canadian Cancer Trials Group

Transcription

Documents pareils

Site FMC - CTG Master Class France

CINQUIEME – SEQUENCE 1 PROJET MUSICAL EdMusicale 2012

“The role of the Infrapatellar fat pad (Hoffa) in knee pain and

booklet

Le programme de jour de Cartier vous attend!

sq1 s1 élèves+job ac 2

Chers anciens - Columbia Business Club France

Working With Children Check - NSW Office of the Children`s Guardian

French Phrases

Posting #T-1416 CONTINUING EDUCATION