Aya Bassatne
SHARP 321A
Clinical Trial Protocol
Administrative information
1- Title: A one year, multicenter, investigator, participants and data analyst blinded,
randomized, parallel group, non-inferiority trial comparing the efficacy of
zoledronate 5mg once yearly vs 4mg twice yearly on aromatase inhibitor induced
bone loss in postmenopausal women with breast cancer
2- Trial Registration
Intended registry: ClinicalTrials.gov NCT-------Table 1: WHO Trial Registration data
Data Category
Primary registration and trial
identifying number
Date of registration in primary
registration
Secondary identifying numbers
Source(s) of monetary or material
support
Primary sponsor
Secondary sponsor(s)
Contact for public queries
Contact for scientific queries
Public title
Scientific title
Countries of recruitment
Health conditions or problems
studied
Interventions
Information
ClinicalTrials.gov: NCT-------Pending
Not applicable
To be submitted to the Medical Practice Plan (MPP) and the
University Research Board (URB) at the American University of
Beirut (AUB)
American University of Beirut Medical Center (AUBMC)
Not applicable
Marlene Chakhtoura: mc39@aub.edu.lb
Marlene Chakhtoura: mc39@aub.edu.lb
Different doses of zoledronate for prevention of aromatase
inhibitor induced bone loss in postmenopausal women with
breast cancer: a randomized controlled trial
A one year, multicenter, investigator, participants and data
analyst blinded, randomized, parallel group, non-inferiority trial
comparing the efficacy of zoledronate 5mg once yearly vs 4mg
twice yearly on aromatase inhibitor induced bone loss in
postmenopausal women with breast cancer
Lebanon
Aromatase inhibitor induced bone loss
Intervention 1: IV zoledronate 5mg once and then placebo IV
infusion after 6 months
Intervention 2: IV zoledronate 4mg every 6 months
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Key inclusion and exclusion
criteria
Inclusion:
 Lebanese postmenopausal women
 Non metastatic estrogen receptor positive breast cancer
(Stage I-IIIa)
 On (<6 months) or starting aromatase inhibitor therapy
 BMD T-score  -1.5
OR T-score  -1 with > 1 risk factor (age>65, low BMI
(<20 kg/m2), family history of hip fracture, personal
history of fractures or smoking)
OR history of fragility fracture (lumbar spine fracture, hip
fracture or ≥ 2 peripheral fractures)
OR FRAX calculated MOF risk > age-dependent
threshold using the Lebanese FRAX calculator
Exclusion:
 Radiological or clinical evidence of metastasis
 Other malignancy
 Chronic conditions that could affect bone turnover
(Cushing’s, uncontrolled thyroid disease, osteomalacia,
hyperparathyroidism, diabetes mellitus…)
 Intake of medications that could affect bone turnover
(anticonvulsants, bisphosphonates within the past 12
months, HRT within the past 12 months, chronic steroid
use for 3-6 months)
 Liver impairment (LFTs three times upper normal limit)
 Renal impairment (GFR <35ml/min)
 Hypocalcemia
 Hypersensitivity reaction to bisphosphonate
Study type
Date of first enrolment
Target sample size
Recruitment status
Primary outcome(s)
Key secondary outcomes
Phase III, triple blinded, randomized, controlled, noninferiority
trial with two parallel groups
Not applicable
92 participants per arm
Not applicable
Percent change lumbar spine BMD at 12 months
Percent change total hip and femoral neck BMD at 12 months
Percent change bone markers (osteocalcin, crosslaps) at 12
months
Percent change lumbar spine BMD at 6 months
Rates of adverse events
Rates of fractures
2
3- Protocol Version
September 28th 2019, Version 1
4- Funding
To be submitted for funding from the Medical Practice Plan (MPP) and University Research
Board (URB) at the American University of Beirut (AUB), Lebanon. We will contact Fattal &
fils to provide the primary investigator with zoledronic acid ampoules manufactured by Novartis.
5- Roles and Responsibilities
a) Protocol contributors
- Ghada El Hajj Fuleihan, MD, MPH: gf01@aub.edu.lb
Professor of Medicine
Calcium Metabolism and Osteoporosis Program, Division of Endocrinology and Metabolism,
Department of Internal Medicine
American University of Beirut Medical Center, Beirut, Lebanon
Principal investigator: responsible for study design and conception, protocol development and
revision, oversight of subjects’ recruitment, data collection, data entry, data analysis and
interpretation, review of manuscript drafts, revision and approval of the final versions.
- Marlene Chakhtoura, MD, MSc: mc39@aub.edu.lb
Instructor of Clinical Medicine
Calcium Metabolism and Osteoporosis Program, Division of Endocrinology and Metabolism,
Department of Internal Medicine
American University of Beirut Medical Center, Beirut, Lebanon
Co- investigator: responsible for study design and conception, protocol development and
revision, oversight of subjects’ recruitment data collection, data entry, data analysis and
interpretation, review of manuscript drafts, revision and approval of the final versions.
- Aya Bassatne, MD: aaa144@mail.aub.edu
Research Fellow
Calcium Metabolism and Osteoporosis Program, Division of Endocrinology and Metabolism,
Department of Internal Medicine
American University of Beirut Medical Center, Beirut, Lebanon
Co-investigator: responsible for proposal development, protocol update(s) and revision(s),
subject recruitment, data entry, analysis and interpretation, and review of manuscript drafts and
approval of the final versions.
- Ziad Mahfoud, PhD: zrm2001@Qatar-med.cornell.edu
Associate Professor of Medicine
Weil Cornell, Qatar
Consultant American University of Beirut, Lebanon.
Co-investigator: trial statistician responsible for advice on clinical trial design, sample size
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calculation and analysis plan, oversight of analyses with the principal investigator and the
research fellow, and approval of the final version of manuscript.
Co-investigators from the Hematology Oncology department at AUBMC will be contacted
and added as contributors accordingly
b) Trial Sponsor
American University of Beirut Medical Center (AUBMC)
Address: Hamra, Beirut, Lebanon
POBox: 11-0236, Riad El Solh, Beirut, Lebanon.
Email: aubmc@aub.edu.lb
Phone: +9611350000
c) Role of study sponsor and funder
The trial sponsor and the funding source will not have any role in the design, implementation,
analyses, or publication of this study.
d) Committees
Trial Steering Committee:
 Dr. Ghada El Hajj Fuleihan
 Dr. Marlene Chakhtoura
 Dr. Aya Bassatne
Responsible for agreeing the final protocol and amendments, providing overall supervision and
monitoring the progress of the study.
Trial management committee:
 Dr. Ghada El Hajj Fuleihan
 Dr. Marlene Chakhtoura
 Dr. Aya Bassatne
Responsible for preparing and managing the budget, reporting and monitoring adverse events,
assisting in IRB applications and verifying the data.
Data manager:
Responsible for maintenance of trial IT system, data entry and data verification.
Data safety monitoring committee:
Responsible for reviewing all trial adverse events, and making recommendations for unblinding
and study termination.
Introduction
6- Background and rationale
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a) Description and justification of the research question
Breast cancer is the most common cancer in women and accounts for 15% of all cancer
related mortality worldwide (1, 2). It is therefore considered a major public health problem and is
estimated to reach an annual incidence of 3.2 million by year 2050 (2). In Lebanon, breast cancer
accounts for 37% of cancer cases among women and 20% of cancer cases overall (3). Incidence
rates have been increasing for years among Lebanese women and are among the highest in the
region and worldwide (3).
Treatment of breast cancer involves various modalities including surgery, radiation,
chemotherapy and hormone therapy. The selection of therapy is based on several factors such as
menopausal state, cancer stage, grade, histology and the presence or absence of estrogen or
progesterone receptors (4). Aromatase inhibitors (AIs) have been shown to be beneficial and
superior to tamoxifen as adjuvant therapy in postmenopausal women with estrogen receptor
positive breast cancer (5, 6). Despite their various benefits, AIs are associated with multiple side
effects that are becoming more prevalent due to the increased survival of women with breast
cancer (7).
Estrogen’s role in maintaining bone metabolism and hemostasis is well established. At
menopause, estrogen levels start to decrease leading to an increase in bone resorption and bone
loss. In the postmenopausal state, the main source of estrogen becomes the peripheral conversion
of adrenal androgens (7). AIs suppress the peripheral conversion of androgen into estrogen (7).
This leads to a more abrupt decrease in estrogen levels, and therefore a faster rate of bone loss at
the Lumbar Spine (LS) or hip (a drop by 1.7-5.8% yearly) compared to that seen in
postmenopausal women not taking aromatase inhibitors (1-2% yearly decrease) (7, 8).
Furthermore, several studies showed deleterious effects of AIs on multiple independent
predictors of fractures. AIs were shown to significantly decrease bone mineral density (BMD),
trabecular bone score and hip structural geometry while they increased bone turnover markers
(9-11). The growing use of AIs in postmenopausal women with breast cancer, dictates the need
for bone health assessment and prevention of bone loss in this population.
Several guidelines were published for the evaluation and management of AI induced
bone loss; however, these were inconsistent regarding the eligibility for treatment, timing of
treatment initiation and monitoring of bone loss (12-14). Several antiresorptive medications were
recommended for the prevention of AI induced bone loss (12). The effect of bisphosphonates on
AI-induced bone loss in postmenopausal women was evaluated in multiple randomized
controlled trials. Oral bisphosphonates at doses used for post-menopausal osteoporosis were
shown to prevent bone loss at the LS in women on AI therapy (15-17). Intravenous (IV)
Zoledronic acid is the most potent bisphosphonate and is approved for treatment of osteoporosis
(7). It has also been investigated in AI induced bone loss but only at the 4mg twice yearly dose
(18-20). Zoledronic acid increased LS BMD significantly by 2.7% at 12 months and 4.3% at 5
years in postmenopausal women (median age 58), receiving AI (19, 20). Most of the participants
had well established menopause (83%) and normal BMD (65-70%) at study entry (19, 20).
Starting zoledronic acid concomitantly with AI therapy was found to be more beneficial than
delaying it until bone loss or fractures occur (18, 19, 21).
IV zoledronate at a dose of 5mg once yearly is approved for treatment of osteoporosis but
has not been investigated for the prevention of AI-induced bone loss in postmenopausal women.
Since oral bisphosphonates at doses similar to those used in osteoporotic women have proven to
be beneficial in preventing AI induced bone loss (15-17), we expect that zoledronic acid will be
also effective at the 5 mg yearly dose. If proven to prevent AI induced bone loss, such dose
would increase compliance and decrease cost and side effects compared to the twice yearly dose
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b) Choice of comparators
Two arms with different zoledronic acid dose:
 IV zoledronate 4mg every 6 months: This dose has been studied in multiple randomized
clinical trials (19, 20) and was proven to be efficient in preventing AI induced bone loss.
Its use is suggested by multiple societies and guidelines (12, 13).
It is unethical to use a placebo arm in patients at risk for bone loss knowing that there is a
beneficial treatment.
 IV zoledronate 5mg once yearly: This dose is approved by the Food and Drug
Administration for use in osteoporosis. If proven to be efficacious against AI induced
bone loss, it would increase compliance and decrease cost and side effects.
7- Objectives
Hypothesis: IV Zoledronate at a dose of 5mg once yearly is non-inferior to 4mg twice yearly in
preventing aromatase inhibitor induced bone loss at the lumbar spine in postmenopausal women
with breast cancer.
Primary Objective: To evaluate the effect of IV zoledronate 5mg once yearly compared to 4mg
twice a year on lumbar spine bone mineral density using DXA at 12 months in postmenopausal
women with breast cancer receiving aromatase inhibitors.
Secondary Objectives: To evaluate the effect of IV zoledronate 5mg once yearly compared to
4mg twice a year on total hip bone mineral density using DXA and serum bone markers at 12
months in postmenopausal women with breast cancer receiving aromatase inhibitors.
8- Trial design
This study is a one year phase III, multicenter, randomized, controlled, investigator, participant
and data analyst blinded, non-inferiority trial with two parallel groups with a 1:1 allocation ratio
to investigate the efficacy of zoledronate 5mg once a year versus zoledronate 4mg twice a year,
on bone density loss at the lumbar spine. We chose to conduct an RCT because it is the highest
level of evidence and the gold standard for assessing causality.
Methods: Participants, interventions and outcomes
9- Study setting
Postmenopausal women with breast cancer will be approached and recruited from the Oncology
specialty clinics and the outpatient departments of all three participating hospitals (AUBMC,
CMC and KMC to be contacted) in Beirut, Lebanon. The study visits, interventions, blood and
urine collection will take place at all centers and samples collected at CMC or KMC will be sent
to AUBMC for analysis. All BMD measurements will take place at AUBMC.
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10- Eligibility criteria
Inclusion criteria:
 Lebanese postmenopausal women
 Non metastatic estrogen receptor positive breast cancer (Stage I-IIIa)
 On (<6 months) or starting aromatase inhibitor therapy
 BMD T-score  -1.5
OR T-score  -1 with > 1 risk factor (age>65, low BMI (<20 kg/m2), family history of
hip fracture, personal history of fractures or smoking)
OR history of fragility fracture (lumbar spine fracture, hip fracture or ≥ 2 peripheral
fractures)
OR FRAX calculated MOF risk > age-dependent threshold using the Lebanese FRAX
calculator
Exclusion criteria:
 Radiological or clinical evidence of metastasis
 Other malignancy
 Chronic conditions that could affect bone turnover (Cushing’s, uncontrolled thyroid
disease, osteomalacia, hyperparathyroidism, diabetes mellitus…)
 Intake of medications that could affect bone turnover (anticonvulsants, bisphosphonates
within the past 12 months, HRT within the past 12 months, chronic steroid use for 3-6
months)
 Liver impairment (LFTs three times upper normal limit)
 Renal impairment (GFR <35ml/min)
 Hypocalcemia
 Hypersensitivity reaction to bisphosphonate
11- Intervention
a) Intervention for each group
We will contact Fattal & Fils to provide us with zoledronic acid and placebo ampoules
manufactured by Novartis. Participants will be randomly allocated in equal proportions to two
different interventions administered by a trained nurse in the oncology outpatient department at
each of the participating centers.
One group will receive an IV infusion of Zoledronic acid 4 mg dissolved in 105mL 0.9%
NaCl over 30 minutes at study entry and after 6 months. The other group will receive an IV
infusion of Zoledronic acid 5 mg dissolved in 100mL 0.9% NaCl over 30 minutes at study entry
and a placebo infusion after 6 months containing 100mL 0.9% NaCl over 30 minutes. All
patients will receive 1,000 mg acetaminophen IV 15 minutes before the infusion and will be
instructed to take 2 pills (500mg each) every 8 hours thereafter for the following 48 hours to
prevent or minimize manifestations of acute reactions. Calcium and Vitamin D supplementation
will be encouraged in both treatment arms depending on their dietary intake and baseline
25(OH)D levels.
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b) Intervention modifications
Intervention should be discontinued in any participant experiencing a decline in renal function
reaching a GRR <35ml/min confirmed on two consecutive readings. Participants who develop
progression of breast cancer to stage >IIIa (locally invasive, or metastatic) or participants who
discontinued aromatase inhibitor therapy should be evaluated by their oncologist who would
assess the risks and benefits of remaining in the study. All participants discontinuing
interventions due to the above criteria, severe side effects or personal request should be followed
till the end of the study with assessment of protocol endpoints.
c) Adherence
Both intervention groups will receive infusions in a hospital setting and therefore adherence to
the intervention itself should not be a problem. Participants would be called in advance by the
research team and reminded of their infusion appointment one week and one day prior to the
actual infusion date. The second infusion will be given after 6 months ± 2 weeks to increase
compliance. Participants will also be called one week prior and then one day prior to each visit
and reminded of the procedures (blood tests, interview, BMD…) occurring at each visit.
Acetaminophen pills will also be provided to participants upon infusion of zoledronic acid, IV
acetaminophen will be given before the infusion by the nurse and a box of 12 pills will be given
to participants to take following the infusion. The research team will explain the importance of
adherence to acetaminophen in decreasing side effects of zoledronic acid.
d) Concomitant care
Participants will be advised to take vitamin D3 (cholecalciferol) 800 IU/d and/or calcium 1,000
mg/d depending on baseline 25(OH)D levels and dietary intake. Participants should continue to
take their home medications. The research team should be made aware of any medication
changes particularly initiation of medications affecting bone metabolism such as steroids,
antiresorptives, anticonvulsants, chemotherapy and hormone therapy.
12- Outcomes
a) Primary outcome: Bone loss at the lumbar spine as measured by DXA scan (BMD) at
the lumbar spine expressed as mean percent change from baseline to12 months in
both intervention groups. The lumbar spine is thought to be the first site that is most
sensitive to sex steroids deficiency and therefore would be more prone to changes
with aromatase inhibitors and was therefore chosen as the primary outcome of this
study (7).
b) Secondary outcomes: BMD and bone markers are surrogates for fractures and are
therefore used as secondary outcomes to prove the efficacy of zoledronic acid.
- Bone loss at the lumbar spine as measured by DXA scan (BMD) at the lumbar
spine expressed as mean percent change from baseline to 6 months in both
intervention groups.
- Bone loss at the total hip as measured by DXA scan (BMD) expressed as mean
percent change from baseline to 12 months in both intervention groups.
8
-
Serum levels of osteocalcin expressed as mean percent change from baseline to 12
months in both intervention groups.
Serum levels of crosslaps (CTX) expressed as mean percent change from baseline
to 12 months in both intervention groups.
Fracture rates and adverse events throughout the study.
13- Participant timeline
Participants will be approached by their treating oncologist. Those who are interested will
meet the research assistant for recruitment and further details:
Pre-Screening visit: The research team would explain the study to participants, obtain
informed consent and screen for eligibility criteria.
Screening visit: Measure weight, height, vital signs, BMD, VFA, TBS, collect blood and
urine studies.
Blood and urine studies include bone markers, CBC, 25(OH)D, Calcium, Phosphorus,
Magnesium, Parathyroid hormone (PTH), hemoglobin A1C, Alkaline phosphatase, liver
enzymes, thyroid stimulating hormone (TSH), BUN, Creatinine, and total protein and 24
hours urine collection for calcium, creatinine and sodium.
Randomization and Intervention visit: Measure weight, height, vital signs, administer IV
zoledronic acid as per randomization protocol, and IV acetaminophen.
3 months visit: Measure weight, height, vital signs and collect blood studies.
Blood studies include liver enzymes, creatinine, calcium and bone markers.
6 months visit: Measure weight, height, vital signs, BMD, TBS, administer IV zoledronic
acid or IV placebo, and IV acetaminophen and collect blood studies.
Blood studies include liver enzymes, creatinine, calcium and bone markers.
12 months visit: Measure weight, height, vital signs, BMD, TBS and collect blood studies.
Blood studies at the 3, 6 and 12 months visits include liver enzymes, creatinine, calcium and
bone markers.
A delay of a maximum of 2 weeks will be allowed between each follow up visit. All visits
including a BMD measurement will be done at AUBMC. For other visits (prescreening,
intervention and 3 months), each participant will present to their original recruitment center.
Blood and urine samples collected in KMC and CMC will be sent to AUBMC for analysis.
During each visit, the importance of adherence to the protocol will be highlighted by the
research personnel and adverse events would be assessed through questionnaires. Food
frequency questionnaire to assess calcium and vitamin D intake along with questionnaires
recording demographic and any change in home medications will also be performed at each
visit. Height will be measured at each visit, if there is a decrease of 2 cm or more between
visits a spine radiograph will be taken to assess for any asymptomatic vertebral fracture.
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Pre-Screening
visit
Screening:
Baseline BMD,
VFA, blood and
urine studies
Randomization
Zoledronic 5mg IV
Zoledronic 4mg IV
3 months visit:
Follow up, blood
studies
3 months visit:
Follow up, blood
studies
6 months visit:
Placebo IV, follow
up, blood studies,
BMD
6 months visit:
Zoledronic acid 4mg
IV, follow up, blood
studies, BMD
12 months visit:
Follow up, BMD,
blood studies
Figure 1: Flow diagram of the study visits
10
12 months visit:
Follow up, BMD,
blood studies
Table 2: Participants timeline
PreScreening
-t2
Enrolment
Eligibility screen
Informed consent
Allocation
Interventions
IV Zoledronic
4mg
IV Zoledronic
5mg
IV Placebo
Assessments
Questionnaires
Vitals
BMD
Bone markers
LFTs
Creatinine
Calcium
Other labs1
1st visit
-t1
Study period
Randomization &
Intervention
t0
3 mo visit
6 mo visit
12 mo visit
t1
t2
t3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
1full
x
x
x
x
x
x
x
set of blood studies including CBC, 25(OH)D, Calcium, Phosphorus, Magnesium, Parathyroid hormone (PTH), hemoglobin A1C, Alkaline phosphatase,
liver enzymes, thyroid stimulating hormone (TSH), BUN, Creatinine, and total protein and 24 hours urine collection for calcium, creatinine and sodium
14- Sample Size
Sample size was calculated for our primary outcome, percent change LS BMD at 12
months using an online calculator (22).
Several superiority trials investigated the effect of IV zoledronic acid 4mg twice a year in
preventing bone loss at the LS in postmenopausal patients with breast cancer on aromatase
inhibitors (18-20, 23). These trials compared zoledronate 4 mg twice a year given immediately
when starting AIs to delaying it until a drop in BMD or a fracture occur. Only 13-14% of the
patients randomized to the delayed group actually received zoledronate we therefore could
consider these trials as comparing zoledronate 4 mg twice a year to placebo (18-20). The
difference in percent change LS BMD at 12 months between the two treatment arms were 4.4%,
5.3%, 5.4% and 5.7% in each of these trials (18-20, 23).
These differences between arms were significant, we therefore considered that dividing
these values by two would give us a non-significant difference (2.2%, 2.65%, 2.7% and 2.85%
respectively), to be considered as the non-significant change in our calculations, a method
commonly used in non-inferiority trials since it would increase the sample size required by 4
folds and would therefore be more conservative (24). To be more conservative with our sample
size calculations, we used the smallest value (2.2%) as the non-significant change (18). Only one
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study reported the standard deviation of the percent change LS BMD in each arm (4.3% for
immediate vs 5.2% for the delayed group) (18). We used the average of these standard deviations
(5%) in our calculations. We calculated the sample size based on different scenarios and based
on non-significant change ranging between 1 and 2.2% (Table 1).
Table 3: Different scenarios for sample size calculation
Dinf
SD
Power
2.2
5
90%
2
5
80%
90%
1.75
Total N
N (20% loss to
follow up)
N (30% loss to
follow up)
5%
178
223
255
5%
128
216
160
270
183
309
5
80%
90%
5%
156
280
195
350
223
400
1.5
5
80%
90%
5%
202
382
253
478
289
546
1.25
5
80%
90%
5%
276
550
345
688
395
787
5
80%
90%
5%
396
858
495
1073
566
1226
620
775
886
1
alpha
80%
In a double blind placebo controlled trial, postmenopausal women were randomized to
receive different doses of denosumab subcutaneously (25). The two optimal doses that provided
maximal effect on bone parameters were found to be 30 mg every 3 months and 60 mg every 6
months. The percent change LS BMD at 12 months was 6.7% and 4.6% in these groups
respectively (25). The 2.1% difference between these two doses is therefore considered nonsignificant and is very closed to the assumption (2.2%) used in our calculations.
Therefore, to perceive non-inferiority between the two groups, with a 2.2% least
significant change, 5% standard deviation, 80% power and a type I error of 5%, 64 participants
per arm are needed. With a 30% drop out rate we would need 92 patients per arm. If we consider
that 50% of patients approached in the clinics will be eligible and willing to enroll in the study, a
total of 368 patients should be screened initially. Assuming that only 30% will accept to join the
study, 1226 patients should be approached.
15- Recruitment
Postmenopausal women with breast cancer on aromatase inhibitor therapy for less than 6 months
or to start aromatase inhibitor therapy will be approached by their treating oncologist in the
Oncology specialty clinics or outpatient departments at AUBMC, KMC and CMC. Information
about the trial will be available at the entrance of each medical center in the form of billboards
and in the waiting areas and inside the clinics as English or Arabic flyers and brochures.
Oncologists will refer interested patients to the research team for more information, assessment,
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screening and consent. The research team will approach the oncologists on a weekly basis to
monitor the process and the recruitment progress. The recruitment process will extend over 1236 months and might continue further until the sample size is achieved.
Methods: Assignment of interventions
16- Allocation
a) Sequence generation
Participants will be randomly allocated to either one of the intervention groups in a 1:1 allocation
ratio. Due to the difference in patient load in the three centers, we will enroll patients from
AUBMC, CMC and KMC in a 4:1:1 ratio respectively. We will generate a randomization
sequence using restricted fixed permuted block randomization through an online sequence
generator for each center separately. The number of blocks and blocks sizes will not be disclosed
to insure concealment. Randomization will be stratified by time since menopause (≤ 5 or >5
years) and by steroid use in chemotherapy. Information about the randomization will be available
in a separate document with limited access only to the pharmacy.
b) Concealment mechanism
To ensure concealment, the pharmacy will not check the treatment allocation until the participant
undergoes the screening visit and is enrolled in the study. Once the participant is enrolled and
presents to the intervention visit, the pharmacy would provide the research assistant with the
appropriate IV bag which will then be transported to the research nurse.
c) Implementation
The statistician will generate the randomization sequence. He will then mail the list to the
pharmacy at AUBMC where the list will be stored. The pharmacist is responsible for treatment
allocation and concealment. Once an eligible patient is enrolled and presents to the intervention
visit, the research team will notify the pharmacist at AUBMC through an email with the
participant’s code. The pharmacist will then prepare the appropriate ampoule according to the
predetermined sentence and present it to the research assistant in a sealed envelope to be
transferred to the nurse performing the infusion.
The research assistant is responsible for screening and enrolling eligible participants and
transporting the IV bag to the nurse. The research nurse is responsible for performing the
infusion. Both the research assistant and nurse will be kept unaware of the allocation.
17- Blinding (Masking)
a) Blinding
The participants, care providers (PI, treating oncologists and nurse performing the
infusion), data collectors (research assistants), outcome assessors and data analysts will be
blinded. Pharmacists will prepare unlabeled ampoules similar in size and color for both
zoledronate doses (4mg and 5mg) and for placebo. Since one group of participants will receive
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zoledronate 4mg twice (6 months interval), we will give those in the 5mg once a year group a
placebo infusion at 6 months to insure blindness to the treatment.
Zoledronic acid infusion is associated with acute phase reaction that occurs within the
first 24 hours after the first infusion. The risk of acute reaction decreases with following
injections but is not completely eliminated. Both groups are at risk of experiencing acute phase
reaction at the first infusion visit since both groups will receive the active drug. At 6 months,
participants receiving the placebo infusion will not experience acute phase reaction and will
therefore not require acetaminophen while the group who receives treatment will experience side
effects and the intervention could therefore be predicted and unblinded. We will therefore
provide all participants with acetaminophen pills to be taken every 8 hours for 48 hours
following each infusion instead of PRN to ensure blinding especially at the 6 months
interventional visit (zoledronic acid 4mg v/s placebo). The lack of side effects could therefore be
attributed to the prophylactic intake of acetaminophen rather than placebo infusion, which would
limit the risk of unblinding.
b) Emergency unblinding
We will try to maintain blinding as far as possible to preserve the reliability and quality of our
trial. Zoledronic acid infusion is commonly associated with acute phase reaction, and the
management of this side effect is not affected by knowing to which arm the participant
experiencing it is randomized to. Emergency unblinding will only occur in cases where the
treatment of the severe adverse event is affected by the kind of intervention received. The
primary investigator should be made aware of all code breaks and contact the pharmacy to
receive the allocation information. The principal investigator should also fill an adverse event
form. Un-blinding does not necessarily mean discontinuation of treatment and the actual
allocation should not be disclosed to other research personnel, participants, data analysts and
outcome assessors.
Methods: Data collection, management and analysis
18- Data Collection methods
a) Plans for data collection and assessment
All data will be collected by trained personnel at the American University of Beirut Medical
Center.
Bone Mineral Density: BMD will be performed at the baseline, 6 months and 12 months visits at
AUBMC, a center accredited by the International Society for Clinical Densitometry (ISCD).
Lumbar spine and total hip BMD will be assessed by certified technicians using Dual energy Xray Absorptiometry (DXA) scans (Hologic, Horizon A, version 13.6.0.5). As part of the BMD
quality control, precision and performance are checked using phantoms and duplicate measures
on select patients on a daily basis. In 2018, the coefficient of variation derived from a total of
177 duplicate for the lumbar spine was 0.401± 0.587 and from a total of 202 duplicates fot the
total hip was 0.383± 0.243.
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Crosslaps (C-terminal telopeptides of type 1 collagen): Crosslaps an index of bone collagen
degradation will be assessed at the baseline, 3 months, 6 months and 12 months visitis. Fasting
serum crosslaps will be measured using ElectroChemiLuminescence ImmunoAssay (ECLIA),
with a reference range of 104-1008 ng/mL in postmenopausal women. Intra-assay CV’s are
7.8%, 2.7%, 3.2% and 1.9% at 0.046, 0.292, 0.709 and 2.94 ng/mL respectively. Inter-assay
CV’s are 7.7 %, 8.5% and 7.8% at 0.291, 0.679 and 2.77 ng/mL respectively.
Osteocalcin: osteocalcin, an index of bone formation will be assessed at the the baseline, 3
months, 6 months and 12 months visits. Fasting serum osteocalcin will be measured using
ECLIA, with a reference range of 8.0-55.9 ng/mL in women between 41 and 70 years of age.
Intra-assay CV’s are 2.8%, 1.3%, 1.2%, and 1.7% at 1.62, 14.5, 83.4 and 178 ng/mL
respectively. Inter-assay CV’s are 2.6 %, 3.2% and 3.9% at 15.8, 87.2 and 186 ng/mL
respectively.
Other laboratory measurements: A complete blood and urine workup will be performed at the
baseline visit including:
- 25(OH)D: assessed using ECLIA (Roche Total II) with the following reference
range: deficient <10 ng/mL, insufficient 10-25 ng/mL, desirable >25 ng/mL. The
inter-assay CVs are 4.1% and 2.5% for 11 and 29.6 ng/mL respectively and the
intra-assay CVs are 5.6% and 3% for 11 and 29.6 ng/mL respectively.
- Alanine Transaminase (ALT/SGPT): assessed using enzymatic rate
spectrophotometry with a reference range of 0-50 IU/L.
- Aspartate Transaminase (AST/SGOT): assessed using enzymatic rate
spectrophotometry with a reference range of 0-50 IU/L.
- Blood Urea Nitrogen (BUN): assessed using Spectrophotometry with a reference
range of 8-25 mg/dL.
- Calcium: assessed using Spectrophotometry, NM-BAPTA with a reference range
of 8.5-10.5 mg/dL.
- Complete Blood Count (CBC): assessed using Coulter-principle of
counting/Volume conductivity and scatter.
- Creatinine: assessed using the enzymatic colorimetric POCT method with a
reference range of 0.5-1.0 mg/dL in women.
- Magnesium: assessed using the colorimetric-xylidyl blue method with a reference
range of 1.6-2.5 mg/dL.
- Phosphate: assessed using the ammonium phosphomolybdate complex with a
reference range of 2.7-4.8 mg/dL.
- PTH: assessed ECLIA with a reference range 15-76 pg/mL.
- TSH: assessed using ECLIA with a reference range of 0.27-4.2 µU/mL.
- Total serum protein: serum albumin, globulin and total protein are assessed using
Spectrophotometry with the following reference ranges: Protein total: 60-83 g/L;
Albumin: 36-53 g/L; Globulin: 18-34 g/L.
- 24 hours urine calcium: measured using Spectrophotometry, NM-BAPTA with a
reference range of 20.0-275.0 mg/24 hour.
- 24 hours urine creatinine: measured using the Jaffe rate with a reference range of
0.6-2.0 g/24 hour.
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-
24 hours urine sodium: measured using Ion-selective electrode with a reference
range of 40-220 mmol/24 hour.
Questionnaires: An interviewer led questionnaire will be administered at the first visit, for each
participant regarding demographic characteristics, medical history, medications, dietary and
social habits. These questionnaires will also be filled at each follow up visit to capture any
changes in the data previously collected. A validated food frequency questionnaire will also be
administered to assess calcium and vitamin D requirements.
b) Retention
The research team will try to optimize and improve retention and follow up using the following
measures:
- Study participants will be provided with a calendar for all scheduled study visits.
- Study participants will be contacted one week and then one day prior to each visit by phone
calls and reminder messages.
- Study participants will be constantly reminded of the importance of their adherence to the study
protocol at each visit and phone call.
- Study personnel will be constantly available for participants in case of any questions or
complaints from 8am till 5pm on Monday-Friday.
- Study personnel will be flexible in scheduling study visits according to the participant’s
preference within 1-2 weeks from their assigned visit date. We would make every effort to
coincide our follow up visits with patient’s clinical visits to their oncologists or chemotherapy
visits to the center.
- Study participants presenting from KMC and CMC will be offered transportation fees.
Participants withdrawal is possible for any reason throughout the study. Study personnel will try
to resolve the reason of withdrawal whenever possible. For participants who withdraw their
consent, data will be collected until consent withdrawal. For those who discontinue or deviate
from intervention protocol, data will be collected until the end of the study. All randomized
participants who stick to their assigned treatment will be included in the per protocol analysis.
19- Data management
Data collected during the study through laboratory measurements and DXA scans done at
AUBMC will be transferred from EPIC health care system into a password secured electronic
database (RedCap). Password will be changed periodically and only accessible to study
personnel. We will assign a specific code for each participant to ensure confidentiality.
Demographics and other data collected through questionnaires will be directly entered into
tablets to decrease transcription errors and then transferred to the same electronic database and
will resemble the paper form approved by the study committees and IRB. Manual entry will be
done in duplicate independently by two research assistants to minimize possible data entry
errors. The printed data and questionnaires will be locked in a storage only accessible by study
personnel and destroyed 5 years after study completion. Data integrity will be improved by
performing range checks and checks for missing data periodically. We will also include alarm
triggers on RedCap for any data entered outside a pre-set range. In addition, a manual checking
of a subset of already entered data will be done periodically to further improve reliability. A
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complete backup of data will be done twice weekly to insure proper storage of data and avoid
losing information.
20- Data analysis
a) Outcomes
Normality for all variables will be assessed visually using histograms. Baseline
demographics and clinical characteristics will be summarized using mean ± standard deviation
(or median and range) for continuous variables or frequencies and percentages for categorical
variables. These variables will be compared between treatment arms using the independent t-test
(or Wilcoxon ranked sum test) for continuous data and the chi-squared test (or Fisher’s exact
test) for categorical data. Any imbalances between these variables will be adjusted for in the
primary analysis of this study.
The primary analysis will consist of comparing the primary outcome, the percent change
in lumbar spine BMD at 12 months between the two treatment arms using the independent t-test
(or Wilcoxon ranked sum test). 95% confidence interval will also be calculated and IV
zoledronate 5mg will be considered non-inferior to the 4mg dose if the confidence interval lies
below our non-inferiority limit of 2.2%. Secondary outcomes including percent change in lumbar
spine BMD at 6 months, percent change in total hip BMD at 12 months, percent change
osteocalcin at 12 months and percent change Crosslaps at 12 months will also be compared
between treatment arms using the independent t-test (or Wilcoxon ranked sum test). Adverse
reactions and fracture rates will be compared between arms using the chi-squared test (or
Fisher’s exact test). 95% confidence interval will be calculated for continuous variables and
relative risks will be calculated for categorical variables.
Analysis will be carried out using SPSS version 25.0 (IBM, USA) and p-value<0.05 will
be considered statistically significant. We will no adjust p-value for secondary outcomes.
b) Additional analyses
We will perform subgroup analyses according to variables that may affect bone
metabolism. We will compare percent change lumbar spine BMD at 12 months according to time
from menopause, time from start of AI therapy and type of chemotherapy received (especially if
steroids were used). We will also adjust our primary analysis for any imbalances in baseline
characteristics using linear regression analysis for continuous outcomes.
We will perform paired t-test (or Wilcoxon signed rank sum test) to compare the percent
change in lumbar spine BMD, total hip BMD, Osteocalcin and Crosslaps at different time points
(baseline, 3 months, 6 months and 12 months) within each treatment group.
c) Analysis population and missing data
The primary analysis will be a Per Protocol analysis, meaning that participants who
deviate from protocol will not be analyzed and only participants who receive the treatment
assigned to them at the beginning of the study will be included in the analysis. Per Protocol
analysis is the preferred analysis for non-inferiority trials (26).
In case of missing data, we will include participants with complete data in our final
analyses. We will compare characteristics of participants with complete data to those of
participants with missing data or who were loss to follow up. We will perform multiple
17
imputation methods (using linear regression, the last reading carried forward or the means of the
missing variables) and compare analyses using these imputations to those resulting from
participants with complete data. Adverse events will be collected and analyzed in all randomized
participants regardless of adherence to protocol.
Methods: Data collection, management and analysis
21- Data monitoring
a) Formal committee
The study investigators will appoint a Data Safety Monitoring Board (DSMB), which will
include experts from various disciplines (clinical experts in endocrinology and oncology, a
biostatistician, a patient advocate and a bioethicist), independent of the trials’ investigators and
sponsors. The role of this committee is to review and approve the protocol, to monitor safety and
effectiveness of the trial, to make sure that all adverse events are clearly documented, to review
the trial’s conduct and to evaluate any emerging problems and suggest solutions. This committee
also assessed serious adverse events and their relation to the intervention. This committee will
meet every 6 months to monitor the progress of the trial. After each meeting, the DSMB will
contact the study sponsor and the investigators and provide them with its observations and
recommendations as to continuation, modification or termination of the trial. This committee can
also request a number of additional interim analyses.
b) Interim analysis
An interim analysis will be planned when half of the total sample size has been randomized and
completed the 12 months visit with BMD measurement. The interim analysis will be performed
by an independent blinded statistician using independent t-test to compare the primary outcome
between the two treatment arms. Since we only plan to perform one interim analysis, we will not
adjust the p-value for our primary outcome. The statistician will then share the results with the
DSMB. The DSMB will have access to unblinded data and will then give recommendations on
continuing, stopping or modifying the trial accordingly. The steering committee will decide on
the continuation of the trial.
22- Harms
Data on adverse events will be collected at each study visit by the study personnel. Participants
will be asked to immediately contact the study team to report any adverse event that occurs
between visits. Participants will be called 24 hours after the infusion to document any adverse
event. An adverse event is any “untoward medical occurrence associated with the use of a drug
in humans, whether or not considered drug related defined by symptoms and signs associated
with the intake of a medication”(27). All cases will be recorded in “an adverse event record
form” which will be assessed based on its severity, anticipation and relation to the study drug by
the investigators. We will also assess whether any intervention was done to treat the adverse
event and its resolution. Serious adverse events are life threatening, require hospitalization, cause
severe impairment or result in death. All adverse events will be reported to the DSMB and the
Institutional Review Board (IRB) as soon as possible within no more than 5 days of its
occurrence. In our study, we expect that some participants will have acute phase reaction to IV
18
zoledronic acid a well-known a common side effect of the infusion. This reaction includes fever
(17.2%), chills (4.4%), flu-like illness (7.8%), myalgia and arthralgia (15.7%) and headache
(5.8%) that occur within the first two days after the infusion (28). Rare side effects include
osteonecrosis of the jaw (1%), atrial fibrillation (1.3%) and atypical femoral fracture (2.3/10,000)
(29).
23- Auditing
The study investigators will meet with the research assistants on a weekly basis and will audit all
CRFs and consent forms. They will also audit data collected on 10% of participants during that
week. The investigators along with the will designate independent members for auditing. The
auditing members will plan at least one onsite visit to each center participating in the study
during the trial period. Each site will be notified 2-3 weeks prior to the monitoring visit to ensure
the availability of the research personnel on the scheduled date. During this visit, the monitor
will evaluate and review the accuracy of the data collection and entry and adherence to protocol.
The monitor will also review all documents and make sure that the regulatory binder is complete
and up to date. The monitor will raise any problem identified and assist the center in solving the
issue. If violations are found during these visits, research personnel will be offered a more
extensive training and another auditing process will be performed at a later time to ensure
resolution of the violations.
Ethics and dissemination
24- Research ethics approval
The final protocol along with the consent forms and all related documents (SOPs, CRFs,
advertisement materials…) will be submitted and reviewed by the IRB at AUBMC with regards
to compliance with human subjects regulations. The trial will not be implemented before
obtaining the IRB approval from each site. The IRB will then review the protocol at least
annually and the principal investigators will also submit progress reports to the IRB including the
number of participants and the DSMB reviews and decisions.
25- Protocol amendments
After approval, any modifications to the protocol that could affect the conduct of the study or
patient safety will be submitted to the IRB as a formal amendment to the protocol prior to
implementation. These modifications include changes to the design, analysis, sample size,
outcomes, eligibility criteria and outcomes. The primary investigator will notify the IRB of any
minor changes that have minimal effect on study conduct. A list of the amendments will be stored
by the principal investigator to track these changes. Amendments of the protocol will also be
communicated with the trial sponsor and updated on the trial registries.
26- Consent or assent
a) Consent
The oncologists will introduce the study to their eligible patients during their follow up visits.
Interested patients will be approached by a trained research assistant who will explain the trial
protocol in a lay language in a private room. The research assistant should make sure that the
19
patients understand he trial and that their participation is voluntary and that they can withdraw
from the trial at anytime. Patients will then be able to make an informed decision and
participants who are willing to participate will sign the informed consent or take it home to
review it and make a decision on their own. All participants will receive a copy of the signed
informed consent. All consent forms will be available in English or Arabic whichever each
participant prefers. Participants will be informed that the withdrawal of their consent is possible
at anytime.
b) Ancillary studies
Additional blood will be collected and stored for use in future studies. Participants will be able to
opt or decline permission for the use of their specimens for any future protocol, or request to be
contacted in the event their stored specimens are to be used for any future studies.
27- Confidentiality
All study visits will take place in private rooms. All study files (consent forms, test results…) will
be stored in a locked compartment only accessible by the research team. All information to be
entered in the databases will be de-identified and labeled with a code specific to each participant
to ensure confidentiality. These databases will be secured by passwords with restricted access to
research personnel only. One master sheet with all participants names and corresponding codes
will be available with restricted access. Participant’s study information will not be released without
permission.
28- Declaration of interests
The investigators report no conflict of interest.
29- Access to data
The principal investigator will have access to the full clean trial dataset with the de-identified
data. Co-investigators will have access to their own site’s datasets and will have access to other
sites data by requesting from the principal investigators. Access to data will be password
protected.
30- Ancillary and post-trial care
We do not expect any significant adverse event resulting from zoledronic acid infusion. Some
participants may develop acute phase reaction which rarely necessitates hospitalization. In case
of any adverse event as a result of the study, there will be no compensation to cover these
expenses in case it is not covered by third party or governmental insurance.
During the trial, we will share results of blood work and tests with those who request it.
However, results of our outcomes (BMD and bone markers) will not be shared until the end of
the trial to prevent any contamination with co-interventions. Once the study is completed and
analyses are performed, participants will be contacted by the research team and asked whether
they would like to know their individual results.
31- Dissemination policy
20
a) Trial results
The main investigators will review all papers and abstracts before publication. Trial results will
be communicated to participants, participating physicians from all study sites, health care
professionals and the public in Lebanon one year after completion of the trial in meetings and
conferences. Results will be published in a peer-reviewed medical journal and will be presented
in conferences and meetings.
b) Authorship
Individuals who fulfill the International Committee of Medical Journal Editors (ICMJE) criteria
for authorship will be mentioned as contributing authors. These include contribution to the
design, analysis and interpretation of the data, drafting or revising manuscripts, approval of final
manuscripts and being accountable and responsible for the integrity of the data (30).
c) Reproducible research
Five years after the completion of analyses on our primary and secondary outcomes we will
share a completely de-identified data set with the public in an appropriate data archive for use by
other researchers.
Appendices
32- Informed consent materials (to be developed)
33- Biological specimens
Additional blood will be collected and stored with the specific participant code for use in future
studies.
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