Clinical trial NCT00824993
Conditions: Hematological Malignancies
Keywords: Blood Cancer Calcium Vitamin D Ibandronate Boniva Hematological Malignancies Bone Marrow Transplantation BMT Osteoporosis Bone Loss Allogeneic Bone Marrow Transplantation
Sponsor: M.D. Anderson Cancer Center
Start date: 2008-12-09; Completion date: 2017-04-07
Enrollment: 78 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to see if ibandronate can help to slow the rate of bone loss that may occur in patients who have received a bone marrow transplant for blood cancer.

This study plans to address the following hypotheses:

1. The addition of Ibandronate initiated immediately after the transplantation will prevent bone loss in patients undergoing allogenic bone marrow transplantation (BMT) with underlying hematologic malignancies or hematologic disorders.
2. BMT patients who require prolonged steroid and other immunosuppressive treatment for Graft versus Host Diseases(GVHD) have a higher rate of bone loss, which can be prevented or attenuated by Ibandronate.

Specific objectives to test these hypotheses are:

1. Primary Objective:

   1\. To prospectively compare the bone mineral density changes of lumbar spine, femoral neck and total hip between patients randomly assigned to ibandronate and control group over 12 months post bone marrow transplantation at the University of Texas MD Anderson Cancer Center.
2. Secondary Objectives:

   1. To measure and compare the accumulated level of steroid used in both treatment and control groups.
   2. To collect and compare the level of serum C-terminal telopeptide (CTX) in both treatment and control groups to monitor the bone turnover rate for the duration of the study.
   3. To conduct a cost-effectiveness analysis of participating patients for both outcomes on bone mineral density (measured data) and skeletal-related events (modeled data).
   4. To record incidence of bone fractures and the graft rate in both treatment and control groups.

Detailed description:
The Study Drug:

Ibandronate is designed to slow the rate of bone loss.

Screening Process:

Before you can receive the study drug, the study doctor will check the results of various tests that you recently had performed as part of standard care for the bone marrow transplant. These test results will help the doctor decide if you are eligible to take part in this study.

Study Groups:

If you are found to be eligible to take part in the study and you choose to take part, you will be randomly assigned (as in the toss of a coin) to 1 of 2 study groups. Group 1 (the "treatment" group) will receive ibandronate in addition to calcium and vitamin D supplements. Group 2 will only receive the calcium and vitamin D supplements. The chance of being in either group is equal.

Study Visits:

For both groups, you will be visited by a research team member during your hospital stay soon after the transplant (at Month Zero \[0\]), and during routine visits to your transplant doctor's office at Months 3, 6, and 9 after the transplant. At each of these study visits, you will be asked how you are feeling, as well as whether you have had any bone fractures (breakages).

At Months 0, 3, 6, and 9 after the transplant, blood (up to 1 tablespoon each time) will be drawn for routine tests for your transplant follow-up. As part of this same blood draw, an additional ½ tablespoon of blood will be drawn during each study visit (at Months 0, 3, 6, and 9). This blood will be tested for a "marker" in the bone that may help researchers predict who may respond to treatment.

If you are in the "treatment" group, you will receive a total of 4 ibandronate infusions by vein (over 15-30 seconds each time). These study drug infusions will take place in the hospital or at your routine visit to the transplant doctor's office at 3-6 weeks after the transplant, and at Months 3, 6, and 9 after the transplant.

At Month 6, all study participants will have a study-related (non-routine) bone density test (an x-ray) performed to check for bone loss. If the test results show that you have lost an abnormally large amount of bone mineral, you will be taken off study and also advised about treatment options.

Vitamin Supplements:

All study participants will receive a supply of calcium and vitamin D to take at home, for general bone health. These supplements should be taken by mouth, twice a day for 12 months. If you do not tolerate the supplements provided by the research study, you may take another brand of calcium/Vitamin D that you buy over-the-counter. The doses that you take each time (twice daily) should be 500 mg for calcium and 400 International Units (IU) for Vitamin D.

Cost Analysis:

Researchers on this study also want to look at how cost-effective the different procedures and treatments are on this study. To do this, they will use information from your patient records, pharmacy records, and other information of yours on M. D. Anderson databases. You will not be asked to actively participate in any interviews or procedures for these studies, but you should be aware that this research will take place while you are study.

End-of-Study Visit:

You will be visited by a research team member during your routine visit to your transplant doctor's office at Month 12 after the transplant. At this visit, you will be asked how you are feeling as well as whether you have had any bone fractures. Your doctor will check this by x-ray, if you do not have an outside x-ray film available. Blood (up to 1 tablespoon) will be drawn for routine tests. As part of this same blood draw, an additional ½ tablespoon of blood will be drawn to test for the same bone marker. You will have a routine bone density test (an x-ray) performed to check for bone loss. After these tests, your participation in this study will be over.

This is an investigational study. Ibandronate is commercially available and FDA approved for use in the prevention and treatment of bone loss in women who have been through menopause. However, its use in slowing the rate of bone loss in patients who have had a bone marrow transplant is considered experimental. For this purpose, the M. D. Anderson Institutional Review Board (IRB) has authorized the use of ibandronate for research only. The IRB is a committee made up of doctors, researchers, and members of the community. The IRB is responsible for protecting the participants involved in research studies and making sure all research is done in a safe and ethical manner.

Up to 200 patients will take part in this study. All will be enrolled at M. D. Anderson.

Arms: arm 1: Ibandronate infusion of 3 mg by vein over 15 to 30 seconds for 4 doses at 3-6 weeks after transplant, and at Months 3, 6, and 9 after the transplant. Calcium 500 mg by mouth everyday for 12 months. Vitamin D 400 units by mouth 2 times a day for 12 months. arm 2: Calcium 500 mg by mouth everyday for 12 months. Vitamin D 400 units by mouth 2 times a day for 12 months.
Interventions: intervention 1: Ibandronate intervention 2: Vitamin Supplements
Intervention descriptions: intervention 1: Infusion of 3 mg by vein over 15 to 30 seconds for 4 doses at 3-6 weeks after transplant, and at Months 3, 6, and 9 after the transplant. intervention 2: Calcium 500 mg by mouth everyday for 12 months

Vitamin D 400 units by mouth 2 times a day for 12 months

Protocol documents:
Prot_SAP_000.pdf: 
Protocol# 2006-0960 
March 8, 2010- Revised 
Page 1 
 
Title: A Randomized, Controlled Study of Ibandronate for the Prevention of Bone Loss in 
Patients Who Have Received Allogeneic Bone Marrow Transplantation for Hematological 
Malignancies or Hematological Disorders 
 
 
 
Principal Investigator:  Huifang Lu, MD PhD 
 
 
Table of Contents 
Page 
 
1.0 
Objective   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
2 
 
 
2.0 
 
Background   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
2 
 
3.0 
Patient Eligibility  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
4 
 
3.1 
Inclusion Criteria    . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
4 
 
3.2 
Exclusion Criteria  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
4 
 
4.0 
Treatment/Study Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
4 
 
5.0 
Statistical Consideration  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
6 
 
5.1 
Data and Protocol Management  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
8 
 
5.2 
Safety Monitoring  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
8 
 
5.3 
Suspected Unexpected Serious Adverse Reactions . . . . . . . . . . . . . . . . . . . .  
8 
 
5.4 
Benefit. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
9 
 
5.5 
Home Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
9 
6.0 
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
9 
 
 


Protocol# 2006-0960 
March 8, 2010- Revised 
Page 2 
 
Title: A Randomized, Controlled Study of Ibandronate for the Prevention of Bone Loss in 
Patients Who Have Received Allogeneic Bone Marrow Transplantation for Hematological 
Malignancies or Hematological Disorders 
 
Principal Investigator:  
Huifang Linda Lu, MD PhD 
Co-PI:  
 
 
Richard Champlin, MD,  Robert Gagel, MD 
Collaborators: 
Carmen Escalante, MD, Maria Cabanillas, MD, Xuemei Wang 
 
Bela B Toth, MD, Lincy Lal, Pharm.D. PhD 
 
William Murphy, MD, Beth Chasen, MD  
 
1.0 Objectives 
 
This study plans to address the following hypotheses: 
 
1.1 The addition of Ibandronate initiated immediately after the transplantation (21 to 60 
days) will prevent bone loss in patients undergoing allogeneic bone marrow 
transplantation (BMT) with underlying hematologic malignancies or hematological 
disorders. 
 
1.2 BMT patients who require prolonged steroid and other immunosuppressive treatment 
for Graft versus Host Diseases (GVHD) have a higher rate of bone loss, which can 
be prevented or attenuated by Ibandronate. 
 
Specific objectives to test these hypotheses are: 
a. Primary Objective: 
1. To prospectively compare the bone mineral density changes of lumbar spine, femoral 
neck and total hip between patients randomly assigned to Ibandronate and control group 
over 12 months post bone marrow transplantation at the University of Texas MD 
Anderson Cancer Center. 
b. Secondary Objectives: 
1.   To measure and compare the accumulated level of steroid used in both treatment and                       
control groups. 
2. To collect and compare the level of serum C-terminal telopeptide (CTX) in both 
treatment and control groups to monitor the bone turnover rate for the duration of the 
study. 
3. To conduct a cost-effectiveness analysis of participating patients for both outcomes on 
bone mineral density (measured data) and skeletal-related events (modeled data). 
4. To record incidence of bone fractures and the graft rate in both treatment and control 
groups. 
 
 
2.0 Background 
 
Bone marrow transplantation (BMT) is performed with increasing frequency and for expanding 
indications, with the majority of patients surviving for many years.  In this context, bone loss is a 
common and serious post-transplant complication.  Bone loss, occurs early and most rapidly 
during the first three to six months after the transplantation, and is often more severe at the 
femoral neck (1, 2).  The degree of bone loss can be severe enough to cause fractures.   Lower 
 
 


Protocol# 2006-0960 
March 8, 2010- Revised 
Page 3 
bone mineral density in femoral neck in this population has also been associated with avascular 
osteonecrosis (3). 
 
Osteoporosis developed after BMT has a complex mechanism involving both the direct effect of 
the transplanted bone marrow on the stromal cell compartment and the effects from 
immunosuppressive therapies (3).  As a result of the decreased osteoblast and increased osteoclast 
activity, there is both increased bone resorption and decreased bone formation.  After the 
transplantation, over 50% of BMT patients develop some form of Graft Versus Host Disease 
(GVHD), which requires prolonged use of glucocorticoid as well as other forms of 
immunosuppression.   In addition, BMT recipients may also experience some bone loss before the 
transplantation (4), that is related to their underlying disease and the modalities used to treat 
them.  Their prior treatment may result in a variety of effects associated with bone loss, including 
glucocorticoid-induced decreases in bone formation and serum 1,25-dihydroxyvitamin D3, or 
chemotherapy-induced hypogonadism.  Therefore patients with hematologic malignancies or 
hematological disorders undergoing bone marrow transplantation are at high risk of bone loss. 
 
In a prospective, randomized 12-month study of Risedronate on bone mass and bone turnover in 
patients who had undergone allogeneic BMT at least 6 months before the treatment, spine and 
femoral neck bone mineral density (BMD) did not change significantly in patients on Risedronate 
and decreased in those taking placebo (5).   However, this study did not answer the question of 
whether bisphosphonates could prevent the rapid bone loss commonly seen during the first three 
months post-BMT.   In another uncontrolled observational study, three monthly intravenous 
Pamidronate infusions attenuated femoral neck bone loss in the first six months after allogeneic 
BMT (2).  In a recent randomized, controlled study in patients undergoing allogeneic stem cell 
transplantation, using Pamidronate initiated before the transplantation decreased the bone loss 
significantly at the lumbar spine, hip, and the femoral neck.  However there was still significant 
bone loss at the hip and femoral neck that was not completely prevented by pamidronate, 
warranting the use of a more potent bisphosphonate for more durable maintenance of bone mass 
after transplantation (6). 
 
Ibandronate (Boniva) has been shown to significantly increase bone mineral density in the lumbar 
spine and the hip bone in postmenopausal patients.  Compared to placebo, Ibandronate taken 
orally at 150 mg once monthly or 3 mg intravenously quarterly significantly increased bone 
mineral density and decreased the rate of new vertebral fractures (7).  Ibandronate is more potent 
than other bisphosphonates such as Pamidronate, Risedronate and Alendronate. 
 
So far there is no consensus on how to effectively prevent and treat osteoporosis associated with 
bone marrow transplantation.  As for steroid induced osteoporosis, the American College of 
Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis recommends 
obtaining a baseline measurement of bone mineral density at the lumbar spine and/or hip when 
initiating long-term (i.e., in a dose of 5 mg/day or higher for more than 3 months) glucocorticoid 
therapy with longitudinal follow ups.  The committee also recommends bisphosphonates used in 
such patients in conjunction with calcium and vitamin D supplementation for the prevention of 
osteoporosis (8).  Such consensus has not been tested in cancer patients receiving BMT. 
 
Although there are known risk factors of osteoporosis associated with bone marrow 
transplantation and the subsequent immunosuppressive treatment, guidelines for the prevention 
and effective treatment of bone loss in this high risk population are lacking. Data on whether 
therapy for osteoporosis treatment or prevention initiated around the time of the transplantation 
reduces fracture risk after transplantation is limited.  Bisphosphonates, in particular, suppress 
 
 


Protocol# 2006-0960 
March 8, 2010- Revised 
Page 4 
bone resorption for up to 12 months after discontinuation of therapy.  Transplantation with 
immediate addition of bisphosphonates may prevent the accelerated bone resorption that develops 
immediately after transplantation and could theoretically mitigate post-transplant bone loss.  
Moreover, anti-resorptive therapy clearly increased bone mineral density and reduces fracture in 
other populations, including patients undergoing solid organ transplant.  Given such, this proposal 
is designed for the prevention of osteoporosis in this high risk population. 
 
 
3.0 Patient Eligibility 
 
The study eligibility requirements will include the following inclusion/exclusion criteria: 
 
3.1 Inclusion criteria: 
1) Age greater than or equal to 18 years. 
2) Patients with the diagnosis of hematologic malignancies or hematological disorders, who 
are immediately post- allogeneic bone marrow transplantation.  
3) Female patients of childbearing potential (i.e. no hysterectomy, no loss of menses for 12 
consecutive months), must be willing to use contraception. 
4) Negative pregnancy test in premenopausal patients. 
5) Patients with GVHD or infections can be entered only if they respond to treatment and 
become controlled. 
 
6) Dental considerations: patients with negative dental screening for jaw osteonecrosis 0-3 
months prior to their transplant and patients that do not have a plan for tooth extraction in 
the near future. 
 
3.2 Exclusion criteria: 
1) Patients with documented relapsed malignancy or recurrence of the original 
hematological disorder after the transplant, uncontrolled acute GVHD, or uncontrolled 
infection. 
2) Patients with hypocalcemia of less than 8.4 (corrected to account for the albumin level). 
3) Patients with hypercalcemia >12.2, due to a cause not related to their hematological 
malignancy or hematological disorder (i.e. hyperparathyroidism, multiple myeloma). 
4) Hypersensitivity to Ibandronate or other bisphosphonates. 
5) Pre-existing osteoporosis, defined as a bone density T-score of –2.5 S.D. or less. 
6) Renal insufficiency (calculated creatinine clearance < 30 ml/min). 
7) Patients already on bisphosphonates (over the past two years), calcitonin, anabolic 
steroids, or daily oral fluoride supplement. 
8) Myeloma patients who have previously been on bisphosphonates over the past two years 
and/or have active bone lesions. 
9) If corrected calcium is above 10.3 and the iPTH is elevated or normal, the patient will be 
excluded from the study.   
10) Patients with a 25-hydroxyvitamin D concentration <20 ng/ml and evidence of 
osteomalacia (low ionized calcium and elevated intact PTH).  
11) Patients with recent tooth extraction with signs of incomplete healing or infection will be 
excluded.   
 
4.0 Treatment/study  Plan 
 
 
 


Protocol# 2006-0960 
March 8, 2010- Revised 
Page 5 
Patients who had hematological malignancies or hematological disorders and underwent 
allogeneic bone marrow transplantation are eligible to participate in the study.  Members of the 
research team 
will enroll eligible patients who meet the inclusion criteria in the study after obtaining agreement 
of their transplant physician.  Patients with GVHD or infections can be entered only if they 
respond to treatment and become controlled.   
 
As part of standard care for pre-BMT work up, all patients will have their 25(OH) Vit D levels 
checked.  Patient with vitamin D deficiency (< 20 ng/ml) will be supplemented to adequate level 
(>= 20 ng/ml). 
 
Patients will then be randomized into the following two groups: 1) treatment:  Ibandronate 3 mg 
intravenously over 15-30 seconds for 4 doses at 0-1.5, 3, 6, and 9 months free of charge; or 2) 
control: Patients will only receive daily oral calcium and vitamin D supplements.  Patient’s prior 
vitamin D supplement status will be considered as one of the randomization factor.  After 
entering the trial, all patients will receive 500 mg of elemental calcium carbonate and Vitamin D 
Analog 400 IU orally twice daily for 12 months to be taken at home during the trial.  Patients who 
do not tolerate the calcium pills provided by the trial are allowed to take another brand of 
calcium/vitamin D at home as tolerated with equivalent dosing.  Patients who are still on weekly 
Ergocalciferol have the option of holding their daily vitamin D 400 IU twice daily and must 
resume the daily vitamin D when they are off the weekly Ergocalciferol. 
 
BMD at lumbar spine, femoral neck and total hip will be determined at baseline (up to 3 months 
prior to the transplant or prior to the enrollment), 6, 12 months (+/- 4 weeks) post transplants for 
all patients in both groups by DEXA at MDACC.  The change of BMD between baseline and 12 
months in both Ibandronate treatment and control groups will be summarized and analyzed for 
statistical significance.   
 
The members of the research team will collect data and/or blood for the following: 
1. Bone turnover marker, the serum CTX will be measured at baseline, 3, 6, and 12 months (+/- 4 
weeks) 
 
2. Routine laboratory monitoring includes calcium, magnesium, alkaline phosphatase, albumin, 
and creatinine at baseline and at 3, 6, 9, and 12 months (+/- 4 weeks) post-transplant. 
 
3. Other factors affecting bone metabolism will be measured which include 25(OH) Vit D and 
intact PTH levels at baseline (as part of pre-transplant workup, or prior to the enrollment) and at 
the end of the trial. If a patient was found to have vitamin D deficiency 3 months prior to the 
transplant and if a patient had been on weekly Ergocalciferol supplement, the patient will be 
eligible for this study and their vitamin D supplementation status will be considered as one of the 
randomization factor.  Patient had prior Ergocalciferol supplement are randomized to either 
treatment or control group  following the stratum 1 of the Randomization Scheme, Appendix F. 
Patients with no prior Ergocalciferol supplement are randomized according to the stratum 2 of the 
Randomization Scheme, Appendix F. 
 
Sex hormones will be measured at the baseline (-/+ 8 weeks) and the 12 months (-/+ 8 weeks) 
(Testosterone or Estradiol, FSH and LH).  Female patients who have documented laboratory 
values indicating postmenopausal state prior to the study entry will not be required to have new 
levels drawn. Female patients whose sex hormone levels showing menopausal state at baseline 
will not have repeat sex hormone study at the end of the trial.  Serum for future research will also 
 
 


Protocol# 2006-0960 
March 8, 2010- Revised 
Page 6 
be collected and banked at baseline and at 3, 6, 9, 12 months post transplant for measurements of 
cytokines and antibodies involved in the metabolism of the bone and the development of GVHD 
after the trial.  Examples of future cytokine measurements may include: Osteoprotegrin (OPG), 
TNFa, Interleukin-6, GM-CSF, and IGF-1.   
 
4. Incidence of fractures will be radiologically confirmed and compared between the two groups. 
Graft rate will be collected at 12 months for both groups and analyzed for statistical difference. 
 
5.  Data collection for the pharmaco-economic benefit model includes drug and administration 
costs via patient medical record databases and MDA Cost Accounting System. 
 
 
 
Table 1:  Summary of Treatment/study Plan 
 
Assessments 
1 month 
(21-45 days) 
3 months 
6 months 
9 months 
12 months 
Medicine (IV) 
x 
x 
x 
x 
 
DEXA 
 (bone mineral density) 
x 
 
x 
 
x 
Serum CTX 
x 
x 
x 
 
x 
Routine lab : 
Ca, Mg, albumin, Cr, Alk 
phos 
x 
x 
x 
x 
x 
25 (OH)VitD,  intact PTH,
 
 
x 
 
 
 
x 
Sex Hormones 
Testosterone or Estradiol, 
FSH and LH (blinded and 
banked) 
x 
 
 
 
x 
Serum collection for future 
testing may include the 
following examples: 
Osteoprotegrin 
(OPG), 
TNFa, Interleukin-6, GM-
CSF, IGF-1 (Banked) 
x 
x 
x 
x 
x 
Graft rate and Fracture rate  
 
 
 
x 
 
 
5.0 Statistical Consideration 
 
This is a randomized phase III trial to determine whether the use of Ibandronate significantly 
decreases the amount of bone loss in patients with BMT, compared to those in the control group.  
Patients will be equally randomized to control or treatment groups at baseline  All transplant 
patients will receive oral calcium 500 mg and vitamin D 400 IU twice daily throughout the trial. 
 
The primary endpoint is the percent reduction in bone mineral density (BMD) of the lumbar 
spine, femoral neck, and total hip measured at 12 month relative to baseline, which we denote 
here as Diff_BMD.  Assuming that the mean Diff_BMD is 12% decrease in the control group and 
is 0.1% in the treatment (Ibandronate) group, a maximum of 120 patients (60 patients per group) 
 
 


Protocol# 2006-0960 
March 8, 2010- Revised 
Page 7 
will be needed in order to have an 80% power to detect this difference at a two-sided significance 
level of 0.05, assuming a common standard deviation of 0.23. Assuming a drop-out rate of 40% 
for the patients due to mortality and relapse in the first year, a maximum of 200 patients will be 
enrolled into the study. The total accrual period will be 20 months, with 10 patients enrolled per 
month.   
 
Two interim analyses are planned for the primary endpoint of the percent reduction in BMD 
between baseline and 12 months, when 40 and 80 patients have been accrued into the study and 
followed for one year, respectively.  A Lan-DeMets spending function with O’Brian-Fleming 
stopping boundaries has been assumed. The two-sided Z-score cut-off values for rejecting the null 
hypothesis are +/- 3.71 and +/- 2.51 for the two interim looks, respectively.  
 
The change of BMD between baseline and 12 months will be summarized by treatment and 
control groups. Data will be transformed as appropriate to satisfy the normality assumption. A 
two-sample t-test on the transformed data or Wilcoxon rank-sum test will be performed to 
compare the two groups in terms of percent change of BMD from baseline to 12 months. 
 
The change of BMD between baseline and 6 months will also be summarized and the percent 
change in BMD over time will be plotted for all patients and by treatment group, respectively. A 
linear mixed-effect model will be fit for the data set to investigate if there is a treatment effect at 
different time points and if the pattern of BMD change over time differs between two groups.  
Similar analysis will also be performed for graft rate, serum C-telopeptide (CTX) measured over 
time, as well as for cytokines associated with bone loss. The incidence rate of fracture will be 
estimated for each arm and will be compared between the two arms using Fisher’s exact test. 
 
The change of BMD between baseline and 12 months will also be summarized for patients with 
and without additional steroid treatment for GVHD after allogeneic bone marrow transplant 
separately. Wilcoxon rank sum test will be used to assess the difference in BMD change between 
patients with and without prolonged steroid and other immunosuppressant use for the treatment of 
GVHD, either in all patients or by treatment group.  A multiple linear model will be fit for the 
BMD at 12 months, adjusting for baseline BMD and using steroid doses in GVHD, treatment as 
well as steroid use in GVHD and treatment interaction as predictors. 
 
We will summarize the change of BMD between baseline and 12 months by disease type (i.e., 
hematological malignancies vs. hematological disorders). Wilcoxon rank sum test will be used to 
assess the difference in BMD change between patients with hematological malignancies and 
those with hematological disorders.  A multiple linear model will be fit for the BMD at 12 
months, using baseline BMD, disease type, treatment arm, as well as the interaction between 
disease type and treatment as covariates. The fitted model will help us address the question 
whether or not the treatment effect is similar in these two disease types. 
 
Based on already published data (9) on risk of skeletal-related events (SRE) with ibandronate, 
modeling will be conducted to determine cost-effectiveness ratio of cost per SRE avoided, with 
sensitivity analysis.  Costs will include the potential cost of treating for SREs and the potential 
cost of treating adverse events due to i.v. Ibandronate.  One-way sensitivity analysis varying the 
key assumption (SRE relative risk reduction rate from 0% to 50% in 5% intervals) over the base 
case will be conducted to determine if it might impact the cost-effectiveness ratio.   
 
Incremental Cost Effectiveness Ratio (ICER):   
 
 
 


Protocol# 2006-0960 
March 8, 2010- Revised 
Page 8 
1. (Cost treatment- Cost control) _____________________________ 
(#SREs treatment - #SREscontrol) 
 
2. (Cost treatment- Cost control) _____________________________ 
(Months free of SREs treatment – Months free of SREs control) 
 
 
TreeAge Pro 2007 by TreeAge Software Inc., will be utilized for the cost-effectiveness 
calculations.  The analysis will compute per-patient costs and benefits for the 12 month study 
period, following an intent-to-treat approach, and produce a cost-effectiveness ratio.  The primary 
outcomes are incremental cost per percent of reduction in BMD and incremental cost per patient 
within one or two SD of normal BMD.   
 
 
 
Two Incremental Cost Effectiveness Ratios (ICER) will be calculated: 
 
1. (Cost treatment- Cost control) _____________________________ 
(%BMD reduction treatment - % BMD reduction control) 
 
2. (Cost treatment- Cost control) _____________________________ 
(#Patients with normal BMD treatment - #Patients with normal BMD control) 
 
 
5.1 
Data and Protocol Management 
A standard procedure to ensure participant confidentiality will be established.  Personal 
identification information will be kept confidential and will be available only to the PI and 
relevant study stuff.  The study database will also be kept confidential and will be password 
protected.  The results of this study will be reported by group results only and no individual 
results will be reported. 
 
5.2 
Safety Monitoring 
In addition, a safety monitoring rule will be implemented using the method of Thall, Simon and 
Estey (1995, 1996). We define the adverse event (AE) as “the percent reduction in BMD is 
greater than or equal to 15% from baseline to 6 months” and denote its probability as p.  The trial 
will be stopped if, for any arm, there is more than 95% chance that p is greater than 30%, ie, stop 
the trial if Prob (p >20% | data) > 0.95. For each arm, assuming a beta (1, 1) prior and applying 
the above stopping rule when every 10 patients have been treated and evaluated after 1-year 
follow-up, the stopping boundaries are as follows:  The trial will be stopped if for any one of the 
two arms, [# patients with AE]/ [# patients evaluated at 6 months] >=6/10, 10/20, 14/30, 17/40, 
21/50, 24/60.  
 
Osteonecrosis, primarily in the jaw, has been reported in patients treated with bisphosphonates. 
Most cases have been in cancer patients undergoing dental procedures, but some have occurred in 
patients with postmenopausal osteoporosis or other diagnoses. All patients will have dental 
screening for jaw osteonecrosis at baseline and every 6 months thereafter.  Patients with recent 
tooth extraction and signs of incomplete healing and/or uncontrolled infection will be excluded.  
During the trial, any dental condition should be treated immediately but conservatively, avoiding 
any invasive surgical procedure. 
 
 
 


Protocol# 2006-0960 
March 8, 2010- Revised 
Page 9 
5.3    Suspected Unexpected Serious Adverse Reactions (SUSAR) Reporting   
 
All suspected Unexpected Serious Adverse Reaction (SUSAR) must be reported to Roche.  Any 
adverse event that is both serious and unexpected (SUSAR), as defined in, and in accordance with 
the time frame indicated in 21 CFR Part 312.  Adverse events will be deemed unexpected if not 
identified in the Safety Reference Document for Compound® (FDA approved Package Insert / 
Investigator’s Brochure), and must be reported by the principal investigator to FDA and Roche by 
telephone or by fax.  For fatal or life-threatening SUSARs, principal investigator must notify 
FDA within 7 calendar days of becoming aware of the event. The initial report must be 
followed by a completed FDA Form 3500A MedWatch Report faxed to FDA within 15 calendar 
days of becoming aware of the event.  For Non-fatal/life-threatening SUSARs, principal 
investigator should notify FDA by fax using FDA Form 3500A MedWatch Report within 15 
calendar days of becoming aware of the event. The completed FDA Form 3500 Medwatch 
Report should be simultaneously transmitted by fax directly to Roche Pharma Development 
Medical Safety Central Operations (PDMS-COps) using the Roche Supported Trials Safety Fax 
Cover Sheet.  PDMS COps faxes receipt acknowledgement and MCN (Manufacture Control 
Number) to site.  The responsible Institutional Review Board should be notified in accordance 
with Good Clinical Practice and all local laws and institutional regulations.  If a SUSAR occurs 
within the context of a multi-center clinical trial, the principle investigator must provide a copy of 
the completed FDA Form 3500A to all participating investigators within the timelines outlined 
above. 
 
The 
MedWatch 
form 
can 
be 
accessed 
at:  
http:/www.accessdata.fda.gov/scripts/MedWatch/. 
 
 
 
 
Contact Information: 
 
FDA: 
 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax:  1-800-FDA-0178 (1-800-332-0178) 
 
 
Roche: 
Pharma Development Medical Safety Central Operations (PDMS – COps) 
 
 
 
Fax: 011-44-1707-373793 
 
The principal investigator will provide Roche PDMS COps with subsequent follow-up 
information as soon as it becomes available using the Roche Supported Trials Safety Fax Cover 
Sheet. The coversheet must have the Manufacturer Control Number (MCN) associated with the 
SUSAR, provided by PDMS COps upon receipt of the FDA Form 3500A MedWatch Report, and 
ensure that the follow-up box is checked. Roche may conduct an independent assessment of the 
SUSAR(s) and in such circumstances the principal investigator and participating institution will 
provide any additional information required to complete the assessment. 
 
5.4     Benefit 
 
Bone marrow transplantation is performed with increasing frequency and success, with the 
majority of patients surviving for many years.  In this context, bone loss is a common and serious 
 
 


Protocol# 2006-0960 
March 8, 2010- Revised 
Page 10 
post-transplant complication.  Bone loss, occurs early and most rapidly during the first three to 
six months after the transplantation, and is often more severe at the femoral neck.  This study will 
address the issue of whether bisphosphonates given immediately following the transplant can 
prevent the early bone loss.   Since bone loss is tightly correlated with the fracture risk, early 
prevention of bone loss potentially prevent the fracture later in patient’s life.   
 
We plan on presenting our findings at national and international meetings and publishing these in 
peer-reviewed journals.  This work will contribute to the management of post-transplant bone loss 
and may facilitate other intervention studies to address such issues. 
  
 
5.5    Home Care 
 
Patients in treatment group receive Ibandronate once every three months.  If the patient is 
unable to receive it at MD Anderson, the PI or PI designated personnel will contact the 
patient's home MD directly to have the infusion done in their office. 
 
6.0 References 
 
1. Gandhi, M.K., Lekamwasam, S., Inman, I, Kaptoge, S., Sizer, L. Love, S., Bearcroft, 
P.W., Milligan, T.P., Price, C.P., Marcus, R.E., Comston, J.E. (2003).  Significant and 
persistent loss of bone mineral density in the femoral neck after hematopoietics stem cell 
transplantation: long-term follow- up of a prospective study.  Br J Haematol. 121(3):462-
8. 
2. Buchs, N., Helg, C., Collao, C., Chapuis, B., Slosman, D., Bonjour, J.P., Rizzoli, R. 
(2001). Allogeneic bone marrow transplantation is associated with a preferential femoral 
neck bone loss.  Osteoporos Int. 12(10):880-6. 
3. Tauchmanova, L., Serio, B., Del Puente, A., Ristano, A.M., Esposito, A., De Rosa, G., 
Lombardi, G., Colao, A., Rotoli, B., Selleri, C. (2002).  Long-lasting bone damage 
detected by dual-energy x-ray absorptiometry, phalangeal osteosonogrammetry, and in 
vitro growth of marrow stromal cells after allogeneic stem cell transplantation.  J Clin 
Endocrinol Metab. 87(11):5050-65 
4. Schute, C., Beelen, D., Schaefer, U., Mann, K. (2000).  Bone loss in long-term survivors 
after transplantation of hematopoietic stem cells: a prospective study.  Osteoporos Int.  
11:344-53. 
5. Tauchmanova, L., Selleri, C., Esposito, M., Do Somma, C., Orio, F. Jr, Bifulco, G., 
Palomba, S., Lombardi, G., Rotoli, B., Colao, A. (2003).  Beneficial treatment with 
risedronate in long-term survivors after allogeneic stem cell transplantation for 
hematological malignancies.  Osteoporos Int.  14(12):1013-9. 
 
6. Grigg, A.P., Shuttleworth J, Reynolds, A.P., Szer J., Bradstock K., Hui C.,  Hermann R.,  
 
and Ebeling P.R.  (2006)  Pamidronate Reduces Bone Loss after Allogeneic Stem Cell  
 
Transplantation.  J Clin Endocrinol Metab 91: 3835-3843.   
7. Guay, D.R. (2006).  Ibandronate, an experimental intravenous bisphosphonate for 
osteoporosis, bone metastases, and hypercalcemia of malignancy.  Pharmacotherapy.  
26(5):655-73. 
8. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced 
Osteoporosis.  (2001). Arthritis Rheum. 44:1496. 
9. Body J.J., Diel I.J., Lichinitser, et al. (2003).  Intravenous ibandronate reduces the 
incidence of skeletal complications in patients with breast cancer and bone metastases.  
Annals of Oncology. 14:1399-1405. 
 
 


Protocol# 2006-0960 
March 8, 2010- Revised 
Page 11