Prevention of Bone Loss After Pediatric Hematopoietic Cell Transplantation
Phase: PHASE2
Conditions: Osteopenia, Osteoporosis
Sponsor: Masonic Cancer Center, University of Minnesota

Department of Pediatrics 
University of Minnesota 
 
 
Prevention of Bone Loss After Pediatric Hematopoietic Cell 
Transplantation 
MT2014-23R 
CPRC #2013LS023 
IND 118,179 
Study Product:  Pamidronate Disodium 
 
 
University of Minnesota 
IND Sponsor/Principal Investigator 
Kyriakie Sarafoglou, MD 
Pediatric Endocrinology 
 
Co-Investigator 
Angela R. Smith, MD, MS 
 
Fred Hutchinson Cancer Research Center 
Institutional Principal Investigator 
K. Scott Baker, MD, MS 
Pediatric Blood and Marrow Transplant 
 
 
 
Biostatisticians 
James Hodges, PhD  
Lei Zhang, MS 
 
 
Protocol Version Date 
July 11, 2019 
Confidential 

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Revision History 
revision 
# 
version date 
summary of revisions 
consent 
form 
changed  
 
10/13/2013 
Original IRB approval 
n/a 
1 
10/20/2014 
prior to enrollment start –formatting change to match the Cancer 
Center’s template (see details in the last bullet) and the following 
revisions: 
• Title page delete Lynda Polgreen as a co-investigator as she has left 
the institution 
• Minor clarifications to the inclusion/exclusion criteria 
• Section 8 – Tests and Procedures:  move research related tests and 
procedures from Study Entry to during BMT work-up period  
• Section 8 - Research specimens will be batched tested in UMN 
Cytokine Lab (previously using Advanced Research and Diagnostic 
Laboratory) 
• Section 8.1.3 – clarified subject reimbursement and compensation 
• Section 12.5 – early stopping rule for excessive toxicity 
• Replaced Amplatz with Masonic throughout document when 
referring to UMN Children’s Hospital 
• Updated protocol to Cancer Center template: 
• Update document cover page to list affiliate institution 
• Add Sponsor and site PI contact information to page 2 
• Added revision history page and schema 
• Section 6 - Added subject registration and randomization in 
OnCore 
• Section 9 - Replaced previous AE reporting section with new 
Event Monitoring, Documentation and Reporting section which 
includes a new targeted toxicity form (appendix IV), affiliate 
institution reporting requirements and updated IRB reporting 
requirements 
• Section 10 – New section covering  study status update, data 
management, compliance with the Cancer Center’s Data and 
Safety Monitoring Plan, affiliate monitoring and record retention 
• Section 13 – New section addressing ethical and regulatory 
considerations  
• Move Vitamin D/calcium supplementation and questionnaires to 
appendix II - IV, add eligibility checklist as appendix I 
 
yes 
2 
12/03/2014 
• Throughout protocol: Revise Day 100 to Day 90 and if appropriate 
generalize the time point as 3 months 
•  Throughout protocol: Delete references to study entry as “day of 
admission for transplant” 
• Throughout the protocol refer to affiliate institution as Fred 
Hutchinson Cancer Research Center as this is where the PI and IRB 
are located, although the study will continue to be conducted at Seattle 
Children’s Hospital 
• Section 6.2, Randomization Day 90 Post-HCT Visit: Add statements 
that we will request to collect data from routine tests (DXA scans done 
at 1 year post-transplant and other relevant data) from subjects who are 
not eligible for or refuse randomization at Day 90  
• Section 7.2, Calcium: Clarify how calcium level will be calculated if 
yes 

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revision 
# 
version date 
summary of revisions 
consent 
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subject’s total calcium level is below the normal range. 
• Section 7.6 and 7.7, Duration of Study Treatment and Participation 
Update and clarify 
• Section 8, Study Related Tests and Procedures: Update 
• Section 8.1.3 Subject Compensation: Update 
• Section 8.2.5 Diet and Activity Questionnaire: Update to reflect that 
subjects will receive paper copies of forms 
• Section 8.3.2 Specimen Processing and Storage: Clarify that research 
samples will be stored for batch testing and destroyed once testing is 
complete. 
• Delete appendix V – Targeted Toxicities as replaced by a more 
detailed CRF 
3 
02/09/2015 
• Study synopsis, section 2:  remove references to Pfizer as a generic 
form of pamidronate will be purchased for the study  
• Section 2.5:  Clarify that at the end of study and after drug 
reconciliation, any remaining pamidronate will be destroyed per local 
institutional policy 
• Synopsis, sections 4, 7.3.1, and 8.1: Pamidronate administration – 
dose will be based on actual body weight or ideal body weight if 
overweight, to a maximum dose of 60 mg, give over 4 hours, 
previously over 3 to 4 hours, post infusion flush of 20 cc’s will be 
given at the same rate as the pamidronate, previously over 1 hour 
• Section 5.2 and checklist – add history of a primary bone malignancy 
involving the lumbar spine as an exclusion criterion 
• Sections 7.3.5 and 8.1:  Expand birth control options from oral only to 
include the contraceptive patch or other effective methods 
• Section 8.1:  delete medical history at days 7 and 21, add record of 
medication usage at screen/study entry and at every study visit 
beginning with day 21 
• Section 8.1.3:  further clarify participant reimbursement and add 
“guidelines” to the section header as reimbursement schedule may 
differ between institutions 
• Section 8.2.3: update to match changes to 8.1 
• Section 9.2: delete day 360 as no pamidronate is given 
• Minor edits and clarifications throughout  
 
yes 

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revision 
# 
version date 
summary of revisions 
consent 
form 
changed  
4 
09/29/2015 
• Section 5.1.1 – clarify eligible diseases 
• Section 6 and appendix I – delete reference to eligibility checklist as 
an eligibility case report form is used instead 
• Sections 6.2, 7.32  and 7.3.5– clarify randomization time window of 
±14 days and time window in association with lab tests required for 
randomization (within 10 days prior for vitamin D and 72 hour hours 
prior for creatinine, pregnancy testing) 
• Sections  6.2, 7.3.6, 7.5, and 7.7 – add disease relapse/progression as 
ineligibility for randomization and a reason to go off study and follow-
up will end if in person post-transplant follow-up ends 
• Section 7.3.1 – add a 72 hour window prior for lab work in association 
with the pamidronate infusion, clarify that laboratory testing 
procedures (blood, urine) must be collected prior to pamidronate 
infusion, but consultations, day 90 DXA and day90  pQCT may occur 
after the infusion as long as done in the +/-14 day window 
• Sections 7.3.1, 8.1 footnote and 8.3.2 – remove language regarding 1st 
of the day timeframe for urine collection and add “A morning 
collection is preferred, but not mandatory.  The time of the urine 
collection must be recorded.” 
• Section 8 – add a row for randomization on day 90 and refer reader to 
section 6.2 
• Section 8.1 and 8.2.3 - add a row for height and weight only and add 
X under days 180 and 270, delete physical exam and anthropometrics 
for these days ; update text in section 8.2.3 
• Section 8.1 - permit Vitamin D level to be drawn at screen or study 
entry   
• Section 8.2.4 – clarify DXA scan requirements 
• Section 9.5 – add a row to the required reporting table for stopping 
rule events  
• Appendix III – delete question regarding type of milk consumed and 
replace with a question regarding formula use 
yes 
5 
02/01/2016 
• Synopsis, Sections 4, 5 - expand enrollment to include persons ≤ 20 
years of age  
• Section 5.2.1 - delete previous HCT from exclusion criteria 
• Section 12.5 – revise in response to DSMC concerns 
• Section 8.1 – increase window for DEXA scan to 6 weeks 
• Section 5.1.4 – remove language surrounding age of assent as this is a 
multi-center study 
Yes  
6 
4/27/2016 
• Section 5.2.9 – clarified eligibility; the intent was to exclude 
investigational drugs that either can interact with pamidronate or have 
an independent effect on the primary endpoint (bone mineral 
content/density), not all investigational drugs.  
• Section 6.2 – permit Vitamin D level to be drawn 14 days (instead of 
10 days) prior to randomization to account for time for lab to send 
back result. 
No 

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revision 
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version date 
summary of revisions 
consent 
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7 
12/02/2016 
• Throughout protocol - University of Minnesota Principal Investigator 
and IND Holder was changed from Dr. Anna Petryk to Dr. Kyriakie 
Sarafoglou. 
• Section 7.1 and Appendix II, clarified timing of repeat Vitamin D 
levels. 
• Section 8.1 and 8.2.2 pregnancy test may be either urine or serum 
• Section 8.2.4 Added that it is not necessary to repeat a lumbar spine    
x-ray if previously performed within past 12 months 
• Section 10.4 and 10.5 updated link to the Masonic Cancer Center 
DSMP 
Yes 
8 
05/21/2017 
• Added non malignant diseases to study eligibility 
• Updated and clarified Vitamin D and Calcium supplementation 
guidelines (Section 7.3 and Appendix II) 
• Updated laboratory reference ranges to current standards 
Yes 
9 
11/30/2017 
• Section 5.2 added inability to complete DEXA scan at randomization 
• Section 6.2 clarified testing windows for randomization and 
randomization procedure 
• Clarified Vitamin D and Calcium supplementation guidelines (Section 
7.3) 
• Section 7.5 added sedation option to DEXA scan, and risks of 
• Sections 8.1, 8.2.3, clarified schedule of height and weight evaluations 
• Section 9.2, clarified that AEs will not be reportable if they occur 
prior to randomization 
• Removed Appendix II as it was a repeat of tables already in the 
protocol 
• Section 10.3 updated data capture method 
• Appendix III added “completed by” line to the assessment tools 
 
9A 
04/16/2018 
• Section 9.2 revised and clarified AE reporting procedures 
No 
10 
07/11/2019 
• Section 7.3 Updated supplementation guidelines for clarity and 
consistency 
• Section 8.1 added footnote to timing of procedures 
No 
 
 
PI Contact Information: 
Sponsor/Investigator 
Kyriakie Sarafoglou, MD 
Associate Professor 
Director, Center for Congenital Adrenal Hyperplasia  
and Disorders of Sex Development  
University of Minnesota Masonic Children's Hospital 
Division of Pediatric Endocrinology 
Division of Genetics & Metabolism 
East Building Room MB661 
2450 Riverside Avenue Minneapolis, MN 55454  
Telephone: 612-624-5409 
Fax: 612-626-5262 
Email:  saraf010@umn.edu 
Principal Investigator – Seattle Children’s 
K Scott Baker, MD, MS 
Professor of Pediatrics 
Fred Hutchinson Cancer Research Center 
FHCRC Box 358080 - MS D5-280 
PO Box 19024 
Seattle, WA 98109-1024 
Telephone:  206-667-4551 
Email:  ksbaker@fhcrc.org 

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Table of Contents 
Study Summary ....................................................................................................................... 8 
Study Schema .......................................................................................................................... 9 
List of Abbreviations ............................................................................................................. 10 
1 Introduction, Background and Rationale ............................................................................ 12 
1.1 Pamidronate Disodium .................................................................................................. 12 
1.2 Pamidronate in Children ............................................................................................... 12 
2 Pamidronate Disodium (Investigational Agent) ................................................................. 14 
2.1 Description.................................................................................................................... 14 
2.2 Indications .................................................................................................................... 14 
2.3 Study Drug Availability................................................................................................ 14 
2.4 Packaging, Storage, and Preparation ............................................................................ 15 
2.5 Final Reconciliation and Destruction of Study Drug ................................................... 15 
3 Study Objectives and Hypotheses ...................................................................................... 15 
3.1 Primary Hypothesis ...................................................................................................... 15 
3.2 Secondary Hypotheses .................................................................................................. 15 
4 Study Design....................................................................................................................... 16 
5 Subject Selection ................................................................................................................ 17 
5.1 Inclusion Criteria .......................................................................................................... 17 
5.2 Exclusion Criteria ......................................................................................................... 18 
6 Study Registration and Randomization .............................................................................. 19 
6.1 Registration with the Masonic Cancer Center Clinical Trials Office ........................... 19 
6.2 Randomization (Day 90 Post-HCT Visit +/- 14 days) ................................................. 19 
7 Treatment Plan .................................................................................................................... 20 
7.1 Vitamin D and Calcium Supplementation .................................................................... 20 
7.2 Calcium ......................................................................................................................... 21 
7.3 Vitamin D and Calcium Supplementation Charts: ....................................................... 21 
7.4 Pamidronate .................................................................................................................. 39 
7.5 Expected Risks of Study Related Procedures ............................................................... 43 
7.6 Prohibited Concomitant Therapy .................................................................................. 43 
7.7 Duration of Study Therapy ........................................................................................... 44 
7.8 Duration of Study Participation .................................................................................... 44 
8 Study Related Tests and Procedures ................................................................................... 46 
8.1 Schedule of Tests and Procedures ................................................................................ 46 
8.2 Clinical Procedures ....................................................................................................... 48 
8.3 Laboratory Testing Procedures ..................................................................................... 50 
8.3.1 Laboratory Testing Procedures ............................................................................... 50 
8.3.2 Specimen Processing and Storage ........................................................................... 51 
8.3.3 
Specimen Processing and Storage - University of Minnesota ................................. 52 

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8.3.4 Specimen Shipping – Fred Hutchinson Cancer Research Center ........................... 52 
8.3.5 Laboratory Testing: Normal Values........................................................................ 53 
9 Event Monitoring, Documentation and Reporting ............................................................. 54 
9.1 Definitions .................................................................................................................... 54 
9.2 Documentation of Adverse Events ............................................................................... 55 
9.3 Documentation of Pregnancy ....................................................................................... 56 
9.4 Required Reporting of Fred Hutchinson Cancer Research Center to UMN (IND 
Sponsor) ........................................................................................................................ 57 
9.5 UMN Required Reporting: FDA, IRB, and MCC’s SAE Coordinator ........................ 58 
10 
Study Status Updates, Data Collection and Monitoring ............................................... 59 
10.1 
Study Status Updates .............................................................................................. 59 
10.2 
Data Management ................................................................................................... 59 
10.3 
Data Capture Methods ............................................................................................ 59 
10.4 
Data and Safety Monitoring Plan (DSMP) ............................................................. 60 
10.5 
Affiliate Site Monitoring ........................................................................................ 60 
10.6 
Record Retention .................................................................................................... 61 
11 
Endpoints ...................................................................................................................... 61 
11.1 
Primary Clinical Endpoint ....................................................................................... 61 
11.2 
Secondary Clinical Endpoints ................................................................................. 61 
12 
Statistical Considerations ............................................................................................. 61 
12.1 
Sample Size ............................................................................................................ 61 
12.2 
Subject Population(s) for Analysis ......................................................................... 62 
12.3 
Randomization Scheme .......................................................................................... 62 
12.4 
Statistical Methods .................................................................................................. 63 
12.5 
Early Study Stopping Rule For Excessive Toxicity ............................................... 64 
13 
Ethical and Regulatory Considerations ........................................................................ 65 
13.1 
Good Clinical Practice ............................................................................................ 65 
13.2 
Ethical Considerations ............................................................................................ 65 
13.3 
Inclusion of Minorities ........................................................................................... 65 
13.4 
Informed Consent ................................................................................................... 67 
13.5 
Protocol Amendments After Study Initiation ......................................................... 67 
13.6 
Anticipated Duration of the Clinical Investigation ................................................. 67 
14 
References .................................................................................................................... 68 
Appendix I – Eligibility Checklist ......................................................................................... 72 
Appendix II – Food Frequency Questionnaire ...................................................................... 72 
Appendix III - Physical Activity Questionnaires ................................................................... 74 
 
 

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Study Summary 
Prevention of Bone Loss After Pediatric Hematopoietic Cell Transplantation 
IND Sponsor/ 
Investigator 
Kyriakie Sarafoglou, MD 
Director, Leo Fung Center for Congenital Adrenal Hyperplasia  
and Disorders of Sex Development   
University of Minnesota Masonic Children's Hospital 
Phase 
Phase 2 
Study Design 
This is a Phase 2, open-label, randomized, controlled clinical study of pediatric 
subjects treated with pamidronate with calcium and vitamin D versus calcium and 
vitamin D alone following hematopoietic cell transplantation (HCT).   
 
Subjects randomized to pamidronate 
treatment 
will receive 
infusions 
at 
approximately Day 90, Day 180, and Day 270 post-HCT.   
 
Laboratory evaluations, dual-energy X-ray absorptiometry (DXA), and peripheral 
quantitative computed tomography (pQCT) will be performed at specified time 
points to evaluate safety and treatment efficacy. 
Primary 
Objective 
To test the hypothesis that subjects receiving pamidronate with calcium and vitamin 
D (Pamidronate Group) will have higher lumbar spine bone mineral content (LBMC; 
adjusted for height, age, sex, Tanner stage, and  race) measured by DXA at 1 year 
post-HCT than subjects receiving calcium and vitamin D alone (Control Group). 
Secondary 
Objectives: 
To test the following hypotheses: 
• Subjects treated with pamidronate will have higher total body BMC (TBMC; 
excluding head; adjusted for height, age, sex, Tanner stage, and race) measured by 
DXA 1 year post-HCT compared to the Control Group. 
• Subjects treated with pamidronate will have higher total bone mineral density 
(BMD), cortical BMD, trabecular BMD, and estimated bone strength measured by 
pQCT 1 year post-HCT compared to the Control Group. 
Correlative 
Objectives: 
• Cytokine levels will increase rapidly in the first 3 weeks after HCT, preceding an 
increase in markers of bone resorption. 
• In the Control Group, increased cytokine levels and receptor activator of nuclear 
factor-κ B ligand (RANKL)/ osteoprogerin (OPG) ratio 3 weeks post-HCT will 
be associated with decreased BMC and BMD at 1 year post HCT. 
• Markers of bone resorption will increase in the first three months after HCT, will 
remain elevated until at least Day 180 in the Control Group, but will decrease 
after initiation of pamidronate at Day 90 in the Pamidronate Group. 
• Markers of bone formation, including osteocalcin (OCN) will decrease in the first 
three months after HCT and in the Control Group lower OCN levels at Day 90 
will be associated with lower BMC and BMD 1 year post-HCT. 
 
Duration of 
Study 
Participation 
1 year from HCT 
Number of 
Subjects 
 
60 evaluable patients (30 per site) over 3.5 years 

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Main 
Inclusion 
Criteria 
Subjects will be ≥1 and ≤20 years of age at the time of enrollment and receiving an 
allogeneic HCT for a hematologic malignancy in complete remission and using a 
myeloablative preparative regimen, non-malignant diseases with a myeloablative or non-
myeloablative preparative regimen, or severe aplastic anemia (SAA) for which any 
conditioning therapy is permitted. 
Standard 
Therapy  
All Subjects - Standard supplementation with calcium and vitamin D beginning at 
admission to the hospital (prior to HCT) and continuing until post-HCT Day 360 visit 
Study Product, 
Dose, Route, 
Regimen 
Pamidronate Group Only 
Pamidronate disodium  single 1 mg/kg intravenous infusion administered every 3 
months for 3 doses - post-HCT Days 90, 180 and 270. 
Endpoints 
The primary study endpoint is lumbar bone mineral content (LBMC). 
Other endpoints are TBMC (excluding head), bone strength, total BMD, cortical 
BMD, trabecular BMD, levels of markers of bone turnover, cytokines, 
RANKL/OPG ratio, and body composition. 
Statistical 
Methods 
The primary analysis will compare the Pamidronate and Control Groups according 
to LBMC measured by DXA using a t-test applied to all available Day 360 
measurements.  A secondary analysis will use multiple imputation to impute Day 
360 BMC and BMD measurements for each subject who does not provide one. 
Study Schema 
Study Entry 
 
 
 
          Randomize 
 
 
Final Study Visit 
 
 
Begin daily 
 
 
 
 
     P                     P                      P 
Vit D/Ca  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCT Day        prep 
0       7      14     21  
   90 
             180 
        270                 360 
 
Key Study Time Points as related to Hematopoietic Cell Transplant (HCT): 
• Enrollment (signing of consent, confirmation of eligibility - occurs during the pre-HCT work-up)  
• Study Entry(DXA scan, blood and urine tests begin during pre-HCT work-up until admission or at the 
time of admission, daily Vitamin D/Calcium begins upon admission to the hospital) 
• Randomization  (Pamidronate versus no Pamidronate) occurs at the Day 90 post-HCT milestone visit 
• Final Study Visit occurs at the Day 360 post-HCT milestone visit  
 
Treatment Plan: 
All subjects: 
Vitamin D and Calcium Supplementation per Section 7.3 begin prior to HCT preparative regimen start 
(e.g. on day of admission for transplant) and continue daily through day 360 post-HCT milestone visit  
Pamidronate Group 
Pamidronate (P) 1 mg/kg IV (to max dose of 60 mg) over 4 hours on Day 90, Day 180, and Day 
270 post-HCT 
 

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List of Abbreviations 
AE 
Adverse Event 
AI 
Adequate Intake 
ALL 
Acute Lymphoblastic Leukemia 
AML 
Acute Myeloid Leukemia 
BMC 
Bone Mineral Content 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
BP 
Bisphosphonate 
CFR 
Code of Federal Regulations 
CML 
Chronic Myelogenous Leukemia 
CNS 
Central Nervous System 
CPRC 
Cancer Protocol Review Committee  
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSI 
Clinical and Translational Science Institute  
CTX 
Carboxy Terminal Collagen Crosslinks  
DPD 
Deoxypyridinoline 
DSMC 
Data and Safety Monitoring Council 
DSMP 
Data and Safety Monitoring Plan    
DXA 
Dual-energy X-ray Absorptiometry 
eCRF 
electronic case report form  
EDTA 
Ethylenediaminetetraacetic Acid     
FDA 
Food and Drug Administration 
FFQ 
Food Frequency Questionnaire      
FHCRC 
Fred Hutchinson Cancer Research Center  
GCP 
Good Clinical Practice 
GnRH 
Gonadotropin-releasing Hormone  
GVHD 
Graft-Versus-Host Disease 
HCT 
Hematopoietic Cell Transplantation 
HIPAA 
Health Insurance Portability and Accountability Act of 1996  
ICH 
International Conference on Harmonisation 
IDS 
Investigational Drug Services 
IL 
Interleukin 
IND 
Investigational New Drug 
iPTH 
Intact Parathyroid Hormone 
IRB 
Institutional Review Board 
IV 
Intravenous 
LBMC 
Lumbar Bone Mineral Content 
LBMD 
Lumbar Bone Mineral Density  
NCI 
National Cancer Institute 
OCN 
Osteocalcin 
OCP 
Oral Contraceptive Pill 
OH 
Hydroxy 
OI 
Osteogenesis Imperfecta 
OnCore 
University of Minnesota’s data capture system 
OPG 
Osteoprogerin 
OTC 
Over-the-counter 
P1NP 
Procollagen Type 1 Terminal Peptide  
PHI 
Protected Health Information 

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PI 
Principal Investigator 
PN 
Parenteral Nutrition 
pQCT 
Peripheral Quantitative Computed Tomography  
qs 
Sufficient Quantity 
RANKL 
Receptor Activator of Nuclear Factor-κ B Ligand 
RDA 
Recommended Dietary Allowance  
REPA 
Report of External Professional Activities 
Rx 
Prescription 
SAA 
Severe Aplastic Anemia 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SST 
Serum Separation Tube 
TBD 
To Be Determined 
TBMD 
Total Body Bone Mineral Density 
TNF-α 
Tumor Necrosis Factor Alpha  
UMN 
University of Minnesota 
USP 
United States Pharmacopeia 
 
 

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1 
Introduction, Background and Rationale 
Low bone mineral density (BMD) is common in children treated with hematopoietic cell 
transplantation (HCT) in both early and late follow-up (1-7). Low BMD in childhood 
is expected to increase the risk of early osteoporosis and increase the risk of fracture 
due to low peak bone mass (7-11). This has serious individual and societal implications 
due to impaired mobility and ability to participate in activities of daily living that 
occurs after fracture. In older adults, fracture has even been associated with an increased 
risk of death. 
 
Bone health is dependent on a balance between bone resorption and bone formation; 
when this balance is disrupted bone loss and ultimately osteoporosis develop. BMD 
decreases in the first 6 months after HCT (1). A recent study has shown that bone 
resorption is significantly increased by 100 days after pediatric HCT and remains 
elevated through at least 180 days after HCT (12), which offers an opportunity for 
intervention. 
1.1 
Pamidronate Disodium 
Pamidronate is a bisphosphonate (BP) that inhibits bone resorption and thus can 
increase bone density by shifting the balance towards bone formation. Although 
its mechanism of antiresorptive action is not completely understood, several 
factors are thought to contribute to this action. Pamidronate disodium adsorbs 
to calcium phosphate (hydroxyapatite) crystals in bone and may directly block 
dissolution of this mineral component of bone. In vitro studies also suggest that 
inhibition of osteoclast activity contributes to inhibition of bone resorption. In 
animal studies, at doses recommended for the treatment of hypercalcemia, 
pamidronate disodium inhibits bone resorption apparently without inhibiting 
bone formation and mineralization (13). 
 
The Food and Drug Administration (FDA) has approved pamidronate for use in 
osteolytic bone metastasis associated with metastatic breast cancer or multiple 
myeloma, hypercalcemia of malignancy (with adequate hydration), and Paget's 
disease in adults. It is also frequently used to treat post-menopausal osteoporosis 
and has been shown to be effective in preventing post-transplant bone loss in 
adults (14-16). 
 
1.2 
Pamidronate in Children 
Pamidronate has not been approved for use in children but clinical trials have been 
conducted in children with various disorders causing osteoporosis or low bone 
density. In children, pamidronate and other BPs have been used safely and 
effectively to treat the most debilitating form of childhood osteoporosis, 
osteogenesis imperfecta (OI) (17, 18). The first case report of beneficial effects 

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of BP treatment in OI was published in 1987 (19) and was followed by over 30 
clinical trials (20-22). In these studies, the most commonly used BP was 
intravenous pamidronate at a dose of 0.6 to 3.75 mg/kg/day over 1 to 3 days every 
1 to 6 months (23, 24).  The patients’ age was 0.04 to 18 years and follow-up 
lasted up to 9 years.  The reported therapeutic effects included improvement in 
bone density (increase in lumbar spine BMD Z-score of about 2.6 or in spine 
BMD of 42 to 48%), grip strength, vertebral height, cortical thickness, 
trabecular number, decreased bone turnover, increased mobility, and decreased 
fracture rate.  Due to these beneficial effects, pamidronate has become the 
standard of care in treating severe OI (25).  BPs are increasingly prescribed in 
children with other diseases, for example neuromuscular disorders (26-28) or 
idiopathic juvenile osteoporosis (29, 30) with improvements noted in the spine, 
femoral neck, and/or total body BMD Z-scores and a reduced fracture rate.  
Pamidronate has also been used in pediatric burn patients to prevent bone loss (31). 
 
There has been 1 retrospective observational study that found BP therapy 
improved BMD in pediatric HCT recipients (32). The study included children who 
survived at least 1 year after allogeneic HCT with 48 control patients receiving 
calcium and vitamin D and 18 patients also receiving BP therapy (17 of the 18 
patients received pamidronate for the majority of the study as monthly infusions 
of 1 mg/kg for 6 months to 2 years). Baseline and follow- up dual energy x-ray 
absorptiometry (DXA) scans (mostly at the lumbar spine) were compared. The 
annualized increase in BMD was 10% per year for the control patients and 33% 
per year for patients that also received BP. To account for expected age-related 
increase in BMD, the interval change in BMD Z-scores was calculated. The 
annualized median change in BMD Z-scores per year was +0.12 among the control 
patients and +1.43 for the BP group. Thus, in this non-randomized retrospective 
study, BP-treated HCT recipients had a significantly greater increase in BMD than 
control patients. 
 
Short- and long-term safety of BPs for children with compromised bone health 
has been recently assessed on behalf of the Drugs and Therapeutics Committee 
of the Pediatric Endocrine Society (25). In most studies, no serious side effects 
have been reported with the exception of 1 case of iatrogenic osteopetrosis in a 12 
year-old boy treated with higher than recommended doses of pamidronate (2.2 
to 3.4 mg/kg every 3 weeks and then less frequent intervals between 7¾ and 
10½ years of age) for idiopathic bone pain with a marked elevation of alkaline 
phosphatase (33). More likely side effects are transient hypocalcemia (24, 34), 
which can be prevented/mitigated by calcium and vitamin D supplementation, and 
an acute-phase reaction, including influenza-like symptoms (24, 35-38), which 
can be mitigated by anti-pyretic/anti-inflammatory agents. Nephrotoxicity has 

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been reported in adults treated with pamidronate (39, 40), but no adverse effect on 
renal function has been reported in children treated with pamidronate or other 
BPs. There has been some concern about long-term effects due to deposition 
of BPs in the skeleton. A half-life of more than 10 years has been reported in 
adults (41). Long-term release of BPs has been shown in children who were treated 
with pamidronate for 4 to 10 years (42). Fractures have been described in OI 
patients following pamidronate discontinuation, at the interface between the 
high density (pamidronate-treated) and low density (newly formed, pamidronate-
naïve) bone (43-45). It is thought, however, that this risk may be limited to patients 
who have persistent risk factors such as a genetic defect (e.g., collagenopathy) as 
opposed to transient exposures. It is unlikely that these potential long-term 
consequences are pertinent to this study, which requires short-term exposure to 
pamidronate and excludes children with any underlying genetic abnormality in 
bone remodeling. 
 
 
2 
Pamidronate Disodium (Investigational Agent) 
2.1 
Description 
Molecular formula: C3H9NO7P2Na2•5H2O  
Molecular weight: 369.1 
 
30 mg single use vial: 3 mg/mL pamidronate disodium, 47 mg/mL mannitol, United 
States Pharmacopeia (USP); water for injection, USP, sufficient quantity (qs); and 
phosphoric acid to adjust pH. 
 
90 mg single use vial: 9 mg/mL pamidronate disodium, 37.5 mg/mL mannitol, USP; 
water for injection, USP, qs; and phosphoric acid to adjust pH. 
 
2.2 
Indications 
Pamidronate disodium was approved by the FDA in 1991  for the treatment of 
osteolytic bone metastasis associated with metastatic breast cancer or multiple 
myeloma, hypercalcemia of malignancy (with adequate hydration), and Paget's 
disease in adults. 
 
Pamidronate has not been FDA-approved for pediatric use but given previous data 
in children (refer to Section 1.2), standard safety monitoring following HCT, and 
the additional safety evaluations included in this protocol, the risk to subject safety 
is relatively low. 
 
2.3 Study Drug Availability 
For the purposes of the study vials of pamidronate disodium will be purchased by 

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the study through each institution’s Investigational Drug Service (IDS).  
 
Study drug inventory will be documented. 
 
2.4 Packaging, Storage, and Preparation  
Packaging and Labelling 
The immediate package of an investigational drug intended for human use shall 
bear a label with the statement: 
Caution: New Drug--Limited by Federal law to investigational use. 
 
Storage 
Vials of pamidronate disodium solution must be stored at 20 to 25°C. 
 
Preparation for Infusion 
Pamidronate disodium solution will be diluted to the recommended subject dose 
in sterile sodium chloride 0.45% or 0.9% or dextrose 5%. The drug will be 
completely dissolved before the solution is withdrawn. Parenteral drug products 
will be visually inspected for particulate matter and discoloration prior to 
administration, whenever solution and container permit.  Refer to the package insert 
for complete details 
2.5 
Final Reconciliation and Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of study agents 
that were purchased, consumed, and remaining at the study site.  This 
reconciliation will be logged on the drug reconciliation form, signed and dated.  
Any discrepancies noted will be investigated, resolved, and documented prior to 
destruction of unused study drug.   
 
Any leftover drug will be destroyed on site according to institutional policies. 
 
3 
Study Objectives and Hypotheses 
3.1 
Primary Hypothesis 
The primary hypothesis is subjects treated with pamidronate and calcium and 
vitamin D (Pamidronate Group) will have higher lumbar bone mineral content 
(LBMC adjusted for height, age, sex, Tanner stage and race) measured by DXA 
1 year post-HCT than subjects receiving calcium and vitamin D alone (Control 
Group). 
 
3.2 
Secondary Hypotheses 
The secondary hypotheses are: 

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• Subjects treated with pamidronate will have higher total body BMC (TBMC; 
excluding head; adjusted for height, age, sex, Tanner stage, and race) 
measured by DXA 1 year post-HCT compared to the Control Group. 
• Subjects treated with pamidronate will have higher total BMD, cortical 
BMD, trabecular BMD, and estimated bone strength measured by 
peripheral quantitative computed tomography (pQCT) 1 year post-HCT 
compared to the Control Group. 
• Cytokine levels will increase rapidly in the first 3 weeks after HCT, 
preceding an increase in markers of bone resorption. 
• In the Control Group, increased cytokine levels and receptor activator of 
nuclear factor-κ B ligand (RANKL)/osteoprogerin (OPG) ratio 3 weeks 
post-HCT will be associated with decreased BMC and BMD 1 year after 
HCT. 
• Markers of bone resorption will increase in the first 3 months after HCT, will 
remain elevated until at least Day 180 in the Control Group, but will decrease 
after initiation of pamidronate at Day 90 in the Pamidronate Group. 
• Markers of bone formation, including osteocalcin (OCN), will decrease in the 
first 3 months after HCT and in the Control Group lower OCN levels at Day 
90 will be associated with lower BMC and BMD 1 year post-HCT. 
 
4 
Study Design 
This is a Phase 2, open-label, randomized, controlled clinical study of pediatric subjects 
(defined as ≥1 year, but ≤20 years of age) treated with pamidronate with calcium and 
vitamin D versus calcium and vitamin D alone following HCT.   
 
All subjects will receive a supplemental dose of vitamin D (based on vitamin D (D2+D3) 
level) beginning upon admission to the hospital for the HCT and calcium if they are not 
meeting the recommended dietary allowance (RDA) or if their serum calcium is low 
(based on ionized calcium level).  Refer to Section 7.3 for supplementation guidelines.   
At the Day 90 post-transplant visit, subjects will be randomized to receive one of the 
following treatment plans t h r o u g h  t h e  Day 360 post-transplant visit: 
 
• Control 
Group: 
continue determined vitamin D per day and calcium 
supplementation, as appropriate to meet the RDA requirement. Refer to Section 7.1 for 
supplementation guidelines. 
• Pamidronate Group: continue determined vitamin D per day and calcium 
supplementation, as appropriate to meet RDA requirement, AND 3 single IV 
infusions of 1 mg/kg (to a max of 60 kg) pamidronate at 3-month intervals (Day 90, 
180 and 270) post-transplant. Refer to Section 7.3 for supplementation guidelines 
 

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Laboratory evaluations, DXA, and pQCT will be performed at specified time points per 
section 8 to monitor safety and evaluate treatment efficacy. 
 
 
5 
Subject Selection  
This study will evaluate bone loss in pediatric patients undergoing a hematopoietic cell 
transplant (HCT).  Study entry is open to persons ≥1, but ≤20 years of age regardless of 
gender, race or ethnic background.  While there will be every effort to seek out and include 
females and minority patients, the patient population is expected to be no different than 
that of hematopoietic cell transplant studies for hematologic malignancies and severe 
aplastic anemia at the University of Minnesota and Fred Hutchinson Cancer Research 
Center. 
Patients will be consented and screened during their pre-transplant evaluation.  Vitamin D 
and calcium, if indicated, will be started at the time of admission for transplant. 
5.1 
Inclusion Criteria 
All of the following criteria must be met: 
5.1.1 Patients in one of the below disease categories: 
5.1.1.1 Allogeneic hematopoietic cell transplant for hematologic 
malignancy (i.e. leukemia, lymphoma including ALL, AML, CML, 
NHL, HL) in complete remission; myelodysplastic syndrome 
(active dysplasia and/or blasts are permitted, but must not have 
active leukemia)  who will be receiving a myeloablative 
preparative regimen, OR 
  
5.1.1.2 Non-malignant diseases including idiopathic severe aplastic 
anemia (SAA) and other bone marrow failure disorders, 
hemoglobinopathies, 
adrenoleukodystrophy, 
immune 
deficiencies/dysregulation disorders who will be receiving 
myeloablative or reduced toxicity preparative regimens that meet 
the following criteria: 
5.1.1.2.1 Regimens include those that are TBI based if the TBI 
dose is > 500cGy single dose or > 800cGy fractionated, 
or doses <500 cGy if combined with busulfan or 
treosulfan.  These also include chemotherapy only based 
regimens that contain myeloablative doses of busulfan 
(>8mg/kg) or treosulfan without TBI 
5.1.1.2.2 Patients with severe aplastic anemia are eligible 
regardless of conditioning regimen 
5.1.2 Male or female ≥1 but ≤ 20 years of age at time of study enrollment 

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5.1.3 Patient or parent(s)/legal guardian(s) is able and willing to provide informed 
consent.  Assent will be obtained per local institutional policy.  Subjects 
who turn 18 during the course of the study will be consented at that time of 
their next visit by a member of the research staff. 
5.2 
Exclusion Criteria 
Patients will be excluded from participation in the study if any of the following 
conditions exist: 
5.2.1 History of a primary bone malignancy involving the lumbar spine 
5.2.2 Treatment with other biphosphonates, Denosumab, or Teriparatide within 
one year prior to enrollment   
5.2.3 Pregnancy or breastfeeding – menstruating females must have a negative 
pregnancy test prior to study enrollment and agree to repeat pregnancy 
testing and contraception use per protocol as pamidronate is Pregnancy 
Category D – positive evidence of human fetal risk based on adverse reaction 
data 
5.2.4 Renal insufficiency, defined as creatinine level greater than the upper limit 
of normal for age 
5.2.5 Hereditary metabolic bone disease or skeletal dysplasia (e.g., osteopetrosis 
or OI) or primary hyperparathyroidism 
5.2.6 Non-malignant diseases with underlying metabolic defects that may affect 
bones such as Hurler’s syndrome and other Mucopolysaccharidoses and 
osteopetrosis, or diseases where the use of hematopoietic cell transplant 
itself is still under investigation, primarily, epidermolysis bullosa. 
5.2.7 Patients with diseases that have increased sensitivity to chemotherapy or 
radiation including (but not limited to) Fanconi anemia, dyskeratosis 
congenita.   
5.2.8 Clinically significant fractures as defined by ISCD (a long bone fracture of 
the lower extremities, vertebral compression fracture, or two or more long 
bone fractures of the upper extremities) (88,89) indicated by a cast or a spine 
x-ray within the last 2 weeks 
5.2.9 Known or suspected allergy to pamidronate or related products 
5.2.10 Planned administration of an investigational study drug or agent that either 
can interact with pamidronate or have an independent effect on bone mineral 
density within the 4 weeks prior to randomization (Day 90) or planned use 
during study participation (Day 90 through Day 360) 
5.2.11 Impending invasive dental procedure that would be expected to occur 
during study participation (through Day 360)  
                       

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6 
Study Registration and Randomization  
Registration will occur after the patient or parent/guardian has signed the appropriate 
subject consent and eligibility is confirmed, but before any treatment has been 
administered.  To be eligible for registration to this study, the patient must meet each 
criteria listed on the eligibility checklist case report form based on the eligibility assessment 
documented in the patient’s medical record.   
6.1 
Registration with the Masonic Cancer Center Clinical Trials Office 
Upon completion of the screening evaluation, eligibility confirmation and obtaining 
written consent, the study coordinator or designee will enroll the patient into 
OnCore. 
OnCore will automatically generate an email alerting key study personnel of the 
registration. 
6.2 
Randomization (Day 90 Post-HCT Visit +/- 14 days) 
Randomization to pamidronate (Pamidronate Group) or no pamidronate (Control 
Group) will occur at Day 90 (+/- 14 days) by the institutional study coordinator 
based on the randomization schedule developed by the study statistician and entered 
into OnCore.   
A brief review of continuing eligibility will be done and subjects will not be eligible 
for randomization if one or more of the following are true: 
• Vitamin D (D2+D3) <20 ng/ml as use of pamidronate is contraindicated due 
to potentially higher risk of hypocalcemia. Levels should be measured 
within 14 days prior to randomization.**Ŧ  
• serum creatinine is > 2 times the baseline value (at Study Entry) -  perform 
within 14 days prior to randomization  
• an investigational study drug or agent, including biphosphonates, 
Denosumab, or Teriparatide, was administered within the previous 4 weeks 
or is planned for use during study participation (Day 90 through Day 360) 
• positive pregnancy test (performed within 14 days prior to randomization) 
• Inability to successfully complete a DEXA scan 
• the parent or adult patient refuse randomization 
• disease relapse has occurred 
 
The randomization will be stratified by age with 2 strata:  < 10 years old and ≥ 10 
years old. 
 
If the patient is ineligible for or refuses randomization, no further research related 
procedures or treatment will occur after the Day 90 visit; however permission to 
continue review of the patient’s medical record through the Day 360 visit for 
routine clinical information is embedded within the consent form document.  This 
information will be collected only if the patient continues care at the enrolling 

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institution.  Patient care will be at the discretion of the treating physician(s) and 
independent of this study. 
 
OnCore will automatically generate an email alerting key study personnel of the 
randomization (or lack of). 
 
7 
Treatment Plan 
7.1 Vitamin D and Calcium Supplementation 
All subjects will receive a supplemental vitamin D (based on Vitamin  D2+D3 levels 
beginning upon admission to the hospital for the HCT (54, 55). Vitamin D and 
Calcium supplementation will be determined by a combination of Vitamin D levels, 
ionized calcium levels, calcium intake, PTH, and TPN.  See section 7.3 for 
supplementation guideline charts. In subjects who require parenteral nutrition 
(PN) and have normal vitamin D (D2+D3) level, vitamin D will be given as part 
of multivitamin supplementation.  
• Adult multivitamin preparations contain 200 IU of cholecalciferol per 10 
ml (or 5 mcg of ergocalciferol, equivalent to 200 IU of ergocalciferol, per 
10 ml).   
Pediatric multivitamin preparations contain 400 IU of cholecalciferol per 5 ml. 
(of 10 mcg of ergocalciferol, equivalent to 400 IU of ergocalciferol, per 5 ml) 
If a subject’s serum vitamin  D (D2+ D3) is <30 ng/mL at any of the designated time 
points starting from study entry through Day 360 post-HCT (including 8 week 
rechecks for subtherapeutic levels), additional supplementation with vitamin D 
will be administered to maintain a serum level between 30 and 70 ng/mL 
according to the protocol as outlined in Section 7.  
 
If serum vitamin D (D2+ D3) levels  are low and supplementation is begun, levels 
will be re-checked after 8 weeks at the next scheduled study visit.  Although the 
proposed regimen should normalize vitamin D level within 6-8 weeks (57), if 
the target range is not reached, supplementation will be continued for additional 8 
weeks, and serum vitamin D level (D2+D3) repeated at the end of treatment.  
Subjects with vitamin D level (D2+D3) <20 ng/ml at Study Entry will be 
excluded from analyses of bone turnover markers until vitamin D level 
(D2+D3) normalizes but otherwise will be included in all analyses. 
 
** Measurement of Vit (D2+D3) levels is recommended instead of 25-hydroxy-
Vitamin D level, as they reflect vitamin D stores accurately and independently of 
whether the subject is on VitD2 (ergocalciferol) or VitD3 (cholecalciferol) 
supplementation. As 25-hydroxyVitamin D assay mainly measures VitD3 stores, it 
cane underestimate overall vitamin D stores in patients supplemented with 

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ergocalciferol (VitD2).  However, 25-hydroxy Vitamin D assay can be used in 
patients who are on cholecalciferol supplementation. 
ŦPer institutional practice, Fred Hutchinson Cancer Research center will measure 
25-hydroxy-Vitamin D level. 
 
7.2 
Calcium 
Study subjects will be assessed to determine if supplemental calcium is warranted 
based on dietary intake and/or ionized calcium values.  At the designated time 
points in the study starting at admission fo r the HCT through Day 360, dietary 
calcium intake will be determined from a Food Frequency Questionnaire (FFQ) 
(Appendix II). Subjects who do not meet the RDA will receive additional 
calcium supplementation (Section 7.3).  
At the designated time points in the study starting at admission for HCT through 
Day 360, ionized calcium or corrected calcium, and vitamin D (D2+D3) levels will 
be assessed.  If the subject’s level is below the normal range at any time, 
supplemental calcium and vitamin D supplementation will be given per Section 7.3  
If a subject’s total calcium level is below the normal range at any time, calculate a 
corrected calcium if a serum albumin level is available (may have been drawn 
anytime within 7 days of the calcium level) using the formula:  
 
Corrected Ca = measured total Ca + [0.8 (4.0 - serum albumin mg/dL)]  
 
If a serum albumin level is not available ionized calcium level should be done. 
 
If a subject’s vitamin D level (D2+D3) is 10-20 ng/mL and their iPTH level is 
>65 pg/mL or if vitamin D level (D2+D3) is <10 ng/mL at any time from Study 
Entry through Day 360, additional calcium carbonate will be administered per 
Section 7.3.  
7.3 
Vitamin D and Calcium Supplementation Charts: 
For all dosing, these charts list the ideal targeted dose, however dosing will be in an acceptable 
range as set by available formulations or insurance barriers 
ŦPer institutional practice, Fred Hutchinson Cancer Research center will measure 25-hydroxy-
Vitamin D level 
 
 

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7.3.1 
For Vitamin D Sufficient Patients 
Age 
All  
Vitamin D 
Calcium (elemental) 
Vitamin D level 
(D2+D3) Ŧ 
sufficient 
 
600 IU/day of 
Vitamin D 
supplementation only 
 
No Supplementation 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
sufficient 
 
Age 
1-3 years 
Vitamin D 
Calcium (elemental) 
Vitamin D level 
(D2+D3) Ŧ 
sufficient 
 
600 IU/day of 
Vitamin D 
 
600 mg/day 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
low 
 
Age 
4-8 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
sufficient 
 
600 IU/day of 
Vitamin D 
 
1,000 mg/day 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
low 
 
Age 
≥ 9 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
sufficient 
 
600 IU/day of 
Vitamin D 
 
1,200 mg/day 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
low 
 
 
 

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Age 
1-3 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
sufficient 
• 600 IU/day 
Vitamin D 
• calcium 
supplementation at 
a dose of 50 mg/kg 
divided 3x/day day 
(max daily calcium 
dose of 2000 
mg/day).  
• Check levels 
weekly, increase as  
• needed to 
normalize ionized 
or corrected 
calcium. 
• Once normalized, 
if dietary calcium 
intake is low the 
participant would 
receive calcium 
600 mg/day 
ionized or corrected 
calcium level 
low 
dietary calcium 
intake based on 
questionnaire 
Low or normal 
 
Age 
4-8 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
sufficient 
• 600 IU/day 
Vitamin D 
• calcium 
supplementation at 
50 mg/kg divided 
3x/day day (max 
daily calcium dose 
of 2000 mg/day).   
• Check levels 
weekly, increase as 
needed to 
normalize ionized 
or corrected 
calcium. 
• Once normalized, 
if dietary calcium 
intake is low the 
participant would 
receive calcium 
1,000 mg/day 
ionized or corrected 
calcium level 
low 
dietary calcium 
intake based on 
questionnaire 
Low or normal 
 

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Age 
≥ 9 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
sufficient 
• 600 IU/day 
Vitamin D 
• calcium 
supplementation at 
50 mg/kg divided 
3x/day day (max 
daily calcium dose 
of 2000 mg/day).   
• Check levels 
weekly, increase as  
needed to 
normalize ionized 
or corrected 
calcium. 
• Once normalized, 
if dietary calcium 
intake is low the 
participant would 
receive calcium 
1,200 mg/day 
ionized or corrected 
calcium level 
low 
dietary calcium 
intake based on 
questionnaire 
Low or normal 
7.3.2 
For Low vitamin D (D2+D3) Levels 
 
Age 
<9 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
20-29 
• 4000 IU/day of 
vitamin D 
supplementation x 
4 weeks 
• Vitamin D (D2+D3) 
level should be 
checked in 4 or 8 
weeks and continue 
supplementation if 
needed 
• Once the Vitamin 
D level is 
normalized the 
participant would 
receive 600 IU/day 
of Vitamin D 
• No 
supplementation 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
sufficient 
 
 
 

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Age 
>9 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
20-29 
• 4000 IU/day of 
vitamin D 
supplementation x 
8 weeks 
• Vitamin D (D2+D3) 
level should be 
checked in 4 or 8 
weeks and continue 
supplementation if 
needed 
• Once the Vitamin 
D level is 
normalized the 
participant would 
receive 600 IU/day 
of Vitamin D 
• No 
supplementation 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
sufficient 
 
Age 
1-3 Years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
20-29 
• 4000 IU /day of 
vitamin D 
supplementation x 
4 weeks 
• Vitamin D (D2+D3) 
level should be 
checked in 4 or 8 
weeks and continue 
supplementation if 
still low 
• Once the Vitamin 
D level is 
normalized the 
participant would 
receive 600 IU/day 
of Vitamin D 
• calcium 600 
mg/day 
 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
low 
 
 
 

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Age 
4-8 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
20-29 
• 4000 IU/day of 
vitamin D 
supplementation x 
4 weeks 
• Vitamin D (D2+D3) 
level should be 
checked in 4 or 8 
weeks and continue 
supplementation if 
still low 
• Once the Vitamin 
D level is 
normalized the 
participant would 
receive 600 IU/day 
of Vitamin D 
• calcium 1,000 
mg/day 
 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
low 
 
Age 
>9 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
20-29 
• 4000 IU/day of 
vitamin D 
supplementation x 
8 weeks; or 50000 
IU (single dose) of 
vitamin D every 
other week x 4 
doses total  
• Vitamin D (D2+D3) 
level should be 
checked in 4 or 8 
weeks and continue 
supplementation if 
still low 
• Once the Vitamin 
D level is 
normalized the 
participant would 
receive 600 IU/day 
of Vitamin D 
• calcium 1,200 
mg/day 
 
ionized or corrected 
calcium level 
low 
dietary calcium 
intake based on 
questionnaire 
Low or normal 
 
 
 

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Age 
1-3 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
20-29 
• 4000 IU/day of 
vitamin D 
supplementation x 
4 weeks 
• Vitamin D (D2+D3) 
level should be 
checked in 4 or 8 
weeks and continue 
supplementation if 
still low  
• Once the Vitamin 
D level is 
normalized the 
participant would 
receive 600 IU/day 
of Vitamin D 
• calcium 
supplementation at 
50 mg/kg divided 
3x/day day (max 
daily calcium dose 
of 2000 mg/day).   
• Check levels 
weekly, increase as 
.needed if low. 
• Once ionized or 
corrected calcium 
is normalized, if 
dietary calcium is 
low, the participant 
would receive 
calcium 600 
mg/day 
ionized or corrected 
calcium level 
low 
dietary calcium 
intake based on 
questionnaire 
Low or normal 
 
Age 
4-8 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
20-29 
• 4000 IU/day of 
vitamin D 
supplementation x 
4 weeks 
• Vitamin D (D2+D3) 
level should be 
checked in 4 or 8 
weeks and continue 
supplementation if 
still low  
• Once the Vitamin 
D level is 
normalized the 
participant would 
receive 600 IU/day 
of Vitamin D 
• calcium 
supplementation at 
50 mg/kg divided 
3x/day day (max 
daily calcium dose 
of 2000 mg/day).   
• Check levels 
weekly, increase as 
needed if low. 
• Once ionized or 
corrected calcium 
is normalized, if 
dietary calcium is 
low, the participant 
would receive 
calcium 1,000 
mg/day 
ionized or corrected 
calcium level 
low 
dietary calcium 
intake based on 
questionnaire 
Low or normal 
 
 
 

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Age 
>9 
Vitamin D 
Calcium (elemental) 
Vitamin D level 
(D2+D3) Ŧ 
20-29 
• 4000 IU/day of 
vitamin D 
supplementation x 
8 weeks; or 50000 
IU (single dose) of 
vitamin D every 
other week x 4 
doses total Vitamin 
D (D2+D3) level 
should be checked 
in 4 or 8 weeks and 
continue 
supplementation if 
still low  
• Once the Vitamin 
D level is 
normalized the 
participant would 
receive 600 IU/day 
of Vitamin D 
• calcium 
supplementation at a 
dose of 50 mg/kg 
divided 3x/day (max 
daily calcium dose 
of 2000 mg/day).   
• Check levels 
weekly, increase as 
needed if low. 
• Once ionized or 
corrected calcium is 
normalized, if 
dietary calcium is 
low, the participant 
would receive 
calcium 1,200 
mg/day 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
low 
 
Age 
<9 
Vitamin D 
Calcium (elemental) 
Vitamin D level 
(D2+D3) Ŧ 
20-29 
• 50000 IU (single 
dose) of vitamin D 
every other week x 
2 doses total 
• Check Vitamin D 
(D2+D3) levels in 4 
weeks   
• Continue vitamin 
D  supplementation 
until Vitamin D  
levels normalize. 
Once normalized 
vitamin D would 
be given as part of 
multivitamin 
supplementation.  
• calcium 
supplementation at a 
dose of 50 
mg/kg/day (max 
daily calcium dose 
of 2000 mg/day)  or 
the maximum 
allowed per TPN 
• Check ionized or 
corrected calcium 
level every week 
ionized or corrected 
calcium level 
low 
Patient on TPN 
Yes 
 
 
 

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Age 
>9 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
20-29 
• 50000 IU (single 
dose) every other 
week x 4 doses 
total 
• Check Vitamin D 
(D2+D3) levels in 8 
weeks   
• Continue vitamin 
D  supplementation 
until Vitamin D  
levels normalize. 
Once normalized 
vitamin D would 
be given as part of 
multivitamin 
supplementation.  
• calcium 
supplementation a 
dose of 50 
mg/kg/day (max 
daily calcium dose 
of 2000 mg/day) or 
the maximum  
allowed per TPN 
• Check ionized or 
corrected calcium 
level every week 
ionized or corrected 
calcium level 
low 
Patient on TPN 
Yes 
 
7.3.3 
Vitamin D Deficiency 
Age 
1-3 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
10-19 
• 4000 IU/day of 
vitamin D 
supplementation x 
8 weeks. Vitamin 
D (D2+D3) level 
should be checked 
in 8 weeks  
• continue  Vitamin 
D supplementation 
if still low 
• Once normalized 
the participant 
would receive 600 
IU/day of Vitamin 
D 
• calcium 
supplementation at 
a dose of 50 mg/kg 
divided 3x/day 
(max daily calcium 
dose of 2000 
mg/day) for 4 
weeks 
• After 4 weeks of 
calcium 
supplementation, if 
dietary calcium is 
low, the participant 
will receive 
calcium 600 
mg/day. 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
normal/low 
PTH* 
>65 
*When PTH is <65 and Vitamin D level (D2+D3) is 10-20 with normal ionized or corrected 
calcium and normal or low dietary calcium intake, calcium supplementation at a dose of 
50mg/kg/day 3 times daily is not needed, otherwise follow the same supplementation 
guidelines.   
 
 

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Age 
4-8 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
10-19 
• 4000 IU/day of 
vitamin D 
supplementation x 
8 weeks. Vitamin 
D (D2+D3) level 
should be checked 
in 8 weeks  
• continue  Vitamin 
D supplementation 
if still low 
• Once normalized 
the participant 
would receive 600 
IU/day of Vitamin 
D 
• calcium 
supplementation at 
a dose of 50 mg/kg 
divided 3x/day 
(max daily calcium 
dose of 2000 
mg/day)  for 4 
weeks 
• After 4 weeks of 
calcium 
supplementation, if 
dietary calcium is 
low, the participant 
will receive 
calcium 1,000 
mg/day 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
normal/low 
PTH* 
>65 
*When PTH is <65 and Vitamin D level (D2+D3) is 10-20 with normal ionized or corrected 
calcium and normal or low dietary calcium intake, calcium supplementation at a dose of 
50mg/kg/day 3 times daily is not needed, otherwise follow the same supplementation 
guidelines.   
Age 
>9 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
10-19 
• 50000 IU (single 
dose)  every week 
x 8 doses total 
• Vitamin D (D2+D3) 
level should be 
checked in 8 weeks  
• continue  Vitamin 
D supplementation 
if still low 
• Once normalized 
the participant 
would receive 600 
IU/day of Vitamin 
D 
• calcium 
supplementation at 
a dose of 50 mg/kg 
divided 3x/day 
(max daily 
calcium dose of 
2.000 mg/day) for 
4 weeks 
• After 4 weeks of 
calcium 
supplementation, 
if dietary calcium 
is low, the 
participant will 
receive calcium 
1,200 mg/day 
ionized or corrected 
calcium level 
normal 
dietary calcium 
intake based on 
questionnaire 
normal/low 
PTH* 
>65 
*When PTH is <65 and Vitamin D level (D2+D3) is 10-20 with normal ionized or corrected 
calcium and normal or low dietary calcium intake, calcium supplementation at a dose of 
50mg/kg/day 3 times daily is not needed, otherwise follow the same supplementation 
guidelines.   

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CPRC# 2013LS023 
 
Age 
1-3 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
10-19 
• 4000 IU/day of 
vitamin D 
supplementation x 
8 weeks 
• Vitamin D (D2+D3) 
level should be 
checked in 8 weeks  
• continue  Vitamin 
D supplementation 
if still low 
• Once normalized 
the participant 
would receive 600 
IU/day of Vitamin 
D 
• calcium 
supplementation at 
a dose of 50 mg/kg 
divided 3x/day 
(max daily calcium 
dose of 2.000 
mg/day) for 4 
weeks 
• Check ionized or 
corrected calcium 
level every week 
and increase 
supplementation as 
needed to 
normalize ionized 
or corrected 
calcium 
• Once ionized or 
corrected calcium 
is normalized, if 
dietary calcium is 
low, the participant 
will receive 
calcium 600 
mg/day 
ionized or corrected 
calcium level 
low 
dietary calcium 
intake 
normal or low 
PTH* 
>65 
* When PTH is <65 and Vitamin D level (D2+D3) is 10-19 with low ionized or corrected 
calcium and normal or low dietary calcium intake, follow the same supplementation 
guidelines.   
 
 
 

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Age 
4-8 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
10-19 
• 4000 IU/day of 
vitamin D 
supplementation x 
8 weeks 
• Vitamin D (D2+D3) 
level should be 
checked in 8 weeks  
• continue  Vitamin 
D supplementation 
if still low 
• Once normalized 
the participant 
would receive 600 
IU/day of Vitamin 
D 
• calcium 
supplementation at 
a dose of 50 mg/kg 
divided 3x/day 
(max daily calcium 
dose of 2.000 
mg/day) for 4 
weeks 
• Check ionized or 
corrected calcium 
level every week 
and increase 
supplementation as 
needed to 
normalize ionized 
or corrected 
calcium 
• Once ionized or 
corrected calcium is 
normalized, if 
dietary calcium is 
low, the participant 
will receive 
calcium 1,000 
mg/day 
ionized or corrected 
calcium level 
low 
dietary calcium 
intake 
normal or low 
PTH* 
>65 
* When PTH is <65 and Vitamin D level (D2+D3) is 10-19 with low ionized or corrected 
calcium and normal or low dietary calcium intake, follow the same supplementation 
guidelines.   
 
 
 
 

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Age 
>9 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
10-19 
• 50000 IU (single 
dose)  every week 
x 8 total doses 
• Vitamin D 
(D2+D3) level 
should be checked 
in 8 weeks  
• Continue  Vitamin 
D supplementation 
if still low 
• Once normalized 
the participant 
would receive 600 
IU/day of Vitamin 
D 
• calcium 
supplementation at 
a dose of 50 mg/kg 
divided 3x/day 
(max daily calcium 
dose of 2.000 
mg/day) for 4 
weeks 
• Check ionized or 
corrected calcium 
level every week 
and increase 
supplementation as 
needed to 
normalize ionized 
or corrected 
calcium 
• Once ionized or 
corrected calcium 
is normalized, if 
dietary calcium is 
low, the participant 
will receive 
calcium 1,200 
mg/day  
ionized or corrected 
calcium level 
low 
dietary calcium 
intake 
normal or low 
PTH* 
>65 
*When PTH is <65 and Vitamin D level (D2+D3) is 10-19 with low ionized or corrected 
calcium and normal or low dietary calcium intake, follow the same supplementation 
guidelines.   
 
 
 

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Age 
<9 
Vitamin D 
Calcium (elemental) 
Vitamin D level 
(D2+D3) Ŧ 
10-19 
• 50000 IU (single 
dose)  of vitamin D 
every other week x 
4 total doses.  
• Check Vitamin D 
(D2+D3) levels in 8 
weeks   
• Continue vitamin 
D  supplementation 
until Vitamin D  
levels normalize. 
Once normalized 
vitamin D would 
be given as part of 
multivitamin 
supplementation. 
• calcium 
supplementation a 
dose of 50 mg/k/day 
(max daily calcium 
dose of 2.000 
mg/day) or the 
maximum allowed 
per TPN 
• Check ionized or 
corrected calcium 
level every week 
ionized or corrected 
calcium levels 
normal or low  
PTH* 
>65 
Oral intake 
No 
Patient on TPN 
Yes 
*When PTH is <65 and Vitamin D level (D2+D3) is 10-19 with normal ionized or corrected 
calcium, calcium supplementation at a dose of 50mg/kg/day 3 times daily is not needed, 
otherwise follow the same supplementation guidelines.   
Age 
>9 
Vitamin D 
Calcium (elemental) 
Vitamin D level 
(D2+D3) Ŧ 
10-19 
• 50000 IU (single 
dose) every week x 
8 total doses 
• Check Vitamin D 
(D2+D3) levels in 8 
weeks   
• Continue vitamin 
D  supplementation 
until Vitamin D  
levels normalize. 
Once normalized 
vitamin D would 
be given as part of 
multivitamin 
supplementation. 
• calcium 
supplementation a 
dose of 50 
mg/kg/day (max 
daily calcium dose 
of 2.000 mg/day) or 
the maximum 
allowed per TPN 
• Check ionized or 
corrected calcium 
level every week 
ionized or corrected 
calcium levels 
normal or low  
PTH* 
>65 
Oral intake 
No 
Patient on TPN 
Yes 
*When PTH is <65 and Vitamin D level (D2+D3) is 10-19 with normal ionized or corrected 
calcium, calcium supplementation at a dose of 50mg/kg/day 3 times daily is not needed, 
otherwise follow the same supplementation guidelines.   
 
 

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7.3.4 
Severe Vitamin D Deficiency 
 
Age 
1-3  years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
<10 
• Vitamin D 50000 
IU (single dose) ; 
then 4000 IU/day 
starting day 2 for 8 
weeks  
• Vitamin D (D2+D3) 
should be checked 
in 8 weeks and 
continue vitamin D 
if still low 
• Once Vitamin D 
normalized the 
participant would 
receive 600 IU/day 
of Vitamin D. 
• calcium 50 mg/kg 
divided 3x/day 
(max daily calcium 
dose of 2.000 
mg/day) for 4 
weeks  
• Check ionized or 
corrected calcium 
every week and if 
low increase 
supplementation as 
needed to 
normalize ionized 
or corrected 
calcium  
• Once ionized or 
corrected calcium 
is normalized, if 
dietary calcium 
intake is low, the 
participant will 
receive calcium 
600 mg/day 
dietary calcium 
intake 
 
PTH 
 
Ionized or corrected 
Calcuim 
 
 
 
 

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Age 
4-8 years 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
<10 
• Vitamin D 50000 
IU (single dose); 
then 4000 IU/day 
starting day 2 for 8 
weeks  
• Vitamin D (D2+D3) 
should be checked 
in 8 weeks and 
continue vitamin D 
if still low 
• Once Vitamin D 
normalized the 
participant would 
receive 600 IU/day 
of Vitamin D. 
• calcium 50 mg/kg 
divided 3x/day 
(max daily calcium 
dose of 2.000 
mg/day) for 4 
weeks  
• Check ionized or 
corrected calcium 
every week and if 
low increase 
supplementation as 
needed to 
normalize ionized 
or corrected 
calcium  
• Once ionized or 
corrected calcium 
is normalized, if 
dietary calcium 
intake is low, the 
participant will 
receive calcium 
1,000 mg/day 
dietary calcium 
intake 
 
PTH 
 
Ionized or corrected 
Calcuim 
 
 
 
 

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Age 
>9 
Vitamin D 
Calcium 
(elemental) 
Vitamin D level 
(D2+D3) Ŧ 
<10 
• 50000 IU (single 
dose) on day 1; and 
then starting day 2, 
give 50000 IU 
(single dose) every 
week for 8 weeks x 
9 doses total 
• Vitamin D (D2+D3) 
should be checked 
in 8 weeks and 
continue vitamin D 
if still low 
• Once Vitamin D 
normalized the 
participant would 
receive 600 IU/day 
of Vitamin D. 
• calcium 
50mg/kg/day 
divided 3x/day 
(max daily calcium 
dose of 2.000 
mg/day) for 4 
weeks  
• Check ionized or 
corrected calcium 
every week and if 
low increase 
supplementation as 
needed to 
normalize ionized 
or corrected 
calcium  
• Once ionized or 
corrected calcium 
is normalized, if 
dietary calcium 
intake is low, the 
participant will 
receive calcium 
1,200 mg/day 
dietary calcium 
intake 
 
PTH 
 
Ionized or corrected 
Calcuim 
 
 
 
 
 

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Age 
<9 
Vitamin D 
Calcium 
(elemental) 
TPN 
No Oral Intake 
• give 50000 IU 
(single dose) of 
vitamin D on day 
1; and then starting 
day 2, 50000 IU 
(single dose) every 
other week x 5 
doses total 
• Vitamin D (D2+D3) 
should be checked 
in 8 weeks and 
continue vitamin D 
if still low  
• Once normalized 
the participant 
would receive 600 
IU/day of Vitamin 
D  
• calcium 
supplementation 50 
mg/kg/day or the 
maximum allowed 
per TPN  
 
 
Age 
>9 
Vitamin D 
Calcium 
(elemental) 
TPN 
No Oral Intake 
• give 50000 IU 
(single dose) of 
vitamin D every 
week x 8 doses 
total 
• Vitamin D (D2+D3) 
should be checked 
in 8 weeks and 
continue vitamin D 
if still low  
• Once normalized 
the participant 
would receive 600 
IU/day of Vitamin 
D  
• calcium 
supplementation 
50mg/kg/day or the 
maximum allowed 
per TPN  
 
If a subject’s total calcium level is below the normal range at any time, calculate a corrected calcium if a 
serum albumin level is available (may have been drawn anytime within 7 days of the calcium level) using 
the formula:  
 
Corrected Ca mg/dl = measured total Ca mg/dl+ [0.8 (4.0 - serum albumin g/dL)]  

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If a serum albumin level is not available ionized calcium level should be done. 
VITAMIN D PREPARATIONS: 
Over-the-counter (OTC): Cholecalciferol (preferred) or Ergocalciferol 400 IU, 800 IU, 
1,000 IU, 2,000 IU, 4,000 IU, or 400 IU/ml 
 
Prescription (Rx): Cholecalciferol (preferred) or Ergocalciferol 50,000 IU gel capsules or tablets 
prescribed for once weekly administration, Ergocalciferol 8,000 IU/ml 
 
CALCIUM PREPARATIONS: 
Over-the-counter (OTC): Calcium Carbonate: e.g., TUMS 500 mg (200 mg elemental calcium,), TUMS 
750 mg (300 mg elemental calcium), TUMS 1,000 mg (400 mg elemental calcium), or TUMS kids 750 
mg (300 mg elemental calcium) cherry flavored. 
 
Rx: Calcium Carbonate: Oral suspension 1,250 mg/5 ml (elemental calcium = 500 mg/5 ml) 
7.4 
Pamidronate 
7.4.1 Treatment Plan 
Subjects randomized to the Pamidronate Group will receive 3 single doses of 
pamidronate at 3-month intervals (Day 90 +/-14 days, Day 180 +/-14 days, 
and Day 270 +/-30 days).  
 
Note:  All time point specific laboratory testing procedures (sections 8.1 and 
8.3) must be collected prior to the pamidronate infusion (except those 
specifically designated post infusion); however for ease of scheduling the 
consultations as well as the Day 90 DXA and Day 90 pQCT may be performed 
after the infusion as long as done within the +/-14 day window. Ionized calcium 
or corrected calcium, and Vitamin D levels (D2+D3) will be drawn prior to 
pamidronate infusions.  If either are low, the subject should receive 
supplemental calcium and/or Vitamin D per Section 7.3.  If the subject is 
receiving supplemental calcium, an ionized or corrected calcium level should 
be drawn after the pamidronate infusion end but prior to discharge from clinic 
on the day of the pamidronate. 
 
Prior to each infusion the patient will be assessed and pamidronate will be held 
if: 
• Serum creatinine is > 2 times the baseline (Study Entry) level – refer to 
section 7.3.2 for monitoring plan – the pre-treatment creatinine may be 
done anytime within 72 hours prior to the planned pamidronate 
administration  

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• Pregnancy test is positive (subject will permanently discontinue study 
drug) per section 7.3.5 – pregnancy testing may be done anytime within 
72 hours prior to the planned pamidronate administration 
 
Pamidronate 1 mg/kg (to a max dose of 60 mg) will be administered via a 
single IV infusion over 4 hours using a line separate from all other drugs.  
Dosing will be based on the patient’s actual weight or, if overweight, on ideal 
body weight (IBW).  This will be followed by a normal saline flush of 20 cc 
total given at the same rate as the pamidronate. 
 
Premedication:  Subjects will be given 15 mg/kg acetaminophen (or maximum 
of 500 mg) prior to pamidronate infusion then every 4 hours as needed for a 
maximum of 24 hours. 
 
Post-Pamidronate Infusion Laboratory Tests:  A serum calcium level will be 
done after the pamidronate infusion end but prior to discharge from clinic on 
the day of the pamidronate.   
 
A serum creatinine and a spot urine albumin and creatinine will be scheduled 
for the morning after each pamidronate infusion in the outpatient lab; however, 
some flexibility in timing is permitted and it will not be considered a deviation 
if testing is done within 7 days post-infusion.  A morning collection is preferred, 
but not mandatory.  The time of the urine collection must be recorded.  If done 
at an outside lab, the institutional study coordinator will oversee the necessary 
arrangements for testing and receipt of the results. 
7.4.2 Treatment Plan Modification for Elevated Serum Creatinine  
If at the time of a planned pamidronate infusion, the patient’s serum creatinine 
level is >2 times that of the baseline level (done at Study Enrollment or 
Study Entry), pamidronate will be held.   
If the creatinine level decreases to ≤ 2 times the baseline level within 2 weeks, 
the pamidronate may be given as planned.  
If it remains elevated for more than 2 weeks, the subject will skip the 
scheduled dose of pamidronate.  If at the time of the next pamidronate dose (if 
applicable) the subject’s creatinine level has not returned to <2 times that of 
the baseline value pamidronate will be permanently discontinued, but the 
subject will continue vitamin D and calcium supplementation. 

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7.4.3 Expected Toxicities  
The most common side effects in adults receiving pamidronate are 
hypertension, 
injection 
site 
reaction, 
hypocalcemia, 
hypokalemia, 
hypomagnesemia, hypophosphatemia, loss of appetite, nausea, vomiting, 
anemia, urinary tract infectious disease, cough, dyspnea, fatigue, and malaise. 
Other serious adverse effects that have been observed in adults are arthralgia, 
aseptic necrosis of bone of jaw, bone pain, myalgia, seizure, deteriorating renal 
function, focal segmental glomerulosclerosis, and nephrotoxicity. 
 
In studies of pamidronate in children, hypocalcemia is also a common side 
effect. Brief acute phase reactions, including fever, headache, nausea, vomiting, 
rash, tachycardia, myalgia, and bone pain have also been noted on first exposure 
in pediatric patients. Uncommon side effects are nephrotoxicity, anterior 
uveitis, and atrial fibrillation. Due to these possible side effects, subjects will 
have laboratory evaluations performed to monitor for hypocalcemia or 
nephrotoxicity. Furthermore, any safety issue that might arise will be quickly 
recognized and treated as these subjects will be undergoing intensive 
monitoring following HCT. 
 
Potential long-term side effects are radiographic metaphyseal bands, iatrogenic 
osteopetrosis, fractures after discontinuation of drug in growing children, 
delayed healing at osteotomy sites, esophageal cancer, and osteonecrosis of the 
jaw.   
 
Long-term side effects are unlikely after a short-term treatment with 
pamidronate in patients without an underlying metabolic bone disease.  There 
have been no reports of either esophageal cancer or osteonecrosis of the jaw 
in children after treatment with pamidronate. 
 
Refer to the prescribing information for additional information. 
7.4.4 Management of Treatment Related Side Effects 
The research staff will monitor, as well as educate the subject and care 
providers, on early signs of potentially serious side effects.  At each visit 
beginning at Day 90 post-HCT an assessment for adverse events will be 
completed per section 9.2. 
Included are the following known risks of pamidronate: 
1. 
Allergic reaction most commonly appearing as skin rash with or without 
itching 
2. 
Anterior uveitis by subject’s report (blurred vision, eye pain, redness, 

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CPRC# 2013LS023 
sensitivity to light, irregular pupil) 
3. 
Atrial fibrillation by the subject’s report (palpitations, chest pain, shortness 
of breath) 
4. 
Osteonecrosis of the jaw by subject’s report (jaw pain, swelling, redness, 
or other signs of infection in the gums, gums or sockets that don't heal after 
dental work, numbness or a heavy feeling in the jaw, draining of pus, 
visible bone in the mouth, roughness of the gums in a particular area) 
and/or physical examination at study visits 
 
Medical confirmation of diagnosis and appropriate intervention including, if 
indicated, referral to a specialist for further care, would be performed. 
 
In the case of CTCAE grade 4 toxicity, no further pamidronate would be given 
per section 7.3.6. 
7.4.5 Pregnancy Testing and Contraception Use 
Since pamidronate is in the category D pregnancy risk group, a pregnancy test 
will be done within 72 hours prior to each dose and no further pamidronate will 
be given in the event of a positive result.  Refer to section 9.3 regarding the 
reporting of pregnancy during study treatment.  Post-menarchal subjects 
randomized to pamidronate will be put on an oral contraceptive pill (Loestrin 
or Orthocept or other OCP that contains 30 mcg ethinyl estradiol) or a birth 
control patch (e.g. Ortho Evra) or other effective means of birth control. 
7.4.6 Criteria for Discontinuation 
Subjects receiving pamidronate will discontinue pamidronate if any of the 
following conditions exist: 
• Clinically significant allergic reaction (tongue or facial swelling or 
wheezing) to pamidronate  
• Subsequently meets any of the study exclusion criteria (section 5.2) except 
for clinically significant current fracture, in which case pamidronate will be 
continued 
• If creatinine level increases to > 2 times baseline level and a dose of 
pamidronate must be skipped for a 2nd time per section 7.3.2. 
• Unacceptable toxicity (e.g. osteonecrosis of the jaw) 
• Positive pregnancy test - Refer to section 9.3 regarding the reporting of 
pregnancy during study treatment. 
• Disease relapse 
• Subject’s well-being, in the opinion of the Investigator, would be 
compromised by continuation of pamidronate administration. 
 

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These subjects will continue to be enrolled in the study, receiving vitamin 
D/calcium and participating in study procedures as planned unless 
contraindicated.  An exception to this plan is for those patients who have a 
worsening of their disease (relapse) and discontinue routine post-HCT follow-
up at the enrolling institution.  In this situation, patients would be taken off 
study with no further study procedures. 
Subjects who discontinue pamidronate treatment after the first dose (Day 90) 
will be included in the statistical analyses as members of the Pamidronate 
Group under the principle of intention-to-treat. 
 
7.5 
Expected Risks of Study Related Procedures 
The risks of venipuncture are transient pain, bleeding, lightheadedness, 
bruising, possible vasovagal reaction, and infection. Only trained certified nursing 
assistants, nurses, nurse practitioners, or physicians will be allowed to perform 
venipuncture to minimize the risk of complication. 
 
The DXA and pQCT scans will expose the subject to ionizing radiation. The 
level of exposure for this study will be approximately 3.4 millirem which is 
approximately 1% of that received from natural sources of radiation by a 
northern US resident in 1 year. Trained staff will perform the scans to minimize 
the risk of additional exposure. Children unable to sit still through the procedure 
may be given the option of mild sedation. The minor side effects of sedation include 
nausea, vomiting, mild allergic reactions, headache and dizziness. 
 
The risks of completing the questionnaires may include feelings of sadness due to 
inability to have an active lifestyle and/or good food intake.  Subjects and/or care 
providers will have the right to refuse to complete any questions that make them 
uncomfortable.  Subjects and/or care providers may also refuse to complete one or 
more of the questionnaires. 
 
7.6 
Prohibited Concomitant Therapy 
Prior and/or concomitant medical therapy with other bisphosphonates, 
Denosumab, or Teriparatide will not be permitted during the study.  
 
Treatment with an investigational agent will also be prohibited within t h e  4 
weeks prior to randomization (Day 90) and for the duration of the study (Day 90 
through Day 360). 
 
All other therapies are permitted. 
 

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7.7 
Duration of Study Therapy 
Refer to section 7.3.6 for regarding criteria for early discontinuation of 
pamidronate.   
 
All subjects will receive calcium and vitamin D supplementation per protocol 
through the Day 360 post-HCT visit unless one of the following occurs: 
• Subject voluntarily withdraws or their parent(s)/legal guardian(s) 
voluntarily withdraws them from the study 
• Subject is not eligible for randomization at the Day 90 visit 
• Subject requires treatment with a prohibited medical therapy per section 7.5 
• Pregnancy 
• Non-compliance 
• Subject’s well-being, in the opinion of the Investigator, would be 
compromised by continuation of pamidronate administration 
• Disease relapse occurs and post-HCT follow-up ends 
• The study ends early 
 
Note:  if a participant assigned to the Control Arm experiences a clinically 
significant fracture after Day 90, if medically appropriate, pamidronate treatment 
may be started (independent of the study and not covered by research funds).   The 
participant could remain on study with analysis within the original study 
assignment (control). 
 
Subjects discontinued from the study therapy but are considered evaluable for 
analysis (i.e. has been randomized and, if applicable has received at least 1 dose of 
pamidronate) will continue study participation per section 8 unless consent is 
withdrawn.   
 
If a subject withdraws after an adverse event (AE), they will be followed until 
resolution of the issue or until their condition is stable.   
 
In the event that a subject becomes pregnant, discontinuation, reporting, and 
follow-up procedures outlined in Section 9.3 will be followed. 
 
7.8 
Duration of Study Participation 
Study participation will end at the Day 360 post-HCT visit (1 year post-HCT) 
unless the subject voluntarily withdraws or their parent(s)/legal guardian(s) 
voluntarily withdraws them from the study or disease relapse occurs and patient 
discontinues the planned post-HCT follow-up.  
 

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If a subject or their parent(s)/legal guardian(s) withdraws consent to participate in 
the study or care is no longer provided by the enrolling institution, attempts will be 
made to obtain survival data through 1 year post-HCT.  
 
 

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8 
Study Related Tests and Procedures  
8.1 
Schedule of Tests and Procedures 
Screena 
 
Study 
Entryb  
Day 
0 
Day 
7 
(±2) 
Day 
14 
(+ 2) 
Day 
21 
(±2) 
Day 
90 
(±14) 
Day 
180 
(±14) 
Day 
270 
(±30)  
Day 
360 
(±30) 
Informed Consent / Assent 
X   or     X 
 
 
 
 
 
 
 
 
Physical Examination 
Xc   or     Xc  
 
 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
X 
Medical History 
X   or     X  
 
 
 
 
X 
X 
X 
X 
Medication Usage 
X   or     X 
 
 
 
X 
X 
X 
X 
X 
Creatinine 
X   or     X 
 
 
 
 
X 
X 
X 
 
Urine or serum Pregnancy 
Testd,e 
X   or     X 
 
 
 
 
X 
Xl 
Xl 
X 
Diet & Activity 
Questionnaire 
 
X 
 
 
 
 
X 
X 
X 
X 
Adverse Event Assessment 
 
 
 
 
 
 
X 
X 
X 
X 
Ionized/ or corrected 
Calcium 
X   or     X 
 
 
 
 
Xf 
Xf 
Xf 
 
Vitamin D (D2+D3) 
X   or     X 
 
 
 
 
Xg 
X 
X 
X 
iPTH 
 
X 
 
 
 
 
X 
 
 
X 
CTX, P1NP, & OCN 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Urinary DPD and 
Creatinine 
 
X 
 
X 
X 
X 
X 
X 
 
X 
RANKL & OPG 
 
X 
 
X 
X 
X 
X 
 
 
 
IL-6, IL-7, & TNF-α 
 
X 
 
X 
X 
X 
X 
 
 
 
DXAh 
 
X 
 
 
 
 
X 
 
 
X 
pQCTi 
 
 
 
 
 
 
X 
 
 
X 
HCT 
 
X 
Vitamin D & Calcium 
Administrationj 
X ----------------------------------------------------------------------------------------- X 
Randomization – refer to 
section  6.2 
 
 
 
 
 
 
X  
 
 
Pamidronate 
Administrationk 
 
 
 
 
 
 
X 
X 
X 
End of  infusion (same 
day) serum calcium  
 
 
 
 
 
 
Xl 
Xl 
Xl 
Post infusion (next a.m.) m 
serum creatinine and spot 
urine for albumin and 
creatinine 
 
 
 
 
 
 
Xl 
Xl 
Xl 
Adverse event assessment 
by telephone 1 week post 
infusion (+/-3 days) 
 
 
 
 
 
 
Xl 
Xl 
Xl 
CTX = carboxy-terminal collagen crosslinks; DXA = dual-energy x-ray absorptiometry; DPD = deoxypyridinoline; HCT = 
hematopoietic cell transplantation; IL = interleukin; iPTH = intact parathyroid hormone; OCN = osteoclacin; OPG = 

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osteoprotegerin; P1NP = procollagen type 1 amino-terminal propeptide; pQCT = peripheral quantitative computed tomography; 
RANKL = receptor activator of nuclear factor-κ B ligand; TNF-α = tumor necrosis factor alpha. 
a Screening will occur during the pre-HCT work-up. 
b Evaluations and tests only in the Study entry column are performed only after consent is signed and must be completed within 
4 weeks (6 weeks for DEXA) prior to beginning pre-HCT conditioning regimen. If DEXA cannot be completed prior to 
conditioning, this will not be considered a protocol deviation 
c Including Tanner staging of pubertal development. 
d Females >10 years only. 
e If documentation of a negative pregnancy test within 7 days prior to DXA scan is available, the pregnancy test does not need to 
be repeated. 
f If result is below the lower limit of normal refer to section 7.2 and 7.3. 
g Subjects who have vitamin D levels (D2+D3) <20 ng/ml at Day 90 will not be eligible for randomization per section per section 
6.2. 
h L1-L4 and total body scans with body composition. 
i Subjects at the University of Minnesota (UMN) only. 
j  All subjects will begin taking supplemental vitamin D per day and calcium, if needed, to meet recommended dietary 
allowance (RDA) requirement upon admission to the hospital for the HCT and continue through Day 360. If a subject has 
low vitamin D (D2+D3), dietary calcium intake is below RDA, or the ionized/or corrected calcium level is below the 
normal range, additional vitamin D and/or calcium supplementation will be given per Section 7.3. 
k  For subjects randomized to the Pamidronate Group, 1 mg/kg (60 mg max) will be administered via intravenous (IV) 
infusion over 4 hours. Subjects will be given 15 mg/kg acetaminophen (or maximum of 500 mg) prior to infusion then every 
4 hours as needed for a maximum of 24 hours.  Postmenarchal subjects randomized to pamidronate will be put on an oral 
contraceptive pill (Loestrin or Orthocept or other OCP that contains 30 mcg ethinyl estradiol), birth control patch or other 
effective method of birth control.  The results of the serum creatinine and pregnancy test (if applicable) must be reviewed before 
drug administration. 
l Pamidronate patients only  
m Serum creatinine level and spot urine collected the morning after each pamidronate infusion; however if not feasible at that 
time may be done anytime within 7 days after pamidronate infusion.  A morning collection is preferred, but not mandatory.  
The time of the urine collection must be recorded. 
 
8.1.1 Study Protocol Compliance/Treatment Adherence 
All doses of pamidronate will be administered at the clinical site. 
 
For all subjects, adherence to the calcium and vitamin D regimen described in 
Section 7 will be evaluated by querying subjects every 3 months either at study 
visits or by telephone. 
8.1.2 Deviations from the Clinical Protocol 
When a deviation from the protocol is necessary for an individual subject, the 
Investigator must contact the Sponsor prior to the deviation (unless the deviation 
is safety related).  The subject may continue in the study by mutual agreement of 
the Sponsor and the Investigator.  A description of the deviation from the protocol 
and justification must be recorded on the Protocol Deviation Form. 
8.1.3 Subject Compensation Guidelines 
A$50 gift card will be given to each participant at study enrollment and at the Day 
90 and 360 visits to partially compensate for the extra time required for study 
related tests and procedures on days of routine transplant associated visits. 

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Travel reimbursement (gas, parking, meals) will be offered at Day 270 study visit 
as it does not coincide with an institution’s standard post-HCT follow-up.   
Reimbursement (lodging, meals) will be offered to patients assigned to 
pamidronate at Day 180 and 270 visits for an overnight stay and meals in order to 
obtain the study related 24 hour post-infusion lab work.   
It is recognized that this is a multi-center trial and the reimbursement days may 
differ between institutions.  Therefore the above is a considered a guideline.  Each 
institution’s treatment consent will document the specific visits for their site which 
will be eligible for reimbursement.   
Reimbursements will be made following individual institutional usual practice. 
8.2 
Clinical Procedures 
8.2.1 Medical History 
A study physician and/or study coordinator will review the following with the 
subject/parent(s) or legal guardian(s): 
• Current and past prescription medications and doses (including calcium, vitamin 
D, oral contraceptives, estrogen or testosterone replacement, gonadotropin-
releasing hormone [GnRH] analogs, L-thyroxine, glucocorticoids, and growth 
hormone), 
• current and past medical history (with particular attention to fracture history, 
age at menarche, date of the last menstrual period, history of delayed puberty, 
and chronic inflammatory diseases), and 
• family history 
 
The subject’s medical history will be reviewed at each study visit. This will 
include medical chart review and query of the subject and parent(s) or legal 
guardian(s) (as applicable) regarding any changes since the last study visit. 
 
Pre-transplant treatment exposure data will be abstracted from the subject’s 
medical records, including pre-transplant chemotherapy (agent and total 
cumulative doses, including glucocorticoids) and radiation therapy (sites and total 
cumulative doses with particular attention to cranial radiation). Transplant 
treatment exposure data is maintained in the electronic database of the Blood and 
Marrow Transplant programs at both sites and includes specific chemotherapy 
agents utilized in the transplant preparative regimen, dose of TBI (if given), and 
prophylaxis and/or treatment (glucocorticoids) for graft- versus-host disease 
(GVHD). 
 
If a subject assigned the control arm is unwilling to return to the clinical site 

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for any visits not associated with a routine post-HCT follow-up, the subject or their 
parent(s)/legal guardian(s) will be contacted via telephone to discuss any changes 
in health since their last study visit. 
8.2.2 Laboratory Evaluations 
At the time points described in Section 8.1, blood will be collected for analysis 
of creatinine, ionized or corrected calcium, Vitamin D (D2+D3), iPTH, CTX, 
P1NP, OCN, RANKL, OPG, IL-6, IL-7, and TNF-α.  Urine will also be collected 
for analysis of DPD, creatinine, and albumin. Analysis will be performed as 
described in Section 8.3. 
For female patients > 10 years of age, a urine or serum pregnancy test will be 
performed at Screening and within 72 hours before administration of each dose 
of pamidronate for subjects randomized to the Pamidronate Group. 
 
8.2.3 Medical Examination and Anthropometrics 
A physical examination will be performed by a trained pediatric provider at study 
screen/entry and at the day 360 visit per section 8.1.  Height will be 
recorded at study entry and on day 360.  Weight will be recorded at 
study screening/entry and on days 90, 180, 270and 360.  Tanner 
staging of pubertal development, including breast and pubic hair development in 
girls (52), and pubic hair development in boys (53) will be performed at each 
physical exam.  Height will be measured standing without shoes with a wall-
mounted stadiometer.  Weight will be measured with subject in light clothing 
or dressing gown with shoes removed.  These measurements will be used to 
calculate BMI as weight (kg) divided by height (m
2
). 
 
8.2.4 DXA and pQCT 
Subjects will have DXA scans of L1-L4 and total body with body composition 
performed at the time points specified in Section 8.1 to compare BMC and body 
composition before and after study treatment.  For the DXA scan, at least 2 
vertebrae are required (i.e. L3-L4) and the same 2 vertebrae must be included on 
all follow-up exams. 
 
If results from the DXA image suggest a compression fracture, the study PI or 
coordinator will confirm that the participant’s primary care team knows of the 
results and appropriate follow-up (i.e. lumbar spine x-ray) is done.  Note that there 
is no need to repeat an x-ray if (1) one was performed within the previous 12 months 
for the evaluation of the same vertebra with the highest BMD Z-score, and (2) was 
negative for fracture. 
 
For subjects enrolled at the UMN, pQCT of the left tibia and non-dominant radius 

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will also be performed at the time points specified in Section 8.1. 
 
8.2.5 Diet and Activity Questionnaire 
A food frequency questionnaire (FFQ) to determine dietary calcium intake 
(Appendix II) and a physical activity questionnaire (Appendix III) will be 
completed by the subjects or their parent(s)/legal guardian(s) at the time points 
described in section 8.1.  
If a subject is unable to return to the clinical site for Day 180 and/or Day 270 
study visits, the study coordinator will send the questionnaires to the 
participant and/or parent/guardian with the intent to complete them via 
telephone at a pre-arranged time. 
8.2.6 Unscheduled Visits 
Additional visits will be scheduled as needed throughout the study period to 
address concerning signs or symptoms reported by subjects. 
 
8.3 
Laboratory Testing Procedures 
During the study, creatinine, total calcium, Vitamin D (D2+D3), and intact 
parathyroid hormone (iPTH) will be analyzed to monitor subject safety. 
 
Additionally, levels of markers of bone formation (OCN and P1NP) and 
resorption (CTX and DPD), cytokines (IL-6, IL-7, and TNF-α), RANKL, and OPG 
will be analyzed in batches or at the end of the study. 
 
8.3.1 Laboratory Testing Procedures 
Specimens for analysis of safety parameters, markers of bone turnover, 
cytokines, RANKL, and OPG will be collected as described in Table below at the 
time points indicated in section 8.1. Venipuncture or blood collection from a 
venous catheter (if the patient has one in place) will be performed by trained 
certified nursing assistants, nurses, nurse practitioners, or physicians and 
collection tubes will be handled per the manufacturer’s recommendations. 
 
Laboratory Analytes and Collection Information 
Analyte 
Matrix 
Tube Type 
Volume 
Carboxy terminal collagen crosslinks 
(CTX)a 
Plasma 
K2EDTA (di-potassium 
ethylenediaminetetraacetic 
acid; purple-top tube) 
3 mL blood (minimum 
700 µl plasma) 
Procollagen type 1 amino terminal 
propeptide (P1NP)a 
Plasma 
K2EDTA (purple-top tube) 
Osteoclacin (OCN)a 
Plasma 
K2EDTA (purple-top tube) 
Receptor activator of nuclear factor-κ B 
ligand (RANKL)a 
Plasma 
K2EDTA (purple-top tube) 
Osteoprogerin (OPG)a 
Plasma 
K2EDTA (purple-top tube) 

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Analyte 
Matrix 
Tube Type 
Volume 
Interleukin (IL)-6b 
Plasma 
K2EDTA (purple-top tube) 
3 mL blood (minimum 
700 µl plasma) 
IL-7b 
Plasma 
K2EDTA (purple-top tube) 
Tumor necrosis factor alpha 
(TNF-α)b 
Plasma 
K2EDTA (purple-top tube) 
Intact parathyroid hormone (iPTH) 
Plasma 
K2EDTA (purple-top tube) 
1 mL blood (minimum 
300 µl plasma) 
Urinary deoxypyridinoline (DPD)d 
Urine 
Urine specimen container 
1 mL 
Urine Creatinined 
Urine 
Urine specimen container 
a Single sample for CTX, P1NP, OCN, RANKL, and OPG analysis collected in the same tube. 
b Single sample for IL-6, IL-7, and TNF-α analysis collected in the same tube. 
c Single sample for total calcium, vitamin D (D2+D3), and creatinine analysis collected in the same tube. 
d Single sample for DPD and creatinine collected in the same container. 
 
8.3.2 Specimen Processing and Storage 
Research samples collected for the purpose of this study will be processed and 
stored frozen until the time of batch testing at the University of Minnesota, unless 
otherwise specified below. Upon completion of batch testing and verification of 
results at the University of Minnesota, any remaining samples will destroyed. 
 
Vitamin D (D2+D3), Total Calcium, and Creatinine: 
This testing will be done by the institutional lab with the results recorded in OnCore 
for the purposes of this study.  Vitamin D will be measured by mass spectrometry. 
 
PTH, intact  
This testing will be done by the institutional lab with the results recorded in OnCore 
for the purposes of this study.  
 
Plasma samples (CTX, P1NP, OCN, RANKL, OPG, IL-6, IL-7, and TNF-α): 
Collect blood in 2 purple-top (ethylenediaminetetraacetic acid [EDTA]) tubes (3 
mL each).   
 
Refer to the Affiliate Lab Manual for sample processing and storage instructions.  
 
Urine sample for DPD and Urine Creatinine: 
Collect at least 1 mL of urine in a preservative-free urine specimen container.  
A morning collection is preferred, but not mandatory.  The time of the urine 
collection must be recorded.  Collect urine mid-stream, voided directly into a sterile 
container (if possible).  Avoid prolonged exposure to light, especially sunlight.  
During routine processing, samples are not affected by normal, artificial laboratory 
lighting. 
 
Refer to the Affiliate Lab Manual for sample processing and storage instructions.  
 

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End of Pamidronate Infusion Serum Calcium: 
A serum calcium level will be done after the pamidronate infusion end and prior to 
discharge from clinic on the day of the pamidronate per section 7.3.1. 
 
Post Pamidronate Spot Urine for Albumin and Creatinine and Serum 
Creatinine: 
Ideally the morning after each pamidronate infusion, the participant will return to 
the study center for a routine serum creatinine and a spot urine for albumin and 
creatinine to calculate albumin to creatinine ratio.  A morning collection is 
preferred, but not mandatory.  The time of the urine collection must be recorded.  
The samples will be processed in the site’s clinical laboratory but charged to 
research. 
 
If the participant is unable or unwilling to return to the study center the morning 
after the pamidronate infusion, the samples may be collected within 7 days after the 
infusion.  A morning collection is preferred, but not mandatory.  The time of the 
urine collection must be recorded.  Arrangements for the testing will be done on a 
per patient basis (i.e. at the study center on a different day or at an outside facility). 
 
8.3.3 Specimen Processing and Storage - University of Minnesota 
Fairview Acute Care Lab will process and store frozen (within 30-60 minutes of 
processing) per the study lab slips all research samples until the time of batch 
transfer to the Cytokine Lab (Dr. Angela Panoskaltsis-Mortari) for analysis. 
8.3.4 Specimen Shipping – Fred Hutchinson Cancer Research Center 
Samples collected at Fred Hutchinson Cancer Research Center will be processed 
at a local laboratory as detailed in the affiliate manual, then frozen in 
aliquots for CTX, P1NP, OCN, RANKL, OPG, IL-6, IL-7, TNF-α, and urinary 
DPD and creatinine and stored at frozen until the time of batch shipping to the 
UMN.  
 
The samples are to be shipped Monday through Thursday only on dry ice in a 
Styrofoam container inside a cardboard sleeve. Send the samples via FedEx Priority 
Overnight to the address below: 
Angela Panoskaltsis-Mortari Laboratory 
Cytokine Lab  
13-127 PWB 
516 Delaware St. SE 
Minneapolis, MN 55455  
Phone: 612-626-7057 

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8.3.5 Laboratory Testing: Normal Values 
Reference ranges for standard analytes are presented in section 8.3.1. 
 
Laboratory Reference Ranges 
 
University of Minnesota (UMN) 
Fred Hutchinson Cancer 
0-21d  
0.33-1.01 
2 months-2 years 
 
 
0.1-0.4 
Creatinine (mg/dL) 
22 days-8 years 
0.15-0.53 
9-14 years 
0.39-0.73 
2-10 years 
0.1-0.6 
15-19y 
0.5-1.0 
10-14 years 
0.2-0.9 
20 y and older, F 
0.52-1.04 
≥14 years 
0.2-1.1 
20 y and older, M 0.66-1.25 
 Calcium (“corrected calcium”?) 
 Age 
mg/dL 
8.7-10.7 
0-11 mo 
8.5-10.7 
1-18 yr 
9.1-10.3 
19 yr & older 
8.5-10.1 
Ionized Calcium 
Age 
mg/dL 
 
0-11 mo 
5.1-6.3 
1 yr and older 
4.4-5.2 
Vit D (D2 + D3) / 25-hydroxy 
(OH) vitamin D (ng/mL) 
20-75 
30-100 
Intact parathyroid hormone (iPTH) 
(pg/mL) 
12-72pg/mL 
12-75 
Interleukin (IL)-6 (pg/mL) 
<3.0 
<3.0 
IL-7 (pg/mL) 
0.66-9.2 
0.66-9.2 
Tumor necrosis factor alpha (TNF-
α) (pg/mL) 
<8.8 
<8.8 
a IL-6, Il-7, and TNF-α samples from Fred Hutchinson Cancer Research Center will be analyzed at UMN. 
 
Laboratory normal ranges for CTX, DPD, P1NP, OCN, RANKL, and OPG vary 
with age. Urinary DPD will be adjusted for urinary creatinine content. 
 
If total calcium or vitamin D (D2+D3)/25-OH vitamin D is below the normal range, 
supplementation will be administered per Section 7.3. 
 
If creatinine level for a subject randomized to receive pamidronate becomes 
elevated during the study (creatinine level >2 times the baseline value at Study 
Entry) refer to section 7.3.2 for treatment modification and monitoring. 
 

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9 
Event Monitoring, Documentation and Reporting 
Toxicity and adverse events will be classified according to NCI's Common Terminology 
Criteria for Adverse Events V 4.0 (CTCAE).  A copy of the CTCAE can be downloaded 
from the CTEP home page 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40  
 
9.1 
Definitions 
The following definitions are based on the Code of Federal Regulations Title 21 
Part 312.32 (21CFR312.32(a)). 
Adverse Event:  Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  
Suspected Adverse Reaction:  Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  
Treatment-Emergent Adverse Event:  Any event not present prior to the 
initiation of the treatment or any event already present that worsens in either 
intensity or frequency following exposure to the treatment.  A treatment emergent 
AE refers to an event temporally related to the study treatment regardless of the 
causality assessment by the investigator. 
Life-Threatening Adverse Event Or Life-Threatening Suspected Adverse 
Reaction: An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the investigator or sponsor, its occurrence 
places the patient or subject at immediate risk of death. 
Serious Adverse Event Or Serious Suspected Adverse Reaction:  An adverse 
event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  

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If either the IND sponsor or the investigator believes the event is life-threatening 
or serious, the event must be evaluated by the sponsor for expedited reporting 
(21CRF 312.32(a)).  
Event Attribution Categories: 
CTCAE does not define an AE as necessarily ‘caused by a therapeutic intervention.  
The clinical investigator must assign attribution for an adverse event after naming 
and grading of the event. 
Attribution 
Description 
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention   
 
Unexpected adverse event or unexpected suspected adverse reaction: An 
adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that 
has been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended.  Thus, adverse events that occur 
as part of the transplant or underlying disease are considered unexpected; however, 
they will not be reportable per section 9.4. 
Expedited (Rapid) Reporting: Certain events may require rapid notification to 
entities providing patient safety oversight (e.g. IRB, FDA) as detailed in section 
9.4. 
9.2 
Documentation of Adverse Events 
The goal of AE monitoring will be to focus on events that are related directly to 
study participation, not the transplant procedure or the disease under treatment 
unless study participation exacerbates the event.  Due to the complex medical 
condition of the post-transplant patient, monitoring for adverse events will focus on 
events beginning with the 1st dose of pamidronate through the Day 360 visit. 
 
For patients assigned to pamidronate, a toxicity assessment will be done in 
conjunction with each infusion (Day 90, 180, and 270) at the following time points:  
• Prior to the pamidronate infusion - within 72 hours before the infusion 
• 1 week (+/- 3 days) after each pamidronate infusion via telephone interview 
• At any unplanned visit 
 

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At each of these time points the worst grade of the targeted toxicity since the 
previous assessment will be recorded in addition to any unexpected toxicities felt 
at least possibly related to pamidronate. 
 
Of special concern are rare, but potentially serious risks associated with 
pamidronate which, if serious enough will lead to the discontinuation of the study 
drug per section 12.5.  These targeted toxicities (based on CTCAE v4) will be 
collected on all patients (control and pamidronate) are: 
• Anterior uveitis by subject’s report (blurred vision, eye pain, redness, 
sensitivity to light, irregular pupil) 
• Atrial fibrillation by the subject’s report (palpitations, chest pain, shortness 
of breath) 
• Osteonecrosis of the jaw by subject’s report (jaw pain, swelling, redness, or 
other signs of infection in the gums, gums or sockets that don't heal after 
dental work, numbness or a heavy feeling in the jaw, draining of pus, visible 
bone in the mouth, roughness of the gums in a particular area) and/or 
physical examination at study visits. 
All targeted toxicities, regardless of grade, and other events, grade 3 or greater that 
are felt at least possibly related to study treatment or cannot be explained by another 
cause (i.e. unexpected, not related to transplant, disease for which the transplant 
was done, underlying medical condition, etc.) will be recorded in OnCore for all 
patients.  
 
After completion of the targeted toxicity form at day 360 formal collection of 
adverse events ends; however the sponsor/investigator must report upon knowledge 
any treatment related event meeting the expedited reporting criteria found in section 
9.1 regardless of timing to pamidronate. 
 
From signing of consent through the Day 360 visit any unexpected adverse event 
that is felt to be at least possibly related to the vitamin D and calcium and/or study 
procedures (research specimen collection, DXA) will be recorded in the study’s 
case report forms. 
 
9.3 
Documentation of Pregnancy 
If a female subject becomes pregnant during the study, she will be withdrawn 
from the study, the reason recorded in OnCore, and the study Sponsor/Investigator 
(Dr. Sarafoglou) notified.  The pregnancy will be reported to the IRB according to 
local institutional reporting guidelines. 
 

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Though the subject will be withdrawn from the study, permission to record 
survival data for the mother to the end of the pregnancy and of the baby at birth will 
be requested 
9.4 
Required Reporting of Fred Hutchinson Cancer Research Center to UMN 
(IND Sponsor) 
Events during the study period meeting the definition of serious, regardless of 
attribution or expectedness must be reported within 24 hours of knowledge to the 
University of Minnesota Study Coordinator. 
Any event meeting the definition of an early study stopping event per section 12.5 
must be reported within 24 hours of knowledge to the University of Minnesota 
Study Coordinator. 
The UMN Study Coordinator will facilitate reporting to the University Of 
Minnesota IRB, Masonic Cancer Center, and the FDA as required. 
University of Minnesota (contact information on page 5) with follow-up reporting 
to MCC Study Coordinator using the Event Report found in OnCore. 
In addition, Fred Hutchinson Cancer Research Center will be responsible for 
submitting reportable events to their institutional IRB and any other required local 
regulatory entities. 
 
 

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9.5 
UMN Required Reporting: FDA, IRB, and MCC’s SAE Coordinator 
 
 
In each IND safety report, the sponsor must identify all IND safety reports 
previously submitted to the FDA concerning a similar suspected adverse reaction 
and must analyze the significance of the suspected adverse reaction in light of the 
previous, similar reports. 
 
The SAE Coordinator will provide the Cancer Center’s Data and Safety Monitoring 
Council (DSMC) with the SAE in an appropriate format depending on the 
individual SAE (as reported or in a summary format). 
 
 
Agency 
Criteria for reporting 
Timeframe 
Form to Use 
Submission 
address/ fax 
numbers 
Copy to: 
UMN IRB 
Events requiring prompt reporting including, 
but not limited to unanticipated death of a 
locally enrolled subject(s); new or increased 
risk; any adverse event  that require a change to 
the protocol or consent form or any protocol 
deviation that resulting in harm  
refer to 
http://www.research.umn.edu/irb/guidance/ae.h
tml#.VC7xraI0-sh  
Within 5 business 
days of event 
discovery 
 
Report Form 
irb@umn.edu 
 
MCC SAE 
Coordinator 
mcc-
saes@umn.edu  
FDA 
Unexpected and fatal or life threatening 
suspected adverse reaction 
As soon as 
possible but no 
later than 7 
Calendar-Day 
FDA prefers 
MedWatch 
3500a Form 
however use of 
the UMCC 
SAE form is 
acceptable 
Submit as an 
amendment to 
IND 
 
With copy to 
the affiliate PI 
 
1) Serious and unexpected suspected adverse 
reaction or 2) increased occurrence of serious 
suspected adverse reactions over that listed in 
the protocol or investigator brochure or 3) 
findings from other sources (other studies, 
animal or in vitro testing) 
 
As soon as 
possible but no 
later than 15 
Calendar-Day 
Note:  Events due to the disease under treatment or the transplant will not require expedited reporting to the FDA for 
the purposes of this study 
MCC SAE 
Coordinator 
 
Stopping Rule Event – any grade 4 or 5 study-
related toxicity in the pamidronate group or 
in either group (pamidronate or control) 
grade 3 or higher of the following selected 
toxicities:  uveitis, atrial fibrillation or 
osteonecrosis of the jaw (ONJ)  
at time of form 
completion 
Event Form 
mcc-
saes@umn.edu 
n/a 

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10 
Study Status Updates, Data Collection and Monitoring 
10.1 
Study Status Updates 
During the trial’s period of active enrollment a weekly summary report will be 
generated from OnCore by the University of Minnesota summarizing enrollment 
and toxicity activity to date, as well as, any relevant clinical information.  Sites will 
be expected to keep OnCore current to meet the demands of this real time summary 
reporting. 
In addition, at least monthly teleconferences will be initially held between the PI 
(Dr. Sarafoglou), UMN study personnel, and key representatives of the affiliate site 
to discuss enrollment, treatment tolerability and toxicity, sample collection, as well 
as other relevant issues.  Depending on the speed of enrollment and the level of 
patient issues, these teleconferences may be held more frequently or cancelled if 
there are no issues to discuss. 
10.2 
Data Management 
This study will report clinical data using The Online Enterprise Research 
Management Environment (OnCoreTM), a web based Oracle® database utilizing 
study specific electronic case report forms.  Key study personnel are trained on the 
use of OnCore and will comply with protocol specific instructions embedded within 
the OnCore forms.  Patient demographics, patient specific study treatment 
calendars, adverse events, reporting of deaths, and other information required for 
IND annual reporting will be placed in OnCore and other research databases 
maintained by MCC IT. 
Subject questionnaire recording will be  recorded in Oncore. 
10.3  Data Capture Methods 
All data will be collected at the site level by trained research study staff or site 
principal investigators using medical record documents, interviews, self-report 
instruments, lab reports, treatment strategies, and all related reports of outcome 
evaluations.  Data from records abstraction, interviews, and participant self-reports 
will be entered by the research coordinator or other trained study staff at each site 
first onto paper CRFs and then into a secure, password-protected online database 
(OnCore). Copies of these paper CRFs will be retained along with other source 
documents in a participant file. 
 
Participant data will be entered from the paper CRFs into  electronic case report 
forms (e-CRFs).  Both the paper and the e-CRFs will be approved by the study’s 

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Principal Investigator and the Biostatistician prior to release for use.  The Study 
Coordinator or designee will be responsible for registering the patient into OnCore 
at time of study entry, completing e-CRFs based on the patient specific calendar, 
and updating the patient record until patient death or end of required study 
participation.   
10.4 
Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan 
(DSMP), which can be accessed at http://z.umn.edu/dmsp . 
 
For the purposes of data and safety monitoring, this study is classified as high risk 
(under a locally held IND).  Therefore the following requirements will be fulfilled: 
 The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) will 
assess the study’s progress at least quarterly. 
 The S/I will comply with at least twice yearly monitoring of the project by the 
Masonic Cancer Center monitoring services. 
 The S/I will oversee the submission of all reportable events per the definition 
of reportable in section 9.4 to the Masonic Cancer Center’s SAE Coordinator, 
the University of Minnesota IRB, and the FDA.   
 
In addition, at the time of the continuing review with the University of Minnesota 
IRB, a copy of the report with any attachments will be submitted to the Cancer 
Protocol Review Committee (CPRC). 
 
IND Annual Reports 
In accordance with regulation 21 CFR § 312.33, the IND sponsor (Dr. Sarafoglou) 
will submit a progress report annually.  The report will be submitted within 60 days 
of the anniversary date that the IND went into effect.   
10.5 
Affiliate Site Monitoring 
The PI (Dr. Sarafoglou) with the CTO has oversight responsibility for trial 
monitoring at affiliate sites.  The affiliate site must self-monitor following the 
University of Minnesota Masonic Cancer Center Data and Safety Monitoring Plan 
(DSMP - http://z.umn.edu/dmsp) and the CTO Affiliate and Satellite Site 
Monitoring SOPs.   
The investigator will permit study-related monitoring, audits, and inspections by 
the study’s S/I and/or any designees, the local IRB, government regulatory bodies, 
and University of Minnesota compliance groups.  The investigator will make 
available all study related documents (e.g. source documents, regulatory 

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documents, data collection instruments, study data, etc.).  The investigator will 
ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.) will be available for trial related monitoring, 
audits, or regulatory inspections. 
10.6 
Record Retention 
The investigator will retain study records including source data, copies of case 
report forms, consent forms, HIPAA authorizations, and all study correspondence 
in a secured facility for at least 6 years after the study file is closed with the IRB 
and FDA.   
 
In addition, the Clinical Trials Office (CTO) will keep a master log of all patients 
participating in the study with sufficient information to allow retrieval of the 
medical records for that patient.  Please contact the CTO before destroying any 
study related records. 
11 
Endpoints 
11.1 
Primary Clinical Endpoint 
The primary endpoint is Lumbar BMC measured by DXA at 1 year after HCT 
(adjusted for height, age, sex, Tanner stage and race). 
11.2 
Secondary Clinical Endpoints 
Other endpoints are: 
• 
TBMC measured by DXA (adjusted for height, age, sex, Tanner stage and 
race). 
• 
Estimated bone strength, total BMD, cortical BMD, and trabecular BMD of 
the left tibia and non-dominant radius measured by pQCT. 
• 
Levels of markers of bone resorption (carboxy-terminal collagen crosslinks 
[CTX] and deoxypyridinoline [DPD]), and bone formation (procollagen type 
1 N-terminal propeptide [P1NP] and OCN) 
• 
RANKL, OPG, and RANKL/OPG ratio. 
• 
Levels of cytokines including interleukin (IL)-6, IL-7, and tumor necrosis 
factor-alpha (TNF-α). 
• 
Body composition: body mass index (BMI) percentile, lean body mass, and 
body fat mass (from DXA) adjusted for height. 
12 
Statistical Considerations 
12.1 
Sample Size  
Sixty (60) subjects total (30 each in the Control and Pamidronate groups) gives 80% 
power to detect a difference between groups of 0.75 standard deviations (SDs) 

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describing variation in LBMC within study group after adjusting for height, 
age, sex, Tanner score, and race. Adjusting for age and sex, this SD is 5-8g (46, 
47); adjusting further for race and height should reduce this SD by about half (48-
50). This gives a within-group SD of about 2.5-4g and a detectable difference of 
2-3g. To have 60 evaluable subjects, 192 need to be screened to allow for a 50% 
consent rate, 10% death rate by Day 90, 20% death rate between Day 90 and Day 
360, and 10% drop out after randomization. 
 
Anticipated Enrollment Over Duration of Study 
Screen 
Study 
Entry 
Day 
-14a 
Day 
7 
Day 
14 
Day 
21 
Day 
90 
Day 
180 
Day 
270 
Day 
360 
Total 
192 
96 
96 
96 
96 
86 
86 
86 
60 
University of 
Minnesota 
(UMN) 
96 
48 
48 
48 
48 
43 
43 
43 
30 
Fred Hutchinson 
Cancer Research 
Center 
96 
48 
48 
48 
48 
43 
43 
43 
30 
a Day 0 is the day of hematopoietic cell transplantation (HCT). 
 
According to data from 2011 to 2012, 36 allogeneic transplants have been 
performed at UMN and 37 have been performed at Fred Hutchinson Cancer 
Research Center. It is expected that screening 28 patients per year will be feasible 
for both sites. 
 
It anticipated that enrollment will take 3.5 years. 
12.2 
Subject Population(s) for Analysis 
All randomized subjects will be included in the primary analysis according to their 
randomized treatment assignment, consistent with the principle of intention-to-
treat. 
12.3 
Randomization Scheme 
The randomization will be stratified by age with 2 strata, < 10 years old and ≥ 10 
years old, with 2/3 of the planned enrollment in the < 10 stratum. These fractions 
roughly reflect the proportion of each age group in the target study population. 
This choice of age groups is also based on our recent data which patients <10 
years are more likely to be more severely affected (51). Each site's randomization 
schedule will use permuted blocks of lengths 2 and 4 within each stratum, so 
the study groups at a site never differ in sample size by more than 2 patients in 

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each stratum. The block lengths of 2 and 4 are alternated at random to make it 
harder 
to 
predict 
future 
treatment assignments. Randomized treatment 
assignments will be issued on Day 90 using a method that conceals the assignment 
until it is issued. 
12.4 
Statistical Methods 
The primary analysis will compare the Pamidronate and Control groups according 
to LBMC measured by DXA using all available Day 360 measurements and 
adjusting for height, age, sex, Tanner score, and race. The analysis will be a 
multiple linear regression; the primary predictor will be randomized treatment 
assignment and adjusters listed above. If preliminary analysis shows that LBMC 
measurements have a grossly non-Gaussian (non- normal) distribution, a 
transformation of LBMC will be analyzed, most likely log10 LBMC Secondary 
analyses will include the following: 
 
• The hypothesis that subjects randomized to pamidronate will have 
higher total BMD, cortical BMD, trabecular BMD, and estimated 
bone strength measured by pQCT at 1 year compared to subjects 
randomized to control (Aim 1 Hypothesis 2) will be tested by applying 
the foregoing analyses to outcomes measured by pQCT, namely bone 
strength, total BMD, cortical BMD, and trabecular BMD, but excluding 
height from the adjusters. 
 
• The hypothesis that cytokine levels will increase rapidly in the first 3 
weeks after HCT, preceding an increase in markers of bone resorption 
(Aim 2 Hypothesis 1) will be tested, for each cytokine, by using all 
available data for each child (up to 4 measurements from Day -14 to Day 
21) and fitting a mixed linear model with a random intercept and time 
trend for each child and testing whether the average time trend differs 
from zero. 
 
• The hypothesis that in the Control Group, increased cytokine levels and 
receptor activator of nuclear factor-κB  ligand/osteoprotegerin ratio at 3 
weeks will be associated with decreased BMC and BMD at 1 year after 
HCT (Aim 2 Hypothesis 2) will be tested using linear regressions with 
dependent variables being each of the BMC and BMD measures at 
Day 360 and predictors being changes in each of the cytokine levels and 
RANKL/OPG ratio (from Day -14 to Day 21). 
 
• For the hypothesis that markers of bone resorption will increase in the first 
3 months after HCT, will remain elevated until at least Day 180 in the 

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Control Group, but will decrease after initiation of pamidronate at Day 90 
(Aim 3 Hypothesis 1), the test of changes up to Day 90 will use the same 
type of analysis as for Aim 2 Hypothesis 1 but with up to 5 measurements 
(Day -14 to Day 90). Tests of changes after Day 90 will include all 
available data for each subject and use a mixed linear model to account 
for correlation of measurements within subject; changes over time will be 
tested separately in the Pamidronate and Control groups using contrasts 
and compared between groups by testing the interaction of group and 
measurement time (i.e., Day 180, Day 360). 
 
For the hypothesis that markers of bone formation, including 
osteocalcin (OCN) will decrease in the first three months and in the 
Control Group lower OCN levels at Day 90 will be associated with lower 
BMC and BMD 1 year post-HCT (Aim 3 Hypothesis 2), the test of 
change in OCN to Day 90 will use all available data and the same type 
of analysis as for Aim 2 Hypothesis 1; the test of change from Day 90 
to Day 360 will use control subjects only and simple linear regression 
with outcome each of the BMC and BMD measures at Day 360 and 
predictor OCN level at Day 90. 
 
For analyses of Aims 2 and 3 and Aim 1 hypothesis 2, further secondary analyses 
will use multiple imputation to impute missing measurements. Finally, 
exploratory analyses will explore risk factors for bone loss, including sex, BMI 
percentile, LBM adjusted for height, calcium and vitamin D intake, CNS 
radiation, TBI vs. no TBI in conditioning regimen, donor stem cell source (cord 
blood vs. other), physical activity, and glucocorticoid exposure for prophylaxis or 
treatment of GVHD. Subjects who experience a bone fracture after HCT will 
be excluded from analyses of bone turnover markers but otherwise will be 
included in all analyses. 
 
12.5 
Early Study Stopping Rule For Excessive Toxicity 
Any grade 4 or 5 study-related toxicity in pamidronate-treated participants will 
result in a pause in study randomization for a re-evaluation of the treatment plan. 
 
In addition to the foregoing, three toxicities will be monitored in participants in 
both the pamidronate and control groups:  uveitis, atrial fibrillation, and 
osteonecrosis of the jaw (ONJ) of grade 3 or higher (as these toxicities will be 
recorded only if they are of grade 3 or higher).  These toxicities will be monitored 
at interim analyses by comparing the two groups using a Lan-DeMets stopping rule 
with an O'Brien-Fleming alpha-spending function.  For this monitoring purpose, 

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the outcome for each participant will be the count of AEs of any of these three 
types, and the P-value for comparing the groups will be computed using a 
permutation test that permutes groups labels on participants, with test statistic the 
difference between groups in their average numbers of AEs.  Interim analyses will 
be performed every 6 months.   
13 
Ethical and Regulatory Considerations 
13.1 
Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory 
requirement(s).  Essential clinical documents will be maintained to demonstrate the 
validity of the study and the integrity of the data collected.  Master files should be 
established at the beginning of the study, maintained for the duration of the study 
and retained according to the appropriate regulations.   
13.2 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki.  The IRB will review all appropriate study documentation 
in order to safeguard the rights, safety and well-being of the patients.  The study 
will only be conducted at sites where IRB approval has been obtained.  The 
protocol, informed consent, written information given to the patients, safety 
updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB by the investigator.   
13.3 
Inclusion of Minorities  
There are no opportunities for any active recruitment or outreach efforts that may 
increase minority participation beyond that of the pool of transplant patients that is 
referred to us.  
  
The ethnic representation of the population within the catchment area in the states 
of Washington and Minnesota according to 2010 census is as follows:   
- American Indian/Alaska Native 1-2%  
- Asian 6-7% 
- Native Hawaiian or Other Pacific Islander 0.04%  
- Black or African American 4-8%  
- White 79-81%  
- More than one race 3-6%  
 
The ethnic representation of children who received transplant at both institutions 
over the last 2-6 years is as follows:   
- American Indian/Alaska Native 1-3%  

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- Asian 7-11%  
- Native Hawaiian or Other Pacific Islander 0-1.5%  
- Black or African American 1.5-9%  
- White 72-77%  
- more than one race 3-4%  
 
This study has no exclusions based on race or ethnicity and will be presented to 
every patient who is referred for HCT who meets the eligibility criteria. Our efforts 
will focus on making sure that potential study subjects who are in the minority 
groups are enrolled in the study. We do expect minority representation in the study 
as indicated in the enrollment table based on the ethnic distributions of patients 
referred to both transplant centers in Minnesota and Washington. We will employ 
the following specific efforts to make sure that every ethnic minority patient with a 
hematologic malignancy or severe aplastic anemia who is referred for HCT will be 
given an opportunity to participate in the study (as listed in the enrollment table, 
particularly 7 Asians and 6 African Americans): 
 
• At each transplant center the standard practice is that every patient who is referred 
for transplant is reviewed by a transplant coordinator for all open research studies 
that they would potentially be eligible for. Since a transplant coordinator is aware 
of all incoming patients, a transplant coordinator will then notify the study 
coordinator and a study PI (either myself or one of the study’s co-investigators) 
about the appointment time for a pre-HCT evaluation who will be on site at the time 
of the visit. The study will be reviewed with the patient/family by a nurse 
coordinator for general overview information and this is then followed up with a 
meeting led by an attending transplant physician and a study PI (either myself or 
one of the study’s co-investigators) where specific details of each study are 
presented, risks/benefits explained, and informed consent obtained.  
 
• Since each transplant program has access to culturally diverse healthcare 
interpreters, we will make sure that they are present at the time of the visit to 
assist in explaining the study and reviewing the consent forms for any non-
English speaking minority patients as well as those who speak English, but are 
not native English speakers.  To ensure a culturally sensitive approach in the 
recruitment of minority subjects who may have English as their first language, 
we will consult with or include in the consent meeting an impartial staff member 
(RN, advanced practice provider, social worker) of the same minority as the 
subject who would be able to facilitate verbal communication and interpretation 
of culturally sensitive issues even if language is not a barrier. We have 
confirmed that both institutions have staff members in the transplant programs 

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that represent at least individuals of African American, Hispanic and Asian 
descent.  
 
• Patients and/or their parents/guardians will be given the option of taking copies 
of the consent documents with them with a phone number for the interpreter, 
and the study coordinator who will contact the patient or parents/legal guardians 
within a few days to schedule a screening visit if they are interested in 
participating. 
 
• Fear and mistrust about clinical research is not uncommon, especially among 
minorities.  Study staff and nurses in the clinic will take care to spend time 
educating each potential participant about clinical research and the goals of this 
study.   
 
13.4 
Informed Consent 
All potential study participants will be given a copy of the IRB-approved consent 
to review. The investigator or designee will explain all aspects of the study in lay 
language and answer all questions regarding the study. If the participant 
(parents/guardians for minors with assent for minor 7 years and older) decides to 
participate in the study, he/she will be asked to sign and date the consent document. 
Patients who refuse to participate or who withdraw from the study will be treated 
without prejudice. 
 
13.5 
Protocol Amendments After Study Initiation 
Should changes in the study plan or protocol become necessary in the course of 
the clinical trial, those specific changes will be discussed and agreed upon by the 
Sponsor, Investigator, and appropriate IRB approval obtained before the changes 
are implemented. All changes must be documented as protocol amendments. As 
a study conducted under an Investigational New Drug (IND), FDA notification 
may be required in addition to the IRB approval. 
13.6 
Anticipated Duration of the Clinical Investigation 
Each subject will be enrolled in the study for approximately 1 year. It is 
expected that each of the study sites will screen 28 patients per year for 3.5 
years with the final subject completing study participation 4.5 years after study 
initiation. The final study report will be completed approximately 5 years after 
study initiation.  
 
If the study is terminated prior to completion, a closeout report will be filed with 
the Institutional Review Board (IRB) within 3 months of study termination. 

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14 
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2 
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Nysom K, Holm K, Michaelsen KF, Hertz H, Jacobsen N, Muller J, Molgaard C 2000 Bone mass 
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Appendix I – Eligibility Checklist 
Refer to the Eligibility Checklist Case Report Form (CRF) 
Appendix II – Food Frequency Questionnaire 
 
Food Frequency Questionnaire 
Name/Age: 
_____________________________________________Date:_________________ 
 
We would like to know about some of the foods you eat. For each food listed please fill in how often you 
usually eat a portion of the size stated. If you eat the food: 
• 
Every day or more than once a day, fill in how many times you have it per day 
• 
Less than once a day but more than one a week, fill in the times per week 
• 
Less than once a week, but more than once a month, fill in the times per month 
• 
Less often than once a month, or never eat it, put an “X” under “do not eat”. 
 
Example: Janice has a glass of orange juice every morning, along with two slices of 
toast. She usually has two sandwiches at lunch, and eats French fries about 3 times 
per week. She almost never eats cauliflower. 
 
Per Day 
Per Week 
Per Month 
Don’t Eat 
Orange juice, 1 cup 
1 
 
 
 
French fries, regular serving 
 
3 
 
 
Cauliflower, ½ cup 
 
 
 
X 
Bread or toast, 1 slice 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NUMBER OF TIMES I EAT THIS FOOD 
 
Per Day 
Per Week 
Per Month 
Don’t Eat 
Bread or toast, 1 slice or 1 roll 
 
 
 
 
Muffin, 1 large 
 
 
 
 
Pizza, 1 medium slice 
 
 
 
 
Cheeseburger or veggie burger 
 
 
 
 
Cheese: 1 slice processed OR 1 piece 
hard cheese (plain or in sandwich) 
 
 
 
 
Broccoli, ½ cup  
 
 
 
 
Ice Cream, ½ cup 
 
 
 
 
Frozen yogurt, ½ cup  
 
 
 
 
Milkshake, 11 oz  
 
 
 
 
Cottage cheese, ½ cup 
 
 
 
 
Yogurt, 8 oz (small carton)  
 
 
 
 
Soft drink, 12oz 
 
 
 
 
Tofu, 2 oz  
 
 
 
 
Milk on cereal, 1 cup  
 
 
 
 
Orange juice, 1 cup  
 
 
 
 

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Milk (any type), 1 cup 
 
 
 
 
Macaroni & cheese, 1 cup 
 
 
 
 
 
 
Is your orange juice fortified with calcium? 
_____No 
_____Yes 
 
 
Formula Intake 
_____Not Applicable 
_____Formula Information:                              Name/Brand:  __________________ 
 
 
Volume/Day  __________ or _________ 
 
 
 
 
 
 
 
 
 
(oz) 
 
(ml) 
 
 
Are you allergic to any foods? 
_____No 
_____Yes: what foods?_________________________________________________________ 
 
 
 
 
 
 
 
 
THANK YOU! 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completed By: ____________________________ 
 
 
Date:_____________________________________ 
 
 

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Appendix III - Physical Activity Questionnaires 
 
Outdoor Playtime Recall Questionnaire 
 
Think for a moment about a typical weekday for your child in the past 7 days. 
 
1. How much time would you say your child spends playing outdoors on a typical weekday? 
 
________ Hours _________Minutes 
 
 
Now think about a typical weekend day for your child in the last month. 
 
2. How much time would you say your child spends playing outdoors on a typical weekend day? 
 
________ Hours _________Minutes 
 
 
3. How many hours per day, during the week, would you say your child spends watching television in 
each season of the year? 
 
_________Too young, does not watch TV 
 
________Spring _________Summer ________Fall _________Winter 
 
 
4. On Saturday and Sunday, how many hours per day, does your child spend watching television in 
each season of the year? 
_________Too young, does not watch TV 
 
Saturday: 
 
________Spring _________Summer ________Fall _________Winter 
 
 
Sunday: 
 
________Spring _________Summer ________Fall _________Winter 
 
 
5. How many hours per day, during the week, does your child recreationally use the computer, play 
video games or participate in other screen-related activities in each season of the year? 
 
_________Too young, does not watch TV 
 
________Spring _________Summer ________Fall _________Winter 
 
 
 

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6. On Saturday and Sunday, how many hours per day does your child recreationally use the 
computer, play video games or participate in other screen-related activities in each season of the year? 
_________Too young, does not watch TV 
 
Saturday: 
 
________Spring _________Summer ________Fall _________Winter 
 
 
Sunday: 
 
________Spring _________Summer ________Fall _________Winter 
 
 
 
 

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Godin Leisure-time Exercise Questionnaire 
 
1. During a typical 7-Day period (a week), how many times on the average do you do the following 
kinds of exercise for more than 15 minutes during your free time (write on each line the appropriate 
number). 
Times per Week 
a. STRENUOUS EXERCISE 
(HEART BEATS RAPIDLY)   
 
 
_______________ 
(e.g., running, jogging, hockey, football, soccer, 
squash, basketball, cross country skiing, judo, 
roller skating, vigorous swimming, 
vigorous long distance bicycling) 
 
b. MODERATE EXERCISE 
(NOT EXHAUSTING)  
 
 
 
_______________ 
(e.g., fast walking, baseball, tennis, easy bicycling, 
volleyball, badminton, easy swimming, alpine skiing, 
popular and folk dancing) 
 
c. MILD EXERCISE 
(MINIMAL EFFORT)   
 
 
 
_______________ 
(e.g., yoga, archery, fishing from river bank, bowling, 
horseshoes, golf, snowmobiling, easy walking) 
 
2.  During a typical 7-Day period (a week), in your leisure time, how often do you engage in any regular 
activity long enough to work up a sweat (heart beats rapidly)? 
 
 
OFTEN 
 
SOMETIMES  
 
NEVER/RARELY 
 
1. [   ]  
 
2. [   ]  
 
 
3. [   ] 
 
 
3. How many hours per day, during the week, do you watch television in each season of the year? 
 
________Spring _________Summer ________Fall _________Winter 
 
 
4. On Saturday and Sunday, how many hours per day, do you watch television in each season of the 
year? 
 
Saturday: 
 
________Spring _________Summer ________Fall _________Winter 
 
 
Sunday: 
 
________Spring _________Summer ________Fall _________Winter 
 
 
 
 

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5. How many hours per day, during the week, do you recreationally use the computer, play video 
games or participate in other screen-related activities in each season of the year? 
 
________Spring _________Summer ________Fall _________Winter 
 
 
6. On Saturday and Sunday, how many hours per day do you recreationally use the computer, play 
video games or participate in other screen-related activities in each season of the year? 
 
Saturday: 
 
________Spring _________Summer ________Fall _________Winter 
 
 
Sunday: 
 
________Spring _________Summer ________Fall _________Winter