Conditions: Osteoporosis
Keywords: Osteoporosis, children and adolescents, zoledronic acid, chronic inflammation, Duchenne muscular dystrophy, glucocorticoids, chronic inflammatory conditions
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
This study was designed to evaluate the efficacy and safety of zoledronic acid compared to placebo in osteoporotic children treated with glucocorticoids

Detailed description:
In March 2017, Novartis stopped enrollment as the study was not feasible to be conducted due to low enrollment and other recruitment challenges. Patients receiving the treatment continued to receive the treatment per protocol.

Arms:
arm 1: Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid arm 2: Twice yearly i.v of infusion of Placebo (similar dosing as active drug)

Interventions: intervention 1: Zoledronic acid intervention 2: Placebo
Intervention descriptions: intervention 1: intravenous infusion intervention 2: intravenous infusion

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
ZOL 446 / zoledronic acid 
Clinical Trial Protocol CZOL446H2337 / NCT00799266
A multicenter, randomized, double-blind, placebo 
controlled efficacy and safety trial of intravenous 
zoledronic acid twice yearly compared to placebo in 
osteoporotic children treated with glucocorticoids 
Document type: 
Amended Clinical Trial Protocol 
EUDRACT number: 
2008-001252-52 
Version number: 
05 (clean) 
Clinical trial phase: 
IIIb 
Release date: 
26-Oct-2015
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 03 (August 2015) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment 5 ...................................................................................................................... 9 
Protocol summary .............................................................................................................. 12 
1 
Introduction ....................................................................................................................... 15 
1.1 
Background ............................................................................................................ 15 
1.2 
Purpose .................................................................................................................. 17 
2 
Study objectives and endpoints ......................................................................................... 17 
2.1 
Primary objective(s) ............................................................................................... 17 
2.2 
Secondary objective(s) ........................................................................................... 17 
 
 17 
2.4 
Objectives and related endpoints ........................................................................... 18 
3 
Investigational plan ........................................................................................................... 20 
3.1 
Study design........................................................................................................... 20 
3.2 
Rationale for study design ..................................................................................... 20 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 20 
3.4 
Rationale for choice of comparator ....................................................................... 21 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 21 
3.6 
Risks and benefits .................................................................................................. 22 
4 
Population .......................................................................................................................... 25 
4.1 
Inclusion criteria .................................................................................................... 25 
4.2 
Exclusion criteria ................................................................................................... 26 
5 
Treatment ........................................................................................................................... 28 
5.1 
Study treatment ...................................................................................................... 28 
5.1.1 
Investigational and control drugs .......................................................... 28 
5.1.2 
Additional treatment .............................................................................. 28 
5.2 
Treatment arms ...................................................................................................... 28 
5.3 
Treatment assignment and randomization ............................................................. 29 
5.4 
Treatment blinding ................................................................................................. 29 
5.5 
Treating the patient ................................................................................................ 29 
5.5.1 
Patient numbering ................................................................................. 29 
5.5.2 
Dispensing the study drug ..................................................................... 30 
5.5.3 
Handling of study and additional treatment .......................................... 30 


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5.5.4 
Instructions for prescribing and taking study treatment ........................ 31 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 32 
5.5.6 
Rescue medication ................................................................................ 32 
5.5.7 
Concomitant medication ....................................................................... 32 
5.5.8 
Prohibited medication ........................................................................... 32 
5.5.9 
Emergency breaking of assigned treatment code .................................. 33 
5.6 
Study Completion and Discontinuation ................................................................. 33 
5.6.1 
Study completion and post-study treatment .......................................... 33 
5.6.2 
Discontinuation of Study Treatment ..................................................... 33 
5.6.3 
Withdrawal of informed consent ........................................................... 34 
5.6.4 
Loss to follow-up .................................................................................. 35 
5.6.5 
Early study termination by the sponsor ................................................. 35 
6 
Visit schedule and assessments ......................................................................................... 35 
6.1 
Information to be collected on screening failures .................................................. 38 
6.2 
Patient demographics/other baseline characteristics ............................................. 38 
6.3 
Treatment exposure and compliance ..................................................................... 39 
6.4 
Efficacy .................................................................................................................. 39 
6.4.1 
Vertebral compression fracture ............................................................. 39 
 
 40 
6.4.3 
DXA measurements .............................................................................. 40 
6.4.4 
Bone Marker Analysis ........................................................................... 41 
 
 41 
6.4.6 
Bone age assessment ............................................................................. 41 
6.4.7 
Pain assessment ..................................................................................... 41 
6.4.8 
Appropriateness of efficacy assessments .............................................. 42 
6.5 
Safety ..................................................................................................................... 42 
6.5.1 
Physical examination ............................................................................ 42 
6.5.2 
Vital signs.............................................................................................. 42 
6.5.3 
 weight ................................................................................. 42 
6.5.4 
Laboratory evaluations .......................................................................... 43 
6.5.5 
Pregnancy and assessments of fertility ................................................. 44 
6.5.6 
Bone Safety Monitoring ........................................................................ 44 
6.5.7 
Appropriateness of safety measurements .............................................. 44 
6.6 
Other assessments .................................................................................................. 45 
 
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6.6.3 
Pharmacokinetics .................................................................................. 46 
7 
Safety monitoring .............................................................................................................. 46 
7.1 
Adverse events ....................................................................................................... 46 
7.2 
Serious adverse events ........................................................................................... 48 
7.2.1 
Definition of SAE ................................................................................. 48 
7.2.2 
SAE reporting........................................................................................ 49 
7.3 
Reporting of study treatment errors including misuse/abuse ................................ 50 
7.4 
Pregnancy reporting ............................................................................................... 50 
8 
Data review and database management ............................................................................. 52 
8.1 
Site monitoring ...................................................................................................... 52 
8.2 
Data collection ....................................................................................................... 52 
8.3 
Database management and quality control ............................................................ 53 
8.4 
Data Monitoring Committee .................................................................................. 53 
9 
Data analysis ...................................................................................................................... 53 
9.1 
Analysis sets .......................................................................................................... 54 
9.1.1 
Intention-to-treat (ITT) population ....................................................... 54 
9.1.2 
Modified Intention-to-treat (MITT) population .................................... 54 
9.1.3 
Per-protocol (PP) population................................................................. 54 
9.1.4 
Safety population .................................................................................. 54 
9.2 
Patient demographics and other baseline characteristics ....................................... 54 
9.3 
Treatments ............................................................................................................. 54 
9.3.1 
Study drug and compliance ................................................................... 54 
9.3.2 
Concomitant therapy ............................................................................. 55 
9.4 
Analysis of the primary variable ............................................................................ 55 
9.4.1 
Variable ................................................................................................. 55 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 55 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 56 
9.4.4 
Sensitivity analyses ............................................................................... 56 
9.5 
Analysis of secondary variables ............................................................................ 57 
9.5.1 
Efficacy variables .................................................................................. 57 
9.5.2 
Safety variables ..................................................................................... 58 
9.5.3 
Pharmacokinetics .................................................................................. 59 
 
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9.7 
Interim analyses ..................................................................................................... 61 
9.8 
Sample size calculation .......................................................................................... 61 
10 Ethical considerations ........................................................................................................ 61 
10.1 
Regulatory and ethical compliance ........................................................................ 61 
10.2 
Informed consent procedures ................................................................................. 62 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 62 
10.4 
Publication of study protocol and results............................................................... 62 
11 Protocol adherence ............................................................................................................ 63 
11.1 
Protocol Amendments ........................................................................................... 63 
12 References ......................................................................................................................... 63 
13 Appendix 1: Clinically notable laboratory values and vital signs ..................................... 66 
14 Appendix 2: Tanner staging .............................................................................................. 71 
15 Appendix 3: Amount of blood to-be Drawn ...................................................................... 72 
16 Appendix 4: Faces Pain Scale – Revised .......................................................................... 73 
 74 
 77 
19 Appendix 7: Other subtypes of Osteoporosis in Children ................................................. 79 
 
List of tables 
Table 2-1 
Objectives and related endpoints- Objectives ....................................... 18 
Table 5-1 
Recommended minimum daily dietary allowances (Ross 2011) .......... 28 
Table 5-2 
Preparation of iv zoledronic acid or placebo infusion .......................... 31 
Table 6-1 
Assessment schedule ............................................................................. 36 
 


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List of abbreviations 
 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMC 
Bone Mineral Content 
BMD 
Bone Mineral Density 
BSAP 
Bone Specific Alkaline Phosphatase 
CDS 
Core Data Sheet (for marketed drugs)  
CRF 
Case Report/Record Form (electronic) 
CRO 
Contract Research Organization 
DXA 
Dual Energy X-ray Absorptiometry 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
FPS-R 
Faces Pain Scale - revised 
FT4 
Free Thyroxine 
GC 
Glucocorticoids  
GCP 
Good Clinical Practice 
GIO 
Glucocorticoid-induced osteoporosis 
IB 
Investigator’s Brochure 
IBD 
Inflammatory Bowel Disease 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IL-6 
Interleukin 6 
i.v. 
intravenous 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LFT 
Liver Function Test  
LS 
Lumbar Spine 
MedDRA 
Medical Dictionary for Regulatory Activities  
NTX 
Cross-linked N-telopeptide 
OC/RDC 
Oracle Clinical/Remote Data Capture  
OI 
Osteogenesis Imperfecta 
ONJ 
Osteonecrosis of the Jaw 
PMO 
Postmenopausal Osteoporosis 
RBC 
Red Blood Cell 
RDA 
Recommended Daily Allowance 
SAE 
Serious Adverse Event 
SLE 
Systemic Lupus Erythematosus 


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SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TRAP-5b 
Tartrate-resistant Acid Phosphatase Isoform 5b 
TNF 
Tumor Necrosis Factor 
TD 
Study Treatment Discontinuation 
UK  
United Kingdom 
WBC 
White Blood Cell 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
 
Assessment  
A procedure used to generate data required by the study 
Enrollment 
Point/time of patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol) 
Investigational drug 
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
Medication pack number 
A unique identifier on the label of each investigational drug package 
Patient ID  
A unique number assigned to each patient upon signing the informed 
consent  
Randomization number 
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment 
Study drug 
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy 
Study Treatment 
Discontinuation (TD) 
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date  
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study 
Withdrawal of consent 
(WoC) 
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained biologic 
material 


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Amendment 5 
Amendment rationale 
• The main purpose of this amendment is to address Health Authority requests to provide a 
Risk Benefit statement (Section 3.6) previously included under introduction and purpose 
(Section 3.6), and allow more countries to apply the contraceptive wording originally 
provided for UK sites only.  
• In addition, the DMC concerns regarding potential for transient symptomatic 
hypocalcemia after first infusion are addressed by adding additional calcium 
supplementation at the recommended daily allowance (RDA) for age in Table 5-1 for up 
to 10 days around time of infusion (in line with Institutional clinical practice guidelines). 
• Table 5-1 has been revised in line with the current minimum RDAs for vitamin D and 
calcium from the Institute of Medicine. 
• This amendment includes clarification of the list of eligible medical conditions other than 
chronic rheumatologic conditions or inflammatory bowel disease or Duchenne muscular 
dystrophy (DMD) already specified previously. These additional conditions are listed in 
Appendix 7 and the eligibility criteria have been revised to address these as follows: 
• Due to the inclusion of some of these additional medical conditions, the exclusion 
criterion of renal impairment previously defined as an estimated glomerular filtration 
rate (GFR) < 35 mL/min/1.73 m2 at screening has been increased to normal renal 
function defined as < 60 mL/min/1.73 m2 based on the Schwartz formula at screening. 
In addition ‘serious renal disease’ in DMD has been removed as this is included under 
the GFR exclusion.  
• The exclusion criterion ‘symptomatic cardiac abnormality’ in DMD has been 
redefined as follows because other conditions or concomitant medications, including 
glucocorticoids can contribute to cardiac disease: Uncontrolled symptoms of cardiac 
failure or arrhythmia. 
• Serum 25-hydroxy vitamin D concentrations have been revised to the currently 
accepted definition of normal i.e. < 20 ng/mL or < 50 nmol/L at screening.  
• The blood volume required for the analysis of certain markers of bone markers has been 
reduced from 8.5 mL to 3 mL.  
• Inconsistencies have been corrected within the protocol and across supporting documents 
especially with respect to Serious Adverse Event reporting from signing informed consent.  
• In this 12 month study, visit windows have been removed and replaced with a requirement 
to perform the visit close to the designated day.  
• The latest Novartis protocol template has been used to aid the reader in navigating the 
protocol and more recent references provided that reflect the increase in knowledge of 
childhood osteoporosis since the protocol was first proposed. 
• The 12 month open label extension study CZOL446H2337E1 has been added for all 
patients who complete this core study. 
These changes are implemented throughout the protocol. 


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Status of the study as of 15-Oct-2015:  
Eighteen (18) patients have been randomized onto this study; the proposed changes will have 
no impact on the interpretation of the data with the exception of the definition of the evaluable 
(MITT) population which clarifies that patients must all have a baseline DXA (identical to 
ITT) and at least one post-baseline DXA. 
Changes to the protocol 
Changes to specific sections of the protocol are shown by track changes in the track changes 
version of the protocol using strike through red font for deletions, and red underlined for 
insertion. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.  
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. The changes herein do not affect the Informed Consent Form to be signed by 
parent(s) or guardian(s). 
Summary of previous amendments 
Amendment 4 
The main purpose of the amendment (16-Aug-2013) was to extend the study population to 
include subjects with Glucocorticoid induced osteoporosis (GIO) associated with underlying 
conditions other than chronic inflammatory disorders.  
Relax the LS-BMD Z-score inclusion criteria from -1.0 to -0.5 or worse 
Include an assessment of urinary concentration of zoledronic acid at 6 months after dosing. 
Amendment 3 
The main purpose of Amendment 3 (dated 15-Jul-2010) was to update the original Schwartz 
Formula to the updated Schwartz formula: 
GFR (mL/min/1.73 m2) = k [height (m)/Scr (mg/dl)] 
k = Constant 
k = 0.41 
Amendment 3 also incorporated changes which only apply to the UK sites when they enroll 
female patients of child bearing potential. 
These changes incorporate additional information on theoretical risks to a developing fetus in 
the Pregnancy section and an additional supervised urine pregnancy test at week 12. 
Amendment 2 
The main purpose of Amendment 2 (dated 23-Sep-2008) was to allow patients to receive their 
first study drug infusion (Visit 2) in the out-patient setting at the clinical discretion of the 
study investigators. In addition, clarification was provided for the definition of “Vitamin D 
and calcium supplementation” and “low trauma fracture”. 


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Amendment 1  
The main purpose of Amendment 1 (dated 17-Jul-2008) was to clarify and amend the 
osteoporosis inclusion criteria to include one or more 
 lower extremity long bone 
fractures and/or two or more 
 upper extremity long bone fractures. The following 
items were also amended to refine the protocol and further ensure patient safety: measuring 
bone-age at screening and month 12; collecting pain assessment by the Faces Pain Scale- 
Revised (FPS-R) at Baseline, months 3, 6, 9 and 12;
 
 


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Protocol summary 
 
Protocol number 
CZOL446H2337 
Title 
A multicenter, randomized, double-blind, placebo controlled efficacy and 
safety trial of intravenous (i.v.) zoledronic acid twice yearly compared to 
placebo in osteoporotic children treated with glucocorticoids  
Brief title 
 
A research study of zoledronic acid in children and adolescents with 
osteoporosis  
Sponsor and Clinical 
Phase 
Novartis  
Phase IIIb 
Investigation type 
Drug 
Study type 
Interventional  
Purpose and rationale 
To evaluate the efficacy and safety of zoledronic acid plus vitamin D and 
calcium compared to placebo plus vitamin D and calcium in osteoporotic 
children treated with glucocorticoids 
Primary Objective(s)  
To demonstrate that 0.05 mg/kg (max 5 mg) zoledronic acid administered 
every 6 months is superior to placebo for the change in lumbar spine (LS) 
bone mineral density (BMD) Z-score at Month 12 relative to baseline. 
Secondary Objectives 
1: To evaluate between-treatment differences for the change in LSBMD Z-
score at Month 6 relative to baseline 
2: To evaluate between-treatment differences for the change from baseline 
in lumbar spine and total body bone mineral content (BMC) at 6 and 12 
months  
3: To evaluate between-treatment differences for the change in serum 
P1NP, NTX, BSAP & TRAP-5b at Months 6 and 12 relative to baseline 
4: To evaluate between-treatment differences for the proportion of patients 
with new vertebral fractures at Month 12 relative to baseline  
5: To evaluate the between-treatment differences for change in vertebral 
morphometry at Month 12 relative to baseline 
6: To evaluate the between-treatment differences for change in pain using 
the Faces Pain Scale-Revised (FPS-R) at Months 3, 6, 9 and 12 relative to 
baseline. 
7: To evaluate the between-treatment differences for change in 2nd 
metacarpal cortical width at Month 12 relative to baseline.  
8: To measure urinary concentration of zoledronic acid at Month 12 
9: To demonstrate that zoledronic acid is safe for the treatment of 
osteoporotic children treated with glucocorticoids for chronic inflammatory 
conditions through the monitoring of relevant clinical and laboratory safety 
parameters. 
Study design 
This will be an international, multi-center, randomized, double-blind, 
placebo controlled efficacy and safety study recruiting patients receiving 
glucocorticoid therapy of any duration within the 12 months preceding 
screening 
Population 
The trial population will consist of male and female patients aged 5 to 17 
years with confirmed diagnosis of non-malignant conditions requiring 
treatment with systemic glucocorticoids.  
Approximately 92 patients will be randomized in a multicenter setting, to 


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yield at least 82 patients evaluable for the primary endpoint. 
Key Inclusion criteria 
• 
Written informed consent before any study related procedure 
• 
Children, male or female, between 5 and 17 years of age at Visit 1 of 
the study  
• 
Confirmed diagnosis of a chronic inflammatory condition including 
rheumatic conditions or inflammatory bowel disease (IBD) non-
malignant conditions requiring treatment with systemic glucocorticoids 
(including but not limited to rheumatic conditions, Inflammatory Bowel 
Disease, Duchenne muscular dystrophy), requiring treatment with 
systemic glucocorticoids (i.v. or oral) within the 12 months preceding 
enrollment in the study (any duration) 
• 
LS-BMD Z-score of -0.5 or worse confirmed by the central imaging 
vendor 
• 
Evidence of at least 1 vertebral compression fracture (at least Genant 
Grade 1 vertebral compression or radiographic signs of vertebral 
compression) confirmed by central reading OR At least one lower OR 2 
upper extremity long-bone, low-trauma, fracture which occurred 
sometime within the 2 years or preceding enrollment in the study, 
confirmed by central reading or radiological report. (Low trauma 
fracture is defined as falling from standing height or less). 
Key Exclusion criteria 
• 
History of primary bone disease (osteogenesis imperfecta, idiopathic 
juvenile osteoporosis, rickets/osteomalacia). 
• 
Prior use of bisphosphonates or sodium fluoride (doses for 
osteoporosis not for dental hygiene). 
• 
Any medical condition that might interfere with the evaluation of LS-
BMD, such as severe scoliosis or spinal fusion.  
• 
Hypocalcemia and hypophosphatemia: any value (age-matched) below 
the normal range at screening  
• 
Vitamin D deficiency (serum 25-hydroxy vitamin D concentrations of < 
20 ng/mL or < 50 nmol/L) at screening 
• 
Renal impairment defined as an estimated glomerular filtration rate 
(GFR) < 60 mL/min/1.73 m2 at screening based on the Schwartz 
formula; a serum creatinine increase between Visit 1 and Visit 2 greater 
than 0.5 mg/dL (44.2 μmol/L) 
• 
Female patients of child bearing potential are eligible only if they are 
not pregnant/non-lactating. Females of child bearing potential must be 
practicing a medically acceptable form of birth control for greater than 2 
months prior to screening visit and consent to pregnancy tests during 
the study. 
Study treatment 
i.v. zoledronic acid (ZOL446 or placebo) 5.0 mg/100 mL solution, supplied 
in a ready-to-infuse plastic bottle 
Efficacy assessments 
Primary Efficacy Assessment: 
LS-BMD Z-score measurement at screening and Month 12. 
Secondary Efficacy Assessments: 
• 
LS-BMD Z-score at Month 6. 
• 
LS and total body BMC at 6 and 12 months. 
• 
Serum P1NP and BSAP at Months 6 and 12. 
• 
Serum NTx and TRAP5b at Months 6 and 12. 
• 
Number of patients with new vertebral fractures at Month 12 and 
baseline, based on a lateral thoracolumbar spine X-ray (including 


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radiographic signs of fractures and Genant classification fractures). 
• 
Vertebral morphometry based on a lateral thoracolumbar spine X-ray, 
at Month 12 and baseline. 
• 
FPS-R at Months 3 6, 9 and 12. 
• 
2nd metacarpal cortical width at Month 12 and baseline. 
Key safety assessments 
Adverse event monitoring, Physical examinations, Monitoring of laboratory 
markers in blood and urine; bone safety monitoring and bone age. 
Other assessments 
Data analysis 
The primary efficacy variable, the change in LS-BMD Z-score at Month 12 
relative to baseline, will be analyzed using an analysis of covariance model 
with treatment, pooled centers, underlying condition, and baseline LS-BMD 
Z-score as explanatory. If conditions of normality are not satisfied, 
appropriate non-parametric methods will be utilized. Other secondary BMD-
related endpoints will be evaluated similarly. 
The analysis of changes in serum BSAP, P1NP, NTX& TRAP-5b will be 
performed based on the relative change from baseline computed as the 
loge ratio of the post-baseline measurement divided by the baseline 
measurement at each time point. 
Between-treatment differences will be evaluated using an ANCOVA model 
with treatment, pooled centers, underlying condition treated with 
glucocorticoids, and 
 
Other variables measured will be presented descriptively in tabular or 
graphical format, as appropriate by treatment group. 
Key words 
Osteoporosis, 
children 
and 
adolescents, 
zoledronic 
acid, 
chronic 
inflammation, Duchenne muscular dystrophy, glucocorticoids 


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1 
Introduction 
1.1 
Background  
Osteoporosis in children is a very different disease to osteoporosis in adults. Children have 
not attained peak bone mass, and sufficient data correlating bone density with fractures are 
not available. The role of lumbar spine bone mineral density (LS-BMD) in the risk of fracture 
has been evaluated in some childhood illnesses, particularly osteogenesis imperfecta (primary 
osteoporosis). Although the diagnosis of osteoporosis in adults is based on BMD, Sbrocchi 
2011 reported a child with glucocorticoid responsive nephrotic syndrome and fragility 
fracture; bone biopsy revealed signs of osteoporosis with marked thinning of the cortices and 
decreased trabecular bone volume, suggesting that DXA-based, LS-BMD should not be relied 
upon exclusively for assessing bone health in children, and that a LS-BMD Z-score of -0.5 is 
sufficient. Further, the International Society for Clinical Densitometry (ISCD) now defines 
pediatric osteoporosis as the finding of one or more low impact vertebral compression 
fractures (Genant Grade 1 or more) in the absence of a change in BMD (Bishop et al 2014).  
Patients receiving high doses of glucocorticoids are at increased risk of significant bone loss 
and fractures; glucocorticoid-induced osteoporosis (GIO) is now recognized as one of the 
most important reasons for secondary osteoporosis in adults as well as children. Prior 
glucocorticoid use confers a substantial increase in fracture risk in adults, and this risk is 
largely independent of BMD or a prior fragility fracture (Kanis et al 2004). Studies in adults 
suggest that glucocorticoid treatment for 3 months is sufficient to increase fracture risk, and 
similar data have been collected in children and adolescents where almost one-half of the 
patients with fractures were asymptomatic (Leblanc et al 2015). The earliest observation of 
vertebral fractures in children with rheumatic disorders is 4 months after starting systemic 
glucocorticoids (Rodd et al 2012). 
The etiology of secondary osteoporosis in children with inflammatory disorders is 
multifactorial and varies with the particular disease. Overlapping risk factors seen in chronic 
inflammatory conditions include poor nutrition and malabsorption of both calcium and fat-
soluble vitamins. Direct detrimental effects on bone due to high circulating levels of pro-
inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha 
have been reported. The treatment of inflammatory bowel disease (IBD), juvenile rheumatoid 
arthritis (JRA), systemic lupus erythematosus (SLE), Duchenne muscular dystrophy (DMD), 
and nephrotic syndrome includes glucocorticoid therapy which further worsens bone mineral 
status.   
While there is no primary bone involvement in DMD, the reduced mechanical loading and 
poor ambulation lead to osteoporosis, which is further compounded by the side effects of 
chronic glucocorticoid therapy. Osteoporosis is most profound in the lower extremities of 
boys with DMD and begins to develop early while still ambulatory (Larson 2000). Other 
examples of diseases of children treated with intermittent high doses of glucocorticoids where 
osteoporosis is also a risk include asthma, myasthenia gravis and Becker’s dystrophy, and etc. 
(see Appendix 7).  


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There is no established treatment for secondary osteoporosis in children, although treatment 
for adult osteoporosis including GIO is currently well established for bisphosphonates. 
Placebo controlled trials using bisphosphonates such as risedronate and alendronate have been 
shown to increase BMD and reduce the risk of vertebral fractures in patients initiating 
glucocorticoids or receiving such a treatment for a longer period of time. In adults, regulatory 
approval for treatment and prevention of osteoporosis has been granted for bisphosphonates. 
Although bisphosphonates have been used experimentally in the treatment of specific 
pediatric metabolic bone disease, only one, neridronate is currently approved in Italy for 
osteogenesis imperfecta (OI). Pamidronate is provided as an example of bisphosphonates for 
consideration in the management of DMD boys with ‘bone demineralization and increased 
fracture risk’ (Bushby et al 2009).  
Zoledronic acid 
Zoledronic acid (ZOL) is representative of a third generation bisphosphonate and is the most 
potent bisphosphonate marketed. In a variety of assays of bone metabolism, ZOL has 
demonstrated inhibition of bone resorption in vitro at concentrations of 0.3-30 nM and in vivo 
at doses of 0.3-30µg/kg without exerting any untoward effects on either bone formation or 
mineralization. A large difference exists between various bisphosphonates in terms of potency 
and effects on mineralization. There is an inverse relationship between potency and 
mineralization defects. These mineralization defects have occurred in patients treated with the 
upper therapeutic dose range of etidronate. In animal models, zoledronic acid has 
demonstrated extremely high potency in terms of antiresorptive effect without adverse effects 
on mineralization even at high doses; hence there appears to be a large therapeutic window 
between the desired inhibition of resorption and unwanted inhibition of mineralization in 
these models [see Investigator’ Brochure (IB)]. 
ZOL is marketed as Aclasta® outside of the US and for Paget’s disease of bone and PMO as 
Reclast® within the US. As Aclasta, ZOL is approved as a single infusion for the treatment of 
Paget’s disease of bone and as once annual dosing for the treatment of postmenopausal 
osteoporosis (PMO), treatment of osteoporosis in men, prevention and treatment of 
glucocorticoid-induced osteoporosis (GIO), prevention of postmenopausal osteoporosis 
(PMO) and prevention of clinical fractures after hip fracture in men and women. Moreover, it 
is approved for the prevention of skeletal-related events (pathological fractures, spinal 
compression, radiation or surgery to bone) or tumor-induced treatment of hypercalcemia of 
malignancy as Zometa® using a 10-fold higher dose on a yearly basis (4mg once monthly). 
Aclasta/Reclast is currently under review for the additional indications of treatment and 
prevention of GIO and the treatment of low bone mass in men with osteoporosis. Further 
information can be found in the current version of the IB. 
A 2007 Cochrane Review (Ward et al 2007) of bisphosphonate therapy for children and 
adolescents with secondary osteoporosis concluded that though there was not enough 
information in the studies included within the review to assess if bisphosphonates would make 
a difference to children’s bone mineral content (BMC), and that further use of 
bisphosphonates in the context of pediatric trials was justified. 


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1.2 
Purpose  
Zoledronic acid is marketed in many countries for adults with weak bones, including 
osteoporosis associated with the use of glucocorticoids (or steroids). The purpose of this study 
is to determine the bone strengthening effect of ZOL compared to placebo in osteoporotic 
children treated with glucocorticoids for Duchenne muscular dystrophy or chronic 
inflammatory conditions including rheumatic conditions and inflammatory bowel disease. In 
addition, the safety of zoledronic acid will be assessed. Patients who complete this 12 month 
study will be offered participation in a 12 month extension study where all patients will 
receive zoledronic acid. 
2 
Study objectives and endpoints 
2.1 
Primary objective(s) 
The primary objective of the study is to demonstrate that 0.05 mg/kg (max 5 mg) zoledronic 
acid administered every 6 months is superior to placebo for the change in lumbar spine (LS) 
bone mineral density (BMD) Z-score at Month 12 relative to baseline. 
2.2 
Secondary objective(s) 
1. To evaluate between-treatment differences for the change in LS-BMD Z-score at Month 6 
relative to baseline. 
2. To evaluate between-treatment differences for the change in LS and total body BMC at 6 
and 12 months. 
3. To evaluate between-treatment differences for the change in serum P1NP, BSAP, NTX, 
and TRAP-5b at Month 6 and Month 12 relative to baseline. 
4. To evaluate between-treatment differences for the proportion of patients with new 
vertebral fractures at Month 12 relative to baseline. 
5. To evaluate the between-treatment differences for change in vertebral morphometry at 
Month 12 relative to baseline. 
6. To evaluate the between-treatment differences for change in pain using the Faces Pain 
Scale-Revised (FPS-R) at Months 3, 6, 9 and 12 relative to baseline. 
7. To evaluate the between-treatment differences for change in 2nd metacarpal cortical width 
at Month 12 relative to baseline. 
8. To measure urinary concentration of zoledronic acid at Month 12. 
9. The safety objective is to demonstrate that zoledronic acid is safe for the treatment of 
osteoporotic children treated with glucocorticoids through the monitoring of relevant 
clinical and laboratory safety parameters. 


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2.4 
Objectives and related endpoints 
Table 2-1 
Objectives and related endpoints- Objectives 
OBJECTIVE 
 
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of Measure 
Stat Analysis  Section 
Primary 
To demonstrate that 
zoledronic acid 0.05 
mg/kg (max 5 mg) 
administered every 6 
months is superior to 
placebo for the change 
in lumbar spine (LS) 
bone mineral density 
(BMD) Z-score at 
Month 12 relative to 
baseline. 
Title: Change in LS-BMD Z-score  
 
Description: LS-BMD Z-score will be determined 
by the central imaging vendor before first 
treatment and at Month 12. The methods to be 
used to measure LS-BMD are described in the 
respective DXA Manuals provided by central 
imaging vendor  
 
Time Frame :  baseline, Month 12 
Section 9.4.1 
Secondary 
To evaluate between-
treatment differences 
for the change in LS-
BMD Z-score at Month 
6 relative to baseline. 
 
Title: Change in LS-BMD Z-score 
Description: LS-BMD will be determined by the 
central imaging vendor before first treatment 
and at Month 6. The methods to be used to 
measure LS-BMD are described in the 
respective DXA Manuals  
Time frame: baseline and 6 months 
Section 9.5.1.1 
To evaluate between-
treatment differences 
for the change in LS 
and total body BMC at 
6 and 12 months. 
Title: Change in LS and total body BMC 
Description: LS and total body BMC will all be 
determined by the central imaging vendor 
before first treatment and at Months 6 and 12. 
The methods to be used to measure BMC are 
described in the respective DXA Manuals  
Time frame: baseline, 6 and 12 months 
Section 9.5.1.2 
To evaluate between-
treatment differences 
for the change in serum 
P1NP, BSAP, NTX, and 
TRAP-5b at Month 6 
and Month 12 relative 
Title: relative change in bone markers  
Description: Serum P1NP, BSAP, NTX, and 
TRAP-5b will be collected before first treatment 
(baseline) and at Months 6 and 12 according to 
the instructions provided in the Laboratory 
Section 9.5.1.3 


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OBJECTIVE 
 
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of Measure 
Stat Analysis  Section 
to baseline. 
manual. The samples will be analyzed in 
batches at the laboratory 
Time frame: baseline, 6 and 12 months 
To evaluate between-
treatment differences 
for the proportion of 
patients with new 
vertebral fractures at 
Month 12 relative to 
baseline.  
Title: Incidence of new vertebral fractures 
Unit of measure: number and percentage of 
new vertebral fractures 
Description: See Section 6.4.1 
Time frame: baseline, and 12 months 
Section 9.5.1.4 
To evaluate the 
between-treatment 
differences for change 
in vertebral 
morphometry at Month 
12 relative to baseline.  
Title: Change in vertebral morphometry 
Description: Quantitative morphometry will be 
performed by a central reader (see Section 
6.4.1) 
Time frame: baseline, and 12 months 
Section 9.5.1.5 
To evaluate the 
between-treatment 
differences for change 
in pain using the Faces 
Pain Scale-Revised 
(FPS-R) at Months 3, 6, 
9 and 12 relative to 
baseline. 
Title: Change in pain scale 
Description: Children will select the face that 
best fits their pain (Appendix 4)  
Time frame: baseline, 3, 6, 9 and 12 months 
Section 9.5.1.7 
To evaluate the 
between-treatment 
differences for change 
in 2nd metacarpal 
cortical width at Month 
12 relative to baseline. 
 
Title: Change in metacarpal cortical width 
Description: The X-ray Manual provides 
instructions on the technique. Skeletal bone age 
will be determined as described in the Imaging 
Charter  
Time frame: baseline and 12 months 
Section 9.5.1.6 
To measure urinary 
concentration of 
zoledronic acid at 
Month 12. 
Title: Pharmacokinetics  
Unit of measure: ng/mL 
Description: urine will be collected overnight or 
for at least 4 waking hours from all patients able 
to provide specimens  
Time frame: 12 months 
Section 9.5.3 
The safety objective is 
to demonstrate that 
zoledronic acid is safe 
for the treatment of 
osteoporotic children 
treated with 
glucocorticoids through 
the monitoring of 
relevant clinical and 
laboratory safety 
parameters 
Title: Safety: adverse events, laboratory 
evaluations and vital signs  
Description: adverse events will be collected 
from the first infusion (Visit 2), blood and urine 
samples, including renal monitoring will be 
collected (See Section 6.5). Also bone safety 
(change in LS-BMD) is monitored at months 6 
and 12. 
Time frame: baseline through 12 months 
Section 9.5.2 


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3 
Investigational plan 
3.1 
Study design 
This will be an international, multicenter, randomized, double-blind, placebo controlled 
efficacy and safety study recruiting osteoporotic children and adolescents receiving 
glucocorticoid therapy within the 12 months preceding screening who manifest a LS-BMD Z-
score of -0.5 or worse plus evidence of low impact/fragility fracture. 
At the baseline visit (Visit 2), patients whose eligibility is confirmed will be randomized to 
one of two treatment groups. Patients may be hospitalized at the discretion of the investigator 
for observation following the first study drug infusion. Ionized calcium will be assessed 
before the first study drug infusion only. Patients will receive the second study drug infusion 
at the Month 6 visit. Safety and efficacy will be assessed at 6 and 12 months, with additional 
telephone visits to assess adverse events 
 and concomitant 
medication at 3 and 9 months. Renal safety utilizing the Schwartz calculation for GFR will be 
assessed at screening, and 10 days after the i.v. infusion of study drug 6 and 12 months.  
3.2 
Rationale for study design 
The patient population will be described in more detail in the Section 4 below. 
A placebo control design is being utilized because currently there is no approved therapy to 
treat children with secondary osteoporosis and there is no clinically accepted off-label gold 
standard of therapy for this pediatric patient population. In adults, an improvement in BMD 
can often be achieved with oral administration of calcium and vitamin D (ACR Task Force 
1996). All children enrolled in this study will be provided with conservative intervention to 
ensure adequate dietary intake of calcium and vitamin D, regardless of their treatment 
assignment (diet with or without supplements). 
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
Zoledronic acid dose selection for Study CZOL446H2337 is based on several sources of 
information, including safety and efficacy data from completed Novartis clinical trials in 
adults with postmenopausal osteoporosis, pediatric patients with severe OI, long-term safety 
in pediatric patients with OI, and a PK study in pediatric patients with severe OI. Published 
data is available from trials in patients with postmenopausal osteoporosis (Reid 2002; Black 
2007). Adults with benign disease (Paget’s and PMO) have received ZOL safely up to 5 mg 
i.v. by slow injection (over 15 minutes) over various dosing frequencies. Cancer patients have 
received between 4 and 8 mg i.v. monthly, in long-term studies (> 1 year). In the Novartis 
ZOL pediatric studies to date, the dose schedule was an infusion of 0.05 mg/kg (max 4 mg) 
administered quarterly. This dose was extrapolated from a comparison with a pamidronate 
infusion in patients with tumor-induced hypercalcemia that showed that 4 mg ZOL was more 
effective than 90 mg pamidronate. The 4 mg dose of ZOL represents an approximate adult 
dose of ZOL of 0.07 mg/kg or a dose of pamidronate of 1.5 mg/kg for a 60 kg adult. 
Pamidronate 1.5 or 3.0 mg/kg administered every 6 months was the dose range and interval 
used in the long-term pamidronate OI study (Glorieux et al 1998). However, in this trial, the 


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pamidronate dosing interval was shortened to a 4-month dosing regimen to improve the 
response in bone markers of disease activity, monitored each month. 
Study CZOL446H2202 (see IB) is the largest Novartis-sponsored trial in pediatric patients 
with metabolic bone disease. This 12-month study compared the efficacy and safety of i.v. 
zoledronic acid 0.05 mg/kg administered quarterly to i.v. pamidronate 1.0 mg/kg on each of 3 
successive days administered quarterly in 155 patients with severe OI. The results showed that 
ZOL was superior to pamidronate in increasing LS-BMD at Month 12 and in reducing 
markers of bone turnover, both formation and resorption. Additionally, clinical fracture 
reduction within treatment was significant overall, and regardless of OI type. The overall 
incidence rate of adverse events was similar between the two treatment groups. There was no 
evidence of a long-term effect on renal function following the administration of ZOL in this 
patient population. The pharmacokinetics of a single infusion of ZOL 0.05 mg/kg, in children 
aged 3-8 years and 9-17 years, were similar to those observed in adult oncology patients at 
approximately the same mg/kg dose. Plasma concentrations in the pediatric patients were 
generally at or below the median concentrations in adults, which may be an advantage in 
consideration of drug safety and tolerability in children. 
In a second trial with OI patients (see IB for study CZOL446H2202E1), the 12-month 
extension study, long-term safety was assessed in 103 patients receiving 0.05 mg/kg 
zoledronic acid either as an annual infusion or twice a year (6 months apart). In this study, 
median increases in LSBMD were approximately 1.3% higher in patients who received the 
twice yearly dosing of zoledronic acid. Though these data from the extension study should be 
interpreted with caution as the sample sizes are too small to make definitive conclusions, it is 
established that there is an effect of puberty on bone degradation, with children demonstrating 
high bone resorption relative to adults.  
Therefore, the zoledronic acid dose and interval selected for this protocol, 0.05 mg/kg as two 
i.v. infusions at a 6 month interval, is expected to provide superior efficacy (as measured by 
change in LS-BMD Z-score) compared to placebo in pediatric patients with osteoporosis. The 
maximum allowable zoledronic acid dose of 5 mg (regardless of patient weight), does not 
exceed the doses already used in adults and is well within the maximum zoledronic acid dose 
tested in Phase I Novartis Oncology trials: zoledronic acid 16 mg by slow i.v. infusion. In this 
study in children with osteoporosis, zoledronic acid will be administered as an i.v. infusion 
over at least 30 minutes. 
3.4 
Rationale for choice of comparator 
A placebo control has been selected because there is no standard treatment for this condition 
and although many pediatricians use bisphosphonates to treat fractures in children, the 
efficacy and safety of bisphosphonate therapy still needs to be determined in a population 
with secondary osteoporosis. 
3.5 
Purpose and timing of interim analyses/design adaptations 
It is not intended that an interim analysis will be conducted for this study.  


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3.6 
Risks and benefits  
Benefit 
The potential benefit of zoledronic acid in children at risk of osteoporosis due to underlying 
disease or intermittent high dose glucocorticoids is outlined below and in the IB.  
There is evidence that bisphosphonates have anti-apoptotic effects on osteoblasts and 
osteocytes which may lead to increased trabecular thickness and thus, may partly explain why 
bisphosphonates produce a greater reduction in fracture risk than that expected from BMD 
gains alone (Plotkin 1999). Furthermore, BMD is greatly influenced by sex steroids, and 
puberty can be delayed in the presence of GC which can also result in short stature which may 
be offset by the use of bisphosphonates (Glorieux et al 1998).  
The most commonly studied bisphosphonate in children has been i.v. pamidronate in the 
treatment of a primary juvenile osteoporosis, osteogenesis imperfecta (OI). The typical 
treatment protocol reported in OI is administration of pamidronate on three consecutive days 
in hospital (Glorieux et al 1998). There is some variation of dosing frequency (typically every 
1 to 4 months, depending upon the age of the patient, with younger patients receiving more 
frequent infusions). Treatment requiring three consecutive days of intravenous therapy every 
several months can cause a significant burden of both time and cost. The efficacy of cyclic 
single-day intravenous pamidronate infusions in a heterogeneous group of patients between 6 
to 21 years of age was studied and demonstrated similar improvements in bone density and in 
fracture rate as reported with 3-day infusions in patients with OI (Steelman 2003).  
A direct comparison of 2-day pamidronate (PAM) to a 2-day infusion of ZOL has been 
published in 23 children with OI (Barros et al 2012). Twelve months after treatment, the PAM 
and ZOL groups average LS-BMD increased by 51.8 % (p = 0.053) and 67.6 % (p = 0.003), 
respectively. LS-BMD Z-score for the ZOL group at the end of treatment was higher 
compared with the PAM group but only a borderline significance (p = 0.053). Only mild side 
effects were reported in both groups and the authors concluded that ZOL was not different 
from PAM in efficacy and safety in this group of children. More recently, a retrospective 
study reviewed treatment with PAM and ZOL and followed up the children for up to 2 years 
(Bowden et al 2015). The authors reported that i.v. bisphosphonate therapy significantly 
increased BMD and reduced fracture rate during the treatment with a beneficial effect in 
BMD maintained for 2 years after discontinuation of therapy. A second retrospective study 
reviewed PAM administered in cycles of 1.5 mg/kg per day over 2 days every 3 months and 
ZOL as a single dose of 0.05 mg/kg every 6 months to patients aged at least 5 years with type 
I or IV OI (Saraff et al 2015). Twenty children were identified in each group; LS-BMD Z-
scores increased significantly in both groups over 12 months (p<0.001) with no significant 
differences shown between PAM and ZOL. Another study has been conducted by the sponsor 
to evaluate the efficacy and safety of ZOL as compared to pamidronate in the treatment of 
children with severe OI (Study CZOL446H2202 described in IB). The ZOL treated group, 
had a mean 42.7% increase from baseline in LS-BMD at Month 12 compared with a mean 
increase of 34.7% in the pamidronate treated group. These changes were consistent with 
pediatric OI literature which has reported an annualized increase in BMD of 41.9% with 
cyclical pamidronate (Glorieux et al 1998). The deviation from normal, as measured by the 
LS-BMD Z-score, at both 6 and 12 months showed an improvement with ZOL. Importantly, 


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both treatments reduced the occurrence of clinical fractures per patient significantly 
(p<0.0001) following 12 months of treatment, although the proportion of patients who had 
clinical fractures in the 12 months of study treatment was similar in the two groups (ZOL: 32 
patients, 43.2%; pamidronate: 31 patients, 40.8%; HR 1.05, 95% CI 0.64 – 1.72). Of note, 
there was a higher risk of clinical fracture in the type I patients treated with ZOL compared to 
pamidronate (HR 2.12, 95% CI 0.96 – 4.69), and a lower risk of clinical fracture in the type 
III and IV patients treated with zoledronic acid compared to those patients treated with 
pamidronate (HR 0.59, 95% CI 0.29 – 1.19). 
The evidence of bisphosphonate therapy in children and adolescents with secondary 
osteoporosis has been reviewed (Ward et al 2007). More recent retrospective studies and 
reviews on zoledronic acid in children with osteoporosis have been published which report 
benefits on BMD, bone pain and fractures (Baroncelli and Bertollini 2014,  Boyce et al 2014, 
Brown and Zacharin 2009) and authors agree that prospective randomized controlled trials are 
still needed to evaluate the benefit risk of bisphosphonates. An increasing number of pediatric 
metabolic bone experts now reserve bisphosphonate therapy for the management of low bone 
mass in children and adolescents who have symptoms of a fragility fracture (Boyce and Gafni 
2011), and there is one recent publication on the prophylactic use of bisphosphonates in the 
management of boys with Duchenne muscular dystrophy (DMD) who are receiving long-term 
glucocorticoids (Sarkozy et al 2014).   
Risks 
Known risks of zoledronic acid 
Since this protocol was first written in 2008, there have been more publications on the 
potential use of bisphosphonates in children with kidney diseases including nephrotic 
syndrome (Gruppen et al 2013, Sbrocchi et al 2011).  
ZOL is concentrated and excreted via the kidney and, like other bisphosphonates, has the 
potential to produce renal injury. Thus, care should be taken when administering the 
compound to patients with renal insufficiency. Although case reports have been published in 
adult medicine regarding the nephrotoxicity of ZOL with an incidence of acute kidney injury 
(AKI) between 9% and 13%, bisphosphonate-induced, AKI in children remains 
undocumented (Patzer 2008).  
• In this protocol, patients are excluded if they have an estimated GFR < 60 mL/min/1.73 
m2 or a rising serum creatinine increase greater than 0.5 mg/dL (44.2 µmol/L) between 
Visit 1 and Visit 2. Patients who have nephrotic syndrome with osteoporosis, who do not 
meet these exclusion criteria, have been stable for 3 months prior to enrollment, and meet 
the remaining eligibility criteria can be considered for this study.  
Post-infusion acute phase reactions are more common after the first infusion and can include 
pyrexia, muscle and joint pain.  
• To reduce the risk of these reactions, children will be instructed to eat and drink as usual, 
NSAIDs or acetaminophen (paracetamol) will be prescribed and an anti-emetic may be 
provided to reduce the risk of symptomatic hypocalcemia if the child develops nausea or 
starts to vomit. Further calcium supplements will be provided for up to 10 days at the time 


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of infusion and parent/guardian instructions provided on the signs to watch for as well as 
an emergency number, if needed. 
Hypersensitivity reactions including anaphylactic reaction, anaphylactic shock, angioedema, 
bronchospasm and urticaria are listed in the IB. Therefore, children with a previous known 
hypersensitivity are excluded. Should a child develop a hypersensitivity reaction, it must be 
reported as an adverse event.  
A rare risk in patients who receive bisphosphonates is osteonecrosis of the jaw (ONJ). This 
condition has been reported primarily in cancer patients whose complex treatment regimens 
include higher doses and frequencies of bisphosphonates, typically administered with other 
treatments such as radiation, chemotherapy and glucocorticoids. To date and to the best of our 
knowledge, ONJ has not been reported in the literature in children or adolescents who have 
received bisphosphonates. Based on available evidence, a causal relationship between ONJ 
and bisphosphonates, including ZOL, has not been established.  
• In this study a lower dose and short duration of zoledronic acid is used than has been 
reported in cases of ONJ in adults, and all children will have an examination of their oral 
cavity during the study and referred to a dentist if necessary. 
Potential risks of zoledronic acid in a pediatric population 
Based on the results from animal studies showing inhibition of bone calcification by first 
generation bisphosphonates (Mashiba 2001), there are theoretical concerns about negative 
effects on growth in children. In growing children, each bisphosphonate treatment cycle leads 
to the accumulation of a thin band of mineralized tissue at the interface between growth plate 
and metaphysis which is evident as a metaphyseal line on the radiograph (Land et al 2006a). 
These lines represent persistent calcified cartilage in the horizontal trabeculae which later 
remodels into secondary bone. This interface between weaker bone and stronger 
bisphosphonate-treated bone could represent a site for potential fracture. However, in clinical 
trials with i.v. bisphosphonates, linear growth in children and adolescents has not been 
observed to be negatively impacted with no observed increase in fracture. To the contrary, 
cyclical i.v. treatment with pamidronate has been shown to be beneficial in children with 
severe forms of OI (Glorieux et al 1998).  
• To investigate this potential risk, a placebo control is used for comparison; all patients will 
have DXA examination at 6 and 12 months and in the event of clinical worsening or 
diagnosis of new fracture, an X-ray will be performed. 
Another concern in children is effects on the reproductive organs. The animal reproduction 
studies of zoledronic acid are described in the Investigator’s Brochure. Teratogenicity was 
observed in the rat, but not the rabbit when treatment during the perinatal period resulted in 
delayed parturition likely resulting from the calcium lowering effect of the compound outside 
of bone, which negatively affects uterine contraction. There were no effects reported in males.  
• Consequently this protocol requires contraception in all girls who are pubertal and may 
become pregnant and in some countries additional pregnancy checks will be made. 
There are potential concerns regarding the i.v. infusion in children. Apart from the potential 
risks at the infusion site of pain, infection, phlebitis, hematoma and extravasation, the infusion 
may also cause fluid overload if the rate is too high and this can result in hypertension, heart 


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failure or pulmonary edema. Additional risks of the infusion can include electrolyte imbalance 
and embolism. 
• The infusion is administered in a hospital or clinic by staff experienced in administering 
i.v. infusions to children. The infusion line is flushed with saline before and after 
administration and the infusion given over at least 30-minutes e.g. in a 25 kg child, 100 
mL may be administered over one hour at a rate of 5 mL/minute. 
Protocol procedures: blood draws and radiology 
The number of blood draws and frequency of hospital visits in this protocol is within the usual 
limit of clinical practice for children with these serious underlying diseases. The radiation 
exposure is increased over routine clinical practice, but within the limits for children who 
have suffered a fracture and no greater than the exposure during a transatlantic flight. Repeat 
blood draws and X-rays/DXA will only be requested when absolutely necessary i.e. safety, 
baseline or end-of-study visits. 
In summary, the risks to the children and adolescents in this trial will be minimized by 
compliance with the eligibility criteria and study procedures, particularly adequate hydration 
at the time of the infusion, adherence to a diet rich in calcium and vitamin D, regular renal 
monitoring and contraception in girls of child bearing potential. A maximum dose of 5 mg 
zoledronic acid (regardless of patient weight) and a minimum 30 minute infusion time 6-
monthly are designed to reduce the risk of possible adverse effects. This dose regimen has 
been used in children with primary and secondary osteoporosis and has shown a favorable 
risk-benefit profile.  
4 
Population 
The trial population will consist of male and female patients aged from 5 to 17 years old, with 
a confirmed diagnosis of non-malignant conditions requiring treatment with systemic 
glucocorticoids (including but not limited to rheumatologic conditions, inflammatory bowel 
disease, Duchenne muscular dystrophy, nephrotic syndrome) and who have been treated with 
systemic glucocorticoids (i.v. or oral) within the 12 months preceding screening; with 
evidence of at least one vertebral compression fracture, or one or more 
 lower 
extremity long bone fractures, or two or more 
 upper extremity long bone 
fractures, confirmed by central reading. Approximately 92 patients will be randomized from 
approximately 30 centers in a multicenter setting, to yield at least 82 patients evaluable for the 
primary endpoint. 
4.1 
Inclusion criteria 
Patients/ eligible for inclusion in this study must fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. An assent 
needs to be provided in accordance with ICH and local regulations.  
2. Children, male or female, between 5 and 17 years of age. 
3. A confirmed diagnosis of non-malignant conditions requiring treatment with systemic 
glucocorticoids (including but not limited to chronic rheumatologic conditions or, 


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inflammatory bowel disease or Duchenne muscular dystrophy) requiring treatment with 
systemic glucocorticoids (i.v. or oral) within 12 months prior to screening. 
a. Chronic rheumatologic conditions may include: Juvenile Idiopathic Arthritis 
(JIA):Systemic onset; JIA: Polyarticular rheumatoid factor positive; JIA: Polyarticular 
rheumatoid factor negative; JIA: Psoriatic arthritis; JIA: Enthesitis-related arthritis; 
JIA: Oligoarticular arthritis; JIA: Unclassified; Systemic Lupus Erythematosus (SLE); 
Juvenile Dermatomyositis; Scleroderma (generalized or localized); Overlap 
Syndromes (including mixed connective tissue disease); Sjogren’s  syndrome; 
Systemic Vasculitis, as defined by the Chapel Hill Consensus Conference on 
Nomenclature: Giant cell (temporal) arteritis, Takayasu’s arteritis, Polyarteritis 
nodosa, Wegener’s granulomatosis, Churg-Strauss syndrome, Microscopic 
polyangiitis, Essential cryoglobulinemic vasculitis, Cutaneous leukocytoclastic 
angiitis, Behcet’s disease, other vasculitis 
b. Inflammatory bowel disease may include: Crohn’s disease and Ulcerative Colitis 
c. Duchenne muscular dystrophy 
d. Nephrotic syndrome who have stable normal renal function for at least 3 months prior 
to screening 
e. Other subtypes of secondary osteoporosis in children taking glucocorticoids, except 
patients with oncologic conditions (such as lymphoma and leukemia) Appendix 7. 
4. Lumbar Spine BMD - Z score of -0.5 or worse confirmed by the central imaging vendor. 
5. Evidence of at least 1 vertebral compression fracture of Genant Grade 1 or higher or 
radiographic signs of vertebral compression fracture seen in X-ray within 1 month of or at 
screening visit, confirmed by central reading. Radiographic signs of fracture include loss 
of endplate parallelism, vertebral buckling and endplate interruption.  
OR 
• One or more, low-trauma*, lower extremity long-bone fracture which occurred 
sometime within the 2 years preceding enrollment in the study, confirmed by 
radiological report 
OR 
• Two or more, low-trauma*, upper extremity long-bone fractures which occurred 
sometime within the 2 years preceding enrollment in the study, confirmed by 
radiological report 
*Low trauma fracture is defined as falling from standing height or less. 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
1. History of primary bone disease (osteogenesis imperfecta, idiopathic juvenile 
osteoporosis, rickets/osteomalacia). 
2. Any prior use of bisphosphonates, or high dose sodium fluoride (i.e. dental use is 
permitted). 


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3. Any medical condition that might interfere with the evaluation of LS-BMD, such as 
severe scoliosis or spinal fusion. Patients with less than 3 evaluable vertebrae by DXA 
evaluation in the region of interest L1-L4, as confirmed by the central imaging 
laboratory, will not be considered eligible for this study.  
4. As per investigator’s judgment, patient is anticipated to have bone surgery within 
subsequent year. 
5. Hypocalcemia and hypophosphatemia: any value (age-matched) below the normal 
range at screening. 
6. Serum 25-hydroxy vitamin D concentrations of < 20 ng/mL or < 50 nmol/L at 
screening. 
7. Renal impairment defined as an estimated glomerular filtration rate (GFR) < 60 
mL/min/1.73 m2 at screening based on the Schwartz formula at screening  
8. A serum creatinine increase between Visit 1 and Visit 2 greater than 0.5 mg/dL (44.2 
μmol/L). 
9. Uncontrolled symptoms of cardiac failure or arrhythmia. 
10. History of hyperparathyroidism or hyperthyroidism within 1 year prior to screening. 
11. History of hypothyroidism unless on a stable treatment regimen for > 6 months, with 
at least one documented normal TSH and FT4 levels during this 6 month period. 
12. History of sarcoidosis. 
13. Diagnosis of active uveitis (symptomatic or asymptomatic) at the time of enrollment in 
the study. 
14. History of hypersensitivity to any of the study drugs or its excipients or to drugs of 
similar chemical classes 
15. Female patients of child bearing potential are eligible only if they are: (1) not 
pregnant/ non-lactating; (2) are sexually abstinent or are surgically sterile or (3) if 
sexually active, must be practicing a medically acceptable form of birth control for 
greater than 2 months prior to screening visit. Females of child bearing potential who 
are sexually active must agree to continue to practice their birth control during the trial 
and at least 1 year after completing the trial and must consent to a pregnancy test prior 
to every dose administration and at the End of Study (EOS) Visit. 
• [For sites and/or regions where additional safeguards are required e.g. UK, Italy, 
Germany, Sweden & etc.: Female patients of child bearing potential are eligible only 
if they are not pregnant/non-lactating.  Females of child bearing potential must be 
practicing a medically acceptable form of birth control for greater than 2 months prior 
to screening visit. At least one and preferably two complementary forms of 
contraception including a barrier method should be used and be continued throughout 
the trial and for at least 1 year after completing the trial.  They must also consent to a 
pregnancy test prior to every dose administration and at the EOS Visit. An additional 
supervised urine pregnancy test will be assessed at Week 12 (See Table 6-1 and 
Section 6.5.5).] 
16. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases.  


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5 
Treatment 
5.1 
Study treatment 
5.1.1 
Investigational and control drugs 
Zoledronic acid (or placebo) 5.0 mg/100 mL solution, supplied in a ready-to-infuse plastic 
bottle. 
5.1.2 
Additional treatment 
Adequate intake of vitamin D and calcium is mandatory for the four weeks prior to 
randomization and throughout the duration of the study, i.e. 12 months, either through 
adequate dietary intake or via supplementation, or a combination of both diet and 
supplementation. Described below are the recommended guidelines for vitamin D and 
calcium intake. It is the responsibility of the investigator to ensure that each patient receives 
the adequate recommended daily allowance of vitamin D and calcium (through diet and/or 
supplementation).  
Table 5-1 
Recommended minimum daily dietary allowances (Ross 2011) 
Age  
Vitamin D  
Calcium 
≥ 5 years to ≤ 8 years  
600 IU  
1000 mg  
≥ 9 years to ≤ 17 years  
600 IU  
1300 mg 
All patients should take at least 600 IU vitamin D daily from Visit 1 until the final Visit 
through diet and/or supplementation.  
Elemental calcium, at least 1000 mg for 5-8 years of age or at least 1300 mg for 9-17 years of 
age, daily will be taken beginning at Visit 1 and during the total duration of the trial, through 
diet and/or supplementation. Calcium carbonate is the preferred form of calcium 
supplementation. If calcium carbonate is not well tolerated, another form of oral calcium 
would be acceptable. 
Any vitamin D and calcium supplements will be recorded on the Concomitant 
medications/Significant non-drug therapies (e)CRF. 
In addition, transient hypocalcemia has been reported especially following the first infusion 
and it can cause symptoms in rare cases. To prevent the development of symptomatic 
hypocalcemia, the parent or guardian of each child will receive an information sheet and all 
patients will receive calcium supplementation at the doses recommended in Table 5-1 starting 
from the day of infusion and for a minimum of 5 days after each infusion (for sites where this 
calcium supplementation usually starts prior to the infusion, the total treatment period is 
approximately 10 days in total) (Hogler et al 2004). 
5.2 
Treatment arms 
At Visit 1, all patients will be counselled regarding adequate dietary intake of calcium and 
vitamin D with or without supplementation. At Visit 2, each patient will be randomized in a 


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1:1 ratio within one of two treatment arms to receive either twice yearly 0.05 mg/ kg (max 
5mg)i.v. infusion (at least 30 minutes) of zoledronic acid at randomization and Month 6 or 
twice yearly i.v. placebo at randomization and Month 6. 
5.3 
Treatment assignment and randomization  
At Visit 2, all eligible patients will be randomized via IRT to one of the treatment arms. The 
investigator or his/her delegate will contact the IRT after confirming that the patient fulfills all 
the inclusion/exclusion criteria. The IRT will assign a randomization number to the patient, 
which will be used to link the patient to a treatment arm and will specify a unique medication 
number for the first package of investigational treatment to be dispensed to the patient. The 
randomization number will not be communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the study drug.  
The stratification of randomization will occur based on the baseline BMD value category: -2.0 
or less vs. -2.0 to -1.0 vs. -1.0 to -0.5 at screening.  
5.4 
Treatment blinding  
Patients, investigational staff, persons performing the assessments, Novartis clinical trial team 
and their agents, central laboratory, central imaging and data analysts will remain blinded to 
the identity of the treatment from the time of randomization until database lock, using the 
following methods: (1) Randomization data are kept strictly confidential until the time of 
unblinding, and will not be accessible by anyone else involved in the study, (2) the identity of 
the treatments will be concealed by the use of study drugs that are all identical in packaging, 
labeling, schedule of administration and appearance. 
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9) and at the 
conclusion of the study. 
5.5 
Treating the patient  
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems. 
5.5.1 
Patient numbering 
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. Upon 
signing the informed consent form, the patient is assigned a patient number by the 
investigator. At each site, the first patient is assigned patient number 00001, and subsequent 
patients are assigned consecutive numbers (e.g. the second patient is assigned patient number 


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00002, the third patient is assigned patient number 00003). The investigator or his/her staff 
will contact the IRT and provide the requested identifying information for the patient to 
register them into the IRT. Only the assigned patient number should be entered in the field 
labeled “Patient ID” on the EDC data entry screen (e.g. enter ‘00001’, ‘00002’, etc.).  Once 
assigned to a patient, the patient number will not be reused.  If the patient fails to be 
randomized for any reason, the IRT must be notified within 2 days that the patient was not 
randomized. The reason for not being randomized will be entered on the Screening Log, and 
the Demography CRF pages should also be completed. The patient numbers are already 
created into eCRF. This patient number should be used in all documents or request forms for 
vendors. 
e.g.: site 0001 patient number 00002 will have the subject number 000100002. 
Additional information to be collected on Screening Failures is described in Section 6.1. A 
patient who is rescreened should be assigned the next consecutive number. 
5.5.2 
Dispensing the study drug  
Each study site will be supplied with study drug in packaging of identical appearance. 
The study medication packaging has a 2-part label. A unique randomization number is printed 
on each part of this label which corresponds to one of the 2 treatment arms. Investigator staff 
will identify the study drug package to dispense to the patient by calling the IRT and 
obtaining the medication number. Immediately before dispensing the package to the patient, 
the investigator staff will detach the outer part of the label from the packaging and affix it to 
the source document (Drug Label Form) for that patient’s unique patient number. 
5.5.3 
Handling of study and additional treatment 
5.5.3.1 
Handling of study treatment  
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis CPO 
Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.  
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 


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completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
5.5.3.2 
Handling of additional treatment  
At physician’s discretion, vitamin D and calcium supplementation may be managed by diet 
alone, and this should be recorded in the source records.  
When dietary supplements are recommended, this non-study treatment has to be recorded in 
the Concomitant medications/Significant non-drug therapies eCRF, specifically: 
• Calcium supplements at the time of infusion (all patients) 
• Multivitamins that contain the RDA for calcium and vitamin D from Visit 1 to Visit 8 in 
line with Table 5-1 
• Calcium or calcium plus vitamin D supplements from Visit 1 to Visit 8 in line with Table 
5.1 
• Vitamin D as a single supplement from Visit 1 to Visit 8 in line with Table 5.1 
Details are described in the CRF completion guidelines. 
5.5.4 
Instructions for prescribing and taking study treatment  
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT. 
Patients will receive a single dose of zoledronic acid or placebo of 0.05 mg/ kg, administered 
as a slow infusion of 100 mL over at least 30 minutes, at Visit 2 and Visit 5 as follows: 
AGE 
DOSE of ZOLEDRONIC ACID 
TIME OF INFUSION 
≥ 5 years to ≤ 17 years 
0.05 mg/kg diluted in 100 mL of 
NS 
30 minute infusion 
 
The zoledronic acid or placebo dose is not to exceed 5.0 mg 
A peripheral intravenous line must be used for the ZOL or placebo infusion. The i.v. infusion 
will be preceded by and followed by a 10 mL normal saline flush of the intravenous line. 
As an example, the following table demonstrates how to prepare drug for a patient who 
weighs 46 kg. 
Table 5-2 
Preparation of iv zoledronic acid or placebo infusion 
Patient 
Weight 
(kg) 
Patient dose 
based on 0.05 
mg/kg 
Total number of 
5.0 mg/100mL 
vials 
Volume of ZOL 
or placebo to 
add to the 
normal saline 
Volume of 
normal 
saline 
Total volume of 
prepared infusion 
46 kg 
Y = 2.3 mg 
1 vial 
46 mL 
100 mL 
146 mL 
X kg 
X kg * 0.05 mg/kg 
= Y or Patient 
dose 
1 vial 
Y  /  
5mg/100mL= 
Patient dose 
100 mL 
100 mL + volume 
of reconstituted 
ZOL or placebo 
to add 
Note: The maximum dose is 5 mg therefore the maximum volume from the 5mg/100mL 
ZOL/placebo vial to be used in this study is 100mL 


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Preparing the patient for the infusion 
In the event of a recent fracture, at least 1 month should elapse between the fracture and 
infusion of study drug. In the event of surgery to bone, at least 3 months should elapse 
between the procedure and infusion of study drug. 
Before the first infusion of study treatment, both the local ionized calcium and serum 
creatinine should be within normal limits. Further details are provided in the Trial Master File. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
Investigational or other treatment dose adjustments and/or interruptions are not permitted. 
5.5.6 
Rescue medication 
Not applicable. 
5.5.7 
Concomitant medication  
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications / significant non-drug therapies eCRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. 
5.5.7.1 
Treatment of study drug related adverse events: 
As with other bisphosphonates, zoledronic acid has been associated with post-dose symptoms 
that may include fever, nausea, myalgia, arthralgia and bone pain, with onset occurring within 
the first 72 hours after the infusion. Typically these symptoms occur with the first infusion of 
bisphosphonate. The symptoms are usually mild to moderate and rarely severe. These 
symptoms may be adequately managed, at the discretion of the investigator, with non-
steroidal anti-inflammatory agents (e.g. acetaminophen/paracetamol or ibuprofen) and/or anti-
emetics by local treatment standards and according to approved local labeling. Based on data 
from controlled trials, treatment with non-steroidal anti-inflammatory agents will reduce the 
incidence of these symptoms by approximately 50%. In managing these symptoms it is 
important to encourage adequate hydration and food intake. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the concomitant medications/significant non-drug therapies CRF after 
start of study treatment. 
5.5.8 
Prohibited medication 
Use of the following treatments is NOT allowed throughout the duration of the trial: 
bisphosphonates, denosumab, high dose sodium fluoride and nephrotoxic drugs e.g. 
methotrexate. 


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5.5.9 
Emergency breaking of assigned treatment code  
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Team that the code 
has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• study drug name (if available) 
• patient number 
In addition, oral and written information must be provided to the patient/parent/guardian on 
how to contact his/her backup in cases of emergency, or when he/she is unavailable, to ensure 
that un-blinding can be performed at any time.  
5.6 
Study Completion and Discontinuation  
5.6.1 
Study completion and post-study treatment  
A patient will be considered to have completed the study when the patient has completed all 
the assessments in the last visit planned in the protocol (Visit 8, Month 12). 
Continuing care should be provided by investigator and/or referring physician based on 
patient availability for follow-up. This care may include: 
• Enrollment in the extension study: Patients who complete the 12 month study will be 
offered a 12 month extension study where all patients will receive zoledronic acid 
CZOL446H2337E1. 
• Alternative therapy may be prescribed at the discretion of the treating physician at Month 
12. 
5.6.2 
Discontinuation of Study Treatment  
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration i.e. before Visit 5, Month 6, and can be initiated by either the 
patient or the investigator.  
The investigator must discontinue study treatment for a given patient if he/she believes that 
continuation would negatively impact the risk/benefit of trial participation. 
Study treatment must be discontinued under the following circumstances:  


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• Patient’s wish  
• Pregnancy (see Section 6.5.5 and Section 7.4) 
• Use of prohibited treatment as per recommendations in Section 5.5.8 
• Any situation in which study participation might result in a safety risk to the patient 
• Emergence of the following adverse events:  
• Osteonecrosis of the jaw 
• Renal failure 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the patient’s overall status, prevents the patient from continuing 
participation in the study 
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the clinic as soon as possible, after 
discontinuation of study drug, for a study treatment discontinuation visit. Treatment 
discontinuation visit assessments detailed in Visit 8, Month 12 in Table 6-1 should be 
completed and recorded in the CRF. The investigator must determine the primary reason for 
the patient’s premature discontinuation of study treatment and record this information on the 
Dosage administration record CRF.  
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should to be collected at clinic visits or via telephone visits:  
• new / concomitant treatments 
• adverse events/serious adverse events 
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient, preferably 
according to the study visit schedule.  
The investigator must contact the IRT to register the patient’s discontinuation from study 
treatment. 
If study drug discontinuation occurs because treatment code has been broken, please refer to  
Section 5.5.9 
5.6.3 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent from the study is defined as when a patient: 
• Does not want to participate in the study anymore 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
and 
• Does not allow analysis of already obtained biologic material  


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In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information in the source document.  
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.  
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in  
Table 6-1. 
5.6.4 
Loss to follow-up  
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed. 
5.6.5 
Early study termination by the sponsor  
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed 
or rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at 
which time all of the assessments listed for the final visit will be performed. At this final visit, 
all dispensed investigational product should be reconciled and the adverse event and 
concomitant medications reconciled on the CRF. 
 


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Table 6-1 
Assessment schedule 
Period  
Screen 
Treatment 
 
Visit  
118 
2 
3 
4T 
5 
6 
7T 
8 and TD and/or 
PSW  
Day  
-28  
11 
10  
90  
180 
190 
270 
365 
Month 
 
 
 
3 
6 
 
9 
12 
Obtain parental informed consent (D) and assent (S) 
x 
 
 
 
 
 
 
 
Medical history (D)  
x 
x 
 
 
 
 
 
 
Inclusion/exclusion criteria (S) 
x 
x 
 
 
 
 
 
 
Prior/concomitant medication, including GC (D) 
x 
x 
x 
x 
x 
x 
x 
x 
Physical Exam (S)8 
x 
x 
 
 
x 
 
 
x 
Vital signs (D)16 
x 
x 
 
 
x 
 
 
x 
Weight (D) 
x 
x 
 
 
x 
 
 
x 
Tanner Staging (D), if applicable 
 
x 
 
 
x 
 
 
x 
Blood and urine for central laboratory analysis2  
x 
(x) 
x 
 
x 
x 
 
x 
Pregnancy test, if applicable3 
x 
x 
 
x12 
x 
 
 
x 
Serum 25 (OH) vitamin D 
x 
 
 
 
 
 
 
x 
Ionized calcium (local lab) (D)5 
 
x 
 
 
 
 
 
 
Serum creatinine (local lab) (D)9 
x 
x 
 
 
 
 
 
 
Biomarkers (serum P1NP, NTX, BSAP, TRAP-5b) 
 
x 
 
 
x 
 
 
x 
Urine collection for PK (D)17 
 
 
 
 
 
 
 
x 
Pain assessment (D)10 
 
x 
 
x 
x 
 
x 
x 
DXA measurements4,6 
x 
 
 
 
x 
 
 
x 
X-ray4,7,11 
x 
 
 
 
 
 
 
x 
AE/SAE(D)15 
x 
x 
x 
x 
x 
x 
x 
x 
Dispense calcium and vitamin D, if required 
x 
x 
 
 
x 
 
 
x 
Contact IRT 
x 
x 
 
 
x 
 
 
x 


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Period  
Screen 
Treatment 
 
Visit  
118 
2 
3 
4T 
5 
6 
7T 
8 and TD and/or 
PSW  
Day  
-28  
11 
10  
90  
180 
190 
270 
365 
i.v. drug administration (ZOL/placebo) (D) 
 
x 
 
 
x 
 
 
 
Study Completion form (D) 
 
 
 
 
 
 
 
x 
1 V1 lab results, including GFR should be available prior to V2 
2 All randomized patients will have limited blood chemistry assessments, GFR & urinalysis performed at Visit 3 (10 days after Visit 2) and Visit 6 (10 days after Visit 
5). An optional repeat at V2 is included, if the time between screening and V2 is close to 4 weeks. 
3 Test to be performed for females with childbearing potential only. Serum test for central laboratory at screening and final visits, local urine test prior to infusion at 
Visits 2 and 5 – if positive, infusion should not be started. 
4 Screening DXA and X-rays should be performed at Visit 1 to ensure the central imaging laboratory can provide status on patient eligibility; these assessments 
should be performed early in the screening process. 
5 Ionized Ca measured pre-dose (local lab) only before the first infusion, if below normal range, treat and repeat test before study drug infusion, if visit needs to be re-
scheduled inform the monitor. 
6 Lumbar spine, total body and 
 
7 Lateral thoracolumbar spine and posteroanterior (PA) left hand/wrist (for bone-age assessment and cortical bone thickness) 
8 Including an oral examination for exposed bone. At screening visit the PI will perform an oral exam and , if needed, will refer the patient to a dentist 
9 For exclusion purposes if increase between Visits 1 and 2 greater than 0.5 mg/dL (44.2 μmol/L). 
10 Pain is assessed using Faces Pain Scale-Revised (FPS-R) 
11 An AP (anteroposterior) spine X-ray will be employed at screening, in order to identify fractures that may not be readily visualized on the lateral spine because of 
rotation/scoliosis/other 
[12 Only sites where additional safeguards required: Supervised urine pregnancy test] 
 
   
15 SAEs only to be collected from signing informed consent 
16 Pulse rate and blood pressure only 
17 Urine collection for PK: either an overnight sample, or collected over at least 4-hours during the day, for details, see Lab Manual 
18 Screening visit can be on different days to permit scheduling of all investigations during the 28-day screening period 
T = Telephone visit, S = Source documentation, D = Database, GC = Glucocorticoid, TD = study treatment discontinuation, PSW = Premature patient 
withdrawal 


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6.1 
Information to be collected on screening failures  
All patients who have signed informed consent but are not randomized will have the study 
completion page for the screening visit, demographics, inclusion/exclusion, and serious 
adverse event (SAE) data collected. Adverse events that are not SAEs will be followed by the 
investigator and collected only in the source data. 
Should the reason for non-eligibility change at a later clinic appointment e.g. treatment of 
vitamin D deficiency, deterioration in LS-BMD Z-score or worsening of fracture & etc., the 
child may be considered for re-screening, subject to medical approval from Novartis – see 
IRT guide and CRF completion guidelines for further details. 
6.2 
Patient demographics/other baseline characteristics  
At the Screening visit, information on age, sex, race, and source of the referral will be 
collected. Relevant Medical History/Current medical conditions will be recorded and updated 
at Screening (Visit 1) and at Baseline (Visit 2), prior to the first dose of study medication. The 
time between Visit 1 and Visit 2 should be as close to 28 days as possible and must not extend 
beyond 8 weeks. Background information collected at Screening and/or Baseline will include: 
• Details of current or past glucocorticoid therapy in the preceding 12 months prior to 
screening, including dose with start and stop dates 
• Current and past concomitant medication 
• Disease (chronic rheumatologic conditions, IBD, DMD, and others) related background/ 
historical information 
• Other medical history and current medical conditions 
• Trauma history, including history of falls 
• Previous fracture history 
• Tanner Pubertal Staging (Appendix 2) 
• Vital signs and physical exams, including oral exam 
• Pain assessment 
• 
 
• 
 
Assessments collected at Screening will include: 
1. AP and Lateral Thoraco-Lumbar X-ray to show evidence of vertebral fracture 
2. Radiological films and radiological reports for suspected clinical fractures (as previously 
described in the inclusion criteria). 
3. Posteroanterior left hand/wrist X-ray for bone-age and cortical bone thickness evaluation 
4. DXA measurements 
5. Central laboratory tests 
6. Local laboratory test (serum creatinine) 


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6.3 
Treatment exposure and compliance  
Concomitant medications/Significant non-drug therapy prior to the first dose of study 
treatment and after start of study treatment will be collected in the CRF, including medication 
name and reason. More details (including dose and dates of intake) will be provided for the 
following categories of treatments: osteoporosis- related medications, nutritional supplements 
(vitamin D/ calcium), and glucocorticoids. A Dosage administration record will be completed 
for each i.v. dose of ZOL/placebo. Information collected will include the date of dose, start 
and stop times of infusion and the reason for each dose. 
Compliance with vitamin D/ calcium will be assessed by the investigator and/or study 
personnel at each visit using information on diet, and supplement use provided by the 
patient/caregiver. All study treatment and any additional treatment (i.e. vitamin D and/or 
calcium provided by Novartis or designee) dispensed and returned must be recorded in the 
Drug accountability log. 
6.4 
Efficacy 
6.4.1 
Vertebral compression fracture 
At Screening, AP and lateral X-rays of the lumbar and thoracic spine will be taken to evaluate 
the presence of vertebral fractures of Genant grade 1 or higher or radiographic signs of 
vertebral compression fracture. AP spine X-ray will be employed at baseline, in order to 
identify fractures that may not be readily visualized on the lateral spine because of 
rotation/scoliosis/other. 
Radiographic signs of fracture include loss of endplate parallelism, vertebral buckling and 
endplate interruption. Patient’s eligibility must be confirmed by the central imaging laboratory 
before the patient can be randomized. AP and lateral thoracolumbar spine X-rays taken within 
1 month of Visit 1 (screening) can be used. The film and report must be sent to central 
imaging for fracture confirmation. 
Lateral thoracolumbar spine X-ray will also be performed at the final visit (Visit 8) to assess 
incident vertebral fractures. Vertebral fractures present at baseline or occurring during the 
study will be defined according to the Semi-Quantitative (SQ) method and confirmed with the 
Quantitative Morphometric (QM) method for vertebral fracture assessment: 
1. Mild (Grade 1) vertebral fracture is defined as greater or equal to (≥) 20% and less or 
equal to (≤) 25% reduction in anterior, middle, and/or posterior vertebral height. 
2. Moderate (Grade 2) vertebral fracture is defined as greater than (>) 25% and less or equal 
to (≤) 40% reduction in any vertebral height. 
3. Severe (Grade 3) vertebral fracture is defined as greater than (>) 40% reduction in any 
vertebral height. 
or based on radiographic signs of vertebral compression fracture including loss of endplate 
parallelism, vertebral buckling and endplate disruption. 
Specific instructions for sending radiographic images will be distributed to investigators prior 
to the start of study. 


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Vertebral morphometry (or concave index) will be calculated using the average ratio between 
mid-height and posterior height from L1 to L4 (Land et al 2006b) 
6.4.3 
DXA measurements 
DXA measurements of the lumbar spine (LS), total body and 
 will be performed 
in all patients. LS-BMD Z-score, LS bone mineral content (BMC), Total Body BMC 
 
 will be assessed at Screening, Month 6 and Month 12. DXA 
will be acquired locally and the results will be sent to a central reader for evaluation. Detailed 
instructions will be provided in the DXA imaging manual. 


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6.4.4 
Bone Marker Analysis 
Specialized serum tests for BSAP, P1NP, TRAP-5b and NTX will be performed. Blood will 
be drawn from patients prior to receiving their first dose of study drug, at Month 6 and Month 
12. Detailed shipping instructions will be provided in the Investigator Laboratory Manual. 
6.4.6 
Bone age assessment 
Left posteroanterior (PA) hand/wrist X-ray will be taken at Visit 1 and at the Month 12 visit 
to assess bone age and the between-treatment differences for change in 2nd metacarpal 
cortical width at Month 12 relative to baseline. 
If a fracture of the left upper extremity precludes radiographic imaging, then the right hand 
will be evaluated for this purpose. In this case, the right hand should be imaged at both Visit 1 
and at Month 12. The information will be used in the assessment of bone density.  
6.4.7 
Pain assessment 
Pain will be evaluated at each visit (in office and telephone visit) at randomization, Months 3, 
6, 9 and 12. A FPS-R will be used for this purpose (Appendix 4). 


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6.4.8 
Appropriateness of efficacy assessments  
Fracture determination by X-ray is the standard endpoint for long-term studies in 
osteoporosis. However, in studies of 12 months duration, change in BMD has become an 
acceptable surrogate and has been shown to be a strong indicator of the efficacy of anti-
resorptive therapies, including bisphosphonates such as ZOL. Bone marker assessments of 
change in BSAP, P1NP, TRAP-5b and NTX often parallel the change in BMD over the same 
time course. NTX and TRAP-5b measure bone resorption while BSAP and P1NP measure 
bone formation. In the growing child, 
 bone age also indicate the overall 
effectiveness of an intervention, but in this study, only trends may be observed over the 12 
month period. Bisphosphonates are considered effective in managing bone pain, including 
fracture pain, and the FPS-R is a scale used to measure pain in children (Bieri et al 1990, 
Hicks et al 2001). 
The efficacy measurements listed above are therefore expected to be appropriate for this 
study. 
6.5 
Safety  
6.5.1 
Physical examination 
Physical examination, including an oral examination of the gums and roof of the mouth, will 
be performed at Screening, Baseline (pre-dose, Visit 2), Month 6 and Month 12. If the 
investigator is concerned about the patient’s oral health then the patient may be referred to a 
dentist.  
Significant findings that are present prior to the first infusion of study drug must be included 
in the Relevant Medical History CRF or current medical conditions CRF. Significant findings 
made after the start of study drug which meet the definition of an AE must be recorded in the 
AE CRF. 
Tanner staging will be performed at Visit 2 (baseline), Month 6 (second dose) and the end of 
study (EOS)/Month 12 visit.  
6.5.2 
Vital signs  
Measurements will be made of sitting blood pressure and pulse rate at Visits 1, 2 (pre-dose), 
Month 6 (pre-dose) and Month 12.  
Clinically notable vital signs are defined in Appendix 1. 
6.5.3 
 weight  
Body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be 
performed at Visits 1, 2, Month 6 and Month 12 and recorded on the Vital sign CRF. 
 
 
 
 


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6.5.4 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected except for ionized 
calcium and serum creatinine (for exclusion purposes). Details on the collections, shipment of 
samples and reporting of results by the central laboratory are provided to investigators in the 
laboratory manual. 
Clinically notable laboratory findings are defined in Appendix 1. 
EMLA cream may be used at all blood draws. EMLA Cream is a topical anesthetic which 
numbs the skin and decreases the sensation of pain. There should be up to three attempts to 
obtain a serum sample from the patient at any blood draw. 
A central laboratory will collect and evaluate blood and urine samples for hematology, 
biochemistry and urinalysis at screening (Visit 1), Month 6 (Visit 5) and Month 12 (Visit 8). 
A repeat at Visit 2 may be needed if the time between screening and Visit 2 is close to or 
more than 4 weeks and/or the Visit 1 result was close to the limits of the normal range. 
Patients with laboratory tests containing clinically significant abnormal values will be 
followed regularly until the values return to normal ranges or until a valid reason for the 
abnormality, other than study drug related adverse event, is identified. 
6.5.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential counts, 
and platelet count will be measured.  
6.5.4.2 
Clinical chemistry 
Non-fasting specimens will be obtained for glucose, creatinine, serum urea, uric acid, total 
protein, SGOT (AST), SGPT (ALT), alkaline phosphatase, sodium, potassium, chloride, 
phosphorus, magnesium, albumin, and calcium. 
Specialized (non-fasting) testing for serum 25-hydroxy vitamin D will be performed at 
screening (Visit 1) and Month 12 (Visit 8). 
Glomerular Filtration Rate (GFR) will be calculated using the Schwartz formula at all visits 
where serum creatinine will be measured (Visits 1, 3, 5, 6 and 8) by the central laboratory.  
Schwartz Formula to calculate Glomerular Filtration 
GFR (mL/min/1.73 m2) = k [Height (m)] / Serum Creatinine (mg/dL) 
k = Constant  
k=0.41 
Additional renal and calcium monitoring will be performed 10 days after each study drug 
infusion (Visit 3 and Visit 6).  
Local laboratory evaluation of serum creatinine will be performed at Visits 1 and 2, if there is 
an increase greater than 0.5 mg/dL (44.2 μmol/L), the patient should be excluded. 


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Serum ionized calcium will be evaluated in the local laboratory at pre-dose (first infusion). If 
the result is close to or below the lower limit of the normal range, the infusion must be 
delayed until the value has returned to normal. 
6.5.4.3 
Urinalysis 
A urine specimen will be obtained at Visits 1, 3, 5, 6 and 8 for routine urinalysis, including 
microscopic examination. 
6.5.5 
Pregnancy and assessments of fertility  
Serum pregnancy tests (β-hCG) will be performed at screening (Visit 1) and at the final visit 
(Visit 8). Urine pregnancy tests will be performed at Visit 2 and Visit 5, prior to the study 
drug infusion. The test will be conducted for all female patients of childbearing potential. If 
menarche occurs during the study, a pregnancy test should be performed at the first visit 
following the first period. 
[For sites where additional safeguards are required only due to local regulations e.g. UK, 
Italy, Germany, Sweden & etc., an additional supervised urine pregnancy test is required at 
Visit 4, 90 days after first study drug administration). In case of a positive test, the patient 
must contact the investigator immediately.] 
6.5.6 
Bone Safety Monitoring 
Measurement of LS-BMD Z-score at Visits 5 and 8 (months 6 and 12) will be subject to 
monitoring from the central imaging lab for the detection of excessive changes in BMD. 
Repeat scans may be requested if technical factors are suspected to be involved. The 
investigator will be notified in the case of an absolute change in LS-BMD greater than -0.5 
compared with screening at the Month 6 or 12 visits or an absolute increase of LS-BMD of 
greater than +2.0. In either event, the investigator should further assess the patient for 
secondary causes (e.g. underlying disease). If it is in the best interests of the patient to 
discontinue the study, discontinuation procedures should be followed as described in Section 
5.6.2 
6.5.7 
Appropriateness of safety measurements  
Safety assessments consist of monitoring and recording of all adverse events and serious 
adverse events, including those known to be associated with bisphosphonate use; renal 
function (serum creatinine and GFR), regular monitoring of hematology, blood chemistry and 
urine values, regular measurement of vital signs and the performance of physical 
examinations including oral examinations for exposed bone. An oral examination of the gums 
and roof of the mouth, will be performed as part of the physical examination at screening, 
randomization, Month 6 and Month 12 visits to assess for signs of ONJ. ONJ is characterized 
by exposed bone in the maxillofacial area that occurs in association with dental surgery, or 
occurs spontaneously, with no evidence of healing. See Section 3.6.  
Tanner staging assesses the sexual maturity of the patient and is important to indicate child-
bearing potential in girls as these girls will require pregnancy tests before each infusion. 


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Vitamin D (25-hydroxy-D) and calcium will be measured at Visit 1 to ensure that all patients 
have adequate vitamin D and calcium levels at study entry, as a precaution to minimize the 
risk of developing hypocalcemia with the first zoledronic acid administration. In addition, 
ionized calcium will be monitored locally, before the first infusion to ensure that the patients 
have normal serum calcium level. Families will be counselled on the importance of a diet rich 
in calcium and vitamin D, and supplements recommended based at the investigators 
discretion. 
Bone safety is monitored by the central imaging laboratory via DXA at Month 6 and 12. In 
case of excessive change in BMD Z-scores compared with screening, the investigator will be 
alerted. 
The safety assessments selected are standard for this indication/patient population. 
6.6 
Other assessments 


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6.6.3 
Pharmacokinetics 
Further details on sample collection, numbering, processing and shipment can be found in the 
Laboratory Manual 
Urine will be collected into a polypropylene container during at least a 4-hour sampling 
period at Visit 8 (Month 12). The first morning sample may be used if the time of the previous 
night’s bladder voiding is recorded, otherwise it should be discarded (see Laboratory Manual 
for further details).  
All samples will be given a unique sample number. The actual sample collection date and 
time will be entered on the PK urine collection page of the eCRF.  
Pharmacokinetic analytical method 
Zoledronic acid will be determined in urine by a validated radio-immunoassay method. The 
Lower Limit of Quantification (LLOQ) is 10 ng/mL. Concentrations below the LLOQ will be 
reported as “zero” and missing data will be labeled as such in the Bioanalytical Data Report. 
Pharmacokinetics parameters 
Aet1-t2 will be calculated as Aet1-t2 = urine volume (t1-t2) × urine concentration. 
7 
Safety monitoring  
7.1 
Adverse events  
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.  
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred. 


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In this protocol, due to the long screening period (at least 4 weeks), although SAEs are 
collected from signing the informed consent, the AE page of the eCRF is only completed from 
the first day of study drug. In the case of randomized patients only, any events that occur prior 
to receiving study treatment, should be recorded in the eCRF as Medical History. 
The occurrence of adverse events must be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  
• they require therapy.  
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1. 
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information: 
• the severity grade  
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
There may be cases where a severe AE that is life-threatening may not necessarily be an SAE 
(e.g. certain laboratory abnormalities in the absence of meeting other seriousness criteria).  
• its relationship to the  
• study treatment (no/yes), or 
• other treatment (no/yes). or 
• both or indistinguishable 
• its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported. 
• whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) 
• action taken regarding investigational treatment  
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:  
• no action taken (e.g. further observation only)  
• investigational treatment dosage adjusted/temporarily interrupted  


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• investigational treatment permanently discontinued due to this adverse event  
• concomitant medication given  
• non-drug therapy given  
• patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and has then to be discussed with the patient. 
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious adverse events  
7.2.1 
Definition of SAE  
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  


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• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline). 
All diagnosed cases of ONJ should be considered as “medically significant” irrespective of 
whether the event meets the definition of “Serious Adverse Event” under current health 
authority guidelines. These cases are therefore reported to Novartis Drug Safety and 
Epidemiology as well as local health authorities under the guideline of SAE reporting. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse event. 
7.2.2 
SAE reporting  
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 30 day 
period after the last study visit should only be reported to Novartis if the investigator suspects 
a causal relationship to study treatment.  
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to each specific component of study treatment (if study treatment consists of 
several components) complete the SAE Report Form in English, and send the completed, 
signed form by fax within 24 hours after awareness of the SAE to the local Novartis Drug 
Safety and Epidemiology Department. The telephone and fax number of the contact persons 
in the local department of Drug Safety and Epidemiology, specific to the site, are listed in the 
investigator folder provided to each site. The original copy of the SAE Report Form and the 


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fax confirmation sheet must be kept with the case report form documentation at the study site. 
Follow-up information should be provided using a new paper SAE Report Form stating that 
this is a follow-up to a previously reported SAE 
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the treatment code was broken or not and whether the patient 
continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries. 
7.3 
Reporting of study treatment errors including misuse/abuse  
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an 
AE/SAE. 
 
Treatment error 
type 
Document in Dose 
Administration (DAR) 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes,  
Yes, even if not associated 
with a SAE 
7.4 
Pregnancy reporting  
There are no adequate data on the use of zoledronic acid in pregnant women. Studies in 
animals with zoledronic acid have shown reproductive toxicological effects including 


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malformations. Teratology studies were performed in two species, both via subcutaneous 
administration. Teratogenicity was observed in rats at doses greater than or equal to 0.2 mg/kg 
and was manifested by external, visceral and skeletal malformations. Dystocia was observed 
at the lowest dose (0.01 mg/kg body weight) tested in rats. No teratological or embryo/fetal 
effects were observed in rabbits, although maternal toxicity was marked at 0.1 mg/kg due to 
decreased calcium levels. No risks in males were identified. The potential risk for humans is 
unknown. Despite this theoretical risk, there have been no human reports to date of an adverse 
effect of bisphosphonates when administered either pre-conception or during pregnancy. This 
appears to stem from the fact that the amount of bisphosphonate that is mobilized from the 
skeleton is clinically insignificant is supported by numerous human reports of bisphosphonate 
administration pre-conception/during pregnancy and newborn outcomes (Levy 2009 and 
Djokanovic 2008). 
[For sites where additional safeguards are required only e.g. UK, Italy, Germany, Sweden & 
etc.: If the patient is a female of child bearing potential, the investigator must ensure that 
patient and parent(s)/guardian(s):  
• understands the theoretical teratogenic risk  
• understands the need for follow-up (e.g. pregnancy testing) on a regular basis  
• has used at least one and preferably two methods of effective contraception including a 
barrier method for at least 2 months prior to screening and is continuing to use effective 
contraception throughout the duration of the trial and for at least 1 year after the end of the 
trial  
• understands and accepts the need for effective contraception  
• follows the advice on effective contraception, even if patient has amenorrhea  
• is capable of complying with effective contraceptive measures  
• is informed and understands the potential consequences of pregnancy and the need to 
rapidly consult if there is a risk of pregnancy  
• has acknowledged the precautions associated with the use of zoledronic acid.]  
 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment.  
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 


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8 
Data review and database management  
8.1 
Site monitoring  
Before study initiation, either at a site initiation visit or at an investigator’s meeting, a 
Novartis representative will review the protocol and CRFs with the investigators and their 
staff. During the study, Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The field monitor will visit the site to 
check the completeness of patient records, the accuracy of entries on the (e)CRFs, the 
adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to 
ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis CRA organization. Additionally, a central analytics organization may analyze data & 
identify risks & trends for site operational parameters, and provide reports to Novartis Clinical 
Teams to assist with trial oversight. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, and the results of any other tests or assessments. All information 
on CRFs must be traceable to these source documents in the patient's file. Data not requiring a 
separate written record will be defined before study start and will be recorded directly on the 
CRFs. The investigator must also keep the original informed consent form signed by the 
patient or parent(s)/guardian(s) [a signed copy is given to the patient or parent(s)/guardian(s)]. 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of consistency of the source data with the CRFs are performed according to the study-
specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 
8.2 
Data collection  
Designated investigator staff will enter the data required by the protocol into the Oracle 
Clinical/Remote Data Capture (OC/RDC) system. Designated investigator site staff will not 
be given access to the system until they have been trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  


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8.3 
Database management and quality control  
Novartis staff (or CRO working on behalf of Novartis) review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data.  
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO). 
DXA and X-ray data will be processed centrally through a central imaging vendor and the 
results will be sent electronically to Novartis. 
Bone-marker analysis will be processed centrally through a central laboratory vendor and the 
results will be sent electronically to Novartis. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis.  
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management. 
8.4 
Data Monitoring Committee  
A Data Monitoring Committee (DMC) will be implemented to safeguard patient safety. All 
members will be independent from the sponsor and study investigators. The DMC will 
conduct regularly scheduled meetings to review study progress and any potential emerging 
safety signals in the study population. 
9 
Data analysis  
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. 


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9.1 
Analysis sets  
9.1.1 
Intention-to-treat (ITT) population 
The ITT population will consist of all patients randomized. Following the ITT principle, 
patients will be analyzed according to the treatment they were assigned to at randomization. 
9.1.2 
Modified Intention-to-treat (MITT) population 
The MITT population will consist of all patients in the ITT population who have an evaluable 
baseline assessment for the endpoint of interest. 
Patients will be included in the MITT population for the analysis of the primary efficacy 
endpoint (change in lumbar spine Z-score at Month 12 relative to baseline) if their DXA 
assessments includes baseline and at least one post-baseline LS-BMD score. 
According to the ITT principle, patients will be analyzed with respect to the treatment to 
which they were randomized. 
9.1.3 
Per-protocol (PP) population 
The PP will include all patients in the ITT population who do not have any major protocol 
deviations. Prior to unblinding, the Clinical Trial Team and Trial Statistician will identify the 
major protocol deviations that will exclude patients from the PP population. 
9.1.4 
Safety population 
The Safety Population will consist of all patients that have been exposed to at least one 
infusion of study drug. Patients will be analyzed according to treatment received. 
9.2 
Patient demographics and other baseline characteristics 
Appropriate summary statistics for the demographic and other baseline characteristics 
variables will be provided for the ITT and MITT populations. In addition, the baseline 
comparability between treatment groups will be evaluated for demographic and other baseline 
characteristics variables. Categorical variables will be evaluated using Fisher’s exact test, and 
the continuous variables will be evaluated using a Wilcoxon rank-sum test. 
Note that these tests of comparability are performed for descriptive purpose only, and will not 
be considered to define any formal basis for determining factors which should be included in 
statistical analysis models. However, when these tests yield significant results they can be 
used as extra information in interpreting any treatment-by-factor interactions that are observed 
in the sensitivity analyses performed on the primary and secondary efficacy variables. 
9.3 
Treatments  
9.3.1 
Study drug and compliance 
Descriptive statistics will be provided by treatment group for duration of infusion and volume 
of infusion. 


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Summary statistics will be provided for the percentage of calcium taken post-infusion and the 
duration of exposure by treatment group. 
9.3.2 
Concomitant therapy 
Concomitant medications will be coded using the WHO Drug Reference List that employs the 
Anatomical Therapeutic Chemical classification system. Summary tables will be provided 
that present the number and percent of patients receiving those medications by preferred term 
and treatment after start of study drug administration. The medications will be sorted in 
decreasing order of frequency with respect to usage in the zoledronic acid group. 
Descriptive summary statistics (mean, median, standard deviation, minimum, maximum) will 
be provided for the dose and duration of use of glucocorticoids by treatment group at baseline 
and during the 12-month double-blind period. Descriptive summary statistics (mean, median, 
standard deviation, minimum, maximum) will also be provided for the duration of exposure to 
glucocorticoid treatment between randomization and the end of double-blind treatment. The 
number and percentage of patients receiving different types of glucocorticoid therapy will be 
presented by preferred term and treatment group. 
Usage of calcium and vitamin D will be summarized by treatment group with respect to the 
forms of calcium and vitamin D taken. 
9.4 
Analysis of the primary variable 
9.4.1 
Variable 
The primary efficacy variable will be the change in LS-BMD Z-score at Month 12 relative to 
baseline, in patients treated with twice yearly i.v. ZOL compared to patients treated with 
placebo. It is derived as (LS-BMD Z-score at Month 12 – LS-BMD Z-score at baseline). 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary efficacy objective is to demonstrate superiority with respect to the change in LS-
BMD Z-score at Month 12 relative to baseline in patients treated with zoledronic acid 
compared to patients receiving placebo. 
Let µZ and µP be the population mean of the change in LS-BMD Z-score at Month 12 relative 
to baseline for patients treated with ZOL and patients receiving placebo, respectively. The 
null hypothesis of no difference between treatment groups (H0 : µZ = µP) will be tested 
against the alternative hypothesis that there is difference between treatment groups (HA : µZ ≠ 
µP). The tests will be done at a nominal significance level of α = 0.05.  
The primary efficacy objective will be demonstrated by showing that the t test statistic, 
, 
is greater than 
 in the modified intent-to-treat population, where d and SE are the 
estimated treatment difference and the estimated standard error of d from an analysis of 
covariance (ANCOVA) model with treatment, pooled centers, underlying condition treated 
with glucocorticoids and baseline LS-BMD Z-score as explanatory variables, df is the 
associated degrees of freedom computed from the error term in the model, and 
 is the 
SE
d |
|
975
.0
,
df
t
975
.0
,
df
t


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97.5% quantile of the t distribution with df degree of freedom. The test and confidence 
intervals based on this test statistic are robust to the assumptions of normality and of equal 
variances when within-center treatment group sample size are equal, which is generally the 
case that treatment allocation is nearly equal within each center because of the manner in 
which the randomization is carried out. Nevertheless, the underlying assumption of normality 
and variance homogeneity for the primary analyses will be reviewed and tested by Shapiro’s 
test and Levene’s test, respectively, prior to unblinding the data. If the underlying assumption 
is violated, a transformation or non-parametric approach, such as van Elteren or Cochran- 
Mantel-Haenszel test (CMH2 from SAS procedure PROC FREQ) adjusted for center, will be 
applied to the data as appropriate for the hypothesis evaluated. 
9.4.3 
Handling of missing values/censoring/discontinuations 
In the modified intent-to-treat population, last observation carried forward (LOCF) will be 
used to impute a value for LS-BMD Z-score at Month 12 for any patient who does not have a 
Month 12 assessment; however, if a patient prematurely discontinues from the study during 
the double-blind phase without providing any LS-BMD measurements at Month 6 or Month 
12, then a zero percent change in LS-BMD will be assumed at Month 12.  
Given that a pediatric population is being studied and patients are expected to experience bone 
growth during the study, an assumption of zero change over 12 months and LOCF from 
Month 6 measurements would be considered conservative. 
9.4.4 
Sensitivity analyses  
Confirmation of the result for the primary efficacy variable will be performed using the per-
protocol population without imputation for missing data using the ANCOVA model applied 
for the primary efficacy analysis. 
As another supportive analysis to the primary analysis, the change in LS-BMD Z-score at 
Month 12 relative to baseline will be compared using the analysis of covariance model with 
treatment, pooled centers, underlying condition treated with glucocorticoids, baseline LS-
BMD Z-score and treatment-by-center interaction as explanatory variables to explore 
treatment-by-center interactions using the MITT population. If p < 0.1000 for the treatment-
by-center interaction test, then, in addition, further work will be done (tabular and/or graphical 
presentations) as necessary to look for a possible explanation to the differences observed 
across centers. Tabular and graphical presentations will also be presented as necessary to 
explain interactions if they exist for underlying condition and baseline pubertal status. 
Additional prognostic factors will be evaluated as necessary descriptively and in model 
fitting. 
In addition, a responder analysis will be done by comparing the proportion of patients who 
increase their lumbar spine z-score at Month 12 in the ZOL group relative to the placebo 
group using the MITT population. Between-treatment differences will be evaluated using a 
logistic regression model with treatment, pooled centers, underlying condition treated with 
glucocorticoids and baseline LS-BMD Z-score as explanatory variable. 


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9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables  
The analyses of secondary 
 efficacy variables will be performed on the MITT 
population without imputation for missing values unless specified otherwise. Descriptive 
statistics (mean, median, standard deviation, minimum and maximum) will be presented by 
treatment group for each continuous variable and the number and percentage of patients will 
be presented by treatment group for each categorical variable, unless otherwise specified. All 
hypothesis tests will be evaluated at a 0.05 level of significance, and the p-values will be 
rounded to the 4th decimal place. Adjustment for multiple comparisons will not be made for 
any of the secondary efficacy variables since none of these variables is intended to be used for 
any promotional claims. If changes are made to this plan, appropriate adjustments for 
multiplicity will be included as part of the report analysis plan (RAP) prior to clinical 
database lock. 
The secondary efficacy variables and their analysis methods are described below.  
9.5.1.1 
Change in lumbar spine BMD Z-score at Month 6 relative to baseline 
The change in LS-BMD Z-score at Month 6 relative to baseline between zoledronic acid and 
placebo will be evaluated using an ANCOVA model with treatment, pooled centers, 
underlying condition treated with glucocorticoids and baseline LS-BMD Z-score as 
explanatory variables. 
9.5.1.2 
Change in lumbar spine and total body BMC at Months 6 and 12 
relative to baseline 
The change in BMC at the lumbar spine and total body at Month 6 and Month 12 relative to 
baseline between zoledronic acid and placebo will be evaluated using an ANCOVA model 
with treatment, pooled centers, underlying condition treated with glucocorticoids and baseline 
BMC as explanatory variables. 
9.5.1.3 
Relative change in biochemical markers of bone turnover (Serum NTX, 
TRAP-5b, BSAP and P1NP) 
A transformation of the log ratio of treatment value vs. baseline value (calculated by dividing 
the post-baseline value by the baseline value and then applying the loge transformation) at 
each visit will be used to normalize the distribution of the biochemical marker parameters. An 
ANCOVA model with treatment group, pooled centers, underlying condition treated with 
glucocorticoids, and loge (baseline value), as explanatory variables will be performed on the 
transformed data at each post-baseline time point. 
The 2-sided 95% confidence intervals in difference of transformed data between zoledronic 
acid and placebo will be constructed using the same method as described for the primary 
analysis based on the described ANCOVA model. In addition, the 2-sided 95% confidence 
intervals obtained from the model will be back transformed to the original scale. 


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9.5.1.4 
Incidence of new vertebral fractures at Month 12 
The number and percentage of patients with new vertebral fractures at Month 12 will be 
presented by treatment group. Between-treatment differences will be evaluated using Fisher’s 
exact test. 
9.5.1.5 
Change in vertebral morphometry at Month 12 relative to baseline 
The change in vertebral morphometry at Month 12 relative to baseline will be evaluated using 
an ANCOVA model with treatment, pooled centers, underlying condition treated with 
glucocorticoids and baseline value as explanatory variables 
9.5.1.6 
Change in metacarpal cortical width at Month 12 relative to baseline 
The change in metacarpal cortical width at Month 12 relative to baseline will be evaluated 
using an ANCOVA model with treatment, pooled centers, underlying condition treated with 
glucocorticoids and baseline value as explanatory variables 
9.5.1.7 
Reduction in pain from baseline 
The reduction in pain from baseline by visit will be evaluated based on whether or not patients 
have a decrease in their Faces Pain Scale-Revised from baseline. If pain remains the same or 
worsens from baseline a patient will be classified as ‘0’ and if the pain scale decreased then 
the patient will be classified as ‘1’. Whether or not a patent experiences a decrease in pain will 
be evaluated using a logistic regression model with treatment, pooled centers, underlying 
condition treated with glucocorticoids and baseline pain score as explanatory variables. 
9.5.2 
Safety variables  
9.5.2.1 
Adverse event 
The number and percentage of patients who report adverse events will be summarized within 
each sub-population by treatment group according to primary system organ class (PSOC), 
preferred term, and severity. If a patient reports more than one adverse event with the same 
preferred term, the adverse event with the greatest severity will be presented. If a patient 
reports more than one adverse event within the same PSOC, the patient will be counted only 
once with the adverse event of greatest severity. 
Death, serious adverse events, adverse events causing permanently discontinuation of study 
drug, and adverse events cause action taken will be presented by treatment group. Listings of 
these events will be provided. 
9.5.2.2 
Laboratory evaluations 
The summary of laboratory evaluations will be presented with respect to three groups of 
laboratory tests (hematology, serum chemistry, and urinalysis).  
Descriptive summary statistics (mean, median, standard deviation, minimum and maximum) 
for the baseline, each study visit, and change from baseline to each study visit will be 
presented. These descriptive summaries will be presented by laboratory test group and 
treatment group within each sub-population. 


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In addition, shift tables will be provided in order to compare a patient’s baseline laboratory 
evaluation relative to each study visit. For the shift tables, the normal laboratory values will 
be used to evaluate whether a particular laboratory test value is normal, low, or high for each 
visit value relative to whether or not the baseline value is normal, low, or high. These 
summaries will be presented by laboratory test group and treatment group within each sub-
population. 
9.5.2.3 
Vital signs 
The number and percentage of patients who have vital sign values that meet the criteria for 
being clinically notable after the first dose of study medication, will be presented by treatment 
group, within each subpopulation. Patient listings will be also provided that presents each 
patient’s vital sign profile for those tests that are outside of the clinically notable ranges. 
9.5.3 
Pharmacokinetics  
ZOL446 urine concentration data will be listed by treatment, subject, and visit/sampling time 
point. 
Descriptive summary statistics will be provided by treatment and visit/sampling time point, 
including the frequency (n, %) of concentrations below the LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics. A geometric mean will not be reported if the dataset includes zero 
values. 
Pharmacokinetic parameters will be calculated as described in Section 6.6.3 and will be listed 
by treatment and subject. Descriptive summary statistics will include mean (arithmetic and 
geometric), SD, and CV (arithmetic and geometric), median, minimum and maximum.  


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9.7 
Interim analyses 
It is not intended that an interim analysis will be conducted for this study. 
9.8 
Sample size calculation 
The sample size is calculated to show superiority of zoledronic acid relative to placebo at 
Month 12. 
The null hypothesis of no difference between treatment groups in the mean change in LS-
BMD Z-score at Month 12 relative to baseline.  In testing this hypothesis, it is assumed that 
the standard deviations for the two treatment groups is 0.93 under H0 and HA. Based on a 
primary endpoint of the change in LS-BMD Z-score at 12 months relative to baseline 
assuming a 0.63 increase in LS-BMD Z-score over 12 months with zoledronic acid and no 
change in the LS-BMD Z-score in the placebo group and a common standard deviation of 
0.93, 82 patients are required to show a significant increase in LS-BMD Z-score at the 0.05 
level with 85% power. Adjusting for a dropout rate of 10%, approximately 46 patients per 
treatment group are required. 
The amount of information from controlled trials in a pediatric GIO population is limited. The 
0.63 increase in LS-BMD Z-score is based on the increase observed with pamidronate-treated 
children on chronic glucocorticoid therapy presented in (Acott et al 2005). The common 
standard deviation of 0.93 was estimated from the pamidronate-treated children and untreated 
control evaluated in (Acott et al 2005). This standard deviation is consistent with the estimate 
of the standard deviation obtained from the zoledronic acid group of pediatric osteogenesis 
imperfecta patients in Study CZOL446H2202. Therefore, it is inferred that the assumption of 
a 0.63 increase in LS-BMD Z-score over 12 months with ZOL is acceptable. 
10 
Ethical considerations  
10.1 
Regulatory and ethical compliance  
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki. 


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10.2 
Informed consent procedures  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so or a child who is not legally allowed to do so, after such consent has been provided by a 
legally acceptable representative(s) of the patient. In cases where the patient’s representative 
gives consent, the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate assent by 
personally signing and dating the written informed consent document or a separate assent 
form. Informed consent must be obtained before conducting any study-specific procedures 
(e.g. all of the procedures described in the protocol). The process of obtaining informed 
consent must be documented in the patient source documents.  
Investigators will be provided by Novartis, a proposed model informed consent form that 
complies with the ICH GCP guideline and regulatory requirements which is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC and a copy of 
the approved version must be provided to the Novartis monitor or designee after IRB/IEC 
approval. 
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study. 
10.3 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, patient recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made. 
10.4 
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results. 


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11 
Protocol adherence  
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.  
11.1 
Protocol Amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed. 
12 
References  
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women with low bone mineral density. NEJM; 346:653-661. 
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zoledronic acid and pamidronate in the treatment of osteogenesis imperfecta in children. Bone 
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Steelman J, Zeitler P (2003) Treatment of symptomatic paediatric osteoporosis with cyclic 
single day intravenous pamidronate infusions. J Pediatr; 142:417–23. 
Schwartz GJ; Muñoz A; Schneider MF et al (2008) Formulas to estimate GFR in children 
with chronic kidney disease. J Am Soc Nephrol; 20(3):629-637. 
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13 
Appendix 1: Clinically notable laboratory values and vital 
signs 
The laboratory results are accessible by Novartis when the results have been sent to the 
investigators. Clinically significant changes should be recorded in the CRF as either Medical 
History, AE or SAE. 
Laboratory 
parameter 
 
Units 
Age/gender 
range 
 
Normal range 
Criteria for clinically significant 
change 
Systolic Blood 
Pressure 
mmHg 
< 12 yrs 
(70.0, 125.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
 
 
12 yrs/male 
(90.0, 127.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
 
 
13 yrs/male 
(90.0, 130.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
 
 
14 yrs/male 
(90.0, 132.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
 
 
15 yrs/male 
(90.0, 135.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
 
 
16 yrs/male 
(90.0, 138.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
 
 
17 yrs/male 
(90.0, 140.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
 
 
12 yrs/female 
(90.0, 126.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
 
 
13 yrs/female 
(90.0, 128.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
 
 
14 yrs/female 
(90.0, 130.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 


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Laboratory 
parameter 
 
Units 
Age/gender 
range 
 
Normal range 
Criteria for clinically significant 
change 
 
 
15 yrs/female 
(90.0, 131.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
 
 
16 yrs/female 
(90.0, 132.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
 
 
17 yrs/female 
(90.0, 132.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 20 unit 
change 
Diastolic 
Blood 
Pressure 
mmHg 
< 12 yrs 
(40.0, 85.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
12 yrs/male 
(50.0, 83.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
13 yrs/male 
(50.0, 84.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
14 yrs/male 
(50.0, 85.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
15 yrs/male 
(50.0, 86.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
16 yrs/male 
(50.0, 87.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
17 yrs/male 
(50.0, 89.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
12 yrs/female 
(50.0, 82.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
13 yrs/female 
(50.0, 84.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 


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Laboratory 
parameter 
 
Units 
Age/gender 
range 
 
Normal range 
Criteria for clinically significant 
change 
 
 
14 yrs/female 
(50.0, 85.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
15 yrs/female 
(50.0, 86.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
16 yrs/female 
(50.0, 86.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
17 yrs/female 
(50.0, 86.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
Heart Rate 
bpm 
< 12 yrs 
(70.0, 130.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
 
 
> 12 yrs 
(50.0, 120.0) 
If within the normal range at 
baseline, a value outside of normal 
range along with at least a 15 unit 
change 
Blood Urea 
Nitrogen 
mg/dL 
< 17 yrs 
(4.0, 24.0) 
Outside the normal range 
Calcium 
mg/dl 
> 2 - 17 yrs 
(8.4, 10.3) 
Outside the normal range 
Chloride 
mEq/L 
< 17 yrs 
(94.0, 112.0) 
Outside the normal range 
Creatinine 
mg/dl 
5 - 7 yrs/ 
Female 
(0.2, 0.5) 
Outside the normal range 
 
 
> 7- 10 yrs/ 
Female 
(0.2, 0.6) 
Outside the normal range 
 
 
> 10 - 13 yrs/ 
Female 
(0.3, 0.7) 
Outside the normal range 
 
 
> 13 - 16 yrs/ 
Female 
(0.4, 0.8) 
Outside the normal range 
 
 
> 16 - 17 yrs/ 
Female 
(0.5, 0.9) 
Outside the normal range 
 
 
5 - 7 yrs/ Male 
(0.2, 0.5) 
Outside the normal range 
 
 
> 7- 10 yrs/ 
Male 
(0.3, 0.6) 
Outside the normal range 
 
 
> 10 - 13 yrs/ 
Male 
(0.3, 0.7) 
Outside the normal range 
 
 
> 13 - 16 yrs/ 
Male 
(0.4, 0.8) 
Outside the normal range 
 
 
> 16 - 17 yrs/ 
Male 
(0.5, 0.9) 
Outside the normal range 


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Laboratory 
parameter 
 
Units 
Age/gender 
range 
 
Normal range 
Criteria for clinically significant 
change 
Magnesium 
mg/dl 
5 - 7 yrs/ 
Female 
(1.7, 2.2) 
Clinically significantly low, if < 1.0 
mg/dL 
 
 
> 7- 10 yrs/ 
Female 
(1.6, 2.2) 
Clinically significantly low, if < 1.0 
mg/dL 
 
 
> 10 - 13 yrs/ 
Female 
(1.6, 2.2) 
Clinically significantly low, if < 1.0 
mg/dL 
 
 
> 13 - 16 yrs/ 
Female 
(1.6, 2.3) 
Clinically significantly low, if < 1.0 
mg/dL 
 
 
> 16 - 17 yrs/ 
Female 
(1.5, 2.2) 
Clinically significantly low, if < 1.0 
mg/dL 
 
 
5 - 7 yrs/ Male 
(1.7, 2.4) 
Clinically significantly low, if < 1.0 
mg/dL 
 
 
> 7- 10 yrs/ 
Male 
(1.6, 2.2) 
Clinically significantly low, if < 1.0 
mg/dL 
 
 
> 10 - 13 yrs/ 
Male 
(1.6, 2.2) 
Clinically significantly low, if < 1.0 
mg/dL 
 
 
> 13 - 16 yrs/ 
Male 
(1.6, 2.3) 
Clinically significantly low, if < 1.0 
mg/dL 
 
 
> 16 - 17 yrs/ 
Male 
(1.5, 2.2) 
Clinically significantly low, if < 1.0 
mg/dL 
Potassium 
mEq/L 
> 1 - 17 yrs 
(3.4, 5.4) 
Outside the normal range 
Phosphorus 
mg/dl 
     5 - 10 yrs 
(3.2, 6.1) 
Outside the normal range 
 
 
> 10 - 15 yrs 
(3.1, 6.0) 
Outside the normal range 
 
 
> 15 - 17 yrs 
(2.2, 5.1) 
Outside the normal range 
Sodium 
mEq/L 
< 17 yrs 
(132.0, 147.0) 
Outside the normal range 
Hemoglobin 
g/dl 
5 - 12 yrs/ 
Female 
(11.2, 15.5) 
Outside the normal range 
 
 
> 12 - 17 yrs/ 
Female 
(11.6, 16.4) 
Outside the normal range 
 
 
5  - 12 yrs/ 
Male 
(11.2, 15.5) 
Outside the normal range 
 
 
> 12 - 17 yrs/ 
Male 
(12.7, 18.1) 
Outside the normal range 
ALT 
u/L 
5- 17 yrs 
( 6 , 200 ) 
Outside the normal range 
AST 
u/L 
5- 17 yrs 
 (10 , 200 ) 
Outside the normal range 
Alkaline 
Phosphatase 
u/L 
5- 17 yrs 
 ( 51 , 315)  
Outside the normal range 
Albumin 
g/dL 
5- 17 yrs 
 ( 2.9 – 4.7 )  
Outside the normal range 
Hematocrit 
% 
5- 6 yrs/ 
Female 
(35.0, 44.0) 
Outside the normal range 
 
 
> 6 - 12 yrs/ 
Female 
(34.0, 44.0) 
Outside the normal range 
 
 
> 12 - 17 yrs/ 
Female 
(34.0, 48.0) 
Outside the normal range 
 
 
5 - 6 yrs/ Male 
(33.0, 43.0) 
Outside the normal range 


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Laboratory 
parameter 
 
Units 
Age/gender 
range 
 
Normal range 
Criteria for clinically significant 
change 
 
 
> 6 - 12 yrs/ 
Male 
(34.0, 44.0) 
Outside the normal range 
 
 
> 12 - 17 yrs/ 
Male 
(39.0, 54.0) 
Outside the normal range 
RBC 
106/uL 
> 3 - 6 yrs/ 
Female 
(4.1, 5.2) 
Outside the normal range 
 
 
> 6 - 12 yrs/ 
Female 
(3.7, 6.0) 
Outside the normal range 
 
 
> 12 - 17 yrs/ 
Female 
(4.1, 5.6) 
Outside the normal range 
 
 
5- 6 yrs/ Male 
(4.1, 5.3) 
Outside the normal range 
 
 
> 6 - 12 yrs/ 
Male 
(3.7, 6.0) 
Outside the normal range 
 
 
> 12 - 17 yrs/ 
Male 
(4.5, 6.4) 
Outside the normal range 
WBC 
103/uL 
5- 6 yrs 
(4.00, 12.00) 
Outside the normal range 
 
 
> 6 - 12 yrs 
(4.35, 13.65) 
Outside the normal range 
 
 
> 12 - 17 yrs 
(4.35, 13.15) 
Outside the normal range 
Lymphocytes 
103/uL 
5- 6 yrs/ 
Female 
(1.50, 8.00) 
Outside the normal range 
 
 
> 6 - 12 yrs/ 
Female 
(1.15, 6.65) 
Outside the normal range 
 
 
> 12 - 17 yrs/ 
Female 
(0.95, 5.25) 
Outside the normal range 
 
 
5- 6 yrs/ Male 
(1.50, 8.00) 
Outside the normal range 
 
 
> 6 - 12 yrs/ 
Male 
(1.15, 6.65) 
Outside the normal range 
 
 
> 12 - 17 yrs/ 
Male 
(0.95, 5.25) 
Outside the normal range 
Neutrophils 
103/uL 
5- 6 yrs/ 
Female 
(1.00, 9.00) 
Outside the normal range 
 
 
> 6 - 12 yrs/ 
Female 
(1.35, 8.15) 
Outside the normal range 
 
 
> 12 - 17 yrs/ 
Female 
(1.65, 8.15) 
Outside the normal range 
 
 
5- 6 yrs/ Male 
(1.35, 8.65) 
Outside the normal range 
 
 
> 6 - 12 yrs/ 
Male 
(1.35, 8.65) 
Outside the normal range 
 
 
> 12 - 17 yrs/ 
Male 
(1.65, 8.15) 
Outside the normal range 
Eosinophils 
103/uL 
< 17 yrs 
(0.00, 0.57) 
Outside the normal range 
Lab normal ranges provided by Covance Labs 


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Appendix 2: Tanner staging 
Male patients - Development of external genitalia 
Stage 1: Pre-adolescent. Testes, scrotum, and penis are of about the same size and proportion 
as in early childhood. 
Stage 2: The scrotum and testes have enlarged and there is a change in the texture of the 
scrotal skin. 
Stage 3: Growth of the penis has occurred, at first mainly in length; these has been further 
growth of testes and scrotum 
Stage 4: Penis further enlarged in length and breadth with development of glans. Testes and 
scrotum further enlarged. There is also further darkening of the scrotal skin 
Stage 5: Genitalia adult in size and shape 
Female patients - Breast development 
Stage 1: Pre-adolescent; elevation of papilla only. 
Stage 2: Breast bud stage; elevation of breast and papilla as a small mound, enlargement of 
areola diameter. 
Stage 3: Further enlargement of breast and areola, with no separation of their contours. 
Stage 4: Projection of areola and papilla to form a secondary mound above the level of the 
breast. 
Stage 5: Mature stage; projection of papilla only, due to recession of the areola to the general 
contour of the breast. 
The girls will be asked at each visit if they had begun to menstruate. 
Male and female patients - Pubic hair 
Stage 1: Pre-adolescent (can see velus hair similar to abdominal wall). 
Stage 2: Sparse growth of long, slightly pigmented, downy hair, straight or only slightly 
curled, appearing chiefly along the labia or the base of the penis. 
Stage 3: Considerably darker, coarser and more curled hair. The hair spreads sparsely over the 
junction of the pubes. 
Stage 4: Hair is now adult in type, but the area covered by is still considerably smaller than in 
most adults. There is no spread to the medial surface of thighs. 
Stage 5: Adult in quantity and type, distributed as an inverse triangle of the classically 
feminine pattern. Spread to the medial surface of the thighs (about age 15 years). 
(Marshall and Tanner 1970; Marshall and Tanner 1969) 
 


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Appendix 3: Amount of blood to-be Drawn 
Period  
Screen 
Treatment 
 
Visit  
1 
2 
3 
4T 
5 
6 
7T 
8 and TD 
and/or PSW 
Day  
-28 
1 
10 
90 
180 
190 
270 
365 
Week 
-4 
 
 
12 
26 
 
39 
52 
Central Laboratory - All Patients 
Hematology 
3 mL 
 
 
 
3 mL 
 
 
3 mL 
Chemistry 
3.5 mL  
[6 mL 
(Australia 
only)] 
 
 
 
3.5 mL  
 
3.5 mL  
[6 mL 
(Australia 
only)] 
 
Renal & Ca monitoring1 
 
 
3.5 mL  
 
3.5 mL  
 
Serum pregnancy2 
2.5mL 
 
 
 
 
 
 
2.5mL 
Specialized serum bone-markers 
 
3 mL 
 
 
3 mL 
 
 
3 mL 
Vitamin D 
2.5 mL 
 
 
 
 
 
 
2.5 mL 
Local Laboratory - All Patients 
Serum creatinine  
2.5 mL 
2.5 mL  
 
 
 
 
 
Serum ionized calcium 
 
2.5 mL  
 
 
 
 
 
TOTALS 
14 mL 
[16.5mL 
(Australia 
only)] 
8 mL 
3.5mL - 
9.5mL 3.5mL - 
14.5 mL 
[17.0mL 
(Australia 
only)] 
1Serum creatinine, urea, electrolytes, calcium, magnesium, phosphorus only 
2Only in girls of child bearing potential 
 


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16 
Appendix 4: Faces Pain Scale – Revised 
©2001 International Association for Study of Pain 
 
 
         0                   2                   4                   6                    8                   10   
 
 
 


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19 
Appendix 7: Other subtypes of Osteoporosis in Children  
 
Allowed 
Disallowed 
Cerebral palsy 
Leukemia 
Becker’s dystrophy 
Solid tumors  
Diabetes mellitus 
Thalassemia 
Celiac disease 
Mastocytosis 
Cystic fibrosis 
Hypogonadism 
 
Growth Hormone deficiency 
 
Hyperthyroidism 
 
Vitamin D deficiency 
 
Anorexia nervosa 
 
Chronic kidney disease 
 
Secondary hyperparathyroidism 
 
Organ transplant recipient 
 
Biliary atresia 
 
Female athletic triad 
 
Spinal cord injury 
 

SAP_001.pdf: 
Clinical Development 
ZOL446 zoledronic acid, Aclasta® 
CZOL446H2337 / NCT00799266 
A multicenter, randomized, double-blind, placebo-
controlled efficacy and safety trial of intravenous 
zoledronic acid twice yearly compared to placebo in 
osteoporotic children treated with glucocorticoids  
RAP Module 3 – Detailed Statistical Methodology 
Author: 
, 
 Statistician 
, Novartis Trial Statistician 
Document type: 
RAP Documentation 
Document status: 
V1.3 
Release date: 
21AUG2017 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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CZOL446H2337/Zoledronic Acid 
 
 
Statistical methods planned in the protocol and determination of 
sample size 
Statistical and analytical plans 
This document describes the statistical methodology for analyses of efficacy and safety in 
Study CZOL446H2337. The purpose of the study is to determine the bone strengthening 
effect of zoledronic acid compared to placebo in osteoporotic children treated with 
glucocorticoids for Duchenne muscular dystrophy or chronic inflammatory conditions 
including rheumatic conditions and inflammatory bowel disease. To ensure adequate intake of 
calcium and vitamin D, all children enrolled in this study will be provided with conservative 
intervention (diet with or without supplements), regardless of their treatment assignment.  
The primary objective of the study is to demonstrate that 0.05 mg/kg (max 5 mg per dose) 
zoledronic acid administered every 6 months is superior to placebo for the change in lumbar 
spine (LS) bone mineral density (BMD) Z-score at Month 12 relative to baseline. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
General considerations 
Baseline definition 
For both efficacy and safety analyses, unless specified otherwise, baseline is defined as the 
last non-missing measurement obtained on or prior to administration of the first infusion of 
the study drug.  All assessments obtained after the administration of first infusion of the study 
drug are considered as post-baseline unless otherwise specified.  
Study day 
The general rules for calculating the study day are as follows:  
• If the event date occurs before the first infusion date, then the study day is defined as the 
date of the event minus the first infusion date 
• If the event date occurs after the first infusion date (inclusive), then the study day is 
defined as the date of the event minus the first infusion date plus 1. 
Visit schedule 
Summaries by visit will be based on the visits collected on the CRF and no visit window will 
be applied. Only scheduled visits will be included in the summary, unless specified otherwise. 
Subjects and treatments  
The following analysis sets will be defined:  
• Intention-to-treat (ITT) population 


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RAP Module 3 
 
CZOL446H2337/Zoledronic Acid 
 • Modified Intention-to-treat (MITT) population  
• Per-protocol (PP) population 
• Safety population  
Intention-to-treat (ITT) population  
The ITT population will consist of all randomized patients.  Following the ITT principle, 
patients will be analyzed according to the treatment they are assigned at randomization. 
Disposition, protocol deviation, demographics, baseline disease characteristics, medical 
history, and disease-related background information will be based on ITT population. 
Modified Intention-to-treat (MITT) population  
The MITT population will consist of all randomized patients who have both baseline and at 
least one post-baseline LS-BMD Z-score. All efficacy analyses will be based on MITT 
population including primary efficacy analysis. 
Safety population  
The Safety population will consist of all patients who have been exposed to at least one 
infusion of study drug. Patients will be analyzed according to the treatment actually taken. All 
safety analyses will be based on Safety population. 
Per-protocol (PP) population 
The PP population will include all patients in the MITT population who do not have any 
protocol deviations that could confound the interpretation of analyses conducted on the MITT 
population. Prior to unblinding, the Clinical Trial Team and Trial Statistician will identify the 
major protocol deviations that will exclude patients from the PP population. Primary efficacy 
endpoint will also be analyzed in the PP population.  
Important protocol deviations for exclusion from analysis sets are specified in Appendix 
section “PD and non-PD criteria leading to exclusion from analysis sets” and others will be 
identified by the clinical team before the final database lock. 
Pooling of centers 
Centers will be pooled into four regions based on the similarity of clinical practice for 
randomization and analysis purpose. The regions are as follows:   
• North America region  
o United States  
o Canada  
• EMEA America region   
o Belgium 
o Finland 
o Germany 
o Hungary 
o Italy 
o Poland 
o Romania 


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RAP Module 3 
 
CZOL446H2337/Zoledronic Acid 
 
o Russia 
o South Africa 
o Sweden 
o Turkey 
o United Kingdom 
• Latin America region   
o Brazil 
• APAC region   
o Australia 
o New Zealand 
Patient disposition 
The number and percentage of patients in the following categories will be tabulated and listed 
by treatment group within the ITT population:  
• Completed study 
• Discontinued study 
Discontinuations will be further broken down by reason.   
In addition, recruitment will be summarized by country and then center.  
A complete listing of patient disposition will be provided for all ITT patients. 
Patients who have signed informed consent but are not randomized are considered screening 
failures. Demographic information and reasons for discontinuing will be provided in a listing 
for screen failure patients.   
Protocol deviations 
Protocol deviations will be summarized in a table and will be listed for all ITT patients by 
treatment group. The number of patients with any protocol deviation will also be summarized.  
Patients excluded from analyses 
The number and percentage of patients in each analysis population (ITT, MITT, PP, Safety) 
will be summarized by treatment group. Listing of these analysis populations will be provided 
as well as a listing of patients that belong to the ITT population but are excluded from the 
efficacy analysis.  
Demographic and other baseline characteristics 
Descriptive statistics for the following demographic variables and baseline characteristics will 
be summarized by treatment group using the ITT and MITT populations:  
• Age at randomization (years) 
• Age group at randomization (> = 5 years to <= 8 years; >=9 years to <=17 years) 
• Sex 


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RAP Module 3 
CZOL446H2337/Zoledronic Acid 
•
Race
•
Ethnicity
 
 
•
Weight (kg)
•
Tanner evaluation (breast development, genital stage, pubic hair, and whether menarche
has occurred)
•
Lumbar spine BMD Z-score
•
Lumbar spine BMD Z-score category
o
<= -2.0
o
> -2.0 to <= -1.0
o
> -1.0 to <= -0.5
•
Lumbar spine Bone Mineral Content (BMC) (g)
•
Total body BMC (g)
•
Serum 25-hydroxy vitamin D (ng/dL)
•
Serum calcium level (mg/dL)
•
Serum NTX (nmol/L)
•
Serum TRAP-5b (U/L)
•
Serum BSAP (U/L)
•
Serum P1NP (ng/mL)
•
Vertebral morphometry
•
Non-vertebral fractures
•
Metacarpal cortical width
•
Pain score
In addition, the baseline comparability between treatment groups will be evaluated for 
demographic and other baseline characteristics variables. Categorical variables will be 
evaluated using Fisher’s exact test, and the continuous variables will be evaluated using a 
Wilcoxon rank-sum test.  


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CZOL446H2337/Zoledronic Acid 
 
Note that these tests of comparability are performed for descriptive purpose only, and will not 
be considered to define any formal basis for determining factors which should be included in 
statistical analysis models. However, when these tests yield significant results they can be 
used as extra information in interpreting any treatment-by-factor interactions that are observed 
in the sensitivity analyses performed on the primary and secondary efficacy variables. 
 
All demographic and baseline characteristic data will be listed as presented above.   
Disease-related background information  
Disease-related background and historical information will be summarized by the following 
type and sub-type of disease as collected on the CRF. 
• Rheumatic conditions:  
o Systemic onset Juvenile Idiopathic Arthritis (JIA) 
o Polyarticular rheumatoid factor positive JIA 
o Polyarticular rheumatoid factor negative JIA  
o Psoriatic arthritis JIA  
o Enthesitis-related arthritis JIA 
o Oligoarticular arthritis JIA 
o Unclassified JIA 
o Systemic lupus erythematosus (SLE)  
o Juvenile dermatomyositis 
o Scleroderma (generalized or localized)  
o Overlap syndromes (including mixed connective tissue disease)  
o Sjogren’s syndrome  
o Giant cell (temporal) arteritis 
o Takayasu’s arteritis  
o Polyarteritis nodosa  
o Wegener’s granulomatosis  
o Churg-Strauss syndrome  
o Microscopic polyangiitis 
o Essential cryoglobulinemic vasculitis  
o Cutaneous leukocytoclastic angiitis  
o Behcet’s disease  
o Other vasculitis 
• Inflammatory bowel disease:  
o Crohn’s disease 
o Ulcerative colitis 
• Duchenne muscular dystrophy  
• Other  
Frequency counts will be provided by treatment group as well as the total in a table. A listing 
will also be generated. 
In addition, the following disease types and sub-types will be derived based on the preferred 
term from the medical history/current medical conditions panel.  


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CZOL446H2337/Zoledronic Acid 
 
• Chronic rheumatic conditions:  
o Juvenile Idiopathic Arthritis (JIA),Systemic onset; JIA  
o Polyarticular rheumatoid factor positive; JIA 
o Polyarticular rheumatoid factor negative; JIA  
o Psoriatic arthritis; JIA  
o Enthesitis-related arthritis; JIA 
o Oligoarticular arthritis; JIA Unclassified 
o Systemic lupus erythematosus (SLE)  
o Juvenile dermatomyositis 
o Scleroderma (generalized or localized)  
o Overlap syndromes (including mixed connective tissue disease)  
o Sjogren’s syndrome  
o Systemic vasculitis 
o Giant cell (temporal) arteritis 
o Takayasu’s arteritis  
o Polyarteritis nodosa  
o Wegener’s granulomatosis  
o Churg-Strauss syndrome  
o Microscopic polyangiitis 
o Essential cryoglobulinemic vasculitis  
o Cutaneous leukocytoclastic angiitis  
o Behcet’s disease  
o Other vasculitis 
• Inflammatory bowel disease:  
o Crohn’s disease 
o Ulcerative colitis 
• Duchenne muscular dystrophy  
• Nephrotic syndrome 
• Other  
Frequency counts will be provided for the derived disease types and sub-types by treatment 
group as well as the total in a table. 
Relevant medical history and current medical conditions 
Relevant medical history/current medical conditions will be summarized by primary system 
organ class, preferred term and treatment group with frequencies and percentages displayed. 
A patient with multiple occurrences of a medical condition for a preferred term or system 
organ class is counted only once in each specific category. A corresponding listing will also 
be provided. 


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Extent of exposure 
A summary table will be provided for the exposure to study medication, including number of 
patients with any infusion, duration for 1st infusion, duration for 2nd infusion, volume for 1st 
infusion, and volume for 2nd infusion.  
Prior/concomitant medications and significant non-drug therapies 
The number and percentage of patients receiving prior and concomitant medications and 
significant non-drug therapies will be summarized by treatment group and preferred term 
according to the WHO Drug Reference List employing the Anatomical Therapeutic Chemical 
(ATC) classification system. Prior medications are defined as those ending prior to the first 
infusion of study drug; medications ending on or after the first infusion of study drug are 
concomitant medications. Prior medications will be presented separately from concomitant 
medications. The summary table will first be sorted by ATC class alphabetically and then by 
preferred term in decreasing order of frequency with respect to usage in the zoledronic acid 
group. 
Furthermore, summarizations by ATC class will be provided with regard to a group of 
specified 
concomitant 
medications/significant 
non-drug 
therapies, 
which 
include 
osteoporosis-related medications, nutritional supplements, and glucocorticoids. The summary 
table will be sorted by ATC class in decreasing order of frequency in the zoledronic acid 
group.  
Missing date convention 
If the medication start and end dates are recorded in the CRFs, medications that start on or 
prior to the first infusion in study and end on or after the first infusion in the study including 
ongoing at end of the study were included in both prior to and after start of study drug 
administration in the study, respectively. 
Partial medication start dates will be imputed as follows: 
• Only day is missing: the partial start date will be imputed using 15MONYYYY if the 
month and year indicate that the medication started prior to the first infusion of study 
medication or 01MONYYYY if the month and year indicate that the medication 
started on or after the first infusion of study medication. 
• Both day and month are missing: the partial start date will be imputed using 
01JULYYYY if the year indicates that the medication started prior to the first 
infusion of study or 01JANYYYY if the year indicates that the medication started on 
or after the first infusion of study medication. 
Partial medication end dates will be imputed as follows: 
• Only day is missing: the partial end date will be imputed using the last date of the 
month. 
• Both day and month are missing: the partial end date will be imputed as December 31 
if the end year is prior to the year of first infusion of study drug or one day after the 


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last study infusion date if end year is equal to or after the year of first infusion of study 
drug. 
Efficacy evaluation 
Analyses of all efficacy endpoints will be performed on the MITT population. Confirmation 
of the result for the primary efficacy endpoint will be conducted using the PP population 
without imputation for missing data. All efficacy measurements will be presented in listings. 
Analysis for the primary objective 
The primary objective is to demonstrate that zoledronic acid administered every 6 months at 
0.05 mg/kg (max 5 mg) is superior to placebo for the change in lumbar spine (LS) bone 
mineral density (BMD) Z-score at Month 12 relative to baseline.  
Variable 
The primary efficacy variable will be the change in LS-BMD Z-score at Month 12 relative to 
baseline, in patients treated with twice yearly intravenous (i.v.) zoledronic acid compared to 
patients treated with placebo. It is derived as (LS-BMD Z-score at Month 12 – LS-BMD Z-
score at baseline). The LS-BMD Z-score will be assessed at Screening, Month 6 and Month 
12.  
Positive changes from baseline indicate an improvement in condition. Treatment difference 
will be calculated as <zoledronic acid minus placebo>.  
Statistical model, hypothesis, and method of analysis 
Let µz and µP be the population mean of the change in LS-BMD Z-score at Month 12 relative 
to baseline for patients treated with zoledronic acid and patients receiving placebo, 
respectively. The null hypothesis of no difference between treatment groups (H0: µz = µP) will 
be tested against the alternative hypothesis that there is difference between treatment groups 
(HA: µz ≠ µP). The test will be conducted at a nominal significance level of α=0.05.  
The primary efficacy analysis will be conducted in the MITT population based on an analysis 
of covariance (ANCOVA) model with treatment, pooled centers, underlying condition treated 
with glucocorticoids and baseline LS-BMD Z-score as explanatory variables and pooled 
centers as random effect. The t-test statistic, |d|/SE, will be computed and compared with tdf, 
0.975 to determine significance, where d and SE are the estimated treatment difference and the 
estimated standard error of d from the ANCOVA model, respectively, df is the associated 
degrees of freedom computed from the error term in the model, and tdf, 0.975 is the 97.5% 
quantile of the t distribution with df degrees of freedom.  
The test and confidence intervals based on this test statistic are robust to the assumptions of 
normality and of equal variances when within-center treatment group sample size are equal, 
which is generally the case that treatment allocation is nearly equal within each center because 
of the manner in which the randomization is carried out. Nevertheless, the underlying 
assumption of normality and variance homogeneity for the primary analyses will be reviewed 
and tested by Shapiro’s test and Levene’s test, respectively, prior to unblinding the data. If the 
underlying assumption is violated, a transformation or non-parametric approach, such as van 


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Elteren or Cochran-Mantel-Haenszel test adjusted for center, will be applied to the data as 
appropriate for the hypothesis evaluated. 
From the model, the treatment difference between zoledronic acid group vs. placebo group 
will be estimated and presented together with two-sided 95% confidence interval (CI). P-
value will be rounded to the 4th decimal place. In the same table, the Least Squares means and 
standard errors for change from baseline in lumbar spine Z-score at Month 12 will be 
presented for each treatment group. Descriptive statistics will also be shown for baseline and 
Month 12 visits. 
A plot will be generated for LS BMD Z-score over time. 
Handling of missing values/censoring/discontinuations 
In the MITT population, last observation carried forward (LOCF) will be used to impute a 
value for LS-BMD Z-score at Month 12 for any patient who does not have a Month 12 
assessment; however, if a patient prematurely discontinues from the study during the double-
blind phase without providing any LS-BMD measurements at Month 6 or Month 12, then a 
zero percent change in LS-BMD will be assumed at Month 12. 
Given that a pediatric population is being studied and patients are expected to experience bone 
growth during the study, an assumption of zero change over 12 months and LOCF from 
Month 6 measurements would be considered conservative.  
Supportive analyses 
Confirmation of the result for the primary efficacy variable will be performed using the per-
protocol population without imputation for missing data using the ANCOVA model applied 
for the primary efficacy analysis.   
As another supportive analysis to the primary analysis, the homogeneity of treatment effects 
across centers will be evaluated by adding the treatment-by-center interaction term into the 
ANCOVA model employed in the primary efficacy analysis. If p < 0.1000 for the treatment-
by-center interaction test, which indicates heterogeneous treatment effects across centers, then 
an additional table will be presented showing the ANCOVA model-based treatment 
comparisons for primary efficacy variable by each center. Furthermore, interactions between 
treatment and underlying condition, treatment and baseline tanner stage in pubic hair, 
treatment and baseline tanner stage in breast development within female population, and 
treatment and baseline tanner stage in genital stage within male population will be evaluated 
and presented in a similar way.   
In addition, a responder analysis will be done by comparing the proportion of patients who 
increase their LS-BMD Z-score at Month 12 compared to baseline in the zoledronic acid 
group relative to the placebo group using the MITT population. Between-treatment 
differences will be evaluated using a logistic regression model with treatment, pooled centers, 
underlying condition treated with glucocorticoids and baseline LS-BMD Z-score as 
explanatory variables. 


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Analysis for secondary objectives 
The analyses of secondary efficacy variables will be performed on the MITT population 
without imputation for missing values unless specified otherwise. Descriptive statistics will be 
presented by treatment group for each continuous variable and the number and percentage of 
patients will be presented by treatment group for each categorical variable, unless otherwise 
specified. All hypothesis tests will be evaluated at a 0.05 level of significance, and the p-
values will be rounded to the 4th decimal place. Adjustment for multiple comparisons will not 
be made for any of the secondary efficacy variables since none of these variables is intended 
to be used for any promotional claims.   
The secondary efficacy variables and their analysis methods are described below. 
• 
Change in LS-BMD Z-score at Month 6 relative to baseline, zoledronic acid group 
vs. placebo 
The change in LS-BMD Z-score at Month 6 relative to baseline between zoledronic acid and 
placebo will be evaluated using an ANCOVA model with treatment, pooled centers, 
underlying condition treated with glucocorticoids and baseline LS-BMD Z-score as 
explanatory variables. 
From the model, the treatment difference between zoledronic acid group vs. placebo group 
will be estimated and presented together with two-sided 95% CI and p-value. In the same 
table, the LS means and standard errors for change from baseline in LS-BMD Z-score at 
Month 6 will be presented for each treatment group. Descriptive statistics will also be shown 
for baseline and Month 6 visits. 
• 
Change in LS and total body BMC at Months 6 and 12 relative to baseline, 
zoledronic acid group vs. placebo 
The change in BMC at the lumbar spine and total body at Month 6 and Month 12 relative to 
baseline between zoledronic acid and placebo will be evaluated using an ANCOVA model 
with treatment, pooled centers, underlying condition treated with glucocorticoids and baseline 
BMC as explanatory variables. 
From the model, the treatment difference between zoledronic acid group vs. placebo group 
will be estimated and presented together with two-sided 95% CI and p-value. In the same 
table, the LS means and standard errors for change from baseline in lumbar spine or total 
body BMC at Month 6 and Month 12 will be presented for each treatment group. Descriptive 
statistics will also be shown for baseline, Month 6 and Month 12 visits. 
• 
Relative change in biochemical markers of bone turnover (Serum NTX, TRAP-5b, 
BSAP and P1NP) at Months 6 and 12 relative to baseline, zoledronic acid group 
vs. placebo 
The analysis of changes from baseline to Month 6 and Month 12 in the biochemical markers, 
serum NTX, TRAP-5b, BSAP, and P1NP will be performed as follows: a transformation of 
the loge ratio of post-baseline value vs. baseline value at each visit will be used to normalize 
the distribution of the biochemical marker parameters. An ANCOVA model with treatment 
group, pooled centers, underlying condition treated with glucocorticoids, and loge (baseline 


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value) as explanatory variables will be used on the transformed data at each post-baseline time 
point.  
From the model, the treatment difference between zoledronic acid group vs. placebo group in 
log scale will be estimated and presented together with two-sided 95% CI and p-value. 
Estimated treatment difference and two-sided 95% CI will then be transformed back to the 
original scale and displayed on the table. In the same table, the LS means and standard errors 
in both log scale and original scale for change from baseline for the biomarkers at Month 6 
and Month 12 will be presented for each treatment group. Descriptive statistics will also be 
shown for baseline, Month 6 and Month 12 visits in both original scale and log scale. A plot 
will be generated for each biochemical marker over time respectively. 
• 
Incidence of new vertebral fractures at Month 12, zoledronic acid group vs. placebo 
The number and percentage of patients with new vertebral fractures at Month 12 will be 
presented by treatment group. Between-treatment differences will be evaluated using Fisher’s 
exact test. 
• 
Change in vertebral morphometry at Month 12 relative to baseline, zoledronic acid 
group vs. placebo 
The change in vertebral morphometry at Month 12 relative to baseline will be evaluated using 
an ANCOVA model with treatment, pooled centers, underlying condition treated with 
glucocorticoids and baseline vertebral morphometry as explanatory variables. 
From the model, the treatment difference between zoledronic acid group vs. placebo group 
will be estimated and presented together with two-sided 95% CI and p-value. In the same 
table, the LS means and standard errors for change from baseline in vertebral morphometry at 
Month 12 will be presented for each treatment group. Descriptive statistics will also be shown 
for baseline and Month 12 visits. 
• 
Change in 2nd metacarpal cortical width at Month 12 relative to baseline, 
zoledronic acid group vs. placebo 
The change in 2nd metacarpal cortical width at Month 12 relative to baseline will be evaluated 
using an ANCOVA model with treatment, pooled centers, underlying condition treated with 
glucocorticoids and baseline metacarpal cortical width as explanatory variables. 
From the model, the treatment difference between zoledronic acid group vs. placebo group 
will be estimated and presented together with two-sided 95% CI and p-value. In the same 
table, the LS means and standard errors for change from baseline in metacarpal cortical width 
at Month 12 will be presented for each treatment group. Descriptive statistics will also be 
shown for baseline and Month 12 visits. 
• 
 Reduction in pain from baseline, zoledronic acid group vs. placebo 
Pain is assessed using Faces Pain Scale-Revised (FPS-R) at randomization, Month 3, 6, 9 and 
12, which ranges from 0 (No Pain) to 10 (Very Much Pain). Details of FPS-R can be found in 
Appendix section “Faces Pain Scale – Revised” in the protocol. 
The reduction in pain from baseline by visit will be evaluated based on whether or not patients 
have a decrease in their FPS-R from baseline. If pain remains the same or worsens from 


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baseline a patient will be classified as ‘0’ and if the pain scale decreased then the patient will 
be classified as ‘1’. Whether or not a patent experiences a decrease in pain will be evaluated 
using a logistic regression model with treatment, pooled centers, underlying condition treated 
with glucocorticoids and baseline pain score as explanatory variables. 


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Pharmacokinetic (PK) evaluations  
Descriptive summary statistics will be provided by treatment for urine concentration of 
zoledronic acid at Month 12, including mean (arithmetic and geometric), standard deviation 
(arithmetic and geometric), coefficient of variation (CV) (arithmetic and geometric), median, 
first quartile (Q1), third quartile (Q3), minimum and maximum. Furthermore, frequency (n, 
%) of zoledronic acid concentrations below the Lower Limit of Quantification (LLOQ) will 
be displayed, which is defined as 10 ng/mL. Concentrations below LLOQ will be treated as 
zero in summary statistics. A geometric mean will not be reported if the dataset includes zero 
values. The same summary statistics will also be provided for PK parameter Aet1-t2 at Month 
12, which is calculated as urine volume (t1-t2) x urine concentration. A listing of 
concentrations of zoledronic acid at Month 12 will also be provided. 
 
Safety evaluation 
All safety analyses will be performed on the Safety Population. The assessment of safety will 
include adverse events, laboratory tests (hematology, blood chemistry and urine values), vital 
signs, and tanner staging score. Patient listings will be provided for all safety data.  
Adverse events 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical 
investigation subject after providing written informed consent for participation in the study 
until the end of study visit. Treatment-emergent adverse events will be defined as adverse 
events that were absent prior to the first infusion and occurred after the first infusion during 
the study or that were present prior to the first infusion and occurred at increased severity after 
the first infusion during the study. Summarization will be based on treatment-emergent 
adverse events. Adverse events will be coded using the Medical dictionary for regulatory 
activities (MedDRA). The number and percentage of patients who report adverse events will 


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be summarized by treatment according to the primary system organ class and preferred term. 
If a patient reports more than one adverse event within the same primary system organ class 
(preferred term), the patient will be counted only once with the greatest severity at the system 
organ class (preferred term) level. Serious adverse events and selected adverse events will be 
presented by treatment group code. Listing of these events will be provided. 
Adverse event tables will be sorted alphabetically by system organ class and then according to 
decreasing frequency of preferred term in the zoledronic acid group. If only system organ 
classes or preferred terms are presented, these will be sorted according to the decreasing 
frequency in the zoledronic acid group. 
The following sets of adverse events will be summarized: 
• 
All adverse events (by primary system organ class and preferred term) 
• 
Adverse events suspected to be related to study drug (by primary system organ class and 
preferred term) 
• 
Adverse events that occurred after first infusion and before second infusion (by primary 
system organ class and preferred term) 
• 
Most frequent adverse events (at least 5% in any group) (by primary system organ class 
and preferred term) 
• 
All adverse events (by primary system organ class, preferred term and maximum 
severity) 
• 
All adverse events (by underlying disease group, primary system organ class and 
preferred term) 
• 
Adverse events that result in death (by primary system organ class and preferred term) 
• 
Serious adverse events (by primary system organ class and preferred term) 
• 
Adverse events causing permanent discontinuation of study drug (by primary system 
organ class and preferred term) 
• 
Adverse events associated with a change in renal function (by preferred term). Time to 
first adverse event associated with a change in renal function will be presented 
separately. 
 
 
• 
Hypocalaemia adverse events (by preferred term). Time to first hypocalaemia occurrence 
based on AE and central lab calcium will be presented separately.  
Incidence of risk as defined in the case retrieval strategy, during the study period, will be 
summarized by treatment group, and MedDRA levels. Relative risk of zoledronic acid group 


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vs. placebo will be presented along with corresponding 95% confidence intervals using the 
Mantel-Haenszel test. 
Missing date convention 
Partial AE start dates: If an AE start date is completely missing, then no imputation is 
implemented. AEs with completely missing start dates will be treated as treatment emergent. 
If the year of an AE start date is missing but the month is available, then the date will be 
imputed as the start date of the first study drug infusion + 1.  
If the year is not missing and the month is missing, then date will be imputed as follows: 
• If the AE year is less than the year the study drug infusion was administered, then July 
1st of the year will be used. 
• If the AE year is equal to the year the study drug infusion was administered, then the 
start date will be imputed as the start date of the first study drug infusion + 1. 
• If the AE year is greater than the year the study drug infusion was administered, then 
the Jan 1st of the year will be used. 
If the year is available and the month is non-missing, then the following rules will be applied 
relative to the month that study drug treatment was given: 
• If the month in which the AE started is less than the month that the study drug infusion 
was administered, then: 
o If the AE year is less than or equal to the year the study drug infusion was 
administered, then the 15th day of the month will be used. 
o If the AE year is greater than the year the study drug infusion was 
administered, then the maximum of the first day of the month and the treatment 
start date + 1 will be used. 
• If the month in which the AE started is equal to the month that the study drug infusion 
was administered, then: 
o If the AE year is less than the year the study drug infusion was administered, 
then the 15th day of the month will be used. 
o If the AE year is greater than or equal to the year the study drug infusion was 
administered, then the maximum of the first day of the month and the treatment 
start date + 1 will be used. 
• If the month in which the AE started is greater than the month that the study drug 
infusion was administered, then: 
o If the AE year is less than the year the study drug infusion was administered, 
then the 15th day of the month will be used. 
o If the AE year is greater than or equal to the year the study drug infusion was 
administered, then the maximum of the first day of the month and the treatment 
start date + 1 will be used. 


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In case that the AE end date was completed, the AE start date imputed as above was after the 
AE end date, the AE start date was re-imputed using the AE end date. 
Partial AE end dates: There is no STL convention to impute partial AE end date. Partial AE 
end date was imputed using (a) the last date of the month if only the day of AE end date is 
missing, (b) December 31 if only the year of AE end date is present. If a patient dies and the 
imputed end date is after the date of death, the date of death was imputed as the AE end date. 
When a patient dies, the end date for ongoing AEs was imputed using the date of death. 
Adverse events associated with change in renal function 
Adverse events associated with change in renal function are defined based on predefined 
search list which describe a clinically significant change in renal function. A search of the 
clinical trial database will occur based on this pre-specified list of MedDRA preferred terms. 
These adverse events will be summarized by preferred term. In addition, the event rate and 
25th percentile (95% CI) of time to first adverse event associated with change in renal function 
will be summarized. The hazard ratio and 95% CI based on a Cox proportional hazards model 
with treatment as a factor will be presented. Between-treatment differences in time to first 
adverse event associated with change in renal function will be evaluated using the log-rank 
test. If a patient experiences an adverse event associated with change in renal function, the 
event time is defined as the earliest of all events if there are multiple. Otherwise, a patient is 
considered censored at the last contact date. Kaplan-Meier estimates will be plotted over time 
if at least 1% of overall population has experienced the event.  
Patient listings will be provided for all adverse events associated with clinically significant 
change in renal function. 
Hypocalcaemia adverse events and laboratory events 
Hypocalcaemia adverse events will be searched based on preferred term and summarized. 
Patients with reported laboratory measurements associated with a signal of hypocalcaemia 
will be summarized by visit. Lab hypocalcaemia (low serum calcium levels) is present if the 
value of serum calcium from central lab is less than the lower limit of normal range provided 
by the central lab.  
The number and percentage of patients who met these criteria will be summarized by 
treatment group overall. 
The event rate and 25th percentile (95% CI) of time to first hypocalaemia occurrence based on 
AE and central lab calcium will be summarized. The hazard ratio and 95% CI based on a Cox 
proportional hazards model with treatment as a factor will be presented. Between-treatment 
differences in time to first hypocalaemia occurrence based on AEs and central lab will be 
evaluated using the log-rank test. If a patient experiences a hypocalaemia and low calcium 
value based on the central lab, the event time is defined as the earlier of these events. 
Otherwise, a patient is considered censored at the last contact date. Kaplan-Meier estimates 
will be plotted over time if at least 1% of overall population has experienced the event.  
Patient listings will be provided for all adverse events associated with hypocalcaemia. 


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Laboratory parameters 
The summary of laboratory evaluations will be presented with respect to three groups of 
laboratory tests (hematology, serum chemistry, and urinalysis).  
• 
Hematology parameters: hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential counts, and platelet count.  
• 
Serum chemistry parameters: non-fasting glucose, creatinine, serum urea, uric acid, total 
protein, SGOT (AST), SGPT (ALT), alkaline phosphatase, sodium, potassium, 
chloride, phosphorus, magnesium, albumin, calcium; and Glomerular Filtration Rate 
(GFR). 
• 
Urinalysis parameters: amorphous crystals, urine bilirubin, urine blood, calcium oxalate 
crystals, urine color, urine glucose, urine ketone, urine leukocytes, urine nitrite, pH, 
urine protein dipstick, specific gravity, urine urobilinogen, and WBC Casts (Urine) 
/LPF.  
GFR will be calculated using the Schwartz equation at all visits where serum creatinine will 
be measured (Visits 1, 3, 5, 6 and 8) by the Central Laboratory. 
GFR (mL/min/1.73 m2) =k[Height (m)]/Serum Creatinine (mg/dL), where k=0.41 
Descriptive summary statistics for baseline, each post-baseline visit, and change from baseline 
to each visit will be presented by laboratory test group and treatment group. Note that if either 
the baseline or the post-baseline value is missing, then the calculation of change from baseline 
will also be missing.   
Also, shift tables for hematology and serum chemistry will be provided in order to compare a 
patient’s baseline laboratory evaluation relative to each study visit. For the shift tables, the 
normal laboratory values will be used to evaluate whether a particular laboratory test value is 
normal, low, or high for each visit value relative to whether or not the baseline value is 
normal, low, or high. These summaries will be presented by laboratory test group and 
treatment group. 
In addition, a summary table will be presented for the incidence rates of newly occurring 
clinically notable laboratory abnormalities, where patients will be counted if they have normal 
or missing baseline value and with at least one post-baseline assessment satisfying the 
clinically notable criteria. Incidence rates of newly occurring hypocalcaemia (based on central 
lab) by visit will be summarized similarly for patients who have normal or missing baseline 
level of serum calcium and clinically notable abnormal serum calcium level at each scheduled 
post-baseline visit. The definition of clinically notable laboratory abnormalities can be found 
in Appendix section “Clinically notable laboratory values and vital signs” in the protocol. 
Furthermore, a summary table will be provided for the number and percentage of patients 
with liver enzyme abnormalities by each study visit and with at least one post-baseline 
assessment satisfying the liver enzyme abnormalities. 
Listings of all laboratory parameter measurements will be displayed. In addition, listings of 
hematology and biochemistry assessments will be provided for patients with newly occurring 
clinically notable laboratory abnormalities. In these listings, all laboratory values will be 


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displayed for any patient who has at least one newly occurring clinically notable laboratory 
abnormality. The abnormal value will be flagged, e.g., L/H for a value being below/above 
normal range, and the lower and upper limit of normal values will be presented as well.  
Central lab calcium values will also be listed for patients with at least one post-baseline 
laboratory signal of hypocalcaemia and the below normal serum calcium results will be 
flagged as L. 
For each numerical laboratory parameter, the number of decimal places to be used for 
laboratory values should be the same as that for the normal range. For continuous variables 
recorded as <lower limit>, these will be imputed as being half of the lower limit. 
All laboratory parameters will be expressed using SI units. 
Vital signs, 
 and weight 
Descriptive summary statistics for the baseline, each study visit, and change from baseline to 
each study visit will be presented for sitting systolic blood pressure, sitting diastolic blood 
pressure, pulse rate, and body weight. 
 
. The number and percentage of patients who 
have vital sign values that meet the criteria for being clinically notable after the first infusion 
of study medication will be presented by treatment group. In addition to the listing of all vital 
sign data, a patient listing will also be provided for patients with newly occurring clinically 
notable vital signs. The definition of clinically notable vital sign abnormalities can be found in 
Appendix section “Clinically notable laboratory values and vital signs” in the protocol. 
Tanner staging scale 
Tanner staging scale data will be summarized at baseline (Visit 2), Month 6 (Visit 5) and End 
of study (Visit 8). The number and percentage of patients in each Tanner staging scale 
category will be included in the summary. The following tanner staging scales will be 
summarized:  
• 
Female 
o breast development 
o pubic hair 
o menarche occurrence  
• 
Male 
o genital stage  
o pubic hair 
A listing of tanner staging scale by treatment and gender will also be provided.   
Determination of sample size 
The sample size is calculated to show superiority of zoledronic acid relative to placebo at 
Month 12. 
The null hypothesis of no difference between treatment groups in the mean change in lumbar 
spine BMD Z-score at Month 12 relative to baseline. In testing this hypothesis, it is assumed 


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that the standard deviations for the two treatment groups is 0.93 under H0 and HA. Based on a 
primary endpoint of the change in lumbar spine BMD Z-score at 12 months relative to 
baseline assuming a 0.63 increase in lumbar spine BMD Z-score over 12 months with 
zoledronic acid and no change in the Z-score in the placebo group and a common standard 
deviation of 0.93, 82 patients are required to show a significant increase in lumbar spine BMD 
Z-score at the 0.05 level with 85% power. Adjusting for a dropout rate of 10%, approximately 
46 patients per treatment group are required. 
The amount of information from controlled trials in a pediatric GIO population is limited. 
However, the 0.63 increase in lumbar spine BMD Z-score is based on the increase observed 
with pamidronate-treated children on chronic glucocorticoid therapy presented in (Acott et al 
2005). 
The common standard deviation of 0.93 was estimated from the pamidronate-treated children 
and untreated control evaluated in (Acott et al 2005). This standard deviation is also 
consistent with the estimate of the standard deviation obtained from the zoledronic acid group 
of pediatric osteogenesis imperfecta patients in Study CZOL446H2202. 
 
 
 


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References 
Acott DA, Lang BA, Wong JA, et al (2005) Pamidronate treatment of pediatric fracture 
patients on chronic steroid therapy. Pediatric Nephrology, vol 20 : 368 - 373  


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Analysis of covariance (ANCOVA) model 
The following is an example of the SAS code used to perform these analyses. 
 
ods output lsmeans=lsmeans 
           diffs=lsmeandiffcl; 
proc mixed data=xxx; 
  class treat center gluco ; 
random center; 
  model CHGVAR = treat center gluco BASVAR; 
  lsmeans treat / pdiff=control (‘1’) alpha=.05 cl; 
quit; 
 
Adjusted change from baseline 
Mean (SE): lsmeans.LSMean (lsmeans.STDERR) 
Diff, 95% CI: lsmeandiffcl.DIFFERENCE (lsmeandiffcl.LowerCL, lsmeandiffcl.UpperCL) 
p-value (pairwise): lsmeans.ProbtDiff 
 
Logistic regression model 
The following is an example of the SAS code used to perform these analyses. 
 
ods output parameterestimates=EST oddsratios=ODDS; 
proc logistic data=xxx descending; 
format _all_; 
  class treat center gluco/param=ref ref=first ; 
  model RESP = treat center gluco BASVAR; 
run; 
 
Odds ratio: ODDS.oddsratioest where EFFECT contains ‘treat’ 
95% CI for odds ratio: ODDS.LOWERCL and ODDS.UPPERCL where EFFECT contains 
‘treat’ 
P-value: EST.PROBCHISQ where VARIABLE=’treat’ 
 


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Appendix 


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PD and non-PD criteria leading to exclusion from analysis sets 
 
Analysis Set 
PD ID (that causes 
subjeects to be excluded) 
Non-PD criteria (that causes 
subjeects to be excluded) 
ITT 
Not randomized 
MITT 
 
Not in ITT; 
No baseline BMD Z-score; 
No post-baseline Z-score 
SAF 
No study drug taken 
PPS 
All inclusion and exclusion 
criteria; S01; S02; S03; M01 
Not in MITT