Clinical trial NCT01197300
Conditions: Osteoporosis
Keywords: Osteoporosis, children and adolescents, zoledronic acid, chronic inflammation, Duchenne muscular dystrophy, glucocorticoids, chronic inflammatory conditions
Sponsor: Novartis Pharmaceuticals
Start date: 2010-10-25; Completion date: 2019-02-27
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This 1-year open-label extension to CZOL446H2337 is designed to evaluate the safety and efficacy of zoledronic acid twice yearly in osteoporotic children treated with glucocorticoids.

Detailed description:

Arms: arm 1: Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Interventions: intervention 1: Zoledronic acid
Intervention descriptions: intervention 1: intravenous infusion

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine
ZOL446 / zoledronic acid
Clinical Trial Protocol CZOL446H2337E1 / NCT01197300
A 1-year, multicenter, open-label, extension to 
CZOL446H2337 to evaluate safety and efficacy of 
zoledronic acid twice yearly in osteoporotic children 
treated with glucocorticoids 
Document type:
Amended Protocol Version
EUDRACT number:
2010-020399-41
Version number:
v03 (clean)
Development phase:
IIIb
Release date:
18-May-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.1 (February 2016)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Amendment 3 ....................................................................................................................10
Protocol Summary.............................................................................................................13
1
Introduction .......................................................................................................................16
1.1
Background............................................................................................................16
1.2
Purpose ..................................................................................................................17
2
Study objectives.................................................................................................................18
2.1
Primary objective...................................................................................................18
2.2
Secondary objective(s)...........................................................................................18
19
3
Investigational plan ...........................................................................................................20
3.1
Study design...........................................................................................................20
3.2
Rationale of study design.......................................................................................21
3.3
Rationale of dose/regimen, duration of treatment .................................................21
3.4
Rationale for choice of comparator .......................................................................22
3.5
Purpose and timing of interim analyses/design adaptations..................................22
3.6
Risks and benefits..................................................................................................22
4
Population..........................................................................................................................25
4.1
Inclusion criteria ....................................................................................................25
4.2
Exclusion criteria...................................................................................................26
5
Treatment...........................................................................................................................27
5.1
Study treatment......................................................................................................27
5.1.1
Investigational and control drugs..........................................................27
5.1.2
Additional treatment..............................................................................27
5.2
Treatment arms......................................................................................................28
5.3
Treatment assignment............................................................................................28
5.4
Treatment blinding.................................................................................................28
5.5
Treating the patient................................................................................................28
5.5.1
Patient numbering .................................................................................28
5.5.2
Dispensing the study drug.....................................................................28
5.5.3
Handling of study and additional treatment..........................................28
5.5.4
Instructions for prescribing and administering study treatment............29


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5.5.5
Permitted dose adjustments and interruptions of study treatment ........30
5.5.6
Rescue medication ................................................................................30
5.5.7
Concomitant medication .......................................................................30
5.5.8
Prohibited medication ...........................................................................31
5.5.9
Emergency breaking of assigned treatment code..................................31
5.6
Study completion and discontinuation...................................................................31
5.6.1
Study completion and post-study treatment..........................................31
5.6.2
Discontinuation of study treatment .......................................................31
5.6.3
Withdrawal of informed consent...........................................................32
5.6.4
Loss to follow-up ..................................................................................33
5.6.5
Early study termination by the sponsor.................................................33
6
Visit schedule and assessments .........................................................................................33
6.1
Information to be collected on screening failures..................................................38
6.2
Patient demographics/other baseline characteristics .............................................38
6.3
Treatment exposure and compliance .....................................................................38
6.4
Efficacy..................................................................................................................38
6.4.1
Vertebral morphometric fractures.........................................................39
39
6.4.3
DXA measurements ..............................................................................40
6.4.4
Bone marker analysis ............................................................................40
40
6.4.6
Bone age and metacarpal cortical width assessment.............................41
6.4.7
Pain assessment.....................................................................................41
6.4.8
Appropriateness of efficacy assessments..............................................41
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..........................................................................42
6.5.5
Pregnancy and assessments of fertility .................................................44
6.5.6
Bone safety monitoring.........................................................................44
6.5.7
Appropriateness of safety measurements..............................................44
45
45
46
6.6.3
Pharmacokinetics ..................................................................................46
6.6.4
DNA Sampling......................................................................................46


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6.6.5
Other biomarkers...................................................................................46
7
Safety Monitoring..............................................................................................................46
7.1
Adverse Events ......................................................................................................46
7.2
Serious adverse event reporting.............................................................................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.............................................................................51
8.1
Site monitoring ......................................................................................................51
8.2
Data collection.......................................................................................................51
8.3
Database management and quality control............................................................52
8.4
Data Monitoring Committee..................................................................................52
8.5
Adjudication Committee........................................................................................52
9
Data analysis......................................................................................................................52
9.1
Analysis sets ..........................................................................................................53
9.2
Patient demographics and other baseline characteristics.......................................53
9.3
Treatments .............................................................................................................54
9.4
Analysis of the primary variable(s) .......................................................................55
9.4.1
Variable.................................................................................................55
9.4.2
Statistical model, hypothesis, and method of analysis..........................56
9.4.3
Handling of missing values/censoring/discontinuations.......................56
9.4.4
Sensitivity analyses ...............................................................................56
9.5
Analysis of secondary variables ............................................................................56
9.5.1
Efficacy variables..................................................................................56
9.5.2
Safety variables .....................................................................................59
9.5.3
Resource utilization...............................................................................59
59
60
9.5.6
Pharmacokinetics ..................................................................................60
9.5.7
Pharmacogenetics/pharmacogenomics .................................................60
9.5.8
Biomarkers............................................................................................61
9.5.9
PK/PD ...................................................................................................61
9.6
Sample size calculation..........................................................................................61
9.7
Interim analyses.....................................................................................................61
10 Ethical considerations........................................................................................................61


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10.1
Regulatory and ethical compliance........................................................................61
10.2
Informed consent procedures.................................................................................61
10.3
Responsibilities of the investigator and IRB/IEC..................................................62
10.4
Publication of study protocol and results...............................................................62
10.5
Quality Control and Quality Assurance.................................................................62
11 Protocol adherence ............................................................................................................62
11.1
Protocol Amendments ...........................................................................................63
12 References .........................................................................................................................63
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................66
14 Appendix 2: Tanner Staging..............................................................................................72
15 Appendix 3: Faces Pain Scale ...........................................................................................73
74
76
18 Appendix 6: Other subtypes of osteoporosis in children...................................................78
19 Appendix 7: Amount of blood to-be Drawn......................................................................79


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List of tables
Table 5-1
Recommended minimum daily dietary allowances ..............................27
Table 5-2
Preparation of i.v. zoledronic acid infusion ..........................................30
Table 6-1
Group 1 Assessment schedule...............................................................34
Table 6-2
Group 2 Assessment schedule...............................................................36
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................50
Table 13-1
Clinical notable criteria for selected laboratory tests............................66


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List of abbreviations
AE 
Adverse Event
AKI 
Acute Kidney Injury
ALT 
Alanine Aminotransferase
AP
Anterior-posterior
AST 
Aspartate Aminotransferase
BMC 
Bone Mineral Content
BMD 
Bone Mineral Density
BSAP 
Bone Specific Alkaline Phosphatase
CQA
Compliance Quality Assurance
CRO 
Contract Research Organization
DAR 
Dose administration record
DMD
Duchenne muscular dystrophy
DXA 
Dual Energy X-ray Absorptiometry
eCRF 
Case Report/Record Form (electronic)
 
EOS 
End of Study
FAS
Full Analysis Set
FPS-R 
Faces Pain Scale - revised
GC
Glucocorticoids
GCP 
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase 
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
IMS
Integrated Medical Safety
i.v. 
intravenous
IRB 
Institutional Review Board
ISCD
International Society for Clinical Densitometry
JRA
Juvenile rheumatoid arthritis
LS 
Lumbar Spine
MCV
Mean cell volume
MedDRA 
Medical Dictionary for Regulatory Activities
MCHC
Mean cell hemoglobin concentration
NTX 
Cross-linked N-telopeptide
OC/RDC 
Oracle Clinical/Remote Data Capture
OI 
Osteogenesis Imperfecta
ONJ 
Osteonecrosis of the Jaw
P1NP
Procollagen type 1 amino-terminal propeptide


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PMO 
Postmenopausal Osteoporosis
RBC 
Red Blood Cell
RDA 
Recommended Daily Allowance
SAE 
Serious Adverse Event
SAF
Safety population
SLE 
Systemic Lupus Erythematosus
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; the point at which 
informed consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol)
Investigational drug
The study 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.”
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 
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Amendment 3
Amendment rationale

The rationale for this amendment is to reflect the changes in the Core protocol 
(CZOL446H2337) v05 which has been amended 
 to 
provide a Risk Benefit statement (Section 3.6), and allow more countries to apply the 
contraceptive wording originally provided for UK sites only.

The introduction (Section 1) has been revised with more recent references that reflect 
the increase in knowledge of childhood osteoporosis since the protocol was first 
proposed.  

The investigational plan (Section 3) and statistical sections (Section 9) have been 
clarified. 

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. 

Visit 9 for Group 1 is now defined as up to 10 months after Visit 5 (month 6) of the 
Core study, to allow patients who are deteriorating at the time of the second infusion 
during the Core study to enter the Extension study rather than be treated off-label.

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 6 and the exclusion criteria for Group 2 have been revised to 
address these as follows: 

Due to the inclusion of some of these additional medical conditions, e.g. 
nephrotic syndrome, 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 Visit 8 (Group 1) or Visit 8A 
(Group 2). 

Schwartz formula has been added under Section 6.5.4.2

In addition ‘serious renal disease’ in DMD has been removed as this is included 
under the GFR exclusion criterion. 

In DMD patients, chronic muscle breakdown results in elevated aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) (frequently higher 
than 10 fold); hence total bilirubin and gamma-glutamyl transpeptidase (GGT) 
have been added as additional markers to detect any potential liver toxicity.


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
The exclusion criterion ‘symptomatic cardiac abnormality’ in DMD has been 
redefined 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 Visit 8A for 
Group 2. 

The blood volume required (Appendix 7) for the analysis of specialized bone 
markers has been reduced from 8.5 mL to 3 mL. 

The local serum creatinine before the second infusion of zoledronic acid has been 
removed because of the need for normal renal function as an eligibility criterion. Renal 
function is reviewed centrally before and 10 days after each infusion.

Inconsistencies have been corrected within the protocol and across supporting documents 
especially with respect to Serious Adverse Event/Adverse Event reporting in Group 2 and 
central laboratory analyses. 

In this 12 month study, visit windows have been removed and replaced with a requirement 
to perform the visit as close to the designated day as possible. For Group 2 only, the time 
between Visit 8A and Visit 9 should be as close to 28 days as possible, but cannot be 
longer than 8 weeks. 
The latest Novartis protocol template has been used to aid the reader in navigating the 
protocol and more some procedures have been revised in line with our current processes.
Status of the study as of 10-May-2016:
Twelve (12) patients have been enrolled onto this study, all were enrolled into Group 1; the 
proposed changes will have no impact on the interpretation of the data.
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 herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Summary of previous amendments:
Amendment 2
The rationale for this amendment (dated 15-Jan-2014) was to reflect the changes in the Core 
(CZOL446H2337) protocol v04 which extended the study population to include subjects with 


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underlying conditions other than chronic inflammatory disorders e.g. Duchenne muscular 
dystrophy (DMD).

Include (Group 2): patients not eligible to enroll into the Core study because of clinically 
significant back pain (significant symptoms) from vertebral fracture and the preexisting 
clinical care at the Investigator’s site is to treat this type of patient with a bisphosphonate. 
Therefore two Baselines are used in the study:

Baseline 1: First visit of the Core for Group 1

Baseline 2: First visit of the Extension for Group 2.

Align with the Core study changes in the Inclusion/Exclusion criteria:

Relax the LS BMD Z-score inclusion criteria from -1.0 to -0.5 or worse.

Modify the exclusion criteria of patients with any prior use of osteoporosis/bone 
modifying therapy. Bisphosphonates and sodium fluoride will be kept in the exclusion 
criteria. Calcitonin, calcitriol, SERMS, LHRH agonists, Growth Hormone and 
medroxyprogesterone will be taken out from the exclusion criteria

Modify the exclusion criteria of patients with any prior use of osteoporosis/bone 
modifying therapy and to allow non-ambulatory patients who require wheelchair 
assistance for mobility to enter the study.

Add exclusion criteria for history of serious renal disease and symptomatic cardiac 
involvement in DMD patients.

Align with the Core study changes in the assessments by adding the following:

Serum 25-hydroxy vitamin D concentration at Month 12 of the Extension.

Eliminated 24-hours and 48-hours post-first dose local serum ionized calcium 
measurements.
Amendment 1
This amendment (dated 29-Nov-2012) applied to United Kingdom (UK) sites only, regarding 
contraception and pregnancy in female patients of child bearing potential.


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Protocol Summary
Protocol 
number
CZOL446H2337E1
Title
A 1-year, multicenter, open-label, extension to CZOL446H2337 to evaluate safety 
and efficacy of zoledronic acid twice yearly in osteoporotic children treated with 
glucocorticoids
Brief title
A 12-month observational 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 safety of zoledronic acid plus vitamin D and calcium in osteoporotic 
children treated with glucocorticoids
Primary 
Objective(s) 
To demonstrate that zoledronic acid given long-term, over an additional 12 months 
from the Core study (CZOL446H2337), is safe for the treatment of osteoporotic 
children treated with glucocorticoids (Group 1 only)
Secondary 
Objectives
Group 1:
1. To evaluate the change from baseline (Visit 1 of the Core study) in LS BMD Z-
score at Month 18 and 24 by core treatment group.
2. To evaluate the change from baseline 1 (Visit 1 of the Core study) in LS and total 
body BMC at Month 18 and 24 by core treatment group.
3. To evaluate the change from baseline 1(Visit 1 of the Core study) in serum N-
terminal propeptide type I collagen (P1NP), cross linked N-telopeptide (NTX), 
bone specific alkaline phosphatase (BSAP) and tartrate-resistant acid 
phosphatase isoform 5b (TRAP-5b) at Month 18 and 24 by core treatment 
group.
4. To evaluate the proportion of patients with new clinical vertebral fractures during 
the 12 month extension period by core treatment group.
5. To evaluate the proportion of patients with new morphometric vertebral fracture 
during the 12 month extension period by core treatment group.
6. To evaluate the change from baseline 1 (Visit 1 of the Core study) in pain using 
the Faces Pain Scale-Revised (FPS-R) at Month 15, 18, 21 and 24 by core 
treatment group.
7. To evaluate the change from baseline 1 (Visit 1 of the Core study) in 2nd 
metacarpal cortical width at month 24 by core treatment group.
8. To evaluate the change from baseline 1(Visit 1 of the Core study) in bone age 
and 2nd metacarpal cortical width at month 24 by core treatment group.
Group 2:
1. To evaluate the change from (Extension) baseline 2 (Visit 8A) in LS-BMD Z-
score at Month 6 and 12.
2. To evaluate the change from (Extension) baseline 2 (Visit 8A) in LS and total 
body BMC at Month 6 and 12.
3. To evaluate the relative change from (Extension) Baseline 2 in serum N-terminal 
propeptide type I collagen (P1NP), cross linked N-telopeptide (NTX), bone 
specific alkaline phosphatase (BSAP) and tartrate-resistant acid phosphatase 


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isoform 5b (TRAP-5b) at Month 6 and 12.
4. To evaluate the proportion of patients with new clinical vertebral fractures during 
the 12 month period.
5. To evaluate the proportion of patients with new morphometric vertebral fracture 
during the 12 month period.
6. To evaluate the change from (Extension) baseline 2 in pain using the Faces Pain 
Scale-Revised (FPS-R) at Month 3, 6, 9 and 12.
7. To evaluate the change from (Extension) baseline 2 in bone age and 2nd 
metacarpal cortical width at Month 12.
8. To demonstrate that zoledronic acid is safe for the treatment of osteoporotic 
children (with symptomatic vertebral fracture) treated with glucocorticoids, 
through the monitoring of relevant clinical and laboratory safety parameters.
Study design
This will be an international multi-center, 1-year open-label extension to the 
CZOL446H2337 Core study with a single treatment arm (zoledronic acid); there will 
be no placebo or active control group. All patients will have received glucocorticoid 
therapy of any duration within the 12 months preceding screening.
Population
The trial population will consist of male and female children and adolescents with a 
confirmed diagnosis of non-malignant conditions requiring treatment with systemic 
glucocorticoids. All patients who complete the Core study (Group 1) will be eligible.
Those patients who were found to be eligible for the Core study but not enrolled due 
to clinically significant back pain associated with the fracture (Group 2).
Approximately 100 patients will be eligible for enrollment into the extension, for both 
groups. Patient recruitment in Group 2 will stop once enrollment in the Core study is 
completed.
Key Inclusion 
criteria
Written informed consent before any study-related procedure.
Group 1:
1. Children and adolescents, male or female, 6-19 years old, who met the inclusion 
criteria for entry into the Core study and who took at least one dose of study 
drug and have completed Visit 8 of the CZOL446H2337 Core study.
2. Patient must be enrolled into the extension at Visit 9 up to 10 months after Visit 5 
(month 6) of the Core study.
3. Patients who followed the regimen of calcium and vitamin D intake as required in 
the Core study through diet or supplementation.
Group 2:
1. Children and adolescents, male or female, 5 - 17 years old who met the inclusion 
criteria for entry into the Core study but were not enrolled because of clinically 
significant back pain from vertebral fracture and the preexisting clinical care at 
the Investigator site is to treat this type of patient with a bisphosphonate.
2. Confirmed diagnosis of non-malignant conditions (including but not limited to 
rheumatic conditions, inflammatory bowel disease, Duchenne muscular 
dystrophy, nephrotic syndrome), treated with systemic glucocorticoids (i.v. or 
oral) within the 12 months preceding enrollment in the study (any duration)
3. LS-BMD Z-score of -0.5 or worse confirmed by the central imaging vendor
4. 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 radiological report. (*Low 
trauma fracture is defined as falling from standing height or less).
Key Exclusion 
1.
Major protocol violation in the Core Study (Group 1 only).


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criteria
2.
Prior use of bisphosphonates (Group 2 only) or sodium fluoride (doses for 
osteoporosis not for dental hygiene).
3.
Hypocalcemia and hypophosphatemia: any value (age-matched) below the 
normal range at Visit 8 or 8A.
4.
Vitamin D deficiency (serum 25-hydroxy vitamin D concentrations of < 20 
ng/mL or < 50 nmol/L) at Visit 8 (Group 1) or Visit 8A (Group 2).
5.
Renal impairment defined as an estimated glomerular filtration rate (GFR) 
< 60 mL/min/1.73 m2 at screening based on the Schwartz formula at Visit 8 
or 8 A; a serum creatinine above the normal range at Visit 9 (Group 1) or 
an increase between Visit 8A and Visit 9 greater than 0.5 mg/dL (44.2 
μmol/L) for Group 2.
6.
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) 5.0 mg/100 mL solution, supplied in a ready-to-infuse 
plastic bottle
Efficacy 
assessments
The efficacy variables will be measured using the following techniques:

vertebral morphometric fractures

DXA measurements

bone marker analysis

bone age and metacarpal cortical width assessment

pain assessment
Key safety 
assessments
Adverse event monitoring, Physical examinations, Monitoring of laboratory markers 
in blood and urine; and bone safety monitoring.
Data analysis
Data analyses will be performed separately for the two populations (Group 1 [SAF-
1] and Group 2 [SAF-2]), if not otherwise specified. 
For the patients in Group 2 (SAF-2); only descriptive statistics will be reported for 
the single treatment arm.
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 (OI)
(primary osteoporosis). Although the diagnosis of osteoporosis in adults is based on BMD, 
Sbrocchi et al 2011 reported a child with glucocorticoid (GC) 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 dual X-ray absorptiometry 
(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 GCs are at increased risk of significant bone loss and 
fractures; GC-induced osteoporosis (GIO) is now recognized as one of the most important 
reasons for secondary osteoporosis in adults as well as children. Prior GC 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 GC 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 GCs (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-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 GC therapy which can further worsen 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 GC therapy. Osteoporosis is most profound in the lower extremities of boys with 
DMD and begins to develop early while still ambulatory (Larson and Henderson 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).
There is no established treatment for secondary osteoporosis in children, although treatment
for adult osteoporosis including GIO is currently well established for bisphosphonates.


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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 2010).
Zoledronic acid
Zoledronic acid is a third generation bisphosphonate and is the most potent bisphosphonate 
marketed. In a variety of assays of bone metabolism, zoledronic acid has demonstrated 
inhibition of bone resorption in vitro at concentrations of 0.3-30 nM and in vivo at doses of 
0.3-30 μ g/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’s Brochure (IB)].
Zoledronic acid 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 adult 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 approximately a 10-fold higher dose on a 
yearly basis (4 mg once monthly). 
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 determine whether bisphosphonates 
would make a difference to children’s bone mineral content (BMC), further use of 
bisphosphonates in the context of pediatric trials was justified.
1.2
Purpose 
The purpose of this study is to extend the period of observation in patients who have 
completed one year of evaluation in the Core study (CZOL446H2337) to evaluate the long-
term safety and efficacy of zoledronic acid in osteoporotic children or adolescents treated with 
GCs. Patients who completed the Core study are referred to in this protocol as patients in 
Group 1. This study will also add to the information available on the management of 


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secondary osteoporosis in children (Hogler and Ward 2015) and will help to determine if there 
is added benefit of a second year of treatment with zoledronic acid.
In addition, the study will evaluate safety and efficacy of zoledronic acid in patients who are 
not eligible to be randomized to the Core study due to clinically significant back pain 
(significant symptoms) from vertebral fracture when the preexisting clinical care at the 
investigator’s site is to treat this type of patient with a bisphosphonate. These patients are
included in this protocol in Group 2.
2
Study objectives
2.1
Primary objective
The primary objective of this study is to demonstrate that zoledronic acid given long-term, 
over an additional 12 months from the Core study (CZOL446H2337), is safe for the treatment 
of osteoporotic children treated with glucocorticoids. This objective applies only to patients 
who completed the Core study (these patients are referred to as Group 1).
2.2
Secondary objective(s)
Group 1 secondary objectives:
1. To evaluate the change from baseline 1 (Visit 1 of the Core study) in LS-BMD Z-score at 
Month 18 and 24 by core treatment group.
2. To evaluate the change from baseline 1 (Visit 1 of the Core study) in LS and total body 
BMC at Month 18 and 24 by core treatment group.
3. To evaluate the change from baseline 1(Visit 1 of the Core study) in serum N-terminal 
propeptide type I collagen (P1NP), cross linked N-telopeptide (NTX), bone specific 
alkaline phosphatase (BSAP) and tartrate-resistant acid phosphatase isoform 5b (TRAP-
5b) at Month 18 and 24 by core treatment group.
4. To evaluate the proportion of patients with new clinical vertebral fractures during the 12 
month extension period by core treatment group.
5. To evaluate the proportion of patients with new morphometric vertebral fracture during 
the 12 month extension period by core treatment group.
6. To evaluate the change from baseline 1 (Visit 1 of the Core study) in pain using the Faces 
Pain Scale-Revised (FPS-R) at Month 15, 18, 21 and 24 by core treatment group.
7. To evaluate the change from baseline 1 (Visit 1 of the Core study) in 2nd metacarpal 
cortical width at month 24 by core treatment group.
8. To evaluate the change from baseline 1(Visit 1 of the Core study) in bone age and 2nd
metacarpal cortical width at month 24 by core treatment group.
Group 2 secondary objectives:
1. To evaluate the change from (Extension) baseline 2 (visit 8A) in LS- BMD Z-score at 
Month 6 and 12.
2. To evaluate the change from (Extension) baseline 2 (visit 8A) in LS and total body BMC 
at Month 6 and 12.


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3. To evaluate the relative change from (Extension) baseline 2 in serum N-terminal 
propeptide type I collagen (P1NP), cross linked N-telopeptide (NTX), bone specific 
alkaline phosphatase (BSAP) and tartrate-resistant acid phosphatase isoform 5b (TRAP-
5b) at Month 6 and 12.
4. To evaluate the proportion of patients with new clinical vertebral fractures during the 12 
month period.
5. To evaluate the proportion of patients with new morphometric vertebral fracture during 
the 12 month period.
6. To evaluate the change from (Extension) baseline 2 in pain using the Faces Pain Scale-
Revised (FPS-R) at Month 3, 6, 9 and 12.
7. To evaluate the change from (Extension) baseline 2 in bone age and 2nd metacarpal 
cortical width at Month 12.
8. To demonstrate that zoledronic acid is safe for the treatment of osteoporotic children (with 
symptomatic vertebral fracture) treated with GCs, through the monitoring of relevant 
clinical and laboratory safety parameters.


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3
Investigational plan
3.1
Study design
This study is a 1-year open-label extension to the CZOL446H2337 Core study. The study uses 
a single treatment arm (zoledronic acid); there will be no placebo or active control group. All 
patients will be osteoporotic children and adolescents receiving GC therapy of any duration 
within the 12 months preceding Baseline (Visit 1 of the Core study for Group 1; Visit 8A of 
this study for Group 2). All patients must manifest a LS-BMD Z-score of -0.5 or worse and 
have evidence of low impact/fragility fracture at either the Baseline of the Core Study (Group 
1) or this study (Group 2).
Group 1: Patients who have received at least one dose of study drug and who have completed 
the Core study and who meet the inclusion/exclusion criteria for this Extension study will be 
eligible to enroll. The final visit of the Core study (Visit 8) will serve as the first (screening)
visit for the Extension study. At Visit 8A, which may take place on the same day as Visit 8, 
patients will complete additional screening assessments for the Extension study.  Patients will 
return at Visit 9 (which can also be on the same day as Visit 8 of the Core study) and all 
patients will receive zoledronic acid. The allowed window for Visit 9 is up to10 months after 
Visit 5 (month 6) of the Core study (up to 4 months after Visit 8 of the Core study). Note that 
Visit 8 and Visit 9 can be combined if the patients or parents or legal guardians have provided 
informed consent to enter into the Extension study prior to Visit 8 and undergone the 
appropriate screening procedures as outlined in Section 6. Central labs from Visit 8 will be 
utilized for the Extension Visit 9, provided the lab samples have been collected within 30 days 
prior to the Visit 9 infusion. Otherwise, the labs must be redrawn and the results reviewed for 
eligibility, prior to infusion at Visit 9. The DXA scans (hip, spine and distal femur) from Visit 
8 will be used for the extension Visit 9 provided the DXAs have been obtained within 3 
months of the Visit 9 infusion; otherwise, the DXA scans must be repeated at Visit 9.
Group 2: Children, male or female, 5 to 17 years of age who otherwise met the inclusion 
criteria for entry into the Core study but did not complete screening on the Core study because 
of clinically significant back pain due to vertebral fracture and the preexisting clinical care at 
the Investigator’s site is to treat this type of patient with a bisphosphonate.
Visit 8 A will serve as the first (screening) visit for Group 2. Patients will return at Visit 9 and 
all patients will receive zoledronic acid. The allowed screening window between Visit 8 A 
and Visit 9 is 30 days. Central labs from Visit 8 A will be utilized for Visit 9, provided the lab 
samples have been collected within 30 days prior to the Visit 9 infusion. Otherwise, the labs 
must be redrawn and the results reviewed for eligibility, prior to infusion at Visit 9. The DXA 
scans (hip, spine and distal femur) and X-rays collected at Visit 8 A will be read centrally and 
if the child/adolescent is eligible, used for Baseline provided the DXAs have been obtained 
within 3 months of Visit 9; otherwise, the DXA scans must be repeated at Visit 9.
All Patients (Group 1 and Group 2) will receive two infusions of i.v. zoledronic acid 
(0.05 mg/kg) with an interval of 6 months at Visit 9 and at Visit 12. 
Safety and efficacy will be assessed at 6 (Visit 12) and 12 months (Visit 15), with additional 
visits 10 days after each infusion to evaluate on renal and calcium (Visit 10 and 13) as well as 


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telephone visits to assess pain, adverse events 
 and concomitant 
medication at 3 (Telephone Visit 11) and 9 (Telephone Visit 14) months.
3.2
Rationale of study design
The study is an open-label study where all patients will be receiving active study drug 
(zoledronic acid 0.05mg/kg).
Group 1: The Core study, CZOL446H2337, is part of a Pediatric Investigational Plan 
(EMEA-000057-PIP01-07), 
. This 
one-year study will extend the period of observation in patients who have completed the Core 
protocol and will collect long-term safety and efficacy data (Group1).  The primary objective 
of the study will focus on general safety. The Extension study is an open-label study where all 
patients will receive active study drug (zoledronic acid 0.05 mg/kg). Given the rapid bone loss 
associated with the use of GCs and the fracture inclusion criteria for enrollment in the Core 
study, an open-label study design addresses ethical considerations for those patients who were 
randomized to receive placebo in the Core study who may deteriorate and require an active 
intervention, while at the same time allowing for the primary objective to be assessed.
Group 2: The study will capture additional safety and efficacy data on zoledronic acid from 
patients who presented with clinically significant back pain (significant symptoms) from 
vertebral fracture who were not enrolled into the Core study (Group 2) because the pre-
existing clinical care at the Investigator’s site is to treat this type of patient with a 
bisphosphonate. 
3.3
Rationale of dose/regimen, duration of treatment
Zoledronic acid dose selection for Study CZOL446H2337E1 is based on several sources of 
information, including safety and efficacy data from completed Novartis clinical trials in 
adults with postmenopausal osteoporosis and GIO, 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 et 
al 2002; Black et al 2007). Adults with benign disease (Paget’s and PMO) have received 
safely up to 5 mg i.v. by slow injection (over 15 minutes) over various dosing frequencies. 
Cancer patients have received up to 4 and 8 mg i.v. monthly, in long term studies (> 1 year). 
In the zoledronic acid clinical development program in pediatrics to date, the dose selection 
was an infusion of 0.05 mg/kg (max 4mg) administered quarterly. This dose was extrapolated 
from a comparison with a pamidronate infusion in patients with tumor-induced hypercalcemia 
that showed that 4 mg zoledronic acid was more effective than 90 mg pamidronate. The 4 mg 
dose of zoledronic acid represents an approximate adult dose of zoledronic acid 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). In this pivotal trial, the pamidronate dosing 
interval was changed to an every 4 month dosing regimen as monthly evaluations of serum 
alkaline phosphatase concentration and urinary calcium excretion increased after 4 months.
The Study CZOL446H2202 is the largest NVS-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 


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successive days administered quarterly in 155 patients with severe OI. The results showed that 
zoledronic acid was superior to pamidronate in increasing LS -BMD at month 12 and in 
reducing markers of bone turnover, both formation and resorption. 
 
 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 
zoledronic acid in this patient population. In addition to efficacy and safety evaluations, Study 
CZOL446H2202 assessed the pharmacokinetics of zoledronic acid. The pharmacokinetics of
a single infusion of zoledronic acid 0.05 mg/kg, in children and adolescents 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 (Study 
CZOL446H2202E1), the 12-month Extension study to CZOL446H2202, long-term safety was 
assessed in 103 patients receiving 0.05 mg/kg zoledronic acid either as an annual infusion or 
twice yearly (6 months apart). In this study, median increases in LS-BMD were 
approximately 1.3% higher in patients who received the twice yearly dosing of zoledronic 
acid. Though these data from Study CZOL446H2202E1 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 the on-going Core protocol, 
0.05 mg/kg as two i.v. infusions with 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.  This same dose and regimen will be used into this protocol. 
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 secondary osteoporosis, zoledronic acid will be administered as at least 
a 30 minute i.v. infusion. Dose limitation and a 30 minute infusion time are designed to 
reduce the risk of possible adverse effects while maintaining efficacy.
3.4
Rationale for choice of comparator
No placebo-treatment arm will be used in this Extension study.
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable.
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 GCs is outlined in Section 1.1 and in the Investigator’s 
Brochure. 


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Additional evidence suggests 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).
The skeletal toxicity of GC is confirmed in adults and children. 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). 
Risks
Known risks of zoledronic acid
Since this protocol was first written in 2010, 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). 
Zoledronic acid 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 
adults regarding the nephrotoxicity of zoledronic acid 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 glomerular filtration rate 
(GFR) < 60 ml/min/1.73 m2. In addition patients considered for Group 2 who have 
nephrotic syndrome with osteoporosis, who do not meet this exclusion criterion, 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 
of infusion and parent/legal guardian instructions provided on the signs to watch for as 
well as an emergency number, if needed.
A rare risk in patients who receive bisphosphonates is osteonecrosis of the jaw (ONJ). This 
condition has been reported in cancer patients whose complex treatment regimens include 
higher doses and frequencies of bisphosphonates, typically administered with other treatments 
such as radiation, chemotherapy and GCs. To date, 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.


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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 et al 2000), 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, all subjects 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 [Section 4.3.5 of 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 
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 


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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
Group 1: Patients who have received at least one dose of study drug, have completed 
participation in the Core study and who meet the inclusion/exclusion criteria for this extension, 
will be eligible to participate.  These patients have been previously diagnosed with non-
malignant conditions (including but not limited to rheumatologic conditions, IBD, DMD, 
nephrotic syndrome) and have been treated with systemic GCs (i.v. or oral) prior to the Core 
study and have evidence of at least 1 vertebral compression fracture confirmed by central 
reading or one or more low-trauma lower extremity long bone fractures or two or more low 
trauma upper extremity long bone fractures confirmed by radiology report. 
Group 2: Patients who were not eligible for the Core study because of clinically significant 
back pain from vertebral fracture and the preexisting clinical care at the Investigator’s site is 
to treat this type of patient with a bisphosphonate.
Approximately 100 patients will be eligible for enrollment into the extension, for both groups. 
Patient recruitment in Group 2 will stop once enrollment in the Core study is completed 
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:

Written informed consent must be obtained before any assessment is performed. An assent 
needs to be provided in accordance with ICH and local regulations.
Group 1:
1. Children and adolescents, male or female, between 6 to 19 years of age who met the 
inclusion criteria for entry into the Core study and who took at least one dose of study 
drug and have completed Visit 8 of the CZOL446H2337 Core study.
2. Patient must be enrolled into the extension at Visit 9 up to 10 months after Visit 5 (month 
6) of the Core study.
3. Patients who followed the regimen of calcium and vitamin D intake as required in the 
Core study (at least 1000 mg calcium for 6-8 years of age or at least 1300 mg calcium for 
9-19 years of age and at least 600 IU daily vitamin D, through diet or supplementation). 
Group 2:
1. Children and adolescents, male or female, between 5 to 17 years of age who met the 
inclusion criteria for entry into the Core study but were not enrolled because of clinically 
significant back pain from vertebral fracture and the preexisting clinical care at the 
Investigator’s site is to treat this type of patient with a bisphosphonate.
2. Confirmed diagnosis of non-malignant conditions (including but not limited to rheumatic 
conditions, inflammatory bowel disease, Duchenne muscular dystrophy, nephrotic 
syndrome who have stable normal renal function for at least 3 months prior to screening or 


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other subtype of secondary osteoporosis in children taking GCs, except patients with 
oncologic conditions (such as lymphoma and leukemia) see Appendix 6), treated with
systemic GCs (i.v. or oral) within the 12 months preceding enrollment in the study (any 
duration)
3. Lumbar Spine areal BMD Z-score of - 0.5 or worse confirmed by central imaging
4. Evidence of at least 1 vertebral compression fracture (at least Genant Grade 1 vertebral 
compression or radiographic signs of vertebral compression*) seen on X-ray within 1 
month of or at screening visit confirmed by central reading.
*Radiographic signs of vertebral compression fracture include loss of endplate parallelism, 
vertebral buckling and endplate interruption.
4.2
Exclusion criteria
1. Patients who demonstrated a major protocol violation in the Core study (Group 1 only)
2. Patients for whom the investigator considers participation in the Extension study is not 
appropriate (Group 1 only).
(For both groups) 
3. Hypocalcaemia and hypophosphatemia: any value (age-matched) below the normal range 
at Visit 8 or 8 A.
4. Vitamin D deficiency (serum 25-hydroxy vitamin D concentrations < 20 ng/mL or 
< 50 nmol/L) at Visit 8 for Group 1, Visit 8 A for Group 2. 
5. Local serum ionized calcium below the normal range at Visit 9.
6. Renal impairment defined as an estimated GFR < 60 ml/min/1.73 m2 based on the 
Schwartz formula at screening Visit 8 or 8 A (in the case of DMD additional methods may 
have been recorded in the source documents). Serum creatinine above the normal range at 
Visit 9 (Group 1) or an increase between Visit 8 A and Visit 9 greater than 0.5 mg/dL 
(44.2 μmol/L) for Group 2.
7. Uncontrolled symptoms of cardiac failure or arrhythmia
8. Any prior use of bisphosphonates (other than study drug during the Core study for Group 
1 only) or sodium fluoride (doses for osteoporosis not for dental hygiene).
9. Current active hyperparathyroidism or hyper/hypothyroidism or during the Core study.
10. New diagnosis of sarcoidosis currently or during the Core study.
11. New malignancy diagnosis currently or during the Core study.
12. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes.
13. History of primary bone disease (OI, idiopathic juvenile osteoporosis, rickets/
osteomalacia).
14. 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. 


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
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 where additional safeguards are required only: 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 preferable 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 
Visit 11 (Month 15) (See Section 6.5.5).
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Zoledronic acid 5.0 mg/100 ml solution supplied in a ready-to-infuse plastic bottle, twice 
yearly.
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, 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 (RDA) of vitamin D and calcium (through diet and/or supplementation)(Ross et al 
2011). 
Table 5-1
Recommended minimum daily dietary allowances 
Age 
Vitamin D 
Calcium
≥ 5 years to ≤ 8 years 
600 IU 
1000 mg 
≥ 9 years to ≤ 20 years 
600 IU 
1300 mg
All patients should take at least 600 IU vitamin D daily from Visit 8/8A until the final 
extension study visit through diet and/or supplementation. 
Elemental calcium, at least 1000 mg for 5-8 years of age or at least 1300 mg for 9-20 years of 
age, daily will be taken beginning at Visit 8/8A and during the total duration of the trial,
through diet and/or supplementation. Calcium carbonate is the preferred form of calcium 


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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 eCRF.
In addition, transient hypocalcemia has been reported following the first infusion and it can 
cause symptoms in rare cases. To prevent the development of symptomatic hypocalcemia, the 
parent or legal 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 at least from 
the day of infusion and for a minimum of 5 days after the 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
All patients will be given open-label zoledronic acid.
5.3
Treatment assignment
Not applicable, as this is an open-label trial.
5.4
Treatment blinding
This is an open-label study and treatment blinding is not applicable.
5.5
Treating the patient
5.5.1
Patient numbering
Group 1: Each patient entering this Extension study will continue to be identified by the 
patient number assigned in the Core study, CZOL446H2337.  
Group 2:  Patient number consists of a four digit Center number (e.g. 0001) followed by a 
five digit patient number. The five digit patient number for the first patient starts at 101 (e.g.
00101). Example of patient number in Group 2:  0001_00101.
5.5.2
Dispensing the study drug
Each study site will be supplied by Novartis with study drug in packaging of identical 
appearance.
The study drug packaging has a 2-part label. Immediately before dispensing study drug to the 
patient, 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. 
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 


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designated assistants have access. Upon receipt, all study drugs should be stored according to 
the instructions specified on the drug labels. Clinical supplies are to be dispensed only in 
accordance with the protocol.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug, but no information about the 
patient. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Monitoring of drug accountability will be performed by 
the field monitor during site visits and at the completion of the trial. Patients will be asked to 
return all unused study drug and packaging at the end of the study or at the time of study drug 
discontinuation. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger 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 of the eCRF specifically:

Calcium supplements at the time of infusion (all patients)

Multivitamins that contain the RDA for calcium and vitamin D from Visit 8/8A to Visit 
15 in line with Table 5-1

Calcium or calcium plus vitamin D supplements from Visit 8/8A to Visit 15 in line with 
Table 5-1

Vitamin D as a single supplement from Visit 8/8A to Visit 15 in line with Table 5-1
Details are described in the CRF completion guidelines.
5.5.4
Instructions for prescribing and administering study treatment
Patients will receive a single dose of zoledronic acid of 0.05 mg/kg, administered as a slow 
infusion of 100 ml over 30 minute, at Visit 9 and Visit 12.
AGE
DOSE 
of 
ZOLEDRONIC 
ACID
TIME OF INFUSION
≥ 5 years to 20 years
0.05 mg/kg diluted in 100 ml 
of normal saline
30 minute infusion
The zoledronic acid dose is not to exceed 5.0 mg.


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A peripheral intravenous site must be used for the zoledronic acid 30 minute 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 i.v. zoledronic acid infusion
Pt Weight   
(kg)
Patient dose 
based on 0.05 
mg/kg
Total
number
of 5.0 
mg/100ml  
vials
Volume
of zoledronic 
acid 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  /  
5 mg / 100 ml= 
Patient dose
100 ml
100 ml + 
volume of 
reconstituted 
zoledronic 
acid to add
Note: The maximum dose is 5 mg therefore the maximum volume from the  5mg/100ml zoledronic 
acid vial to be used in this study is 100ml
The investigator should promote compliance by instructing the patient to take the study drug 
exactly and additional treatment as prescribed and by stating that compliance is necessary for 
the patient’s safety and the validity of the study. The patient should be instructed to contact 
the investigator if he/she is unable for any reason to take the study drug as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments and/or interruptions are not permitted.
5.5.6
Rescue medication
Not applicable.
5.5.7
Concomitant medication
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study drug. All medications and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the patient
starts treatment with study drug must be listed on the Concomitant medications/Significant 
non-drug therapies after start of study drug eCRF. 
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-


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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. 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 of infusion and 
parent or legal guardian instructions provided on the signs to watch for as well as an 
emergency number, if needed.
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 eCRF 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, high dose sodium fluoride, denosumab.
5.5.9
Emergency breaking of assigned treatment code
Not applicable in this open-label study.
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 15, Month 24).
Continuing care should be provided by investigator and/or referring physician based on 
patient availability for follow-up. This care may include:

Alternative therapy may be prescribed at the discretion of the treating physician at Visit 15 
(EOS).
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 12, Month 18, and can be initiated by either the 
patient, parent/legal guardian 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: 

Patient or parent/legal guardian’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:


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
ONJ

Renal failure

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject 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 (TD) visit. Treatment 
discontinuation visit assessments detailed in Visit 15 (Month 24) in Table 6-1 or Table 6-2
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 and the study completion CRF. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone visits: 

new / concomitant treatments

adverse events (AEs)/serious adverse events (SAEs)
If the patient, parent/legal guardian cannot or is unwilling to attend any visit(s), the site staff 
should maintain regular telephone contact with the patient and parent/legal guardian, or with a 
person pre-designated by the patient or parent/legal guardian. This telephone contact should 
preferably be done according to the study visit schedule and changes recorded in the relevant 
pages of the CRF. 
5.6.3
Withdrawal of informed consent 
Patients and/or parents/legal guardians may voluntarily withdraw consent to participate in the 
study for any reason at any time. Withdrawal of consent (WoC) from the study is defined as 
when a patient, parent/legal guardian:

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 
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s or parent’s/legal guardian’s decision to 
withdraw his/her consent and record this information. 
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. 


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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 and Table 6-2.
5.6.4
Loss to follow-up 
For subjects 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 subject, 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 and Table 6-2 list all of the assessments and indicate 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.
Patients will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment.


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Table 6-1
Group 1 Assessment schedule
Final 
visit of 
Core 
study
Infusion visit
Tele-
phone
Infusion 
visit
Tele-
phone
Notes
Visit
8
8A
9
10
11
12
13
14
15/EOS and 
TD and/or 
PSW
Visit 8 is the Core study completion visit.  Visit 8A 
lists the additional assessments which need to be 
completed for the Extension study.  Visits 8 and 8A 
assessments must be completed on the same day.  
Visits 8, 8A, and 9 can occur on the same day
Months relative to the Core study 
(after Visit 9 - Baseline of Extension 
study)
up to 10 
months after 
V5 (Core 
study)
10
days 
after 
V9
15 (3 
months  
after V9)
18 (6 
months 
after V9)
10
days 
after 
V12
21 (9 
months 
after V9)
24 (12 
months after 
V9)
Obtain informed consent (D) and 
assent (S)
X
Inclusion/exclusion criteria (S)
X
X
Prior/concomitant medications
including GCs (D)
X
X
X
X
X
X
X
X
X
Adverse events (D)
X
X
X
X
X
X
X
X
X
Any AEs that occur after Visit 8 but prior to first 
dose of Extension study (Visit 9) will be collected 
on the AE (e)CRF
Vital signs (D)
X
X
X
X
Pulse rate and blood pressure only
Physical examination (S)
X
X
X
X
Including an oral examination for exposed bone
Tanner staging (D), if applicable
X
X
Weight (D)
X
X
X
X
Pain assessment
X
X
X
X
X
X
Pain is assessed using Faces Pain Scale-Revised 
(FPS-R)
Central laboratory test (hematology, 
biochemistry including urinalysis)
X
X
X
X
X
X
All patients will have limited blood chemistry 
assessments, GFR and urinalysis performed at 


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Final 
visit of 
Core 
study
Infusion visit
Tele-
phone
Infusion 
visit
Tele-
phone
Notes
Visit
8
8A
9
10
11
12
13
14
15/EOS and 
TD and/or 
PSW
Visit 8 is the Core study completion visit.  Visit 8A 
lists the additional assessments which need to be 
completed for the Extension study.  Visits 8 and 8A 
assessments must be completed on the same day.  
Visits 8, 8A, and 9 can occur on the same day
Months relative to the Core study 
(after Visit 9 - Baseline of Extension 
study)
up to 10 
months after 
V5 (Core 
study)
10
days 
after 
V9
15 (3 
months  
after V9)
18 (6 
months 
after V9)
10
days 
after 
V12
21 (9 
months 
after V9)
24 (12 
months after 
V9)
Visit 10 and Visit 13
Serum creatinine (local lab)
X
For exclusion purposes
Ionized calcium (local lab)
X
Measured pre-dose, (local lab) prior to first infusion  
of Extension study
Bio-markers (Serum P1NP, NTX, 
BSAP, Trap-5b)
X
X
X
X
Not required at Visit 9 if it occurs within 30 days of 
Visit 8
Serum 25 hydroxy vitamin D
X
X
X
Pregnancy Test
X
X
[X]
X
X
To be performed for females with childbearing 
potential only
[Only for sites where additional safeguards are 
required:  Supervised urine pregnancy test]
i.v. drug administration (zoledronic 
acid)
X
X
Dispense calcium and vitamin D, if 
required
X
X
X
DXA measurements (lumbar spine, 
total body and distal femur)
X
X
X
X
Not required if obtained 3 months prior to Visit 9
X-ray
X
X
Lateral thoraco-lumbar spine and postero-anterior 
left hand/wrist 
Study completion
X
X
S = Source data, D = Database, TD = study treatment discontinuation,  PSW = premature patient withdrawal


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Table 6-2
Group 2 Assessment schedule
Screening 
Visit 
Infusion 
Visit1
Tele-
phone
Infusion
Visit
Tele-
phone
Notes
Visit
8A
9
10
11
12
13
14
15/EOS
and TD 
and/or 
PSW
Screening period from Visit 8A to Visit 9 should be 
as close to 28 days as possible, but cannot be 
longer than 8 weeks
Months relative to the Core study 
(after Visit 9 - Baseline of Extension 
study)
28 days 
from V8A
10 days 
after V9
3 months 
after V9
6 months 
after V9
10 days 
after V12
9 months 
after V9
12 months 
after V9
Obtain informed consent (D) and 
assent (S)
X
Inclusion/exclusion criteria (S)
X
X
Medical History (D)
X
X
Prior/concomitant medication, including 
GCs (D)
X
X
X
X
X
X
X
X
Vital signs (D)
X
X
X
X
Pulse and blood pressure
Physical examination (S)
X
X
X
X
Including an oral examination for exposed bone
Tanner staging (D), if applicable
X
X
Weight (D)
X
X
X
X
Pain assessment
X
X
X
X
X
Pain is assessed using Faces Pain Scale-Revised 
(FPS-R)
Central laboratory test (hematology, 
biochemistry including urinalysis)
X
[X]
X
X
X
X
All patients will have limited blood chemistry, GFR 
and urinalysis performed at Visit 10 and Visit 13. 
[Visit 9 lab draw only if more than 4 weeks from Visit 
8A].
Serum creatinine (local lab)
X
X
For exclusion purposes
Ionized calcium (local lab)
X
Measured pre-dose (local lab) prior to first infusion


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Screening 
Visit 
Infusion 
Visit1
Tele-
phone
Infusion
Visit
Tele-
phone
Notes
Visit
8A
9
10
11
12
13
14
15/EOS
and TD 
and/or 
PSW
Screening period from Visit 8A to Visit 9 should be 
as close to 28 days as possible, but cannot be 
longer than 8 weeks
Bio-markers (Serum P1NP, NTX, 
BSAP, Trap-5b)
X
X
X
Serum 25 hydroxy vitamin D
X
X
Pregnancy Test
X
X
[X]
X
X
To be performed for females with childbearing 
potential only
[Only for sites where additional safeguards are 
required:  Supervised urine pregnancy test]
i.v. drug administration (zoledronic 
acid)
X
X
Dispense calcium and vitamin D, if 
required
X
X
X
DXA measurements (lumbar spine, 
total body and distal femur
X
X
X
X-ray
X
X
Lateral thoraco-lumbar spine and postero-anterior 
left hand/wrist 
Adverse events and SAEs (D)
X
X
X
X
X
X
X
X
SAEs only collected between Visit 8A and Visit 9
(AEs during this time recorded as medical history)
Study completion
X
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6.1
Information to be collected on screening failures
Patients may discontinue from the study from Visit 8/8A through Visit 9, prior to any open-
label medication being administered.
Patients discontinuing prior to first infusion in the Extension study are considered screening 
failures.
If a patient discontinues before entering the open-label treatment period, the demographic 
information, reason for non-eligibility and screening log should be completed on the eCRF.
6.2
Patient demographics/other baseline characteristics
Group 1: Baseline demographical information for continuing patients was collected at the 
beginning of the Core study and will not be collected again in the Extension study.  Visit 1 of 
the Core study will be considered as Baseline 1. Any adverse events that occur after Visit 8 of 
the Core study but prior to the first dose of the Extension study (Visit 9) will be also collected 
on the adverse event eCRF.
Group 2: Baseline demographical information, medical history, concomitant medications, 
physical exam and laboratory/imaging assessments will be collected at Screening visit (Visit 
8A) or Visit 9; this will be considered as Baseline 2.
6.3
Treatment exposure and compliance
Concomitant Medications/Non-drug therapy prior to the first dose of study medication in the 
Extension study and after start of study drug will be collected, 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 GCs. A Dosage Administration Record will be completed for each i.v. dose 
of zoledronic acid. 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. This information should be captured in the source document, at each visit, 
and in the Concomitant Medication/Non-significant therapy eCRF. 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
The efficacy variables will be measured using the following techniques:

vertebral morphometric fractures

DXA measurements

bone marker analysis


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
bone age and metacarpal cortical width assessment

pain assessment
6.4.1
Vertebral morphometric fractures
Group 2 only: 
At Visit 8A, anterior-posterior (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 enrolled. AP and lateral thoracolumbar spine X-rays taken within 1 
month of Visit 8A (screening) can be used. The film and report must be sent to central 
imaging for fracture confirmation.
All patients:
Lateral thoraco-lumbar spine X-ray will be performed at the final visit of the Extension study 
(Visit 15) 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. A mild (Grade 1) vertebral fracture is defined as greater than or equal to (≥)20% and less 
than or equal to (≤) 25% reduction in anterior, middle, and/or posterior vertebral height.
2. A moderate (Grade 2) vertebral fracture is defined as greater than (>) 25% and less than or 
equal to (≤) 40% reduction in any vertebral height.
3. A severe (Grade 3) vertebral fracture is defined as greater than (>) 40% reduction in any 
vertebral height. 
or based on radiographic signs of 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.
Vertebral morphometry (or concave index) will be calculated using the average ratio between 
mid-height and posterior height from the first to the fourth lumbar vertebrae (L1 to L4) (Land 
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6.4.3
DXA measurements
DXA measurements of the lumbar spine (LS), total body and distal femur will be performed 
on all patients. LS- BMD Z-score, LS bone mineral content (BMC), Total body BMC 
 
 will be assessed at the final visit of the Core study (for Group 1) or 
Visit 8A-Screening Visit (for Group 2), Visit 9 (Month 18) and Visit 15 (Month 24) (final 
extension study visit/EOS). DXA will be acquired locally and the results will be sent to a 
central reader for evaluation.
Group 1: The DXA scans (hip, spine and distal femur) from Visit 8 will be used for the 
extension Visit 9 provided the DXAs have been obtained within 3 months of the Visit 9 
infusion; otherwise, the DXA scans must be repeated at Visit 9.
Group 2: Lumbar Spine-BMD-Z score of -0.5 or worse at Visit 8A needs to be confirmed by 
central imaging vendor.
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 at the final visit Core study (for Group 1) or Visit 9 (for Group 2), at 
Visit 12 (Month 18) and Visit 15 (Month 24) (final extension study visit/EOS). Detailed 
shipping instructions will be provided in the Investigator Laboratory Manual.


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6.4.6
Bone age and metacarpal cortical width assessment
Left postero-anterior (PA) hand/wrist X-ray will be taken at the final visit of Core study (for 
Group 1) or Visit 8A-Screening visit for Group 2 and at Visit 15/EOS (Month 24) for both 
Groups to assess bone age. The change in 2nd metacarpal cortical width at Month 24 relative 
to the respective baseline will be calculated.
If a fracture of the left upper extremity precludes radiographic imaging, (or precluded this    
X-ray in the Core study for Group 1) then the right hand will be evaluated for this purpose. In 
this case, the right hand should be imaged at both Visit 8 and at Visit 15/EOS (Month 24). 
The information will be used in the assessment of bone density.
6.4.7
Pain assessment
A Faces Pain Scale Revised (FPS-R) will be used for this purpose.
Pain will be evaluated at each visit (at office and telephone visit) at the final visit of the Core 
study (Group 1 only) and first visit of the Extension study (Visit 9), Visits 11, 12, 14 and 15. 
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 


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formation. In the growing child, height and 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.
The efficacy measurements listed above are therefore expected to be appropriate for this study.
6.5
Safety
Safety assessments will consist of:

monitoring and recording of all adverse events and serious adverse events, 

renal function (serum creatinine and GFR), 

the regular laboratory monitoring of hematology, blood chemistry and urinalysis, regular 
measurement of vital signs, and 

the performance of physical examinations including oral examinations for exposed bone.
6.5.1
Physical examination
Physical examination, including an oral exam of the gums and roof of the mouth, will be 
performed at Visits 9, 12 and 15. If the investigator is concerned about the patient’s oral 
health then the patient may be referred to a dentist. 
Significant findings made after the start of study drug which meet the definition of an AE 
must be recorded in the Adverse Event case report form. Significant findings prior to study 
drug would be entered on the Medical History CRF for Group 2 only.
Tanner staging will be performed at Visit 8 (Group 1 only), Visit 9 (Group 2 only) and the 
end of the extension study visit (Visit 15/EOS), when applicable. 
6.5.2
Vital signs
Measurements will be made of sitting blood pressure and pulse rate at Visits 8 (Group 1 only), 
8A (Group 2 only), 9, 12 and 15. 
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 8 (Group 1 only), 8A (Group 2 only), 9, 12 and 15 and recorded on the 
Vital sign eCRF.
 
 
 
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 


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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 Visit 8A (Group 2 only) and Visits 9, 12 and 15.
An additional lab test for renal monitoring will be performed at Visits 9, 10, 12, 13 and 15. 
6.5.4.1
Hematology
Hemoglobin, hematocrit, platelet count, red blood cell count (RBC), mean cell volume 
(MCV), mean cell hemoglobin concentration (MCHC), RBC morphology, white blood cell 
count (WBC) and differential white blood cell counts.
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, total bilirubin, gamma-glutamyl transpeptidase (GGT) and 
calcium.
Glomerular Filtration Rate (GFR) will be calculated using the Schwartz equation at all visits 
where serum creatinine will be measured (Visits 8A (Group 2 only) 9, 10, 12, 13 and 15) 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
Specialized (non-fasting) testing for serum 25-hydroxy vitamin D will be performed at 
Visit 8/8A and Visit 15. Additional local laboratory evaluation of serum ionized calcium will 
be evaluated in the local laboratory at pre-dose (first infusion). If local serum ionized calcium 
at Visit 9 is less than the normal range, the infusion must not be given. The patient may retest 
once at the investigator’s discretion. If the serum ionized calcium retest is in the normal range, 
the patient may be dosed.
Also, local laboratory evaluation of serum creatinine will be performed at Visit 8A (Group 2 
only) and Visit 9 for exclusion purposes.  If local serum creatinine at Visit 9 is less than the 
normal range, the infusion must not be given.  The patient may retest once at the 
investigator’s discretion.  If the serum creatinine retest is in the normal range, the patient may 
be dosed.


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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 
6.5.4.3
Urinalysis
A urine specimen will be obtained at Visit 8A (Group 2 and Group 1 if more than 28 days has 
lapsed since Visit 8 of the Core study), Visits 9, 10, 12, 13 and 15 for routine urinalysis, 
including microscopic examination.
6.5.5
Pregnancy and assessments of fertility
Serum pregnancy tests (β-hCG) will be performed at Visit 8 of the Core study or Screening 
visit (for Group 2) and at the final visit (Visit 15) of the Extension study.  Urine pregnancy 
tests will be performed at Visit 9 and Visit 12, prior to study drug infusion. The test will be 
conducted for all female patients of childbearing potential.
[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 will be conducted at 
Visit 11 (Month 15) 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 Visit 12 and 15 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.
Vitamin D (25-hydroxy-D) and calcium will be measured before the first infusion in the 
Extension study to ensure that all patients have adequate vitamin D and calcium levels at 


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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 Visits 12 and 15. In 
case of excessive change in LS-BMD Z-scores compared with the relevant baseline for each 
Group, the investigator will be alerted.
Patients may be hospitalized at the discretion of the primary investigator for observation 
following the first study drug infusion. Alternatively, they may be treated in an out-patient 
setting. Ionized calcium will be monitored pre-dose during this visit. 
The safety assessments selected are standard for this indication/patient population.


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6.6.3
Pharmacokinetics
Not applicable.
6.6.4
DNA Sampling
Pharmacogenetics/pharmacogenomics
Not applicable.
6.6.5
Other biomarkers
Not applicable.
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 patient or 
clinical investigation subject occurring after starting the study drug even if the event is not 
considered to be related to study drug. 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.
Group 1: all AEs following completion of the Core study (Visit 8) will be recorded in the 
eCRF of this extension study.
Group 2: 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; any events that occur prior to receiving study treatment, should be recorded 
in the eCRF as Medical History.
The occurrence of adverse events should 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, laboratory test, or 
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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 
patients and identifying adverse events. Alert ranges for laboratory and other test 
abnormalities are included in Appendix 1.
Adverse events must be recorded on 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 

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) and which seriousness criteria have been met

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 temporarily adjusted/interrupted 

investigational treatment permanently discontinued due to this adverse event

concomitant medication 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
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
its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown).
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should 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/parent/legal guardian
informed consent and should be discussed with the 
patient/parent/legal guardian 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/parent/legal guardian.
The investigator must also instruct each patient and parent/legal guardian to report any new 
adverse event (beyond the protocol observation period) that the patient or parent/legal 
guardian, 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 event reporting
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 

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 

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 
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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 Integrated Medical Safety 
(IMS) 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 suspected causality, occurring after the 
patient or parent/legal guardian has provided informed consent and until 30 days after the 
patient has stopped study participation (defined as time of last dose of study drug taken or last 
visit whichever is later) must be reported to Novartis within 24 hours of learning of its 
occurrence. Any SAEs experienced after this 30 day period after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit whichever is later) 
should only be reported to Novartis if the investigator suspects a causal relationship to the 
study drug. 
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 should be reported separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the Serious Adverse Event Report Form; all applicable sections of the form must be 
completed in order to provide a clinically thorough report. The investigator must assess the 
relationship of each SAE to each specific component of study treatment (if study treatment 
consists of several components), complete the SAE Report Form in English, and submit the 
completed, signed form within 24 hours after awareness of the SAE to the local Novartis Drug 
Safety and Epidemiology Department specific to the site, and listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form must be kept with the case 
report form documentation at the study site.


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Follow-up information is submitted as instructed in the investigator folder. 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. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated and whether the patient
continued or withdrew from study participation. 
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 drug 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.
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
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
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 


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the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy should 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 pregnancy must be 
reported on the SAE Report Form.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and eCRFs with the investigators and their staff. 
During the study, several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data will be employed. The field monitor will visit the site to 
check the completeness of patient records, the accuracy of entries on the eCRFs, 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.
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, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient or parent(s)/legal guardian(s) [a signed copy is given to the patient or 
parent(s)/legal guardian(s)].
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the eCRFs 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 


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the data entered into the eCRFs are complete and accurate. After database lock, the 
investigator will receive copies of the patient data for archiving at the investigational site. 
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. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and
forward to the CRO. The signed copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions 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).
Radiographic images will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
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. 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
8.5
Adjudication Committee
Not required.
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.
Data analyses will be performed separately for two group populations (Group 1 and Group 2), 
if not otherwise specified. No inferential statistical analysis or treatment group comparison 
will be performed for the patients in Group 2; only descriptive statistics will be reported for 
the single treatment arm. Baseline comparison will be performed with respect to baseline 1 


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and baseline 2 for Group 1 population whereas the same will be performed with respect to 
baseline 2 for Group 2 population.
9.1
Analysis sets
The following analysis sets are described:
Group 1 (patients who were randomized into the Core protocol)

Full Analysis Set-1 (FAS-1)

Safety Analysis Set-1 (SAF-1)
Group 2 (patients who were not randomized into the Core protocol)

Full Analysis Set-2 (FAS-2)

Safety Analysis Set-2 (SAF-2)
Full Analysis Set-1(FAS-1)
FAS-1 includes all patients who have completed the Core study and have received at least one 
dose of study medication in the Extension study.
Screen failure patients are not considered as enrolled and excluded from FAS-1.  Patients will 
be analyzed according to the treatment they were assigned to at the Core study randomization. 
Full Analysis Set-2 (FAS-2)
FAS-2 includes all patients who are enrolled in this Extension study and were not eligible to 
be randomized to the Core study because of having symptomatic (significant back-pain) 
vertebral fracture. Patients will be analyzed according to the treatment received at the 
Extension study. 
All efficacy analyses will be performed separately using FAS-1 and FAS-2.
Safety Analysis Set-1 (SAF-1)
SAF-1 includes all patients who have completed the Core study and have received at least one 
dose of study medication in the Extension study. Patients will be analyzed according to the 
treatment received during the Core study. Patients will be analyzed as receiving zoledronic 
acid in the Core study if they received at least one dose of zoledronic acid in the Core study.  
Safety Analysis Set-2 (SAF-2)
SAF-2 includes all patients those were not eligible to be randomized to the core study because 
of having symptomatic (significant back- pain) vertebral fractures and receive at least one 
dose of study medication in the Extension study.

All safety analyses will be performed separately using SAF-1 and SAF-2.
9.2
Patient demographics and other baseline characteristics
Descriptive statistics (mean, median, standard deviation, minimum, and maximum for 
continuous variables and number and percentage for categorical variables) for the 


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demographic and other baseline characteristics variables will be provided for the 2 
randomized Core treatment groups. In addition, the baseline comparability between these two
treatment groups will be evaluated for key demographic and other baseline characteristics 
variables for Group 1. Categorical variables will be evaluated using Fisher’s exact test, and 
the continuous variables will be evaluated using a one-way analysis of variance (ANOVA).
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 key secondary efficacy variables.
All analyses will be performed based on the FAS-1 for Group 1. 
Similar descriptive statistics for single treatment arm will be reported on FAS-2 for Group 2 
also.  
The relevant medical history/current medical conditions for the Extension study include 
relevant medical history/current medical conditions recorded in the Core study and adverse 
events occurring during the Core study or after the end of Core study but before the first study 
drug infusion in the Extension study for Group 1. The number and percentage of patients with 
relevant medical history/current medical conditions for the Extension study will be presented 
for each core treatment by primary system organ class and preferred term of the MedDRA 
dictionary.  The number and percentages of adverse events that started before the Extension 
study and is still present at the first drug infusion in the Extension study will be presented for 
each core treatment by primary system organ class and preferred term. Similar medical 
history/current medical conditions except adverse events will also be recorded for Group 2. 
The number and percentage of patients with relevant medical history/current medical 
conditions for the Extension study will be presented for single treatment arm by primary 
system organ class and preferred term of the MedDRA dictionary.
All analyses will be performed separately based on the FAS-1 and FAS-2.
9.3
Treatments 
Study drug and compliance
Descriptive statistics will be provided by core treatment group for duration of infusion and 
volume of infusion. 
Concomitant therapy
Concomitant medications will be coded using the WHO Drug Reference List that employs the 
Anatomical Therapeutic Chemical (ATC) classification system. Summary tables will be 
provided that present the number and percent of patients receiving those medications by 
preferred term and treatment for medications prior to the first dose in the extension and during 
the 12-month extension period. The medications will be sorted in decreasing order of 
frequency with respect to usage in the zoledronic acid group.


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Descriptive statistics will be provided by core treatment group for the dose and duration of 
use of GCs prior to the first dose in the extension and during the 12-month extension period
for Group 1.  The number and percentage of patients receiving different types of GC therapy 
will be presented by preferred term and Core treatment group (zoledronic acid or placebo).
Similar summary tables will be provided that present the number and percent of patients 
receiving those medications by preferred term and treatment for medications prior to the first 
dose in the extension and during the 12-month extension period for Group 2.
9.4
Analysis of the primary variable(s)
9.4.1
Variable
This study is designed to observe the long-term safety of zoledronic acid in pediatric patients 
who were treated with GCs and completed the Core study CZOL446H2337 (Group 1) and 
those who were not enrolled onto Core study due to symptomatic vertebral fracture but 
enrolled in this Extension study CZOL446H2337E1 (Group 2). Particular attention will be 
given to general safety and renal safety.
All safety evaluations will be performed separately using SAF-1 and SAF-2. The assessment 
of safety will be based mainly on the frequency of adverse events, serious adverse events and 
on the number of laboratory values that fall outside of pre-determined ranges. Other safety 
data (e.g. vital signs and special tests) will also be reported.
Adverse events and serious adverse events will be summarized by presenting the number and 
percentage of patients in which events occur, by primary system organ class, 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 primary system organ class, the patient will be counted 
only once with the greatest severity. Death, serious adverse events, adverse events causing 
permanently discontinuation of study drug, and adverse events causing concomitant 
medication taken will be presented by the core treatment group. 
Laboratory data will be presented with respect to three groups of laboratory tests (hematology, 
serum chemistry, and urinalysis).  
Summary statistics (means, medians, standard deviations, ranges) of raw data and change 
from baseline values) will be presented. In addition, shift tables using extended normal ranges 
(baseline to post-baseline value) 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 and by the core treatment group. For 
Group 1, both changes from Baseline 1 (first visit of the Core) and Baseline 2 (first visit of the 
Extension) will be reported. The number and percentage of patients who have lab values that 
meet the criteria for being clinically notable after the first dose of study medication will be 
presented by the Core treatment group. Patient listings that present each patient’s lab profile 
for those tests that are outside of the clinically notable ranges will also be provided. 


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The ranges of the normal laboratory values as well as the alert values for the safety 
monitoring will be provided in the Laboratory Manual, which will be attached to the protocol 
as an exhibit.
Data from other assessments (e.g. vital signs) will be listed, notable values will be flagged, 
and any other information collected will be listed as appropriate. 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 the Core treatment group. Any 
statistical tests performed to explore the data will be used only to highlight any interesting 
comparisons that may warrant further consideration.
No statistical test will be performed for Group 2.
Details will be available in statistical analysis plan. 
9.4.2
Statistical model, hypothesis, and method of analysis
The statistical analyses conducted will be descriptive with summary statistics (mean, standard 
deviation, median, minimum, maximum) presented by the Core treatment group for 
continuous variables and the number and percentage of patients presented by the Core  
treatment group for categorical variables for Group 1. Similar statistics will be presented for
the single treatment arm for Group 2.
9.4.3
Handling of missing values/censoring/discontinuations
All patients in the SAF-1 and SAF-2 will be included to calculate the percentage of adverse 
events. Laboratory tests and vital signs will be summarized based on the available data.
9.4.4
Sensitivity analyses
All supportive analyses are included in Section 9.4.1. 
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
If otherwise not specified, the efficacy data for Group 1 will be summarized and analyzed 
with respect to Baseline 1 (first visit of the Core) and Baseline 2 (first visit of the Extension)
will be presented by the Core treatment group and visit. However only summary statistics will 
be presented with respect to Baseline 2 and will be presented only for the single treatment. 
Data will be presented in summary tables, graphs, and listings to give an overview of the 
long-term efficacy maintenance. The mean, median, standard deviations, and range of each 
variable and its change from baseline measured on a continuous scale, will be presented by 
treatment group and visit. Frequency tables will be provided for categorical variables by 
treatment group and visit. All hypothesis tests (only for Group 1) will be evaluated at a 0.05 
level of significance, and the p-values will be rounded to the 4th decimal place. Change from 
baseline at Month 18/24 is defined as value at Month 18/24 value at baseline. Percentage 
change baseline is defined as 100 times the change from baseline divided by the baseline 
value. Missing values will not be imputed or replaced.
All efficacy analysis will be performed using FAS-1 and FAS-2 separately.


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Data from all centers will be combined so that an adequate number of patients are available 
for analysis. Small centers will be pooled using an algorithm specified before database lock.
9.5.1.1
Change in lumbar spine areal BMD Z-score at Months 18 and 24 
relative to baseline
Group 1: the percentage change in LS-BMD Z-score at Months 18 and 24 relative to both 
baselines between zoledronic acid and placebo (the Core treatment groups) will be evaluated 
using an ANCOVA model with treatment, pooled center, underlying condition treated with 
GCs and baseline LS-BMD Z-score as explanatory variables. The 2-sided 95% confidence 
intervals for the difference in least squares means between zoledronic acid and placebo will be 
provided.
Group 2: percentage changes in LS-BMD Z-score at Months 18 and 24 relative to Baseline 2 
(Visit 8A/9) for zoledronic acid will be evaluated.
9.5.1.2
Change in lumbar spine and total body BMC at Months 18 and 24 
relative to baseline
Group 1: change in BMC at the lumbar spine and total body at Months 18 and 24 relative to 
both baselines between zoledronic acid and placebo will be evaluated using an ANCOVA 
model with treatment, pooled center, underlying condition treated with GCs and baseline 
BMC (Visit 1 of Core study) as explanatory variables. The 2-sided 95% confidence intervals 
for the difference in least squares means between zoledronic acid and placebo will be 
provided.
Group 2: change from Baseline 2 (Visit 8A/9) in BMC at the lumbar spine and total body at 
Months 18 and 24 in zoledronic acid group will be presented.  
9.5.1.3
Relative change in biochemical markers of bone turnover (Serum NTX, 
TRAP-5b, BSAP and P1NP)
Group 1: 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 center, underlying 
condition treated with GCs, 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 for the difference in least squares means of transformed 
data between zoledronic acid and placebo will be provided using the described ANCOVA 
model and then back transformed to the original scale.
Group 2: summary statistics and relative change from Baseline 2 (Visit 8A/9) of biochemical 
markers of bone turnover will be presented.
9.5.1.4
Incidence of new clinical vertebral fractures and new morphometric 
vertebral fractures during the 12 month extension period
Group 1: The number and percentage of patients with new vertebral fractures and new 
morphometric vertebral fractures during the 12 month extension period will be presented by


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Core treatment group. Between-treatment differences will be evaluated using Fisher’s exact 
test. A new morphometric vertebral fractures during the 12 month extension period is defined 
as a morphometric vertebral fracture present at Month 24 X-ray which is not present at the 
extension baseline (Core Visit 8 and Visit 1 X-rays).
Group 2: number and percentage of patients with new vertebral fractures and new 
morphometric vertebral fractures during the 12 month extension period will be presented.
9.5.1.5
Change in metacarpal cortical width at Month 24 relative to baseline
Group 1: the change in metacarpal cortical width at Month 12 relative to both baselines will 
be evaluated using an ANCOVA model with treatment, pooled center, underlying condition 
treated with GCs and baseline bone age as explanatory variables. The 2-sided 95% confidence 
intervals in difference in least squares means between zoledronic acid and placebo will be 
provided.
Group 2: summary statistics will be reported. 
9.5.1.6
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 center, underlying 
condition treated with GCs and baseline pain score as explanatory variables.
Regression analysis will be carried out for Group 1 with respect to both the baselines. 
However the number and percentage of patients with classified status of pain with respect to 
baseline 2 will be reported for Group 2.


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9.5.1.10 Other analyses
The following Core data for the patients in the extension FAS-1 will be summarized and 
analyzed similarly at Core visits to give an overall profile during the 24 months core and 
extension combined period:

Change in LS-BMD Z-score relative to baseline

Change in lumbar spine and total body BMC relative to baseline

Relative change in biochemical markers of bone turnover (Serum NTX, TRAP-5b, 
BSAP and P1NP)

Change in metacarpal cortical width relative to baseline
Similar analyses will be performed for FAS-2 for the zoledronic acid group.
9.5.2
Safety variables
Safety is the primary objective.  Analysis of safety variables are described in Section 9.4.
9.5.3
Resource utilization
Not applicable.


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9.5.6
Pharmacokinetics
Not applicable.
9.5.7
Pharmacogenetics/pharmacogenomics
Not applicable.


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9.5.8
Biomarkers
Biochemical markers of bone turnover are secondary efficacy variables.  The analyses are 
described in Section 9.5.1.3
9.5.9
PK/PD
Not applicable.
9.6
Sample size calculation
Participation in the Extension study will be available to all patients completing the Core study 
CZOL446H2337 and also for the patients who were not eligible to be enrolled to the Core 
study due to clinically significant back pain from vertebral fracture. Approximately 100
patients in total will be enrolled into the Extension study. Patient recruitment in Group 2 will 
stop once randomization in the Core study is completed.
9.7
Interim analyses
An interim analysis will not be conducted for this study.
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 Code of Federal 
Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
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, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should 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 (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and 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.


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Women of child bearing potential should 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 
should 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, subject 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 Clinical 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.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group independent from those 
involved in conducting, monitoring or performing quality control of the clinical trial. The 
clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
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/subjects 
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.


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Investigators ascertain they will apply due diligence to avoid protocol deviations. If the 
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 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 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
References are available upon request
Bishop N, Arundel P, Clark E et al (2014) Fracture prediction and the definition of 
osteoporosis in children and adolescents: The ISCD 2013 Pediatric Official Positions. J Clin 
Densitometry; 17(2):275-280.
Black DM, Delmas PD, Eastell R, et al (2007) Once-yearly zoledronic acid for treatment of 
postmenopausal osteoporosis. N Engl J Med; 356: 1809-22.
Bushby K, Finkel R, Birnkrant DJ et al (2010) Diagnosis and management of Duchenne
muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management.
Lancet Neurol; 9(2):177-89.
Glorieux FH, Bishop NJ, Plotkin H (1998) Cyclic administration of pamidronate in children 
with severe osteogenesis imperfecta. N Engl J Med; 339: 947–52.
Gruppen M, Davin J-C, Oosterveld MJ et al (2013) Prevention of steroid-induced low bone 
mineral density in children with renal diseases: a systematic review. Nephrol Dial Transplant; 
0: 1–8.
Hogler W, and Ward L. (2015) Osteoporosis in children with chronic disease. In: Allgrove J, 
Shaw NJ (eds): Calcium and bone disorders in children and adolescents. 2nd revised edition.
Endocr Dev. Basel, Karger, 28: 176–195.
Hogler W, Yap F, Little D, et al (2004) Short-term safety assessment in the use of intravenous 
zoledronic acid in children. J Pediatr; 145:701-4.
Kanis J, Johansson H, Oden A, et al (2004) A meta-analysis of prior corticosteroid use and 
fracture risk. J Bone Miner Res; 19:893– 899.


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Levy S, Fayez I, Taguchi N, et al (2009) Pregnancy outcome following in utero exposure to 
bisphosphonates. Bone; 44: 428-430. 
Land C, Rauch F, Glorieux, FH (2006a) Cyclical intravenous pamidronate treatment affects 
metaphyseal modeling in growing patients with osteogenesis imperfecta. J Bone Miner Res; 
21:374–379.
Land C, Rauch F, Munns CF, et al (2006b) Vertebral morphometry in children and 
adolescents with osteogenesis imperfect-Effect of intravenous pamidronate treatment. Bone; 
39: 901-906.
Larson CM and Henderson RC (2000) Bone mineral density and fractures in boys with 
Duchenne muscular dystrophy. J Pediatr Ortho; 20:71-74.
Leblanc CM, Ma J, Taljaard M, et al (2015) Incident vertebral fractures and risk factors in the 
first three years following glucocorticoid initiation among pediatric patients with rheumatic 
disorders. JBMR; 30(9):1667-1675. 
Mashiba T, Hirano T, Turner CH, et al (2000) Suppressed bone turnover by bisphosphonates 
increases microdamage accumulation and reduces some biomechanical properties in dog rib.
JBMR; 15(4):613-620.
Marshall WA and Tanner JM (1969) Variations in the pattern of pubertal changes in girls. 
Arch Dis Child; 44:291-303.
Marshall WA and Tanner JM (1970) Variations in the pattern of pubertal changes in boys. 
Arch Dis Child; 45:13-23.
Patzer L (2008) Nephrotoxicity as a cause of acute kidney injury in children. Pediatr Nephrol;
23:2159–2173.
Plotkin LI, Weinstein RS, Parfitt AM et al (1999) Prevention of osteocyte and osteoblast 
apoptosis by bisphosphonates and calcitonin. J Clin Invest; 104: 1363-1374.
Reid IR, Brown JP, Burckhardt P, et al (2002) Intravenous zoledronic acid in postmenopausal 
women with low bone mineral density. N Engl J Med; 346: 653-661.
Rodd C, Lang B, Ramsay T, et al (2012) Incident vertebral fractures among children with 
rheumatic disorders 12 months after glucocorticoid initiation: a national observation study.
Arthritis Care Res (Hoboken); 64: 122-131.
Ross AC, Manson JE, Abrams SA, et al (2011) The 2011 Report on dietary reference intakes 
for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J 
Clin Endocrinol Metab; 96(1): 53–58.
Sbrocchi AM, Rauch F, Matzinger M et al (2011) Vertebral fractures despite normal spine 
bone mineral density in a boy with nephrotic syndrome. Pediatr Nephrol; 26:139–142.


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Ward L, Tricco AC, Phuong P, et al (2007) Bisphosphonate therapy for children and 
adolescents with secondary osteoporosis. Cochrane Database of Systematic Reviews 2007; 
Issue 4, Art No: CD005324.


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13
Appendix 1: Clinically notable laboratory values and vital 
signs
Table 13-1
Clinical notable criteria for selected laboratory tests
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 – 20 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
17-20 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
17-20 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
17-20 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
Clinical Chemistry
Blood Urea 
Nitrogen
(serum urea)
mg/dL
< 20 yrs
(4.0, 24.0)
Outside the normal range
Calcium
mg/dl
> 2 - 20 yrs
(8.4, 10.3)
Outside the normal range
Chloride
mEq/L
< 20 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 - 20 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


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Laboratory 
parameter
Units
Age/gender
range
Normal range
Criteria for clinically significant 
change
> 16 - 20 yrs/ 
Male
(0.5, 0.9)
Outside the normal range
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 - 20 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 - 20 yrs/ 
Male
(1.5, 2.2)
Clinically significantly low, if < 1.0 
mg/dL
Potassium
mEq/L
> 1 - 20 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 - 20 yrs
(2.2, 5.1)
Outside the normal range
Sodium
mEq/L
< 20 yrs
(132.0, 147.0)
Outside the normal range
ALT
U/L
5- 20 yrs
( 6 , 200 )
Outside the normal range
AST
U/L
5- 20 yrs
(10 , 200 )
Outside the normal range
Alkaline 
Phosphatase
U/L
5- 20 yrs
( 51 , 315) 
Outside the normal range
Albumin
g/dL
5- 20 yrs
( 2.9 – 4.7 ) 
Outside the normal range
GGT
U/L
5 – 10 yrs/ 
Female 
(0, 24) 
Outside the normal range
10 – 18 yrs/ 
Female
(0, 33)
Outside the normal range
18 – 20 yrs/ 
Female 
(4, 49)
Outside the normal range
5 – 10 yrs/ 
Male 
(0, 24)
Outside the normal range
10 – 18 yrs/ 
Male
(0, 51)
Outside the normal range
18 – 20 yrs/ 
Male 
(10, 61)
Outside the normal range
Total bilirubin
µmol/L
5 - 20 yrs 
(3, 21)
Outside the normal range
Hematology


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Laboratory 
parameter
Units
Age/gender
range
Normal range
Criteria for clinically significant 
change
Hemoglobin
g/dl
5 - 12 yrs/ 
Female
(11.2, 15.5)
Outside the normal range
> 12 - 20 yrs/ 
Female
(11.6, 16.4)
Outside the normal range
5  - 12 yrs/ 
Male
(11.2, 15.5)
Outside the normal range
> 12 - 20 yrs/ 
Male
(12.7, 18.1)
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 - 20 yrs/ 
Female
(34.0, 48.0)
Outside the normal range
5 - 6 yrs/ Male
(33.0, 43.0)
Outside the normal range
> 6 - 12 yrs/ 
Male
(34.0, 44.0)
Outside the normal range
> 12 - 20 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 - 20 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 - 20 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 - 20 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 - 20 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 - 20 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


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Laboratory 
parameter
Units
Age/gender
range
Normal range
Criteria for clinically significant 
change
> 6 - 12 yrs/ 
Female
(1.35, 8.15)
Outside the normal range
> 12 - 20 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 - 20 yrs/ 
Male
(1.65, 8.15)
Outside the normal range
Eosinophils
103/uL
< 20 yrs
(0.00, 0.57)
Outside the normal range
MCV
fL
5 – 6 yrs/ 
Female 
(74, 89)
Outside the normal range
6 – 12 yrs/ 
Female
(76, 93)
Outside the normal range
12 – 20 yrs/ 
Female
(79, 98)
Outside the normal range
5 – 6 yrs/ Male 
(74, 89)
Outside the normal range
6 – 12 yrs/ 
Male
(76, 93)
Outside the normal range
12 – 20 yrs/ 
Male
(79, 96)
Outside the normal range
MCHC
g/L
5 - 20 yrs
(310, 380)
Outside the normal range
RBC Morph
5 - 20 yrs
Normal
Outside the normal range
Urinalysis
5 – 20 yrs
Normal
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: Faces Pain Scale
2001International Association for Study of Pain
   0                       2                   4                    6                      8                    10  


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Appendix 6: Other subtypes of osteoporosis in children 
Allowed
Disallowed
Cerebral palsy
Leukemia or lymphoma
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


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Appendix 7: Amount of blood to-be Drawn
Only the laboratory samples which apply to the Visits in the Extension study are included.
Period 
Visit
8A
9
10
11T
12
13
14T
15/EOS and 
TD and/or 
PSW
Day
-60 to -30
0
10
days 
after 
V9
90
days 
after 
V9
180
days 
after 
V9
190
days 
after 
V9
270
days 
after 
V9
365 days after 
V9
Week
-8 to-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 mL3
3 mL
3 mL
Vitamin D
2.5 mL
2.5 mL
Local Laboratory - All Patients
Serum creatinine 
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
3Only repeated in Group 1 if more than 30 days after Visit 8 of the Core study

SAP_001.pdf: 
Clinical Development 
ZOL446 zoledronic acid 
CZOL446H2337E1 / NCT01197300
A 1-year, multicenter, open-label extension to 
CZOL446H2337 to evaluate safety and efficacy of 
zoledronic acid twice yearly in osteoporotic children 
treated with glucocorticoids  
 RAP Module 3 – Detailed Statistical Methodology 
Author: 
 
 
 Novartis Trial Statistician 
Document type: 
RAP Documentation 
Document status: 
V1.1 
Release date: 
04JUN2018 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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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 CZOL446H2337E1. The purpose of this study is to extend the period of observation in 
patients who have completed one year of evaluation in the Core study (CZOL446H2337) to 
evaluate the long-term safety and efficacy of zoledronic acid in osteoporotic children or 
adolescents treated with glucocorticoids. 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 this study is to demonstrate that zoledronic acid given long-term, 
over an additional 12 months from the Core study (CZOL446H2337), is safe for the treatment 
of osteoporotic children treated with glucocorticoids.  
The secondary objectives include: 
1. To evaluate the change from core baseline in LS-BMD Z-score at Month 18 and 24 by core 
treatment group. 
2. To evaluate the change from core baseline in LS and total body BMC at Month 18 and 24 
by core treatment group. 
3. To evaluate the change from core baseline in serum N-terminal propeptide type I collagen 
(P1NP), cross linked N-telopeptide (NTX), bone specific alkaline phosphatase (BSAP) and 
tartrate-resistant acid phosphatase isoform 5b (TRAP-5b) at Month 18 and 24 by core 
treatment group. 
4. To evaluate the proportion of patients with new clinical vertebral fractures during the 12 
month extension period by core treatment group. 
5. To evaluate the proportion of patients with new morphometric vertebral fracture during the 
12 month extension period by core treatment group. 
6. To evaluate the change from core baseline in pain using the Faces Pain Scale-Revised 
(FPS-R) at Month 15, 18, 21 and 24 by core treatment group. 
7. To evaluate the change from core baseline in 2nd metacarpal cortical width at month 24 by 
core treatment group. 
8. To evaluate the change from core baseline in bone age and 2nd metacarpal cortical width at 
month 24 by core treatment group. 
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 
Unless otherwise specified, the following general rules will be applied for defining baseline. 
 Core baseline: core baseline is defined as the last non-missing measurement on or 
prior to the date of first study drug infusion in core study. 


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 Extension baseline: extension baseline is defined as the last non-missing measurement 
on or prior to the date of first study drug infusion in the extension study. If no 
extension assessments are available on or prior to the first drug infusion in the 
extension study, the last assessment in core study will be used instead. 
Study day 
The general rules for calculating the study day are as follows:  
Core Study Day: 
 If the event date occurs before the first infusion date in core study, then the core study day 
is defined as the date of the event minus the first infusion date in core study; 
 If the event date occurs after the first infusion date (inclusive) in core study, then the core 
study day is defined as the date of the event minus the first infusion date in core study plus 
1. 
Extension Study Day: 
 If the event date occurs before the first infusion date in the extension study, then the 
extension study day is defined as the date of the event minus the first infusion date in the 
extension study; 
 If the event date occurs after the first infusion date (inclusive) in the extension study, then 
the extension study day is defined as the date of the event minus the first infusion date in 
the extension study 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:  
 Full Analysis Set (FAS) 
 Safety Analysis Set (SAF) 
Full Analysis Set (FAS)  
FAS includes all patients who have completed the core study and have received at least one 
dose of study medication in the extension study. 
Screen failure patients are not considered as enrolled and excluded from FAS. Patients will be 
analyzed according to the treatment they were assigned to at the core study randomization. 
All efficacy analyses will be performed using FAS. 
Safety Analysis Set (SAF)  
SAF includes all patients who have completed the core study and have received at least one 
dose of study medication in the extension study. Patients will be analyzed according to the 


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CZOL446H2337E1/Zoledronic Acid 
 
treatment received during the core study. Patients will be analyzed as receiving zoledronic 
acid in core study if they received at least one dose of zoledronic acid in core study.  
All safety analyses will be performed using SAF. 
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 
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 core treatment group within the FAS:  
 Completed extension study 
 Discontinued extension 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 FAS. 
Demographic information and reasons for discontinuing will be provided in a listing for 
screen failure patients.   


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Protocol deviations 
Protocol deviations will be summarized in a table and will be listed for all FAS patients by 
core treatment group. The number of patients with any protocol deviation will also be 
summarized.  
Patients in each analysis set 
The number and percentage of patients in each analysis set (FAS, SAF) will be summarized 
by core treatment group. Listing of these analysis sets will be provided as well.  
Demographic and other baseline characteristics 
Demographic variables and baseline characteristics will be summarized at both core and 
extension baselines.  
Baseline demographical information for continuing patients was collected at the beginning of 
the Core study and will not be collected again in the extension study.  
Descriptive statistics for the following demographic variables and baseline characteristics will 
be summarized for core period by core treatment group using FAS. Similar summaries will be 
performed for extension period but sex, race, ethnicity and non-vertebral fractures will be 
excluded. Vertebral morphometry will be removed as well because it is no longer an endpoint 
in the extension period. 
Age at extension enrollment (years) 
 Age group at extension enrollment (> = 6 years to <= 9 years; >=10 years to <=19 years) 
 Sex 
 Race  
 Ethnicity 
 Weight (kg)  
 BMI (kg/m^2). The baseline standing height will be used in BMI calculation.  
 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 


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o > -1.0 to <= -0.5 
 Lumbar spine Bone Mineral Content (BMC) (g) 
 Total body BMC (g) 
 Serum 25-hydroxy vitamin D (nmol/L) 
 Serum calcium level (mmol/L)  
 Serum NTX (nmol BCE/L) 
 Serum TRAP-5b (U/L) 
 Serum BSAP (ng/mL) 
 Serum P1NP (ng/mL) 
 Vertebral morphometry 
 Non-vertebral fractures 
 Metacarpal cortical width (mm) 
 
 Pain score 
In addition, the core baseline comparability between core 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. 
 
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 type of disease 
(Duchenne muscular dystrophy, rheumatic condition or inflammatory bowel disease) and by 
type (as specified in the CRF) within rheumatic condition and inflammatory bowel disease. 
Counts and percentages will be provided by core treatment group. 
 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 


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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  
 Others  
Frequency counts will be provided by core treatment group as well as the total in a table. A 
listing will also be generated. 
Relevant medical history and current medical conditions 
The relevant medical history/current medical conditions for the extension study include 
relevant medical history/current medical conditions recorded in Core study and adverse events 
occurring during the Core study or after the end of Core study but before the first study drug 
infusion in the extension study. The number and percentage of patients with relevant medical 
history/current medical conditions for the extension study will be presented for each core 
treatment by primary system organ class and preferred term of the MedDRA dictionary. A 
patient with multiple occurrences of a medical condition/adverse event for a preferred term or 
system organ class is counted only once in each specific category. A corresponding listing 
will also be provided. 
All analyses will be performed separately based on the FAS. 
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.  


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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 core 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 in the extension study; medications ending on or after the first infusion 
of study drug in the extension study 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 the extension study and end on or after the first infusion in the 
extension study including ongoing at end of the extension 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 
extension study medication or 01MONYYYY if the month and year indicate that the 
medication started on or after the first infusion of extension 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 extension study medication or max(01JANYYYY, treatment start date+1) 
if the year indicates that the medication started on or after the first infusion of 
extension 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 extension study medication or one 
day after the last extension study infusion date if end year is equal to or after the year 
of first infusion of extension study medication. 


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Efficacy evaluation 
Analyses of all efficacy endpoints will be performed on FAS. All relevant efficacy 
measurements will be presented in listings. Core study measurements will be listed as well for 
analyses that require both core and extension study measurements. 
Analysis for efficacy variables 
If otherwise not specified, the efficacy data will be summarized and analyzed with respect to 
core baseline only and will be presented by the core treatment group and visit. The mean, 
median, standard deviations, and range of each variable and its change from baseline 
measured on a continuous scale, will be presented by core treatment group and visit. Number 
and percentage of patients will be presented for categorical variables by core treatment group 
and visit. 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. Change from baseline at Month X is defined 
as value at Month X - value at baseline. Percentage change from baseline is defined as 100 
times the change from baseline divided by the baseline value. Missing values will not be 
imputed or replaced. 
The efficacy variables and their analysis methods are described below. 
 
Percent change in lumbar spine areal BMD Z-score at Months 18 and 24 relative to 
baseline, zoledronic acid group vs. placebo 
The percent change in LS-BMD Z-score at Months 18 and 24 relative to core baseline 
between zoledronic acid and placebo (the core treatment groups) will be evaluated using an 
ANCOVA model with core treatment, pooled center, underlying condition treated with 
glucocorticoids and core baseline LS-BMD Z-score as explanatory variables and pooled 
centers as random effect.  
From the model, core treatment difference in least squares means 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 percent change from baseline 
in LS-BMD Z-score at Month 18 and Month 24 will be presented for each core treatment 
group. Descriptive statistics will also be shown for baseline, Month 18 and Month 24 visits. 
 
Change in lumbar spine and total body BMC at Months 18 and 24 relative to 
baseline, zoledronic acid group vs. placebo 
The change in BMC at the lumbar spine and total body at Months 18 and 24 relative to core 
baseline between zoledronic acid and placebo will be evaluated using an ANCOVA model 
with core treatment, pooled center, underlying condition treated with glucocorticoids and core 
baseline BMC as explanatory variables and pooled centers as random effect.  
From the model, core treatment difference in least squares means 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 18 and Month 24 will be presented for each core 
treatment group. Descriptive statistics will also be shown for baseline, Month 18 and Month 
24 visits. 


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 
Relative change in biochemical markers of bone turnover (Serum NTX, TRAP-5b, 
BSAP and P1NP) at Months 18 and 24 relative to baseline, zoledronic acid group 
vs. placebo 
The analysis of changes from core baseline to Month 18 and Month 24 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 core treatment group, pooled centers, underlying condition treated with 
glucocorticoids, and loge (core baseline value) as explanatory variables and pooled centers as 
random effect will be used on the transformed data at each post-baseline time point.  
From the model, core treatment difference in least squares means 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 core 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 18 and Month 24 will be presented for each core treatment group. 
Descriptive statistics will also be shown for baseline, Month 18 and Month 24 visits in both 
original scale and log scale. A plot will be generated for each biochemical marker over core 
and extension study period respectively. 
 
Incidence of new vertebral fractures and new morphometric vertebral fractures 
during the 12 month extension period, zoledronic acid group vs. placebo 
The number and percentage of patients with new vertebral fractures and new morphometric 
vertebral fractures during the 12 month extension period will be presented by core treatment 
group. Between-treatment differences will be evaluated using Fisher’s exact test. New 
vertebral fractures are defined as fractures of Genant grade 1 or higher that occur at lumbar or 
thoracic spine from first extension dose infusion to the end of the extension study. New 
morphometric vertebral fractures during the 12 month extension period is defined as a 
morphometric vertebral fracture present at Month 24 X-ray which is not present at extension 
baseline. 
 
Change in 2nd metacarpal cortical width at Month 24 relative to baseline, zoledronic 
acid group vs. placebo 
The change in 2nd metacarpal cortical width at Month 24 relative to core baseline will be 
evaluated using an ANCOVA model with core treatment, pooled center, underlying condition 
treated with glucocorticoids and core baseline bone age as explanatory variables and pooled 
centers as random effect.  
From the model, core treatment difference in least squares means 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 2nd 
metacarpal cortical width at Month 24 will be presented for each core treatment group. 
Descriptive statistics will also be shown for baseline and Month 24 visits.  
Above analysis will be carried out with respect to both baselines (core baseline as well as 
extension baseline). 


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 
 Reduction in pain from baseline, zoledronic acid group vs. placebo 
Pain is assessed using Faces Pain Scale-Revised (FPS-R) at first infusion in the extension 
study (Visit 9), Month 15, 18, 21 and 24, which ranges from 0 (No Pain) to 10 (Very Much 
Pain). Details of FPS-R can be found in Appendix section “Faces Pain Scale” in the protocol. 
The reduction in pain from core 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 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 core treatment, pooled centers, underlying 
condition treated with glucocorticoids and baseline pain score as explanatory variables. 
Regression analysis will be carried out with respect to both baselines (core baseline as well as 
extension baseline). 
 


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Other analyses 
The following core data for the patients in the extension FAS will be summarized and 
analyzed similarly at core visits to give an overall profile during the 24 months core and 
extension combined period: 
 Change in LS-BMD Z-score relative to baseline 
 Change in lumbar spine and total body BMC relative to baseline 
 Relative change in biochemical markers of bone turnover (Serum NTX, TRAP-5b, 
BSAP and P1NP) 
 Change in 2nd metacarpal cortical width relative to baseline 
Pharmacokinetic (PK) evaluations  
Not applicable. 
 


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Safety evaluation 
All safety analyses will be performed on the SAF. 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.  
Analysis for the primary objective 
The primary objective is to demonstrate that zoledronic acid given long-term, over an 
additional 12 months from the Core study (CZOL446H2337), is safe for the treatment of 
osteoporotic children treated with glucocorticoids. 
Adverse events 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical 
investigation subject after starting the study drug even if the event is not considered to be 
related to study drug. Treatment-emergent adverse events will be defined as adverse events 
that were absent prior to the first infusion in the extension study and occurred after the first 
infusion during extension study or that were present prior to the first infusion in the extension 
study and occurred at increased severity after the first infusion during extension 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 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 core 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 in the extension study and before second 
infusion in the extension study (by primary system organ class and preferred term) 
 
All adverse events (by primary system organ class, preferred term and maximum 
severity) 


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 
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 causing concomitant medication taken (by primary system organ class 
and preferred term)   
 
Adverse events associated with a change in renal function (by preferred term). Time 
from first infusion in the extension study to first adverse event associated with a change 
in renal function will be presented separately. 
 
 
 
Hypocalcemia adverse events (by preferred term). Time from first infusion in the 
extension study to first hypocalcemia 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 core treatment group, and MedDRA levels. Relative risk of zoledronic acid 
group vs. placebo (core treatment A vs. core treatment B) will be presented along with 
corresponding 95% confidence intervals using the Mantel-Haenszel test.  
Missing date convention 
Please note that for below AE missing date imputation, all infusion dates or treatment dates 
refer to those in the extension study. 
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: 


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 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. 
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 will be 
summarized. The hazard ratio, 95% CI and p-value based on a Cox proportional hazards 
model with core treatment and underlying condition treated with glucocorticoids 
(stratification factor) as explanatory variables will be presented. Meanwhile, to aid in the 
assessment that the treatment differences are not inconsistent across the strata, the treatment-
by-stratification interaction term will be added to the model described above. P-value for the 
interaction term will be reported. 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 


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multiple. Otherwise, a patient is considered censored at the last contact date. Kaplan-Meier 
estimates will be plotted over time if at least 10% of overall population has experienced the 
event.  
Patient listings will be provided for all adverse events associated with clinically significant 
change in renal function. 
Hypocalcemia adverse events and laboratory events 
Hypocalcemia adverse events will be searched based on preferred term and summarized. 
Patients with reported laboratory measurements associated with a signal of hypocalcemia will 
be summarized by visit. Lab hypocalcemia (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 core 
treatment group and overall. 
The hazard ratio, 95% CI and p-value based on a Cox proportional hazards model with core 
treatment and underlying condition treated with glucocorticoids (stratification factor) as 
explanatory variables will be presented. Meanwhile, to aid in the assessment that the 
treatment differences are not inconsistent across the strata, the treatment-by-stratification 
interaction term will be added to the model described above. P-value for the interaction term 
will be reported.  If a patient experiences a hypocalcemia 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 10% of overall population has experienced the event.  
Patient listings will be provided for all adverse events associated with hypocalcemia. 
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, platelet count, red blood cell count 
(RBC), mean cell volume (MCV), mean cell hemoglobin concentration (MCHC), 
RBC morphology, white blood cell count (WBC) and differential white blood cell 
counts. 
 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, total bilirubin, gamma-glutamyl 
transpeptidase (GGT), 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 


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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 9, 10, 12, 13 and 15) 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 both baselines, each post-baseline visit, and change from 
both baselines to each visit will be presented by laboratory test group and core 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, including changes from both baselines, will be 
presented by laboratory test group and core treatment group. 
In addition, summary tables will be presented based on both baselines 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 hypocalcemia 
(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, summary tables 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 compared against both baselines. 
Listings of all laboratory parameter measurements will be displayed. 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 hypocalcemia 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, 
 weight 
Descriptive summary statistics for the baseline, each study visit, and change from both 
baselines to each study visit will be presented for sitting systolic blood pressure, sitting 
diastolic blood pressure, pulse rate, and body weight. 
 


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 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 in the extension study will be presented by core 
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 extension Baseline and End of study (Visit 
15). 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.   
Statistical model, hypothesis, and method of analysis 
The statistical analyses conducted will be descriptive with summary statistics (mean, standard 
deviation, median, minimum, maximum) presented by the core treatment group for 
continuous variables and the number and percentage of patients presented by the core 
treatment group for categorical variables. 
Handling of missing values/censoring/discontinuations 
All patients in SAF will be included to calculate the percentage of adverse events. Laboratory 
tests and vital signs will be summarized based on the available data. 
Sensitivity analyses 
All supportive analyses are included in analysis of primary objective section. 
Determination of sample size 
Participation in the extension study will be available to all patients completing the Core study 
CZOL446H2337.  
 
 
 


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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’ 
 
Note: In case of non-availability of enough patients, center effect will be dropped from all 
above statistical methodology. 
 
 


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Appendix