Clinical trial NCT02452931
Conditions: Precocious Puberty, Central
Sponsor: Tolmar Inc.
Start date: 2015-08-31; Completion date: 2018-09-05
Enrollment: 64 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study determines the effectiveness of leuprolide acetate 45 mg for injectable suspension for treatment of children with Central Precocious Puberty.

Detailed description:
Leuprolide acetate is a GnRH agonist that inhibits pituitary gonadotropin secretion by binding to the GnRH receptors and blocking downstream hormone synthesis. The steady decrease in hormone synthesis (LH and FSH) leads to a suppression of testicular and ovarian steroidogenesis. In children with CPP, this steady decrease in hormone synthesis disrupts the progression of puberty.

Arms: arm 1: Leuprolide acetate 45 mg will be administered as a subcutaneous injection at 6-month intervals for the 12 month study period.
Interventions: intervention 1: Leuprolide Acetate 45 mg
Intervention descriptions: intervention 1: Subcutaneous injection

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
An Open-label, Single Arm, Multicenter Study on the Efficacy, Safety, and 
Pharmacokinetics of Leuprolide Acetate 45 mg for Injectable Suspension 
Controlled Release in Subjects with Central (Gonadotropin-Dependent) Precocious  
Puberty 
NCT02452931 
25 August 2015 


CPP Treatment with Leuprolide Acetate 
TOLMAR Inc. 
Clinical Study Protocol: TOL2581A FINAL 
25 August 2015 
Version 3.0 
CONFIDENTIAL 
An Open-label, Single Arm, Multicenter Study on the Efficacy, Safety, and 
Pharmacokinetics of Leuprolide Acetate 45 mg for Injectable Suspension 
Controlled Release in Subjects with Central (Gonadotropin-Dependent) 
Precocious Puberty  
Protocol Number: 
TOL2581A 
Sponsor: 
TOLMAR Inc. 
701 Centre Avenue 
Fort Collins, Colorado 80526, US 
Tel: 970-212-4500 
Fax: 970-449-5033 
www.TOLMAR.com 
Clinical Study Type: 
Pivotal: Efficacy, Safety, Pharmacokinetics 
Version History: 
3.0 
2.0 
1.0 
25 August 2015 
21 April 2015 
28 January 2015 
Proprietary and Confidential 
The information contained in this document is privileged and confidential, and is the property of 
TOLMAR Inc. Nothing herein is to be reproduced, published, or disclosed to others in any form 
without the prior express written consent of TOLMAR Inc. Persons to whom this or any information 
related to the contents of this document is to be disclosed must be informed that the information is 
privileged and confidential and must not be further disclosed by them. 




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Principal Investigator Agreement 
Protocol No: TOL2581A 
Protocol Title: An Open-label, Single Arm, Multicenter Study on the Efficacy, Safety, and 
Pharmacokinetics of Leuprolide Acetate 45 mg for Injectable Suspension Controlled Release in 
Subjects with Central (Gonadotropin-Dependent) Precocious Puberty 
I have carefully read and understand the aforementioned Protocol and agree that it contains all 
the necessary information for conducting this study safely. I will conduct this study in strict 
accordance with this Protocol, International Conference on Harmonisation (ICH) guidelines for 
Good Clinical Practice (GCP), the Code of Federal Regulations, the Health Insurance Portability 
and Accountability Act (HIPAA), and local regulatory and privacy guidelines for clinical studies. 
I will ensure that the rights, safety, and welfare of subjects under my care are protected. I will 
ensure control of the study drugs under investigation in this study. I will provide copies of the 
Protocol and all other study-related information supplied by TOLMAR Inc. to all personnel 
responsible to me who participate in the study. I will discuss this information with them to 
ensure that they are informed regarding the data integrity, safety of the subjects, study drug and 
conduct of the study. I agree to keep records on all subject information (electronic case report 
forms, source documents, medical records, and all other information collected during the study) 
and drug disposition (shipment and drug return forms) in accordance with standards set forth by 
the U.S. Food and Drug Administration (FDA) and local regulations applicable to clinical 
studies. I will not enroll any subjects into this Protocol until the applicable Independent Review 
Board (IRB) or Independent Ethics Committee (IEC) and Sponsor or designee approvals of the 
site are obtained. Only I, as the Principal Investigator, will sign the electronic Case Report Form 
(eCRF) and I may not designate this activity to anyone else. I will make all efforts to complete 
the study within the time designated. 
Principal Investigator Name (Print) 
Principal Investigator Signature 
Date 


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1. SYNOPSIS
Title of Study 
An Open-label, Single Arm, Multicenter Study on the Efficacy, Safety, and 
Pharmacokinetics of Leuprolide Acetate 45 mg for Injectable Suspension 
Controlled Release in Subjects with Central (Gonadotropin-Dependent) 
Precocious Puberty 
Clinical Study Type 
Adaptive Design Interventional (Efficacy, Safety and Pharmacokinetics) 
Clinical Study Phase Phase III (Pivotal) 
Study Period 
Total study enrollment is expected to take approximately 12 months for 
Part A and approximately 10 months for Part B. 
Part A: Approximately 24 months for first subject first visit (FSFV) to last 
subject last visit (LSLV) 
Part B (Extension): Continuation into Part B will be dependent on results 
from Part A. If this extension is invoked, the study will be extended for 
2 more injections; therefore, FSFV to LSLV (altogether for both Parts A 
and B) will be approximately 34 months.  
Duration of 
Participation 
Screening Period: Up to 28 days 
Treatment Period, Part A: 1st and 2nd injections separated by approximately 
6 months (24 weeks); subject participation is approximately 12 months  
Treatment Period if Part B is conducted: additional 3rd and 4th injections 
separated by approximately 5 months; subject participation is a total of 
approximately 21 months from first dose in Part A 
Investigational 
Product (Study 
Drug) 
Leuprolide acetate 45 mg for injectable suspension, controlled release for 
subcutaneous injection (ELIGARD® 45 mg, TOLMAR Inc.) 
Objectives 
Primary: 
•
Determine the effectiveness of leuprolide acetate 45 mg for injectable
suspension for treatment of children with Central Precocious Puberty
(CPP).
Secondary: 
•
Evaluate the safety and tolerability of leuprolide acetate 45 mg for
injectable suspension in children with CPP.
•
Characterize the burst kinetics of leuprolide acetate 45 mg after the first
administration.
•
Characterize the pharmacodynamic (PD) relationship of leuprolide
serum concentrations to concentrations of serum luteinizing hormone
(LH), follicle stimulating hormone (FSH) and to testosterone/estradiol.
•
Assess percent changes in height velocity and bone age progression
after the first administration.
•
Assess changes in physical signs of puberty as measured by changes in
Tanner stages or in changes or onset of menses.
•
Determine the dosing interval (5 or 6 months) at which leuprolide
acetate is able to suppress LH concentration to <4 mIU/mL (after


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gonadotropin releasing hormone agonist [GnRHa] stimulation test), as 
data permit. 
Study Design 
This will be an adaptive design study conducted in two parts as illustrated 
below. 
Subjects will only receive Injections #3 and #4 if Part B is conducted, based on Part A interim data. 
Part A: This will be a multicenter, open-label, single-arm 12-month study. 
Pediatric subjects who have been diagnosed with CPP but have not yet 
received GnRH agonist therapy (drug-naïve) will be eligible (see 
Inclusion/Exclusion Criteria). All subjects will have a GnRHa stimulation 
test to confirm a diagnosis of CPP.  
Pediatric subjects will receive their first study drug injection at their 
baseline visit on Day 0 and the second injection at the Month 6 visit with 
periodic evaluations and monitoring for up to a total of 12 months following 
the first injection. Subjects will return to the clinic as indicated in the 
Schedule of Assessments (SoA) periodically for 12 months from start of 
dosing for efficacy, safety and pharmacokinetic (PK) assessments.  
All subjects will participate in Part A to evaluate the efficacy of leuprolide 
acetate injection suspension 45 mg (study drug) in suppressing LH after a 
GnRHa stimulation test. An independent Data Safety Monitoring Board 
(DSMB) will review the safety of the drug throughout the study.  
An interim analysis of LH suppression from the GnRHa stimulation test 
results will be conducted after approximately 40% of the 40 subjects 
anticipated to complete 6 months of assessments have data through the 
Month 6 visit (N = approximately 16). Based on this analysis, if LH 
concentrations, after the GnRHa stimulation test, are suppressed to 
< 4 mIU/mL in < 85% of these subjects, then Part B of the study will be 
invoked. All subjects still undergoing therapy in the Part A of the study and 
those yet to enroll in the study, if eligible, will be asked to participate in the 
Part B extension study for additional dosing at shorter intervals. The 
progression to Part B extension will be based on evaluations by the DSMB 
and Sponsor. 
Part B Extension: This will be a multi-center, open-label, single-arm 
extension following Part A. Because the interim analysis will only provide 
data from a very small sample size informing the decision to conduct Part B 
of the study with a 5-month dosing interval, ALL new subjects being 
enrolled into the study will begin with Part A of the study with the first 
6-month dosing interval before proceeding to Part B. In this manner, there
will be adequate data for comparison of dosing intervals for assessment of
optimal efficacy. Only subjects who have received Injection #2 of study
drug in Part A will be permitted to enter Part B. Injections #3 and #4 will be


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administered in 5-month intervals after Injection #2. Subjects will return to 
the clinic periodically up to an additional 10 months from start of Part B for 
efficacy and safety assessments. 
Number of Study 
Sites 
Multicenter: approximately 20 sites in the United States, Mexico, 
Argentina, Canada, South Korea, Australia, and New Zealand. Clinical sites 
in other countries may be added as necessary.  
Number of Subjects 
Part A: Approximately 60 subjects will be screened and/or enrolled in 
order to have approximately 40 evaluable subjects that complete 6 months 
of the study. 
Part B Extension: If this part is invoked, it is anticipated that 
approximately 27 of the enrolled subjects in Part A will participate. 
Eligibility Criteria 
Inclusion Criteria: 
1.
Females age 2 to 8 years (inclusive) or males age 2 to 9 years
(inclusive)
2.
Confirmed diagnosis of CPP within 12 months of Baseline Visit (Day 0)
but have not received prior GnRH agonist treatment for CPP
3.
Pubertal-type LH response following an abbreviated GnRHa stimulation
test before treatment initiation > 5 mIU/mL
4.
Clinical evidence of puberty, defined as Tanner stage ≥ 2 for breast
development in females or testicular volume ≥ 4 mL in males
5.
Willing and able to participate in the study
6.
Difference between bone age (Greulich and Pyle method) and
chronological age ≥ 1 year
7.
Signed Institutional Review Board/Independent Ethics Committee
(IRB/IEC)-approved informed consent form (ICF) by one or both
parents (per IRB/IEC requirements), by the custodial parent or by the
legal guardian(s) (if required)
8.
Signed Assent by subjects as per IRB/IEC requirements
Exclusion Criteria: 
1.
Gonadotropin-independent (peripheral) precocious puberty: extra
pituitary secretion of gonadotropins or gonadotropin-independent
gonadal or adrenal sex steroid secretion
2.
Prior or current GnRH treatment for CPP
3.
Non-progressing isolated premature thelarche
4.
Presence of an unstable intracranial tumor or an intracranial tumor
requiring neurosurgery or cerebral irradiation. Subjects with hamartomas
not requiring surgery are eligible.
5.
Any other condition, chronic illness or treatment that, in the opinion of
the Investigator, may interfere with growth or other study endpoints
(eg, chronic steroid use [except mild topical steroids], renal failure,


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diabetes, moderate to severe scoliosis, previously treated intracranial 
tumor). 
6.
Prior or current therapy with medroxyprogesterone acetate, growth
hormone or insulin-like growth factor-1 (IGF-1)
7.
Major medical or psychiatric illness that could interfere with study visits
8.
Diagnosis of short stature (ie, 2.25 standard deviations (SD) below the
mean height for age)
9.
Positive urine pregnancy test
10. Known hypersensitivity to GnRH or related compounds
11. Any other medical condition or serious intercurrent illness that, in the
opinion of the Investigator, may make it undesirable for the subject to
participate in the study
12. Any other condition(s) which could significantly interfere with Protocol
compliance
13. Treatment with an investigational product within 5 half-lives of that
product in prior clinical studies before the baseline visit (Day 0)
14. Known history of seizures, epilepsy, and/or central nervous system
disorders that may be associated with seizures or convulsions
15. Prior (within 6 months of Baseline (Day 0)) or current use of medications
that, per Investigator opinion, have been associated with seizures or
convulsions
Dose and Mode of 
Administration 
Part A: Each subject will receive a total of 2 subcutaneous (SC) injections 
of leuprolide acetate 45 mg for injectable suspension (study drug) at 
6-month intervals: one at Baseline (Day 0) and one at the Month 6 visit.
Part B Extension: If invoked, eligible subjects will receive a 3rd and 4th SC 
injection of study drug at 5-month intervals, one at the Month 11 visit and 
one at the Month 16 visit. 
Study Visits 
Part A: Subjects will come to the clinic for Screening and, if eligible, for 
8 subsequent study visits for up to 12 months. If Part B Extension is 
invoked, subjects will participate in the first 6 study visits in Part A prior to 
entering Part B. 
Part B Extension: Subjects will come to the clinic for 5 additional visits 
for up to an additional 10 months (totaling 21 months altogether for both 
Parts A and B). 
Efficacy 
(Pharmacodynamic) 
Parameters 
Blood samples will be collected during the study to measure concentrations 
of the following hormones: luteinizing hormone (LH), follicle stimulating 
hormone (FSH), testosterone/estradiol. The primary endpoint will be the 
percentage of subjects with serum LH concentrations < 4 mIU/mL, 
30 minutes following an abbreviated GnRHa stimulation test. Other 
hormonal changes will provide supportive evidence of efficacy. 


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Pharmacokinetic 
Parameters 
Blood samples will be collected during the study for analysis of serum 
leuprolide concentrations. Blood samples will be assayed and used to 
characterize initial burst phase and baseline or trough concentrations of 
leuprolide acetate following administration of the first dose of the study drug 
and the relationship of leuprolide to changes in serum concentrations of LH, 
FSH, and testosterone/estradiol.  
Statistical Methods 
Data Sets to be Analyzed: 
Safety population: All subjects providing consent/assent and who received 
at least one dose of the study drug.  
Intent-to-Treat (ITT) population: Subjects providing consent/assent who 
received at least one dose of the study drug, fulfilled the protocol eligibility 
criteria, and provided at least one PD laboratory assessment post dosing.  
Per Protocol (PP) population: Subjects who have received at least one dose 
of the study drug and have fulfilled the protocol in terms of eligibility, 
interventions and outcome assessments for at least 6 months.  
Efficacy: 
Primary Efficacy Endpoint 
•
Part A: the percentage of subjects with serum LH concentrations
< 4 mIU/mL 30 minutes following an abbreviated GnRHa stimulation
test at the Month 6 visit
•
Part B: the percentage of subjects with serum LH concentrations
< 4 mIU/mL 30 minutes following an abbreviated GnRHa stimulation
test at the Month 21 visit (5 months after the Injection #4 of leuprolide
acetate)
Secondary Efficacy Endpoint: Parts A & B 
•
The percentage of subjects with suppressed serum LH concentrations
(< 4 mIU/mL) 30 minutes post GnRHa stimulation test at all assessed
timepoints
•
Changes in height velocity (growth rate) and bone age advancement will
be evaluated relative to chronological age from baseline to end of study
•
Change in physical signs of puberty as measure by changes in Tanner
stages from baseline to end of study
Exploratory Endpoints: Parts A & B 
•
Bone age progression will be further evaluated using descriptive
statistics and figures at all assessed timepoints. Changes in bone age
progression will be described for each individual and for the ITT and PP
population over the entire treatment period
•
Descriptive statistics will be used to describe changes in physical signs
of puberty as measured by changes in Tanner stages at each assessed
timepoint. Changes in Tanner staging will be described for each
individual and for the ITT and PP population over the entire treatment
period
•
The percentage of subjects with LH (< 4 mIU/mL), FSH
(< 2.5 mIU/mL), estradiol (< 20 pg/mL) or testosterone (< 30 ng/dL)


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suppression to prepubertal levels and serum leuprolide levels at all 
assessed timepoints 
•
Evaluation of the incidence rate of GnRH antagonist reports (see
Section 8.5.1) that occurred within the 2 weeks (± 2 days) following
first drug administration will be descriptively compared to the incidence
rate within the 2 weeks (± 2 days) after each subsequent drug
administration
•
Evaluation of the incidence rate of GnRH antagonist reports that
occurred within 2 weeks (± 2 days) following drug administration will
be descriptively compared to the incidence rate within the 2 weeks
(± 2 days) prior to each scheduled visit.
Pharmacokinetics: 
Leuprolide serum concentrations will be analyzed for characterization of 
burst and trough serum concentrations. Leuprolide concentrations will be 
associated with changes in LH, FSH, and testosterone/estradiol changes over 
time to characterize the pharmacokinetic/pharmacodynamic (PK/PD) 
relationship.  
Safety: 
Statistical analysis of safety will be descriptive only. Continuous data will be 
summarized in tables listing the mean, standard deviation, minimum, 
maximum, and number of subjects in each part of the study. Changes in 
GnRH antagonist reports over time will be evaluated by a comparison of 
reported reactions for the 2 weeks after dosing to those reported at each of 
the scheduled visits. Categorical data will be summarized in tables listing 
frequency and the percentage of subjects. All data will be listed by subject. 


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TABLE OF CONTENTS 
1.
SYNOPSIS ...............................................................................................................................4 
2.
LIST OF IN-TEXT TABLES ...............................................................................................13 
3.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................14 
3.1 
ABBREVIATIONS ................................................................................................................14 
4.
ETHICS ..................................................................................................................................16 
4.1 
INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD ...........................16 
4.2 
ETHICAL CONDUCT OF THE STUDY ....................................................................................16 
4.3 
SUBJECT INFORMATION AND CONSENT ..............................................................................16 
4.4 
CONFIDENTIALITY OF DATA ..............................................................................................16 
5.
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .........................17 
6.
INTRODUCTION .................................................................................................................17 
6.1 
BACKGROUND ....................................................................................................................17 
6.2 
RATIONALE ........................................................................................................................19 
7.
STUDY OBJECTIVES .........................................................................................................19 
7.1 
PRIMARY OBJECTIVE .........................................................................................................19 
7.2 
SECONDARY OBJECTIVES ...................................................................................................19 
8.
INVESTIGATIONAL PLAN ...............................................................................................20 
8.1 
OVERALL STUDY DESIGN AND PLAN .................................................................................20 
8.1.1 
Duration of Study .......................................................................................................21 
8.1.2 
Number of Subjects....................................................................................................21 
8.1.3 
Subject Recruitment/Enrollment ................................................................................21 
8.1.4 
Randomization ...........................................................................................................21 
8.2 
STUDY POPULATION ..........................................................................................................21 
8.2.1 
Subject Inclusion Criteria ..........................................................................................22 
8.2.2 
Subject Exclusion Criteria .........................................................................................22 
8.2.3 
Criteria for Early Discontinuation .............................................................................23 
8.2.4 
Early Discontinuation of Subjects .............................................................................23 
8.3 
INVESTIGATIONAL PRODUCT (STUDY DRUG) .....................................................................24 
8.3.1 
Treatments Administered ...........................................................................................24 
8.3.2 
Description of Investigational Product ......................................................................24 
8.3.3 
Method of Blinding ....................................................................................................24 
8.3.4 
Investigational Product Storage .................................................................................24 
8.3.5 
Method for Assigning Subject Numbers....................................................................25 
8.3.6 
Investigational Product Accountability ......................................................................25 
8.3.7 
Concomitant Medications ..........................................................................................26 
8.4 
STUDY PROCEDURES ..........................................................................................................26 
8.4.1 
Schedule of Assessments ...........................................................................................27 


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8.4.2 
Demographic Information ..........................................................................................32 
8.4.3 
Medical History .........................................................................................................32 
8.4.4 
Prior and Concomitant Medications / Treatments .....................................................32 
8.4.5 
Vital Signs ..................................................................................................................32 
8.4.6 
Weight ........................................................................................................................32 
8.4.7 
Height .........................................................................................................................32 
8.4.8 
Physical Examination.................................................................................................32 
8.4.9 
Tanner Stages .............................................................................................................33 
8.4.10 Clinical Laboratory Assessments ...............................................................................33 
8.4.11 Pregnancy Test ...........................................................................................................33 
8.4.12 Hand and Wrist X-Ray...............................................................................................33 
8.4.13 Basal LH, FSH, Testosterone/Estradiol Concentrations ............................................33 
8.4.14 Abbreviated GnRHa Stimulation Test .......................................................................33 
8.4.15 Pharmacokinetic Assessment .....................................................................................34 
8.5 
SAFETY EVALUATION ........................................................................................................34 
8.5.1 
Safety Parameters.......................................................................................................34 
8.5.2 
Investigator/Sponsor Safety Review ..........................................................................35 
8.5.3 
Data Safety Monitoring Board ...................................................................................35 
8.5.4 
Definition of Terms....................................................................................................36 
8.5.5 
Reporting of Adverse Events .....................................................................................36 
8.5.6 
Serious Adverse Events .............................................................................................38 
8.5.7 
Pregnancies ................................................................................................................39 
8.6 
STUDY VISITS ....................................................................................................................40 
8.6.1 
Screening Visit ...........................................................................................................40 
8.6.2 
Part A, Visit 1 (Baseline, Day 0)—Injection #1 ........................................................40 
8.6.3 
Telephone Contact 1(14 days ± 2 days): ....................................................................41 
8.6.4 
Part A, Visit 2 (~Month 1/Week 4 ± 7 days) .............................................................41 
8.6.5 
Part A, Visit 3 (~Month 3/Week 12 ± 7 days) ...........................................................42 
8.6.6 
Part A, Visit 4 (~Month 5/Week 20 ± 7 days) ...........................................................42 
8.6.7 
Part A, Visit 5 (~Month 6/Week 24 ± 7 days)—Injection #2 ....................................42 
8.6.8 
Telephone Contact 2 (14 days ± 2 days) Post Injection #2 ........................................43 
8.6.9 
Part A, Visit 6 (~Month 9/Week 36 ± 7 days) ...........................................................43 
8.6.10 Part A, Visit 7 (~Month 11/Week 44 ± 7 days) .........................................................44 
8.6.11 Part A, Visit 8 (~Month 12/Week 48 ± 7 days) End of Treatment or Early 
Discontinuation .........................................................................................................44 
8.6.12 Part B, Visit 7 (~Month 11/Week 44 ± 7 days)—Injection #3 ..................................44 
8.6.13 Telephone Contact 3 (14 days ± 2 days) Post Injection #3 ........................................45 
8.6.14 Part B, Visit 8 (~Month 15/Week 60 ± 7 days) .........................................................45 
8.6.15 Part B, Visit 9 (~Month 16/Week 64 ± 7 days)—Injection #4 ..................................46 
8.6.16 Telephone Contact 4 (14 days ± 2 days) Post Injection #4 ........................................46 
8.6.17 Part B, Visit 10 (~Month 20/Week 76 ± 7 days) .......................................................46 
8.6.18 Part B, Visit 11 (~Month 21/Week 80 ± 7 days)—End of Treatment or Early 
Discontinuation .........................................................................................................47 
8.6.19 Unscheduled Visits ....................................................................................................47 
8.6.20 Study Termination .....................................................................................................48 


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9.
STATISTICAL PLAN ..........................................................................................................48 
9.1 
SAMPLE SIZE DETERMINATION ..........................................................................................48 
9.2 
STATISTICAL METHODS .....................................................................................................49 
9.2.1 
Demographics and Other Baseline Characteristics ....................................................49 
9.2.2 
Efficacy Evaluations ..................................................................................................49 
9.2.3 
Pharmacokinetic and Pharmacodynamic Evaluations ...............................................50 
9.2.4 
Interim Analysis .........................................................................................................51 
9.2.5 
Accounting for Missing Data .....................................................................................51 
9.2.6 
Safety Analyses ..........................................................................................................51 
9.3 
SUBJECT POPULATIONS FOR ANALYSIS ..............................................................................52 
10. STUDY MANAGEMENT ....................................................................................................52 
10.1 POSTING OF INFORMATION ON CLINICALTRIAL.GOV ..........................................................52 
10.2 SITE REGULATORY DOCUMENTS REQUIRED FOR INITIATION .............................................52 
10.3 PRIMARY SOURCE DOCUMENTS .........................................................................................53 
10.4 STUDY MONITORING ..........................................................................................................53 
10.5 ELECTRONIC DATA CAPTURE AND ELECTRONIC CASE REPORT FORM ...............................55 
10.6 MODIFICATIONS TO THE PROTOCOL ...................................................................................55 
10.7 MAINTENANCE AND RETENTION OF RECORDS ...................................................................56 
10.8 AUDITS AND INSPECTIONS .................................................................................................56 
10.9 COMPLETION OF THE STUDY ..............................................................................................56 
11. CONFIDENTIALITY, USE OF INFORMATION, AND PUBLICATION ....................57 
11.1 CONFIDENTIALITY..............................................................................................................57 
11.2 DISCLOSURE OF INFORMATION ..........................................................................................57 
11.3 PUBLICATION .....................................................................................................................57 
12. REFERENCES ......................................................................................................................58 
13. APPENDICES .......................................................................................................................59 
13.1 CLINICAL LABORATORY PARAMETERS ..............................................................................59 
13.2 TANNER STAGES ................................................................................................................60 


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2. LIST OF IN-TEXT TABLES
Table 1 
Schedule of Assessments—Part A ........................................................................... 27 
Table 2 
Blood Sampling Times by Parameter for Visit 1—Part A ...................................... 30 
Table 3 
Schedule of Assessments—Part B ........................................................................... 31 
Table 4 
GnRH Antagonist Evaluations ................................................................................. 35 
Table 5 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
Severity Grading Scale ............................................................................................ 37 
Table 6 
Criteria for Determining Relationship of Adverse Event to Investigational 
Product ..................................................................................................................... 38 


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3. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
3.1 Abbreviations
Term 
Definition 
°C 
Degree Celsius 
°F 
Degree Fahrenheit 
µg 
microgram 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area under the Serum Concentration-Time Curve 
CFR 
Code of Federal Regulations 
CPP 
Central Precocious Puberty 
CRO 
Contract Research Organization 
DSMB 
Drug Safety Monitoring Board 
eCRF 
Electronic Case Report Form(S) 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration (United States) 
FSFV 
First Subject First Visit 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyltransferase 
GnRH 
Gonadotropin Releasing Hormone 
GnRHa 
Gonadotropin Releasing Hormone Agonist 
HbsAg 
Hepatitis B surface antigen 
HCVAb 
Hepatitis C antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ITT 
Intent-to-Treat 
kg 
Kilogram(s) 
LC/MS/MS 
Liquid Chromatography/Mass Spectrometry/Mass Spectrometry 
LH 
Luteinizing Hormone 
LSLV 
Last Subject Last Visit 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscle volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
mIU 
Milli International Units 


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Term 
Definition 
mL 
Milliliter(s) 
mm Hg 
Millimeters of Mercury 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ng 
Nanogram 
OTC 
Over-the-counter 
PD 
Pharmacodynamic 
PE 
Physical Examination 
pg 
Picogram 
PHI 
Private Health Information 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
SD 
Standard Deviation 
SoA 
Schedule of Assessment 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
US 
United States 
WHO 
World Health Organization 


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4. ETHICS
4.1 Independent Ethics Committee or Institutional Review Board
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) will approve the 
Protocol, Informed Consent Form (ICF), Assent Form (if required), and all other necessary 
documents prior to starting the study. All Protocol Amendments must be sent to the IRB/IEC for 
approval prior to implementation. All sites participating in this Protocol must have IRB/IEC 
approval before starting any study activities. IRB/IEC approvals must be provided to the 
Investigators in writing. 
The IRB/IEC-approved ICF and Assent Form (if required) must be signed by one or both parents 
(per IRB/IEC requirements), by the custodial parent or by the legal guardian(s) (when 
applicable). An Assent Form signed by the subject may be mandated as per the local IRB/IEC 
requirements.  
4.2 Ethical Conduct of the Study 
The study will be conducted in accordance with International Conference on Harmonisation 
(ICH) E6, Good Clinical Practice (GCP): Consolidated Guideline and the principles of ICH E8: 
General Considerations for Clinical Trials. This study will also comply with the United States 
(US) Code of Federal Regulations (CFR) and local regulations governing the protection of 
human subjects, the obligations of clinical investigators and requirements for an Investigational 
New Drug (IND) applications. In addition, the study will be carried out in accordance with all 
local laws and regulations concerning clinical studies. 
4.3 Subject Information and Consent 
The ICF and Assent Form (if required) used for the study must comply with the applicable local 
and federal laws and regulations and ICH E6 GCP: Consolidated Guideline and must be 
approved by the Sponsor or designee prior to review by the IRB/IEC. Any subsequent changes 
required by the IRB/IEC must also be approved by the Sponsor or designee. Subjects and the 
legal guardian(s) must be informed about all aspects of the clinical study that are necessary to 
make the decision to participate in the clinical study. Subjects and the parent/guardian(s) must be 
informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. Documentation of the discussion, the study personnel who 
managed/administered the ICF, and the date of informed consent must be recorded in the source 
documentation. Parent/guardian(s) of subjects must give informed consent in writing and each 
subject must sign the Assent Form, as required. Each signed ICF and Assent (if required) will be 
kept on file by the Investigator for inspection at any time. A copy of the signed and dated ICF 
and Assent (if required) will be given to the subject. 
The informed consent process must be conducted, and the form(s) must be signed, before the 
subject undergoes any screening or baseline procedures that are performed solely for the purpose 
of determining eligibility for the study, in compliance with 21 CFR Part 50. 
4.4 Confidentiality of Data 
Subjects will not be identified individually in any publications that result from this study. 
Confidential subject information, including medical records and test results, will be available 


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only to persons affiliated with the institution at which the subject is being treated and persons 
employed by, or associated with, the Sponsor, except where required by law. The Food and Drug 
Administration (FDA) may audit any site, which includes review of medical records of study 
subjects, any time following submission of the data to FDA. 
5. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
This study will be conducted at approximately 20 sites in the US, Canada, Mexico, Argentina, 
Australia, New Zealand and South Korea. 
Sponsor 
TOLMAR Inc.  
701 Centre Avenue 
Fort Collins, CO  80526 
Phone: (970) 212-4500 
Fax: (970) 449-5033 
Contract Research Organization 
Orphan Reach USA, LLC 
PO Box 423, Audubon, NJ  08106 
Or 
QED Clinical Services Limited 
The Learning House 
Winterhill, Snowdon Drive 
Milton Keynes, MK6 1BP 
United Kingdom 
6. INTRODUCTION
6.1 Background
Gonadotropin releasing hormone (GnRH)-dependent Central Precocious Puberty (CPP) is 
characterized by early pubertal changes accompanied by advanced bone age, accelerated growth 
velocity and GnRH-axis activation (Antoniazzi 2004; Kim 2013). Determining if the cause of 
CPP is idiopathic (genetic/undetermined) or organic (central nervous system tumor/lesion) is 
essential to treatment. Idiopathic CPP is more prevalent in females; whereas, in males 
distinguishable organic pathologies are more common (Fuqua 2013; Kaplowitz 1999). Both 
forms of CPP may benefit from GnRH agonist (GnRHa) therapies. 
The current standard for differential diagnosis for CPP is the GnRHa stimulation test (Carretto 
2014, Chi 2012). For this test, a dose of 20 µg/kg body weight of aqueous leuprolide acetate is 
administered; serum luteinizing hormone (LH), follicle stimulation hormone (FSH) and 
testosterone/estradiol are measured 30 minutes post infusion (Houk 2008; Chi 2012). Serum 
concentrations of LH ≥ 5 mIU/mL at 30 minutes are diagnostic for CPP (Houk 2008). 
Supportive diagnostic criteria for CPP include a combination of clinical and physical aspects 
before initiating treatment (Antoniazzi 2004). These tests include determining the Tanner stage 
(Marshall 1969) and bone age. Bone age is determined via X-ray of the non-dominant hand, 
from which bone length and epiphyseal plate size are used by the Greulich and Pyle method to 


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determine bone age (Antoniazzi 2004, Fuqua 2013). A bone age ≥ 1.5 years of chronologic age 
indicates accelerated bone growth and CPP. 
Leuprolide acetate is a GnRHa that inhibits pituitary gonadotropin secretion and suppresses 
testicular and ovarian steroidogenesis. In the original studies with leuprolide acetate in subjects 
with CPP, daily subcutaneous (SC) administration was shown to decrease concentrations of LH 
and FSH in pediatric patients (Kappy 1988). These inhibitory effects are reversible when drug 
therapy is discontinued. Since that time, new formulations of leuprolide acetate have been 
developed to allow for less frequent dosing.  
Leuprolide acetate has been approved as an injection formulation (Lupron Depot-PED, Product 
Insert-06/2013) for treatment of CPP. This formulation can be administered as once monthly 
intramuscular injection at doses of 7.5 mg, 11.25 mg, or 15 mg, or as once every three months at 
doses of 11.25 mg or 30 mg. 
Leuprolide acetate is also available as a suspension formulation for SC injection (under the brand 
name ELIGARD®), which is currently approved for palliative treatment of advanced prostate 
cancer (Product Insert-05/2014), up to a maximum dose of 45 mg administered every 6 months. 
The leuprolide acetate 45 mg in the study drug is in a controlled release injection solution 
formulation with the polymer Atrigel™ and has been used extensively in over 1 million 
administrations for the treatment of prostate cancer.  
Each different extended formulation of leuprolide acetate has different release characteristics to 
optimize the GnRHa activity. For example, clinical experience with leuprolide acetate has 
demonstrated prolonged testosterone suppression with daily administration of as little as 1 mg, or 
after administration in depot formulations at intervals of one month or longer (Chrisp 1991). The 
pharmacokinetics of GnRH agonists, includes an initial 'flare-up' of the pituitary-gonadal axis, 
followed by a reduced luteinizing hormone secretion by desensitization of pituitary GnRH 
receptors. During the first weeks of treatment, clinical signs of puberty, such as vaginal bleeding, 
may occur. This is a common initial effect of drugs with leuprolide acetate. The new 
signs/symptoms of puberty can continue beyond the second month of treatment. In the Package 
Insert for Eligard under Section17 (Information for Patients), it includes information, as with 
other GnRH agonists, that patients may experience hot flashes (flares) after injection and in the 
first few weeks of treatment may also experience increased bone pain, increased difficulty in 
urination, and the onset or aggravation of weakness or paralysis and that these symptoms should 
be reported. Patients should also be told that the injection site may have transient 
burning/stinging, slight pain, bruising, and redness that are usually mild and reversible. Rarely 
allergic reactions do occur and should be reported immediately.  
Benefits of leuprolide acetate for the treatment of CPP include increases to or restoration of 
projected adult height, and protection from the psychosocial harm associated with clinically 
significant early puberty (Kim 2013). Leuprolide acetate has been shown to be safe and effective 
during treatment periods from three months to one year at doses up to 20 mg/day in humans 
(Yamanaka 1985). 
ELIGARD® has not been approved for use in subjects with CPP; therefore, in this study, it will 
be considered as an investigational product or the study drug. 


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6.2 Rationale 
The purpose of this study is to determine the safety, efficacy and tolerability of leuprolide acetate 
45 mg injections in children with CPP. Efficacy is defined as suppression of serum LH 
concentration to levels below 4 mIU/mL. GnRH agonists are the only products approved for use 
in CPP. ELIGARD® 45 mg is an injectable suspension of leuprolide acetate administered 
periodically (currently every 6 months) to provide controlled release characteristics, which has 
been shown to have a favorable safety profile in adults. The 45 mg injectable formulation of 
leuprolide acetate is expected to provide convenience for children with CPP by less frequent 
office visits and thus greater compliance for maintenance of an effective and safe dose of a well-
described GnRH agonist.  
An adaptive protocol design has been chosen for this study due to the remote possibility that, in 
children with CPP, the controlled release characteristics of the leuprolide acetate 45 mg 
formulation may not completely suppress LH levels after 6 months but would be able to provide 
adequate suppression after 5 months. Therefore, the Part A of this design will evaluate the 
efficacy, tolerability and safety of administration of the leuprolide acetate 45 mg after 
2 administrations with a dose interval of 6 months. Since this formulation has not been 
administered to children, who may not metabolize the injectable formulation of leuprolide in the 
same manner as adults, a Part B extension is planned as a contingency in which the study drug 
will be administered at shorter intervals (5 months). The progression to Part B extension of the 
study will be based on levels of LH suppression at 6 months after the first dose, in a subset of 
subjects, as evaluated by the a Data Safety Monitoring Board (DSMB) and Sponsor.  
7. STUDY OBJECTIVES
7.1 Primary Objective
Determine the effectiveness of leuprolide acetate 45 mg for injectable suspension for treatment 
of children with CPP. 
7.2 Secondary Objectives 
•
Evaluate the safety and tolerability of leuprolide acetate 45 mg for injectable suspension in
children with CPP
•
Characterize the burst kinetics of leuprolide acetate 45 mg after the first administration
•
Characterize the pharmacodynamic (PD) relationship of leuprolide serum concentrations to
concentrations of serum LH, FSH and to testosterone/estradiol
•
Assess percent changes in height velocity and bone age progression after the first
administration
•
Assess changes in physical signs of puberty as measured by changes in Tanner stages or in
changes or onset of menses
•
Determine the dosing interval (5 or 6 months) at which leuprolide acetate is able to suppress
LH concentration to <4 mIU/mL (after GnRHa stimulation test), as data permit


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8. INVESTIGATIONAL PLAN
8.1 Overall Study Design and Plan
This will be an adaptive design study conducted in two parts as illustrated in Figure 1. 
Figure 1 
Study Design 
Subjects will only receive Injections #3 and #4 if Part B is conducted, based on Part A interim data. 
Part A: 
This will be a multi-center, open-label, single-arm 12-month study. Pediatric subjects with CPP 
will receive their first SC injection of the study drug (leuprolide acetate 45 mg for injectable 
suspension) at the start of the study and the second injection at the Month 6 visit. Subjects will 
return to the clinic periodically for 12 months from the start of dosing for assessment of efficacy, 
safety and pharmacokinetics (PK). 
An independent DSMB will review the safety of the drug throughout the study. 
An interim analysis of LH suppression from the GnRHa stimulation test results will be 
conducted after approximately 40% of the 40 subjects anticipated to complete 6 months of 
assessments have data through the Month 6 visit (N = approximately 16). Based on this analysis, 
if LH concentrations after the GnRHa stimulation test are suppressed to < 4 mIU/mL in < 85% of 
these subjects, then Part B of the study will be invoked. All subjects still undergoing therapy in 
the Part A of the study and those yet to enroll in the study, if eligible, will be asked to participate 
in the Part B extension study for additional dosing at shorter intervals. The progression to Part B 
extension will be based on evaluations by the DSMB and Sponsor.  
Part B Extension: 
This part of the study will be conducted based on analysis of interim data from Part A. 
NOTE: Because the interim analysis will only provide data from a very small sample size 
informing the decision to conduct Part B of the study with a 5-month dosing interval, ALL new 
subjects being enrolled into the study will begin with Part A of the study with the first 6-month 
dosing interval before proceeding to Part B. In this manner, there will be adequate data for 
comparison of dosing intervals for assessment of optimal efficacy. 
If invoked, this will be a multi-center, open-label, single-arm extension following Part A. Only 
subjects who have received the second injection of the study drug in Part A will be permitted to 


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enter Part B extension. Injections #3 and #4 will be administered in 5-month intervals after 
Injection #2 in Part A. The dosing interval will be dependent on emerging data from Part A. 
Subjects will return to the clinic periodically up to approximately an additional 10 months from 
start of Part B for efficacy, safety and PK assessments. 
8.1.1 Duration of Study 
In Part A, after a 28-day screening period, each subject will participate in the study for 48 weeks. 
Six months after Injection #1 in Part A, subjects will receive Injection #2 of the study drug. 
There will be a total of 7 study visits during Part A for a total duration of approximately 
12 months.  
Part A of the study is expected to take up to 24 months from first subject first visit (FSFV) to last 
subject last visit (LSLV), if Part B is not conducted. 
After the interim analysis, if the DSMB and the Sponsor make the decision to conduct Part B of 
the study then all currently enrolled eligible subjects and all newly enrolled subjects will receive 
a total of 4 injections of the study drug. Subjects who have gone beyond the Month 11 visit will 
not be considered eligible to participate in Part B extension as they would be considered to be 
out-of-window for Injection #3.  
If Part B of the study is invoked, the study length (for both Parts A and B) will be expected to be 
extended for approximately 10 more months for a total of approximately 34 months from FSFV 
(Injection #1) to LSLV. With the addition of Part B, commitment of each subject in the study 
will increase from 12 months to 21 months. 
8.1.2 Number of Subjects 
Approximately 60 pediatric subjects with CPP will be enrolled in this multicenter study so that 
approximately 40 subjects complete 6 months of the study. 
If Part B extension of the study is invoked, it is expected that approximately 27 subjects will 
complete outcome assessments to the Month 21 visit (5 months after the 4th study drug 
administration).  
8.1.3 Subject Recruitment/Enrollment 
Subjects will be evaluated for study inclusion only after written ICF and Assent (if required) has 
been obtained. Prior to enrollment during the Screening Period, each subject’s 
inclusion/exclusion criteria information, including current and recent medications, will be 
reviewed to verify that the subject qualifies for the study and is not receiving any prohibited 
medications/treatment. After meeting all of the inclusion and none of the exclusion criteria, 
subjects will be eligible to enroll in the study.  
8.1.4 Randomization 
There is only one Investigational Product (referred to as study drug) in this study; hence, there is 
no randomization to study groups. 
8.2 Study Population 
Deviations from the inclusion or exclusion criteria are not allowed because they can potentially 
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Therefore, strict adherence to the criteria as specified is essential. Subjects whose 
parent/guardian(s) have provided consent along with Assent (as required) to participate in the 
study, but fail to meet all study eligibility criteria will be considered screen failures. Screen 
failure subjects are not eligible for re-screening. Retesting of laboratory safety parameters, if 
considered necessary by the investigator, to support the re-evaluation of a medical condition or 
serious intercurrent illness that, in the opinion of the Investigator, would make it undesirable for 
the subject to participate in the study, may be permitted upon consultation with the Medical 
Monitor.  
8.2.1 Subject Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for participation in the study: 
1. Females age 2 to 8 years (inclusive) or males age 2 to 9 years (inclusive)
2. Confirmed diagnosis of CPP within 12 months of Baseline Visit (Day 0) but have not
received prior GnRH agonist treatment for CPP
3. Pubertal-type LH response following an abbreviated GnRHa stimulation test before
treatment initiation > 5 mIU/mL
4. Clinical evidence of puberty, defined as Tanner stage ≥ 2 for breast development in
females or testicular volume ≥ 4 mL in males
5. Willing and able to participate in the study
6. Difference between bone age (Greulich and Pyle method) and chronological age ≥ 1 year
7. Signed IRB/IEC-approved ICF by one or both parents (per IRB/IEC requirements), by
the custodial parent or by the legal guardian(s) (if required)
8. Signed Assent by subjects as per IRB/IEC requirements
8.2.2 Subject Exclusion Criteria 
Subjects who meet any of the following criteria are ineligible for participation: 
1. Gonadotropin-independent (peripheral) precocious puberty: extra pituitary secretion of
gonadotropins or gonadotropin-independent gonadal or adrenal sex steroid secretion
2. Prior or current GnRH treatment for CPP
3. Non-progressing isolated premature thelarche
4. Presence of an unstable intracranial tumor or an intracranial tumor requiring
neurosurgery or cerebral irradiation. Subjects with hamartomas not requiring surgery are
eligible.
5. Any other condition, chronic illness or treatment that, in the opinion of the Investigator,
may interfere with growth or other study endpoints (eg, chronic steroid use [except mild
topical steroids], renal failure, diabetes, moderate to severe scoliosis, previously treated
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6. Prior or current therapy with medroxyprogesterone acetate, growth hormone or insulin-
like growth factor-1 (IGF 1)
7. Major medical or psychiatric illness that could interfere with study visits
8. Diagnosis of short stature (ie, 2.25 standard deviations (SD) below the mean height for
age)
9. Positive urine pregnancy test
10. Known hypersensitivity to GnRH or related compounds
11. Any other medical condition or serious intercurrent illness that, in the opinion of the
Investigator, may make it undesirable for the subject to participate in the study
12. Any other condition(s) which could significantly interfere with Protocol compliance
13. Treatment with an investigational product within 5 half-lives of that product in prior
clinical studies before the baseline visit (Day 0)
14. Known history of seizures, epilepsy, and/or central nervous system disorders that may be
associated with seizures or convulsions
15. Prior (within 6 months of Baseline (Day 0)) or current use of medications that, per
Investigator opinion, have been associated with seizures or convulsions
8.2.3 Criteria for Early Discontinuation 
Subjects may be discontinued from the study for any of the following reasons: 
1. Parent/guardian(s) and/or subject withdrawal of consent/assent
2. Discretion of Investigator
3. Subject becomes pregnant
4. Changes in the subject's condition that, in the judgment of the Investigator, render the
subject unacceptable for further treatment with the study drug
5. Serious adverse event(s) or adverse event(s) that, in the judgment of the Investigator,
render the subject unacceptable for further Treatments with the study drug
6. Subject noncompliance with Protocol scheduled visits
7. Termination of the study by the Sponsor, IRB/IEC, or other regulatory authorities
8. Subject fails suppression of LH concentration to <4 mIU/mL (after GnRHa stimulation
test) at Visit 3 (~Month 3/Week 12 ± 7 days)
8.2.4 Early Discontinuation of Subjects 
In the event that a subject is prematurely discontinued from the study, efforts should be made to 
collect all clinical and laboratory data as scheduled for End of Treatment visit (See Section 8.4.1) 
and the subject should be followed up for safety, as appropriate. See Section 8.5.6.2 for details 
on following up on AEs. In addition, the Investigator should complete and report, as thoroughly 
as possible, the reasons for withdrawal.  


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Subjects who discontinue from the study will be treated as per the Investigator’s discretion and 
standard of care for children with CPP. 
8.3 Investigational Product (Study Drug) 
8.3.1 Treatments Administered 
8.3.1.1 During Study Period 
In Part A of the study each subject will receive a total of 2 single doses of the study drug 
administered as a SC injection into the abdominal area over the 12 month study period. The 
2 injections of the study drug will be at 6-month intervals: one at Baseline (Day 0) and one at the 
Month 6 visit (24 weeks).  
If Part B extension is conducted, then subjects will receive 2 additional SC administrations of the 
study drug at 5-month intervals: one at the Month 11 visit and one at the Month 16 visit.  
8.3.2 Description of Investigational Product 
The study drug, manufactured by TOLMAR, is a suspension of leuprolide acetate (ELIGARD®) 
for SC injection, provided in a single-use kit. The kit consists of a two-syringe mixing system, a 
sterile needle (18-gauge, 5/8-inch), a silicone desiccant pouch to control moisture uptake. Each 
syringe is individually packaged. One syringe contains the ATRIGEL® Delivery System and the 
other contains leuprolide acetate. When constituted, the study drug is administered as a single 
dose.  
8.3.3 Method of Blinding 
There will be no blinding of the study drug. 
8.3.4 Investigational Product Storage 
The Investigational Product or study drug is to be stored in a secure location. The kit should be 
stored refrigerated at 2°C to 8°C (36°F to 46°F).  
Prior to the injection time, the two-syringe mixing system kit should be brought to room 
temperature at least 30 min prior to administration. The provided Pharmacy Manual contain 
detailed instructions on the necessary steps for mixing of the leuprolide acetate prior to 
administration. Once the contents of the two syringes are mixed, the final product must be 
administered in ≤ 30 minutes.  
8.3.4.1 Administration 
The specific location chosen for the study drug should be an area with sufficient soft or loose 
subcutaneous tissue (eg, upper- or mid-abdominal areas). Avoid areas with brawny or fibrous 
subcutaneous tissue or locations that could be rubbed or compressed (eg, with a belt or clothing 
waistband).  
Topical or local anesthetic to “numb” the study drug injection site is permissible but must be 
recorded as a concomitant medication including the time of its administration.  


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8.3.4.2 Treatment Compliance 
All study drug injections will be administered by study staff at the clinic. The date and time of 
doses administered in the clinic will be recorded in the source documents.  
8.3.5 Method for Assigning Subject Numbers 
A unique subject number will be assigned to each subject. Neither subject initials nor other 
private health information (PHI), except date of birth and sex, will be collected on study 
documents.  
8.3.6 Investigational Product Accountability 
The accounting for the receipt, administration and disposition of all investigational product/study 
drug by each clinical site is required. This information will consist of the date the study drug has 
been received at the clinical site, date administered, the subject number, and if and when 
investigational product/study drug was destroyed or returned. The Investigator must maintain a 
complete and current dispensing and inventory record in accordance with the Protocol and any 
applicable laws and regulations. Throughout the study, Investigational Product/study drug 
accountability review and reconciliation for the study drug must be maintained, and any 
discrepancies must be investigated and their resolution documented. 
Inventory records must be readily available for inspection by the study monitor and/or auditor, 
and open to regulatory authority inspection at any time. 
All study drug receipt, inventory, dispensing, dosing and reconciliation records will be 
maintained in compliance with FDA and local regulations. 
8.3.6.1 Accountability and Investigational Product Use 
The Investigator agrees to ensure that dispensation of the study drug occurs only at the study 
site(s) listed on the Form FDA 1572 (or investigator agreement/statement). The Investigator or 
designee also agrees that only subjects enrolled in the study may receive administration of the 
study drug at the clinical site. Clinical supplies may not be used for any purpose other than as 
stated in this Protocol. 
The dispensing of all the study drug will be recorded in a dispensing log. The subject number, 
time of administration, and the initials and date of the person dispensing the medication will be 
documented on this form. The dispensing log will include the study drug identification lot 
numbers of the kit and both syringes.  
8.3.6.2 Disposition of Used Supplies 
The Investigator is responsible for accounting for all used study drug. This information will be 
recorded on the Drug Dispensing Log or other appropriate study drug inventory log. Used 
supplies should be disposed of in an appropriate manner according to institutional policy. 
8.3.6.3 Inventory of Unused Supplies 
The Investigator is responsible for accounting for all unused study drug. Periodically throughout 
and at the conclusion of the study, an inventory of unused study drug will be conducted by a 
representative of the Sponsor. 


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8.3.7 Concomitant Medications 
All concomitant medications including over-the-counter (OTC) medications, herbal, botanical 
and nutritional supplements used during the study must be recorded in the appropriate eCRF 
(Concomitant Medication Form) along with the indication for which it was used. The generic 
name of the medications should be specified along with the dosage, frequency and duration of 
treatment.  
Any medication considered necessary for the subject’s welfare, which is not expected to interfere 
with the PK assessment of study drug, may be given at the discretion of the Investigator.  
8.3.7.1 Permitted Medications 
Medications that are used to treat acute conditions are permitted. Any medications that are used 
for previously identified conditions may be continued but must be recorded in the medical 
history and in the list of concomitant medications.  
Local or topical anesthetics may be used and must be recorded as a concomitant medication with 
the generic name, time of administration, type and route of administration.  
8.3.7.2 Prohibited Medications 
Subjects shall receive no other GnRH or GnRH agonist therapy for any indication during this 
study. No additional hormonal therapies of any kind are permitted during this study. Subjects 
shall not receive any concomitant medications that, in the Investigator’s opinion, have been 
associated with seizures or convulsions or will put the child at risk of seizures or convulsions. 
8.3.7.3 Concomitant Procedures 
Any diagnostic, therapeutic or surgical procedures performed during the study must be recorded 
in the eCRF, including the date, indication, description of the procedure(s), any clinical findings, 
and outcome. 
8.4 Study Procedures 
The by-visit schedule of study activities are provided in Table 1 and Table 2 for Part A and in 
Table 3 for Part B. Every attempt should be made to have each subject attend each visit as 
scheduled.  












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8.4.2 Demographic Information 
Demographic and baseline characteristics, including date of birth, sex, race (American Indian; or 
Alaska Native; Asian; Black or African American; Native Hawaiian or Other Pacific Islander; 
White), and ethnicity (Hispanic or Latino; Not Hispanic or Latino) will be collected. 
8.4.3 Medical History 
Relevant medical history will be collected including prior and ongoing medical illnesses, 
conditions, and surgical procedures within the 24 months prior to enrollment. 
8.4.4 Prior and Concomitant Medications / Treatments 
All prior and concomitant medications, as well as any diagnostic, therapeutic, or surgical 
procedures performed, will be recorded from the time of signing the ICF/Assent Form (if 
required) throughout the subject’s participation in the study. 
8.4.5 Vital Signs 
Vital signs will be measured after the subject has been in a seated or supine position for 
5 minutes. Vital sign assessments will include the measurement of blood pressure (mm Hg), 
heart rate (beats per minute), respiration rate (breaths per minute), and temperature (oral, 
tympanic, or temporal; °C or °F). 
8.4.6 Weight  
Body weight (kg) will be measured at every visit. 
8.4.7 Height 
Standing height will be recorded with a calibrated stadiometer (eg, “Harpenden” stadiometer) 
that has increments in millimeters (mm) and a functional Frankfort Plane perpendicular to the 
standing surface. Preferably, the same stadiometer and the same health care provider trained in 
the use of the stadiometer will do the repetitive measurements on any subject in the study.  
The feet must be flat and either the knees or feet together in the center of the measuring board, 
making sure the legs are straight. The position of the legs is important. The mid-axillary line 
should be perpendicular to the base of the board. The subject should be looking straight ahead. In 
overweight, obese and older children, when the head is placed in proper position, according to 
the Frankfort Plane, there may be a space between the back of the child's head and the back of 
the measuring board. Use the Frankfort Plane on the stadiometer to determine the actual standing 
height to ± 1 mm.  
8.4.8 Physical Examination 
A complete physical exam (PE) will be performed by study personnel who are qualified to 
perform such examinations. At a minimum, the PE should include the cardiovascular system, the 
respiratory system, and the abdomen.  
Thereafter, a directed or targeted PE will be performed covering body systems related to the 
disease, including Tanner stages, and/or to assess any ongoing AEs. 


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8.4.9 Tanner Stages 
Sexual development in puberty will be assessed by Tanner staging, a system developed by 
Marshall and Tanner (1969) to categorize pubertal maturation. See Appendix 13.2 for details on 
the Tanner stages. Note any changes or onset of menses.  
8.4.10 Clinical Laboratory Assessments 
Clinical laboratory assessments (hematology, clinical chemistry, fasting serum lipids, hepatitis B 
& C, and urinalysis parameters) are listed in Appendix 13.1. Urinalysis assessments will be by 
“dipstick” assessments using urinalysis kits that will be provided to the sites by the Sponsor and 
evaluated locally. All other laboratory assessments will be from the blood samples collected at 
the appropriate assessment times and analyzed by a central laboratory. 
8.4.11 Pregnancy Test 
Urine pregnancy tests will be performed on female subjects. All female subjects must have a 
negative pregnancy test prior to receiving each injection of study drug. The pregnancy test will 
also be performed at End of Treatment in Part A or Part B extension (if invoked), and at the 
discretion of the Investigator.  
8.4.12 Hand and Wrist X-Ray 
A single X-ray of the non-dominant hand and wrist will be obtained periodically throughout the 
study to determine bone age using a Greulich and Pyle Atlas. A local reader will determine study 
eligibility during screening. All X-rays taken at designated study visits will be sent to a blinded 
central reader for evaluation of bone age; however, these evaluations will not be used to verify 
eligibility (eg, overrule local reader) for subject participation in the study. 
8.4.13 Basal LH, FSH, Testosterone/Estradiol Concentrations 
Blood samples for serum LH, FSH, testosterone (males) / estradiol (females) concentrations (as 
appropriate) will be collected at the appropriate assessment times and analyzed by a central 
laboratory according to current validated assays. It is important that ALL these samples are 
obtained BEFORE each study drug injection.  
These samples MUST be collected BEFORE the GnRHa stimulation tests. 
Blood samples will be collected and processed at the clinical site, and then shipped to the Central 
Laboratory for analysis according to the instructions provided in a Central Laboratory Manual.  
Serum LH and FSH concentrations will be measured at the Central Laboratory using current 
validated chemiluminescent microparticle immunoassay with a lower sensitivity range to at least 
0.5 mIU/mL (such as ARCHITECT System, Abbott Laboratory Diagnostics, USA). The lower 
limit of detection for testosterone/estradiol will be at least 3 ng/dL and 7.5 pg/mL, respectively. 
In addition, samples will be batched and analyzed by LC-MS/MS for publication purposes only. 
8.4.14 Abbreviated GnRHa Stimulation Test 
Baseline blood samples for serum LH, FSH, and testosterone/estradiol concentrations MUST 
first be obtained PRIOR to the start of the GnRHa stimulation test. A standard dose of 20 µg/kg 
body weight of aqueous leuprolide acetate will be administered SC. Blood samples to measure 
serum LH, FSH and testosterone/estradiol concentrations will be obtained again 30 minutes later. 


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Serum LH and FSH concentrations will be measured using current validated chemiluminescent 
microparticle immunoassay, as described in Section 8.4.13 
8.4.15 Pharmacokinetic Assessment 
All blood samples for analysis of leuprolide concentrations will be processed by a central 
bioanalytical laboratory. Instructions for collecting, processing, storing, and shipping blood 
samples will be provided in a separate PK Sample Collection, Handling and Shipping Manual. 
A validated bioanalytical liquid chromatography-tandem mass spectrometry (LC/MS/MS) 
method will be used to measure leuprolide concentrations in serum samples. 
8.5 Safety Evaluation 
8.5.1 Safety Parameters 
Safety parameters to be measured/assessed include eligibility assessments, medical history, vital 
signs, physical examinations, clinical laboratory tests, and pregnancy tests. Any abnormal 
hematology, serum chemistry, serum lipid, or urinalysis parameters considered clinically 
significant by the Investigator will be captured as AEs. 
Subjects will be monitored throughout the study for AEs, as well as for changes in clinical status, 
vital signs, and laboratory data. Any non-serious AEs occurring from the time the ICF and 
Assent forms, if required, are signed until just prior to receiving the first injection of study drug 
will be considered as non-TEAEs unrelated to study drug administration.  
Serious adverse events (SAEs) that occur as a result of study-mandated procedures during the 
time period after the ICF and Assent forms are signed, as appropriate, but prior to receiving the 
first injection of study drug will be collected but not designated as TEAEs. 
In order to evaluate changes in the acute (within two weeks of administration) and chronic 
hormonal responses associated with GnRH antagonist treatments over time,  subjects (or their 
parents/guardians) will be asked two weeks (14 days ± 2 days) after every study drug 
administration (by telephone contact), and at each scheduled visit, the following question(s):  
•
How have you felt in the last two weeks?
or alternatively (if the parent or guardian is answering on behalf of the subject) 
•
How has your child felt in the last two weeks?
Investigators will record any adverse events that are reported at that time. 
In addition the investigators will categorize the more specific responses that have been identified 
in the table (Table 4), which are often associated with GnRH antagonist injectable treatments. If 
the subject (or parent/guardian) does not report any condition (within the last two weeks) that fits 
into the Table 4 categories, the Investigator will check the response that no conditions associated 
with GnRH antagonists were reported (“NO”). If any of the conditions reported by the subject 
(or parent/guardian) fit into one (or more) of the categories, then the Investigator will check 
“YES” for each applicable category. This reported information will be collected by completing 
Table 4:  


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Table 4 
GnRH Antagonist Evaluations 
Any GnRH antagonist conditions reported? 
Yes/No 
If the answer is “Yes”, please categorize as described below: 
Flare or hot flashes 
Yes/No 
Injection site reactions (if “Yes”, please categorize below) 
a.
burning/stinging
b.
pain
c.
bruising
d.
redness
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Difficulty in urination 
Yes/No 
Bone pain 
Yes/No 
Aggravation of weakness or other muscle symptoms 
Yes/No 
Onset of allergic reactions 
Yes/No 
All AEs should still be reported as described in Section 8.5.5. The categorization of the answers 
must be completed prior to any study drug administration to evaluate the chronic reports.  
8.5.2 Investigator/Sponsor Safety Review 
The Medical Monitor will be responsible for the ongoing evaluation of safety throughout the 
study. The study will be reviewed for safety on a continual basis. The Medical Monitor will have 
access to all laboratory data and will review all SAEs. Clinical judgment by the Medical 
Monitor, in consultation with the Investigator and Sponsor, will be used to determine if the study 
should be stopped or suspended at any time for additional review of subject safety. The Medical 
Monitor will make an initial determination of the expectedness of an event based on the 
reference safety information (Investigator Brochure and ELIGARD® Package Insert). The 
Medical Monitor may present summary of safety information to the DSMB. 
8.5.3 Data Safety Monitoring Board 
An independent DSMB will review the safety and efficacy of the drug throughout the study. The 
frequency of subject evaluations will be at least quarterly. The full extent of responsibilities of 
the DSMB will be defined in their charter.  
The DSMB will review the data from the interim analysis looking at LH suppression from the 
GnRHa stimulation test in a subset of subjects completing the 6-month assessments to make 
recommendations on the progression to the Part B extension study. See Section 9.2.4 for criteria 
for the interim analysis data.  


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8.5.4 Definition of Terms 
8.5.4.1 Adverse Event Definition 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related (21 CFR 312.32 (a)). An AE can, therefore, be 
any unfavorable and unintended sign (eg, an abnormal laboratory finding considered clinically 
significant by the Investigator), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality. For this protocol, any unfavorable and unintended 
sign, symptom, or disease occurring after signature of Informed Consent/Assent will be collected 
as AEs.  
8.5.4.2 Suspected Adverse Reaction Definition 
A suspected adverse reaction is defined as any AE for which there is reasonable possibility that 
the drug caused the AE (21 CFR 312.32 (a)). 
8.5.4.3 Unexpected Adverse Event Definition 
An AE or suspected adverse reaction is considered unexpected if it is not listed in the 
ELIGARD® Package Insert, or is not listed in the Investigator Brochure. 
8.5.4.4 Serious Adverse Event Definition 
An SAE is defined as any untoward medical occurrence at any dose of study drug that results in 
any of the following outcomes (see FDA 21 CFR 312.32 and/or ICH E6 for Good Clinical 
Practice: Glossary of Terms): 
•
Death
•
A life-threatening adverse event
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an 
event, which hypothetically might have caused death if it were more severe.  
•
Inpatient hospitalization or prolongation of existing hospitalization
•
A persistent or significant disability/incapacity (substantial disruption of the ability to
conduct normal life functions)
•
A congenital anomaly/birth defect
The following events should also be considered as serious: 
•
Important medical events: Events that are not immediately life threatening or do not
result in death or hospitalization, but they do require urgent and intensive intervention to
prevent one of the other outcomes listed in the definition above (eg, intensive treatment at
home or in an emergency room for bronchospasm or seizure and a persistent high fever
with temperatures over 101°F [38°C]).
8.5.5 Reporting of Adverse Events 
All AEs that are observed by the Investigator or one of his/her medical collaborators, or reported 
by the subject, will be reported even if they are potentially attributable to unrelated medical 


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conditions or other medications the subject may be taking. The information recorded for AEs 
will include start date, a description of the AE, severity, causal relationship to Investigational 
Product/study drug, action taken, outcome of the event (including any treatment and/or 
hospitalization), and stop date. In addition, start time will be collected for events beginning on 
the day of the first injection. 
Medical conditions or diseases present before a subject is enrolled in the study are only 
considered AEs if they worsen after the subject is enrolled. 
For each AE, the seriousness, severity, and causal relationship to study drug will be assessed and 
entered in the source document. All items on the AE page of the eCRF should be completed for 
each AE.  
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. Planned surgical measures and the conditions leading to these 
measures are not AEs, if the condition(s) was (were) known before the study treatment. In the 
latter case, the condition should be reported as medical history.  
8.5.5.1 Severity of Adverse Events 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
grading scale uses Grades 1 through 5 to provide unique clinical descriptions of severity for AEs. 
Each AE will be rated according to NCI-CTCAE (version will be specified in the statistical 
analysis plan [SAP]) severity grading scale as outlined in Table 5. A complete description of 
each grade of the NCI-CTCAE rating system can be found on the NCI website (NCI-CTCAE 
version 4.0, 2010). 
Table 5 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
Severity Grading Scale 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADLa. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADLb. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
ADL: Activities of Daily Living 
a.
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing
money, etc.
b.
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and
not bedridden.
Source: NCI-CTCAE version 4.0, 2010 
An AE that is assessed as severe should not be confused with an SAE. An event is defined as 
‘serious’ when it meets one of the pre-defined outcomes as described in Section 8.5.4.4. 


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8.5.5.2 Criteria for Determining Relationship of Adverse Events to Investigational 
Product 
All AEs must be rated for their causal relationship to study drug according to the categories 
outlined in Table 6. 
Table 6 
Criteria for Determining Relationship of Adverse Event to Investigational 
Product 
Adverse 
Event 
Relationship 
Definition 
Criteria 
Not Related 
This category applies to those 
AEs that the Investigator, 
after careful consideration, 
believes are clearly due to 
extraneous causes (disease, 
environment, etc) and are not 
related to the administered 
investigational product. 
An adverse experience may be considered not 
related if, for example, the following apply: 
• It does not follow a reasonable temporal sequence
from administration of Investigational Product
• It could readily have been produced by the
subject’s clinical state, environment or toxic
factors, or other modes of therapy administered to
the subject
• It does not follow a known pattern of response to
Investigational Product
Related 
This category applies to those 
AEs that the Investigator 
believes are related to the 
administrated Investigational 
Product. 
An AE may be assigned as related if, for example, 
the following apply: 
• It follows a reasonable temporal sequence from
administration of Investigational Product.
• It could not be reasonably explained by the
known characteristics of the subject’s clinical
state, environmental or toxic factors, or other
modes of therapy administered to the subject.
• It disappears or decreases on cessation or
reduction in dose of study drug and recurs with
re-exposure.
­ NOTE: This is not to be construed as
requiring re-exposure of the subject. 
• It follows a known pattern of response to the
Investigational Product.
8.5.6 Serious Adverse Events 
All SAEs occurring after administration of study drug and within 6 months following last dose of 
study drug must be reported to the representatives of TOLMAR within 24 hours after the 
Investigator or site personnel have been informed or first becoming aware of the event. All 
events that meet the definition of an SAE or suspected unexpected serious adverse reactions 
(SUSAR) that occur as a result of study mandated procedures during the time period after the 
subject signs the ICF but prior to receiving the first infusion of study drug must also be reported. 


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8.5.6.1 Reporting of Serious Adverse Events 
When an SAE or SUSAR occurs, the Investigator or designee must log into the electronic data 
capture (EDC) system and complete the SAE Report form within 24 hours of first becoming 
aware of the SAE. All SAEs (including deaths of any cause) that occur after administration of 
study drug and within 6 months after the last administration of study drug in Part A, or within 5 
months after the last administration of study drug in Part B is invoked, whether or not considered 
related to study drug must be reported. The Investigator must also report SAEs to the Sponsor or 
representative (contract research organization [CRO]) and to the IRB/IEC as required by local 
and national laws. The Investigator must maintain documentation of all communications to and 
from the IRB/IEC. The SAE Report from the site should include date and time of onset, 
description of event, severity, duration, outcome, etiology, relationship to study drug, action 
taken and other relevant details as available. The Investigator is also responsible for updating the 
SAE Report Form as additional information becomes available. The Investigator may be 
requested for additional follow-up information by the Sponsor or the pharmacovigilance service 
provider in order to have more complete information for regulatory reporting.  
All SAEs/SUSARS will be monitored by the CRO Medical Monitor or pharmacovigilance 
service provider prior to submission to the regulatory authorities. Events associated with this 
clinical trial will be recorded in the ELIGARD® global safety database that is maintained for 
reporting and analysis. 
The Sponsor will adhere to all AE regulatory reporting requirements in accordance with local 
regulation and local authorities.  
Additional safety instructions will be provided to clinical sites including contact numbers and 
schedules to report all AEs, SAEs and SUSARs associated with this study. 
8.5.6.2 Follow Up of Adverse Events by Investigator 
After the initial SAE report, the Investigator is required to proactively follow each subject and 
provide further information to CRO on the subject’s condition. Any AEs related to study drug 
will be followed for 28 days or through resolution, stabilization, until deemed clinically 
insignificant, or until the subject is lost to follow-up. For SAEs, follow-up is required on an 
expedited timeline, within 24 hours of the initial report, as described in Section 8.5.6.1.  
New or updated information will be recorded in the “SAE” eCRF. The medical monitor and 
TOLMAR will be notified of the SAE within 24 hours as per the CRO’s established processes 
(Section 8.5.6.1). 
8.5.7 Pregnancies 
If a subject becomes pregnant at any time after the first injection, she must NOT receive the 
subsequent injections.  
Pregnancies are not considered to be AEs or SAEs; however, pregnancies will be followed 
through to outcome. If a pregnancy occurs, the Investigator or designee must complete the 
Pregnancy Report form within 24 hours of first becoming aware of the pregnancy. In 
pregnancies that progress to term, any congenital abnormalities in the offspring of a subject who 
received study drug should be reported as an SAE. 


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8.6 Study Visits 
Each subject is considered to be enrolled in the study when the subject’s parent/guardian has 
signed the ICF along with the subject’s signed Assent (as per IRB/IEC requirement) and has 
been assigned a subject number. A subject is considered to have discontinued from the study 
after the subject and parent/guardian have withdrawn consent/assent or has been discontinued 
under the conditions specified in Section 8.2.3. 
The following sections (Sections 8.6.1 to 8.6.199) outline the procedures required at each visit. 
8.6.1 Screening Visit 
Screening assessments will be performed during the 28-day Screening period and prior to the 
first injection, unless otherwise specified. During screening, the following procedures and 
evaluations will be performed: 
1. Informed consent and assent (if required); may be signed up to 28 days prior to
Baseline/Day 0
2. Inclusion/exclusion criteria
3. Demographics
4. Medical History
5. Vital signs – measured prior to any blood draws
6. Prior and concomitant medications
7. Physical Examination-complete
8. Tanner stage
9. Height and weight
10. X-ray of non-dominant hand and wrist
11. Urine for urinalysis, performed using dipstick supplied by Sponsor
NOTE: results must be evaluated before dosing
12. Blood samples for clinical laboratory assessments
•
Hematology and chemistry parameters as per Appendix 13.1
•
Serum lipids, fasting for ≥8 hours (water permitted)
•
Hepatitis B Surface Antigen (HBsAg) and hepatitis C antibody (HCBAb)
13. Blood samples for basal LH, FSH, testosterone/estradiol concentrations PRIOR to the
GnRHa stimulation
14. Blood samples for basal leuprolide concentrations PRIOR to the GnRHa stimulation
15. GnRHa stimulation: aqueous leuprolide acetate 20 µg/kg body weight administered SC
16. Blood samples for LH, FSH, testosterone/estradiol concentrations 30 ± 5 minutes AFTER the
GnRHa stimulation
17. Schedule/confirm next visit
8.6.2 Part A, Visit 1 (Baseline, Day 0)—Injection #1
Day 0 Predose: 
1. Evaluate hematology, chemistry and urinalysis results from Screening Visit
2. Inclusion/exclusion criteria – review to verify that subject continues to meet all of the
inclusion and none of the exclusion criteria.
3. Physical Examination-directed


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4. Prior and concomitant medications
5. Vital signs – measured prior to any blood draws
6. Height and weight
7. Urine pregnancy test, females only
NOTE: Results must be negative prior to receiving study drug injection
8. Serum lipids, fasting for ≥8 hours (water permitted)
9. Blood samples for basal LH, FSH, testosterone/estradiol concentrations ≥30 minutes before
planned injection time
10. Predose blood sample for serum leuprolide concentrations ≥30 minutes before planned
injection time
11. Record all non-treatment emergent AEs from the time of informed consent/assent until first
study drug administration
Day 0 Study Drug administration: 
12. Pharmacy - prepare study drug for injection (see Pharmacy Manual for complete instructions)
a.
Remove kit from refrigerator at least 30 minutes prior to planned administration and
allow the study drug to reach room temperature
b. Start mixing process with the product kit within ≤ 30 minutes prior to the injection time.
13. Apply topical or local anesthetic (per Investigator discretion) to injection site prior to planned
injection time; record medication, dose, route, and time
14. Administer first injection of study drug
Day 0 Postdose: 
15. Blood sample for LH, FSH, testosterone/estradiol, and serum leuprolide concentrations post
study drug injection time:
a.
1 hour ± 5 minutes
b. 4 hours ± 10 minutes
c.
6 hours ± 15 minutes
16. Final AE assessment prior to subject discharge from clinic
17. Schedule/confirm next visit
8.6.3 Telephone Contact 1(14 days ± 2 days):
1. Query subject or parent: “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
8.6.4 Part A, Visit 2 (~Month 1/Week 4 ± 7 days) 
1. Query subject or parent: “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs - measured prior to any blood draws
3. Physical Examination—directed
4. AE and concomitant medications assessments
5. Height and weight
6. Clinical laboratory assessments (hematology, chemistry) as per Appendix 13.1
7. Urine for urinalysis, performed using dipstick supplied by Sponsor


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8. Blood samples for basal LH, FSH, testosterone/estradiol concentrations
9. Blood sample for basal serum leuprolide concentrations
10. Schedule/confirm next visit
8.6.5 Part A, Visit 3 (~Month 3/Week 12 ± 7 days)
1. Query subject or parent: “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs - measured prior to any blood draws
3. AE and concomitant medications assessments
4. Physical Examination—directed
5. Tanner stage
6. Height and weight
7. Blood samples for basal LH, FSH, testosterone/estradiol concentrations PRIOR to the
GnRHa stimulation
8. Blood sample for basal serum leuprolide concentrations PRIOR to the GnRHa stimulation
9. GnRHa stimulation: aqueous leuprolide acetate 20 µg/kg body weight administered SC
10. Blood samples for LH, FSH, testosterone/estradiol concentrations 30 ± 5 minutes AFTER the
GnRHa stimulation
11. Schedule/confirm next visit
NOTE: Subjects who do not show adequate suppression of LH concentration to <4 mIU/mL
(after GnRHa stimulation test) will be discontinued.
8.6.6 Part A, Visit 4 (~Month 5/Week 20 ± 7 days) 
1. Query subject or parent: “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs
3. Height and weight
4. AE and concomitant medications assessments
5. Blood samples for basal LH, FSH, testosterone/estradiol concentrations
6. Blood sample for basal serum leuprolide concentrations
7. Schedule/confirm next visit
8.6.7 Part A, Visit 5 (~Month 6/Week 24 ± 7 days)—Injection #2
Predose: 
1. Query subject or parent: “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs - measured prior to any blood draws
3. AE and concomitant medications assessments
4. Physical Examination—directed
5. Tanner stage
6. Height and weight
7. X-ray of non-dominant hand and wrist
8. Clinical laboratory assessments (hematology, chemistry) as per Appendix 13.1
9. Urine for urinalysis, performed using dipstick supplied by Sponsor


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10. Urine pregnancy test, females only
NOTE: Results must be negative prior to receiving Injection #2
11. Blood samples for basal LH, FSH, testosterone/estradiol concentrations PRIOR to the
GnRHa stimulation
12. Blood sample for basal serum leuprolide concentrations PRIOR to the GnRHa stimulation
13. GnRHa stimulation: aqueous leuprolide acetate 20 µg/kg body weight administered SC
14. Blood samples for LH, FSH, testosterone/estradiol concentrations 30 ± 5 minutes AFTER the
GnRHa stimulation
Study Drug Administration: 
15. Pharmacy - prepare study drug for injection (see Pharmacy Manual for complete instructions)
a.
Remove kit from refrigerator, at least 30 minutes prior to planned administration and
allow the study drug to reach room temperature
b. Start mixing process with the product kit within ≤ 30 minutes prior to the injection time.
16. Apply topical or local anesthetic (per Investigator discretion) to injection site prior to planned
injection time; record medication, dose, route, and time
17. Administer second injection of study drug
Postdose: 
18. Final AE assessment prior to subject discharge from clinic
19. Schedule/confirm next visit
8.6.8 Telephone Contact 2 (14 days ± 2 days) Post Injection #2
1. Query Subject or parent: “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
8.6.9 Part A, Visit 6 (~Month 9/Week 36 ± 7 days) 
1. Query subject or parent “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs - measured prior to any blood draws
3. AE and concomitant medications assessments
4. Physical Examination—directed
5. Tanner stage
6. Height and weight
7. Blood samples for basal LH, FSH, testosterone/estradiol concentrations PRIOR to the
GnRHa stimulation test
8. Blood sample for basal serum leuprolide concentrations PRIOR to the GnRHa stimulation
test
9. GnRHa stimulation: aqueous leuprolide acetate 20 µg/kg body weight administered SC
10. Blood samples for LH, FSH, testosterone/estradiol concentrations 30 ± 5 minutes AFTER the
GnRHa stimulation test
11. Schedule/confirm next visit


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8.6.10 Part A, Visit 7 (~Month 11/Week 44 ± 7 days) 
NOTE: DO NOT complete Part A, Visit 7, if a decision has been made to conduct Part B 
extension study. In this case, follow procedures for Part B (Visits 7 to 13) beginning in 
Section 8.6.12.  
1. Query subject or parent: “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs - measured prior to any blood draws
3. Height and weight
4. AE and concomitant medications assessments
5. Blood samples for basal LH, FSH, testosterone/estradiol concentrations
6. Blood sample for basal serum leuprolide concentrations
7. Schedule/confirm next visit
8.6.11 Part A, Visit 8 (~Month 12/Week 48 ± 7 days) End of Treatment or Early
Discontinuation 
1. Query subject or parent “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs – measured prior to any blood draws
3. AE and concomitant medications
4. Physical Examination-complete
5. Tanner stage
6. Height and weight
7. X-ray of non-dominant hand and wrist
8. Urine pregnancy test, females only
9. Clinical laboratory assessments (hematology, chemistry) as per Appendix 13.1
10. Urine for urinalysis, performed using dipstick supplied by Sponsor
11. Blood samples for basal LH, FSH, testosterone/estradiol concentrations PRIOR to the
GnRHa stimulation test
12. Blood sample for serum leuprolide concentrations PRIOR to the GnRHa stimulation test
13. GnRHa stimulation: aqueous leuprolide acetate 20 µg/kg body weight administered SC
14. Blood samples for LH, FSH, testosterone/estradiol concentrations 30 ± 5 minutes AFTER the
GnRHa stimulation test
8.6.12 Part B, Visit 7 (~Month 11/Week 44 ± 7 days)—Injection #3 
The decision to conduct Part B extension of the study will be based on the results of the interim 
analysis (see Section 9.2.4). 
Predose: 
1. Informed consent and assent (may be signed up to 28 days prior to Part B, Visit 7)
2. Query subject or parent “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
3. Vital signs - measured prior to any blood draws
4. AE and concomitant medications assessments
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6. Tanner stage
7. Height and weight
8. X-ray of non-dominant hand and wrist
9. Clinical laboratory assessments (hematology, chemistry)
a.
Hematology and chemistry parameters as per Appendix 13.1
b. Serum lipids, fasting for ≥8 hours (water permitted)
10. Urine for urinalysis, performed using dipstick supplied by Sponsor
11. Urine pregnancy test, females only
NOTE: Results must be negative prior to receiving Injection #3)
12. Blood samples for basal LH, FSH, testosterone/estradiol concentrations PRIOR to the
GnRHa stimulation
13. Blood sample for basal serum leuprolide concentrations PRIOR to the GnRHa stimulation
14. GnRHa stimulation: aqueous leuprolide acetate 20 µg/kg body weight administered SC
15. Blood samples for LH, FSH, testosterone/estradiol concentrations 30 ± 5 minutes AFTER the
GnRHa stimulation test
Study Drug Administration: 
16. Pharmacy - prepare study drug for injection (see Pharmacy Manual for complete instructions)
a.
Remove kit from refrigerator, at least 30 minutes prior to planned administration and
allow the study drug to reach room temperature
b. Start mixing process with the product kit within ≤ 30 minutes prior to the injection time.
17. Apply topical or local anesthetic (per Investigator discretion) to injection site prior to planned
injection time; record medication, dose, route, and time
18. Administer third injection of study drug
Postdose: 
1. Final AE assessment prior to subject discharge from clinic
2. Schedule/confirm next visit
8.6.13 Telephone Contact 3 (14 days ± 2 days) Post Injection #3
1. Query subject or parent “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
8.6.14 Part B, Visit 8 (~Month 15/Week 60 ± 7 days) 
1. Query subject or parent “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs - measured prior to any blood draws
3. AE and concomitant medications assessments
4. Physical Examination—directed
5. Tanner stage
6. Height and weight
7. Blood samples for basal LH, FSH, testosterone/estradiol concentrations
8. Blood sample for basal serum leuprolide concentrations
9. Schedule/confirm next visit


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8.6.15 Part B, Visit 9 (~Month 16/Week 64 ± 7 days)—Injection #4 
Predose: 
1. Query subject or parent “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs - measured prior to any blood draws
3. AE and concomitant medications assessments
4. Physical Examination—directed
5. Tanner stage
6. Height and weight
7. X-ray of non-dominant hand and wrist
8. Clinical laboratory assessments (hematology, chemistry) as per Appendix 13.1
9. Urine for urinalysis, performed using dipstick supplied by Sponsor
10. Urine pregnancy test, females only
NOTE: Results must be negative prior to receiving Injection #4)
11. Blood samples for basal LH, FSH, testosterone/estradiol concentrations PRIOR to the
GnRHa stimulation
12. Blood sample for basal serum leuprolide concentrations PRIOR to the GnRHa stimulation
13. GnRHa stimulation: aqueous leuprolide acetate 20 µg/kg body weight administered SC
14. Blood samples for LH, FSH, testosterone/estradiol concentrations 30 ± 5 minutes AFTER the
GnRHa stimulation test
Study Drug Administration: 
15. Pharmacy - prepare study drug for injection (see Pharmacy Manual for complete instructions)
a.
Remove kit from refrigerator, at least 30 minutes prior to planned administration and
allow the study drug to reach room temperature
b. Start mixing process with the product kit within ≤ 30 minutes prior to the injection time.
16. Apply topical or local anesthetic (per Investigator discretion) to injection site prior to planned
injection time; record medication, dose, route, and time
17. Administer third injection of study drug
Postdose:
18. Final AE assessment prior to subject discharge from clinic
19. Schedule/confirm next visit
8.6.16 Telephone Contact 4 (14 days ± 2 days) Post Injection #4
1. Query subject or parent “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
8.6.17 Part B, Visit 10 (~Month 20/Week 76 ± 7 days) 
1. Query subject or parent “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs - measured prior to any blood draws


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3. AE and concomitant medications assessments
4. Physical Examination—directed
5. Tanner stage
6. Height and weight
7. Blood samples for basal LH, FSH, testosterone/estradiol concentrations
8. Blood sample for basal serum leuprolide concentrations
9. Schedule/confirm next visit
8.6.18 Part B, Visit 11 (~Month 21/Week 80 ± 7 days)—End of Treatment or Early
Discontinuation 
1. Query subject or parent “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs - measured prior to any blood draws
3. AE and concomitant medications assessments
4. Physical Examination—complete
5. Tanner stage
6. Height and weight
7. X-ray of non-dominant hand and wrist
8. Urine pregnancy test, females only
9. Clinical laboratory assessments (hematology, chemistry) as per Appendix 13.1
10. Urine for urinalysis, performed using dipstick supplied by Sponsor
11. Blood samples for basal LH, FSH, testosterone/estradiol concentrations PRIOR to the
GnRHa stimulation
12. Blood sample for basal serum leuprolide concentrations PRIOR to the GnRHa stimulation
13. GnRHa stimulation: aqueous leuprolide acetate 20 µg/kg body weight administered SC
14. Blood samples for LH, FSH, testosterone/estradiol concentrations 30 ± 5 minutes AFTER the
GnRHa stimulation test
8.6.19 Unscheduled Visits 
If additional visits are needed, either during Part A or Part B, the following procedures and 
evaluations may be performed as deemed appropriate by the Investigator. If the subject is 
expected to return for subsequent visits the GnRHa stimulation test will be optional, while blood 
samples for hormones must be collected:  
1. Query subject or parent “How have you felt in the last two weeks?” or “How has your child
felt in the last two weeks?” Complete Table 4
2. Vital signs - measured prior to any blood draws
3. AE and concomitant medications assessments
4. Physical Examination—complete
5. Tanner stage
6. Height and weight
7. Urine pregnancy test, females only
8. Clinical laboratory assessments (hematology, chemistry) as per Appendix 13.1
9. Urine for urinalysis, performed using dipstick supplied by Sponsor
10. Blood samples for basal LH, FSH, testosterone/estradiol concentrations PRIOR to the
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11. Blood sample for basal serum leuprolide concentrations PRIOR to the optional GnRHa
stimulation test
12. At investigator’s discretion: GnRHa stimulation: aqueous leuprolide acetate 20 µg/kg body
weight administered SC
13. If GnRH stimulation is performed, blood samples for LH, FSH, testosterone/estradiol
concentrations will be collected 30 ± 5 minutes AFTER the GnRHa stimulation
14. Schedule/confirm next visit, if appropriate
8.6.20 Study Termination
The clinical study may be stopped at any time at the discretion of the Sponsor or by regulatory 
authorities (IRB/IEC or governing competent authority). The clinical study may be stopped if the 
extent (incidence and/or severity) of emerging effects/clinical endpoints is such that the 
risk/benefit ratio to the study population as a whole is unacceptable. 
Further recruitment in the study or at a particular site(s) may be stopped due to insufficient 
compliance with the Protocol, ICH-GCP and/or other applicable regulatory requirements, 
procedure-related problems, or if the number of discontinuations for administrative reasons is too 
high. 
Upon study termination, all site closure activities with the investigator or site staff, as 
appropriate, will be conducted in accordance with applicable regulations including ICH-GCP and 
sponsor procedures.  
After the completion of the study subjects will be managed for their underlying disease 
according to the local standard of care, and based on the subject’s previous medical history. 
Continued treatment will not be conducted as part of this protocol. 
9. STATISTICAL PLAN
Prior to the database lock, a finalized Statistical Analysis Plan (SAP) will be completed and 
approved. The SAP will contain a comprehensive explanation of the methodology used in the 
statistical analyses. The SAP will also contain the rules and data handling conventions that will 
be used to perform the analyses, and the procedure that will be used to account for missing data. 
9.1 Sample Size Determination 
To determine the percentage of subjects with suppression of serum LH to < 4 mIU/mL following 
treatment with leuprolide acetate 45 mg, it is estimated that approximately 40 subjects would be 
sufficient for assessment of Part A and approximately 27 subjects for Part B, if invoked. 
Approximately 60 subjects may be enrolled in the study in order to get an appropriate number of 
assessable subjects. 
The sample size was pragmatically determined based on the clinical trial size and response rate 
of other GnRH antagonists studies in CPP subjects.   
The descriptive finding that will conclude efficacy is that ≥ 80% of subjects will exhibit 
< 4 mIU/mL LH suppression. This is conservative, since the dropout rate is unknown, and it is 
anticipated that the percent of subjects suppressed is likely to be at least 85%. Thus, 85% 
suppression or 90% suppression might be reasonably expected. However, the drop out in this 


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study could be slightly more than 50%, if Part B is invoked, thus depending on whether only Part 
A is carried out or Part B is invoked, the final available sample size after drop out could vary 
between 25 and 50 subjects given the planned recruitment of 60 subjects. Suppression to 
< 4 mIU/mL in approximately 70% of the subjects is considered to be clinically important if the 
full expectations of all drop-out are completed. Thus, the study is thought to have a sufficient 
number of subjects. If 85% of subjects enrolled are found to be suppressed we would expect a 
lower 95% one sided confidence interval under a fully realized drop out scenario (ie, 25 final 
subjects) of slightly more that 70%.  
9.2 Statistical Methods 
The purpose of this study is to demonstrate suppression of LH at a level of < 4 mIU/mL at 
30 minutes after GnRHa stimulation in a majority of subjects (≥ 80%) who are treated with 
leuprolide acetate 45 mg in an injectable suspension. Descriptive outcomes for the primary and 
secondary efficacy variables will be used to evaluate the efficacy of this treatment.  
If suppression in ≥ 85% of the first 16 subjects to be evaluated at Month 6 is found, the study 
will terminate under Part A without the invocation of Part B as a follow-on adaptive dosing 
schedule. If study termination under Part A occurs, the criterion variable for adaptive change 
applied to the first 16 patients at six months, namely, percent of patients with < 4 mIU/mL 
suppression, will also function as the primary outcome variable when applied to all patients in 
the study. As was the case for evaluating adaptive change in design, an absolute descriptive 
rather than inferential statistical outcome will be used to assess efficacy for the primary outcome 
variable. Efficacy will be claimed if ≥ 80% of the subjects exhibit < 4 mIU/mL suppression.  
If suppression in < 85% of the first 16 subjects to be evaluated at Month 6 is found, the study 
will be adapted and Part B will be invoked. As would be the case if the study were to terminate 
with Part A, the percent of subjects with < 4 mIU/mL suppression will serve as the primary 
outcome variable under Part B. If < 4 mIU/mL suppression in ≥ 80% of the patients in the study 
at Visit 11 (Month 21) is found, efficacy will be claimed.  
9.2.1 Demographics and Other Baseline Characteristics 
Demographic variables will include age, race, ethnicity, sex, height, and weight. Subject 
demographics will be summarized with descriptive statistics, as appropriate.  
9.2.2 Efficacy Evaluations 
Primary Efficacy Endpoint 
•
Part A: the percentage of subjects with serum LH concentrations < 4 mIU/mL 30 minutes
following an abbreviated GnRHa stimulation test at the Month 6 visit
Leuprolide Acetate 45 mg will be considered effective for the treatment of children with
CPP if ≥ 80% of subjects exhibit LH suppression < 4 mIU/mL at Month 6
•
Part B Extension: the percentage of subjects with serum LH concentrations < 4 mIU/mL
30 minutes following an abbreviated GnRHa stimulation test at the Month 21 visit (5 months
after the Injection #4 of leuprolide acetate)


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Leuprolide acetate 45 mg will be considered effective for the treatment of children with CPP 
if ≥ 80% of subjects exhibit LH suppression < 4 mIU/mL at the Month 21 visit (5 months 
after the last of 4 administrations of the study drug) 
NOTE:  If Part B extension is conducted, the primary efficacy endpoint for Part A will 
become a secondary efficacy endpoint of Part B. 
Secondary Efficacy Endpoint: Parts A & B 
•
The percentage of subjects with suppressed serum LH concentrations (< 4 mIU/mL)
30 minutes post GnRHa stimulation test at all assessed time points
•
Changes in height velocity (growth rate), and bone age advancement will be evaluated
relative to chronological age using descriptive statistics from baseline to end of study
•
Changes in physical signs of puberty as measured by changes in Tanner stages from
baseline to end of study
Exploratory Assessments: Parts A & B 
•
Bone age progression will be further evaluated using descriptive statistics and figures at all
assessed timepoints. Changes in bone age progression will be described for each individual
and for the ITT and PP population over the entire treatment period
•
Descriptive statistics will be used to describe changes in physical signs of puberty as
measured by changes in Tanner stages at each assessed timepoint. Changes in Tanner staging
will be described for each individual and for the ITT and PP population over the entire
treatment period.
•
The percentage of subjects with LH (< 4 mIU/mL), FSH (< 2.5 mIU/mL), estradiol
(< 20 pg/mL) or testosterone (< 30 ng/dL) suppression to prepubertal levels and serum
leuprolide levels at all assessed timepoints
•
Evaluation of the incidence rate of GnRH antagonist reports (see Section 8.5.1) that occurred
within the 2 weeks (± 2 days) following first drug administration will be descriptively
compared to the incidence rate within the 2 weeks (± 2 days) after each subsequent drug
administration
•
Evaluation of the incidence rate of GnRH antagonist reports that occurred within 2 weeks
(± 2 days) following drug administration will be descriptively compared to the incidence rate
within the 2 weeks (± 2 days) prior to each scheduled visit.
9.2.3 Pharmacokinetic and Pharmacodynamic Evaluations 
Leuprolide concentrations from each assessment time will be listed and descriptively analyzed. 
“By subject” serum concentrations versus time will be plotted on both linear and log scales. The 
characteristics of the burst of leuprolide concentration will be statistically described by the serum 
concentrations of leuprolide that are collected in the first week after each administration. The 
steady-state or baseline concentrations will be the statistical description of the leuprolide 
concentration collected at each assessment point at least one month after the first administration 
and prior to any GnRHa stimulation test or prior to subsequent administration of the leuprolide 
45 mg injection solution. An approximation of the AUC of the systemic leuprolide concentration 
between each dose and for the entire treatment period will be provided. 


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Each of the hormones assessed, and in particular, LH and FSH, and testosterone/estradiol will be 
statistically described for each assessment point and for changes in concentration from baseline 
values. The ratio of LH to FSH will be provided for each assessment point will be presented with 
an additional analysis of percent change from baseline for the ratio.  
For each assessment point the LH suppression from the GnRHa stimulation test results will be 
statistically described for the LH concentration 30 minutes after the agonist administration and 
the percent change in the LH concentration after the GnRHa stimulation test will be statistically 
compared to the baseline concentration of the GnRHa tests administered prior to the first dose. 
Additionally, the LH concentration 30 minutes after the agonist administration will be 
statistically contrasted to the leuprolide concentration at each assessment point to provide an 
assessment of the PK/PD relationship. Similar comparisons will be conducted to evaluate the 
relationship of leuprolide to changes in serum concentrations of FSH and testosterone/estradiol. 
9.2.4 Interim Analysis 
An interim analysis of LH suppression from the GnRHa stimulation test results will be 
conducted after approximately 40% of the 40 subjects anticipated to complete 6 months of 
assessments have data through the Month 6 visit (N = approximately 16). Based on these data, if 
LH concentrations after the GnRHa stimulation test are suppressed to < 4 mIU/mL in < 85% of 
these subjects, then Part B of the study will be invoked. All subjects still undergoing therapy in 
the Part A of the study and those yet to enroll in the study, if eligible, will be asked to participate 
in the Part B extension study for additional dosing at shorter intervals. The progression to Part B 
extension will be based on evaluations by the DSMB and Sponsor. Subjects that progress to 
Part B of the study will be provided information about Part B in an ICF and Assent Form (if 
required), which will be signed by appropriate parent/guardian(s) and the subject.  
9.2.5 Accounting for Missing Data 
Imputation of missing data will not be performed for baseline, efficacy, and safety endpoints. 
9.2.6 Safety Analyses 
A listing of all AEs, including SAEs and events leading to discontinuation, will be provided. The 
Data Management team will compile a list of all AEs based on the information entered in the 
eCRF. This listing will be sent to TOLMAR and the CRO Safety Department for the proper 
reconciliation of the study and safety databases. These listings will include: event term as 
reported, event term as coded with the Medical Dictionary for Regulatory Activities (MedDRA 
version(s) will be documented in the final Clinical Study Report), start date, start time (only for 
events beginning on the day of the first injection), stop date, outcome, seriousness, severity, 
relationship to Investigational Product, and action taken with Investigational Product. AEs 
recorded after signing of the ICF/Assent but PRIOR to the first injection will be reported as non-
TEAEs.  
The number and percent of subjects reporting AEs will be tabulated. Summaries will be 
presented by body system organ class (SOC) and preferred term (PT), and further by severity and 
relationship to the study drug.  
SAEs will be discussed within the clinical study report. Data collected pertaining to SAEs will be 
presented in data listings. 


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Continuous serum chemistry and hematology laboratory results will be summarized using mean, 
standard deviation, median, minimum, and maximum for each study visit, each cohort and each 
treatment cycle with each cohort. Urinalysis results by dipstick will be listed. Laboratory test 
results that are normal at Screening and become abnormal during treatment will be reported. 
Vital signs will be summarized at each time point with mean, standard deviation, median, 
minimum, and maximum by each cohort and each treatment period with each cohort. 
Other medical history data and the physical examination data will be tabulated. 
Concomitant medications will be classified according to the World Health Organization (WHO) 
Drug Dictionary (version(s) will be documented in the final Clinical Study Report) and will be 
presented in data listings. 
9.3 Subject Populations for Analysis 
Safety population: All subjects providing consent/assent and who received at least one dose of 
the study drug. 
ITT population: Subjects providing consent/assent who received at least one dose, fulfilled the 
protocol eligibility criteria, and provided at least one PD laboratory assessment post dosing.  
PP population: Subjects who have received at least one dose of the study medication and have 
fulfilled the protocol in terms of eligibility, interventions and outcome assessments for at least 
6 months. 
10. STUDY MANAGEMENT
10.1 Posting of Information on Clinicaltrial.gov
Study information from this protocol will be posted on clinicaltrials.gov before the start of 
subject enrollment. 
10.2 Site Regulatory Documents Required for Initiation 
CRO will receive the following documents prior to the initiation of the study at each site: 
•
Completed, signed Form FDA 1572
•
Current curricula vitae, signed and dated, for the Principal Investigator and
Sub-Investigators named on Form FDA 1572
•
Documentation of IRB/IEC approval of the study Protocol, Principal Investigator, and
ICF
•
Current IRB/IEC membership list or assurance number
•
A copy of the Protocol signature page signed by the Principal Investigator
•
Non-disclosure Agreements for the Principal Investigator and Sub-Investigators named
on Form FDA 1572
•
Debarment Certifications for the Principal Investigator and Sub-Investigators named on
Form FDA 1572


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•
Financial Disclosure Statements for all individuals named on Form FDA 1572
•
Additional documents may be collected per local regulatory requirements
10.3 Primary Source Documents 
The Investigator will maintain adequate and accurate records for each subject who has 
appropriate consent/assent to participate in the study. Source documents such as hospital, clinic 
or office charts, laboratory reports, radiology reports, and signed ICF/Assent (if required) 
documents are to be included in the subject’s study chart. The Investigator will document the 
informed consent/assent process in the source documents; including documentation that the 
ICF/Assent were signed prior to the subject’s participation in the study and that a copy of the 
signed and personally dated ICF/Assent were provided to the parent/guardian(s) and subject, as 
appropriate. 
The Investigator must maintain primary source documents supporting significant data for each 
subject’s medical notes. These documents are considered source data and should include 
documentation of: 
•
Demographic information
•
Evidence supporting the diagnosis/condition for which the subject is being studied
•
General information supporting the subject’s participation in the study
•
General history and physical findings
•
Hospitalization or Emergency Room records (if applicable)
•
Each study visit by date, including any relevant findings/notes by the Investigator(s) or
designee, occurrence (or lack) of AEs, and changes in medication usage, including the
date and time infusion was started and ended
•
Any additional visits during the study
•
Any relevant telephone conversations with the subject regarding the study or possible
AEs
•
An original, signed ICF/Assent (if required) for study participation
The Investigator must also retain all subject-specific printouts/reports of tests and procedures 
performed as a requirement of the study. During monitoring visits the monitor will validate data 
in the eCRF against these sources of data. 
10.4 Study Monitoring 
This study will be closely monitored by the CRO throughout its duration. Monitoring will be in 
the form of personal visits with the Investigator and his/her staff as well as through other 
appropriate communications by telephone, FAX, email, or mail. It is the monitor’s responsibility 
to inspect the eCRF at regular intervals throughout the study to verify the completeness, 
accuracy, and consistency of the data, and to verify adherence to the Protocol, current ICH-GCP 
guidelines, and any applicable local regulations.  


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All data must be available in source documents before entry into the eCRF, and all data entered 
into the eCRF will be source data verified. Data that is required according to this Protocol is to 
be recorded in the eCRF. For data collected with the EDC system, source data documentation is 
defined as the first place the data are recorded. All source documents must be retained and 
retrievable at the site in study specific files. 
Every effort will be made to maintain the anonymity and confidentiality of subjects during this 
study. However, because of the experimental nature of this treatment, the Investigator agrees to 
allow representatives of the Sponsor as well as authorized representatives of the Regulatory 
Agencies, such as the FDA, to inspect the facilities used in this study and to inspect, for purposes 
of verification, the hospital or clinic records of all subjects enrolled into this study. The 
Investigator agrees to cooperate with the monitor to ensure that any problems detected during the 
course of these monitoring visits are resolved. 
Medical supervision for the conduct of this Protocol is the responsibility of the Investigator. The 
Principal Investigator must name all Sub-Investigators and may delegate certain tasks to named 
Sub-Investigators qualified and trained to do such tasks, but retains the overall personal 
responsibility for adequate supervision of study staff and ensuring that the study is conducted 
properly and in accordance with the design and intent herein. The Investigator must ensure that 
there is adequate training for all staff participating in the conduct of the study, including any new 
staff joining the study after it has begun. The Investigator must ensure that he or she has 
sufficient time to properly conduct and supervise the clinical study, and should develop a plan 
for the supervision and oversight of the study. A document outlining the specifics of the 
delegation will be maintained at the investigational site, in the study files, and will be updated as 
appropriate.  
Investigators are responsible for protecting the rights, safety, and welfare of subjects under their 
care during a clinical study (ICH E6 GCP Section 4). This responsibility should include: 
•
Providing adequate medical care to study subjects for any AEs, including clinically
significant laboratory values, related to the study
•
Providing decisions for medical care by a qualified physician who is an Investigator or
Sub-Investigator for the study
•
Conducting the study in compliance with the Protocol.
The Investigator should inform the subject's primary physician about the subject's participation 
in the study if the subject has a primary physician and the subject agrees to the primary physician 
being informed. The Investigator is responsible for ensuring that drugs and devices are available 
for treating possible medical emergencies. The Investigator is required to ensure compliance 
with respect to the investigational drug schedule, visit schedule, and procedures as required by 
the Protocol. The Investigator is responsible for ensuring that the study is conducted according to 
sound medical practices, following local regulatory compliance, and ICH-GCP. 
The Investigator will be responsible for ensuring that an annual update is sent to the IRB/IEC 
and/or appropriate local review board to facilitate their continuing review of the study (ICH E6 
ICH-GCP Sections 3 and 4.4) and that the IRB/IEC and/or appropriate local review board is 
informed about the end of the study. Copies of the update, subsequent approvals, and final letter 


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must be sent to the CRO. Copies of all correspondence (eg, letters, email) to and from the 
IRB/IEC and/or appropriate local review board must be kept on file at the site and be available 
for review by the Sponsor or Sponsor’s representative during monitoring visits or audits.  
10.5 Electronic Data Capture and Electronic Case Report Form 
An electronic case report form (eCRF) is required to be completed for each individual subject. 
The eCRFs will be provided for transfer of all research data by site personnel from data source 
documentation to a computer database. Each responsible person at a site, the CRO, or Sponsor 
will have user access with a unique username and password, with permissions providing each 
person their needed access. Some personnel will have data entry, data review, and query 
resolution permissions, while others may only have data read permissions, based on their 
individual study roles. 
Study monitors will verify computerized data against its source. Monitoring will be enhanced by 
computer-assisted data management identifying missing or possibly erroneous data as soon as 
data is entered into the EDC system. This approach will allow initial remote monitoring, and 
communication between study monitors and site personnel before and between site visits, and 
will expedite data review and cleaning. The flow of data from start to finish will be as follows: 
site personnel will enter subject data that meets all mandatory requirements per system edit 
checks, and will mark the data as complete, at which time the data will only be changeable via a 
query issued by the study monitor or data management group. Site personnel will respond to all 
queries. Study monitors will review, query and ultimately resolve those queries. The subject’s 
data will then be locked by data management, with only read access provided to authorized 
personnel. 
All study data are housed in a secure computing environment. The EDC system will include a 
complete audit trail of all data entry, monitoring, and query activity that is compliant with Health 
Insurance Portability and Accountability Act (HIPAA) and 21 CFR Part 11 requirements. 
Study data required by study monitors, other authorized representatives of the Sponsor, and 
appropriate regulatory authority inspectors will be available through the EDC system during the 
study. At the end of the study, a compact disc with site-specific data information will be 
provided to each site for archiving. 
All required study information must be entered into the EDC system. eCRFs are considered 
complete when all data fields are complete and acknowledged as correct by the Study Monitor. It 
is the Investigator’s responsibility to ensure completion, accuracy, review, and approval of all 
eCRFs. The Principal Investigator must sign an Investigator’s Statement at study completion for 
each subject to document that the Investigator has met these responsibilities. 
10.6 Modifications to the Protocol 
The procedures defined in the Protocol and eCRF will be carefully reviewed so that all parties 
involved with the study fully understand the Protocol. Only the Sponsor may initiate an 
amendment to the Protocol. Protocol amendments must be submitted and approved by the 
IRB/IEC prior to implementation.  
Protocol deviations affecting the safety of the subjects or the integrity of the data and must be 
avoided. However, deviations from the Protocol may be made if necessary to eliminate apparent 


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immediate hazard(s) to a subject or subjects. In this instance, the Investigator must notify the 
CRO and the IRB/IEC immediately after the deviation. The Sponsor will evaluate the 
circumstance and determine if the issue is broad enough to warrant a Protocol Amendment. 
Other deviations from the protocol must be submitted by Investigator to the IRB/IEC per their 
reporting requirements. A missed telephone call at two weeks (14 days ±2 days) after each 
administration will be considered a minor protocol deviation and will not remove a subject from 
the PP population.  
10.7 Maintenance and Retention of Records 
The study will be conducted in compliance with ICH-GCP. Investigators will follow the 
procedures of 21 CFR 312.62 and ICH E6, “Good Clinical Practice: Consolidated Guideline”, 
for retention of study records and data. It is the responsibility of the Investigator to maintain a 
comprehensive and centralized filing system of all relevant documentation. 
Investigators will be instructed to retain all study records required by the Sponsor, in a secure 
and safe facility with limited access. Records are to be retained for at least 2 years after approval 
of the application or withdrawal of the application unless otherwise notified by the Sponsor. 
Study documents should be retained for a longer period if required by local regulatory 
requirements. If the Investigator retires, relocates, or withdraws from this responsibility, custody 
may be transferred to a person who will accept this responsibility. The Sponsor must be notified 
in writing of the name of the new custodian. 
The records to be archived include all documents pertaining to subject information (eg, IRB/IEC 
correspondence, ICF, and HIPAA authorization form), receipt and return or destruction of 
Investigational Product, final signed eCRF casebooks including a copy of the audit trail, and 
correspondence with the CRO. No documents shall be destroyed without first notifying the 
Sponsor, and receiving confirmation of the notification by the Sponsor, at least 30 days prior to 
the planned date of destruction. 
10.8 Audits and Inspections 
During the course of the study and/or after it has been completed, one or more site audits may be 
conducted by authorized representatives of TOLMAR. The purpose of the audit would be to 
determine whether or not the study is being conducted and monitored in compliance with 
recognized ICH-GCP guidelines and regulations. 
Additionally, the study may be inspected by regulatory agencies. These inspections may take 
place at any time during the study or after completion of the study and are based on the local 
regulations. 
10.9 Completion of the Study 
The Principal Investigator for each participating site must submit a final report to TOLMAR and 
IRB/IEC within 12 months of study completion or termination. 


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11. CONFIDENTIALITY, USE OF INFORMATION, AND PUBLICATION
11.1 Confidentiality
During the course of the study, user access to the files with subject identifiers and files with 
study outcomes will be restricted to core staff with any exceptions to be approved by the 
Principal Investigator. 
In addition to the use of passwords and other security measures, all documents containing 
identifying information on individuals or physicians are considered confidential materials and 
will be safeguarded to the greatest possible extent.  
11.2 Disclosure of Information 
Information concerning the study, patent applications, processes, scientific data, or other 
pertinent information is confidential and remains the property of TOLMAR. The Investigator 
may use this information for the purposes of the study only. 
It is understood by the Investigator that the Sponsor will use information developed in this 
clinical study in connection with the development and marketing of TOLMAR formulation and, 
therefore, the Sponsor may disclose study information, as required, to other clinical investigators 
and to regulatory agencies. In order to allow the use of the information derived from this clinical 
study, the Investigator understands that he/she has an obligation to provide complete test results 
and all data developed during this study to the Sponsor. 
Verbal or written discussion of results prior to study completion and full reporting should only 
be undertaken with written consent from the Sponsor. 
11.3 Publication 
The Investigator shall not make any publication related to this study without the express written 
permission of the Sponsor. Should the Investigator wish to publish or present the results of this 
study, the Investigator agrees to provide the Sponsor with an abstract, manuscript, and/or 
presentation for review 90 days prior to submission for publication/presentation. The Sponsor 
retains the right to delete from the manuscript confidential information and to object to suggested 
publication and/or its timing (at the Sponsor’s sole discretion). 


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12. REFERENCES
Antoniazzi F and Zamboni G. Central precocious puberty: current treatment options. Pediactr. 
Drugs 2004; 6 (4): 211-231. 
Carretto F, Salinas-Vert I, Granada-Yvern ML, et al. The Usefulness of the Leuprolide 
Stimulation Test as a Diagnostic Method of Idiopathic Central Precocious Puberty in Girls. 
Horm Metab Res. 2014. DOI http://dx.doi.org/. 10.1055/s-0034-1387790. Published online: 2014 
Chi CH, Durham E, Neely EK. Pharmacodynamics of aqueous leuprolide acetate stimulation 
testing in girls: correlation between clinical diagnosis and time of peak luteinizing hormone 
level. J Pediatr. 2012;161(4):757-759 e751. 
Chrisp P; Sorkin EM. Leuprorelin-a review of its pharmacology and therapeutic use in prostatic 
disorders. Drugs Aging 1991; I (6): 487-509. 
Fuqua JS. Treatment and outcomes of precocious puberty: an update. J Clin Endocrinol Metab 
2013; 98: 2198-2207. 
Houk CP, Kunselman AR, et al. The diagnostic value of a brief GnRH analogue stimulation test 
in girls with central precocious puberty: a single 30-mintue post stimulation LH sample is 
adequate. J Pediatr Endocrinol Metab. 2008; Dec; 21(12): 113-118. 
Kaplowitz PB, Oberfield SE, et al. Reexamination of the age limit for defining when puberty is 
precocious in girls in the United States: implications for evaluation and treatment. Pediatrics 
1999; 104: 936-941. 
Kappy MS, Stuart T, Perelman A. Efficacy of leuprolide therapy in children with central 
precocious puberty. Am J Dis Child. 1988;142(10):1061-1064. 
Kim YJ, Lee HS, et al. Multicenter clinical trial of leuprolide acetate depot ( Luphere depot 3.75 
mg) for efficacy and safety in girls with central precocious puberty. Annals Ped Endo Med 2013; 
18: 173-178. 
Marshall WA and Tanner JM. Variations in Pattern of Pubertal Changes in Girls. 1969;44:291-
303. 
National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events (CTCAE) 
version 4. http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Accessed October 2014. 
Yamanaka H, Makino T, et al. Efficacy of (D-Leu6)-des-Gly-NH210 - LH-RH ethylamide 
against prostatic cancer. Prostate 1985; 6: 27-34. 


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13. APPENDICES
13.1 Clinical Laboratory Parameters
All hematology and clinical chemistry parameters as well as the listed screening tests will be 
analyzed at a central laboratory. Urinalysis parameters, assessed by dipsticks, will be analyzed 
locally using provided kits. Sample for clinical laboratory tests will be collected at times 
specified in Table 2 
Blood Sampling Times by Parameter for Visit 1—Part A. 
Hematology 
Platelet Count 
RBC Indices: 
Automated WBC Differential: 
RBC Count 
MCV 
Neutrophils 
WBC Count (absolute) 
MCH 
Lymphocytes 
Reticulocyte Count 
MCHC 
Monocytes 
Hemoglobin 
Eosinophils 
Hematocrit 
Basophils 
Clinical Chemistry 
Urea 
Potassium 
AST (SGOT) 
Total and direct bilirubin 
Creatinine 
Chloride 
ALT (SGPT) 
Uric Acid 
Glucose 
Total CO2 
GGT 
Albumin 
Sodium 
Calcium 
Alkaline phosphatase 
Total Protein 
Other Parameters 
HBsAg (Hepatitis B Surface Antigen); 
HCVAb (Hepatitis C antibody) 
Pregnancy test (urine) 
Fasting serum lipid measurements to include: total cholesterol, HDL, LDL, triglycerides 
Urinalysis 
pH, glucose, protein, blood and ketones by dipstick provided by sponsor


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13.2 Tanner Stages 
The Tanner stages, developed by Marshall and Tanner (1969) is a commonly used system to 
categorize pubertal maturation in terms of sequence, timing and tempo as described below. 
Boys - development of external genitalia 
Stage 1: 
Prepubertal 
Stage 2: 
Enlargement of scrotum and testes; scrotum skin reddens and changes in texture 
Stage 3: 
Enlargement of penis (length at first); further growth of testes 
Stage 4: 
Increased size of penis with growth in breadth and development of glans; testes 
and scrotum larger, scrotum skin darker 
Stage 5: 
Adult genitalia 
Girls - breast development 
Stage 1: 
Prepubertal 
Stage 2: 
Breast bud stage with elevation of breast and papilla; enlargement of areola 
Stage 3: 
Further enlargement of breast and areola; no separation of their contour 
Stage 4: 
Areola and papilla form a secondary mound above level of breast 
Stage 5: 
Mature stage: projection of papilla only, related to recession of areola 
Boys and girls - pubic hair 
Stage 1: 
Prepubertal (can see velus hair similar to abdominal wall) 
Stage 2: 
Sparse growth of long, slightly pigmented hair, straight or curled, at base of penis 
or along labia 
Stage 3: 
Darker, coarser and more curled hair, spreading sparsely over junction of pubes 
Stage 4: 
Hair adult in type, but covering smaller area than in adult; no spread to medial 
surface of thighs 
Stage 5: 
Adult in type and quantity, with horizontal distribution ("feminine") 

SAP_001.pdf: 
Statistical Analysis Plan 
 
An Open-label, Single Arm, Multicenter Study on the Efficacy, Safety, and 
Pharmacokinetics of Leuprolide Acetate 45 mg for Injectable Suspension 
Controlled Release in Subjects with Central (Gonadotropin-Dependent) Precocious  
Puberty 
 
NCT02452931 
 
04 September 2018 
 




TOLMAR Inc. 
 
Statistical Analysis Plan 
Protocol: TOL2581A 
 
Final V1.4 
CONFIDENTIAL 
 
Page 2 of 44 
 
1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ........................................................................................................ 2 
2. 
LIST OF TABLES................................................................................................................... 5 
3. 
LIST OF ABBREVIATIONS ................................................................................................. 6 
4. 
BACKGROUND AND PURPOSE ......................................................................................... 8 
5. 
STUDY OBJECTIVES ........................................................................................................... 9 
5.1. 
Primary Objective ............................................................................................................ 9 
5.2. 
Secondary Objectives ....................................................................................................... 9 
6. 
STUDY METHODS.............................................................................................................. 10 
6.1. 
Overall Study Design and Plan ...................................................................................... 10 
6.1.1. 
Criterion for an Adaptive Change in Design .......................................................... 10 
6.1.2. 
Design and Procedures for Part A and Part B ......................................................... 10 
6.2. 
Selection of Study Population ........................................................................................ 16 
6.3. 
Treatment and Random Assignment .............................................................................. 16 
6.4. 
Treatment Masking (Blinding) ....................................................................................... 16 
6.5. 
Analyses and Reporting ................................................................................................. 16 
6.6. 
Criterion for Treatment Efficacy .................................................................................... 16 
6.7. 
Sample Size Determination ............................................................................................ 16 
7. 
PLANNED STUDY ANALYSES ........................................................................................ 17 
8. 
BASELINE INFORMATION AND TREATMENT EMERGENT EFFICACY, 
PHARMACOKINETIC AND SAFETY ENDPOINTS ............................................................... 22 
8.1. 
Baseline and Related Information .................................................................................. 22 
8.1.1. 
Demographic Information ....................................................................................... 22 
8.1.2. 
Medical History ...................................................................................................... 22 
8.1.3. 
Prior and Concomitant Medications and Treatments.............................................. 22 
8.1.4. 
Vital Signs ............................................................................................................... 22 
8.1.5. 
Weight ..................................................................................................................... 22 
8.1.6. 
Height ...................................................................................................................... 23 
8.1.7. 
Physical Examination.............................................................................................. 23 
8.1.8. 
Tanner Stages and Menses ...................................................................................... 23 
8.1.9. 
Clinical Laboratory Assessments ............................................................................ 23 
8.1.10. 
Pregnancy Test .................................................................................................... 23 
8.1.11. 
Hand and Wrist X-Ray (Bone Age) .................................................................... 23 


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8.1.12. 
Basal LH, FSH, Testosterone/Estradiol Concentrations ..................................... 23 
8.1.13. 
Abbreviated GnRHa Stimulation Test ................................................................ 24 
8.1.14. 
Pharmacokinetic Assessment .............................................................................. 24 
8.2. 
Efficacy Endpoints and Assessments ............................................................................. 24 
8.2.1. 
Primary Efficacy Endpoints and Assessments ........................................................ 24 
8.2.2. 
Secondary Efficacy Endpoints and Assessments .................................................... 24 
8.2.3. 
Exploratory Efficacy Endpoints and Assessments ................................................. 25 
8.3. 
Pharmacokinetic/Pharmacodynamic Endpoints and Assessments ................................. 26 
8.3.1. 
PK/PD Parameters .................................................................................................. 26 
8.3.2. 
PK/PD Analyses...................................................................................................... 26 
9. 
SAFETY ASSESSMENTS ................................................................................................... 28 
10. ANALYSIS POPULATIONS ............................................................................................... 28 
10.1. Safety population............................................................................................................ 28 
10.2. ITT population................................................................................................................ 28 
10.3. PP population ................................................................................................................. 28 
11. GENERAL CONSIDERATIONS ......................................................................................... 29 
11.1. Significance Testing ....................................................................................................... 29 
11.2. Continuous and Presumed Continuous Data .................................................................. 29 
11.3. Categorical Data ............................................................................................................. 29 
11.4. Statistical Software ......................................................................................................... 29 
12. IMPUTATION AND MISSING DATA ............................................................................... 29 
12.1. Stratification by Site ....................................................................................................... 31 
12.2. Unscheduled and/or Repeated Laboratory Results ........................................................ 31 
12.3. Handling of Early Termination Visit Information ......................................................... 31 
13. CDISC ................................................................................................................................... 31 
13.1. Clinical Data – CDISC Study Data Tabulation Model (SDTM) ................................... 31 
13.2. Analysis Data – CDISC Analysis Data Model (ADaM) ................................................ 31 
14. ADDITIONAL INFORMATION RELEVANT TO THE ANALYSES .............................. 32 
14.1. Protocol Deviations ........................................................................................................ 32 
14.2. Safety .............................................................................................................................. 32 
14.2.1. 
Concurrent Illness and Medical Conditions ........................................................ 32 
14.2.2. 
Prior and Concurrent Medications ...................................................................... 32 
14.3. Subject Enrollment ......................................................................................................... 32 
14.4. Adverse Events ............................................................................................................... 33 


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14.4.1. 
Deaths .................................................................................................................. 33 
14.4.2. 
Serious Adverse Events ....................................................................................... 33 
14.4.3. 
Adverse Events Leading to Discontinuation of Study Drug Injection ................ 33 
14.5. Clinical Laboratory Evaluations..................................................................................... 33 
14.6. Physical Examinations ................................................................................................... 34 
15. TABLES, LISTINGS AND FIGURES ................................................................................. 34 
16. BASELINE VALUES OF DROPPED SUBJECTS .............................................................. 34 
17. DATA SAFETY MONITORING BOARD .......................................................................... 34 
18. CONVENTIONS ................................................................................................................... 35 
18.1. Reporting Conventions ................................................................................................... 35 
18.2. Population Summary Conventions ................................................................................. 36 
19. APPENDICES ....................................................................................................................... 37 
19.1. Appendix 1:  Tanner Stages ........................................................................................... 37 
19.2. Appendix 2:  Clinical Laboratory Parameters ................................................................ 38 
19.3. Appendix 3:  Global Interview Symptom Assessment .................................................. 39 
19.4. Appendix 4:  SAP Modifications (TBD) ....................................................................... 40 
19.5. Appendix 5:  Mock Tables, Listings and Figures (TBD) ............................................... 42 
 
 
 
 


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2. 
LIST OF TABLES 
Table 1 
Schedule of Assessments—Part A ............................................................................. 11 
Table 2 
Blood Sampling Times by Parameter for Visit 1—Part A ......................................... 14 
Table 3 
Schedule of Assessments—Part B .............................................................................. 15 
Table 4  
Numeric Results for One-Sided Lower-Limit Confidence Intervals for One 
Proportion Confidence Interval Formula: Simple Asymptotic with Continuity 
Correction ................................................................................................................... 17 
Table 5 
Type of Analysis Applied to Baseline, Efficacy, Safety and PK Variables ............... 20 
Table 6 
Cross-classification of Various Endpoints with the Analysis Populations................. 28 
 
 


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3. 
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION OR DESCRIPTION 
C 
Degree Celsius 
F 
Degree Fahrenheit 
ADaM 
CDISC Analysis Dataset Model 
AE 
Adverse event 
ALP  
Alkaline phosphatase 
ALT 
Alanine aminotransferase or SGPT 
AST 
Aspartate transaminase or  SGOT 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the Serum Concentration-Time Curve 
CDISC 
Clinical Data Interchange Standards Consortium 
Cmax 
Maximum drug concentration 
CPP 
Central Precocious Puberty 
CSR 
Clinical study report 
CV 
Coefficient of Variation 
DD 
Day 
dL 
deciliter 
EMEA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GnRH 
Gonadotropin Releasing Hormone 
GnRHa 
Gonadotropin Releasing Hormone Agonist 
ICH 
International Conference on Harmonization of Technical 
Requirements of Pharmaceuticals for Human Use 
ICF 
Informed Consent Form 
kg  
Kilogram(s) 
LH 
Luteinizing Hormone 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mIU 
Milli International Units 
mL 
Milliliter(s) 
mm Hg 
Millimeters of Mercury 
N 
Sample Size 
ng 
Nanogram 


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PD 
Pharmacodynamic 
PE 
Physical Examination 
pg 
Picogram 
PK 
Pharmacokinetic 
PP 
Per-protocol [population] 
SAP 
Statistical analysis plan 
SC 
Subcutaneous(ly) 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
TBL  
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time of maximum (peak) drug concentration 
ULRR 
Upper limit of the reference range 
WHO-Drug 
World Health organization  
 
 
 
 
 
 
 
 
 
 
 


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4. 
BACKGROUND AND PURPOSE 
This Statistical Analysis Plan (SAP) describes the planned procedures and analyses for 
TOLMAR study TOL2581A:  An Open-label, Single Arm, Multicenter Study on the Efficacy, 
Safety, and Pharmacokinetics of Leuprolide Acetate 45 mg for Injectable Suspension Controlled 
Release in Subjects with Central (Gonadotropin-Dependent) Precocious Puberty.  This study is a 
multicenter, open-label, single-arm,  adaptive, interventional study to assess efficacy, safety and 
pharmacokinetics/pharmacodynamics  with up to two study phases (Part A and Part B) 
distinguished by dosing schedule.   
This SAP is compliant with the principles set forth in guidance documents by the Food and Drug 
Administration (FDA), the European Medicines Agency (EMEA), the American Statistical 
Associationi, the Royal Statistical Societyii and the International Conference on Harmonization of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH):  Guidance 
on Statistical Principles in Clinical Trials (E9)iii.   
Additional analyses and modifications to those found in this SAP will be allowed.  Any such 
changes that are added prior to examination of the data by the statistician will be listed in a 
future appendix to this document (i.e., Appendix 4).   Procedures in the final version of this SAP 
and the noted appendix may be referenced as a priori in documents describing the safety, 
efficacy and pharmacokinetics outcomes of TOLMAR Study TOL2581A.  Any statistical 
analyses for Study TOL2581A that fall outside those described in the final version of this SAP 
and the noted appendix will be designated as “post hoc”.   
To ensure that the evaluative data for this study are accurate, edit checks will be described in and 
implemented according to a Data Management Plan.  
This SAP assumes reader familiarity with the Study TOL2581A protocol and any protocol 
amendments. 
 
 
 
 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective 
The primary objective of this study is to determine the effectiveness of leuprolide acetate 45 mg 
for injectable suspension for the treatment of children with central precocious puberty (CPP). 
5.2. 
Secondary Objectives 
The secondary objectives of this study are to: 
• 
Evaluate the safety and tolerability of leuprolide acetate 45 mg for injectable suspension 
in children with CPP; 
• 
Characterize the burst kinetics of leuprolide acetate 45 mg after the first administration; 
• 
Characterize the pharmacodynamic (PD) relationship of leuprolide serum concentrations 
to concentrations of serum luteinizing hormone (LH), follicle stimulating hormone (FSH) 
and testosterone/estradiol; 
• 
Assess percent change from baseline in height and bone age after the first treatment 
administration; 
• 
Assess growth velocity of height in cm/year after the first treatment administration; 
• 
Assess changes in physical signs of puberty as measured by changes in Tanner stages or 
in changes or onset of menses; and  
• 
Determine the dosing interval (5 or 6 months) at which leuprolide acetate is able to 
suppress LH concentration to <4 mIU/mL (after gonadotropin releasing hormone agonist 
[GnRHa] stimulation test) as data permits. 
 


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6. 
STUDY METHODS 
6.1. 
Overall Study Design and Plan 
6.1.1. 
Criterion for an Adaptive Change in Design 
This multicenter, open-label, single-arm, adaptive, interventional study potentially has two parts 
with Part B contingent upon the outcome of Part A.  Whether or not Part B is to be invoked will 
be decided as follows.  When approximately 16 subjects enrolled in the study reach Month 6, the 
stimulation data from these subjects will be evaluated to determine if LH concentration at 30 
minutes after GnRHa stimulation is suppressed to < 4 mIU/mL. 
1) If ≥ 85% of these first subjects are suppressed at 6 months then Part B will not be invoked and 
all subjects will be seen through the final planned Part A visit (i.e., Visit 8).   
2) If approximately < 85% of subjects (N ≥ 3) exhibit suppression the study will immediately 
proceed to Part B.  If Part B is invoked subjects currently enrolled in Part A and have not yet 
received a 2nd injection, will be entered into Part B on Visit 7. Then, all future subjects enrolled 
in the study will undergo the equivalent of Visits 1 through 6 of Part A followed by Part B 
beginning on Visit 7.     
6.1.2. 
Design and Procedures for Part A and Part B 
Subjects enrolled in Part A will receive their first injection on Visit 1 (Day 0).   Part A will 
continue over 12 months with Visits 2, 3, 4, 5, 6, 7 and 8 respectively planned at Months 1, 3, 5, 
6, 9, 11 and 12.  Part B if invoked is planned over an additional 10 months and will begin at Visit 
7 of Part A and continue through Visits 8, 9, 10 and 11 which shall correspond to Months 15, 16, 
20 and 21.   
Whether or not Part B is invoked, all subjects under Part A will receive a first treatment injection 
at Visit 1 (Day 0); and a second injection at Visit 5 (Month 6). If Part B is invoked then all 
subjects additionally will experience treatment injections on Visit 7 (Month 11) and Visit 9 
(Month 16) under Part B. If only Part A is completed, the percent of subjects with suppression at 
30 minutes after GnRHa stimulation of < 4 mIU/mL at six (6) months will constitute the primary 
outcome variable.  If part B is invoked, the primary outcome variable will be the percent of 
subjects with suppression at twenty-one (21) months. 
The planned visits and data to be collected under Part A and under Part B (if invoked) are 
presented in the schematics that follow.   












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6.2. 
Selection of Study Population 
Children falling within the following profile will be entered into the study:  females age 2 to 8 
years (inclusive) or males age 2 to 9 years (inclusive);  confirmed diagnosis of CPP within 12 
months of Baseline Visit (Day 0) but have not received prior GnRH agonist treatment for CPP;  
pubertal-type LH response following an Abbreviated GnRHa Stimulation Test before treatment 
initiation > 5 mIU/mL; clinical evidence of puberty, defined as Tanner stage ≥ 2 for breast 
development in females or testicular volume ≥ 4 mL in males; and difference between bone age 
(Greulich and Pyle method) and chronological age ≥ 1 year. 
6.3. 
Treatment and Random Assignment 
This single arm study does not require the use of randomization.  All subjects will be treated 
identically with respect to procedures carried out in either Part A or Part B of this study. 
6.4. 
Treatment Masking (Blinding) 
This is an open label study.  Neither subjects, the sponsor or study staff are blind to the 
treatment. 
6.5. 
Analyses and Reporting 
In this study both a) the need for an adaptive change in study design and b) treatment efficacy 
will be based on an absolute descriptive finding rather than an inferential significance level.   
6.6. 
Criterion for Treatment Efficacy 
If suppression in ≥ 85% of the first 16 subjects to be evaluated at Month 6 is found, the study 
will terminate under Part A without the invocation of Part B as a follow-on adaptive dosing 
schedule.  If study termination under Part A occurs, the criterion variable for adaptive change 
applied to the first 16 children at six months, namely, percent of children with < 4 mIU/mL 
suppression, will also function as the primary outcome variable when applied to all children in 
the study.  As was the case for evaluating the requirement for an adaptive change in design, an 
absolute descriptive rather than inferential statistical outcome will be used to assess efficacy for 
the primary outcome variable.  Using the same variable as that used to omit or invoke Part B, 
efficacy will be claimed if ≥ 80% of the children exhibit < 4 mIU/mL suppression. 
If suppression in approximately < 85% of the first 16 subjects (N ≥ 3) to be evaluated at Month 6 
is found, the study will be adapted and Part B will be invoked.   As would be the case if the study 
were to terminate with Part A, the percent of subjects with < 4 mIU/mL suppression will serve as 
the primary outcome variable under Part B.  If < 4 mIU/mL suppression in ≥ 80% of the children 
in the study at Visit 11 (Month 21) is found, efficacy will be claimed.  The primary variable if 
only Part A of the study were carried out will then become a secondary outcome variable. 
6.7. 
Sample Size Determination 
The expected final sample size is between 25 and 50 subjects, depending on dropout rate and 
whether the study is prolonged by the inclusion of Part B.  If for the final sample size ≥ 80% of 


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subjects exhibit < 4 mIU/mL suppression, efficacy will be claimed.  It is actually expected that 
85% to 90% response is likely.  The table immediately below shows the lower one-sided 95% 
confidence limits for final sample sizes varying from 25 to 50 in increments of five subjects 
under the expectations of 85% suppression and 90% suppression.
 
Table 4  
Numeric Results for One-Sided Lower-Limit Confidence Intervals for One 
Proportion Confidence Interval Formula: Simple Asymptotic with Continuity Correction1 
 
 
 
Actual 
 
 
 
 
Sample 
Distance 
 
 
 
Confidence 
Size 
from P to 
Proportion 
Lower 
Upper 
Level 
(N) 
Lower Limit 
(P) 
Limit 
Limit 
0.950 
25 
0.137 
0.850 
0.713 
1 
0.950 
25 
0.119 
0.900 
0.781 
1 
0.950 
30 
0.124 
0.850 
0.726 
1 
0.950 
30 
0.107 
0.900 
0.793 
1 
0.950 
35 
0.114 
0.850 
0.736 
1 
0.950 
35 
0.098 
0.900 
0.802 
1 
0.950 
40 
0.105 
0.850 
0.745 
1 
0.950 
40 
0.091 
0.900 
0.809 
1 
0.950 
45 
0.099 
0.850 
0.751 
1 
0.950 
45 
0.085 
0.900 
0.815 
1 
0.950 
50 
0.093 
0.850 
0.757 
1 
0.950 
50 
0.080 
0.900 
0.820 
1 
 
In Table 4 the lower one sided confidence limit never falls below 70%.  Suppression to < 4 
mIU/mL in 70% of the subjects is considered to be clinically important by TOLMAR.  Thus the 
sample size is thought to be adequate. 
7. 
PLANNED STUDY ANALYSES 
Statistical analyses for this study will be comprised of descriptive statistics presented over time 
or at predesignated time points of special interest.  Baseline, efficacy, safety and PK endpoints 
will be evaluated using descriptive statistics.  For example, comparisons between two time points 
will be carried out by contrasting descriptive outcomes that exist for each of those time points. 
Descriptive evaluation will in general take one of four forms depending on the underlying metric 
of the variable under analysis.   
1) If the metric is categorical the following information at minimum will be provided:  
count (numerator), base (denominator) and percentage (numerator/denominator) for each 
category and overall. For dichotomous categorical variables, confidence intervals may in 
                                                 
1 Hintze, J. (2014). PASS 13. NCSS, LLC. Kaysville, Utah, USA. www.ncss.com. 


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selected instances be provided. The term used hereafter to denote this type of analysis 
will be categorical descriptive analysis. 
2) If the metric is continuous or presumed continuous the following information at 
minimum will be provided:  number of subjects, mean, standard deviation, coefficient of 
variation, minimum and maximum. Confidence intervals may in some instances be 
provided. The term used hereafter to denote this type of analysis will be continuous 
descriptive analysis. 
3) Categorical variables compared across time may be presented as a shift table.  For 
example, a laboratory test result could be normal, low abnormal or high abnormal.  A 
shift table comparing values between baseline and end-of-study would show the number 
and percent of subjects with shift outcomes of the form normal to normal, normal to low 
abnormal, normal to high abnormal, high abnormal to normal, high abnormal to low 
abnormal, high abnormal to high abnormal, low abnormal to normal, low abnormal to 
low abnormal, and low abnormal to high abnormal.  A simpler version of the table that 
omits direction of abnormality might be normal to normal, normal to abnormal, abnormal 
to normal, abnormal to abnormal. The term used hereafter to denote this type of analysis 
will be shift table analysis. 
4) Serum concentrations will be analyzed by evaluating concentration at each time point 
using continuous descriptive analysis; and by evaluating the PK parameters AUC, Cmax 
and Tmax using continuous descriptive analysis.  Since the PK sampling frequency in 
this trial is limited due to the age of the subjects, it will be expected that the PK 
parameters will have larger intra-patient variability.  Concentration plots in the original 
and log scale will be created, combined over subjects and by subject.  Continuous 
descriptive analysis will be provided for absolute values of AUC, Cmax and Tmax as 
well as log transformed values of these parameters.  All together the above analyses in 
part or whole will be referred to as PK analysis. 
Because this study collects data at many interim time points, extensive use of graphs to display 
categorical descriptive analysis results and continuous descriptive analysis results over time will 
be employed.  This will facilitate an assessment of trend.  
Further note that because tables containing categorical descriptive analysis and continuous 
descriptive analysis will exist for the various outcome parameters at each time point, selected 
time points of interest can be compared to each other for a specific purpose.  For example, the 
medical writer can compare descriptive outcomes at visits after injection 2 to visits after injection 
4 to evaluate GnRHa simulation results under a six and a five month injection separation 
schedule.  Using specific comparisons of descriptive statistics at designated time points, 
objectives for the assessment of efficacy (see Protocol Section 9.2.2: Efficacy Evaluations) can 
be accommodated. 
Plots of individual subject outcomes will be generated for all variable concentrations used in the 
PK/PD analyses (Leuprolide, LH, FSH, testosterone and estradiol concentration), bone age and 
height.  


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The table that follows summarizes the planned analyses for baseline, efficacy, safety and PK 
variables. 


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Table 5 
Type of Analysis Applied to Baseline, Efficacy, Safety and PK Variables 
Variable Class 
Variable(s) 
Analysis 
Listed/Not 
Analyzed1 
Time Points Analyzed 
(Visits)2 
Categorical 
Descriptive 
Analysis 
Continuous 
Descriptive 
Analysis 
Shift 
Table 
Analysis 
PK 
Analysis 
Baseline 
Presence of Informed Consent 
x 
 
 
 
 
Screening, Visit 7 
Baseline 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
Screening 
Baseline 
Demographics (categorical) 
x 
 
 
 
 
Screening  
Baseline 
Demographics (continuous) 
 
x 
 
 
 
Screening 
Baseline 
Medical History (categorical) 
x 
 
 
 
 
Screening 
Baseline 
Medical History (descriptive) 
 
 
 
 
x 
Screening 
Baseline 
Meds/Treatments  History 
 
 
 
 
x 
Screening 
Baseline, Safety 
Vital Signs 
 
x 
 
 
 
Screening, All Visits 
Baseline, Safety 
Weight 
 
x 
 
 
 
Screening, All Visits 
Baseline, 
Efficacy 
Height 
 
x 
 
 
 
Screening, All Visits 
Baseline, 
Safety  
Complete Physical Exam 
(categorical) 
x 
 
 
 
 
Screening, Visit 11 
Baseline, Safety 
Complete Physical Exam 
(descriptive) 
 
 
 
 
x 
Screening, Visit 11 
Safety 
Directed Physical Exam 
(categorical) 
x 
 
 
 
 
Visits 1, 2,3,5,6,7,8, 9 10 
Safety 
Directed Physical Exam 
(descriptive) 
 
 
 
 
x 
Visits 1, 2,3,5,6,7,8, 9 10 
                                                 
1 All collected and derived variable values will be in listings. However, this column highlights information that is closely related to information found in an 
adjacent row of this table; will not be descriptively analyzed; but will be presented in a listing. 
2 This table assumes that Part B will be invoked.  If Part B is not invoked visits will be altered to conform to the Schedule of Assessments: Part A.   


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Variable Class 
Variable(s) 
Analysis 
Listed/Not 
Analyzed1 
Time Points Analyzed 
(Visits)2 
Categorical 
Descriptive 
Analysis 
Continuous 
Descriptive 
Analysis 
Shift 
Table 
Analysis 
PK 
Analysis 
Safety 
Flare Symptoms 
x 
x3 
 
 
 
Telephone interview  
weeks 26 & 46, Visits 2-11 
Safety 
Pregnancy Test 
x 
 
 
 
 
Visits 1, 5,7, 9, 11 
Safety 
Adverse Events 
Reported in Listings and Summarized in Tabulations4 
Throughout Study 
Baseline, Safety 
Laboratory Tests5 
x 
x 
x 
 
 
Screening, All Visits 
Baseline 
Hepatitis B/C Antibody 
x 
 
x 
 
 
 
Baseline, Safety 
Serum Lipids (fasting) 
x 
x 
 
 
 
Screening, Visits 1,7 
Efficacy 
Leuprolide, LH, FSH, Testosterone, 
Estradiol  (basal) 
 
x 
 
x 
 
Screening, All Visits  
Efficacy 
LH, FSH, Testosterone, Estradiol  
(GnRHa stimulation)6 
x 
x 
 
 
 
Screening, All Visits 
PK 
Serum Leuprolide (basal) 
 
x 
 
x 
 
Screening, All Visits 
Efficacy 
Tanner Staging7 and Menses 
Presence or Change 
x 
x 
x 
 
 
Screening, Visits 3, 5, 7, 8, 
9, 10, 11 
Efficacy 
All Exploratory Efficacy Endpoints8 
x 
x 
 
 
 
Screening, All Visits 
                                                 
3 See Appendix 3:  Global Interview Symptom Assessment.  Each item will be analyzed separately using categorical descriptive analysis.  A count of total 
number of symptoms will be analyzed using continuous descriptive analysis. 
4 AEs will be coded using MedDRA which in turn will allow quantification of events. Number and percent of subjects reporting AEs will be tabulated for the 
Safety Population.   Tabular summaries will be presented by System Organ Class (SOC) and Preferred Term (PT), and further by severity and relationship to the 
investigational product. In summaries of severity, subjects who reported more than one event that are mapped to the same SOC and/or PT will be counted only 
once under the strongest severity. In summaries of relationship, subjects who reported more than one event that are mapped to the same SOC and/or PT will be 
counted only once under each applicable relationship. 
5 Laboratory values include urinalysis, hematology and chemistry.  Data are predominately continuous with a few categorical scales. 
6 For these variables a dichotomy will be evaluated (LH < 4 mIU/mL, FSH < 2.5 mIU/mL, estradiol < 20 pg/mL, testosterone < 30 ng/dL) using categorical 
descriptive analysis.   
7 Each five stage rating will be treated as a categorical scale and as a presumed continuous scale.  Respectively, these will be analyzed using categorical 
descriptive analysis and continuous descriptive analysis. Categorical descriptive analysis will be applied to menses presence and menses change. Baseline to end-
of-study stage shift tables for each Tanner category will be constructed. 
8 Exploratory efficacy endpoints are described in the Exploratory Efficacy Endpoint section.  Some endpoints are categorical and others continuous, thus both 
categorical descriptive analysis and continuous descriptive analysis will be required.  


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8. 
BASELINE INFORMATION AND TREATMENT 
EMERGENT EFFICACY, PHARMACOKINETIC AND 
SAFETY ENDPOINTS 
Baseline, efficacy, pharmacokinetic (PK) and safety information to be collected as described 
below. 
8.1. 
Baseline and Related Information 
Some baseline variables in the sub-sections to follow may also serve as efficacy, safety and PK 
endpoints when captured post treatment.  In such instances, variables may be located in more 
than one section of this SAP.   
The variables that will be used to characterize study subjects at baseline are presented below.     
8.1.1. 
Demographic Information 
Demographic characteristics will be collected, including date of birth, sex, race (American 
Indian; or Alaska Native; Asian; Black or African American; Native Hawaiian or Other Pacific 
Islander; White), and ethnicity (Hispanic or Latino; Not Hispanic or Latino).  
8.1.2. 
Medical History 
Relevant medical history will be collected including prior and ongoing medical illnesses, 
conditions, and surgical procedures within the 24 months prior to enrollment. 
8.1.3. 
Prior and Concomitant Medications and Treatments 
All prior and concomitant medications, as well as any diagnostic, therapeutic, or surgical 
procedures performed, will be recorded from the time of signing the ICF/Assent Form (if 
required) throughout the subject’s participation in the study. 
8.1.4. 
Vital Signs 
Vital signs will be measured after the subject has been in a seated or supine position for 
5 minutes. Vital sign assessments will include the measurement of blood pressure (mm Hg), 
heart rate (beats per minute), respiration rate (breaths per minute) and temperature (oral, 
tympanic, or temporal; C or F). 
8.1.5. 
Weight 
Body weight (kg) will be measured. 


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8.1.6. 
Height 
Standing height will be recorded with a calibrated stadiometer (e.g., “Harpenden” stadiometer) 
that has increments in millimeters (mm) and a functional Frankfort Plane perpendicular to the 
standing surface. The Frankfort Plane will be used on the stadiometer to determine the actual 
standing height to ± 1 mm. 
8.1.7. 
Physical Examination 
A complete physical exam (PE) will be performed by study personnel who are qualified to 
perform such examinations.  At a minimum, the PE should include the cardiovascular system, 
the respiratory system, and the abdomen.  
Thereafter, a directed or targeted PE will be performed covering body systems related to the 
disease, including Tanner stages, and/or to assess any ongoing AEs. 
8.1.8. 
Tanner Stages and Menses 
Sexual development in puberty will be assessed by Tanner staging, a system developed by 
Marshall and Tanneriv to categorize pubertal maturation. See Appendix 1 for details on the 
Tanner stages.  The presence of menses and any change in menses will be collected. 
8.1.9. 
Clinical Laboratory Assessments 
Clinical laboratory assessments (hematology, clinical chemistry, fasting serum lipids, hepatitis B 
& C, and urinalysis parameters) are listed in Appendix 2. Urinalysis assessments will be by 
“dipstick” assessments using urinalysis kits that will be provided to the sites by the Sponsor and 
evaluated locally. All other laboratory assessments will be from the blood samples collected at 
the appropriate assessment times and analyzed by a central laboratory. 
8.1.10. 
Pregnancy Test 
Urine pregnancy tests will be performed on female subjects. All female subjects must have a 
negative pregnancy test prior to receiving each injection of study drug. The pregnancy test will 
also be performed at End of Treatment in Part A or Part B extension (if invoked), and at the 
discretion of the Investigator. 
8.1.11. 
Hand and Wrist X-Ray (Bone Age) 
A single X-ray of the non-dominant hand and wrist will be obtained to determine bone age using 
a Greulich and Pyle Atlas. Although a local reader will determine study eligibility during 
screening, X-rays will be sent to a blinded central reader for the bone age evaluations that will be 
analyzed. 
8.1.12. 
Basal LH, FSH, Testosterone/Estradiol Concentrations 
Blood samples for serum LH, FSH, testosterone (males) / estradiol (females) concentrations (as 
appropriate) will be collected and analyzed by a central laboratory according to current validated 


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assays. All samples will be obtained before each study drug injection and before GnRHa 
stimulation tests.  A central laboratory will be used.  
8.1.13. 
Abbreviated GnRHa Stimulation Test 
Baseline blood samples for serum LH, FSH, and testosterone/estradiol concentrations will be 
obtained prior to the start of a GnRHa stimulation test. A standard dose of 20 µg/kg body weight 
of aqueous leuprolide acetate will be administered SC. Blood samples to measure serum LH, 
FSH and testosterone/estradiol concentrations will be obtained again 30 minutes later.  
8.1.14. 
Pharmacokinetic Assessment 
Blood samples for analysis of leuprolide concentrations as well as basal LH, FSH, testosterone 
and estradiol concentrations will be processed by a central bioanalytical laboratory. Date and 
time of each sample will be recorded. 
8.2. 
Efficacy Endpoints and Assessments 
8.2.1. 
Primary Efficacy Endpoints and Assessments 
As described in the Study Methods section, subjects will at minimum undergo Part A of the 
study where two treatment injections separated by six months will be given starting at Visit 1 
(Day 0); an Abbreviated GnRHa Stimulation Test six months after a subject’s first treatment 
injection will be used to determine treatment efficacy; and a 12 month follow-up will occur.  
Alternatively subjects will undergo the first six visits of Part A and then at Visit 7 (Month 11) 
undergo Part B of the study (if invoked).  In Part B of the study an additional two treatment 
injections separated by 5 months will be given starting at Visit 7 (Month 11), and an  GnRHa 
Stimulation Test five months after the fourth treatment injection (i.e., at the 21st month visit) will 
be used to determine treatment efficacy at the end of the study.  Two primary endpoints are 
defined contingent upon the invocation of Part B.   
 If only Part A is carried out, the primary endpoint is defined as the percentage of subjects 
with serum LH concentrations < 4 mIU/mL at 30 minutes following an abbreviated 
GnRHa Stimulation Test at Visit 5 (Month 6).  LH concentrations < 4 mIU/mL are 
considered prepubertal.  The Investigational Product, Leuprolide Acetate 45 mg, will be 
considered effective for the treatment of children with CPP if ≥ 80% of subjects exhibit 
LH suppression < 4 mIU/mL at the Month 6 visit. 
 
 If Part B is invoked, the primary endpoint is defined as the percentage of subjects with 
serum LH concentrations < 4 mIU/mL at 30 minutes following an abbreviated GnRHa 
Stimulation Test at Visit 11 (Month 21).   Leuprolide acetate 45 mg will be considered 
effective for the treatment of children with CPP if ≥ 80% of subjects exhibit LH 
suppression < 4 mIU/mL at the Month 21 visit.   
8.2.2. 
Secondary Efficacy Endpoints and Assessments 
Serving as secondary endpoints will be the following variables. 


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 The percentage of subjects with serum LH concentrations < 4 mIU/mL at 30 minutes 
following an abbreviated  GnRHa Stimulation Test for any available measurement other 
than the measurement constituting the primary outcome variable (see above). 
 The percent change from baseline in height at each available post-baseline measurement.    
Percent change is defined as (((change from Baseline)/(Baseline)) x 100). 
 The growth velocity of height in cm/year at each available post-baseline measurement.  
Growth velocity is defined for each visit as (change from Baseline)/[(number of weeks 
since Baseline)/52)]. 
 The ratio of bone age at each given measurement point to chronological age at the same 
measurement points.   
 Baseline to end-of-study stage shifts for each Tanner category.  
 The percent change from baseline in hormonal concentration (LH, FSH, Testosterone, 
and Estradiol) at each available post-baseline measurement.    Percent change is defined 
as (((change from baseline)/(baseline)) x 100). 
 The percent change from baseline in systemic leuprolide concentration at each available 
post-baseline measurement.    Percent change is defined as (((change from 
baseline)/(baseline)) x 100). 
8.2.3. 
Exploratory Efficacy Endpoints and Assessments 
The following exploratory efficacy endpoints will be evaluated. 
 Height at each available measurement point. 
 Bone age at each available measurement point. 
 Bone age progression at each available post-baseline measurement point.  Bone age 
progression is defined as (((change from baseline)/(baseline)) x 100), which is percent 
change from baseline. 
 Ratio of bone age at a given measurement point to chronological age at start of study.   
 A GnRH Antagonist Evaluation will occur for the two week period following each 
treatment (see Appendix 3) and at each visit to assess flare symptoms.  The percent of 
subjects who affirm (or whose parent/guardian affirms) each symptom domain in the 
global interview will be obtained.   Percentages will be compared across all available 
time points to assess trend.  Focused pairwise comparisons will occur between the 
outcome 2 weeks (± 2 days) after the first injection and each of the outcomes 2 weeks (± 
2 days) after subsequent injections; and outcomes at 2 weeks (± 2 days) after each 
injection and the corresponding nearest adjacent outcome in the two weeks (± 2 days) 
prior to each scheduled visit.  
 Percent of subjects exhibiting each stage of each Tanner category across all available 
time points to assess trend. 
 The percentage of subjects with FSH, estradiol and testosterone suppression to 
prepubertal levels (FSH < 2.5 mIU/mL, estradiol < 20 pg/mL and testosterone < 30 
ng/dL) at each available time point. 
 For each basal hormone (LH, FSH, Testosterone, and estradiol) at each available time 
point the following will be presented:  a) a plot of the mean and standard deviation over 
time points; b) a plot of the mean and standard deviation of the change from baseline 


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(screening) over time points; c) a time point by individual concentration scatterplot; and 
d) a time by percent subjects at prepubertal level histogram plot.   
 Changes in the ratio of LH/FSH at each time point including baseline. 
 
8.3. 
Pharmacokinetic/Pharmacodynamic Endpoints and Assessments 
The primary pharmacokinetic (PK) endpoint is Leuprolide concentration.  Secondary PD 
endpoints are the changes in LH, FSH, testosterone and estradiol concentrations due to the 
leuprolide acetate injections.  At Visit 1 concentration at multiple time points will be collected at 
≥ 30 minutes prior to treatment injection, and at 1 hours (± 5 minutes), 4 hours (± 10 minutes) 
and at 6 hours (± 15 minutes) after treatment injection. Basal concentration at a single time point 
per visit will be collected within a 28 day screening period and at all visits subsequent to Visit 1.   
8.3.1. 
PK/PD Parameters 
The following PK/PD parameters will serve as endpoints. 
 Visit 1 (baseline, 1 hr, 4 hrs, 6 hrs) 
o Concentration Value at each time point 
o AUC  over six hours 
o Cmax over six hours 
o Tmax over six hours 
 
 Basal Measurement over Study Period  (Screening, first Visit 1 measurement, Visit 2 and 
greater) 
o Concentration Value at each visit 
o AUC (over study period (i.e., 0 to infinity)) 
o AUC (over set time periods (e.g. 0 to 6 hours, 0 to 6 mo, Day 7 to 6 mo)) 
o Cmax (post each treatment administration) 
o Tmax (post each treatment administration) 
 
 
 Post GnRHa stimulation (screening; Visits 3, 5, 6 and 8 in Part A; Visits 7, 9 and 11 
in Part B)) 
o Concentration Value of LH post 30 min of test initiation 
 
8.3.2. 
PK/PD Analyses 
Analysis for each PK/PD variable will include the following.  
 
 Serum concentrations will be analyzed by evaluating concentration at each time point 
using continuous descriptive analysis; and by evaluating the PK parameters AUC, 
Cmax and Tmax using continuous descriptive analysis. This will be done for Visit 1 
time points and for basal time points. 
 


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 Concentration plots in the original and log scale will be created, combined over 
subjects (mean and standard deviation) and by subject.   
 
 Additional continuous descriptive analysis will be provided for log transformed 
values of the PK parameters.   
 
 Burst leuprolide concentrations will be evaluated by examining PK measurements 
over the first 6 hours post injection. 
 
 Steady state will be evaluated by examining together the leuprolide concentrations 
collected at each assessment point that are at least one month after the first 
administration and prior to any Abbreviated GnRHa Stimulation Test or prior to 
subsequent administration of the leuprolide 45 mg injection solution.   
 
 Change from baseline (screening) for post-baseline basal concentration values will be 
computed, submitted to continuous descriptive analysis and plotted over each non-
baseline time point. Two plots will be created.  One will contain means and standard 
deviations by time point.  The second will be a scatterplot displaying individual 
values at each time point. 
 
 The ratio between prior basal and post GnRHa stimulation concentration will be 
computed at each available time point, submitted to continuous descriptive analysis 
and plotted over time points.   Two plots will be created.  One will contain means and 
standard deviations by time point.  The second will be a scatterplot displaying 
individual values at each time point. 
 
 The ratio between the basal concentration at screening and post GnRHa stimulation 
concentration will be computed at each available time point, submitted to continuous 
descriptive analysis and plotted over time points.  Two plots will be created.   One 
will contain means and standard deviations by time point.  The second will be a 
scatterplot displaying individual values at each time point. 
 
 The basal LH to FSH ratio will be computed for each available time point and 
plotted; and percent change from baseline for this ratio will be computed and plotted.  
Two plots will be created.  One will contain means and standard deviations by time 
point.  The second will be a scatterplot displaying individual values at each time 
point. 
 
 Further analysis will be accomplished using scatter plots.  The pairwise relationship 
between the various PK/PD variables (leuprolide, LH, FSH, testosterone and estradiol 
serum concentration) will be captured in scatter plots that use mean concentration 
values, geometric mean concentration values and individual subject concentration 
values. 
 


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9. 
SAFETY ASSESSMENTS 
Selected endpoints described under “Baseline and Related information” also will serve as safety 
parameters.  These endpoints are included in the list below. 
 
 Vital Signs 
 Weight 
 Physical Examination 
 Clinical Laboratory Assessments 
 Pregnancy Test 
 Adverse Events 
 Serious Adverse Events 
 
Categorical descriptive analysis, continuous descriptive analysis and shift table analysis will be 
applied to safety endpoints as described in Section 7:  Planned Study Analyses. 
10. 
ANALYSIS POPULATIONS 
10.1. 
Safety population 
The safety population will consist of all subjects providing consent/assent and who received at 
least one dose of the study drug.  
10.2. 
ITT population 
The intent to treat (ITT) population will consist of subjects providing consent/assent who 
received at least one dose, fulfilled the protocol eligibility criteria, and provided at least one PD 
laboratory assessment post dosing.  
10.3. 
PP population 
The per protocol population (PP) will consist of subjects who have received at least one dose of 
the study medication and have fulfilled the protocol in terms of eligibility, interventions and 
outcome assessments for at least 6 months. 
The table below cross-classifies the various endpoints with the analysis populations. 
Table 6 
Cross-classification of Various Endpoints with the Analysis Populations 
Type of Endpoint 
Study Population 
Safety Intent to Treat Per Protocol 
Baseline Endpoints 
 
x 
x 
Primary Efficacy Endpoint 
 
x 
x 
Secondary Efficacy Endpoint 
 
x 
x 
Exploratory Efficacy Endpoints 
 
x 
x 


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Safety Endpoints 
x 
 
 
PK Endpoints 
 
x 
 
 
Efficacy will be based on findings using the ITT population.  It is noted that for some variables 
the ITT and PP populations may be identical.  
11. 
GENERAL CONSIDERATIONS 
11.1. 
Significance Testing 
The purpose of this study is to demonstrate suppression of LH at a level of < 4 mIU/mL at 30 
minutes after GnRHa stimulation in a majority of subjects (≥ 80%) who are treated with 
leuprolide acetate 45 mg in an injectable suspension.  Inferential statistical testing will not be 
provided.  Rather, descriptive outcomes for the primary and secondary efficacy variables will be 
used to evaluate the efficacy of this treatment.    If requested by the medical writer or the FDA 
reviewer, inferential significance levels will be formally provided on an as needed basis.  
11.2. 
Continuous and Presumed Continuous Data 
Throughout the study, variables that fall on scales that are or can be presumed to represent 
continuous dimensions will be captured.  Standard descriptive statistics (number of subjects, 
mean, standard deviation, coefficient of variation, minimum value and maximum value) will be 
used to characterize continuous and presumed continuous data.  In general minimum and 
maximum will be reported to the numbers of decimal digits as recorded for the original 
(observed) data; the mean and median will be reported to one decimal digit more than in the 
original (observed) data; the standard deviation will be reported to two decimal digits; and the 
coefficient of variation percentage (CV %) will be quoted to one decimal digit. 
11.3. 
Categorical Data 
Some variables in this study will be captured in the form of a categorical scale.  Frequency 
distributions (number [n] and percentage of subjects [%] for each category) will be used to 
summarize categorical variables. In general, percentages will be reported to one decimal digit.  
11.4. 
Statistical Software 
All analyses will be performed using SAS® Software version 9.2 or later. 
12. 
IMPUTATION AND MISSING DATA 
Unless otherwise indicated, imputation of missing data will not be performed for baseline, 
efficacy and safety variable values.  Each table containing an analysis that reflects an outcome at 
a given time point in the study will contain only subjects in the analysis population under 
examination who have data available at that time point.   


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If a missing concentration datum is surrounded by non-missing values, interpolation will be used 
in the calculation of AUC, Cmax and Tmax. Otherwise, the nearest non-missing point in time 
will be used.  
If missing date and time values are evident in data not used to develop PK parameters, the 
following missing date and time algorithm may be applied. 
For partial start date/time: 
 If the year is unknown, then the date will not be imputed and will be assigned a 
missing value. 
 If the month is unknown, then:  
o If the year matches the year of the dose of study drug date, then the month 
and day of the dose of study drug date will be imputed. 
o Otherwise, ‘January’ (01) will be assigned. 
 If the day is unknown, then:  
o If the month and year match the month and year of the dose of study drug 
date, then the day of the dose of study drug date will be imputed. 
o Otherwise, ‘01’ will be assigned. 
 If the day is unknown, then:  
o If the month and year match the month and year of the dose of study drug 
date, then the day of the dose of study drug date will be imputed. 
o Otherwise, ‘01’ will be assigned. 
 If the time is unknown, then:  
o If the date (day, month, and year) matches the date of the dose of study drug 
date, then the time of the dose of study drug time will be imputed. 
o Otherwise, ‘00’ will be assigned. 
 For partial stop date/time: 
o If the year is unknown, then the date will not be imputed and will be assigned a 
missing value. 
o If the month is unknown, then ‘December’ (12) will be assigned. 
o If the day is unknown, then the last day of the month will be assigned. 
o If the time is unknown, then the last time of the day will be assigned. 
If time to an event were needed when only the hour, and not the minutes, are reported for the 
time of the event, then the minutes will be set to zero. 
Any deviations from the implementation of the missing date and time algorithms will be 
documented in the dataset documentation and final report. 


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12.1. 
Stratification by Site 
The impact of treatment is not expected to vary over site. Unless otherwise indicated, analyses 
will not be presented by site.  Many, if not most, sites are expected to enroll a small number of 
subjects.   
12.2. 
Unscheduled and/or Repeated Laboratory Results 
Unscheduled or repeated laboratory results will be placed together in a separate listing and 
discussed in a dedicated section of the clinical study report.  If any of these values are to replace 
the values in planned procedures to acquire analysis tables, all such decisions will be justified in 
the clinical study report. 
12.3. 
Handling of Early Termination Visit Information 
Early termination visit data for safety variables will be analyzed at the closest scheduled visit.  If 
the closest visit has valid data, the early termination data will be assigned to the next available 
visit. 
13. 
CDISC 
To meet recent current FDA Guidance (December 2014) on the submission of standardized study 
data, the study data will be formulated into data sets to provide transparency, traceability, and 
integrity of trial analysis results from the collection source. Reference is made to FDA Study 
Data Technical Conformance Guide (March 2015) for adherence to the FDA Guidancev. The 
observed study data will be mapped to the current CDISC Study Data Tabulation Model (SDTM) 
and serve as the source data from the trial. All study analyses will be completed using analysis 
data sets that are derived from the SDTM and follow the CDISC Analysis Data Model (ADaM) 
architecture. 
13.1. 
Clinical Data – CDISC Study Data Tabulation Model (SDTM) 
Domains will be mapped to CDISC SDTM using Implementation Guide (IG) version 3.2 or 
higher. No derived data other than age and converted units of measure that will be analyzed are 
to be included in the SDTM domains. All SDTM domains will be fully documented with define 
documents (DEFINE.XML) and a reviewer’s guide after database lock and final analyses are 
completed. 
13.2. 
Analysis Data – CDISC Analysis Data Model (ADaM) 
All planned a priori and unplanned “post hoc” analyses will be completed using the ADaM data 
sets derived from the SDTM domains for this study. Analysis data sets will contain all derived 
study endpoints required for analyses, graphs and specifically designated listings.   All analysis 
data sets will be fully documented with define documents (DEFINE.XML) and a reviewer’s 
guide after database lock and final analyses are completed. 


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Additional analysis data sets may be developed to support unplanned analyses after database 
lock. The SAP will not be amended for additional analysis data sets defined for the study and 
these additional data sets will be documented in the define documentation completed after all 
analyses are completed for the trial and the clinical study report is written. 
14. 
ADDITIONAL INFORMATION RELEVANT TO THE 
ANALYSES  
14.1. 
Protocol Deviations 
Protocol deviations will be summarized in a listing. Important protocol deviations are defined as 
deviations that could potentially bias the conclusion. A summary of the number and percentage 
of subjects with important deviations by deviation category will be provided. A listing of 
important protocol deviations by subjects and country will also be provided. 
14.2. 
Safety 
14.2.1. 
Concurrent Illness and Medical Conditions 
The number and percent of subjects with individual concurrent illness and medical histories will 
be summarized over all subjects in the safety population.  Individual subject listings will also be 
provided for concurrent illness and medical history. The medical history data will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) Version 18.0. A data listing of the 
body system, verbatim condition/abnormality/procedure, date of onset, and an indicator of 
continued presence will be provided. A summary table will be provided. 
14.2.2. 
Prior and Concurrent Medications 
The number and percent of subjects who took prior and concurrent medications will be 
summarized descriptively by the ATC class and preferred term as coded in the WHO-Drug 
dictionary overall subjects.  Concomitant medications will be summarized similarly.  Prior and 
concomitant medications will be summarized for the Safety Population. Prior and concomitant 
medication with the verbatim, ATC level 3 category, preferred term, indication, dosage, route, 
unit, frequency and start/stop dates of administration will be provided in the listings. 
14.3. 
Subject Enrollment 
A summary of subject disposition will display the number of subjects who enrolled, who 
received study drug, and who remained in the study. Also included in this summary will be the 
number of subjects who terminated from the study by reason and termination date. Subject 
enrollment and disposition with reason for termination will be presented in a listing.   Reasons 
for termination (discharge from the study) will also be present in a listing, ordered by primary 
reason for early termination, then by subject ID. 


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14.4. 
Adverse Events 
Adverse events (AEs) will be coded using current MedDRA (ex. Version 18.0).  Number and 
percent of subjects reporting AEs will be tabulated for the Safety population. Summaries will be 
presented by System Organ Class (SOC) and Preferred Term (PT), and further by severity and 
relationship to the investigational product. In summaries of severity, subjects who reported more 
than one event that are mapped to the same SOC and/or PT will be counted only once under the 
strongest severity. In summaries of relationship, subjects who reported more than one event that 
are mapped to the same SOC and/or PT will be counted only once under each applicable 
relationship. 
All TEAEs will be listed individually by subject.  In addition, a separate listing will be produced 
for AEs that are not treatment-emergent, where appropriate.  
14.4.1. 
Deaths 
All deaths, regardless of causality, will be provided in listings and written clinical narratives. 
14.4.2. 
Serious Adverse Events 
The number and percent of subjects with Serious Adverse Event (SAE) will be displayed by 
system organ class and preferred term, and relationship to study medication.  Within each 
preferred term, subjects will be counted only once if they had more than one SAE event reported 
during the treatment period.  
Clinical narratives for each SAE observed will be written to include important data and safety 
findings related to the individual SAE and included in the final clinical study report. 
14.4.3. 
Adverse Events Leading to Discontinuation of Study Drug Injection 
The number and percent of subjects with AE’s leading to discontinuation, or interruption, of 
study drug will be displayed by system organ class and preferred term for each treatment group.  
Within each preferred term, subjects will be counted only once if they had more than one AE 
leading to discontinuation, or interruption, of study drug reported during the treatment period.  
A listing will be produced for all subjects who reported serious TEAEs or who discontinued 
study medication due to TEAEs. 
14.5. 
Clinical Laboratory Evaluations 
In addition to categorical and continuous descriptive analyses as noted earlier, scatter plots of the 
baseline value (x-axis) and end of study (y-axis) will be completed for each clinical laboratory 
parameter. Reference ranges will be highlighted on the plots to identify laboratory assessments 
that are out of range. 


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14.6. 
Physical Examinations 
Physical examination results will be listed by subject for baseline and end of study assessment. 
Changes in physical examination from baseline to end of study will be recorded as adverse 
events.  
15. 
TABLES, LISTINGS AND FIGURES 
Organized listings of data will be provided that show by variable the values for each subject.   At 
the medical writer’s direction, listings that show specified variables by subject may be created.  
Selected details involving the listings are found below.  Mock headings that specify the obtained 
and derived variables that are to be placed in listings will be included with this SAP. 
 Inclusion and exclusion criteria will be provided in separate data listing by subject. 
 A summary of observed values (all vital sign measurements, bone age, and tanner stage) 
for each scheduled visit will be presented in the listings. 
 Physical examination body system, results (normal, abnormal), date and time of 
evaluation, clinical significance and a comment describing the abnormality and clinical 
significance of the abnormality will be in the listings. 
 Clinical laboratory test results will be presented in the data listings. Values that are 
outside of the reference range will be flagged. 
 All qualitative pregnancy test results (positive, negative) will be provided with date and 
study day of collection in the listings. 
 All literal and MedDRA adverse events will be in the listings.  System organ class, 
preferred term, severity and relationship to treatment will be presented.  
Mock tables that present the analyses planned for this study and mock figures that contain the 
planned exhibits will be formulated and included with this SAP. 
Appendix 5 will be added to this SAP and will contain mock tables, listings and figures. 
16. 
BASELINE VALUES OF DROPPED SUBJECTS 
If the study terminates with Part A, subjects not available for primary efficacy evaluation at six 
months will be compared to available subjects on key baseline parameters as directed by the 
medical writer.  If Part B is invoked, subjects not available for primary efficacy evaluation at 21 
months will be compared to available subjects on key baseline parameters as directed by the 
medical writer.  
17. 
DATA SAFETY MONITORING BOARD 
An Independent Data Safety Monitoring Board (DSMB) will be used to a) monitor safety 
throughout the study and b) determine whether Part B of the study is to be invoked.  DSMB 


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responsibilities will be specified in a DSMB charter.  The statistician will prepare data reports as 
directed in the charter and will be available to the DSMB. 
18. 
CONVENTIONS 
Unless otherwise indicated by prevailing considerations, the following conventions will be used.   
18.1. 
Reporting Conventions 
 
All tables and data listings will be developed in Landscape Orientation, unless 
presented as part of the text in a CSR. 
 
Figures will be presented in Landscape Orientation, unless presented as part of the 
text in a CSR. 
 
Legends will be used for all figures with more than one variable or item 
displayed. 
 
Figures will be presented in color with treatment groups distinguished by different 
symbols and colors.  Lines in figures should be wide enough to view the line after 
being photocopied.  
 
Specialized text styles, such as bolding, italics, borders, shading, superscripted 
and subscripted text will not be used in tables, figures, and data listings unless 
they add significant value to the table, figure, or data listing.  
 
Only standard keyboard characters should be used in tables and data listings. 
Special characters, such as non-printable control characters, printer specific, or 
font specific characters, will not be used on a table, figure, or data listing.  
Hexadecimal character representations are allowed (e.g.,,,). 
 
All titles will be centered on a page.  The ICH numbering convention is to be used 
for all tables, figures, and data listings. 
 
All footnotes will be left justified and the bottom of a page.  Footnotes must be 
present on the page where they are first referenced.  Footnotes should be used 
sparingly and must add value to the table, figure, or data listing.  If more than four 
footnote lines are planned then at the programmer’s discretion a cover page may 
be used to display footnotes. 
 
Missing values for both numeric and character variables will be presented as 
blanks in a table or data listing.  A zero (0) may be used if appropriate to identify 
when the frequency of a variable is not observed. 
 
All date values will be presented as YYYY-MM-DD (e.g., 2013-05-17) ISO 8601 
format. 
 
All observed time values will be presented using a 24-hour clock HH:MM:SS 
format (e.g., 01:35:45 or 11:26).  Seconds should only be reported if they were 
measured as part of the study, also in ISO 8601 format. 


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 
Time durations will be reported in mixed HHh MMm SSs notation (e.g., 5h 32m, 
or 27h 52m 31s).  The use of decimal notation to present (display) time durations 
should be avoided (e.g. 0.083h = 5m) unless it is necessary to show the 
computation of time differences in a table, figure, or data listing, in which case 
both notations may be used to display the time duration.  
 
All tables, figures, and data listings will have the Table, Listing, or Graph status 
(DRAFT, FINAL), and a date/time stamp on the bottom of each output.  
 
All analysis programs developed for a table, figure, or data listing display will be 
self-contained to facilitate transfer of programs to multiple computing 
environments and transfer to a regulatory agency (if requested).  
18.2. 
Population Summary Conventions 
 
Population(s) represented on the tables or data listings will be clearly identified in 
the last title of the Table as “Population: <name of population>” and will be 
identical in name to that identified in the protocol or SAP. 
 
Consistent terminology will be used to define and identify a population.   
 
Sub-population(s) or special population(s) descriptions will provide sufficient 
detail to ensure comprehension of the population (e.g., FAS Females, Per-
Protocol Males >60 years of age) used for analysis in a table or figure. 
 
Population sizes may be presented for each treatment or dosing category as totals 
in the column header as (N=xxxx), where appropriate.  
 
Population sizes shown with summary statistics are the samples sizes (n) of 
subjects with non-missing values.  
 
All population summaries for categorical variables will include all categories that 
were planned and for which the subjects may have had a response. Percentages 
corresponding to null categories (cells) will be suppressed.    
 
All population summaries for continuous variables will include at least  N, mean, 
SD, minimum, and maximum.  Other summaries (e.g. number missing, median, 
quartiles, 5%, 95% intervals, CV or %CV) may be used as appropriate. 
 
All percentages are rounded and reported to xx.x%. A percentage of 100% will be 
reported as 100%.    Any computation that results in 0% will be reported as 0% 
unless otherwise indicated.  
 
 


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19. 
APPENDICES 
19.1. 
Appendix 1:  Tanner Stages 
Tanner stages4 are commonly used to categorize pubertal maturation in terms of sequence, 
timing and tempo as described below. 
Boys - development of external genitalia 
Stage 1: 
Prepubertal 
Stage 2: 
Enlargement of scrotum and testes; scrotum skin reddens and changes in texture 
Stage 3: 
Enlargement of penis (length at first); further growth of testes 
Stage 4: 
Increased size of penis with growth in breadth and development of glans; testes 
and scrotum larger, scrotum skin darker 
Stage 5: 
Adult genitalia 
 
Girls - breast development 
Stage 1: 
Prepubertal 
Stage 2: 
Breast bud stage with elevation of breast and papilla; enlargement of areola 
Stage 3: 
Further enlargement of breast and areola; no separation of their contour 
Stage 4: 
Areola and papilla form a secondary mound above level of breast 
Stage 5: 
Mature stage: projection of papilla only, related to recession of areola 
 
Boys and girls - pubic hair 
Stage 1: 
Prepubertal (can see velus hair similar to abdominal wall) 
Stage 2: 
Sparse growth of long, slightly pigmented hair, straight or curled, at base of penis 
or along labia 
Stage 3: 
Darker, coarser and more curled hair, spreading sparsely over junction of pubes 
Stage 4: 
Hair adult in type, but covering smaller area than in adult; no spread to medial 
surface of thighs 
Stage 5: 
Adult in type and quantity, with horizontal distribution ("feminine") 
 
 


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19.2. 
Appendix 2:  Clinical Laboratory Parameters 
All hematology and clinical chemistry parameters as well as the listed screening tests will be 
analyzed at a central laboratory. Urinalysis parameters, assessed by dipsticks, will be analyzed 
locally using provided kits.  
Hematology 
Platelet Count  
RBC Indices: 
Automated WBC Differential: 
RBC Count 
MCV 
Neutrophils 
WBC Count (absolute)  
MCH 
Lymphocytes 
Reticulocyte Count 
MCHC 
Monocytes 
Hemoglobin 
 
Eosinophils 
Hematocrit 
 
Basophils 
Clinical Chemistry 
Urea 
Potassium 
AST (SGOT) 
Total and direct bilirubin 
Creatinine 
Chloride 
ALT (SGPT) 
Uric Acid 
Glucose 
Total CO2 
GGT 
Albumin 
Sodium 
Calcium 
Alkaline phosphatase 
Total Protein 
Other Parameters  
HBsAg (Hepatitis B Surface Antigen);  
HCVAb (Hepatitis C antibody) 
Pregnancy test (urine) 
Fasting serum lipid measurements to include: total cholesterol, HDL, LDL, triglycerides 
Urinalysis 
pH, glucose, protein, blood and ketones by dipstick provided by sponsor 
 
 
 


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19.3. 
Appendix 3:  Global Interview Symptom Assessment 
Any GnRH antagonist conditions reported? 
Yes/No 
If the answer is “Yes”, please categorize as described below:  
 
Flare or hot flashes 
Yes/No 
Injection site reactions (if “Yes”, please categorize below) 
a. burning/stinging 
b. pain 
c. bruising 
d. redness 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Difficulty in urination 
Yes/No 
Bone pain 
Yes/No 
Aggravation of weakness or other muscle symptoms 
Yes/No 
Onset of allergic reactions 
Yes/No 
 




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1.4 
04 Sep 2018 
Administrative Changes: 
 
Section 5.2 – Bullet #5 was Added: 
“Assess growth velocity of height in 
cm/year after the first treatment 
administration.” 
 
Section 8.2.2 – Bullet #3 was Added; 
“The growth velocity of height in 
cm/year at each available post-baseline 
measurement.  Growth velocity is defined 
for each visit as (change from 
Baseline)/[(number of weeks since 
Baseline)/52)] 
 
 (EMB) 


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19.5. 
Appendix 5:  Mock Tables, Listings and Figures (TBD)




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End Notes 
i US Federal Register.  International Conference on Harmonization; Guidance on Statistical Principles for Clinical 
Trials.  Department of Health and Human Services: Food and Drug Administration [Docket No. 97D-0174].  Federal 
Register Volume 63, Number 179, pages 49583-49598.  September 16, 1998. 
ii American Statistical Association.  Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, August 7, 1999. http://www.amstat.org/about/ethicalguidelines.cfm 
iii Royal Statistical Society.  The Royal Statistical Society:  Code of Conduct, August 1993. http://www rss.org.uk 
iv Marshall WA and Tanner JM.  Variations in Pattern of Pubertal Changes in Girls. 1969; 44:291-303. 
v Office of Communications, Division of Drug Information Center for Drug Evaluation and Research, Food and 
Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993 Phone: 
855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: druginfo@fda.hhs.gov 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm Guidance for 
Industry Providing Regulatory Submissions In Electronic Format – Standardized Study Data. December 2014.