Clinical trial NCT03695237
Conditions: Central Precocious Puberty (CPP)
Keywords: Central Precocious Puberty (CPP) Leuprolide Acetate (LA)
Sponsor: AbbVie
Start date: 2018-10-24; Completion date: 2023-11-29
Enrollment: 45 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to assess the safety and efficacy of a leuprolide acetate (LA) 45 mg 6-month depot formulation for the treatment of CPP in children who are either naïve to treatment with a gonadotropin-releasing hormone agonist (GnRHa) or who have been previously treated with a GnRHa.

Detailed description:

Arms: arm 1: Participants received leuprolide acetate (LA) 45 mg every 6 months administered as an intramuscular injection for up to 144 weeks.
Interventions: intervention 1: Leuprolide Acetate (LA)
Intervention descriptions: intervention 1: Administered intramuscularly as an injection

Protocol documents:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
4
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO SUBJECTS
7
3
OBJECTIVES AND ENDPOINTS
8
3.1
PRIMARY ENDPOINT
9
3.2
SECONDARY ENDPOINTS
9
3.3
OTHER EFFICACY ENDPOINTS
9
3.4
SAFETY ENDPOINTS
10
3.5
PHARMACOKINETIC/PHARMACODYNAMIC ENDPOINTS
10
4
INVESTIGATIONAL PLAN
11
4.1
OVERALL STUDY DESIGN AND PLAN
11
4.2
DISCUSSION OF STUDY DESIGN
14
5
STUDY ACTIVITIES
15
5.1
ELIGIBILITY CRITERIA
15
5.2
PROHIBITED MEDICATIONS AND THERAPY
16
5.3
PRIOR AND CONCOMITANT THERAPY
17
5.4
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
17
5.5
FOLLOW-UP FOR SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
18
5.6
STUDY DRUG
18
5.7
RANDOMIZATION/DRUG ASSIGNMENT
19
5.8
PROTOCOL DEVIATIONS
20
6
SAFETY CONSIDERATIONS
20
6.1
COMPLAINTS AND ADVERSE EVENTS
20
6.2
OTHER SAFETY DATA COLLECTION
23
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
24
7.1
STATISTICAL AND ANALYTICAL PLANS
24
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7.2
DEFINITION FOR ANALYSIS POPULATIONS
24
7.3
STATISTICAL ANALYSES FOR EFFICACY
24
7.4
STATISTICAL ANALYSES FOR SAFETY
25
8
ETHICS
25
8.1
INSTITUTIONAL REVIEW BOARD
25
8.2
ETHICAL CONDUCT OF THE STUDY
25
8.3
SUBJECT CONFIDENTIALITY
25
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
25
10 DATA QUALITY ASSURANCE
25
11 COMPLETION OF THE STUDY
26
12 REFERENCES
26
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
13
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
27
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
29
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
30
APPENDIX D.
ACTIVITY SCHEDULE
31
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
37
APPENDIX F.
OPERATIONS MANUAL
38
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
Proportion of subjects with suppression of the physical 
signs of puberty (breast development in females; 
testicular volume or genital development in males) at 
each scheduled assessment using modified Tanner 
staging.

Incremental growth rate (cm/year) at each scheduled 
assessment.

Ratio of change from Baseline in bone age/change from 
Baseline in chronological age at each scheduled 
assessment.

Other efficacy endpoints:

Peak stimulated LH concentrations at each scheduled 
assessment.

Number and percentage of subjects who fail suppression 
of peak stimulated LH per primary endpoint analysis at 
each scheduled assessment.

Number and percentage of female subjects with 
menstrual bleeding.

Change from Baseline in basal and peak stimulated LH 
and FSH, as well as basal and stimulated estradiol (for 
females) and testosterone (for males), to each scheduled 
assessment.

Ratio and change from Baseline in the ratio of bone age 
to chronological age at each scheduled assessment.

Regression or no progression in pubic hair in both females 
and males.

Change from Baseline in uterine length, uterine volume, 
and ovarian volume to each scheduled assessment.

Number and percentage of subjects with endometrial 
stripe presence by baseline endometrial stripe presence 
status (yes/no) at each scheduled assessment.

Change from Baseline in testicular length (cm), penile 
length (cm), and penile width (cm) by physical 
examination, and in testicular volume by Prader beads to 
each scheduled assessment.

Change from Baseline in BMI standardized score to each 
scheduled assessment.

Change from Baseline in height standardized score to 
each scheduled assessment.

PedsQL and PROMIS questionnaires at each scheduled 
assessment.

Safety evaluations are adverse event monitoring, physical 
examinations, vital sign measurements, LA 45 mg injection site 
reactions, hormonal flare and acute-on-chronic (AOC) 
response, and clinical laboratory testing.
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2 INTRODUCTION
2.1 Background and Rationale
Why This Study is Being Conducted
Central precocious puberty (CPP) is an orphan disease that affects the pediatric population.  
Gonadotropin-releasing hormone agonists (GnRHa) are the treatment of choice for CPP.  The goal of 
therapy is to suppress pituitary gonadotropins (luteinizing hormone [LH] and follicle-stimulating 
hormone [FSH]) and peripheral sex steroids (estradiol and testosterone) and to arrest premature 
progression of secondary sexual characteristics.  Children with CPP may require extended therapy (up to 
10 years) to achieve continuous hormonal suppression until they reach an age at which the patient, 
family, and practitioner agree that puberty should resume.
Leuprolide acetate (LA) is a GnRHa that is approved in the United States (US) and other countries for the 
treatment of children with CPP.  It is marketed as Lupron Depot-PED® in the US.  Lupron Depot is also 
approved in the US and other countries for the treatment of prostate cancer, endometriosis, and uterine 
leiomyomata.  Lupron Depot-PED is available in 1-month formulations (7.5, 11.25, and 15 mg) and 
3-month formulations (11.25 and 30 mg) for the treatment of children with CPP in the US.
The Lupron Depot 45 mg 6-month dose is approved for the treatment of adults with prostate cancer; 
this is the same formulation that is being investigated for use for treatment of CPP and contains the 
same active ingredient as the 1- and 3-month formulations of Lupron Depot-PED in a prefilled dual 
chamber syringe.
The currently approved Lupron Depot-PED regimens for CPP require 4 to 12 injections per year.  The 
need for frequent injections can cause distress for both the child and the parents (or legal guardians) 
and may require absences from school for the child and absences from work for parents (or legal 
guardians).  While longer-acting GnRHa treatments (implants) are available, these treatments require 
general anesthesia to surgically place and remove.  Development of a longer-acting depot formulation 
for children with CPP would reduce the number of injections and provide more treatment options for 
health care providers; a longer-acting formulation may also reduce the number of occurrences of 
injection site pain, which is the most commonly reported adverse event related to treatment of children 
with CPP with Lupron Depot-PED (see Section 2.2).  LA 45 mg 6-month has not been studied in children 
with CPP.
2.2 Benefits and Risks to Subjects
The benefits of treatment with LA for children with CPP are well documented:  improvements in the 
signs and symptoms of CPP, suppression of pubertal gonadotropin and/or sex steroid levels, halting the 
progression and/or promoting the regression of Tanner stages, and slowing or halting of epiphyseal 
closures that may lead to an increase in final adult height.1
The overall safety of Lupron Depot-PED 11.25 mg 3-month and 30 mg 3-month is well characterized, 
with approximately 
 doses having been administered to pediatric patients worldwide, 
representing approximately 
 patient-years of exposure.  In addition, Lupron Depot-PED 11.25 mg 
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3-month and 30 mg 3-month were evaluated in a study in children with CPP (Study L-CP07-167)2 and in a 
36-month extension study (Study L-CP07-177).3  The safety profile of LA 45 mg 6-month in children with 
CPP is expected to be similar to that of the approved Lupron Depot-PED formulations for the treatment 
of CPP with similar hormonal changes (initial flare effect with corresponding LH/estradiol/testosterone 
elevations followed by a rapid decline to prepubertal levels).
Since LA 45 mg 6-month is administered as an intramuscular injection, injection site pain following 
dosing is a potential safety risk.  Injection site pain following Lupron Depot dosing was the most 
commonly reported adverse event in children with CPP in Study L-CP07-167 (Lupron Depot-PED 11.25 
and 30 mg 3-month formulations); injection site pain was also a commonly reported adverse event in 
adults with prostate cancer in a 6-month study of the 45 mg formulation (Study L-PC07-169).  Injection 
site pain occurred in 26% of pediatric subjects in the 30 mg group and 19% of pediatric subjects in the 
11.25 mg group in Study L-CP07-167.  Injection site pain occurred in 18% of adult subjects with prostate 
cancer in the 45 mg 6-month study (Study L-PC07-169).
All adverse events of injection site pain in pediatric subjects were mild to moderate in intensity in the 
11.25 mg 3-month and 30 mg 3-month groups in Study L-CP07-167, with the exception of a severe 
adverse event of injection site pain in 1 subject in the 30 mg group.  Similarly, in Study L-CP07-177 (an 
extension of Study L-CP07-167), only 1 severe event of injection site pain was reported (1 subject in the 
11.25 mg group).  No increase in incidence over time or worsening in intensity was apparent.
See the current package inserts for a more comprehensive listing of known and potential safety risks 
and benefits.
3 OBJECTIVES AND ENDPOINTS
Objectives and Hypotheses
Primary
To assess the safety and efficacy of LA 45 mg 6-month depot formulation for the treatment of CPP in 
children who are either naïve to treatment with a GnRHa or who have been previously treated with a 
GnRHa.
The hypotheses corresponding to the primary objective are that treatment of children with CPP with LA 
45 mg 6-month is well tolerated and effectively maintains continuous hormonal suppression following 
administration.  Administration of 1 intramuscular dose of LA 45 mg 6-month provides sufficient 
leuprolide serum concentrations to achieve suppression of LH (determined by peak stimulated LH 
< 4 mIU/mL) at Week 24 in children with CPP.
Secondary
To evaluate the pharmacokinetic profile and pharmacodynamics of leuprolide following intramuscular 
administration of the LA 45 mg 6-month depot formulation in subjects with CPP.
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3.1 Primary Endpoint
The primary efficacy endpoint is the proportion of subjects with suppression of GnRHa-stimulated LH 
(< 4 mIU/mL) at Week 24 after the first dose of study drug but before the Week 24 dose.
3.2 Secondary Endpoints
Secondary endpoints:

Proportion of subjects with suppression of GnRHa-stimulated LH (< 4 mIU/mL) at Weeks 12, 20, 
44, and 48.

Proportion of female subjects with suppression of basal estradiol to < 20 pg/mL at Weeks 12, 20, 
24, 44, and 48.

Proportion of male subjects with suppression of testosterone to < 30 ng/dL at Weeks 12, 20, 24, 
44, and 48.

Proportion of subjects with maintenance of suppression of GnRHa-stimulated LH (< 4 mIU/mL) 
at Weeks 72, 96, 120, and 144.

Proportion of female subjects with maintenance of suppression of basal estradiol to < 20 pg/mL 
at Weeks 72, 96, 120, and 144.

Proportion of male subjects with maintenance of suppression of testosterone to < 30 ng/dL at 
Weeks 72, 96, 120, and 144.

Proportion of subjects with suppression of the physical signs of puberty (breast development in 
females; testicular volume or genital development in males) at each scheduled assessment using 
modified Tanner staging.4,5

Incremental growth rate (cm/year) at each scheduled assessment.

Ratio of change from Baseline in bone age/change from Baseline in chronological age at each 
scheduled assessment.
3.3 Other Efficacy Endpoints
Other efficacy endpoints:

Peak stimulated LH concentrations at each scheduled assessment.

Number and percentage of subjects who fail suppression of peak stimulated LH per primary 
endpoint analysis at each scheduled assessment.

Number and percentage of female subjects with menstrual bleeding.

Change from Baseline in basal and peak stimulated LH and FSH, as well as basal and stimulated 
estradiol (for females) and testosterone (for males), to each scheduled assessment.

Ratio and change from Baseline in the ratio of bone age to chronological age at each scheduled 
assessment.
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
Regression or no progression in pubic hair in both females and males.

Change from Baseline in uterine length, uterine volume, and ovarian volume to each scheduled 
assessment.

Number and percentage of subjects with endometrial stripe presence by baseline endometrial 
stripe presence status (yes/no) at each scheduled assessment.

Change from Baseline in testicular length (cm), penile length (cm), and penile width (cm) by 
physical examination, and in testicular volume by Prader beads to each scheduled assessment.

Change from Baseline in body mass index (BMI) standardized score to each scheduled 
assessment.

Change from Baseline in height standardized score to each scheduled assessment.

Pediatric Quality of Life Inventory (PedsQL) and Patient Reported Outcomes Measurement 
Information System (PROMIS) questionnaires at each scheduled assessment.
3.4 Safety Endpoints
Adverse events, physical examinations, vital sign measurements, LA 45 mg injection site reactions, 
hormonal flare and acute-on-chronic (AOC) response, and clinical laboratory test results will be assessed 
throughout the study.
3.5 Pharmacokinetic/Pharmacodynamic Endpoints
The pharmacokinetics of leuprolide will be evaluated using population pharmacokinetic analysis.  
Furthermore, the relationship between leuprolide pharmacokinetics and clinical response 
(pharmacodynamics of leuprolide measured as LH, testosterone [males], and estradiol [females]) in 
children with CPP will be examined.
The objectives of this population pharmacokinetic/pharmacodynamic analysis are as follows:

To estimate the mean pharmacokinetic and pharmacodynamic (LH, testosterone [males], and 
estradiol [females]) parameters in a population of pediatric subjects with CPP.

To investigate and identify fixed effect sources of variability (covariates) that may influence the 
pharmacokinetics/pharmacodynamics of leuprolide.

To estimate the magnitude of inter-individual variability of the parameters.

To measure the random residual variability.
Serum leuprolide and gonadotropin/sex hormone concentrations will be modeled using an appropriate 
pharmacokinetic/pharmacodynamic model to describe factors that influence leuprolide 
pharmacokinetic and pharmacodynamic response in children with CPP.
Other parameters, including parameters that describe leuprolide absorption characteristics, may be 
estimated if useful in the analysis.
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4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
Study M16-904 is a Phase 3, open-label, multicenter study that will be conducted in 2 parts (Parts 1 and 
2) at approximately 20 sites (US and Puerto Rico).  The safety, efficacy, pharmacokinetics, and 
pharmacodynamics of the LA 45 mg formulation administered with a 6-month dosing interval in children 
with CPP will be evaluated.  Approximately 40 subjects who were previously treated with GnRHa 
therapy (minimum of 15 previously treated subjects) or who are naïve to previous GnRHa treatment 
(minimum of 15 naïve subjects) will be enrolled in the study.  See Section 5 for information regarding 
eligibility criteria.
LH and sex steroid suppression and pubertal symptom progression will be assessed.  Efficacy endpoints 
are based on hormonal suppression.  Stabilization or regression of signs of puberty and effects on bone 
age and growth rate will be evaluated.
The total duration of the study (Parts 1 and 2) will be 160 weeks as follows:

Part 1:  52 weeks (4-week screening period + 48-week treatment period)

Part 2:  108 weeks (additional 96-week treatment period + 12-week follow-up period)
The Screening Period may be extended in certain circumstances (e.g., pending laboratory test results) 
following consultation with the sponsor.
Part 1:  The safety, efficacy, pharmacokinetics, and pharmacodynamics of the LA 45 mg 6-month dose 
will be evaluated in subjects with CPP from Baseline to Week 48.  In all subjects, blood samples for 
efficacy assessments (analysis of LH, FSH, testosterone concentrations [males], and estradiol 
concentrations [females]) will be collected at Baseline and at Weeks 1, 4, 12, 20, 24, 44, and 48 after 
dosing.  In the first subjects who are enrolled (20 subjects total, with at least 8 naïve and 8 previously 
treated), concentrations of leuprolide will be measured at each study visit following administration of LA 
45 mg 6-month to characterize the leuprolide concentration-time profile, rate of absorption, and 
pharmacokinetic/pharmacodynamic relationship of leuprolide and LH.  Investigative sites will be notified 
when the pharmacokinetic subset has been fulfilled.
Leuprolide and appropriate measures of efficacy (LH, FSH, estradiol in females, testosterone in males) 
will be monitored upon data availability to evaluate the appropriateness of the 24-week dosing interval 
for the 6-month formulation for CPP.
Part 2:  Following completion of Part 1 assessments, subjects will continue to Part 2 of the study 
(extension period) to evaluate long-term administration of LA 45 mg 6-month (up to 24 months).  Study 
visits during the extension period will start at Week 48 and continue once every 24 weeks for 96 weeks 
(24 months) until the subject discontinues treatment of LA 45 mg 6-month or withdraws from the study.  
Subjects will be assessed for continued maintenance of LH suppression and safety throughout this 
extension period.
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Note:  Week 48 is the end of Part 1 and also the start of Part 2.  See Appendix D of the protocol and 
Section 2 of the Operations Manual for details.
Some of the study visits and visit activities (including but not limited to clinical laboratory tests and 
concomitant medication assessment) may be conducted in a non-hospital/clinic environment (e.g., the 
subject's home) by qualified individuals at the request of the Investigator and with the agreement of 
AbbVie, the subject, and subject's parent or legal guardian.
If a subject cannot come to the site because of an unforeseen circumstance (e.g., the COVID-19 
pandemic), study visits may be conducted virtually by site staff (e.g., by phone or video) or by a qualified 
home healthcare nurse in a non-hospital/clinic environment (e.g., the subject's home) at the request of 
the investigator and with the agreement of the subject's parent or legal guardian.  AbbVie should be 
notified if this occurs.
Details of the study procedures are located in the Operations Manual (Appendix F).
A schematic of the study is shown in Figure 1.
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Figure 1.
Study Schematic
Children with CPP (N = ~40)
AOC = acute-on-chronic; CPP = central precocious puberty; E2 = estradiol; T = testosterone; FSH = follicle-stimulating hormone; IM = intramuscular; LH = luteinizing hormone; 
PK/PD = pharmacokinetic/pharmacodynamic
a.
At the beginning of Part 2, half of the subjects will be randomly selected for AOC biochemical assessments 48 hours after the injection of study drug at Weeks 48, 72, 96, 
and 120.
b.
For subjects randomly selected for AOC biochemical assessments 48 hours after the injection of study drug at Weeks 48, 72, 96, and 120, a single telephone assessment will 
take place 7 days following the injection of study drug.  For subjects not selected for the AOC biochemical assessments, a telephone assessment will take place 1 day and 7 days 
following the injection of study drug at Weeks 48, 72, 96, and 120.
Notes:
The Screening Period may be extended in certain circumstances (e.g., pending laboratory test results) following consultation with the sponsor.  Week 0 = Day 1 (Baseline).  
See Operations Manual (Appendix F) for details of the study schematic.
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Rescreening
Subjects who initially fail screening may be permitted to rescreen following re-consent.  Sites must 
contact the AbbVie Therapeutic Area Medical Director (TA MD) to confirm whether subjects should or 
should not be rescreened.  The subject must meet all eligibility criteria at the time of rescreening to 
qualify for the study.  There is no minimum period of time a subject must wait to rescreen.
Laboratory assessments will not need to be repeated for subjects in rescreening if the time between 
screening and rescreening is less than 28 days; however, laboratory assessments will need to be 
repeated at Baseline if the time between laboratory assessments during previous Screening and 
Baseline is greater than 28 days.
4.2 Discussion of Study Design
Choice of Control Group
For ethical reasons, this study does not have a placebo control group, as intervention in this patient 
population is essential, and treatment should start immediately to maximize possible benefits of GnRHa 
treatment.  Also, for ethical reasons, this study does not have an active control group, as differences in 
dosing frequencies would require sham injections.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be used in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with CPP.  All clinical 
and laboratory procedures in this study are standard and generally accepted.6
Suitability of Subject Population
Both treatment-naïve subjects and those who were previously treated with a GnRHa were selected for 
this study, as both populations may benefit from the proposed extended dosing interval either as initial 
therapy or maintenance therapy, respectively.
Selection of Doses in the Study
The LA 45 mg 6-month dose in this study was chosen to extend the dosing interval to reduce the 
number of injections.  The formulation chosen for this study is the same as the approved Lupron Depot 
45 mg 6-month dose for prostate cancer and contains 45 mg of LA in a prefilled dual chamber syringe.  
LA is the same active ingredient as in the approved Lupron Depot-PED 11.25 mg 3-month and 30 mg 
3-month CPP formulations.  The injection volume for the 45 mg 6-month dose is also the same as that in 
the approved 11.25 mg 3-month and 30 mg 3-month CPP formulations.  The same prefilled, dual 
chamber syringes and needles are used for the 3-month and 6-month formulations.
The average monthly dose of LA with a 45 mg 6-month dose is expected to be 7.5 mg because of the 
sustained release characteristics of the 45-mg formulation.  This is consistent with that of the lower 
dose, shorter-duration formulations.  This monthly exposure to leuprolide is identical to the lowest 
Lupron Depot-PED dose that is approved in the US (7.5 mg 1-month formulation) and is half that of the 
highest approved Lupron Depot-PED dose (15 mg 1-month formulation).
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5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria to be included in the study.  Anything other than a 
positive response to the questions below will result in exclusion from the study.
Consent
1. Parent or legal guardian has voluntarily signed and dated an informed consent form, 
approved by an institutional review board (IRB), after the nature of the study has been 
explained and the subject and the subject's parent or legal guardian has had the opportunity to 
ask questions.  The informed consent must be signed before any study-specific procedures are 
performed or before any concomitant medication is discontinued for the purpose of the study. 
Pediatric subjects will be included in all discussions in order to obtain verbal and/or written 
assent.
Disease Activity
2. Children with a diagnosis of CPP, either treatment-naïve or previously treated with a GnRHa.
3. Chronological age at the appearance of pubertal changes < 8 years in females and < 9 years in 
males at Day 1 of the study.
Demographic and Laboratory Assessments
4. Bone age advancement over chronological age at least 1 year at time of CPP diagnosis or 
first GnRHa therapy.
5. Bone age < 13 years for females and < 14 years for males.
6. In general good health with no uncontrolled, clinically significant disease that could interfere 
with bone maturation or mask the objectives of this protocol as assessed by the investigator.
7. No abnormal laboratory value that suggests a clinically significant underlying disease or 
condition that may prevent the subject from entering the study.
8. Willing and able to comply with procedures required in this protocol.
9. No diagnosis of short stature, i.e., more than 2.25 SD below the mean height for age (growth 
chart assessment).
Subject History
10. No diagnosis of incomplete precocious puberty, peripheral precocious puberty; evidence of 
any abnormal pituitary, hypothalamic, adrenal, thyroid, and gonadal function other than 
premature secretion of gonadotropins not adequately controlled; no unstable intracranial 
tumors (unresponsive to treatment/expanding) except hamartoma.
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11. No concomitant medical condition that, in the opinion of the investigator, may expose a 
subject to an unacceptable level of safety risk or that affects subject compliance.
12. No history of clinically significant medical conditions or any other reason that the 
investigator determines would interfere with the subject's participation in this study or would 
make the subject an unsuitable candidate to receive study drug.
13. No history of an allergic reaction or significant sensitivity to constituents of the study drug 
(and its excipients) and/or other products in the same class.
Pregnancy
14. A negative serum pregnancy test for female subjects ≥ 10 years of age at Screening and 
negative urine pregnancy test on Day 1 prior to study drug administration.  For female subjects 
< 10 years of age, pregnancy tests may be performed at Screening and on Day 1 at the discretion 
of the principal investigator.
Concomitant Medications
15. Must have discontinued therapy with medroxyprogesterone acetate, growth hormone, 
insulin-like growth factor-1 (IGF-1), or estrogen or testosterone preparations at least 5 half-lives 
or 4 weeks prior to Screening, whichever is longer.
16. Must not have been treated with any investigational drug within 30 days or 5 half-lives of 
the drug (whichever is longer) prior to Screening or is currently enrolled in another clinical 
study.
Additional Criteria for Subjects Naïve to GnRHa treatment
17. Females 2 – 8 years of age, inclusive, or males 2 – 9 years, inclusive, on Day 1.
18. Pretreatment pubertal response to GnRHa stimulation test (LH ≥ 6 mIU/mL) at Screening.
19. Breast pubertal staging (modified Tanner) of at least 2 in females; testicular volume of at 
least 4 cc in males at Screening.
Additional Criteria for Subjects Previously Treated with a GnRHa
20. Females 2 – 10 years of age, inclusive, or males 2 – 11 years of age, inclusive, on Day 1.
21. Must have been on GnRHa therapy for at least 6 months prior to Day 1.
22. Should have documented maintenance of LH suppression as evidenced by peak stimulated 
LH < 4 mIU/mL at Screening.
5.2 Prohibited Medications and Therapy
All other investigational drugs are prohibited during the study.
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Any medications with a known positive or negative effect on either growth or the assessment of sex 
steroids will not be permitted for use during the study.  Examples are as follows:

GnRH agonists other than study drug*

GnRH antagonists

High dose corticosteroids (e.g., doses greater than hydrocortisone 5 mg/m2 body surface 
area/day)

Growth hormone

IGF-1

Testosterone

Estrogen
*The GnRH agonist required to perform the stimulation test is allowed during the study (see Operations 
Manual Section 3.15).
5.3 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving within 30 days prior to Screening, at the time of 
enrollment, and during the study must be recorded through the 12-week follow-up phone call.
All medications used to treat the subject's CPP in the last 12 months prior to Screening, including all 
GnRHa medications, will be recorded in the appropriate electronic case report form (eCRF).
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact (TA MD).  Information regarding potential drug interactions with LA is located in the Lupron 
Depot package insert.
5.4 Withdrawal of Subjects and Discontinuation of Study
Study subjects and/or their parent or legal guardian have the right to prematurely withdraw from the 
study at any time.
The investigator may discontinue any subject's participation for any reason, including an adverse event, 
safety concerns, or failure to comply with the protocol.
Subjects will be withdrawn from the study immediately if any one of the following occurs:

Clinically significant abnormal laboratory results or adverse events, which rule out continuation 
of study drug, as determined by the Investigator or the AbbVie TA MD.

The subject requests withdrawal from the study.

It is in the subject's best medical interest.
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
Eligibility criteria violation was noted after the subject started study drug and continuation of 
study drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of study drug would place 
the subject at risk.

An adverse event occurs that the investigator feels is detrimental to the subject.

The subject requires treatment with another drug that will interfere with evaluation of the 
investigational product.

Subject is significantly noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial.

Subject demonstrates severe allergic reaction to the investigational product.

Subject is pregnant.

Subject is not adequately suppressed on therapy as evidenced by peak stimulated LH level of 
≥4 mIU/mL at or after Week 24 and subject has an accelerated progression of pubertal 
symptoms any time after Week 24, specifically > 1-stage progression in breast or genitalia (not 
pubic hair) from the last visit as assessed by the same individual, if possible.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 phone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
5.5 Follow-Up for Subject Discontinuation of Study Drug or from Study
To minimize missing data, subjects who prematurely discontinue study drug treatment should continue 
to be followed for all regularly scheduled visits, unless subjects and their parent or legal guardian have 
decided to discontinue study participation entirely (withdrawal of informed consent).  Subjects and their 
parent or legal guardian should be advised on the continued scientific importance of their data even if 
they discontinue treatment with study drug early.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit should be completed as soon as possible, 
preferably within 2 weeks.  In addition, if the subject and parent or legal guardian is willing, a 12-week 
follow-up phone call after the last visit may be completed to ensure all treatment-emergent adverse 
events/serious adverse event (SAE) have been resolved.
5.6 Study Drug
LA 45 mg 6-month drug product, manufactured by Takeda Pharmaceuticals for AbbVie, will be injected 
intramuscularly beginning on Day 1, and will be administered by study site staff under the supervision of 
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the principal investigator or designee.  In unforeseen circumstances (e.g., the COVID-19 pandemic), the 
study drug injection may be administered by a home healthcare nurse at the subject's home.  Details are 
provided in Operations Manual Section 3.19.
LA 45 mg 6-month drug product will be provided by AbbVie in quantities sufficient to accommodate the 
study design.  Each kit will be labeled per local requirements, and this label must remain affixed to the 
kit.  Upon receipt, study drug should be stored at controlled room temperature (15° to 25°C/59° to 77°F) 
and kept in a secure location.  Each kit will contain a unique kit number.  This kit number is assigned to a 
subject via interactive response technology (IRT) and encodes the appropriate study drug to be 
administered at the subject's corresponding study visit.  The site staff will complete the blank space on 
the label with the subject number before administering the study drug.  Study drug will only be used for 
the conduct of this study.
AbbVie will provide instructions for drug preparation (refer to Section 7.3 of the Operations Manual).
AbbVie, the sponsor of this study, will source the generic LA aqueous solution for the GnRHa stimulation 
test and provide it to participating sites.  The generic LA aqueous solution will either be from a 
US-registered source or an ex-US registered source (an investigative product comparable with the 
US-registered material).  If a label is mandated by local agencies, a label may be applied.  There may be 
times when the sponsor is unable to provide the generic LA aqueous solution.  Under these 
circumstances, participating sites have the option to obtain this product through an external licensed 
pharmacy or wholesaler or from local site supplies.  In unforeseen circumstances (e.g., the COVID-19
pandemic), the GnRHa stimulation test may be performed by a home healthcare nurse at the subject's 
home.  Details are provided in the Operations Manual Section 3.15.
5.7 Randomization/Drug Assignment
All subjects in this study will receive the same treatment; therefore, subjects will not be randomized.
All subjects will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  Enrollment will be limited by previous treatment status to ensure that a minimum of 15 subjects 
are treatment naïve and that a minimum of 15 subjects are previously treated with a GnRHa.
At Baseline, the IRT will assign 20 subjects to the pharmacokinetic subset.  The first subjects enrolled in 
the study will automatically be assigned to the pharmacokinetic subset for collection of blood samples 
for the quantification of leuprolide concentration, with a minimum of 8 subjects naïve to GnRHa 
treatment (maximum of 12 subjects) and a minimum of 8 subjects who have been previously treated 
with a GnRHa (maximum of 12 subjects).
At the beginning of Part 2, using the IRT system, half of the subjects will be randomly selected to have 
AOC biochemical assessment 48 hours after the injection of study drug at Weeks 48, 72, 96, and 120.  
Randomization will be stratified based on previous GnRHa treatment status (treatment-naïve or 
previous treated with a GnRHa).  The randomization schedule will be generated and kept by the 
statistics department at AbbVie and a copy will be forwarded to the IRT provider.
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5.8 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified), the investigator is responsible for notifying the independent 
review board (IRB), regulatory authorities (as applicable), and AbbVie.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An adverse event is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  An adverse event, therefore, can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product, whether or not the event is considered causally related to the 
use of the product.
Any worsening of a pre-existing condition or illness is considered an adverse event.  Worsening in 
severity of a reported adverse event should be reported as a new adverse event.  Laboratory 
abnormalities and changes in vital signs are considered to be adverse events only if they result in 
discontinuation from the study, necessitate therapeutic medical intervention, and/or if the investigator 
considers them to be adverse events.
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Investigators will monitor each subject for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study.  All adverse events will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an adverse 
event if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure was pre-planned prior study entry.  However, if the pre-existing condition 
deteriorates unexpectedly during the study (e.g., surgery performed earlier than planned), then the 
deterioration of the condition for which the elective surgery/procedure is being done will be considered 
an adverse event.
If an adverse event, whether associated with study drug or not, meets any of the following criteria, it is 
to be reported to AbbVie clinical pharmacovigilance or contract research organization (as appropriate) 
as an SAE within 24 hours after the site becomes aware of the SAE (refer to Section 4.2 of the 
Operations Manual for reporting details and contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
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Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All adverse events reported from the time of study drug administration until 12 weeks after the end of 
the effect of study drug (24 weeks after the date of the last administration of study drug) will be 
collected, whether solicited or spontaneously reported by the subject.  In addition, all SAEs and study
procedure-related nonserious adverse events will be collected from the time the subject's parent or 
legal guardian signs the study-specific informed consent until study drug administration.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product in accordance with global and local regulations.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Events of Special Interest
The following adverse events of special interest must be captured:

Bone fracture/osteoporosis/osteopenia

Slipped capital femoral epiphysis

Neuropsychiatric events

Seizure/convulsion

Injection site reaction*

Hypersensitivity reaction
*All injection site reactions, whether associated with study drug administration or with the stimulation 
test, must be captured as adverse events.  Any injection site reaction that reaches seriousness criteria as 
stated above will be captured as an SAE and reported as described.
Adverse Event Severity and Relationship to Study Drug
The investigator will use the following definitions to rate the severity of each adverse event:
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Mild:  The adverse event is transient and easily tolerated by the subject.
Moderate:  The adverse event causes the subject discomfort and interrupts the subject's usual activities.
Severe:  The adverse event causes considerable interference with the subject's usual activities and may 
be incapacitating or life-threatening.
The investigator will use the following definitions to assess the relationship of the adverse event to the 
use of study drug:
Reasonable Possibility:  After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is sufficient evidence (information) to suggest 
a causal relationship.
No Reasonable Possibility:  After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship.
Pregnancy
While not an adverse event, pregnancy in a study subject must be reported to AbbVie within 24 hours
after the site becomes aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued (Section 5.4).  If a pregnancy occurs in a study subject, information regarding the 
pregnancy and the outcome will be collected.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
6.2 Other Safety Data Collection
Disease-Related Events
Abnormal laboratory, diagnostic procedural, or physical examination findings related to the disease 
under study will not be captured as an adverse event, unless the investigator deemed appropriate.  
Findings such as progression of pubertal staging are not considered to be adverse events but should be 
recorded in the subject's source documents and appropriate eCRF.
Drug-Related Events
LA is known to cause gonadotropins and sex steroids to temporarily rise above baseline levels because 
of the stimulatory effects of the drug within the first several weeks following initial administration.  
Therefore, an increase in clinical signs and symptoms, such as menses or spotting in females and 
behavioral changes in males, may occur at this time.  These events should be recorded in the subject's 
source documents and appropriate eCRF. 
The investigator will assess the subject for any LA-related symptoms at office visits or during parent or 
legal guardian phone calls that occur after each injection of study drug, whether expected or 
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unexpected; any worsening of pre-existing conditions (such as rapid progression of CPP symptoms) will 
be reviewed to determine whether they should be reported as adverse events.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the database lock.  The statistical 
analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
At the end of Part 1, an analysis of the primary, secondary, and other efficacy variables that were 
collected during Part 1 of the study, along with demographic and safety variables, will be performed 
after the last subject completes the Week 48 assessment.  These analyses will only include data 
collected during Part 1 and will not include data collected during Part 2 or during the Follow-Up Period.  
The database will be versioned for an interim soft lock and any discrepant data will be clarified before 
the versioning.  AbbVie will perform the analyses.
At the end of Part 2, an analysis of the appropriate efficacy and safety variables will be performed after 
the last subject completes the study.
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) consists of all subjects who received at least 1 dose of study drug.  The FAS 
will be used for all efficacy and baseline analyses.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.
7.3 Statistical Analyses for Efficacy
Primary Analysis
The primary efficacy endpoint is the proportion of subjects with suppression of GnRHa-stimulated LH 
(< 4 mIU/mL) at Week 24 after the first dose of study drug but before the Week 24 dose.  95% 
confidence interval based on the binomial distribution (Clopper-Pearson exact method) will be provided 
for the primary efficacy endpoint.
Additional details on the primary and other efficacy analyses are provided in the SAP.
Sample Size Estimation
No formal sample size calculation was performed.  Based on previous studies and historical precedent 
that was used for registration (N = ~40), 40 subjects are sufficient to support the safety and efficacy for 
this class of compounds in this patient population.  The planned sample size of 40 subjects will provide 
an observed response rate (of suppression of peak stimulated LH) that is within 16.7% of the true 
response rate with 95% confidence.
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7.4 Statistical Analyses for Safety
Analysis of safety will be detailed in the SAP.
8 ETHICS
8.1 Institutional Review Board
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the informed consent 
form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study.  In addition, all 
changes to the consent form(s) will be IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, 
applicable regulations and guidelines governing clinical study conduct, and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the investigator are specified in 
Appendix B.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
10 DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits to ensure human subject protection and reliability of study results.  Data will be 
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generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11 COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit or the actual date of follow-up 
contact, whichever is later.
12 REFERENCES
1.
Badaru A, Wilson DM, Bachrach LK, et al. Sequential comparisons of one-month and three-month 
depot leuprolide regimens in central precocious puberty. J Clin Endocrinol Metab. 
2006;91(5):1862-7.
2.
Lee PA, Klein K, Mauras N, et al. Efficacy and safety of leuprolide acetate 3-month depot 11.25 
milligrams or 30 milligrams for the treatment of central precocious puberty. J Clin Endocrinol Metab. 
2012;97(5):1572-80.
3.
Lee PA, Klein K, Mauras N, et al. 36-month treatment experience of two doses of leuprolide acetate 
3-month depot for children with central precocious puberty. J Clin Endocrinol Metab. 
2014;99(9):3153-9.
4.
Brown RT. Adolescent growth and development. In: Holland-Hall C, Brown RT, editors. Adolescent 
Medicine Secrets. Philidephia, PA: Hanley & Belfus; 2002. p. 21-8.
5.
Travers S, Slover R. Disorders of Puberty. In: MTM, editor. Endocrine Secrets. 4th ed. Philadelphia, 
PA: 2005. p. 354-67.
6.
Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing 
hormone analogs in children. Pediatrics. 2009;123(4):e752-62.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ACTH
adrenocorticotropic hormone
AOC
acute-on-chronic
ATEMS
AbbVie Temperature Excursion Management System
Beta-hCG
beta human chorionic gonadotropin
BMI
body mass index
CAH
congenital adrenal hyperplasia
CDSM
clinical drug supply management
COVID-19
Corona virus disease 2019
CPP
central precocious puberty
CRO
contract research organization
CT
computed axial tomography
DFP
direct-from-patient
DHEA
dehydroepiandrosterone
DTP
direct-to-patient
eCRF
electronic case report form
FAS
full analysis set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GnRH
gonadotropin-releasing hormone
GnRHa
gonadotropin-releasing hormone agonist
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
IGF-1
insulin-like growth factor-1 
IM
intramuscular
IRB
Institutional Review Board
IRT
Interactive response technology
LA
leuprolide acetate
LH
luteinizing hormone
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
PedsQL
Pediatric Quality of Life Inventory
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PRO
patient-reported outcome
PROMIS
Patient Reported Outcomes Measurement Information System
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA MD
AbbVie therapeutic area medical director
US
United States
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-904:  A Phase 3, Multicenter, Open-Label, Two-Part Study to Evaluate the Safety, Efficacy, 
Pharmacokinetics, and Pharmacodynamics of Leuprolide Acetate 45 mg 6-Month Depot Formulation in 
Children with Central Precocious Puberty (CPP)
Protocol Date:  05 August 2020
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and 
local regulations and guidelines governing the study at the site location.  In signing the Investigator 
Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
1.
Personally conducting or supervising the described investigation(s).
2.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
3.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
4.
Reading the information in the approved full US Prescribing Information/safety material 
provided, including the instructions for use and the potential risks and side effects of the 
investigational product(s).
5.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
6.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
7.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
8.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
9.
Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Executive Medical Director
General Medicine Clinical Development
Senior Director
Statistics Therapeutic Area Head
Medical Director
General Medicine Clinical Development
Principal Medical Writer
Medical Writing
Program Lead I
Clinical Program Development
Director
Clinical Pharmacokinetics and Pharmacodynamics
Director
Data and Statistical Sciences
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Version
Protocol
Date
Version 1.0
08 December 2017
Version 2.0
27 June 2018
The purpose of this amendment is primarily to provide alternative study procedures related to subject 
safety in response to the COVID-19 pandemic.  Other administrative revisions and clarifications, as well 
as template update and typographical corrections were made throughout the protocol.
Alternative study procedures related to subject safety in response to the COVID-19 pandemic were 
added to the following sections:
Protocol
Section 4.1
Section 5.6
Operations Manual
Section 2
Section 3.8
Section 3.13
Section 3.14
Section 3.15
Section 3.19
Section 3.20
Section 4.2
Section 6.1
Section 6.4
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APPENDIX F. OPERATIONS MANUAL
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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1 CONTACTS
Sponsor/Emergency 
Medical Contact 
Therapeutic Area 
Medical Director
 MD
AbbVie Inc.
1 North Waukegan Road 
North Chicago, IL 60064
Office:
Mobile:
Fax:
EMERGENCY 24-hour Number:  
+1 973-784-6402
Email:
Safety Concerns
Metabolic Safety Team 
AbbVie Inc.
Dept. R48S, Bldg. AP51-3
1 North Waukegan Road
North Chicago, IL 60064
Phone:
+1 847-935-7577
Email:
GPRD_SafetyManagement_Hormones @abbvie.com
SAE Reporting outside 
of RAVE
Pharmacovigilance
Fax:
+1 847-938-0660
Email:
PPDINDPharmacovigilance @abbvie.com
Protocol Deviations
AbbVie Inc.
Study Management Associate 
III
1 North Waukegan Road 
North Chicago, IL 60064
OR
AbbVie Inc.
Study Project Manager II
1 North Waukegan Road
North Chicago, IL 60064
Office:
Mobile: 
Email:
Office:
Mobile:
Fax:
Email:
Certified Clinical 
Laboratory
Covance CLS
8211 SciCor Drive
Indianapolis, IN 46214
Phone:
+1 866-762-6209
Bioanalytical 
Laboratory
Bioanalysis
AbbVie Inc.
Dept. R46W, Building AP13A
Room 2326
1 North Waukegan Road
North Chicago, IL 60064
inVentiv/Syneos Health, Inc.
2500 rue Einstein
Quebec (Quebec), Canada
G1P 0A2
Phone:
+1 847-936-1382
Fax:
+1 847-938-9898
Phone:
+1 418-527-4000
Fax:
+1 418-527-3456
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Bone Age Imaging
PAREXEL International, LLC
195 West Street
Waltham, MA 02451
Phone:
+1 978-313-3900
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
6
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES (SCREENING AND PART 1)
7
2.2
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES (PART 2)
12
2.3
INDIVIDUAL POSTTREATMENT PERIOD VISIT ACTIVITIES
18
3
STUDY PROCEDURES
18
3.1
SUBJECT INFORMATION AND INFORMED CONSENT AND ASSENT
18
3.2
ELIGIBILITY CRITERIA
19
3.3
MEDICAL AND CPP HISTORY
19
3.4
FAMILY HISTORY
20
3.5
MENSTRUAL HISTORY
20
3.6
ADVERSE EVENT ASSESSMENT
20
3.7
PRIOR AND CONCOMITANT MEDICATIONS
20
3.8
PATIENT-REPORTED OUTCOMES
20
3.9
COMPLETE AND BRIEF PHYSICAL EXAMINATIONS
21
3.10 PUBERTAL STAGING MODIFIED TANNER
21
3.11 HEIGHT AND WEIGHT
22
3.12 VITAL SIGNS
22
3.13 CLINICAL LABORATORY TESTS
22
3.14 PHARMACOKINETIC BLOOD COLLECTION FOR LEUPROLIDE CONCENTRATION
24
3.15 GNRHA STIMULATION TEST AND BLOOD COLLECTION FOR GONADOTROPIN AND SEX STEROID CONCENTRATIONS
25
3.16 ADRENAL STEROIDS
27
3.17 ACTH STIMULATION TEST
27
3.18 BETA-HCG (MALE SUBJECTS)
28
3.19 ADMINISTRATION OF STUDY DRUG
28
3.20 LA 45 MG INJECTION SITE REACTION ASSESSMENT
29
3.21 HORMONAL FLARE AND ACUTE-ON-CHRONIC RESPONSE ASSESSMENT
29
3.22 MENSTRUAL BLEEDING CALENDAR (FEMALE SUBJECTS)
30
3.23 BONE AGE RADIOGRAPH
30
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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3.24 BRAIN MAGNETIC RESONANCE IMAGING OR COMPUTED AXIAL TOMOGRAPHY SCAN
31
3.25 ADRENAL (ALL SUBJECTS) AND TESTICULAR (MALE SUBJECTS) ULTRASOUND
31
3.26 TRANSDERMAL PELVIC ULTRASOUND (UTERINE AND OVARIAN VOLUME) (FEMALE SUBJECTS)
32
3.27 SUBJECT WITHDRAWAL FROM STUDY
32
4
SAFETY MANUAL
32
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
32
4.2
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
33
5
COUNTRY-SPECIFIC REQUIREMENTS
34
5.1
SUSAR REPORTING
34
5.2
TREATMENT AFTER END OF STUDY
34
6
STUDY DRUG
34
6.1
TREATMENTS ADMINISTERED
34
6.2
PACKAGING AND LABELING
35
6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
36
6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
36
7
APPENDICES
37
7.1
PUBERTAL STAGES WORKSHEET MALE
37
7.2
PUBERTAL STAGES WORKSHEET FEMALE
38
7.3
DOSE PREPARATION FOR LEUPROLIDE ACETATE 45 MG FORMULATION
39
7.4
LEUPROLIDE ACETATE 45 MG INJECTION SITE ASSESSMENT FORM
43
7.5
HORMONAL FLARE AND ACUTE-ON-CHRONIC RESPONSE FORM
44
7.6
MENSTRUAL BLEEDING CALENDAR
45
LIST OF TABLES
TABLE 1.
PHARMACOKINETIC BLOOD COLLECTION FOR LEUPROLIDE
25
TABLE 2.
GNRHA STIMULATION TEST AND BLOOD COLLECTION FOR GONADOTROPINS AND SEX STEROIDS 26
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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2 PROTOCOL ACTIVITIES BY VISIT
A list of activities performed during each visit, organized by visit, is presented in this section.  
Unscheduled visits may occur at any time as deemed appropriate by the investigator.
Activities are grouped by category (Interview, Exam, etc.).  Further information about each activity is 
provided in Section 3.
If a subject cannot come to the site because of an unforeseen circumstance (e.g., the COVID-19 
pandemic), study visits may be conducted virtually by site staff (e.g., by phone or video) or by a qualified 
home healthcare nurse in a non-hospital/clinic environment (e.g., the subject's home) at the request of 
the investigator and with the agreement of the subject's parent or legal guardian.  AbbVie should be 
notified if this occurs, and the respective COVID-19 electronic case report forms (eCRFs) should be 
completed if applicable.  Any visits conducted virtually or partially should be recorded as such on the 
respective COVID-19 eCRFs if applicable.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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Rules and regulations for the consent or assent process of minors differ among countries with 
participating principal investigators.  The investigator is responsible for ensuring compliance with all 
applicable rules.  In general, a subject who is a minor should be informed within the limits of his/her 
understanding and with age-appropriate words.  When deemed necessary by the IRB, the documented 
assent for subjects who are minors must be obtained.
Where assent is required, the investigator or his/her representative will explain the nature of the study 
to the subject and the subject's parent/legal guardian and answer all questions regarding this study.  
Subjects will be included in all discussions in order to obtain verbal or written assent.  Prior to any study-
specific screening procedures being performed on the subject, the informed consent statement will be 
reviewed and signed and dated by the subject's parent/legal guardian, the person who administered the 
informed consent, and any other signatories according to local requirements.  Additionally, in keeping 
with each institution's IRB requirements, an informed assent form may also be obtained by each subject 
prior to any study-related procedures being performed.  A copy of the informed consent form and the 
assent form will be given to the subject and the subject's parent/legal guardian, and the original will be 
placed in the subject's medical record.  If a subject becomes of legal age during the course of the study, 
the consent procedure needs to be repeated.
3.2 Eligibility Criteria
Eligibility criteria will be assessed at Screening and on Day 1 (Baseline).
The results of certain retrospective procedures that were performed prior to informed consent that are 
considered standard of care and/or part of establishing a diagnosis of CPP, and that are used to establish 
eligibility for this study, may be used if the procedure was performed within the specified retrospective 
windows, as allowed by the protocol (see Section 3.15, Section 3.16, Section 3.18, and Sections 3.23
through 3.26).  Any results from prior procedures or blood tests that were used to establish eligibility 
must be available in the subject's source file; if not available in the subject's source file, the required 
test/procedure will be repeated and results reviewed prior to the subject receiving the first injection of 
study drug.
3.3 Medical and CPP History
Medical History
A complete medical history will be taken at Screening.  The subject's medical history will be updated at 
the Day 1 visit.  This updated medical history will serve as the Baseline for clinical assessment.  Medical 
history will include the subject's race, ethnicity, sex, and full date of birth; and a review of all major 
organ systems, including any history of cancer, diabetes mellitus, gastrointestinal, cardiac, neurologic 
(including any trauma to the central nervous system), pulmonary, immunodeficiency, hepatic, renal, 
endocrine, or other systems.  The disease and condition will be captured, as well as date of onset and 
whether the disease/condition is ongoing.
CPP History
Medical history will also focus on the subject's history of CPP and will record the date of any sign of 
puberty first noticed, and the date first visit seen by a physician for CPP.  The diagnostic test(s) 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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performed, the results, and progression of symptoms of CPP will be recorded.  Whether the subject is 
naïve to gonadotropin-releasing hormone agonist (GnRHa) treatment or previously treated with a 
GnRHa, and any prior GnRHa medications used in the treatment of CPP will also be recorded.  A 
historical height (at least 6 months prior to Screening) is needed, and if available, historical information 
on subject's annual growth (height and date of height measurement) will be collected.
3.4 Family History
Family history:  parental actual height and age of puberty onset will be collected for both the birth 
mother and biological father, when available.  It is recommended that the actual heights of both parents 
be measured in triplicate, if possible, at the site by the study staff using stadiometry equipment.  
Otherwise measurements of actual height as reported will be captured.
3.5 Menstrual History
A history of menstrual periods (female subjects), including date of first occurrence (menarche) will be 
collected.  Refer to Section 3.22 for the menstrual bleeding calendar.
3.6 Adverse Event Assessment
Please refer to Section 4.1.
3.7 Prior and Concomitant Medications
Prior and concomitant medications will be assessed at the time points specified in Section 2.
3.8 Patient-Reported Outcomes
The subject's parent or legal guardian will complete the patient-reported outcome (PRO) instruments.  
The subject's parent or legal guardian should be instructed to follow the instructions provided with the 
instruments and to provide the best possible response to each item.  The instrument that corresponds 
to the age at which the subject entered the study will be used throughout the study.
Site personnel shall not provide interpretation or assistance to subject or subject's parent or legal 
guardian other than encouragement to complete the tasks.  Site personnel may read the questionnaires 
to the subject's parent or legal guardian who is functionally unable to read the instruments.  Site 
personnel will encourage completion of the instruments at all specified visits (see Section 2) and will 
ensure that a response is entered for all items.
If a subject cannot come to the site because of unforeseen circumstances (e.g., the COVID-19 
pandemic), patient-reported outcome entries may be administered by site staff over the phone and 
responses collected on paper (source) and transcribed into electronic data capture (EDC) or entered by 
site staff directly into an electronic collection system.  AbbVie should be notified if this occurs.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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Two different PRO instruments will be used: Pediatric Quality of Life Inventory™ (PedsQL™) (all subjects) 
and Patient Reported Outcomes Measurement Information System (PROMIS) Peer Relationships 
(subjects 5 years of age and older):

Ages 2 – 4 years:

PedsQL Parent Report for Toddlers (2 – 4 years).

Ages 5 – 7 years:

PedsQL Parent Report for Young Child (5 – 7 years).

PROMIS Peer Relationships Guardian Proxy Format.

Ages 8 – 12 years:

PedsQL Parent Report for Child (8 – 12 years).

PROMIS Peer Relationships Guardian Proxy format.
The information will be collected at Baseline and at Weeks 12, 24, 48, 72, 96, 120, and 144.  This 
information will also be collected at the Discontinuation Visit if the subject discontinues the study 
prematurely. 
3.9 Complete and Brief Physical Examinations
A complete or brief physical examination will be performed at the study visits specified in Section 2.  Any 
significant physical examination findings after the first injection of study drug will be recorded as 
adverse events.  All findings, whether related to an adverse event or part of each subject's medical 
history, will be captured on the appropriate eCRF page.
At any time, the investigator can perform a symptom-directed physical examination, as deemed 
necessary.
3.10 Pubertal Staging Modified Tanner
Pubertal staging will be assessed in all subjects using modified Tanner staging as described below.  All 
data will be captured in the source documentation and entered into the appropriate eCRF.
Breast:  (Female subjects) Breast development will be assessed for Stages 1 through 5.
Pubic Hair:  (All subjects) Pubic hair will be assessed for Stages 1 through 5.
Genitalia:  (Male subjects) Development of external genitalia will be assessed for Stages 1 through 5.  
Measurements to assess changes in testes and penile size will be captured and will include testicular 
length (centimeters) and volume (milliliters) measured via orchidometer (Prader beads) and penile 
length and width (centimeters).
The same individual, if possible, will rate pubertal staging for all subjects and for male subjects measure 
penile length and width and testicular length and volume at each designated study visit.  Pubertal stage 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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will be rated according to Section 7.1 and Section 7.2, "Pubertal Stages Worksheet Male" and "Pubertal
Stages Worksheet Female."
Progression of CPP-related symptoms are not to be documented in the adverse event eCRF but should 
be documented in Pubertal Staging eCRFs (for male or female subjects as applicable).  Refer to 
Section 6.2 of the Protocol "Disease-Related Events" and Section 3.21 "Hormonal Flare and Acute-on-
Chronic Response Assessment."
3.11 Height and Weight
Height and weight will be measured at the time points specified in Section 2.
AbbVie will calculate growth rate (centimeter/year), both prior to treatment in the study and during the 
study.  Two measurements of height at least 6 months apart are needed for the baseline calculation.  
Thus, a historical height that was obtained at least 6 months prior to Screening will be recorded along 
with the date of measurement.  Height should be measured in triplicate using standard stadiometer 
equipment, such as Harpenden stadiometer or recumbent length table.  Height should be measured 
using the same measurement tools, and if possible, the same study staff member should be conducting 
the measurements at each study visit.  Height will be recorded in the source documentation and 
captured in the eCRFs.
3.12 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, body temperature (rectal, 
oral, aural, or axillary), and respiratory rate will be obtained at the visits specified in Section 2.
3.13 Clinical Laboratory Tests
A certified laboratory will be used to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.
Instructions for the collection, processing, and shipping of these samples will be provided by the central 
laboratory listed in Section 1.
If a subject cannot visit the site because of unforeseen circumstances (e.g., the COVID-19 pandemic), 
samples may be collected by a home healthcare service and sent to the central laboratory. If the central 
laboratory cannot be used to test samples because of unforeseen circumstances (e.g., the COVID-19 
pandemic), samples may be collected and tested at a local laboratory. AbbVie should be notified if any 
of those situations occur.
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
test result to be clinically significant, the investigator will:

repeat the test to verify the out-of-range value;

follow the out-of-range value to a satisfactory clinical resolution; or
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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
discontinue the subject from the study or require the subject to receive treatment; in this case, 
the laboratory result will be recorded as an adverse event.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Chorionic Gonadotropin, Human, β-hCG 
CBC:  RBC count and WBC count 
Hematocrit
Hemoglobin
Mean corpuscular hemoglobin
MCHC
Mean corpuscular volume
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelet count
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Sodium
Potassium
Bicarbonate
Chloride
Calcium
Creatinine
Glucose
Lactate dehydrogenase
Magnesium
Phosphorus
Total bilirubin
Direct bilirubin
Indirect bilirubin
Total protein
Uric acid
Quantitative β-hCG (male subjects)
Adrenal Steroids
CAH pediatric panel:
    androstenedione, cortisol,
    DHEA, 17 OH-progesterone,
    total testosterone 
If initial screening results of CAH panel
    are inconclusive as per investigator's
    judgment, CAH panel may be repeated
    prior to and following an ACTH
    stimulation test. 
Urine
Gonadotropins and Sex Steroids
Macroscopic chemical analysis:
    color & clarity, specific
    gravity, pH, protein, glucose,
    ketones, bilirubin,
    urobilinogen, blood, nitrite,
    leukocyte esterase
Urinalysis, microscopic (if
    macroscopic analysis is
    abnormal)
Basal and GnRHa-stimulated
LH
FSH
E2 (females)
T (males)
ACTH = adrenocorticotropic hormone; β-hCG = beta human chorionic gonadotropin; CBC = complete blood count; 
CAH = congenital adrenal hyperplasia; DHEA = dehydroepiandrosterone; E2 = estradiol; FSH = follicle-stimulating hormone; LH = 
luteinizing hormone; MCHC = mean corpuscular hemoglobin concentration; RBC = red blood cell; T = testosterone; WBC = white 
blood cell
Pregnancy Tests
For female subjects ≥ 10 years of age, a serum pregnancy test will be performed at the central 
laboratory at Screening and a urine pregnancy test will be performed at the site on Day 1.  For female 
subjects < 10 years of age, pregnancy tests may be performed at the investigator's discretion.  The 
pregnancy test must be negative before the first dose of study drug can be administered.  Additional 
urine pregnancy tests may be performed at the discretion of the principal investigator.
Urinalysis
Urinalysis will be completed at all required visits.  Specified abnormal macroscopic urinalyses defined as 
leukocytes, nitrite, protein, ketones, or blood greater than negative, or glucose greater than normal will 
be followed up with a microscopic analysis at the central laboratory.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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3.14 Pharmacokinetic Blood Collection for Leuprolide Concentration
Blood samples will be collected in a subset of 20 subjects for leuprolide analysis to coincide with the 
GnRHa stimulation test time points when possible.  Investigative sites will be notified when the 
pharmacokinetic subset has been fulfilled.  Blood samples will be collected at the time points indicated 
in Section 2.
On Day 1, blood samples will be collected immediately prior to (0 minutes) and 30 (± 5) minutes and 
60 (± 5) minutes after the leuprolide acetate (LA) 45 mg intramuscular injection.  At Weeks 1, 4, 12, 20, 
24 (time of second injection of study drug), 44, and 48 (time of third injection of study drug for subjects 
who continue to Part 2), subjects who are in the pharmacokinetic subset will return to the clinic for 
blood collection for leuprolide concentration.  At visits where there is a GnRHa stimulation test, blood 
should be collected prior to the GnRHa stimulation test.  At Week 24 and Week 48 (for subjects who 
continue to Part 2), the stimulation test is performed prior to the LA 45 mg injection.  Blood draw for
pharmacokinetics should only be performed at the premature discontinuation visit if the subject 
discontinues at any time during Part 1.  For Part 1 of the study, 10 blood samples will be collected across 
study visits for the quantitation of serum leuprolide concentrations (see Table 1).
For each pharmacokinetic sample, a whole blood sample will be collected for serum leuprolide 
determination.  Blood samples will be collected as close as possible to the specified times indicated in 
Table 1.  The pharmacokinetic samples should be collected at the same time as the samples are 
collected for serum testosterone, estradiol, luteinizing hormone (LH), and follicle-stimulating hormone 
(FSH), when applicable.  In each sample, leuprolide concentration will be determined with a validated 
method under the supervision of AbbVie.  Refer to the Laboratory Manual for sample collection and 
shipment instructions.
If a subject who is participating in the pharmacokinetic subset cannot come to the site because of
unforeseen circumstances (e.g., the COVID-19 pandemic), the pharmacokinetic samples collection may 
be performed by a home healthcare nurse at the subject's home. AbbVie should be notified if this 
occurs.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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Table 1.
Pharmacokinetic Blood Collection for Leuprolide
Day 1 
1st LA 45 mg 
Injection
Week 1
Weeks 4 – 20 
(Each Visit)
Week 24 
2nd LA 45 mg 
Injection
Weeks 44, 48, and 
Premature 
Discontinuationa,b
Time Relative to:
Study drug
Injection (no 
stimulation test)
No reference point 
(no stimulation 
test)
Stimulation Test 
Stimulation Test
Stimulation Test
0 minutes 
(immediately 
before) 
Leuprolide
Leuprolide
Leuprolide
Leuprolide
Leuprolide
30 (± 5) minutes 
after
Leuprolide
--
--
--
--
60 (± 5) minutes 
after
Leuprolide
--
--
--
--
LA = leuprolide acetate
a.
Subjects who continue to Part 2 will receive their third LA 45 mg injection at Week 48.
b.
A pharmacokinetic sample will also be collected for subjects who discontinue prematurely before Week 48.
Notes:
The LA 45 mg injection must be administered after the last blood collection for the stimulation test. 
3.15 GnRHa Stimulation Test and Blood Collection for Gonadotropin 
and Sex Steroid Concentrations
Blood samples for hormones and GnRHa stimulation tests will be conducted at the time points indicated 
in Section 2.  GnRHa stimulation tests will be performed using an LA aqueous formulation at 20 µg/kg 
subcutaneous injection at the weeks indicated in Table 2.  Injection site reactions to stimulation test 
should be documented in appropriate eCRF.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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Table 2.
GnRHa Stimulation Test and Blood Collection for Gonadotropins and Sex 
Steroids
Timing
Screening
Day 1 
1st LA 45 mg 
Injection
Week 1
Weeks 4 –
20 
(Each Visit)
Week 24 
2nd LA 
45 mg 
Injection
Weeks 24, 
48, 72, 96, 
120a,b
Weeks 44, 48, 
72, 96, 120, 144, 
and Premature 
Discontinuation
Time 
Relative to:
Stimulation 
Test
Study drug
injection 
(no 
stimulation 
test)
No 
reference 
point (no 
stimulation 
test)
Stimulation 
Test
Stimulation 
Test
Study 
drug
injection
Stimulation Test
0 minutes 
(immediately 
before)
LH, FSH,
E2, T
LH, FSH,
E2, T
LH, FSH, 
E2, T
LH, FSH,
E2, T
LH, FSH,
E2, T
--
LH, FSH,
E2, T
30 (± 5)
minutes 
after
LH, FSH
LH, FSH
--
LH, FSH
LH, FSH
--
LH, FSH
60 (± 5)
minutes 
after
LH, FSH,
E2, T
LH, FSH,
E2, T
--
LH, FSH,
E2, T
LH, FSH,
E2, T
--
LH, FSH,
E2, T
48 hours 
after
--
--
--
--
--
LH, FSH, 
E2, T
--
AOC = acute-on-chronic; E2 = estradiol; FSH = follicle-stimulating hormone; GnRHa = gonadotropin-releasing hormone agonist; 
LA = leuprolide acetate; LH = luteinizing hormone; T = testosterone
a.
LH, FSH, E2, T must be obtained for AOC biochemical assessment.
b.
Blood collection 48 hours after the injection of study drug at Weeks 48, 72, 96, and 120 applies only to those subjects who 
are randomly selected for AOC biochemical assessment.
Note:
For visits with a stimulation test and a study drug injection, the study drug injection must be administered after the 
last blood collection for the stimulation test.
The GnRHa stimulation tests will be performed and blood samples will be collected for gonadotropins 
(LH, FSH) and sex steroids (estradiol in female subjects and testosterone in male subjects) as shown in 
Table 2.  For samples that will be collected in reference to either the stimulation test or the LA 45 mg 
6-month injection; the 0 minute samples are to be drawn immediately prior to their reference points.  It 
is recommended that the stimulation test be performed preferably in the morning and as close to the 
same time at each visit as possible.
Subjects naïve to GnRHa treatment will not need to repeat a screening stimulation test if a stimulation 
test was performed within 1 month prior to the screening visit and a diagnosis of CPP was established.  
The agent (GnRHa) and dose used for the stimulation test, the test result, and the date performed will 
be captured in the source documentation and in the appropriate eCRF.  Note:  even when the Screening 
stimulation test is not required, a screening LH, FSH, testosterone (male) or estradiol (female) sample is 
still required.
Subjects previously treated with a GnRHa will have a stimulation test during Screening to demonstrate 
adequate LH suppression (LH < 4 mIU/mL) prior to receiving their first dose of study drug (LA 45 mg 
6-month).
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Dates and times of sample collection for these tests will be recorded in the source documentation and in 
the eCRFs.
During Screening, blood samples for LH, FSH, testosterone (in male subjects) or estradiol (in female 
subjects) will be collected and measured using a clinical laboratory test at the central laboratory 
identified in Section 3.13 to assess eligibility.
From Day 1 and onward, blood samples for LH and FSH (4 mL, which includes the blood volume for 
leuprolide) will be collected and shipped according to the instructions in the laboratory manual for the 
determination of LH and FSH following a validated method under the supervision of the sponsor, 
AbbVie.
From Day 1 and onward, 3-mL blood samples for testosterone (in male subjects) or estradiol (in female 
subjects) will be collected and shipped according to the instructions in the laboratory manual for the 
determination of testosterone and estradiol following a validated method under the supervision of the 
sponsor, AbbVie.
At Week 24 (and Weeks 48, 72, 96, and 120 for subjects who continue to Part 2), the LA 45 mg study 
drug injection must be administered after the last blood collection (60 minutes) for the stimulation test.  
If the Week 24 (and Weeks 48, 72, 96, and 120 for subjects who continue to Part 2) stimulation test 
results indicate inadequate peak LH suppression (≥4 mIU/mL), the subject may be asked to return to the 
clinic to be evaluated for signs/symptoms of puberty progression.  If this occurs, the visit will be 
documented as an unscheduled visit.  Unscheduled blood samples for basal or stimulated LH, FSH, 
testosterone (in male subjects), or estradiol (in female subjects) may be collected according to the 
investigator's clinical judgment at any time throughout the study and sent to the central laboratory for 
analysis and resulting.
If a subject cannot come to the site because of unforeseen circumstances (e.g., the COVID-19 
pandemic), the GnRHa stimulation test and required gonadotropins and sex steroids blood samples 
collection may be performed by a home healthcare nurse at the subject's home. AbbVie should be 
notified if this occurs.  Refer to the Laboratory Manual for sample collection instructions.
3.16 Adrenal Steroids
Adrenal steroid testing for all subjects to rule out congenital adrenal hyperplasia (CAH) will be 
performed at Screening, if not previously performed.  If previously performed, the date and test result 
must be available in the source documentation.  If the results are not available in the source 
documentation, the test must be repeated to establish eligibility.  This testing (pediatric CAH panel) will 
include androstenedione, cortisol, dehydroepiandrosterone (DHEA), 17 OH-progesterone, and 
testosterone.
3.17 ACTH Stimulation Test
The ACTH stimulation test is not required if CAH and adrenal disorders have been ruled out as per 
investigator's evaluation and results of previous or basal adrenal steroid testing.  If the screening CAH 
panel results are inconclusive as per investigator's judgment, subjects should have the 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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adrenocorticotropic hormone (ACTH) stimulation test performed during the Screening period and prior 
to study drug administration.  The ACTH stimulation test procedure will be conducted per standard of 
care.  Two blood samples, 0 minutes and 60 minutes after the intravenous injection of commercially 
available corticotropin, will be collected and sent to central laboratory for analysis of androstenedione, 
cortisol, DHEA, 17-OH-progesterone, and testosterone levels.
3.18 Beta-hCG (Male Subjects)
Beta human chorionic gonadotropin (β-hCG) levels to rule out a chorionic gonadotropin-secreting tumor 
will be performed for male subjects at Screening, unless performed prior to Screening.  If previously 
performed, the date and test result must be available in the source documentation, or the assessment 
must be repeated to establish eligibility.
3.19 Administration of Study Drug
Study drug will be administered to subjects beginning at Baseline (Day 1) and at the time points 
specified in Section 2 as follows:
Part 1:  LA 45 mg 6-month, given as a single intramuscular injection.  The first injection will be 
administered on Day 1, and the second injection will be administered at Week 24.
For subjects who were previously treated with GnRHa therapy, the first injection of study drug should be 
administered at the end of the previous GnRHa treatment cycle.
Part 2:  LA 45 mg 6-month, given as a single intramuscular injection at 24-week intervals (up to 
24 months) starting at Week 48 until Week 120.
Study site staff will administer all injections of LA 45 mg 6-month.  Each injection of study drug should be 
administered in the gluteal area, anterior thigh, or deltoid.  Injection sites should be alternated to 
minimize injection site reactions.
If a subject cannot come to the site because of unforeseen circumstances (e.g., the COVID-19 
pandemic), the injection of study drug may be administered by a home healthcare nurse at the subject's 
home.  AbbVie should be notified if this occurs.
Refer to Section 7.3 for dose preparation instructions.
Depending on local regulations, provisioning of study drug and generic LA for stimulation test for 
direct-to-patient (DTP) and direct-from-patient (DFP) transfer because of unforeseen circumstances 
(e.g., the COVID-19 pandemic) will be available upon request.  AbbVie should be notified if this occurs.  
Sites can use Marken, a third-party vendor with which AbbVie has an agreement, for drug shipment in 
these circumstances or sites may use a local courier.
Sites will be responsible for meeting IRB reporting requirements and submitting the booking form 
(which will be provided) to the local IRB (as applicable).
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The investigator must discuss the DTP process with the subject's parent or legal guardian:

Obtain consent to provide delivery information to Marken and/or local courier and record this in 
source documentation.

Obtain and review results of required safety procedures as applicable before registering subject 
dispensation of study drug in interactive response technology (IRT).

Confirm that the subject’s parent or legal guardian will be available to accept delivery.

The site will follow-up with the subject's parent or legal guardian after shipment is received.
Sites will be required to retain documentation of the shipment for investigational product accountability 
and monitoring.
3.20 LA 45 mg Injection Site Reaction Assessment
Study site staff (or home healthcare nurse if applicable) will assess the injection site on the day of the LA 
45 mg injection prior to the subject leaving the investigative site.  The time of the assessment (post 
injection) as well as a description of the injection site will be recorded in the source documentation and 
entered into the appropriate eCRF.  At the Day 1 visit, the site will discuss with the parent or legal 
guardian how to assess the injection site and when a call to the investigative site is needed for clinical 
assessment.  Additionally, the site will phone the parent or legal guardian or there will be an on-site visit 
(or a home healthcare visit if applicable) at the time points specified in Section 2 to obtain a description 
of the injection site.  Refer to Section 7.4 for a sample of the Leuprolide Acetate 45 mg Injection Site 
Assessment Form.  If required, the subject may be asked to come in to the clinic for an assessment, 
based on investigator discretion.  A description of the injection site will be recorded in the source 
documentation and in the appropriate eCRF.  All injection site reactions will be captured as adverse 
events.  Any injection site reaction that reaches serious criteria as stated in Section 6.1 of the protocol 
will be captured as a serious adverse event (SAE) and reported as described in the protocol.
If a subject cannot come to the site because of unforeseen circumstances (e.g., the COVID-19 
pandemic), and the injection of study drug was administered by a home healthcare nurse at the 
subject's home, the injection site reaction assessment may be conducted by the home healthcare nurse.  
AbbVie should be notified if this occurs.
3.21 Hormonal Flare and Acute-on-Chronic Response Assessment
Blood samples for AOC biochemical assessment of basal hormones (FSH, LH, and estradiol in females or 
testosterone in males) will be collected as follows:
Part 1:  Week 1 and 48 hours after the second injection of LA 45 mg 6-month at Week 24 in all subjects 
enrolled.
Part 2:  48 hours after the injection of LA 45 mg 6-month at Weeks 48, 72, 96, and 120 in those subjects 
who are randomly selected for AOC biochemical assessment.  Subjects will be randomly assigned to the 
AOC subgroup at Week 48 when the visit is registered in IRT.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Following each injection of LA 45 mg 6-month, the sites (or home healthcare nurse if applicable) will 
assess clinical signs and symptoms of hormonal flare and AOC response to an increase in sex steroids 
(e.g., breast tenderness and vaginal discharge in female subjects; frequent or prolonged erections, age-
inappropriate behavior that may be sexual in nature in male subjects; or in both female and male 
subjects, exacerbation or acceleration of pubertal symptoms, substantial mood swings, or new 
symptoms).  Sites (or home healthcare nurse if applicable) will assess for any events on the day of each 
study drug injection before the subject leaves the site.  Sites will call the parent or legal guardian after 
each study drug injection at the time points specified in Section 2.
The site will record reported events in the source documentation and on the appropriate eCRF.
If unusual or unexpected clinical effects are reported during the phone call, or are spontaneously 
reported by the parent or legal guardian, subjects may be asked to return to the clinic at the 
investigator's discretion, and have a blood sample collected for AOC biochemical assessment of basal 
hormone levels (LH, FSH, and estradiol in females or testosterone in males).  If this occurs, the visit will 
be documented as an Unscheduled Visit.  Refer to Section 7.5 for a sample of the Hormonal Flare and 
Acute-on-Chronic Hormonal Response form.
When assessing these events, refer to Section 6.1 of the protocol.
3.22 Menstrual Bleeding Calendar (Female Subjects)
Information on menses will be collected as part of medical history for female subjects.  Female subjects 
and/or their parent or legal guardian will be asked to record any menses that occurs from the time of 
signing the consent and assent form, through the end of study participation on a menstrual bleeding 
calendar.  The site will train the subject (if deemed appropriate) and/or the parent or legal guardian on 
how to complete the menstrual bleeding calendar.  The calendar will be distributed at the Screening visit 
and will be reviewed by the site at each subsequent study visit.  Refer to Section 7.6.
The subject and/or parent or legal guardian will record only days with menstrual spotting or bleeding.  
All menstrual bleeding calendar entries must be captured in the appropriate eCRF.
3.23 Bone Age Radiograph
Bone age hand and wrist radiographs will be performed to assess bone maturation at Screening, unless 
performed within 3 months prior to Screening, and at the time points specified in Section 2.  These 
radiographs will be performed at a facility specified by the study investigator and will be sent to an 
imaging vendor for Fels bone age measurement using the BoneXpert automated system.  If a previous 
bone age radiograph is available from within 3 months prior to Screening and the radiograph meets the 
technical requirements of the imaging vendor, that radiograph may be used, and no additional bone age 
radiographs will be performed during the Screening Period.  The bone age results will be used to assess 
subject eligibility.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.24 Brain Magnetic Resonance Imaging or Computed Axial 
Tomography Scan
Magnetic resonance imaging (MRI) or computed axial tomography (CT) high resolution scan of the brain 
(including pituitary and hypothalamus), to rule out intracranial tumor will be performed at Screening, 
unless previously performed prior to the start of Screening (provided nothing has changed in the 
subject's medical history to warrant a repeat test).  The MRI or high resolution CT scan of the brain for a 
subject who had this test done prior to Screening can be repeated at Screening as warranted based on 
the investigator's opinion.
The date the MRI or CT scan was performed should be available in the source documentation and will be 
documented in the eCRFs, including the presence or absence of tumor and type, if present.  If the results 
of a previously performed MRI or CT scan are not available in the source documentation, the test must 
be repeated to establish eligibility.
Results of prior diagnostic tests used to establish eligibility should be recorded in the source 
documentation and entered into the appropriate eCRF.
3.25 Adrenal (All Subjects) and Testicular (Male Subjects) Ultrasound
An adrenal (all subjects) and testicular (male subjects) ultrasound will be performed at Screening unless 
performed prior to Screening.  All ultrasounds should be performed by a trained ultrasonographer at a 
facility determined by the principal investigator.  In addition, if the investigator has ruled out adrenal or 
testicular steroid secreting tumors based on previously conducted laboratory testing, the adrenal or 
testicular ultrasound testing to rule out such hormone secreting tumors is not required.  Results of prior 
diagnostic tests should be recorded in source documentation and eCRF.  If the results and all of the 
required variables listed below of a previously performed adrenal and testicular ultrasound are not 
available in the source documentation, the ultrasound must be repeated to establish eligibility.
Testicular Ultrasound (Male Subjects)
If hormone levels or testicular consistency or symmetry suggests a testicular tumor, an ultrasound of the 
testes, if not done previously to rule out steroid-secreting tumors, will be performed.  Testes ultrasound 
variables to be evaluated will include volume, by measuring the length, width, and depth, and presence 
or absence of abnormality, and characterization (location, size) of the abnormality, if present.
Adrenal Gland Ultrasound (All Subjects)
An ultrasound of the adrenal gland may need to be performed if not done previously to rule out steroid-
secreting tumors of the adrenal glands based on hormone levels.  Adrenal ultrasound variables to be 
evaluated will include presence or absence of abnormality and characterization (location, size) of the 
abnormality, if present.
All results of prior diagnostic ultrasounds and tests used to establish eligibility should be recorded in 
source documentation and eCRF.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.26 Transdermal Pelvic Ultrasound (Uterine and Ovarian Volume) 
(Female Subjects)
A transdermal pelvic ultrasound (to assess uterine and ovarian volume) for female subjects will be 
performed at Screening (unless performed prior to the start of Screening) and at other time points as 
specified in Section 2.  A trained ultrasonographer should perform all ultrasounds (location determined 
by the principal investigator).  Results of prior diagnostic ultrasounds and tests should be recorded in 
source documentation and eCRF.  If the results and all of the required variables listed below of a 
previously performed ultrasound are not available in the source documentation, the ultrasound must be 
repeated to establish eligibility. The following transdermal pelvic ultrasound variables will be evaluated: 
ovarian and uterine volume by measuring the length, width and depth, presence of an endometrial 
stripe and thickness (double-layer in millimeters) if visible, presence or absence of abnormality, and 
characterization (including location, size) of the abnormality, if present.
3.27 Subject Withdrawal from Study
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page; however, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject will be treated in accordance with the 
investigator's best clinical judgment, irrespective of whether the subject or the subject's parent or legal 
guardian decides to continue participation in the study.
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All SAEs and study procedure-related nonserious adverse events, will be collected from the time the 
subject's parent or legal guardian signed the study-specific informed consent until study drug 
administration.
All adverse events and SAEs will be collected whether solicited or spontaneously reported by the subject 
and/or parent or legal guardian from the time of study drug administration through the end of the last 
dosing interval (24 weeks) and the 12-week Follow-up Period.
All adverse events of special interest (bone fractures/osteoporosis/osteopenia, slipped capital femoral 
epiphysis, neuropsychiatric events, and seizure/convulsion, injection site reaction [associated with study 
drug administration or stimulation test], hypersensitivity reaction) will be collected and captured.  See 
Protocol Section 6.1, "Adverse Events of Special Interest."
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
COVID-19 Pandemic-Related Reporting
Supplemental study case report forms should be completed in the event of COVID-19 related 
missed/virtual visits, study drug interruptions or discontinuations, or adverse events (including capture 
of specific signs/symptoms of infection and testing results).
COVID-19 infections should be captured as adverse events.  If the event meets the criteria for an SAE, 
then follow the SAE reporting directions per the protocol and above.  The following COVID-19 related 
supplemental eCRFs should be completed:

COVID -19 Supplemental Signs/Symptoms

COVID-19 Status Form
If a subject has a confirmed or suspected COVID-19 infection and study drug was interrupted, the 
investigator should contact the sponsor emergency medical contact listed above before reintroducing 
study drug.
5 COUNTRY-SPECIFIC REQUIREMENTS
5.1 SUSAR REPORTING
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
guidelines, and the United States Package Insert (USPI) will serve as the Reference Safety Information 
(RSI).  The RSI in effect at the start of a Product Safety Update Report (PSUR) reporting period serves as 
the RSI during the reporting period.  For follow-up reports, the RSI in place at the time of occurrence of 
the "suspected" Serious Adverse Reaction will be used to assess expectedness.
5.2 Treatment After End of Study
Subjects will continue study treatment throughout the study for a period of up to 144 weeks or until 
premature discontinuation of study drug.  At the subject's last visit, the investigator will discuss the 
appropriate subsequent treatment with the subject's parent or legal guardian.  LA is commercially 
available; AbbVie will not provide LA or any other therapy once the subject's participation is concluded.
6 STUDY DRUG
6.1 Treatments Administered
Study drug (LA 45 mg 6-month) will be administered at the visits listed in Section 2.  LA 45 mg 6-month 
drug product will be injected intramuscularly once every 24 weeks.  Each injection should be 
administered in a different anatomical site to minimize injection site reactions.
LA 45 mg 6-month drug product will be provided by AbbVie as a pre-filled dual chamber syringe 
containing sterile lyophilized microspheres, which when mixed with diluent, become a suspension 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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intended for intramuscular injections to be given once every 24 weeks.  The front chamber of the LA 
formulation pre-filled dual chamber syringe contains LA (45 mg), and the second chamber contains 
diluent.  Study drug must be prepared as described in the instructions for drug preparation (refer to
Section 7.3).
Study drug must not be administered without contacting the IRT system.  Study drug may only be 
administered to subjects enrolled in the study through the IRT system.  If a subject cannot come to the 
site because of unforeseen circumstances (e.g., the COVID-19 pandemic), the site may contact the IRT 
for kit assignment.  Study drug can then be dispensed as described in Section 3.19.
At the end of the Treatment Period or at the Premature Discontinuation Visit, the site will contact the 
IRT system to provide visit date information.
The GnRHa stimulation test will be conducted using generic LA aqueous solution.  For the stimulation 
test, 20 µg/kg of generic LA aqueous solution will be administered subcutaneously.  Generic LA aqueous 
solution will be supplied to the sites for the purpose of conducting the stimulation test.  Each site will be 
responsible for maintaining drug accountability records, including product description, manufacturer, lot 
numbers, and administration to subjects.  Sites should use their standard of care practice for 
preparation of the injection site and injection of generic LA aqueous solution.  If a subject cannot come 
to the site because of unforeseen circumstances (e.g., the COVID-19 pandemic), the GnRHa stimulation 
test may be performed by a home healthcare nurse at the subject's home.
There may be times when the sponsor is unable to provide the generic LA aqueous solution.  Under 
these circumstances, the participating sites have the option to obtain this product through an external 
licensed pharmacy or wholesaler or from local site supplies.
AbbVie will not supply drug other than the study drug LA 45 mg 6-month depot formulation and the 
generic LA aqueous solution for the stimulation test.
6.2 Packaging and Labeling
Study drug will be supplied as open-label LA 45 mg unit dose syringes.  Each kit will contain 1 pre-filled 
dual chamber syringe for injection.
Each kit will be labeled as required per country requirements.  The label must remain affixed to the kit.  
The site staff will complete the blank space on the label with the subject number before administering 
study drug.
Storage and Disposition of Study Drug
LA 45 mg 6-month must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  The 
investigational product is for investigational use only and is to be used only within the context of this 
study.  The study drug supplied for this study must be maintained under adequate security and stored 
under the conditions specified on the label until administered.  Unused study drug should be destroyed 
on site as appropriate or returned to AbbVie in accordance with local regulatory requirements and 
AbbVie requirements.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Generic LA aqueous solution for the stimulation test should be stored per the US-approved commercial 
label or the clinical study label.
Temperature excursions must be reported to AbbVie immediately.  Sites should use the AbbVie 
Temperature Excursion Management System (ATEMS) module via IRT for reporting temperature 
excursions for study drug (LA 45 mg 6 month), or if not accessible, fax or email copies of the Storage 
Temperature Excursion Reporting Form indicating the extent of the excursion (time, duration of the 
temperature excursion, minimum/maximum values and study drugs affected) to AbbVie Clinical Drug 
Supply Management (CDSM).  In case of a temperature excursion, study drug should be quarantined and 
not administered until AbbVie CDSM or ATEMS deems the medication as acceptable.  For reporting 
temperature excursions for generic LA aqueous solution, fax or email copies of the Storage Temperature 
Excursion Reporting Form to AbbVie CDSM.  In case of a temperature excursion, generic LA should be 
quarantined and not administered until AbbVie CDSM deems the product as acceptable.
6.3 Method of Assigning Subjects to Treatment Groups
This is an open-label, nonrandomized, single-arm study.  All subjects will receive the same dosage of LA 
(45 mg intramuscular every 24 weeks) for the duration of the study.
At the Screening Visit, all subjects will be assigned a unique subject number through the use of the IRT.  
For subjects who do not meet the study selection criteria, site personnel must contact the IRT system
and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number assigned at the Screening Visit throughout 
the study.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site.
6.4 Selection and Timing of Dose for Each Subject
All subjects who are enrolled in the study will receive the same dose of LA (45 mg) administered 
intramuscularly once every 24 weeks.  Study drug will be administered by site staff at scheduled study 
visits.  If a subject cannot come to the site because of unforeseen circumstances (e.g., the COVID-19 
pandemic), the study drug injection may be administered by a home healthcare nurse at the subject’s 
home. AbbVie should be notified if this occurs.
See Section 7.3 and Section 7.4 for study drug injection preparation instructions and injection site 
assessment instructions, respectively.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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7 Appendices
7.1 PUBERTAL STAGES WORKSHEET MALE
Subject Number:___________ Visit Date ____________
Height (in triplicate) 1._______cm
2._______cm
3._______cm
Weight _______kg
Height Mode of Collection: ☐Stadiometer ☐Harpenden ☐Other, please specify ______________
Sources:
1.
Brown RT.  Adolescent growth and development.  In:  Holland-Hall C, Brown RT, eds.  Adolescent Medicine Secrets.  
Philadelphia, PA:  Hanley & Belfus Inc; 2002:21-8.
2.
Travers SH, Slover RH.  Disorders of Puberty.  In:  MT M, ed.  Endocrine Secrets.  4th ed.  Philadelphia, Pa; 2005:354-67.
Testicular volume comments/observations:
Notes:
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
Prepubertal No pubic hair
Testicular length <2.5 cm
Sparse growth of slightly 
curly pubic hair, mainly at 
base of penis
Testes >2.5 cm in longest 
diameter; scrotum thinning 
and reddening
Thicker, curlier hair spread 
to  mons pubis 
Growth of penis in wid h and 
length; further growth of 
testes
Adult-type hair that does not 
yet  spread to medial 
surface of thighs
Penis further enlarged; 
testes larger, with darker 
scrotal skin color
Adult-type hair spread to 
medial surface of thighs
Genitalia adult in size and 
shape
Pubic hair comments/observations:
Notes:
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
General comments/observations:
Notes:
______________________________
______________________________
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
CONFIDENTIAL INFORMATION
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7.2 PUBERTAL STAGES WORKSHEET FEMALE
Subject Number:____________ Visit Date ____________
Height (in triplicate) 1._______cm
2._______cm
3._______cm
Weight _______kg
Height Mode of Collection: ☐Stadiometer ☐Harpenden ☐Other, please specify ______________
Sources:
1.
Brown RT.  Adolescent growth and development.  In:  Holland-Hall C, Brown RT, eds.  Adolescent Medicine Secrets.  
Philadelphia, PA:  Hanley & Belfus Inc; 2002:21-8.
2.
Travers SH, Slover RH.  Disorders of Puberty.  In:  MT M, ed.  Endocrine Secrets.  4th ed.  Philadelphia, Pa; 2005:354-67.
3.
Bonat S, Pathomvanich A, Keil MF, Field AE, Yanovski JA.  Self-assessment of pubertal stage in overweight children.  
Pediatrics.  2002;110(4):743-7.
Breast development 
comments/observations:
Notes:
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
Prepubertal: No pubic hair
Elevation of papilla only
No palpable glandular tissue
Sparse growth of long, straight 
or slightly curly, minimally 
pigmented hair, mainly of labia
Palpable breast bud that does 
not extend beyond the areola; 
enlargement of areola
Considerably darker and 
coarser hair spreading over 
mons pubis
Further enlargement of breast 
and areola, with no separation 
of contours; palpable breast 
extends beyond the areola
Thick, adult-type hair that 
does not yet spread to medial 
surface of thighs
Projection of areola and 
papilla to form secondary 
mound above level of breast
Hair adult in type and 
distributed in classic inverse 
triangle
Adult contour breast with 
projection of papilla only
Pubic hair comments/observations:
Notes:
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
______________________________
General comments/observations:
Notes:
______________________________
______________________________
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.3 DOSE PREPARATION FOR LEUPROLIDE ACETATE 45 MG 
FORMULATION
Reconstitution and Administration for Injection of LUPRON DEPOT

Reconstitute and administer the lyophilized microspheres as a single intramuscular 
injection.

Inject the suspension immediately or discard if not used within two hours, because LUPRON 
DEPOT does not contain a preservative.
1.
Visually inspect the LUPRON DEPOT powder.  DO NOT USE the syringe if clumping or caking is 
evident.  A thin layer of powder on the wall of the syringe is considered normal prior to mixing 
with the diluent.  The diluent should appear clear and colorless.
2.
To prepare for injection, screw the white plunger into the end stopper until the stopper begins 
to turn (see Figure 1 and Figure 2).
Figure 1
Figure 2
3.
Hold the syringe UPRIGHT.  Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the 
plunger until the first middle stopper is at the blue line in the middle of the barrel (see Figure 3).
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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Figure 3
4.
Keep the syringe UPRIGHT.  Mix the microspheres (powder) thoroughly by gently shaking the 
syringe until the powder forms a uniform suspension.  The suspension will appear milky.  If the 
powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to 
disperse.  DO NOT USE if any of the powder has not gone into suspension (see Figure 4).
Figure 4
5.
Keep the syringe UPRIGHT.  With the opposite hand pull the needle cap upward without 
twisting.
6.
Keep the syringe UPRIGHT.  Advance the plunger to expel the air from the syringe.  Now the 
syringe is ready for injection.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
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7.
After cleaning the injection site with an alcohol swab, administer the intramuscular injection by 
inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid; 
injection sites should be alternated (see Figure 5).
Figure 5
NOTE:  If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the 
luer lock (see Figure 6) and can be seen through the transparent LuproLoc® safety device.  If 
blood is present, remove the needle immediately.  Do not inject the medication.
Figure 6
8.
Inject the entire contents of the syringe intramuscularly.
9.
Withdraw the needle.  Once the syringe has been withdrawn, immediately activate the 
LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with 
Page 79 of 85
 
 


p. 42 of 45
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is 
fully extended and a CLICK is heard or felt (see Figure 7).
Figure 7
10. Dispose of the syringe according to local regulations/procedures.
Reference:  LUPRON DEPOT Package Insert, March 2019.
Page 80 of 85
 
 




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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.5 HORMONAL FLARE AND ACUTE-ON-CHRONIC RESPONSE FORM
Phone Call Assessment  
On-site Assessment  
Home healthcare nurse assessment  
Subject Number:  
Date:  
Time:  
1.
Since receiving the leuprolide acetate (45 mg) injection, is your child exhibiting any behavior that is different 
than their usual behavior?      
   Yes   
   No
If yes, please describe:
_________________________________________________________________
_________________________________________________________________
_________________________________________________________________
_________________________________________________________________
2.
Is your child exhibiting any physical symptoms that are different than usual? 
  Yes
  No
If yes, please describe:
_________________________________________________________________
_________________________________________________________________
3.
Do the symptoms require a follow-up phone call? 
   Yes 
  No
4.
Should the child come in to the office for an assessment/additional assessment? 
  Yes
  No
Comments:  
Initials of person/parent spoken to:  __________________
Signature of person completing form: ____________________  Date:  _____/______/_____
Printed name of person completing form:  ________________________________
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-904 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.6 MENSTRUAL BLEEDING CALENDAR
Subject Number:  _________
Date Calendar Given to Subject/Parent or Legal Guardian:  ___________________
Instructions:

Circle the dates when vaginal bleeding requires protection GREATER than a panty shield.

Mark "S" on the dates when spotting occurs that DOES NOT require protection greater than a 
panty shield.

Place no marks on the calendar on the dates when there's no bleeding or spotting.

Initial this page (person who completes the calendar).
See Example Calendar Below:
November 2017
Initials and date:  ________________
Page 83 of 85
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Lupron Depot
M16-904 – Statistical Analysis Plan
Version 4.0 – 21 December 2021
1
1.0
Title Page
Statistical Analysis Plan for Study M16-904
A Phase 3, Multi-Center, Open-Label, Two-Part Study 
to Evaluate the Safety, Efficacy, Pharmacokinetics 
and Pharmacodynamics of Leuprolide Acetate 45 mg 
6-Month Depot Formulation in Children with Central 
Precocious Puberty
Date:  21 December 2021
Version 4.0
 
NCT03695237


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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................4
4.0
Study Background...................................................................4
4.1
Objective....................................................................................................4
4.2
Study Design..............................................................................................4
4.2.1
Study Design and Design Diagram............................................................5
4.2.2
Variables Used for Stratification at Enrollment.........................................6
4.3
Endpoint.....................................................................................................7
4.3.1
Primary Efficacy Endpoint ........................................................................7
4.3.2
Secondary Efficacy Endpoints...................................................................7
4.3.3
Other Efficacy Endpoints...........................................................................8
4.3.4
Safety Endpoints ........................................................................................9
4.4
Sample Size Justification ...........................................................................9
4.5
Interim Analysis.........................................................................................9
4.6
End of Part 1 Analysis ...............................................................................9
4.7
End of Part 2 Analysis ...............................................................................9
4.8
Multiplicity Testing Procedures for Type-I Error Control ......................10
4.9
Missing Data Imputation..........................................................................10
5.0
Analysis Populations and Important Subgroups ...............10
5.1
Analysis Population .................................................................................10
5.2
Subgroup Analysis ...................................................................................10
6.0
Study Drug Duration.............................................................11
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................11
7.1
Demographics and Baseline Characteristics............................................12
7.2
Medical History .......................................................................................13
7.3
Prior and Concomitant Medications ........................................................13
8.0
Efficacy Analyses...................................................................13
8.1
General Considerations............................................................................13
8.2
Primary Efficacy Analysis .......................................................................14
 


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8.3
Secondary Efficacy Analyses...................................................................14
8.4
Other Efficacy Analyses ..........................................................................15
9.0
Safety Analyses ......................................................................15
9.1
General Considerations............................................................................15
9.2
Analysis of Adverse Events.....................................................................16
9.2.1
Treatment-Emergent Adverse Events ......................................................16
9.2.1.1
Adverse Event Overview .........................................................................16
9.2.1.2
Adverse Events by System Organ Class and Preferred Term..................17
9.2.1.3
Adverse Events by Preferred Term..........................................................17
9.2.1.4
Adverse Events by Maximum Relationship ............................................17
9.2.1.5
Adverse Events by Maximum Severity ...................................................17
9.2.1.6
Adverse Events of Special Interest ..........................................................18
9.2.1.7
Hormonal Flare Response Adverse Events..............................................18
9.3
Analysis of Laboratory Data....................................................................19
9.4
Analysis of Vital Signs and Weight.........................................................20
10.0
Summary of Changes ............................................................21
10.1
Summary of Changes Between the Previous Version and the 
Current Version........................................................................................21
10.2
Summary of Changes in Previous Version ..............................................21
List of Figures
Figure 1.
Study Schematic.........................................................................................6
List of Appendices
Appendix A.
Definition of Adverse Events of Special Interest (AESI)........................23
 


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analysis to be completed by 
AbbVie Clinical Statistics Department for leuprolide acetate Study M16-904.
The SAP will provide details to further elaborate statistical methods as outlined in the 
protocol and will describe analysis conventions to guide the statistical programming work.  
Unless noted otherwise, all analyses will be performed using SAS version 9.4 or later 
(SAS Institute Inc., Cary, NC 27513) under the UNIX operating system.
4.0
Study Background
4.1
Objective
Primary objective:
●
To assess the safety and efficacy of LA 45 mg 6-month depot formulation for 
the treatment of CPP in children who are either naïve to treatment with a 
GnRHa or who have been previously treated with a GnRHa.
Secondary objective:
●
To evaluate the pharmacokinetic profile and pharmacodynamics of leuprolide 
following intramuscular administration of the LA 45 mg 6-month depot 
formulation in subjects with CPP.
4.2
Study Design
This is a Phase 3, open-label, 2-part study in which the safety, efficacy, and 
pharmacokinetics/pharmacodynamics of a leuprolide acetate 45 mg 6-month (LA 45 mg 
6-month) formulation will be evaluated in children with CPP.  Part 1 (initial treatment) 
will be 52 weeks in duration, including at 4-week Screening Period and 48-week 
treatment period.  Part 2 (a long-term extension of Part 1) will be 108 weeks in duration, 
including a 96-week treatment period and a 12-week follow-up period.
 


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4.2.1
Study Design and Design Diagram
The total duration of the study (Parts 1 and 2) will be 160 weeks as follows:
●
Part 1:  52 weeks (4-week screening period + 48-week treatment period)
●
Part 2:  108 weeks (additional 96-week treatment period + 12-week follow-up 
period)
Part 1:  The safety, efficacy, pharmacokinetics, and pharmacodynamics of the LA 45 mg 
6-month dose will be evaluated in subjects with CPP from Baseline to Week 48.  In all 
subjects, blood samples for efficacy assessments (analysis of LH, testosterone 
concentrations [males], and estradiol concentrations [females]) will be collected at 
Baseline and at Weeks 1, 4, 12, 20, 24, 44, and 48 after dosing.  In the first subjects who 
are enrolled (20 subjects total, with at least 8 naïve and 8 previously treated), 
concentrations of leuprolide will be measured at each study visit following administration 
of LA 45 mg 6-month to characterize the leuprolide concentration-time profile, rate of 
absorption, and pharmacokinetic/pharmacodynamic relationship of leuprolide and LH.  
Investigative sites will be notified when the pharmacokinetic subset has been fulfilled.
Leuprolide and appropriate measures of efficacy (LH, estradiol in females, testosterone in 
males) will be monitored upon data availability to evaluate the appropriateness of the 
24-week dosing interval for the 6-month formulation for CPP.
Part 2:  Following completion of Part 1 (the initial 48-week treatment period) 
assessments, subjects will continue to Part 2 of the study (extension period) to evaluate 
long-term administration of LA 45 mg 6-month (up to 24 months).  Study visits during the 
extension period will start at Week 48 and continue once every 24 weeks for 96 weeks 
(24 months) until the subject discontinues treatment of LA 45 mg 6-month or withdraws 
from the study.  Subjects will be assessed for continued maintenance of LH suppression 
and safety throughout this extension period.
A schematic of the study is shown in Figure 1.
 


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Figure 1.
Study Schematic
Children with CPP (N = ~40)
AOC = acute-on-chronic; E2 = estradiol; T = testosterone
a.
At the beginning of Part 2, subjects will be randomly selected for AOC biochemical assessments 48 hours 
following the injection at Weeks 48, 72, 96, and 120.
Note:
Week 0 = Day 1 (Baseline).
Note:
See Operations Manual for details.
4.2.2
Variables Used for Stratification at Enrollment 
All subjects in this study will receive the same treatment; therefore, no treatment 
randomization will be performed. A minimum of 15 of whom must be naïve to treatment 
with a GnRHa, and a minimum of 15 of whom must have been previously treated with a 
GnRHa.
At the beginning of Part 2, using the IRT system, half of the subjects will be randomly 
selected to have AOC biochemical assessment 48 hours after the injection at Weeks 48, 
72, 96, and 120.  Randomization will be stratified based on previous GnRHa treatment 
status (treatment-naïve or previous treated with a GnRHa).  The randomization schedule 
will be generated and kept by the statistics department at AbbVie and a copy will be 
forwarded to the IRT provider.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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4.3
Endpoint
Efficacy endpoints will be based on hormonal suppression.  Stabilization or regression of 
signs of puberty, and effects on bone age and growth rate will be studied.
4.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects with suppression of 
GnRHa-stimulated LH (< 4 mIU/mL) at Week 24 after the first dose of study drug but 
before the Week 24 dose.  The null hypothesis is that less than 75% of subjects will 
achieve suppression of GnRHa-stimulated LH (< 4 mIU/mL) at Week 24.
4.3.2
Secondary Efficacy Endpoints
The following key secondary efficacy endpoints will be summarized:
●
Proportion of subjects with suppression of GnRHa-stimulated LH 
(< 4 mIU/mL) at Weeks 12, 20, 24, 44, and 48.
●
Proportion of female subjects with suppression of basal estradiol to < 20 pg/mL 
at Weeks 12, 20, 24, 44, and 48.
●
Proportion of male subjects with suppression of testosterone to < 30 ng/dL at 
Weeks 12, 20, 24, 44, and 48.
●
Proportion of subjects with maintenance of suppression of GnRHa-stimulated 
LH (< 4 mIU/mL) at Weeks 72, 96, 120, and 144.
●
Proportion of female subjects with maintenance of suppression of basal 
estradiol to < 20 pg/mL at Weeks 72, 96, 120, and 144.
●
Proportion of male subjects with maintenance of suppression of testosterone to 
< 30 ng/dL at Weeks 72, 96, 120, and 144.
●
Proportion of subjects with suppression of the physical signs of puberty (breast 
development in females; testicular or genital development in males) at each 
scheduled assessment using modified Tanner staging.
●
Incremental growth rate (cm/year) at each scheduled assessment.
●
Ratio of change from Baseline in bone age to change from Baseline in 
chronological age at each scheduled assessment.
 


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4.3.3
Other Efficacy Endpoints 
The following other efficacy endpoints will be summarized:
●
Peak stimulated LH concentrations at each scheduled assessment (not already 
specified in Section 4.3.2).
●
Number and percentage of subjects who fail suppression of peak stimulated LH 
per primary endpoint analysis at each scheduled assessment.
●
Number and percentage of female subjects with menstrual bleeding.
●
Change from baseline in basal and peak stimulated LH, FSH, as well as basal 
and stimulated estradiol (for females) and testosterone (for males), to each 
scheduled assessment.
●
Ratio and change from baseline in the ratio of bone age to chronological age at 
each scheduled assessment.
●
Regression or no progression in pubic hair in both females and males.
●
Change from baseline in uterine length, uterine volume, and ovarian volume to 
each scheduled assessment.
●
Number and percentage of subjects with endometrial stripe presence by 
baseline endometrial stripe presence status (yes/no) at each scheduled 
assessment.
●
Change from baseline in testicular length (cm), penile length (cm), and penile 
width (cm) by physical examination, and in testicular volume by Prader beads 
to each scheduled assessment.
●
Change from baseline in BMI standardized score to each scheduled assessment
●
Change from baseline in height standardized score to each scheduled 
assessment
●
PedsQL and PROMIS questionnaires at each scheduled assessment.
 


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4.3.4
Safety Endpoints
Safety evaluations are adverse events, physical examinations, vital sign measurements, 
LA 45 mg injection site reactions, hormonal flare and acute-on-chronic (AOC) response, 
and clinical laboratory testing as measures of safety and tolerability for the duration of the 
entire study.
4.4
Sample Size Justification
No formal sample size calculation was performed.  Based on previous studies and 
historical precedent used for registration (n = ~40), 40 subjects are sufficient to support 
the safety and efficacy for this class of compounds in this patient population.  The planned 
sample size of 40 subjects will provide an observed response rate (of suppression of peak 
stimulated LH) that is within 16.7% of the true response rate with 95% confidence.
4.5
Interim Analysis
No interim analysis will be performed.
4.6
End of Part 1 Analysis
At the end of Part 1, an analysis of the primary, secondary and other efficacy variables 
collected during part 1 of the study, along with demographic and safety variables, will be 
performed after the last subject completes the Week 48 assessment.  These analyses will 
include data collected during Part 1 and should not include data collected during Part 2 or 
during the Follow-Up Period with the exception that Week 48 may include limited data 
after Week 48 dose if the data is considered as Week 48.  The database will be versioned 
for an interim soft lock and any discrepant data will be clarified before the versioning.  
Analyses will be performed by AbbVie.
4.7
End of Part 2 Analysis
At the end of Part 2, an analysis of the appropriate efficacy and safety variables will be 
performed after the last subject completes the study.  Analyses will be performed by 
AbbVie.
 


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4.8
Multiplicity Testing Procedures for Type-I Error Control
There will be no adjustment for multiple endpoints as there is no hypothesis being tested.
4.9
Missing Data Imputation
Unless otherwise stated, data will be summarized as observed, i.e., missing data will not 
be imputed.  
For the endpoint of suppression of GnRHa-stimulated LH, subjects who received study 
drug at the Day 1 visit and are missing GnRHa-stimulated LH results at a scheduled visit 
in Part 1 will be counted as LH suppression failures for that visit.
5.0
Analysis Populations and Important Subgroups
5.1
Analysis Population
The Full Analysis Set (FAS) consists of all subjects who received at least 1 dose of study 
drug.  The FAS will be used for all efficacy and baseline analyses.  
The safety Analysis Set consists of all subjects who received at least 1 dose of study drug.
5.2
Subgroup Analysis
Analysis of the primary efficacy endpoint will be conducted for the following subgroups 
by previous GnRHa treatment status and combined:
●
Sex (males, females)
●
Race (White, Black, or Other)
●
Baseline LH value (< 4 miU/mL, ≥4 mIU/mL)
●
Time between onset of puberty and start of treatment ((Median, > Median)
●
Age at onset of puberty (Median, > Median)
●
Predicted adult stature compared to lower bound of range of target height (<, ≥
●
Baseline BMI SD score (Median, > Median)
 


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6.0
Study Drug Duration
Duration (days) of treatment will be summarized for the Safety Analysis Set using the 
number of subjects treated, mean, standard deviation, median, minimum, and maximum.
Study drug duration will be summarized as follows:
Part 1 of the Treatment Period:
Last day of study drug for Part 1 – First dose date for Part 1 + 1
Part 2 of the Treatment Period:
Last day of study drug for Part 2 – First dose date for Part 2 + 1
In addition, the number and percentage of subjects will be summarized separately for Part 
1 and Part 2 for the following categories: 
●
Number of injections that each subject received (1 or 2)
●
Compliance or non-compliance with the dosing scheme.  A subject will be 
considered non-compliant with the dosing scheme if there was a gap larger 
more than 3 days gap between the last day of one injection and the day of the 
next injection.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline characteristics, medical history, prior medication, and 
concomitant medication will be summarized by previous GnRHa treatment status and 
overall using the Full Analysis Set.  Categorical variables will be summarized with the 
number and percentage of subjects; percentages will be calculated based on the number of 
non-missing observations.  Continuous variables will be summarized with descriptive 
statistics (number of non-missing observations, mean and standard deviation, median, 
minimum, and maximum).
 


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7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, body mass index (BMI), 
and BMI SD score.  Categorical demographic variables include sex, ethnicity, and race.
For CPP history, age at onset of CPP (in years), time between onset of puberty and start of 
CPP treatment (in years), time since first seen by a physician for CPP to start of CPP 
treatment (in years) will be summarized by sex and overall.
For family history, target height, mother's age at puberty and height, father's age at 
puberty and height will be summarized by sex and overall. 
For bone age (in years) and height (in cm) related parameters, bone age, BA/CA (ratio of 
bone age to chronological age), BA-CA (bone age minus chronological age), and growth 
rate (cm/year) will be summarized by sex and overall.
For diagnostic results for CPP at baseline, brain tumor presence by MRI, brain tumor 
presence by CT scan, other brain abnormality by MRI, other brain abnormality by CT 
scan, and adrenal gland abnormality (yes) will be summarized by sex and overall.
In addition, the following baseline disease characteristics will be summarized for female 
and male:
●
For female: tanner staging of breast, tanner staging of pubic hair, menarche 
status (yes/no), age at first menstruation (in years), bleeding per month (in 
days), spotting per month (in days), bleeding or spotting per month (in days), 
uterine length (in cm), uterine/ovary abnormality presence (yes), uterine 
volume, left ovarian volume, right ovarian volume, endometrial stripe presence 
(yes), thickness of endometrial stripe (in mm).
●
For male: tanner staging of genitalia, tanner staging of pubic hair, left testicular 
volume, left testicular length, right testicular volume, right testicular length, 
and testicular abnormality presence (yes).
 


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7.2
Medical History
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized for the FAS.  The system organ class (SOC) will be presented in alphabetical 
order, and the preferred terms will be presented in alphabetical order within each SOC.  
Subjects reporting more than one condition/diagnosis will be counted only once in each 
row (SOC or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic drug name using the 
World Health Organization (WHO) Drug Dictionary.
Prior medications are those medications with a start date prior to the first study drug 
administration date.  Prior medications will be summarized separately for prior CPP 
medications and other medications.
Concomitant medications during Part 1 are those medications, other than study drug, 
taken during the Part 1 of Treatment Period with an end date after the first dose of study 
drug or ongoing at the end of the study, and a start date prior to the last day of study drug 
for Part 1.  Concomitant medications during Part 2 are those medications, other than study 
drug, taken during the Part 2 of Treatment Period with an end date after the first dose of 
study drug at Part 2 or ongoing at the end of the study, and a start date prior to the last day 
of study drug for Part 2.  
8.0
Efficacy Analyses
8.1
General Considerations
For all efficacy endpoints, the descriptive statistics will be provided by previous GnRHa 
treatment status (naïve or previously treated) and combined.  The descriptive statistics 
 


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include the number of observations, mean, standard deviation, minimum, median, and 
maximum for continuous variables; and number and percentage for categorical variables.
Subjects with missing GnRHa-stimulated LH test results at a specific scheduled visit will 
be counted as suppression failures for that visit.
8.2
Primary Efficacy Analysis
The primary efficacy endpoint is the proportion of subjects with suppression of GnRHa-
stimulated LH (< 4 mIU/mL) at Week 24, after the first dose of study drug but before the 
Week 24 dose.  The numerator will be the number of subjects with suppression of GnRHa 
stimulated LH (< 4 mIU/mL) at Week 24, and the denominator will be the number of 
subjects who received study drug at the Day 1 visit.  The proportion of subjects 
suppressed and the two-sided 95% confidence interval based on the binomial distribution 
(Clopper-Pearson exact method) will be provided by previous GnRHa treatment status 
and overall.  Peak stimulated LH will be calculated by taking the maximum LH 
concentrations observed at 30 or 60 min following a GnRHa stimulation test for 
scheduled assessments.  
8.3
Secondary Efficacy Analyses
Unless otherwise specified, categorical data will be summarized by number and 
percentage; and continuous data will be summarized by sample size, mean, median, 
standard deviation, minimum, and maximum.
For the proportion of subjects with LH suppression at each scheduled assessment, the 
numerator will be the number of subjects with suppression of GnRHa stimulated LH 
(< 4 mIU/mL) at that visit, and the denominator will be the number of subjects who 
received study drug at the Day 1 visit.  The proportion and the two-sided 95% confidence 
interval based on the binomial distribution (Clopper-Pearson exact method) will be 
provided by previous GnRHa treatment status and overall.
 


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For the number and percentage of subjects with suppression of basal sex steroids, the 
two-sided 95% confidence intervals based on the binomial distribution (Clopper-Pearson 
exact method) will be provided by previous GnRHa treatment status and overall.  For the 
percentage of subjects with suppression of basal sex steroids, if a subject did not received 
study drug at the prior scheduled injection visit, the subject will be excluded from the 
denominator.  For example, if Week 24 injection is not done then any assessments after 
Week 24 the subject will be excluded from the denominator. 
8.4
Other Efficacy Analyses 
Unless otherwise specified, categorical data will be summarized by number and 
percentage; and continuous data will be summarized by sample size, mean, median, 
standard deviation, minimum, and maximum.
For the number and percentage of subjects who fail suppression of peak stimulated LH 
per primary endpoint analysis, the 95% confidence intervals will also be provided.
9.0
Safety Analyses
9.1
General Considerations
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.  
All safety analyses will be performed by previous GnRHa status (naïve or previously 
treated), and overall.
The following summary statistics will be presented for subjects who have both baseline 
and post-baseline values for laboratory parameters and vital signs:  the mean value at 
baseline and at each respective protocol specified visit, and the mean, standard deviation 
and median for changes from Baseline.  Categorical data will be summarized using 
frequencies and percentages.
 


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9.2
Analysis of Adverse Events
9.2.1
Treatment-Emergent Adverse Events
Treatment emergent adverse events are defined as any event with an onset date that is 
after the first dose of study drug and with an onset date no more than 12 weeks after the 
end of the effect of study drug (24 weeks after the date of the last administration of study 
drug).  Events where the onset date is the same as the study drug start date are assumed to 
be treatment emergent.
9.2.1.1
Adverse Event Overview
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be summarized for the following AE categories. In addition, the number and 
percentage of subjects experiencing treatment-emergent adverse events per 
100 patient-years will be summarized.
●
Any treatment-emergent adverse events
●
Any treatment-emergent adverse events related to COVID-19
●
Any treatment-emergent adverse events that was rated as related to study drug 
by the investigator
●
Any treatment-emergent severe adverse events
●
Any treatment-emergent serious adverse events
●
Any treatment-emergent adverse events leading to discontinuation of study 
drug
●
Any treatment-emergent adverse events leading to death
○
Deaths occurring ≤ 36 weeks after last dose of study drug
○
Deaths occurring > 36 weeks after last dose of study drug
●
Any treatment-emergent adverse event of special interest
 


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9.2.1.2
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be tabulated using primary Medical Dictionary for Regulatory Activities (MedDRA) 
by System Organ Class (SOC) and Preferred Term (PT).  Subjects reporting more than 
one adverse event for a given PT will be counted only once for that term (most severe 
incident for the severity tables and most related incident for the relationship tables).  
Subjects reporting more than one type of adverse event within a SOC will be counted only 
once for that SOC.  Subjects reporting more than one type of adverse event will be 
counted only once in the overall total.
9.2.1.3
Adverse Events by Preferred Term
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be tabulated by Preferred Term (PT) by decreasing frequency of overall.
9.2.1.4
Adverse Events by Maximum Relationship
Treatment emergent adverse events will be summarized by maximum relationship to 
study, as assessed by the investigator.  If a subject has an adverse event with unknown 
relationship, then the subject will be counted in the relationship category of "unknown," 
even if the subject has another occurrence of the same event with a relationship present.  
The only exception is if the subject has another occurrence of the same adverse event with 
a relationship assessment of "Reasonable Possibility."  In this case, the subject will be 
counted under the "Reasonable Possibility" category.
9.2.1.5
Adverse Events by Maximum Severity
Treatment-emergent adverse events will be summarized by maximum severity.  If a 
subject has an adverse event with unknown severity, then the subject will be counted in 
the severity category of "unknown," even if the subject has another occurrence of the 
same event with a severity present.  The only exception is if the subject has another 
occurrence of the same adverse event with the most extreme severity – "Severe."  In this 
case, the subject will be counted under the "Severe" category.
 


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9.2.1.6
Adverse Events of Special Interest
Adverse events of special interest will be summarized by SOC and PT and will be based 
on standardized or company MedDRA queries (SMQs or CMQs), or based on 
adjudication results.  
The following Adverse Events of Special Interest (AESI) will be summarized:
●
Bone fracture
●
Slipped capital femoral epiphysis
●
Neuropsychiatric events
●
Seizure/convulsion
●
Injection site reaction
●
Hypersensitivity reactions
Detailed information about the search criteria is provided in Appendix A.
9.2.1.7
Hormonal Flare Response Adverse Events
The number and percentage of subjects with hormonal flare response adverse events will 
be by summarized by SOC and PT.
Data on acute-on-chronic symptoms collected from phone calls and visits after study drug 
injections will be summarized with number and percentage for who reported abnormal 
behavior, abnormal physical symptoms or any abnormalities. 
A blood sample will be collected 48 hours after the second injection (Week 24) of LA 
45 mg 6-month, which will be used to assess the biochemical AOC phenomenon by 
measuring LH and estradiol (female subjects) or testosterone (male subjects) in all 
subjects (both pre-treated and naïve).  The AOC biochemical definition is LH > 
4 mIU/mL and estradiol > 20 pg/mL or testosterone > 30 ng/dL 48 hours after the second 
injection of leuprolide acetate at the Week 24 visit.  The number and percentage of 
subjects with biochemical AOC phenomenon will be provided.
 


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9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests defined in the protocol operations manual (i.e., hematology and 
clinical chemistry) will be summarized.
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean. The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline.
Below are selected laboratory variables:
Hematology
Platelet count, hemoglobin, white blood cell (WBC) count, 
Lymphocytes, Neutrophils 
Chemistry
Albumin, Alkaline Phosphatase, ALT, AST, Bilirubin, Creatinine, 
Glucose, Potassium, Magnesium, Sodium
Changes in selected laboratory parameters will be tabulated using shift tables by NCI 
CTC criteria and categorized as low, normal, or high based on the normal ranges of the 
laboratory used for each sample.  A shift table from baseline either to the worse value 
(based on NCI CTC criteria) during treatment or to minimum and maximum value (based 
on normal range), will be created.  A similar shift table will be provided to summarize 
shifts from baseline to the final post-baseline value.
In addition, the number and percentage of subjects who have potentially clinically 
significant (PCS) laboratory values meeting the following criteria any time during the 
appropriate Treatment Period will be summarized.  Listings will be provided to 
summarize subject-level laboratory data for subjects meeting PCS criteria.
 


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Analyte
PCS Low Threshold
PCS High Threshold
Hematocrit 
≤24%
≥ 54%
Hemoglobin 
≤8.0 g/dL
≥ 16 g/dL
Red Cell Count 
≤2.5 106/uL
≥ 7.0 106/uL
MCV 
≤0.8 LLN
≥ 1.2 ULN
MCH 
≤0.8 LLN
≥ 1.2 ULN
MCHC 
≤0.8 LLN
≥ 1.2 ULN
White Cell Count 
≤3 103/uL
≥ 16 103/uL
Platelet Count 
≤100 103/uL
≥ 800 103/uL
Neutrophils Absolute 
≤1.0 103/uL
≥ 12.0 103/uL
Lymphocytes Absolute 
2y – 4y:   ≤1.0 103/uL
> 4y:        ≤0.5 103/uL
> 2y-4y: ≥ 15 103/uL
> 4y:       ≥ 10 103/uL
Monocytes Absolute 
≤0.1 103/uL
≥ 3.0 103/uL
Eosinophils Absolute
≥ 1.0 103/uL
Basophils Absolute
≥ 0.6 103/uL
Albumin
≤2.0 g/dL
≥ 6.0 g/dL
Alkaline Phosphatase
≥ 2 ULN
ALT 
≥ 2 ULN
AST 
≥ 2 ULN
Bilirubin
≥ 2 ULN
Lactate Dehydrogenase 
≥ 2 ULN
Creatinine
≤0.3 mg/dL
≥ 1.5 mg/dL or increase by 0.3 mg/dL
Magnesium
≤1.0 mg/dL
≥ 3.5 mg/dL
Glucose
≤50 mg/dL
≥ 180 mg/dL
Chloride
≤90 mEq/L
≥ 115 mEq/L
Bicarbonate
≤16 mEq/L
≥ 35 mEq/L
Calcium
≤7.0 mg/dL
≥ 13.0 mg/dL
Potassium
≤3.0 mEq/L
≥ 6.0 mEq/L
Sodium
≤130 mEq/L
≥ 155 mEq/L
9.4
Analysis of Vital Signs and Weight
For blood pressure, respiratory rate, temperature, weight, BMI, and BMI SD score, the 
sample size, mean, standard deviation, median, minimum, and maximum will be 
 


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summarized.  In addition, mean changes from baseline to each scheduled assessment will 
be summarized with the baseline mean, visit mean, change from baseline mean, standard 
deviation, and median.
10.0
Summary of Changes
10.1
Summary of Changes Between the Previous Version and the 
Current Version
Remove the laboratory values in Section 9.3 that are not supported by CTCAE criteria 
4.03.
10.2
Summary of Changes in Previous Version
Summary of changes between the second version and the third version include:
●
Section 4.9 Missing Data Imputation has been updated for the endpoint of 
suppression of GnRHa-stimulated LH.  Subjects who received study drug at 
Day 1 visit and are missing results in Part 1 will be considered as LH 
suppression failures. 
●
Addition of Subgroup Analysis in Section 5.2
●
Addition of Study Drug Duration in Section 6.0
●
Addition of Section 7.0 for analyses for demographics, baseline characteristics, 
medical history, and prior/concomitant medications
●
Section 9.2.1.1 Adverse Event Overview has been updated to include AE 
related to COVID-19 and deaths occurring ≤ or > 36 weeks after last dose of 
study drug
●
Section 9.2.1.4 Adverse Events by Maximum Relationship has been updated to 
change "Possibly or Definitely related" to "Reasonable Possibility" to align 
with eCRF. 
●
Section 9.2.1.7 Hormonal Flare Response Adverse Events has been updated to 
add a description of analysis for hormonal flare response adverse event and to 
update the definition of biochemical AOC phenomenon
●
Section 9.3 Analysis of Laboratory Data has been updated with more details
●
Addition of Appendix A for definition of AESI
 


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Summary of changes between the initial and second version includes the following:
The primary, secondary and other efficacy endpoints have been updated to reflect changes 
in protocol.  The primary efficacy endpoint has been changed to the proportion of subjects 
with suppression of GnRHa-stimulated LH (< 4 mIU/mL) at Week 24 after the first dose 
of study drug.  The secondary and other efficacy endpoints have been updated in 
Section 4.3.2 and Section 4.3.3.  The analysis for the primary efficacy endpoint has been 
changed to two-sided 95% confidence interval based on the binomial distribution 
(Clopper-Pearson exact method).
 


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Appendix A.
Definition of Adverse Events of Special Interest (AESI)
Adverse Events of Special Interest (AESI) will be identified using the following search 
criteria:
Item of Safety Interest
Method of Surveillance
Bone fracture
Bone fractures CMQ
Slipped capital femoral epiphysis
Fractures HLGT and Epiphyseal disorders HLT (limit to under 
18 years of age)
Neuropsychiatric events
Suicide/self-injury SMQ_Narrow
Seizure/convulsion
Convulsions SMQ_Broad
Injection site reaction
Injection site reaction CMQ
Hypersensitivity reactions
Hypersensitivity SMQ Narrow