Clinical trial NCT03019575
Conditions: Hypogonadotropic Hypogonadism
Sponsor: Organon and Co
Start date: 2017-02-02; Completion date: 2020-05-05
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to investigate whether corifollitropin alfa (MK-8962), administered alone for 12 weeks and then in combination with human chorionic gonadotropin (hCG) for 52 weeks, increases the testicular volume in adolescent males aged 14 to \<18. In addition, the study will evaluate participants for safety, tolerability and for the development of corifollitropin alfa antibodies. No formal hypothesis will be tested for this estimation study

Detailed description:

Arms: arm 1: Participants received 100 μg (if body weight was ≤60 kg) or 150 μg (if body weight was \>60 kg) of CFA as a subcutaneous (SC) injection once every 2 weeks for 64 Weeks (Day 1, Week 0 through Week 64) and 500-5000 IU of hCG reconstituted with 1 ml of 0.9% sodium chloride solution, as a SC injection twice a week for 52 weeks (last day of Week 12 through Week 64). The total treatment duration was 64 Weeks.
Interventions: intervention 1: Corifollitropin alfa intervention 2: hCG
Intervention descriptions: intervention 1: CFA administered 100 μg (if body weight ≤60 kg) or 150 μg (if body weight \>60 kg) by SC injection, once every 2 weeks for 64 weeks (Day 1, Week 0 through Week 64). intervention 2: hCG 500-5000 IU reconstituted with 1 ml of 0.9% sodium chloride solution, as a SC injection twice a week for 52 weeks (last day of Week 12 through Week 64).

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03019575 
Document Date: 
24-Apr-2018
A Phase III, Multi-Center, Open Label, Single-Group Trial to Investigate the 
Efficacy and Safety of MK-8962 (corifollitropin alfa) in Combination with human 
Chorionic Gonadotropin (hCG) for Initiation or Restoration of Puberty as 
Assessed by Increased Testicular Volume in Adolescent Males 14 to <18 Years 
Old with Hypogonadotropic Hypogonadism (Phase III; Protocol No. 
MK-8962-043-06)


Product:  MK-8962 
1
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, U.S.A. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase III, Multi-Center, Open Label, Single-Group Trial to Investigate the Efficacy and 
Safety of MK-8962 (corifollitropin alfa) in Combination with human Chorionic 
Gonadotropin (hCG) for Initiation or Restoration of Puberty as Assessed by Increased 
Testicular Volume in Adolescent Males 14 to <18 Years Old with Hypogonadotropic 
Hypogonadism (Phase III; Protocol No. MK-8962-043-06)
IND NUMBER:  Not Applicable
EudraCT NUMBER:  [2015-001878-18]
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
2
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
TABLE OF CONTENTS
SUMMARY OF CHANGES.................................................................................................. 9
1.0
TRIAL SUMMARY.................................................................................................. 11
2.0
TRIAL DESIGN........................................................................................................ 12
Trial Design ........................................................................................................... 12
2.1
Trial Diagram........................................................................................................ 13
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 14
Primary Objective(s) & Hypothesis(es) .............................................................. 14
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 14
3.2
4.0
BACKGROUND & RATIONALE.......................................................................... 14
Background ........................................................................................................... 14
4.1
Pharmaceutical and Therapeutic Background .................................................... 14
4.1.1
Rationale................................................................................................................ 17
4.2
Rationale for the Trial and Selected Subject Population .................................... 17
4.2.1
Rationale for Dose Selection/Regimen/Modification......................................... 18
4.2.2
4.2.2.1
Rationale for Single Arm Design................................................................. 18
Rationale for Endpoints ...................................................................................... 20
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 20
4.2.3.2
Safety Endpoints .......................................................................................... 21
4.2.3.3
Pharmacokinetic Endpoints ......................................................................... 22
4.2.3.4
Future Biomedical Research........................................................................ 22
Benefit/Risk ........................................................................................................... 23
4.3
5.0
METHODOLOGY ................................................................................................... 23
Entry Criteria........................................................................................................ 23
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 23
5.1.1
Subject Inclusion Criteria.................................................................................... 23
5.1.2
Subject Exclusion Criteria .................................................................................. 24
5.1.3
Trial Treatment(s) ................................................................................................ 27
5.2
Dose Selection for MK-8962 and Dose Modification for hCG.......................... 28
5.2.1
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
3
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
5.2.1.1
Dose Selection (Preparation) ....................................................................... 28
5.2.1.2
Dose Titration for hCG ................................................................................ 28
Timing of Dose Administration .......................................................................... 29
5.2.2
Trial Blinding/Masking....................................................................................... 30
5.2.3
Randomization or Treatment Allocation............................................................ 30
5.3
Stratification.......................................................................................................... 30
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 30
5.5
Rescue Medications & Supportive Care............................................................. 31
5.6
Diet/Activity/Other Considerations..................................................................... 31
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 31
5.8
Subject Replacement Strategy............................................................................. 32
5.9
Beginning and End of the Trial ........................................................................... 32
5.10
Clinical Criteria for Early Trial Termination ................................................... 32
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 33
7.0
TRIAL PROCEDURES ........................................................................................... 38
Trial Procedures ................................................................................................... 38
7.1
Administrative Procedures.................................................................................. 38
7.1.1
7.1.1.1
Informed Consent/Assent............................................................................. 38
7.1.1.1.1
General Informed Consent/Assent........................................................ 38
7.1.1.1.2
Consent/Assent and Collection of Specimens for Future 
Biomedical Research ............................................................................ 39
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 39
7.1.1.3
Subject Identification Card .......................................................................... 39
7.1.1.4
Medical History ........................................................................................... 39
7.1.1.5
Prior and Concomitant Medications Review ............................................... 39
7.1.1.5.1
Prior Medications.................................................................................. 39
7.1.1.5.2
Concomitant Medications..................................................................... 39
7.1.1.6
Assignment of Screening Number............................................................... 39
7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 40
7.1.1.8
Trial Compliance (Medication).................................................................... 40
Clinical Procedures/Assessments........................................................................ 40
7.1.2
7.1.2.1
Physical Examination................................................................................... 40
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
4
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
7.1.2.2
Vital Signs, Height, and Weight .................................................................. 41
7.1.2.3
Testicular Ultrasound................................................................................... 41
7.1.2.4
Tanner Staging of Pubertal Development.................................................... 42
7.1.2.5
Adverse Events Monitoring ......................................................................... 42
Laboratory Procedures/Assessments .................................................................. 42
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology and Chemistry)..................... 42
7.1.3.2
Panel of Endocrine Parameters .................................................................... 43
7.1.3.3
Pharmacokinetic Evaluations....................................................................... 43
7.1.3.3.1
Flow Chart of Blood Sample Collection for Pharmacokinetic 
Assessments of MK-8962a................................................................... 44
7.1.3.4
Anti-MK-8962 Antibodies........................................................................... 44
7.1.3.5
Future Biomedical Research Sample Collection ......................................... 45
Other Procedures................................................................................................. 45
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 45
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 45
7.1.4.2
Blinding/Unblinding .................................................................................... 45
7.1.4.3
Domiciling ................................................................................................... 46
7.1.4.4
Calibration of Equipment............................................................................. 46
Visit Requirements.............................................................................................. 46
7.1.5
7.1.5.1
Screening...................................................................................................... 46
7.1.5.2
Treatment Period.......................................................................................... 46
7.1.5.3
Post-Treatment............................................................................................. 47
Assessing and Recording Adverse Events .......................................................... 49
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 49
Immediate Reporting of Adverse Events to the Sponsor.................................... 50
7.2.2
7.2.2.1
Serious Adverse Events ............................................................................... 50
7.2.2.2
Events of Clinical Interest............................................................................ 51
Evaluating Adverse Events ................................................................................. 51
7.2.3
Sponsor Responsibility for Reporting Adverse Events ...................................... 54
7.2.4
TRIAL GOVERNANCE AND OVERSIGHT................................................... 54
7.3
Scientific Advisory Committee........................................................................... 54
7.3.1
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 54
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
5
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Statistical Analysis Plan Summary ..................................................................... 54
8.1
Responsibility for Analyses/In-House Blinding ................................................. 55
8.2
Hypotheses/Estimation ......................................................................................... 55
8.3
Analysis Endpoints ............................................................................................... 55
8.4
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..................................... 55
8.4.1
Safety Endpoints ................................................................................................. 56
8.4.2
Analysis Populations............................................................................................. 56
8.5
Efficacy Analysis Populations ............................................................................ 56
8.5.1
Safety Analysis Populations ............................................................................... 57
8.5.2
Statistical Methods................................................................................................ 57
8.6
Statistical Methods for Efficacy Analyses.......................................................... 57
8.6.1
8.6.1.1
Primary Efficacy Analysis ........................................................................... 57
8.6.1.2
Secondary Efficacy Analysis ....................................................................... 58
Statistical Methods for Safety Analyses ............................................................. 60
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 60
8.6.3
8.6.3.1
Demographic and Baseline Characteristics ................................................. 60
8.6.3.2
Disposition of Subjects ................................................................................ 60
8.6.3.3
Pharmacokinetic Analysis............................................................................ 60
Interim Analyses ................................................................................................... 61
8.7
Multiplicity ............................................................................................................ 61
8.8
Sample Size and Power Calculations .................................................................. 61
8.9
Sample Size and Power for Efficacy Analyses ................................................... 61
8.9.1
Subgroup Analyses and Effect of Baseline Factors ........................................... 63
8.10
Compliance (Medication Adherence).................................................................. 63
8.11
Extent of Exposure................................................................................................ 63
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 63
Investigational Product ........................................................................................ 63
9.1
Packaging and Labeling Information ................................................................. 64
9.2
Clinical Supplies Disclosure................................................................................. 64
9.3
Storage and Handling Requirements.................................................................. 64
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 65
9.5
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
6
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Standard Policies................................................................................................... 65
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 65
Confidentiality....................................................................................................... 65
10.1
Confidentiality of Data ....................................................................................... 65
10.1.1
Confidentiality of Subject Records ..................................................................... 65
10.1.2
Confidentiality of Investigator Information........................................................ 66
10.1.3
Confidentiality of IRB/IEC Information............................................................. 66
10.1.4
Compliance with Financial Disclosure Requirements....................................... 66
10.2
Compliance with Law, Audit and Debarment ................................................... 67
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 68
10.4
Quality Management System............................................................................... 69
10.5
Data Management................................................................................................. 69
10.6
Publications ........................................................................................................... 69
10.7
11.0
LIST OF REFERENCES......................................................................................... 70
12.0
APPENDICES........................................................................................................... 73
Merck Code of Conduct for Clinical Trials........................................................ 73
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 75
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ...................................................................................... 79
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................... 90
Instructions on home-administration of MK-8962 (as provided to 
12.5
subjects) ................................................................................................................. 92
Tanner Staging (Male).......................................................................................... 94
12.6
Blood Pressure and Anthropometric Measurements ........................................ 95
12.7
List of Abbreviations ............................................................................................ 97
12.8
13.0
SIGNATURES........................................................................................................... 99
Sponsor's Representative ..................................................................................... 99
13.1
Investigator............................................................................................................ 99
13.2
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
7
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
LIST OF TABLES
    
Table 1
Prohibited Medications, Supplements, and Other Substances for Entry Into the 
Trial ........................................................................................................................ 26
Table 2
Trial Treatment ....................................................................................................... 27
Table 3
MK-8962 and hCG Dosing Schedule..................................................................... 30
Table 4
Laboratory Tests ..................................................................................................... 43
Table 5
Evaluating Adverse Events..................................................................................... 52
Table 6
Analysis Strategy for Key Efficacy Variables........................................................ 59
Table 7
The 95% Confidence Limits for Geometric Mean Increase in Testicular 
Volume (mL) by Underlying Difference and SD Assumptions (log-scale) for 
10 Completers......................................................................................................... 62
Table 8
Product Descriptions............................................................................................... 64
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
8
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
LIST OF FIGURES
Figure 1
Trial Design Diagram ......................................................................................... 13
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
9
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.2
Dose Titration for hCG
A note was added to allow for 
human Chorionic Gonadotropin 
(hCG) dose titration outside of 
the suggested range of 500 IU to 
5000 IU following consultation 
with the Sponsor.
The previous protocol version indicates 
that the dose of hCG may be titrated 
between 500 IU and 5000 IU twice 
weekly. However, it does not clearly 
indicate 
that 
in 
some 
cases, 
the 
investigator may need to adjust the hCG 
dose outside of the suggested range of 
500 IU to 5000 IU twice weekly, based 
on total testosterone (Total T) and 
estradiol (E2) levels and/or clinical 
assessments, following consultation with 
the Sponsor. Therefore, this specific 
wording was added to the protocol to 
allow for hCG dose titration in the 
instances outlined above.
2.2
Trial Diagram
A 
footnote 
was 
added 
to 
Figure 1, Table 2, and Table 3 to 
allow for hCG dose titration 
outside of the suggested range of 
500 IU to 5000 IU
following 
consultation with the Sponsor.
5.2
Trial Treatment(s)
5.2.2
Timing of Dose Administration
8.1
Statistical Analysis Plan Summary
The
hCG 
dose 
range 
was 
removed from the Treatment 
Assignment.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
10
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
NA
Title Page
The Sponsor’s name and address have 
been updated.
The Sponsor’s legal name and address 
have been updated.
5.1.3
Subject Exclusion Criteria
An exclusion criterion has been added 
for subjects with renal insufficiency as 
determined by the investigator.
To harmonize the exclusion criteria with 
the 
Elonva 
Summary 
of 
Product 
Characteristics (SmPC) and Company 
Core Data Sheet (CCDS) and to align 
with the country specific amendment for 
Denmark (P043-05).
7.1.3.2
Panel 
of 
Endocrine 
Parameters
Follicle stimulating hormone (FSH) and 
luteinizing 
hormone 
(LH) 
testing 
performed as part of the optional 
gonadotrophin 
releasing 
hormone 
(GnRH) agonist stimulation test or 
GnRH intravenous (IV) infusion test 
should
be performed at the local 
laboratory.
To clarify that the LH and FSH assays 
that are part of the GnRH agonist 
stimulation test or GnRH IV infusion 
test should be performed locally, as 
these are optional procedures to be 
performed under the discretion of the 
Principal Investigator.
7.1.4.4
Calibration of Equipment
The 
specification
of 
“critical” 
equipment and the list of equipment 
requiring 
calibration
have 
been 
removed.
Textual revisions were applied to clarify 
investigator responsibility for calibration 
and 
maintenance 
of 
study/trial 
equipment.
All
All
Clerical and formatting changes.
Consistency throughout the document.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
11
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
1.0 TRIAL SUMMARY
Abbreviated Title
MK-8962 (corifollitropin alfa) in adolescent males 14 to <18 years old 
with hypogonadotropic hypogonadism (HH)
Trial Phase
Phase III
Clinical Indication
Treatment of adolescent males 14 to <18 years old with HH
Trial Type
Interventional
Type of control
Uncontrolled
Route of administration
Subcutaneous (SC) injection
Trial Blinding
Unblinded Open-label
Treatment Groups
MK-8962 100 μg (for subjects with body weight ≤60 kg) or 150 μg
(for subjects with body weight >60 kg) once every two weeks for 12 
weeks, followed by 52 weeks of combined treatment with MK-8962 
once every two weeks and human Chorionic Gonadotropin (hCG) 
twice a week 
Number of trial subjects
Approximately 15 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 2.5
years from the time the first subject signs the informed consent/assent
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 73 weeks
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  After a screening phase of up to 6 weeks,
each subject will be treated for 12 weeks with MK-8962 alone (i.e., 
priming phase).  After completion of the Priming Phase, the subject 
will start on combined treatment with both MK-8962 and hCG for 52
weeks.  At the end of the combined treatment phase or at premature 
discontinuation, a post-treatment follow-up visit will be scheduled at 
least 21 days after the last MK-8962 injection (and at least 7 days after 
the last hCG injection).
After the post-treatment follow-up visit, 
subjects who prematurely discontinue study medication but do not 
withdraw consent will continue to be followed up until they have 
reached Week 64 after initial treatment allocation. 
Subjects 
discontinued from the treatment due to the presence of neutralizing 
anti-drug antibodies (ADAs) may continue to be followed until the 
ADA result becomes negative or until clinically stable for up to 12 
months after treatment discontinuation.
A list of abbreviations used in this document can be found in Section 12.8.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
12
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
2.0 TRIAL DESIGN
Trial Design
2.1
This is a multi-center, open-label, single-group trial of MK-8962 (corifollitropin alfa) in 
adolescent males 14 to <18 years old with hypogonadotropic hypogonadism (HH).
The primary efficacy endpoint for this trial is the change from baseline in testicular volume 
after 64 weeks of treatment with MK-8962 (given alone once every two weeks for 12 weeks,
then in combination with twice-weekly doses of human Chorionic Gonadotropin (hCG) for 
52 weeks).
The primary safety endpoint is the presence of anti-drug antibodies (ADA) 
against MK-8962. Subjects with neutralizing anti-MK-8962 antibodies in the ADA assay 
will discontinue treatment and will be followed with repeat ADA testing, until the ADA 
result becomes negative or until the subject is clinically stable for up to 12 months after 
treatment discontinuation, whichever comes first. Each subject will be followed for safety 
monitoring until the last protocol-specified visit or contact.
This study will be approximately 73 weeks in duration. After signing the informed 
consent/assent at Visit 1 (V1), the subject will undergo a screening period of up to 6 weeks. 
Eligible subjects will be allocated to a 12-week MK-8962 priming phase at Visit 2 (V2)/Day 
1 (Week 0). The first 3 doses of MK-8962 will be self-administered by the subject (or 
administered by an appropriately trained person designated by the subject’s legal guardian 
(e.g., caregiver, parent/legal guardian) and witnessed by qualified personnel at the trial site at 
V2/Day 1, Visit 7 (V7)/Week 2 (Day 15), and Visit 8 (V8)/Week 4 (Day 29). 
A 
pharmacokinetic (PK) sample will be collected from each subject prior to the first injection 
of MK-8962 at V2/Day 1. During the first two weeks of the priming phase, frequent PK
sampling will be performed from Visit 2 (V2/Day 1) through Visit 6 (V6/Day 11) to collect 
PK samples post first dose of MK-8962. Additional PK samples will be collected at other 
visits throughout the trial as specified in the PK flow chart (see Section 7.1.3.3.1).
A
telephone contact (TC) will be conducted at Week 8 to monitor AEs, concomitant 
medication, and study medication compliance.
At Visit 9 (V9)/Week 12 (Day 85), the subject will enter a 52-week MK-8962 and hCG 
combined treatment phase. The first dose of hCG will be self-administered (or administered 
by an appropriately trained person designated by the subject’s legal guardian) at the trial site 
as a witnessed dose at V9. During the combined treatment phase, the subject will have site 
visits every 8 to 12 weeks from V9 until treatment completion at Visit 15 (V15)/Week 64. 
Telephone contacts will be conducted every 4 weeks between site visits to monitor AEs, 
concomitant medication, and study medication compliance. The last dose of MK-8962 is 
scheduled to be home-administered by the subject (or an appropriately trained person 
designated by the subject’s legal guardian) on Week 62. The subject (or the designated 
person) will continue to home-administer the twice-weekly hCG and the last dose will be 
administered in Week 64. A post-treatment follow-up visit is to be scheduled at least 21 days 
(but no more than 45 days) after the last dose of MK-8962, and at least 7 days after the last 
dose of hCG (whether the subject completed the trial or discontinued from the study 
treatment prematurely).  (See Figure 1)
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
13
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
The subject and his legal guardian (or someone designated by the subject’s legal guardian 
such as a caregiver or parent) will receive instructions on MK-8962 and hCG home-injection 
prior to the initiation of treatment. After the first three doses of MK-8962 and the first dose 
of hCG, the subsequent medication will be dispensed by the investigational site to the subject 
for home-administration unsupervised by the investigator.  A paper diary will be used to 
record the time and amount of MK-8962 and hCG administration.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
2.2
Figure 1
Trial Design Diagram
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
14
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
In adolescent males 14 to <18 years old with HH:
1) Objective:  To estimate the change from baseline in testicular volume (measured as 
the sum of volumes of left and right testes by ultrasound) after 64 weeks of treatment 
with MK-8962 (in combination with hCG for the last 52 weeks).
2) Objective:
To evaluate the safety and tolerability of MK-8962 over 64 weeks of 
treatment, including evaluation of development of antibodies to MK-8962.
Secondary Objective(s) & Hypothesis(es)
3.2
In adolescent males 14 to <18 years old with HH, to evaluate the following parameters over 
64 weeks of treatment with MK-8962 (in combination with hCG for the last 52 weeks):
1) Objective: the change from baseline in inhibin B concentrations.
2) Objective: growth velocity (height).
3) Objective: the change from baseline in Tanner Stage of pubertal development.
4) Objective: 
the change from baseline in levels of endocrine parameters (i.e., 
luteinizing hormone [LH], calculated free testosterone [T], total testosterone [Total 
T], estradiol [E2], sex hormone-binding globulin [SHBG], and anti-Müllerian 
hormone [AMH].
5) Objective: testicular sonographic pattern reflecting pubertal development.
6) Objective: the PK of MK-8962 (based on serum MK-8962 concentrations).
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-8962.
Pharmaceutical and Therapeutic Background
4.1.1
The testes, or testicles, are the primary organs of the male reproductive system. The testes 
are immature until the time of puberty, at which time they begin to produce adult levels of T 
as well as spermatozoa. The first physical sign of puberty in males is testicular enlargement 
(gonadarche) that is induced by the pulsatile release of hypothalamus-derived gonadotropin 
releasing hormone (GnRH). 
Development of male secondary sexual characteristics, 
including spermarche, male hair growth patterns, and development of adult male T levels
then follows.  While the average age of puberty varies by race, the onset of puberty generally 
occurs between the ages of 10 and 13 and is considered to be delayed when there is a lack of 
pubertal development, specifically gonadarche, by the age of 15.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
15
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Successful puberty requires an intact hypothalamic-pituitary-testicular axis. Initially, GnRH 
stimulation results in an increase in follicle stimulating hormone (FSH) levels that acts at the 
testes to induce proliferation of the Sertoli cells and an increase in gonadal size. The 
subsequent exposure to LH halts further proliferation through terminal differentiation of the 
Sertoli cells, increases T levels and induces further development of secondary sexual 
characteristics [1]. This sequential exposure is thought to be necessary for normal testicular 
development and subsequent fertility.
HH is a disease of inadequate production of pituitary derived FSH and LH.  HH can be the 
result of failed gonadotropin secretion by the pituitary or absent or inadequate GnRH 
secretion by the hypothalamus. The clinical manifestations of HH depend on the stage of 
development at which the deficiency occurred (pre or post-pubertal). When the deficiency 
occurs prior to puberty (pre-pubertal), the pubertal transition is delayed or absent.  The 
condition can be congenital or acquired, and can occur in isolation (idiopathic HH [IHH]), in 
association with anosmia/hyposmia (Kallmann syndrome), or as part of a multiple pituitary 
hormone deficiency syndrome.  IHH is the rarest form, with an incidence of between 
1:10,000 and 1:86,000, whereas acquired HH is more common because there are multiple 
etiologies that lead to the disease [2]. The primary goal in the treatment of male HH is to 
increase testosterone levels, leading to the development of secondary sexual characteristics.  
Another important goal is to stimulate spermatogenesis, at an appropriate time, supporting 
fertility.  Historically, boys with HH were not treated with FSH in adolescence as FSH leads 
to spermatogenesis, which is not the goal of treatment at this age [3; 4].  Instead, these boys 
were given exogenous testosterone in sufficient quantity to induce the development of male 
secondary sexual characteristics and then to maintain normal male T levels.  However, boys 
that are not exposed to FSH during the critical pubertal window required for Sertoli cell 
proliferation may miss this critical state of testicular development. Exposure to LH (or T) 
causes terminal differentiation of the Sertoli cells, limiting the ability of FSH to induce 
Sertoli cell proliferation in future exposures.  As a result, the testes do not fully develop, and 
this could have an impact on future fertility [1; 5].  This has been confirmed in studies of 
adult men who had achieved normal male T levels only using testosterone supplementation 
in adolescence but then fail to achieve normal range sperm counts, inhibin B levels and adult 
testicular size when exposed to GnRH therapy later in life [5]. Thus, modern treatment 
protocols for adolescent males with HH use a 3-staged approach, first using FSH-only for a 
short time, followed by the combination of FSH and hCG, which occupies the LH receptor 
and has a longer half-life than an LH [3; 4], until full testicular volume is achieved.  In the 
3rd stage of treatment, gonadotropin therapy is stopped and testosterone supplementation is 
used to maintain secondary male characteristics until such time when fertility is desired.  
This approach allows for both the induction of puberty as well as maturation of the testicular 
tissue in males with early onset HH so that spermatogenesis and future fertility are not 
compromised.
During the second stage of this 3-stage approach to testicular maturation, injectable 
recombinant human FSH (recFSH) is used to promote Sertoli cell function and hCG is used
to induce Leydig cell function and increase T production [3; 4]. hCG is preferred over T 
because hCG can stimulate a small amount of additional testicular growth if the testes are 
still of a sub-optimal volume. [3; 4] Previous studies have shown that this 3-stage therapy
protocol has successfully induced puberty as indicated by an increase in testicular size and a 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
16
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
rise in circulating inhibin B levels, findings suggesting proliferation of immature Sertoli 
cells.
Inhibin B has been shown to be a useful surrogate for monitoring spermatogenic 
activity in boys treated with hCG when semen analysis is not feasible [3; 4], and will be used 
to monitor testicular development in this study.
MK-8962 (Elonva®, corifollitropin alfa) is a recombinant gonadotropin consisting of the -
subunit of human FSH and a hybrid subunit composed of the sequence of the -subunit of 
human FSH and the carboxy-terminal peptide (CTP) part of the -subunit of the hCG.  It has 
the same pharmacodynamic (PD) profile as FSH, but different PK properties.  MK-8962 has 
an approximately 2-fold longer elimination half-life and an almost 4-fold extended time 
interval to peak serum levels as compared to that of recombinant human FSH (follitropin 
beta) [6].  Both MK-8962 and recFSH work via the same FSH receptor in the ovary or testes, 
therefore either can be used for gonadal stimulation.  Three Phase III randomized, controlled 
clinical trials comparing MK-8962 to recFSH in women undergoing ovulation induction in 
an Assisted Reproductive Technology (ART) cycle confirmed either non-inferiority (Trials 
38819 [7] and P06029 [8]) or equivalence (Trial 107012 [9]) in the clinical outcomes of 
pregnancy rates or number of oocytes retrieved.  In P031[10], a clinical trial in 18 adult 
males with HH, MK-8962 use resulted in a more than doubling of the mean testicular volume 
along with induction of spermatogenesis in 77% of adult males who remained azoospermic 
after treatment with hCG. These findings are consistent with the findings of Trial 37618 [11]
where recFSH use resulted in a doubling of mean testicular volume and induction of 
spermatogenesis in 43% of adult men who remained azoospermic after hCG administration.  
Although the percentage of men who achieved spermatogenesis was higher in trial P031, the 
small size of both studies (N= 18 in P031 and N=30 in Trial 37618) limits quantitative 
comparisons; the stimulation of spermatogenesis in a substantial portion of treated subjects 
suggests both agents had clinically relevant FSH activity.  While there are no comparative 
trials between MK-8962 and recFSH in HH males, the fact that both drugs work at the same 
FSH receptor site, have both been successful in stimulating spermatogenesis in men and both 
have non-inferior/equivalent clinical outcomes in women, it is a reasonable assumption that
MK-8962 use in HH males would have a similar response as that seen with the use of 
recFSH.  And since treatment of infertility in HH males usually requires up to 24 months of 
treatment with frequent injections of FSH, the need for fewer injections with MK-8962 may 
result in fewer medication errors and improved compliance, a specific benefit for the 
adolescent population.
MK-8962 is currently approved for Controlled Ovarian Stimulation (COS) in women 
participating in ART programs in 81 countries worldwide, including all 27 member states of 
the European Union (EU), Norway, Iceland, Liechtenstein, and 51 countries outside of 
Europe. As noted above, the efficacy and safety of both 100 and 150 µg of MK-8962 in 
comparison to daily doses of 150-300 IU of recFSH has been established in women.  In 
addition, two studies have been conducted in HH men:

One Phase 1, open label, repeated dose trial with 15 µg MK-8962 (Trial 38801 [12])
has been conducted in 13 adult HH men to study the first human exposure to 
corifollitropin alfa. Subjects received four subcutaneous injections of 15 µg MK-
8962 with an interval of ~4 weeks. In these men, a single dose of 15 µg -8962 was 
able to induce a rise in serum inhibin B concentrations [12].  Analysis of 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
17
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
pharmacokinetic data from this trial and later Phase I - III trials in women suggest 
that drug clearance is 40% lower in men as compared to women.  

The safety and efficacy of MK-8962 for the treatment of HH in adult men has been 
evaluated in a Phase III, multi-center, open-label, single-group trial of MK-8962 in 
combination with hCG in 18 adult HH men 18-50 years of age (Trial P031 [10]). The 
dose and interval selection for this trial was based on modeling and simulation
(M&S) using PK data from MK-8962 Phase I - III trials as well as recFSH Trial 
37618. The M&S showed 150 µg MK-8962 once every two weeks are expected to 
achieve trough serum FSH-IR Levels comparable to that of ≥4 IU/L seen after 
treatment with recFSH in Trial 37618.
Trial P031 was conducted to establish the 
benefit/risk ratio of MK-8962 in adult HH men before the start of the pediatric trial in 
HH adolescent boys.  As noted above, this study showed that 150 µg MK-8962 
adminstered once every two weeks in combination with twice weekly hCG injections 
resulted in an increase of testicular volume and induced spermatogenesis.  There were 
no safety concerns with respect to adverse events and immunogenicity.  Since the 
metabolic clearance of MK-8962 in adolescent males over 14 years of age is expected 
to be similar to that of adult males, the PK data from P031 has been used to predict 
the exposure in adolescents and to determine final dose selection in the current trial.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
The current trial will evaluate MK-8962 in HH adolescent boys between 14 and <18 years of 
age.  This trial is a multi-center, open-label, single-group trial to study the treatment of MK-
8962 in combination with hCG to induce and/or restore puberty and induce and/or restore 
spermatogenesis in adolescent males with HH.
The major difference in the treatment schedule between this trial and the previous adult male 
trial is the use of MK-8962 alone for the first 12 weeks of the trial.  This 12 week “priming” 
period allows for FSH exposure to induce Sertoli cell proliferation to occur before exposure 
to hCG, which is not applicable to the adult male population who have previously been 
virilized.  The priming period is followed by 52 weeks of combined MK-8962 and hCG 
stimulation to evaluate the safety and efficacy of longer term use.
Adolescent males aged 14 to <18 years with an established diagnosis of HH (either 
congenital or acquired with onset prior to puberty) will be evaluated for eligibility to 
participate in this trial.
Adolescent males who lack signs of pubertal development (e.g., development of secondary 
sexual characteristics, testicular enlargement, etc.) by the age of 14 years, and have 
inappropriately low testosterone and gonadotropin levels (LH and FSH), are considered to 
have HH.
According to International Council on Harmonisation (ICH)/ Committee for 
Medicinal Products for Human Use (CHMP) E11 guideline, the range of 12 to 16-18 years 
(depending on region) is defined as “adolescents”. However, for the purpose of this study, 
the selected age group would be a subgroup of the ICH category: only males from 14 to <18 
year category who are diagnosed with HH will be studied. The lower limit of 14 has been 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
18
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
chosen because the diagnosis of HH in males < 14 years of age is difficult to establish, and 
more importantly, this condition generally does not require any treatment to induce puberty 
below 14 years of age.
Rationale for Dose Selection/Regimen/Modification
4.2.2
Population pharmacokinetics (PopPK) analyses were performed on the pooled data from the 
studies P031 [10] and 38801 [12], which used the protein-free (pf) formulation and non-
protein (non-pf) free formulation of MK-8962, respectively. The pharmacokinetics of MK-
8962 was well described by a one-compartment model with first-order absorption. A relative 
bioavailability fraction was estimated to account for differences in formulation (the current pf
formulation and the non-pf formulation) used in the two studies. FSH-immunoreactivity 
(FSH-IR) data were integrated into the analysis by estimating a scaling factor between FSH-
IR and MK-8962 concentrations. Body weight was found to be an important covariate for 
both clearance and volume of distribution (CL and V).
Based on derivations from the PopPK model, treatment with 150 µg MK-8962 every two 
weeks in Trial P031 [10] resulted in a mean trough serum FSH-IR level of 4.86 IU/L.  These 
results were comparable to the trough serum FSH-IR levels of ≥4 IU/L seen after treatment 
with recFSH in Trial 37618 [11], where 225 IU twice weekly or 150 IU three times weekly 
was found to double the mean testicular volume and induced spermatogenesis in 43% of 
azoospermic adult males with HH. As noted in Section 4.1.1, the treatment with MK-8962 is 
expected to be similar to treatment with recFSH, therefore the results of these two trials were 
considered in selecting a trough FSH-IR level of ≥4 IU/L as the main criteria for dose 
selection in this adolescent trial. 
Simulations using the PopPK model demonstrate that trough serum FSH-IR levels are 
expected to remain above 4 IU/L when adolescent males are treated once every two weeks 
with either 100 µg (for a body weight of ≤60 kg) or 150 µg (for a body weight of >60 to 100 
kg) of MK-8962. When treating adolescent males weighing >100 kg, 150 µg MK-8962 
every two weeks would result in a trough serum FSH-IR level slightly below 4 IU/L in the 
majority of subjects.
4.2.2.1
Rationale for Single Arm Design
HH is a rare disease affecting between 1-10:100,000 of all (male and female) live births [6].  
Due to the small number of subjects with this disease, recruitment of a sufficient number of 
subjects for both a treatment and comparator arm would be challenging, likely limiting the 
size of the MK-8962 group and hence experience.  Based upon prior information on MK-
8962, as well as information on the natural history of HH in adolescent males, trial objectives 
can be met in a single-arm, non-controlled study. Rationale supporting the use of a single 
arm study for the use of MK-8962 in adolescent boys with HH is provided below.
Rationale for not including a placebo arm
HH is associated with extremely low levels of the pituitary hormones (FSH and LH) required 
for pubertal development, leaving the subject in an infantile developmental state.  The 
psychosocial impact of this condition is significant, leading to depression, anxiety, sexual 
dysfunction and a lower quality of life, all of which improve significantly with treatment 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
19
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
[13].  The possible negative psychosocial impact in untreated subjects raises ethical 
considerations that preclude the use of a placebo in this trial.  
Since it is possible that some patients diagnosed with HH could have constitutional delay of 
puberty—and therefore spontaneously progress through puberty—the lack of a placebo group 
could impact conclusions regarding proportion of patients responding to active treatment 
(i.e., overestimating treatment response).  However, given the small size of a placebo group 
that could be recruited into this study, robust comparisons to placebo would be limited.  
Moreover, since no placebo group is planned, the study’s enrollment criteria have been 
carefully crafted to avoid the inclusion of subjects with a constitutional delay of puberty that 
are misdiagnosed with HH.  
The diagnosis of HH will be confirmed using physical findings as well as strict endocrine 
parameters (Section 5.1.2). The strict enforcement of these enrollment criteria will minimize 
the possibility of a misdiagnosis and ensure that spontaneous progression to puberty is an 
uncommon event in this trial.  LH levels will be monitored during the study to identify any 
subjects with spontaneous recovery of endogenous pituitary function.
It is also recognized that spontaneous improvement in HH resulting in improvement in the 
primary outcomes parameters is a possibility.  However, in a review of 308 patients with 
confirmed HH that specifically looked for evidence of spontaneous reversal of HH, only 39 
males and 5 female patients had any physiologic evidence of spontaneous improvement of 
endocrine functions [14].  When stricter criteria for spontaneous progression based on 
recovery of serum testosterone, menstrual cyclicity, and/or fertility were applied, the 
numbers dropped to 29 men and 4 women (~10%), and the earliest age at which this recovery 
was evident in males was 19.1 years (mean age - 28.3 years) [14].  Additionally, spontaneous 
reversal of function has not been reported in any treatment naïve subject [14]. Given these 
findings, it would be unlikely that changes seen in these subjects over the course of the 
current study would be the result of spontaneous reversal of the disease. As noted, LH levels 
will be monitored during the study to identify any subjects with spontaneous recovery of 
endogenous pituitary function. Subjects with LH levels >3 IU/L during the trial will be 
excluded from the analysis.
Based on the possible negative impact of withholding treatment, the use of strict inclusion 
criteria, and the low possibility of spontaneous improvement of HH, the use of a placebo in 
this trial is not planned.
Rationale for not including a comparator arm
The pharmacodynamic profile of MK-8962 had been shown to be similar to that of FSH, and 
has been well-documented in trials with women undergoing COS [7], [8], [9] and in Trial 
P031 [10] of adult males with HH.  In addition, the use of FSH preparations to induce 
testicular maturation and pubertal development in the adolescent HH male population is well-
documented in the literature [1, 15, 16]. Therefore, it is anticipated that MK-8962 use should 
result in changes in testicular development that are similar to what is seen with recFSH.  
Given the small population available to enter the trial, the robustness of any comparison to 
recFSH would be very limited.  In addition, the strong evidence for appropriate FSH activity 
of MK-8962, and the prior literature studies looking at response to FSH in this population, 
support that the single arm study being implemented here should be interpretable.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
20
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
The primary efficacy endpoint is the change from baseline (Day 1) to Week 64 in log-
transformed testicular volume (measured as the sum of volumes of left and right testes by 
ultrasound).
The initiation of spermatogenesis is dependent on both an increase in testicular volume and 
an increase in intra-gonadal testosterone levels [17], both of which occur in puberty when the 
hypothalamic-pituitary-gonadal axis becomes active. Although an increase in testicular size, 
in response to FSH and to a lesser degree LH stimulation, is required for spermatogenesis, 
there are little data linking an increase in testicular volume with spermatogenesis in HH 
adolescent boys.
However, data do show an association between testicular volume and 
future success with fertility-inducing treatments in adult men. Specifically, several studies 
have found that a small testicular volume (<4 mL) at the initiation of fertility-inducing 
treatment is a negative predictor of success [15, 18]. Further, there are reports of a longer 
time to response with smaller testicular volume [19], [20] and better outcomes with hCG 
mono-therapy in adult men with larger initial testicular volume increases [15], and higher 
sperm count associated with higher initial testicular volume [21]. From these data it can be 
inferred that an increase in testicular size in adolescence would result in a greater chance of 
spermatogenesis later in life. Therefore, the induction of pubertal changes, with the aim of 
increasing testicular volume and protecting future fertility, is becoming the standard of care 
for HH adolescent boys.
While semen analysis would be a standard approach to assess changes in spermatogenesis, 
semen analysis would be difficult to implement in this adolescent population.  There are 
several other endpoints that provide additional support for testicular development and 
spermatogenesis, as described below.

Serum inhibin B concentration has been shown to be a useful surrogate biomarker for 
spermatogenesis [1] and will be monitored over the treatment period.

Testicular echogenicity. Patients with
HH or Kallmann syndrome have a 
hypoechogenic pattern of the testicular parenchyma, which becomes
more 
normoechogenic with testicular maturation following gonadotropin treatment [22],
suggesting that this endpoint may be useful to demonstrate maturation. 
The 
ultrasound pattern of the testicular parenchyma will be monitored for this change in 
this study to determine treatment effect.
To date there is no generally accepted 
standard grading system for testicular echogenicity. To ensure standardization across 
the study sites, the ultrasound images will be read by a Sponsor-validated central 
imaging vendor. The assessments will be made according to a categorization system 
developed by the central imaging vendor and approved by the Sponsor, as described 
in the Independent Review Charter for imaging. 

Growth velocity (height measurement) and Tanner Stage of Development are well 
recognized markers for pubertal progress.  These will be monitored in all subjects 
during this study. Details for the growth velocity and Tanner Stage assessment can 
be found in Section 7.1.2.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
21
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential

Endocrine parameters to be measured in this study include calculated free T, Total T, 
E2, SHBG, and AMH. These hormones will serve as markers for the progress of 
puberty as a result from the study treatment.

In addition, serum hCG levels will be measured to monitor treatment compliance.
During the course of the trial, endogenous LH is expected to remain low in patients 
with HH. A subject with delayed puberty might experience pituitary maturation with 
MK-8962 and hCG treatment, which would result in an increase of the LH level. 
Therefore LH will also be measured during the trial to confirm the initial HH 
diagnosis.  
4.2.3.2
Safety Endpoints
The pre-specified safety endpoint is the confirmed presence of anti-MK-8962 antibodies, 
which may have an impact on drug response. Previous studies in both men and women have 
not identified a safety concern with anti-MK-8962 antibodies. A total of 2511 women were 
tested for the development of anti-corifollitropin alfa antibodies in 3075 cycles.  All 2511 
women were tested after a single injection of MK-8962, 372 were tested after two injections 
of MK-8962, and 192 were tested after three injections of MK-8962. Of all these women, 4 
developed non-neutralizing antibodies to MK-8962 which showed cross-reactivity with 
human FSH (hFSH), including one woman who was tested positive only after the second
exposure to MK-8962. However, these antibodies did not interfere with the response to 
pituitary stimulation or with the normal physiologic responses of the Hypothalamic-Pituitary-
Ovarian axis.  Therefore, these antibodies were judged to be not clinically relevant.  Of the 
18 adult men who were exposed to MK-8962 for long term treatment of HH, one subject had
a positive antibody test that was later deemed to be a false positive.   
Subjects in this study will be monitored by the Sponsor on an ongoing basis for the 
development of ADA against MK-8962. Subjects with confirmed presence of such ADA will 
be discontinued from the treatment because of the unknown implication of such ADAs. 
ADA antibodies that cross-react (depletion confirmed) with FSH have been noted in women 
without any significant clinical implications.  However, the ability to predict the outcome of 
an ADA exposure in boys who are naïve to FSH and whom have never been exposed to 
normal levels of endogenous FSH based on exposures in women with normal to elevated 
endogenous FSH levels remains uncertain.  Yet the implications of a boy developing 
antibodies that would block the action of FSH and might prevent further pubertal 
development are somewhat more serious than the development of these same antibodies in a 
woman who had completed puberty and had desired ovulation induction for the treatment of 
infertility. For this reason, in order to mitigate any possible negative outcome from the 
development of such ADAs, a subject testing positive for neutralizing anti-MK-8962 
antibody will be discontinued from the treatment. These subjects will be followed with 
repeat ADA antibody testing.  This will continue until the ADA result becomes negative or 
until the subject is clinically stable (e.g., in the absence of hCG use, no clinically meaningful 
change in testicular volume or testosterone levels for 3 months; if hCG continues to be used, 
an appropriate response to hCG with stable testosterone levels) for up to 12 months after 
treatment discontinuation, whichever comes first.
(Refer to Section 7.1.5.3 for details on 
follow-up procedures for these subjects).
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
22
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Other safety endpoints in this trial are laboratory assessments, vital sign measurements 
(blood pressure [BP], heart rate [HR], and body weight), and adverse experiences which are 
monitored routinely. 
4.2.3.3
Pharmacokinetic Endpoints
The PK of MK-8962 will be based on serum MK-8962 concentrations determined by a 
validated immunoassay. Serum FSH concentration will also be measured to support the PK 
analysis.
MK-8962 is indicated for the treatment of female infertility with a dose regimen based on 
age and weight: 

100 µg for subjects with body weight ≤60 kg and age ≤ 36 years 

150 µg for subjects with body weight > 60 kg regardless of age, or body weight ≥50 
kg and age > 36 years)
Single dose pharmacokinetics of MK-8962 has been studied in pituitary-suppressed female 
volunteers and in normogonadotropic female patients undergoing COS with MK-8962 using 
a GnRH antagonist protocol to prevent premature LH surges. 
A clinically-relevant 
relationship between drug-exposure and body weight was demonstrated. Prospective clinical 
studies demonstrated that in subjects ≤36 years old, exposure to MK-8962 was similar 
between women who weigh ≤60 kg and who received 100 µg of MK-8962 and women who 
weight >60 kg and who received 150 µg of MK-8962.
Distribution, metabolism and elimination of MK-8962 are very similar to other 
gonadotropins, such as FSH, hCG and LH. Elimination of MK-8962 predominantly occurs 
via the kidneys and may be impaired in patients with renal insufficiency. Hepatic metabolism 
contributes to a minor extent to the elimination of MK-8962. Prior studies confirmed that PK 
profiles appear similar between males and females. When corrected for body weight, CL in 
males would be estimated to be about 30% lower compared to females, in line with the 
original assumption of a 40% difference. MK-8962 has the same mechanism of action as 
recFSH and interacts only with the FSH receptor on the Sertoli cell. The clearance of MK-
8962 in adolescent males aged 14 years or older is expected to be similar to that in adults.
A female population PK model was modified with data from the HH adult male trial (P031) 
and used to predict serum MK-8962 concentration in HH adolescent males. 
Dose 
recommendation for adolescents was selected through simulations based on the modified 
population PK model. 
It is anticipated, based on maturated kidney elimination and metabolic drug clearance 
systems, that PK data of adolescent males aged 14 years or older will be similar to PK data of 
adult males.  To further support the expectation that PK data will be similar, PK sampling 
will be performed in the current study in adolescent males to confirm predicted exposure 
levels.
4.2.3.4
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial. This research may include genetic analyses (DNA), 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
23
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the 
measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male subjects with HH aged 14 to <18 years will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Have a legal representative who understands the study procedures, alternative treatments 
available and risks involved with the study, and voluntarily agrees to the subject’s 
participation by giving written informed consent, and the subject has an age-appropriate 
understanding of the same to give informed written assent if applicable (i.e., in 
accordance with local requirements). Subjects with an illiterate legal representative may 
be included if, in the opinion of the investigator, the legal representative fully 
understands the risks of the subject’s participation and provides consent. In addition, the 
legal representative may also consent to (and in accordance with local requirements, the 
subject may assent to) have the subject participate in Future Biomedical Research by 
signing a separate consent. Note: otherwise eligible patients will be able to participate in 
the main study even if they opt to not participate in FBR.
2. Be male.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
24
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
3. Be 14 to <18 years of age at the time when consent/assent is signed, with treatment to 
begin prior to the subject’s 18th birthday.
4. Have been diagnosed with hypogonadotropic hypogonadism (either isolated or associated 
with panhypopituitarism), either congenital or acquired with onset prior to puberty.
Note:
Subjects with drug-induced hypogonadotropic hypogonadism (e.g., misuse of 
anabolic steroids, chronic use of glucocorticoids or narcotic analgesics, etc.) are 
excluded.
5. Have bilateral pre-gonadarche testes as defined by testicular volume <4.0 mL for each 
testicle, as determined by ultrasound and assessed by the investigator (if qualified) or 
local radiologist with appropriate training and expertise in reading testicular ultrasound.
Note: subjects with a volume of <4.0 mL in one testicle and a volume of 4-8 mL in the 
other testicle are considered to be pre-gonadarche and may participate, if there is no 
history or evidence of a primary testicular disorder (see Exclusion Criteria 1 and 2).
6. Have circulating levels of Total T less than the lower limit of normal (LLN) of 8.3 
nmol/L as specified by the central lab for a young healthy adult male.  
7. Have FSH ≤2 IU/L and LH ≤2 IU/L.
8. Have inhibin-B levels ≤35 pg/mL. [23]
Note: if the subject has inhibin-B levels >35 pg/mL, but meets all of the other 
inclusion/exclusion criteria, either a GnRH agonist (GnRHa) stimulation test or GnRH 
IV infusion test may be performed. The subject may be enrolled if either of the 
following is met: 

GnRH agonist (GnRHa) stimulation test: LH level of <3 IU/L at all of the 
following timepoints: 0, 60, 120, and 180 minutes after subcutaneous 
administration of a GnRH agonist, e.g., 500 micrograms of leuprolide acetate.
[24]

GnRH IV infusion test: LH peak <5.8 IU/L and FSH peak <4.6 IU/L at all of 
the following timepoints: 0, 15, 30, 45, 60 and 120 minutes during intravenous
infusion of GnRH 100 micrograms over 120 minutes.[19]
9. Be in good general physical and mental health, in the opinion of the investigator/sponsor, 
as assessed by physical examination and routine clinical laboratory tests.
10. Have a parent/guardian able and willing to support the subject’s participation by 
supporting adherence to study drug dosing and visit schedules.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Has a history of bilateral cryptorchidism (maldescended testes)
or unilateral 
cryptorchidism treated after the age of 2 years.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
25
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
2. Has a history or presence of clinically significant testicular problems (e.g., epididymitis, 
orchitis, testicular torsion, varicocele Grade
III, testicular atrophy, occlusive 
azoospermia, etc.) that in the opinion of the investigator would impair the subjects 
response to treatment or has had known damage or injury to the vas deferens.
3. Has had any previous treatment with GnRH, gonadotropins (e.g., hCG, FSH) or 
androgens (e.g., testosterone, etc.).  Note:
Use of GnRH and gonadotropins for 
diagnostic testing purposes only is allowed. Subjects with use of hCG and androgen 
therapy prior to the age of 2 years old can be included in the trial. Subjects with transient 
use of androgens (i.e., for less than 2 weeks) that was stopped at least 6 months prior to 
signing informed consent can also be included in the trial.
4. Has an untreated or inadequately treated pituitary or hypothalamic tumor.
5. Has uncontrolled endocrinopathies, including thyroid, adrenal, and pituitary disorders not 
on stable replacement therapies (i.e., subject has not been on stable doses for at least 3 
months).
Note:  The subject with a free T4 level outside of the normal laboratory range at the 
time of screening will be excluded, but may be rescreened once he has been on a stable 
dose of replacement therapies for at least 3 months.
6. Has a history of active pituitary hypersecretion as evidenced by hyperprolactinemia or 
Cushing’s disease, or acromegaly, or any other active pituitary hypersecretion syndrome. 
Note: Subjects who have been treated and are clinically stable, with no evidence of 
hypersecretion for at least 12 months prior to screening, may participate.
7. Has had hypophysectomy within a period of 12 months prior to the start of screening.
8. Has history of oncologic chemotherapy treatment. 
9. Has had brain radiotherapy within 12 months of the start of treatment for a primary 
tumor, or any history of brain radiotherapy for metastatic disease.
10. Has diabetes mellitus.
11. Has a history of Human Immunodeficiency Virus (HIV).
12. Has renal insufficiency as determined by the investigator based on serum creatinine, 
blood urea nitrogen, and estimated glomerular filtration rate.
13. Has clinically significant liver disease, including active viral hepatitis or cirrhosis.  
Subjects with a prior history of liver disease which is now inactive or successfully treated 
may be enrolled if all liver function values (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], total bilirubin) performed within the past year have been normal 
and are within the normal range (per central lab) at V1.  Liver function testing may be 
repeated once prior to allocation of treatment at the discretion of the investigator if results 
are inconsistent with the subject’s clinical status or recent laboratory results.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
26
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
14. Has had a recent history (i.e., within 1 year prior to signing the informed consent) of 
recreational (e.g., for non-medical purposes) or illicit drug use, including marijuana; or 
routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or 
engages in binge drinking.
Note: (1) Alcohol abuse is defined as routinely consumes >2 alcoholic drinks per day. 
One alcoholic drink is defined as 5 oz (150 mL) of wine, or 12 oz (350 mL) of beer, or 
1.5 oz (50 mL) of 80-proof liquor.
Note: (2) Binge drinking is defined as a pattern of 5 or more alcoholic drinks (male), or 
4 or more alcoholic drinks (female) in about 2 hours.
15. Has received any treatment listed in Table 1 more recently than the indicated wash-out 
period prior to Screening.
Table 1
Prohibited Medications, Supplements, and Other Substances for Entry Into the 
Trial
Prohibited Medications, Supplements, 
and Other Substances
Wash-out Period Prior to Screening
Sex hormone preparations other than the trial medication
no prior use allowed (see Exclusion 
Criterion #3 for exceptions)
Drugs that are known to impair testicular function, such as 1:

gonadotoxic chemotherapy agents such as alkylating 
agents,
e.g., cyclophosphamide

sulfasalazine

cimetidine

nitrofurantoin

neuroleptics such as valproic acid

illicit drugs such as marijuana, phencyclidine (PCP), 
lysergic 
acid 
diethylamide 
(LSD) 
and 
other 
hallucinogens, cocaine, amphetamines, rohypnol, and 3,4-
methylenedioxy-methamphetamine (“Ecstasy”)

opiates

narcotics

benzodiazepines

chloral hydrate

paraldehyde

ketamine
1 month
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
27
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Prohibited Medications, Supplements, 
and Other Substances
Wash-out Period Prior to Screening
Agents known to affect sex hormones through induction of 
liver enzymes and affecting the bioavailability of steroids, such 
as 1:

anti-epileptics (e.g., phenytoin, barbiturates, primidone, 
carbamazepine, 
oxcarbazepine, 
topiramate, 
and 
felbamate)

bosentan

rifampicin

anti-HIV drugs (e.g., ritonavir, nelfinavir, nevirapine, 
efavirenz)

griseofulvin

anti-psychotics such as risperidone and amisulpride

herbal 
remedies 
containing 
hypericum 
perforatum 
(e.g., St John’s wort)
1 month
1 In addition to the drugs listed in this table, if there are concerns on any other concomitant medications, the investigator 
should contact the Sponsor Clinical Director for advice prior to enrolling the subject.
16. Has an allergy/sensitivity to gonadotropins or its/their excipients.
17. Has any clinically significant condition or situation that, in the opinion of the 
investigator, would interfere with the trial evaluations or optimal participation in the trial.
18. Has used an investigational drug and/or participated in any other clinical trial within the 
past 8 weeks (prior to V2), or will participate in any other clinical trials (excluding 
surveys) during the course of this trial.
19. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 2.
Table 2
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
MK-8962
Body 
weight 
≤60 kg: 100 
µg
Body 
weight 
>60 kg: 150 
µg
Once every two 
weeks
SC
Day 1 (Week 0) through 
Week 64. The last dose 
will be administered on 
the last day of Week 62 
(Day 435).
Experimental
hCGa
500-5000 IU
Twice a week
SC
The first dose will be 
administered on the last 
day of Week 12 (Day 
85), and treatment will
be continued from Week 
13 through Week 64.
Standard 
of 
care 
a Note: A dose of hCG outside of this range may be appropriate in certain subjects, based on the subject’s Total T and/or E2 
levels and/or any clinically relevant signs or symptoms (e.g., gynecomastia, breast pain, and/or tenderness), and will require 
prior consultation with the Sponsor.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
28
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
The subject and his legal guardian (or someone designated by the subject’s legal guardian 
such as a caregiver or parent) will receive instructions on MK-8962 and hCG home- injection 
prior to the initiation of treatment. The first 3 doses of MK-8962 will be self-administered or 
administered by the legal guardian (or a legal guardian-designated person who has been 
appropriately trained) at the trial site as witnessed doses at Visit 2 (Day 1/Week 0), Visit 
7/Week 2 (Day 15), and Visit 8/Week 4 (Day 29). Note: The first dose of MK-8962 is to be 
administered after completion of all Visit 2/Day 1 trial procedures (except for the collection 
of PK sample #02 which is to be performed 6-24 hours after the first MK-8962 injection).
The first dose of hCG will be self-administered or administered by the legal guardian (or a 
legal guardian-designated person who has been appropriately trained) at the trial site as 
witnessed dose at Visit 9/Week 12 (Day 85). 
The site should record in the source document when the instructions have been provided to 
the subject and his legal guardian (or someone designated by the subject’s legal guardian 
such as a caregiver or parent) for home administration of MK-8962 and hCG.
The subsequent medication will be dispensed to the subject, for home-administration
unsupervised by the investigator.  A paper diary will be used to record the time and amount 
of hCG and MK-8962 administration.  The site will collect the diary dispensed at the 
previous visit, and dispense a new diary to the subject at visits specified in the Trial Flow 
Chart (Section 6.0).  The information as recorded on the diary by the subject serves as the 
source for data entry on the dosing/medication electronic Case Report Form (eCRF).
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection for MK-8962 and Dose Modification for hCG
5.2.1
5.2.1.1
Dose Selection (Preparation)
The rationale for dose selection of MK-8962 to be used in this trial is provided in Section 4.0
– Background & Rationale. Subjects with body weight ≤60 kg will be given MK-8962 100 
μg and subjects with body weight >60 kg will be given MK-8962 150 μg.
During the course of the trial, for subjects receiving MK-8962 100 μg, the dose of MK-8962 
should be adjusted to 150 μg if the subject’s body weight increases by 2 kg or more from the 
previous visit to a value greater than 60 kg. For subjects receiving MK-8962 150 μg, the 
dose should not be down-titrated for the rest of the trial regardless of any changes in body 
weight.
5.2.1.2
Dose Titration for hCG
The dose of hCG can be adjusted between 500 IU and 5,000 IU (inclusive) in order to keep 
the Total T and E2 levels within the normal ranges as defined in the paragraph below. As 
specified in the flow chart (Section 6.0), blood samples collected at Visit 9/Week 12 and 
each of the subsequent visits will be evaluated for the Total T and E2 levels.  Based on the 
results of these tests, the investigator or qualified designee should log into the Interactive 
Voice/Web Response System (IVRS/IWRS) between pre-specified visits to request 
additional medication if hCG up-titration is needed. Note: A dose of hCG outside of this 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
29
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
range may be appropriate in certain subjects, based on the subject’s Total T and/or E2 levels 
and/or any clinically relevant signs or symptoms (e.g., gynecomastia, breast pain, and/or 
tenderness), and will require prior consultation with the Sponsor.
The normal range for Total T for this study is defined as the mean ± 2 standard deviation 
(SD) for a young, healthy male population, and the exact limits are assay-specific.  The 
reference range used by the Sponsor-designated central lab is 240.00 – 950.00 ng/dL (or 8.3 
– 33.0 nmol/L). During hCG treatment, serum E2 levels should also be evaluated to avoid 
clinically relevant elevations of E2 levels (should be monitored towards maintaining <40% 
above the upper limit of normal in men [the ULN from the Sponsor-designated central 
laboratory is 40.00 pg/mL]).
Timing of Dose Administration
5.2.2
MK-8962
Throughout the 64-week treatment period, a single dose of MK-8962 100 μg (body weight 
≤60 kg) or 150 μg (body weight >60 kg) is to be administered subcutaneously in the 
abdominal wall once every two weeks in the morning on the same day of the week 
throughout the trial. The fixed day of the week is chosen by the subject depending on 
individual preference. For the convenience of visit scheduling, a weekday injection is 
preferred, as most protocol-specified site visits fall on the same day of a scheduled MK-8962 
administration. The time and dose of MK-8962 administration should be recorded in a paper 
diary.
Note:  The subject should adhere to the same MK-8962 injection schedule (e.g., on every 
other Monday, etc.) throughout the trial, whenever possible.  In the event that the subject 
misses a dose on a scheduled dosing day (e.g., a holiday, etc.), the make-up dose should be 
administered as soon as possible, and can only be administered within one week immediately 
following the missed dose.  Otherwise, the missed dose should be skipped and the subject 
should continue on with the next regularly scheduled injection.
hCG
Starting from the last day of Week 12 (Day 85), hCG is to be injected twice a week in the 
morning, on fixed days of the week throughout the trial. The scheduling of hCG injection 
should be coordinated with the MK-8962 injection, as illustrated in Table 3 below. After 
addition of the solvent to the freeze-dried substance, the reconstituted hCG solution should 
be administered by subcutaneous injection. The time and dose of hCG administration should 
be recorded in a paper diary. Note that Table 3 is meant for illustration only, and the subject, 
in consultation with the investigator, may utilize any schedule that meets dosing interval 
requirements for hCG and MK-8962.
Note:  The subject should adhere to the same twice-weekly injection schedule throughout the 
trial.  In the event that the subject misses a scheduled hCG dose, the make-up dose should be 
administered as soon as possible, up to the day before the next scheduled injection day. This 
instruction for the handling of a missing hCG dose should be followed whether or not the 
subject also misses the MK-8962 dose at the same time.  
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
30
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Table 3
MK-8962 and hCG Dosing Schedule
Examples of Dosing 
Schedule Scenario
MK-8962 100 μg or 150 μg
hCGa
A
Every other Monday
Every Monday and Thursday
B
Every other Tuesday
Every Tuesday and Friday
C
Every other Wednesday
Every Wednesday and Saturday
D
Every other Thursday
Every Thursday and Monday
E
Every other Friday
Every Friday and Tuesday
a
The dose of hCG may be titrated between 500 IU and 5000 IU twice weekly to keep the Total T and E2 levels within 
acceptable ranges. A dose of hCG outside of this range may be appropriate in certain subjects, based on the subject’s 
Total T and/or E2 levels and/or any clinically relevant signs or symptoms (e.g., gynecomastia, breast pain, and/or 
tenderness), and will require prior consultation with the Sponsor.
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
Dispensing of medication and assignment of screening and randomization numbers will be 
performed via the IVRS/IWRS. After signing informed consent, the investigator or qualified 
designee should enter the subject in the IVRS/IWRS and the system will assign a screening 
number.  After evaluation of all screening data, indicating that the subject complies with all 
selection criteria, the subject can be assigned a randomization number to enter the MK-8962 
priming phase.  (Assignment of the randomization number should be done immediately prior 
to the initiation of MK-8962 treatment [i.e., on Day 1]).
Note: Even though the trial has an open-label, non-randomized design, a randomization 
number will be assigned per the Sponsor’s standard procedure indicating the subject receives 
the trial medication. Therefore, in this protocol, the term randomization is equivalent to the 
term allocation. 
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
31
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
5.7
Subjects do not need to adhere to any diet restrictions during the course of the trial. 
However, subjects should be counseled to refrain from excess intake of alcoholic beverages 
(>2 per day or binge drinking) and use of illicit substances during course of trial.
Subject Withdrawal/Discontinuation Criteria
5.8
A subject’s consent may be withdrawn by the subject or the subject’s legally acceptable 
representative (as appropriate) at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent/assent.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

The subject develops an immediate or delayed study drug-related hypersensitivity 
reaction.

The subject has neutralizing ADA against MK-8962.

The subject, in the opinion of the investigator, persistently fails to comply with 
dosing, evaluation or other requirements of the trial.

Any medical condition or personal circumstance which, in the opinion of the 
investigator, exposes the patient to risk by continuing with the study medication or 
does not allow the patient to adhere to the requirements of the protocol.

The subject develops any condition for which corifollitropin alfa, or hCG is 
contraindicated in accordance with the local drug label of the country where the 
subject is participating.

The subject has a serious drug-related adverse event
If a subject discontinues study medication (i.e., MK-8962 and hCG obtained through the 
study), he should complete all Discontinuation Visit procedures as described in Section 6.0. 
Please refer to Section 7.1.5.3 on how to manage patients who discontinue study medication 
but who do not withdraw consent.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
32
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent/assent form.  The 
overall trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
33
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
6.0 TRIAL FLOW CHART
Trial Period:
MK-8962 Priming Phase
Combined Treatment Phase  (MK-8962 / hCG)a
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Visit/Contact Title:
Screening
Treatment 
Allocation
T C
TC
TC
TC
TC
TC
TC
TC
D/Cb
Follow-
up c
Scheduled Weekd:
-1
0
1
1
1
2
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64e
Scheduled 
Study 
Day:
-7 to -1
1f
3
5
8
11
15
29
57
85
113
141
169
197
225
253
281
309
337
365
393
421
449
+7 c
Scheduling Window
(Days):
-42 to -1
+/-
7
+/-
3
+/-
7
+/-
3
+/-
7
+/-
7
+/-
3
+/-
7
+/-
7
+/-
3
+/-
7
+/-
7
+/-
3
+/-
7
+/-
7
+/-
7
+/-
7
+24
Administrative 
Procedures
Informed 
Consent 
and Assentg
X
Informed 
Consent
and Assent for Future 
Biomedical 
Researchh
X
Assignment 
of 
Screening Numberi
X
Inclusion/Exclusion 
Criteria
X
X
Subject Identification 
Card
X
Medical 
History
/Hypogonadotropic 
Hypogonadism 
History
X
Prior/Concomitant 
Medication Reviewj
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assignment 
of 
Randomization 
Number
X
Diary Instructions
X
X
Dispense/collect 
Paper Diary
X
X
X
X
X
X
X
X
X
X
X
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
34
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Trial Period:
MK-8962 Priming Phase
Combined Treatment Phase  (MK-8962 / hCG)a
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Visit/Contact Title:
Screening
Treatment 
Allocation
T C
TC
TC
TC
TC
TC
TC
TC
D/Cb
Follow-
up c
Scheduled Weekd:
-1
0
1
1
1
2
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64e
Scheduled 
Study 
Day:
-7 to -1
1f
3
5
8
11
15
29
57
85
113
141
169
197
225
253
281
309
337
365
393
421
449
+7 c
Scheduling Window
(Days):
-42 to -1
+/-
7
+/-
3
+/-
7
+/-
3
+/-
7
+/-
7
+/-
3
+/-
7
+/-
7
+/-
3
+/-
7
+/-
7
+/-
3
+/-
7
+/-
7
+/-
7
+/-
7
+24
Review 
Diary 
to 
monitor 
compliance 
with Trial Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial Medication
Dispense MK-8962k
X
X
X
X
X
X
X
X
X
Treatment with MK-
8962
Once every two weeks (first dose on Day 1/Week 0 and last dose on Day 435 /Week 62)
Dispense hCG l
X
X
X
X
X
X
Treatment with hCG
Twice weekly (e.g., every Monday and Thursday, or every Tuesday and 
Friday)m
Clinical Procedures/
Assessments
Full 
Physical 
Examination
X
X
X
Focused 
Physical 
Examination n
X
X
X
Vital Signs (HR, BP 
measured twice)
X
X
X
X
X
X
Weight 
(measured 
twice)
X
X
X
X
X
X
X
X
X
X
X
X
Height for Growth 
Velocity (measured 3 
times)
X
X
X
X
X
X
Testicular ultrasound 
o
X
(X) t
X
X
X
X p
(X) p
Tanner Staging q
X
X
X
X
X
X
Adverse 
Events 
Monitoring
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
35
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Trial Period:
MK-8962 Priming Phase
Combined Treatment Phase  (MK-8962 / hCG)a
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Visit/Contact Title:
Screening
Treatment 
Allocation
T C
TC
TC
TC
TC
TC
TC
TC
D/Cb
Follow-
up c
Scheduled Weekd:
-1
0
1
1
1
2
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64e
Scheduled 
Study 
Day:
-7 to -1
1f
3
5
8
11
15
29
57
85
113
141
169
197
225
253
281
309
337
365
393
421
449
+7 c
Scheduling Window
(Days):
-42 to -1
+/-
7
+/-
3
+/-
7
+/-
3
+/-
7
+/-
7
+/-
3
+/-
7
+/-
7
+/-
3
+/-
7
+/-
7
+/-
3
+/-
7
+/-
7
+/-
7
+/-
7
+24
Laboratory 
Procedures/
Assessments
Serum for free T4
X
Hematology
X
X
X
X
X
X
Chemistry Panel
X
X
X
X
X
X
Serum for endocrine 
parameters
r: FSH, 
LH, hCG, inhibin-B, 
AMH, Calc. Free T, 
and SHBG
X
X
X
X
X
X p
(X) P
Serum for endocrine 
parameters r: Total T 
and E2
X
X
X
X
X
X
X
X
X
X P
(X) P
Pharmacokinetic 
(PK) sampling for 
MK-8962 
concentration s
see Section 7.1.3.3.1 Flow Chart for Pharmacokinetic Assessments
Sampling for Anti-
MK-8962 antibodies r
X
X
X
X
X
X
X
X
X
AMH = anti-Müllerian hormone; E2 = estradiol; FSH = follicle stimulating hormone; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; LH 
= luteinizing hormone; SHBG = sex hormone-binding globulin; TC = telephone call; T = testosterone 
a
The Combined Treatment Phase starts at the end of Week 12.
b
The Discontinuation (D/C) Visit is to be performed only if the subject does not complete the 64 week treatment. The D/C visit should be performed as soon as possible 
once the subject has prematurely stopped the study medication.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
36
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
c
The post-treatment follow-up visit is to be scheduled at least 21 days (but no more than 45 days) after the last dose of MK-8962, and at least 7 days after the last dose of 
hCG (whether subject completed the trial or discontinued from the trial prematurely).  Follow-up blood samples will be collected for assessment of anti-MK-8962 
antibodies and PK for MK-8962 concentration. AEs and concomitant medication will also be assessed.  For subjects wishing to continue on post-trial gonadotropin 
treatment, such treatment should not be started until after blood sample collection at this visit.  For subjects who prematurely discontinue study medication, after the post-
treatment follow-up visit, subjects who do not withdraw consent should:  (1)  return to the clinic for key visits (V9/Week 12, V12/Week 36 and/or V15/Week 64 as 
applicable) to have the following procedures performed: focus physical examination, vital signs, weight and height, Tanner staging, testicular ultrasound, laboratory 
assessment of endocrine parameters, and safety parameters (chemistry panel and hematology), and collection of concomitant medications and adverse events.  Subjects 
discontinued from the treatment due to the presence of neutralizing ADAs will also have serum samples collected for ADA testing.  Subjects who are unable or unwilling to 
return to the clinic at key visits will be contacted by phone to obtain adverse events and concomitant medications.  (2) be contacted by phone in a timeframe similar to their 
original study visit schedule at visits that are not key visits, i.e., at V10, V11, V13, V14, up until the subject has reached Week 64 after V2, to assess for serious adverse 
events and concomitant medications.  (3) Subjects discontinued from the treatment due to the presence of neutralizing antibodies may continue to be followed until the 
ADA result becomes negative or until clinically stable for up to 12 months after treatment discontinuation.  Refer to Section 7.1.5.3 for further details.
d
For visits not involving PK sampling, a scheduling window of ± 7 days is allowed.
e
No further injection of MK-8962 or hCG is administered at the Week 64 visit.
f
Day 1/Week 0 designates the first dose administration of MK-8962.  The study medication is to be administered after completion of all Visit 2/Day 1 trial procedures
(except for the collection of PK sample #02 which is to be performed 6-24 hours after the first MK-8962 injection).  Visit 2 should be scheduled approximately 7 days after 
sample collection at Visit 1, when the central lab results are available to evaluate the Day 1 inclusion criteria.
g
Consent form must be signed prior to any study specific procedures; informed consent will be obtained from parent/legal guardian and assent (if applicable) will be 
obtained from subject.
h
Leftover main study serum from endocrine parameters, anti-MK-8962 antibodies, and PK for MK-8962 concentration will be stored at the end of the study for future 
biomedical research (FBR) if the subject consents to FBR. Eligible subjects will be able to participate in the main study even if they opt to not participate in FBR.          
i
After obtaining the informed consent from the parent/legal guardian and the assent from the subject, the subject should be entered in the Interactive Voice/Web Response 
System (IVRS/IWRS) to obtain a screening number.
j
Any medication used from 30 days prior to screening through the end of the trial should be recorded.
k
Subject and his legal guardian (or someone designated by the subject’s legal guardian such as a caregiver or parent) will be instructed at Visit 2 on home-administration of 
MK-8962 injections.  The first 3 doses of MK-8962 will be administered by the subject at the site on Day 1, Week 2 and Week 4 as witnessed doses.  Later injections can 
be self-administered by the subject or administered by the subject’s legal guardian (or the designated person who has been appropriately trained) at home.  
l
Subject and his legal guardian (or someone designated by the subject’s legal guardian such as a caregiver or parent) will be instructed at Visit 9 on home-administration of 
hCG injections.  The first dose of hCG will be administered by the subject at the site as a witnessed dose, and later injections can be self-administered by the subject or 
administered by the subject’s legal guardian (or the designated person who has been appropriately trained) at home. 
m
Treatment with hCG in combination with MK-8962 will start only if the subject has completed the 12-week MK-8962 priming phase.
n
The focused exam will include only heart, lungs, abdomen, extremities, and genitourinary exam.
o
At Visit 1/Screening, testicular ultrasound images will be read locally by the investigator (if qualified) or a local radiologist with appropriate training and expertise in 
reading testicular ultrasound. This local reader will calculate testicular volume to evaluate Inclusion Criterion #5, and evaluate the ultrasound for any presence of local 
pathology that would exclude the subject from participating (see Section 5.1.3 Subject Exclusion Criteria). In addition, all testicular ultrasound images will be sent to a 
central imaging vendor, and will be read in a masked manner after the subject completes participation in the study to assess study endpoints (i.e., testicular volume and 
sonographic pattern).
p
If testicular ultrasound or endocrine parameters is not able to be completed at study completion (V15) or on the day of D/C, the site should make an effort to schedule a 
visit within 4 weeks from the last dose of MK-8962 to perform these procedures. This visit can be combined with the post-treatment follow-up visit if it is scheduled at 21-
28 days after the last dose of MK-8962. Testicular ultrasound does not need to be performed at D/C if this visit is ≤6 weeks from the last scheduled testicular ultrasound 
measurement.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
37
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
q
The investigator will use clinical assessment to assign the Tanner Stage for pubic hair and Tanner Stage for genital growth (e.g., penial length and scrotum development) 
separately, and perform a testicular ultrasound to measure testicular parameters as according to the procedures outlined in the Site Imaging Manual provided to the 
investigator site. The Tanner Stage for testicular volume will not be assessed clinically by the investigator and will be completed by the central imaging vendor according 
to the method described in the Independent Review Charter for imaging.
r
These blood sample collections should be performed prior to the injection(s) of MK-8962 or hCG, if there is any injection(s) scheduled for that day. Leftover main study 
serum will be stored at the end of the study for future biomedical research if the subject consents to future biomedical research.
s
A total of 13 PK samples are collected at various time points at Days 1 (2 time points), 3, 5, 8, 11, 29, 85, 169, 253, 337 and 449, as well as the follow-up visit. For details, 
see Section 7.1.3.3.1 Flow Chart for Pharmacokinetic Assessments. Leftover main study serum will be stored at the end of the study for future biomedical research if 
the subject consents to future biomedical research.
t
Testicular ultrasound is only to be performed at Visit 2 if the window is greater than 6 weeks between Visit 1 and Visit 2.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
38
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent and/or assent (if applicable) be obtained from 
the subject.  In these cases, such evaluations/testing will be performed in accordance with 
those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent/Assent
The investigator or qualified designee must obtain documented consent/assent (if applicable)
from each potential subject or each subject’s legally acceptable representative prior to 
participating in a clinical trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent/Assent
Consent/assent must be documented by the subject’s dated signature or by the subject’s 
legally acceptable representative’s dated signature on a consent/assent form along with the 
dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent/assent form should be given to the subject before 
participation in the trial.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form and any written information provided to the subject must receive the 
IRB/ERC’s approval/favorable opinion in advance of use.  The subject or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the subject’s willingness to continue participation in the 
trial.  The communication of this information will be provided and documented via a revised 
consent/assent form or addendum to the original consent/assent form that captures the 
subject’s dated signature or by the subject’s legally acceptable representative’s dated 
signature.
Specifics about a trial and the trial population will be added to the consent/assent form 
template at the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.  The assent, as applicable, will adhere to IRB/ERC requirements, 
applicable laws and regulations and Sponsor requirements.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
39
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
7.1.1.1.2 Consent/Assent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research 
consent/assent to the subject, answer all of his/her questions, and obtain written informed 
consent/assent before performing any procedure related to the Future Biomedical Research 
sub-trial.  A copy of the informed consent/assent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent/assent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee at screening.
Include any medical history related to andrologic history on this form (e.g., 
hypogonadotropic hypogonadism; prior genital, pelvic or inguinal surgery; infections such as 
epididymitis or orchitis; presence of varicocele, including grade; etc).
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use (i.e., used within 6 
months of starting the trial) by the subject. Additionally, the use of any medications noted in
Table 1 should be reviewed to determine that the required washout periods have been met.  
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
40
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a subject, it can never be re-assigned to 
another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.8
Trial Compliance (Medication)
A paper diary will be used to record the time and dosage of MK-8962 and hCG 
administration.  The first paper diary will be dispensed at Visit 2, and the site staff should 
train subjects on how to complete the paper diary. At subsequent visits specified in the Trial 
Flow Chart (Section 6.0), the site will collect and review the diary dispensed at the previous 
visit, and dispense a new diary to the subject.  The information as recorded on the diary by 
the subject serves as the source for data entry by the site on the medication eCRF.
At all protocol-specified visits, the investigator or qualified designee is to record whether 
treatment has been taken per protocol in the preceding interval.  If not, the date(s) and reason 
for each dosing noncompliance must be recorded.
Interruptions from the protocol specified treatment (in the case when the subject misses more 
than 2 doses of MK-8962 or more than 2 consecutive doses of hCG) require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
Administration of the first 3 doses of MK-8962 and the first dose of hCG will be witnessed 
by the investigator and/or trial staff.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Physical Examination
A full physical examination will be performed at screening and at the end-of trial or 
discontinuation visit. Focused physical examinations will be performed during the trial, as 
specified in the Trial Flow Chart (Section 6.0). Focused physical examination will involve 
an examination for abnormalities of the heart/lungs, abdomen, extremities, and genitourinary 
exam.  Only abnormal findings should be recorded on eCRFs, either as medical history 
(present at the screening visit) or as an adverse event (new findings during the trial). Refer to 
Section 7.2 for instructions on adverse event reporting.
These exams should be conducted by a licensed clinician (i.e., physician, physician’s 
assistant, or nurse practitioner).
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
41
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
7.1.2.2
Vital Signs, Height, and Weight
Vital signs (including HR and BP), body weight and height will be obtained at screening and 
at subsequent visits specified in the Trial Flow Chart (Section 6.0).
BP and HR will be measured (to be performed in duplicate) using an electronic blood 
pressure monitor.
Body weight will be measured (to be performed in duplicate) using a calibrated digital scale.
Height will be measured (to be performed in triplicate) using a wall-mounted calibrated 
stadiometer.
The Sponsor will calculate growth velocity of height based on these 
measurements.
For details on measuring techniques, refer to Section 12.7.
7.1.2.3
Testicular Ultrasound
A testicular ultrasound scan (USS) should be performed at protocol specified visits (see 
Section 6.0, Trial Flow Chart) to assess the testicular volume and testicular sonographic 
pattern. To avoid variability, the site should designate a single staff member who is trained 
in the technique of testicular ultrasound to perform the exam whenever possible.  The same 
ultrasound equipment should be used throughout the trial. 
At Visit 1/Screening, testicular ultrasound images will be read locally by the investigator (if 
qualified) or a local radiologist with appropriate training and expertise in reading testicular 
ultrasound. This local reader will calculate testicular volume to evaluate Inclusion Criterion 
#5, and evaluate the ultrasound for any presence of local pathology that would exclude the 
subject from participating (see Section 5.1.3 Subject Exclusion Criteria). Testicular volume is 
calculated using the formula for prolate ellipsoid, i.e., [pi/6] x (longitudinal) x (antero-
posterior) x (transverse) diameters. The screening ultrasound assessment made by the site 
should be recorded on the source document. Additionally, the testicular ultrasound of each 
testis will be evaluated by the investigator or a local radiologist with appropriate training and 
expertise in reading testicular ultrasound for any pathological findings throughout the trial. 
These findings will be recorded on the source document, and reported in the eCRF as a pre-
existing condition in the medical history (if noted at screening), or as an adverse event (if 
new findings during the trial). Refer to Section 7.2 for instructions on adverse event 
reporting.
All testicular ultrasound images will be sent to a Sponsor-validated central imaging vendor to 
be read in a masked manner after the subject completes participation in the study to assess 
study endpoints (i.e., testicular volume and sonographic pattern). The central imaging vendor 
will assess adequacy of all submitted ultrasound scans; if a scan is deemed inadequate, the 
site will be contacted and a repeat scan requested. The ultrasound images will be read by the
central imaging vendor according to the description in the Independent Review Charter for 
imaging to calculate the total testicular volume (i.e., the sum of left and right testes). The 
process for image collection and transmission to the central imaging vendor can be found in 
the Site Imaging Manual. The evaluation of the echogenicity will also be made by the 
vendor according to criteria described in the Independent Review Charter for imaging.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
42
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
7.1.2.4
Tanner Staging of Pubertal Development
At protocol specified visits (see Section 6.0, Trial Flow Chart), Tanner Staging will be 
assessed by genital development and pubic hair distribution as noted in Section 12.6. The 
investigator will use clinical assessment to assign the Tanner Stage for pubic hair and Tanner 
Stage for genital growth (e.g., penial length and scrotum development) separately.  The 
investigator will perform testicular ultrasound to measure testicular parameters as according 
to the procedures outlined in Site Imaging Manual provided to the investigator site. 
However, the Tanner Stage for testicular volume will not be assessed clinically by the 
investigator and will be completed by the central imaging vendor according to the method 
described in the Independent Review Charter for imaging.  Each score will be considered 
independently and there will not be a composite score.  
7.1.2.5
Adverse Events Monitoring
Adverse events will be monitored throughout the trial.  Refer to Section 7.2 for details.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood to be drawn over the course of the trial (from 
pre-trial to post-trial visits), including approximate blood volumes drawn by visit and by 
sample type per subject can be found in Section 12.4.
7.1.3.1
Laboratory Safety Evaluations (Hematology and Chemistry)
Laboratory tests for hematology and chemistry to be performed by a central laboratory are 
specified in Table 4. Blood samples for safety laboratory tests should be taken pre-dose, i.e., 
prior to administration of MK-8962 or hCG on the day of the visit, whenever possible. 
See the Trial Flow Chart (Section 6.0) for the sampling times. For handling, storage and 
shipment of these samples please refer to the Central Laboratory Manual.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
43
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Table 4
Laboratory Tests
Hematology
Chemistry
Other
Hematocrit
Albumin
Free T4
Hemoglobin
Alkaline phosphatase
Platelet count
Alanine aminotransferase (ALT)
WBC (total and differential)
Aspartate aminotransferase (AST)
Bicarbonate
Calcium
Chloride
Creatinine (for determination of eGFR)
Glucose (non-fasting)
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin is elevated 
above the upper limit of normal
Total protein
Blood Urea Nitrogen
eGFR: estimated glomerular filtration rate
7.1.3.2
Panel of Endocrine Parameters
The following hormones will be assessed by the Sponsor designated central laboratory: FSH, 
LH, hCG, inhibin-B, AMH, Total T, calculated free T, E2 and SHBG. All blood sample 
collection for endocrine parameters should be performed prior to injection(s) of MK-8962 or
hCG on the day of visit, if there is any injection(s) scheduled for that day.
See the Trial Flow Chart (Section 6.0) for the sampling times. For handling, storage and 
shipment of these samples please refer to the Central Laboratory Manual. 
Note: The LH and FSH assays that are part of the optional GnRHa stimulation test or GnRH 
IV infusion test as described in Inclusion Criterion 8 (Section 5.1.2) should be performed by 
the local laboratory; refer to local laboratory instructions as appropriate.
7.1.3.3
Pharmacokinetic Evaluations
A total of 13 serum samples for assessment of MK-8962 concentration will be collected at 
specified time points indicated in Section 7.1.3.3.1, Flow Chart of Pharmacokinetic 
Assessments. For handling, storage and shipment of these samples please refer to the Central 
Laboratory Manual. Concentrations of MK-8962 in serum will be determined using a 
validated assay.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
44
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
7.1.3.3.1 Flow Chart of Blood Sample Collection for Pharmacokinetic Assessments of 
MK-8962a
Scheduled 
Week
Scheduled 
Study Day
Visit Number
Time
[range]
Sample Number
0
1
V2
15 minutes 
prior to first MK-8962 injection
01
0
1
V2
6–24 h after first dose b
02
1
3
V3
32-52 h after first dose and –at least 12 
hours after sample 02 b
03
1
5
V4
96 ±24 [72-120] h after first dose b
04
1
8
V5
168 ±24 [144-192] h after first dose b
05
2
11
V6
240 ±24 [216-264] h after first dose b
06
4
29
V8
Predose to 3rd
MK-8962 injection c
07
12
85
V9
Predose to 7th
MK-8962 injection and prior to 1st hCG 
injection c
08
24
169
V11
Predose to 13th
MK-8962 injection and prior to  hCG 
injection c
09
36
253
V12
Predose to 19th
MK-8962 injection and prior to hCG 
injection c
10
48
337
V13
Predose to 25th
MK-8962 injection and prior to  hCG 
injection c
11
64
449
V15
--
12
--
--
Discontinuation
(if Subject did 
not complete 
V15)
--
12
Post 7 days
--
Follow-up
--
13
a
Blood serum samples for MK-8962 will be processed according to the central laboratory procedures outlined in 
their manual for handling biological samples. The timing of each sampling is to be recorded on the eCRF.
b
Samples 02 through 06 may be obtained at any time-point within the specified time frame. The timing of each 
sampling is to be recorded on the eCRF.
c
A visit window of ±3 days is allowed.   
7.1.3.4
Anti-MK-8962 Antibodies
Serum samples will be collected for the assessment of anti-MK-8962 antibodies. Baseline 
samples MUST be taken prior to the first dose of MK-8962. See the Trial Flow Chart 
(Section 6.0) for the sampling times. All blood sampling for antibodies should be performed 
prior to injection(s) of MK-8962 or hCG on the day of visit, if there is any injection(s) 
scheduled for that day. 
For handling, storage and shipment of these samples please refer to the Central Laboratory 
Manual.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
45
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
7.1.3.5
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover main study serum from endocrine parameters, anti-MK-8962 antibodies, and 
PK for MK-8962 concentration stored for future research
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the Discontinuation Visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
Refer to Section 7.1.5.3 on how to manage patients who 
discontinue study medication but who do not withdraw consent.
7.1.4.1.1 Withdrawal From Future Biomedical Research
A Subject’s consent for Future Biomedical Research may be withdrawn by the subject or the 
subject’s legally acceptable representative (as appropriate) Subjects may withdraw their 
consent for Future Biomedical Research and have their specimens and all derivatives 
destroyed.  A subject’s consent may be withdrawn Subjects may withdraw consent at any 
time by contacting the principal investigator for the main trial.  If medical records for the 
main trial are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@merck.com), and a form will be provided by the 
Sponsor to obtain appropriate information to complete specimen withdrawal.  Subsequently, 
the subject's specimens will be removed from the biorepository and be destroyed.  A letter 
will be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
46
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
7.1.4.3
Domiciling
No domiciling is required. At Visit 2/Day 1, the first and second PK serum samples will be 
collected at two time points: one at about 15 minutes before the first dose of MK-8962, 
another at 6-24 hours after the first dose of MK-8962. Subjects will report to the site in the 
morning for the pre-dose blood sample collection. Subject is not required to remain at the 
site to wait for the collection of the second PK sample, as long as he returns within the 
window of 6-24 hours after first MK-8962 injection to have the second PK sample collected.  
7.1.4.4
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical trial that provides information
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
trial site.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
At V1 (approximately 7 days prior to treatment allocation), potential subjects will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.1.
Screening safety labs may be repeated once per protocol if results are inconsistent with the 
subject’s clinical status or any other recent laboratory evaluations. The period between V1 
and treatment allocation (V2) is up to 6 weeks. This time limit may be increased under
special circumstances after the site obtains the agreement from the Sponsor. 
Subjects may only be rescreened once.
7.1.5.2
Treatment Period
The Study Days when the visits should be scheduled are prespecified in Section 6.0 (Trial 
Flow Chart). Subjects should adhere to the visit schedule described in the Flow Chart as 
much as possible.
The allowed windows for the sampling time of each of the 13 PK samples are designated in 
Section 7.1.3.3 (Flow Chart of Pharmacokinetic Assessment). The first PK sample should be 
collected approximately 15 minutes before the first witnessed dose of MK-8962, and samples 
#02 to #06 are to be collected within the window after first MK-8962 dose, as specified in the 
PK Flow Chart. For subsequent PK assessment visits V8 to V13 (corresponding to the 
collection of PK samples #07 to #11, respectively), a scheduling window of up to 3 days is 
allowed.
For V8 (corresponding to the collection of PK sample #07), if a subject is to adjust the visit 
by up to 3 days (e.g., returns to the clinic 3 days earlier or 3 days later than the prespecified 
Scheduled Study Day in the Trial Flow Chart), the site should ensure that blood samples 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
47
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
(including PK samples) are collected prior to the witnessed injection of MK-8962 at that 
visit.   
For PK assessment visits V9 through V13, if the subject returns to the clinic up to 3 days 
earlier or up to 3 days later than the prespecified Scheduled Study Day in the Trial Flow 
Chart, he should keep his regularly scheduled injection of MK-8962 and not change it to 
correspond to the PK visit. For example, if the subject is to delay V9 (prespecified for Day 
85 in the Trial Flow Chart) by three days to Day 88, the site should remind the subject to 
administer the home-injection of his 7th MK-8962 dose as originally scheduled (i.e., on Day 
85 according to the Trial Flow Chart), and return to the clinic on Day 88 for collection of PK 
sample #08. The actual timing of each injection and each PK sample collection should be 
accurately documented, whether or not any variation to the protocol-specified schedule 
occurs.
Subjects should adhere to their hCG injection schedules independent of the visit deviations or 
altered MK-8962 dosing schedules discussed above. PK sample #12 is to be collected at 
study completion (V15) or discontinuation (D/C), and the last PK sample (#13) is to be 
collected at the post-treatment follow-up visit.
For visits where no PK samples are collected (V7, V10, and V14), a 7-day visit adjustment 
window is allowed. If a non-PK visit is adjusted to a non-prespecified Study Day, the subject 
should not change his regular injection schedules of MK-8962. When an adjustment in the 
schedule is required for a specific visit, this should not impact subsequent visits and the 
schedule for subsequent Study Days should remain as specified in the Trial Flow Chart.  This 
is to ensure adherence to the 64 week treatment period for this study.
There may be cases where visits need to be scheduled outside the allowed visit window. 
These should be rare incidences. In these cases, the subjects should be scheduled as soon as 
possible to the required time point, taking into consideration a subject’s supply of the trial 
medication.  
Phone visits are required visits and should be conducted within the protocol-specified time 
frame (see Section 6.0).
Any visits scheduled outside the specified visit window for that particular visit is not 
considered a major protocol deviation and the Sponsor does not need to be contacted for 
approval.
7.1.5.3
Post-Treatment

Post-treatment Follow-up Visits for Subjects Who Complete the Study or Who 
Discontinue Treatment but Do Not Withdraw Consent 
The last dose of MK-8962 is scheduled to be self-administered or administered by the 
subject’s legal guardian (or someone designated by the legal guardian who has been 
appropriately trained) on Week 62. The subject will continue twice-weekly hCG injections 
with the last two doses administered in Week 64. A post-treatment follow-up visit is to be 
scheduled at least 21 days (but no more than 45 days) after the last dose of MK-8962, and at 
least 7 days after the last dose of hCG, whether the subject completed the trial or 
discontinued from the trial treatment prematurely.
Follow-up blood samples will be 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
48
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
collected for assessment of anti-MK-8962 antibodies and endocrine parameters. AEs and 
concomitant medication will also be assessed. For subjects wishing to continue on post-trial 
gonadotropin treatment, such treatment should not be started until after blood sample 
collection at this visit.
For subjects who discontinue treatment but do not withdraw consent, after the
discontinuation visits and post-treatment follow-up visit, they should:
1. Return to the clinic for key visits (V9/Week 12, V12/Week 36 and/or V15/Week 64 as 
applicable) to have the following procedures performed: focus physical examination, 
vital signs, weight and height, Tanner staging, testicular ultrasound, laboratory 
assessment of endocrine parameters, and safety parameters (chemistry panel and 
hematology), and collection of concomitant medications and adverse events. Subjects 
who discontinued treatment due to presence of ADA will also have serum samples 
collected for ADA testing at these visits.  Subjects who are unable or unwilling to return 
to the clinic at key visits will be contacted by phone to obtain adverse events and
concomitant medications. 
2. Be contacted by phone in a timeframe similar to their original study visit schedule at 
visits that are not key visits, i.e., at V10, V11, V13, V14, up until the subject has reached 
the Week 64 visit. The purpose of these telephone contacts will be to assess for serious 
adverse events that occurred and to collect the subject’s concomitant medications. The 
date of the telephone contact should be recorded and any serious adverse events that have 
occurred and concomitant medications that were used should be recorded in the eCRF.
3. In addition to the above procedures, if a subject discontinues treatment due to the 
presence of neutralizing ADA, he may continue to be followed every three months with 
repeat ADA testing after the Week 64 visit.  This will continue until the ADA result 
becomes negative or until the subject is clinically stable (e.g., in the absence of hCG use, 
no clinically meaningful change in testicular volume or testosterone levels for 3 months; 
if hCG continues to be used, an appropriate response to hCG with stable testosterone 
levels) for up to 12 months after treatment discontinuation, whichever comes first.
Note: Study sites must make all reasonable efforts to counsel the subject to stay in the 
study even if they discontinued the study medication, and make all reasonable efforts to 
contact the subject. Subjects must be counseled regarding the importance of complete 
follow up, even when they are not continuing on study medication.  Sites should make at 
least three attempts to make telephone contact. If telephone contacts are not successful, 
sites should make at least two attempts to reach the subject via certified letter before 
considering the subject as lost to follow-up.
If any adverse event requires supplemental procedures, they should be performed as 
medically necessary and recorded in the Procedures eCRF.

Follow Up of Subjects Who Withdraw Consent Prior to Study Completion
Subjects who withdraw consent and discontinue from the study will not be contacted for 
post-trial follow-up.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
49
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through the follow-up visit 
(i.e., at least 21 days following last dose of MK-8962) following cessation of treatment, all 
adverse events must be reported by the investigator. Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets.  The reporting timeframe 
for adverse events meeting any serious criteria is described in section 7.2.2.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events 
for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose for MK-8962 is any dose exceeding the doses as prescribed by the 
protocol, or if two doses of MK-8962 are given less than 7 days apart. For hCG, 
investigators/site personnel are to consult the local approved hCG product label for guidance 
on the definition of overdose.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a non-serious adverse event, unless other 
seriousness criteria are met.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
50
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious adverse event, using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.2
7.2.2.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. 
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 5 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through the follow-up 
visits following cessation of treatment, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause, whether or not related to the Sponsor's 
product, must be reported within 24 hours to the Sponsor either by electronic media or paper. 
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
51
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.2.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through the follow-up 
visits following cessation of treatment, any ECI, or follow up to an ECI, whether or not 
related to the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by 
electronic media or paper.  Electronic reporting procedures can be found in the EDC data 
entry guidelines.  Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Events of clinical interest for this trial include:
1. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
2. Hypersensitivity reaction: A potential sign or symptom of a hypersensitivity reaction 
after injection of MK-8962 such as new emergent skin rash, urticaria, hypotension, 
allergic asthma, chest tightness, broncho-spasm, dyspnea, or wheezing.
Minor 
localized skin rash not suggesting hypersensitivity will not be considered an ECI.
Evaluating Adverse Events
7.2.3
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 5. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 5 for instructions in evaluating adverse events.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
52
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Table 5
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Overdose, although not serious per ICH definition, whether accidental or intentional, with or without an accompanying adverse event/serious adverse event, is reportable 
to the Sponsor within 24 hours to meet certain local requirements.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, 
ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The criteria below 
are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
53
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to 
Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency with 
Trial Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable possibility 
of Sponsor's product relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
54
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Sponsor Responsibility for Reporting Adverse Events
7.2.4
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Scientific Advisory Committee
7.3.1
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to study finalization, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2 to 8.12.  
Study Design Overview
A phase III, multi-center, open label, single-group trial to investigate 
the efficacy and safety of MK-8962 (corifollitropin alfa) in 
combination with human Chorionic Gonadotropin (hCG) for initiation 
or restoration of puberty as assessed by increased testicular volume in 
adolescent males 14 to <18 years old with hypogonadotropic 
hypogonadism
Treatment Assignment
Open-label treatment with MK-8962.
During 12 weeks of Priming phase, all subjects receive 100 μg (for 
subjects with body weight ≤ 60 kg) or 150 μg (for subjects with body 
weight > 60 kg) MK-8962 once every two weeks, followed by 52 
weeks of combined treatment with MK-8962 and hCG (titrated to 
maintain appropriate Total T and E2 levels) twice a week.
Analysis Populations
Efficacy: Full Analysis Set (FAS), Completers
Safety: All Subjects as Treated (ASaT)
Pharmacokinetics: 
 
All-Subjects-Pharmacokinetically-Evaluable 
(ASPE)
Primary Endpoint(s)
Change from baseline (Day 1) to Week 64 in log-transformed 
testicular   volume (measured as the sum of volumes of left and right 
testes by ultrasound);
Key Secondary Endpoints
N/A
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The mean change from Day 1 (Baseline) in log-transformed testicular 
volume will be evaluated by using a mixed model with a fixed effect 
for baseline and time point and a random effect for subject. The 
geometric mean increase from Day 1 to Week 64 in testicular volume 
and its 95% CI will be obtained by exponentiation.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
55
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Statistical Methods for Key 
Safety Analyses
The percentage of subjects with anti-MK-8962 antibodies and its 
exact 95% CI will be calculated using the exact binomial method of 
Clopper Pearson.
Interim Analyses
No interim analyses are planned
Multiplicity
No multiplicity adjustment is planned as this is an estimation study
Sample Size and Power 
This is an estimation study.
Assuming a screen failure rate of approximately 50-60%, 
approximately 30-40 subjects will be screened to enroll approximately 
15. Assuming a discontinuation rate of 30%, it is estimated that 10 
subjects will complete. If the discontinuation rate exceeds 30%, 
enrollment will be re-opened to assure the target number of 
completers. The total number of enrolled subjects shall not exceed 35.
Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is being conducted as a single-group, open-label study, i.e., subjects, investigators, 
and SPONSOR personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the allocation schedule(s) for study 
treatment assignment.  Randomization will be implemented in an interactive voice response 
system (IVRS).
Hypotheses/Estimation
8.3
Objectives of the study are stated in Section 3.0. This is an estimation study, no hypothesis 
will be tested.
Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated are listed below, followed by the 
descriptions of the derivations of selected endpoints.
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
8.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint for this trial is the Change from Baseline (Day 1) to Week 64
in log-transformed testicular volume (measured as the sum of volumes of left and right testes 
by ultrasound).
Secondary Efficacy Endpoint

Change from baseline in serum inhibin B concentrations at Week 64;

Growth velocity at Week 36 and Week 64;

Tanner Stage of pubertal development at Weeks 12, 36 and 64.

Characterization of MK-8962 pharmacokinetics (based on serum MK-8962 
concentrations) through 64 weeks of treatment.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
56
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential

Characterization of testicular sonographic pattern reflecting pubertal development 
through 64 weeks of treatment;

Changes from baseline in endocrine parameters (LH, calculated free testosterone, 
Total T, E2, SHBG, and AMH at Weeks 12, 36 and 64;
Safety Endpoints
8.4.2
Initial description of safety measures is provided in Section 4.2.3.2.
The pre-specified safety endpoint is the presence of anti-MK-8962 antibodies.
Events of Clinical Interest
Liver function: an elevated AST or ALT lab value that is ≥3 x the upper limit of normal 
(ULN) and an elevated total bilirubin lab value that is ≥2 x ULN and, at the same time, an 
alkaline phosphatase lab value that <2 x ULN, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.
Hypersensitivity reaction: a potential sign or symptom of a hypersensitivity reaction after 
injection of MK-8962 such as new emergent skin rash, urticaria, hypotension, allergic 
asthma, chest tightness, broncho-spasm, dyspnea, or wheezing. Minor localized skin rash not 
suggesting hypersensitivity will not be considered an ECI.
Other safety endpoints include:

Change from baseline for laboratory safety parameters and vital signs;

Clinical review of adverse events;

Predefined limits of changes (PDLCs) for laboratory values. Details about the safety 
ranges for each parameter (hematology/biochemistry) will be specified in the sSAP.
Analysis Populations
8.5
Efficacy Analysis Populations
8.5.1
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study.  The FAS population consists of all randomized subjects who:

receive at least one dose of study treatment

have baseline and at least one post-baseline measurement of testicular volume

have LH levels ≤3 IU/L during anytime of the study

have received at least 36 weeks1 of treatment (12 weeks of priming with MK-8962 
followed by 24 weeks of combined treatment with MK-8962 and hCG) and have no 
more than 4 weeks from the last dose of MK-8962 when the last measurement is 
made
1 This time point is based on the observations regarding changes in testicular volume 
in a study of males with HH pre-treated with recFSH for 4 months followed by 24 
months of pulsatile GnRH therapy (equivalent of combined treatment with FSH and 
LH/hCG) [17].
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
57
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
A supportive analysis using the Completers population will be performed for the primary 
efficacy endpoint only if there are at least 5 completers.  The Completers population 
comprises subjects who remained on the study treatment regimen and completed through 
Week 64.
Another supportive analysis using the modified Intent-to-Treat population will be performed 
for the primary efficacy endpoint. The modified ITT population comprises all randomized 
subjects who have received at least 36 weeks of treatment (12 weeks of priming with MK-
8962 followed by 24 weeks of combined treatment with MK-8962 and hCG), and have 
baseline and at least one post-baseline measurement of testicular volume at ≥36 weeks of 
treatment.
Safety Analysis Populations
8.5.2
The All-Subjects-as-Treated (ASaT) population consists of all randomized subjects who 
received at least one dose of MK-8962 and will be used for the analysis of safety data in this 
study.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
All-Subjects-Pharmacokinetically-Evaluable (ASPE) population: Consists of all subjects 
from the ASaT group, for whom at least one PK parameter can be calculated according to the 
protocol and who did not have any protocol violation interfering with PK. Subjects included 
in the ASaT group, but excluded from the ASPE group will be listed including the reason(s) 
for exclusion.
The final determination on major protocol deviations interfering with PK, and thereby the 
composition of the ASPE population, will be made prior to the finalization of the database
and will be documented in a separate memo.  
Statistical Methods
8.6
Statistical testing and inference for safety analyses are described in 8.6.2. 
Statistical Methods for Efficacy Analyses
8.6.1
All efficacy analyses will be performed for the FAS.
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
8.6.1.1
Primary Efficacy Analysis
The mean change from Day 1 (Baseline) in log-transformed testicular volume will be 
analyzed using a mixed model with a fixed effect for baseline and time point and a random 
effect for subject. For each time point (i.e., Week 1-64), the mean change from Day 1 to that
time point and the associated 95% confidence interval (CI) will be calculated. The geometric 
mean increase in testicular volume and its 95% CI will be obtained by exponentiation.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
58
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
The mean change from the first day of combined treatment (Week 12) to Week 64 in log-
transformed testicular volume will also be analyzed using a mixed model with a fixed effect 
for time point and a random effect for subject. For each time point, the mean change from 
Week 12 to that time point and the associated 95% CI will be calculated. The geometric 
mean increase in testicular volume and its 95% CI will be obtained by exponentiation.
An unstructured covariance matrix will be used to model the correlation among repeated 
measurements. In the event of model convergence issues, other covariance structures will be 
considered.
In addition, the change from Day 1 to Week 12 (i.e., during the priming phase alone) in log-
transformed testicular volume will be summarized. The associated geometric mean increase 
and its 95% CI will be obtained by exponentiation.
Sensitivity analyses
A supportive analysis using only subjects who completed Week 64 will be performed for the 
primary efficacy endpoint only if there are at least 5 such completers. The mean change 
from Day 1 (Baseline) to Week 64 in log-transformed testicular volume will be analyzed 
using an Analysis of Covariance (ANCOVA) model including baseline as a covariate. The 
geometric mean change in testicular volume and its 95% CI will be obtained by 
exponentiation. The mean change from the first day of combined treatment (Week 12) to 
Week 64 will also be analyzed for the completers only.
Changes in log-transformed testicular volume will also be analyzed separately for the left and 
right testes using the same mixed model as for the primary analysis. Last Observation 
Carried Forward (LOCF) approaches will be used to investigate the robustness of the results
for the testicular volume (as the sum of volumes of left and right testes) as well as for the left 
and right testes separately.
Accounting for Missing Data
Assuming that data are Missing at Random (MAR), the mixed model for the primary efficacy 
analysis accounts for missing data. 
8.6.1.2
Secondary Efficacy Analysis
The change in serum inhibin B concentrations after 64 weeks will be summarized. In 
addition, changes from Day 1 to Week 12, and from Week 12 to Week 64 will also be 
summarized. A listing by subject and time point will also be provided for each treatment 
phase.
The growth velocity (cm/year) will be summarized as follows:
For each subject, the growth velocity over the 36 and 64 week treatment periods will be 
extracted using the slopes estimated from an overall mixed random intercept and random 
slope model of height (cm) and time (in years) and age as covariates. Overall growth 
velocity slope over 36 and 64 weeks will also be presented based on the same model. An 
unstructured covariance matrix will be used to model the correlation among repeated 
measurements. In the event of model convergence issues, other covariance structures (i.e. AR
or compound symmetry) will be considered.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
59
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
In addition, growth in cm over 12, 36 and 64 weeks will be listed for each age (14, 15, 16 and 
17 years of age at randomization). Annualized growth velocity (cm/year) at 36 and 64 weeks 
will also be calculated and listed.
For each male subject, Tanner Staging will be recorded for both pubic hair and testicular 
volume. Tanner Stage of development at Baseline, week 12, week 36 and at the end of the 64
weeks of combined treatment will be summarized by shift table. A listing of Tanner Stage by 
time point and subject will also be provided.
Descriptions of sonographic testicular patterns will be listed at Baseline and weeks 12, 36 
and 64. Any changes over time will be described.
For continuous variables, summary statistics will include the number of observations, mean, 
standard deviation, median, minimum and maximum. For categorical variables, frequency 
distributions will be provided.
Serum concentrations of hormones (LH, Total T, E2, SHBG, and AMH) will be summarized 
by assessment (Week 1-64). Additional summary statistics will include first and third 
quartile as well as geometric mean together with coefficient of variation. Values below the 
Lower Limit of Quantification (LLOQ) will be set to ½ times the LLOQ for the calculation 
of descriptive statistics. The number and percentage of values below the LLOQ will be 
reported. Additionally, serum hormone concentrations will be summarized by treatment 
phase.
The summary of the key efficacy analyses is provided in Table 6.
Table 6
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary 
vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
Change from Baseline to 
Week 64 in log-transformed 
testicular volume (measured 
as the sum of volumes of left 
and 
right 
testes 
by 
ultrasound);
P
Linear Mixed Model #
FAS
Model-based
Change from Baseline to 
Week 64 in log-transformed 
testicular volume (measured 
as the sum of volumes of left 
and 
right 
testes 
by 
ultrasound);
S
Linear Mixed Model #
FAS
LOCF§§
Change from Baseline to 
Week 64 in log-transformed 
testicular volume (measured 
as the sum of volumes of left 
and 
right 
testes 
by 
ultrasound);
S
ANCOVA
Completers
N/A
 †
P=Primary approach; S=Supportive approach.
  # Linear Mixed Model with terms for treatment.
§§
LOCF = last-observation-carried-forward method.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
60
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Statistical Methods for Safety Analyses
8.6.2
All safety analyses will be conducted for the ASaT.
Due to the small study size and single treatment, the tiered approach will not be followed for 
this study.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests and vital signs measurements.
For this protocol, the percentage of subjects with confirmed presence of anti-MK-8962 
antibodies and its exact 95% CI will be calculated using the exact binomial method of 
Clopper Pearson. The presence of anti-MK-8962 antibodies will be summarized at each visit 
as well as overall and by treatment phase.
Adverse events (specific terms as well as system organ class terms) and predefined limits of 
change in laboratory and vital signs parameters will be summarized by treatment phase.  
In addition, the broad AE categories consisting of the percentage of subjects with any AE, a 
drug related AE, a serious AE, an AE which is both drug-related and serious, and who 
discontinued due to an AE will be summarized by treatment phase.  
Continuous measures such as changes from baseline in laboratory and vital signs parameters 
will be summarized: summary statistics for baseline, on-treatment, and change from baseline 
values will be provided by treatment phase in table format. 
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
8.6.3.1
Demographic and Baseline Characteristics
The comparability of the treatment phases for each relevant characteristic will be assessed by 
the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
The cumulative percentage of subjects that discontinued treatment prematurely will be 
calculated by treatment phase and overall using the Kaplan-Meier method and plotted against 
trial week. Demographic variables (e.g., age [yrs], body weight [kg], body height [cm], body 
mass index [BMI] [kg/m2] and race), baseline characteristics [testicular volume (left and 
right testes, as well as total)], results from serum hormone levels [FSH, LH, hCG, Total T, 
E2, SHBG, inhibin-B, and AMH], primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized either by descriptive statistics or categorical 
tables.
8.6.3.2
Disposition of Subjects
The number of subjects that enter the MK-8962 priming phase, the number of subjects that 
enter the combined treatment phase (MK-8962 and hCG) and the number of subjects that 
complete the combined treatment phase will be tabulated. All subjects that discontinue will 
be listed by main reason for discontinuation.
8.6.3.3
Pharmacokinetic Analysis
The PK analysis will be conducted in the ASPE group.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
61
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
For characterization of MK-8962 PK in adolescents, serum samples will be collected at 
specific time points throughout the study (see flowchart in Section 6.0). 
Serum MK-8962 concentrations will be obtained using a solid phase enzyme-immunoassay 
specific for MK-8962. Descriptive statistics for the serum concentrations by time-point will 
be calculated and will comprise number of observations (n), number of missing or substituted 
observations, arithmetic mean together with standard deviation and coefficient of variation, 
geometric mean together with coefficient of variation, minimum, median and maximum.
The existing PopPK model in HH men will be updated using the serum MK-8962 
concentration data obtained in the current study. A covariate analysis will be performed to 
identify important relationships between PK parameters (ka MK-8962, CL MK-8962, V MK-
8962, f MK-8962, and FSH baseline) and patient characteristics (i.e., gender, body weight, 
height, BMI, age). The updated model will be used to derive estimates for at least the 
following PK parameters in adolescent males: AUCss, Cmax_ss, Cmin_ss, Cl and V.
Descriptive statistics for the PK parameters will be calculated and will comprise number of 
observations (n), arithmetic mean, standard deviation and arithmetic coefficient of variation, 
geometric mean and geometric coefficient of variation, minimum, median and maximum.
In addition, through the PopPK approach, analysis will be performed using the serum MK-
8962 concentration data obtained in this study relative to prior studies in adult HH men and 
in women to identify possible differences in MK-8962 PK between females, HH men and 
adolescent males. It was identified based on the HH adult men PopPK analysis that MK-
8962 clearance was 30% lower in male subjects as compared to female subjects. The 
updated PopPK model in adolescent males will be used to validate the assumptions also 
apply to adolescent males. This analysis will be reported separately.
Interim Analyses
8.7
No interim analyses are planned for this study.
Multiplicity
8.8
No multiplicity adjustment is planned as there is a single estimation of one treatment using 
one endpoint. No hypothesis will be tested. Other efficacy analyses will be considered 
supportive and/or explanatory.
Sample Size and Power Calculations
8.9
Sample Size and Power for Efficacy Analyses
8.9.1
This is an estimation study.
Assuming a screen failure rate of 50-60%, approximately 30-40 subjects will be screened to 
enroll approximately 15. Assuming a discontinuation rate of 30%, it is estimated that 10 
subjects will complete the study.  If the discontinuation rate exceeds 30%, enrollment will be 
re-opened to assure the target number of completers (i.e., 10). The total number of enrolled 
subjects shall not exceed 35.
Table 7 summarizes estimates of the geometric mean increase in testicular volume (mL)
under various assumptions. These calculations are based on a difference in paired means with 
10 completed subjects at an overall one-sided 2.5% alpha-level and are carried out using 
[SAS v9.3].
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
62
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
In P031 (adult men with HH) the estimated geometric mean increase in testicular volume 
from Day 1 to Week 52 was 2.30 (95% CI: 2.03-2.62). This corresponds to a difference from 
baseline and SD (both on log-scale) of 0.84 and 0.47, respectively. These finding are
consistent with similar results observed in other studies [1, 17] where at least a doubling of 
mean testicular volume of adolescent males was observed after recFSH treatment.
Based 
upon these experiences, a 2-fold (or greater) increase in testicular volume is expected.  
Applying generally similar SD as observed in P031, the study should be able to estimate a 
larger than 2-fold increase with the lower margin of the 95% CI excluding an increase of less 
than 1.7-fold.  The CI, with 10 completers, suggests reasonable precision to estimate the 
change in testicular volume.  
Table 7
The 95% Confidence Limits for Geometric Mean Increase in Testicular Volume 
(mL) by Underlying Difference and SD Assumptions (log-scale) for 10 
Completers
Underlying Difference 
from Baseline to Week 64 
(log-scale)
Underlying SD (log-scale)
Geometric Mean 
Increase
95% Confidence Limit†
0.45
1.18, 1.89
0.4
0.5
1.49
1.15, 1.93
0.55
1.12, 1.99
0.45
1.30, 2.08
0.5
0.5
1.65
1.27, 2.14
0.55
1.24, 2.19
0.45
1.44, 2.30
0.6
0.5
1.82
1.40, 2.36
0.55
1.37, 2.43
0.45
1.59, 2.54
0.7
0.5
2.01
1.55, 2.61
0.55
1.51, 2.68
0.45
1.76, 2.81
0.8
0.5
2.23
1.72, 2.89
0.55
1.67, 2.96
† One-sided 95% CI based on a difference in paired means.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
63
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Subgroup Analyses and Effect of Baseline Factors
8.10
The primary endpoint of log-transformed testicular volume may also be summarized by 
weight group (≤60 kg, >60 kg) if there are a sufficient number of subjects in each category.
Compliance (Medication Adherence)
8.11
Drug accountability data for MK-8962 will be collected during the study. Compliance rates 
will be summarized (N, mean, median, SD, range [min and max]) by treatment phase and 
overall. The compliance rate for a subject will be defined as the total number of injections 
divided by the total number of injections the subject was supposed to have during the 
treatment period. 
Extent of Exposure
8.12
The extent of exposure to study treatment will be evaluated by summary statistics (N, mean, 
median, standard deviation) and frequencies for the “Number of Days on Therapy” by 
treatment phase and overall.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 8. This includes 
both MK-8962 (investigational product of this trial) and hCG (standard of care). For hCG 
and/or its solvent, if local regulations do not permit use of the centrally sourced supplies OR 
centrally sourced supplies become unavailable, a local source may be used but requires prior 
approval from the Sponsor.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
64
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Table 8
Product Descriptions
Product Name 
& Potency
Dosage Form
Source/Additional Information
corifollitropin alfa 
(MK-8962) 100 μg/0.5 mL
Pre-filled syringe 
(Sterile Solution for 
subcutaneous Injection, 0.5 mL)
Provided centrally by the Sponsor.
corifollitropin alfa 
(MK-8962) 150 μg/0.5 mL
Pre-filled syringe 
(Sterile Solution for 
subcutaneous Injection, 0.5 mL)
human Chorionic 
Gonadotropin (hCG) 1500 IU
Ampoule or vial
(Sterile Dry Powder for 
subcutaneous injection after 
reconstitution)
Provided centrally by the Sponsor. 
If local regulations do not permit 
use 
of 
the 
centrally 
sourced 
supplies
OR centrally sourced 
supplies become
unavailable, a 
local source may be used but 
requires prior approval from the 
Sponsor.
human Chorionic 
Gonadotropin (hCG) 5000 IU
Ampoule or vial
(Sterile Dry Powder for 
subcutaneous injection after 
reconstitution)
Sodium Chloride Solution 
0.9%, 1 mL
Ampoule or vial 
(Sterile Solution for 
Reconstitution of hCG, 1 mL)
All supplies indicated in Table 8 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 8 will be provided by the trial site, 
subsidiary or designee. Every attempt should be made to source these supplies from a single 
lot/batch number. The trial site is responsible for recording the lot number, manufacturer, 
and expiry date for any locally purchased product as per local guidelines unless otherwise 
instructed by the Sponsor.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label kits of Pre-filled syringe and ampoules (or vials) to maintain 
the dosing schedule. 
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
65
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
66
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifyin g 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
67
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
68
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the 
Sponsor of the trial is solely responsible for determining whether the trial and its results are 
subject 
to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialregister.eu or other local registries. Merck, as Sponsor of this trial, will 
review 
this 
protocol 
and 
submit 
the 
information 
necessary 
to 
fulfill 
these 
requirements. Merck entries are not limited to FDAAA or the EMA clinical trials directive 
mandated trials. Information posted will allow subjects to identify potentially appropriate 
trials for their disease conditions and pursue participation by calling a central contact number 
for further information on appropriate trial locations and trial site contact information.   
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
69
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
70
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1. Raivio T, Wikstrom AM, Dunkel L. Treatment of gonadotropin-deficient boys with 
recombinant human FSH: long-term observation and outcome. Eur J Endocrinol 2007; 
156: 105–11
2. Seminara SB, Hayes FJ, Crowley WF. Gonadotropin-releasing hormone deficiency in 
the human (Idiopathic Hypogonadotropic Hypogonadism and Kallmann’s Syndrome): 
pathophysiological and genetic considerations. Endocr Rev 1998;19(5): 521–39. 
3. AACE Hypogonadism Task Force. American association of clinical endocrinologists 
medical guidelines for clinical practice for the evaluation and treatment of 
hypogonadism in adult male patients – 2002 update. Endocr Pract 2002; 8: 439-56. 
4. Han TS, Bouloux PMG. What is the optimal therapy for young males with 
hypogonadotropic hypogonadism? Clin Endocrinol 2010; 72: 731-37. 
5. Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley WF Jr. Predictors of 
outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic 
hypogonadism. J Clin Endocrinol Metab. 2002 Sep;87(9):4128-36.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
71
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
6. Fauser BC, Mannaerts BM, Devroey P, Leader A, Boime I, Baird DT. Advances in 
recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained 
follicle-stimulating activity and reduced injection frequency. Hum Reprod Update 
2009;15:309–21.
7. Clinical Study Report, Multicenter: A phase III, randomized, double-blind, active-
controlled, non-inferiority clinical trial to investigate the efficacy and safety of a single 
injection of Org 36286 (corifollitropin alfa) to induce multifollicular development for 
controlled ovarian stimulation using daily recombinant FSH as a reference (Protocol 
P05787). (Protocol 38819). 
8. Clinical Study Report, Multicenter Study: A phase III, randomized, double-blind, active-
controlled, non-inferiority trial to investigate the efficacy and safety of a single injection 
of MK-8962( corifollitropin alfa) to induce multifollicular development for controlled 
ovarian stimulation (COS) using daily recombinant FSH (recFSH) as a reference in 
women aged 35 to 42 years (PURSUE) (Protocol P06029).
9. Clinical Study Report, Multicenter Study: A phase III, randomized, double-blind, active-
controlled, equivalence clinical trial to investigate the efficacy and safety of a single 
injection of 100 μg Org 36286 (corifollitropin alfa) to induce multifollicular 
development for controlled ovarian stimulation (COS) using daily recombinant FSH 
(recFSH) as a reference. (Protocol P05690). (Protocol 107012).
10. Clinical Study Report, Multicenter Study: A phase III, multi-center, open label, 
uncontrolled trial to investigate the efficacy and safety of MK-8962 (corifollitropin alfa) 
in combination with human Chorionic Gonadotropin (hCG) in inducing increased 
testicular
volume and spermatogenesis in adult men with
hypogonadotropic 
hypogonadism who remain azoospermic when treated with hCG alone. (Protocol P031) 
(Protocol SCH 900962, P07937).
11. Clinical Study Report: An Open-Label, Multicenter, Efficacy and Safety Study of 
Puregon® in Hypogonadotropic Hypogonadal Male Subjects (Protocol 37618).
12. Bouloux PMG, Handelsman DJ, Jockenhovel F, Nieschlag E, Rabinovici J, Frasa WLH, 
Bie de JJ, Voortman G, Itskovitz-Eldo on behalf of the FSH-CTP study group. First 
human exposure to FSH-CTP in hypogonadotropic hypogonadal males. Hum Reprod. 
2001, 16 (8), 1592-97. 
13. Aydogan U, Aydogdu A, Akbulut H, Sonmez A, Yuksel S, Basaran Y, et al. Increased 
frequency of anxiety, depression, quality of life and sexual life in young 
hypogonadotropic hypogonadal males and impacts of testosterone replacement therapy 
on these conditions. Endocr J. 2012;59(12):1099-1105.
14. Sidhoum VF, Chan YM, Lippincott MF, Balasubramanian R, Quinton R, Plummer L, et 
al.  Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of 
the reproductive neuroendocrine system.  J Clin Endocrinol Metab. 2014;99(3):861-70.
15. Dwyer AA, Raivio T, Pitteloud N. Gonadotrophin replacement for induction of fertility 
in hypogonadal men. Best Pract Res Clin Endocrinol Metab. 2015 Jan;29(1):91-103.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
72
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
16. Zacharin et al, 2012 Zacharin, M., Sabin, M.A., Nair, V.V. et al, Addition of 
recombinant follicle-stimulating hormone to human chorionic gonadotropin treatment in 
adolescents and young adults with hypogonadotropic hypogonadism promotes normal 
testicular growth and may promote early spermatogenesis. Fertil Steril. 2012;98:836–42.
17. Dwyer AA, Sykiotis GP, Hayes FJ, Boepple PA, Lee H, Loughlin KR, et al. Trial of 
recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in 
patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab 
2013;98(11):E1790-E1795. 
18. Büchter D1, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic 
gonadotropin/human menopausal gonadotropin as effective treatment for men with 
hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol. 1998 
Sep;139(3):298-303.
19. Liu PY, Baker HW, Jayadev V, Zacharin M, Conway AJ, Handelsman DJ. Induction of 
spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient 
infertile men: predictors of fertility outcome. J Clin Endocrinol Metab. 2009 
Mar;94(3):801-8. 
20. Warne DW, Decosterd G, Okada H, Yano Y, Koide N, Howles CM. A combined 
analysis of data to identify predictive factors for spermatogenesis in men with 
hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating 
hormone and human chorionic gonadotropin. Fertil Steril. 2009 Aug;92(2):594-604. 
21. Miyagawa Y, Tsujimura A, Matsumiya K, Takao T, Tohda A, Koga M, et al. Outcome 
of Gonadotropin therapy for male Hypogonadotropic Hypogonadism at university 
affiliated male infertility centers: A 30-year retrospective study. J Urol 2005;173:2072-
5. 
22. Behre HM, Kliesch S, Schädel F, Nieschlag E. Clinical relevance of scrotal and 
transrectal ultrasonography in andrological patients. Int J Androl. 1995 Dec;18 Suppl 
2:27-31.
23. Coutant R, Biette-Demeneix E, Bouvattier C, Bouhours-Nouet N, Gatelais F, Dufresne 
S, Rouleau S, Lahlou N. Baseline inhibin B and anti-Mullerian hormone measurements 
for diagnosis of hypogonadotropic hypogonadism (HH) in boys with delayed puberty. J 
Clin Endocrinol Metab. 2010 Dec;95(12):5225-32. 
24. Kletter GB, Rolfes-Curl A, Goodpasture JC, Solish SB, Scott L, Henzl MR, Beitins IZ. 
Gonadotropin-releasing hormone agonist analog (nafarelin): a useful diagnostic agent 
for the distinction of constitutional growth delay from hypogonadotropic hypogonadism. 
J Pediatr Endocrinol Metab. 1996 Jan-Feb;9(1):9-19.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
73
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
74
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
75
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.5 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
76
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
77
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
78
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained). 
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
79
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
80
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
81
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
82
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
83
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
84
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
85
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
86
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
87
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
88
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
89
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
90
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.4
Sample Types
Approximate Blood Volume for Laboratory Safety Evaluations 
(Hematology and Chemistry)
Trial Visit:
Screening
Visit 1
Treatment 
Visit 2
Treatment
Visit 9
Treatment 
Visit 12
Treatment
Visit 15/
D/C Visit 
Blood Parameter 
Approximate Blood Volume (mL)
Hematology
2.00-3.00
2.00-3.00
2.00-3.00
2.00-3.00
2.00-3.00
Serum Chemistry
0.50
0.50
0.50
0.50
0.50
Serum for Free T4
0.35
N/A
N/A
N/A
N/A
Expected Total (mL)
2.85-3.85
2.85-3.85
2.85-3.85
2.85-3.85
2.85-3.85
Approximate Blood Volume for Panel of Endocrine Parameters
Trial 
Visit:
Screening
Visit 1
Treatment 
Visit 2
Treatment
Visit 9
Treatment 
Visit 10
Treatment 
Visit 11
Treatment 
Visit 12
Treatment 
Visit 13
Treatment 
Visit 14
Treatment
Visit 15/
D/C Visit/
Post-
Treatment
Blood 
Parameter
Approximate Blood Volume (mL)
Serum 
Estradiol
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
Serum 
FSH
0.35
0.35
0.35
0.35
0.35
Serum LH
0.40
0.40
0.40
0.40
0.40
Serum 
SHBG
0.30
0.30
0.30
0.30
0.30
Serum 
AMH
0.35
0.35
0.35
0.35
0.35
Serum 
Inhibin B
0.30
0.30
0.30
0.30
0.30
Serum 
hCG
0.27
0.27
0.27
0.27
0.27
Calculated 
Free T
1.00
1.00
1.00
1.00
1.00
Total T
0.70
0.70
0.70
0.70
0.70
0.70
0.70
0.70
0.70
Expected 
Total (mL)
4.67
4.67
4.67
1.70
1.70
4.67
1.70
1.70
4.67
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
91
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Approximate Blood Volume for Anti-MK-8962 Antibodies
Trial Visit:
Treatment
Visit 2
Treatment 
Visit 8
Treatment
Visit 9
Treatment 
Visit 11
Treatment 
Visit 12
Treatment 
Visit 13
Treatment
Visit 15/
D/C Visit 
Post-
Treatment
Blood 
Parameter 
Approximate Blood Volume (mL)
Sampling 
for 
Anti-MK-8962 
antibodies
3.00
3.00
3.00
3.00
3.00
3.00
3.00
3.00
Approximate Blood Volume for Pharmacokinetic Evaluations
Trial 
Visit:
Treatme
nt
Visit 2
Treat
ment
Visit 3
Treat
ment 
Visit 4
Treat
ment 
Visit 5
Treat
ment 
Visit 6
Treat
ment
Visit 8
Treat
ment
Visit 9
Treat
ment 
Visit 
11
Treat
ment 
Visit 
12
Treat
ment 
Visit 
13
Treat
ment 
Visit 
15/ 
D/C 
Visit
Post-
Treat
ment
Sample 
Number:
01
02
03
04
05
06
07
08
09
10
11
12
13
Blood 
Paramete
r
Approximate Blood Volume (mL)
Pharmaco
kinetic 
sampling 
for 
MK-
8962 
concentrat
ion
3.
00
3.
00
3.00
3.00
3.00
3.00
3.00
3.00
3.00
3.00
3.00
3.00
3.00
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
92
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Instructions on home-administration of MK-8962 (as provided to subjects)
12.5
Components of the MK-8962 syringe with needle
Injections should be administered in the morning once every two weeks from Visit 2 (Day 1) 
onwards subcutaneously into the abdominal wall. Please see the Medication Diary for detailed 
injection schedule.
Wash your hands thoroughly and clean the skin area where the needle will enter with a disinfectant.
Preparing the injection 
Step 1:
Break the label perforation and pull off the needle-cap.
Leave the needle shield on the needle.
Place the needle shield (containing the needle) on a clean dry surface, while 
preparing the syringe.
Step 2:
Peel off the label on the syringe.
Hold the syringe with the grey cap pointing upwards.
Tap the syringe gently with your finger to help air bubbles rise to the top.
Check that the liquid in the syringe is clear.  Do not use if it is not clear or has 
particles in it.
Step 3:
Keep the syringe pointing upwards.
Unscrew the syringe cap counter-clockwise.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
93
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Step 4:
Keep the syringe pointing upwards.
Screw the needle shield from Step 1 (containing the needle) clockwise onto the 
syringe.
Step 5:
Keep the syringe pointing upwards.
Remove the needle shield by pulling straight up and then discard the shield.
BE CAREFUL with the needle.
Injecting
Step 6:
Take the syringe between your index and middle finger, keeping the needle 
pointed upwards.  Place your thumb on the plunger.
Carefully push the plunger upwards until a tiny droplet appears at the tip of the 
needle.
Step 7:
Pinch a fold of the abdomen skin between your thumb and index finger.
Insert the entire needle at a 90 degree angle into the fold of the skin.
CAREFULLY press the plunger until it cannot go any further.
Keep holding down the plunger and COUNT TO FIVE to ensure that all of the 
solution is injected. 
Step 8:
Release your thumb from the plunger.
The needle will withdraw automatically into the syringe where it will be locked 
permanently.
Properly discard the used syringe into a bio-hazard container. 
Note: Please record the date and time of injection on the medication diary
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
94
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Tanner Staging (Male)
12.6
Pubic hair  

Tanner I -- none (prepubertal state)

Tanner II -- small amount of long, downy hair with slight pigmentation at the base of 
the penis and scrotum 

Tanner III -- hair becomes more coarse and curly, and begins to extend laterally

Tanner IV -- adult-like hair quality, extending across pubis but sparing medial thighs

Tanner V -- hair extends to medial surface of the thigh
Genitals

Tanner I -- prepubertal (testicular volume less than 1.5 ml; small penis)

Tanner II -- testicular volume between 1.6 and 6 ml; skin on scrotum thins, reddens 
and enlarges; penis length unchanged

Tanner III -- testicular volume between 6 and 12 ml; scrotum enlarges further; penis 
begins to lengthen

Tanner IV -- testicular volume between 12 and 20 ml; scrotum enlarges further and 
darkens; penis increases in length and circumference

Tanner V -- testicular volume greater than 20 ml; adult scrotum and penis
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
95
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Blood Pressure and Anthropometric Measurements
12.7
Blood Pressure
Ensure patient has not had any caffeine or tobacco within 30 minutes. BP should be
measured in the sitting position. The patient will remain in the sitting position for at least 5 
minutes before any blood pressure readings are recorded. The same arm, preferably the non-
dominant arm, should be used for all blood pressure determinations at each visit. Systolic and 
diastolic BP will be determined by obtaining two measurements, 1 to 2 minutes apart. The 
consecutive systolic BP readings should be within 5 mm Hg of each other and the 
consecutive diastolic BP readings should be within 5 mm Hg of each other. The final BP 
measurement must be recorded.
Weight
Weight will be taken on the same calibrated digital scale throughout the study, after voiding 
and while wearing only a gown and underwear (no street clothes, no shoes or socks). 
Subjects should step gently onto the scale, place both feet together in the center of the scale 
and stand straight with eyes directed ahead. Subjects should be instructed to stand still 
and not sway. Measurement will be recorded after the weight has stabilized.
Weight will be measured after voiding (to the nearest 0.2 kg). Measurements will be
collected until 2 consecutive measurements do not differ by more than 0.2 kg from each 
other. The final weight measurement must be recorded. The same digital scale must be 
used throughout the study.
The SPONSOR will provide a scale and/or 10-kg certified weight to study sites that do not 
have them. The scale must be calibrated according to the manufacturer’s instructions at 
set-up and when it is transferred or moved. Additional calibration should be performed 
according to the manufacturer’s instructions.
Height
Standing height will be measured without shoes using a stadiometer.
Standing height will be assessed through maximum vertical stature for persons who can stand 
unassisted. Hair ornaments, barrettes, braids, jewelry, or cornrows should be moved or 
removed from the top of the head before the measurement is taken.
A fixed stadiometer with vertical backboard, fixed floorboard and movable headboard must 
be used. Subjects should stand with the heels of their feet against the vertical backboard with 
feet pointing outward at approximately a 60-degree angle. Body weight should be distributed 
evenly with both feet flat on the floor. The examiner should check several contact points with 
the vertical backboard, including heels, buttocks, shoulder blades, and the back of the head. 
This may be difficult for subjects with certain body shapes. However, the head should be in 
the Frankfort plane (an imaginary line from the ear canal to just below the lower orbit of the 
eye should be parallel to the floor). Subject should be looking straight ahead, and be asked to 
take a deep breath and stand tall. Once the subject is positioned, the headboard will be placed 
on top of the head, with sufficient pressure to compress the hair. The measurement is 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
96
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
recorded in cm, to the nearest mm. Measurements will be collected until 3 consecutive 
measurements do not differ by more than 1.0 cm from each other. The final height 
measurement must be recorded. Some patients may have physical conditions that may 
limit the ability to measure height accurately (e.g., kyphosis). In such cases, height should be 
measured to the best of the examiner’s ability, a note should be made of the condition and
measurements should be repeated in the same manner for the rest of study.
The stadiometer must be calibrated upon mounting the stadiometer to the wall, and 
according to the manufacturer’s instructions thereafter.
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
97
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
List of Abbreviations
12.8
Abbreviation/Term
Definition
ADA
Anti-drug antibodies
AE
Adverse event
ALT
Alanine aminotransferase
AMH
Anti-Müllerian hormone
ANCOVA
Analysis of covariance
ART
Assisted Reproductive Technology
ASaT
All-Subjects-as-Treated
ASPE
All-Subjects-Pharmacokinetically-Evaluable
AST
Aspartate aminotransferase
BMI
Body mass index
BP
Blood pressure
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence Interval
CL
Clearance
COS
Controlled Ovarian Stimulation
CTP
Carboxy-terminal peptide
DNA
Deoxyribonucleic acid
E2
Estradiol
ECI
Event of Clinical Interest
eCRF
Electronic Case Report Form
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
ERC
Ethics Review Committee
FAS
Full Analysis Set
FBR
Future Biomedical Research 
FSH
Follicle stimulating hormone
FSH-IR
Follicle stimulating hormone-immunoreactivity
GnRH
Gonadotropin releasing hormone
GnRHa
Gonadotropin releasing hormone agonist
hCG
Human chorionic gonadotropin, choriogonadotropin 
beta
hFSH
Human follicle stimulating hormone
HH
Hypogonadotropic hypogonadism
HIV
Human Immunodeficiency Virus
HR
Heart rate
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IHH
Idiopathic hypogonadotropic hypogonadism (HH) 
IRB
Institutional Review Board
IU
International unit
IVRS/IWRS
Interactive Voice/Web Response System 
LH
Luteinizing hormone
LLN
Lower limit of normal
LLOQ
Lower limit of quantification
LOCF
Last observation carried forward
LSD
Lysergic acid diethylamide
MAR
Missing at Random
non-pf
Non-protein free
PCP
Phencyclidine 
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
98
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
Abbreviation/Term
Definition
PD
Pharmacodynamic
PDLC
Predefined limits of changes
pf
Protein free
PK
Pharmacokinetic
PopPK
Population pharmacokinetics (PK)
RCF
relative centrifugal force
recFSH
Recombinant human follicle stimulating hormone 
(FSH)
RNA
Ribonucleic acid
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation
SHBG
Sex hormone-binding globulin
SOC
System Organ Class
sSAP
Supplemental Statistical Analysis Plan (SAP)
T
Testosterone
TC
Telephone contact
Total T
Total testosterone
ULN
Upper limit of normal
USS
Ultrasound scan
V
Volume of distribution
WBC
White blood cell
 
 
04WZY9
 
 
05M0ZB


Product:  MK-8962 
99
Protocol/Amendment No.: 043-06 
MK-8962-043-06 Final Protocol
24-Apr-2018
Confidential
13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
04WZY9
 
 
05M0ZB