Clinical trial NCT02908074
Conditions: Hypogonadotropic Hypogonadism
Keywords: Hypogonadotropic hypogonadism testosterone
Sponsor: Mereo BioPharma
Start date: 2016-11-15; Completion date: 2018-11-21
Enrollment: 143 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase IIb, multicentre, double-blind, randomised, placebo-controlled parallel-group 36-week study evaluating safety and efficacy of BGS649 in male obese subjects with hypogonadotropic hypogonadism (HH)

Detailed description:
This is a 6 months, active treatment, extension study, open to subjects who have completed full 24 weeks in Study MBGS205 (A Phase IIb multicentre, double-blind, dose-ranging, randomised, placebo-controlled study evaluating safety and efficacy of BGS649 in male obese subjects with hypogonadotropic hypogonadism \[HH\]).The main purpose of Study MBGS206 is to evaluate long term safety and efficacy parameters in subjects after 12 months exposure with BGS649.

Arms: arm 1: Drug: BGS649 Dose 1 weekly arm 2: Drug: BGS649 Dose 2 weekly arm 3: Drug: BGS649 Dose 3 weekly
Interventions: intervention 1: BGS649
Intervention descriptions: intervention 1: Capsules will be taken weekly for a maximum of 24 weeks

Protocol documents:
Prot_000.pdf: 
Mereo BioPharma 2 Ltd 
CONFIDENTIAL 
Protocol MBGS206 
Amended Protocol Version 2.0, 28 Mar 2017 
Page 1 of 72 
1 
TITLE  PAGE 
CLINICAL STUDY PROTOCOL 
A 6 month, double-blind safety extension study of MBGS205 evaluating the effects of 
long term treatment with BGS649 on bone mineral density 
Protocol No.:  MBGS206 
EUDRACT/IND No.: 2015-005760-42 
Test Product: 
BGS649  
Indication: 
Hypogonadotropic hypogonadism 
Sponsor: 
Mereo BioPharma 2 Ltd 
Development Phase: 
Phase IIb 
Sponsor Signatory: 
Dr. Alastair MacKinnon 
Sponsor Medical Expert: 
Dr. Jackie Parkin 
Date of the Protocol: 
28 March 2017 
Version of the Protocol: 
Final Version 2.0 
The confidential information in this document is provided to you as an investigator, potential 
investigator or consultant for review by you, your staff and applicable Independent Ethics 
Committee and/or Institutional Review Board. It is understood that the information will not 
be disclosed to others without written authorisation from Mereo BioPharma 2 Ltd except to 
the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. 


Mereo BioPharma 2 Ltd 
CONFIDENTIAL 
Protocol MBGS206 
Amended Protocol Version 2.0, 28 Mar 2017 
Page 2 of 72 
SUMMARY AND JUSTIFICATION OF CHANGES  
This amendment includes revisions to Protocol Version 1.0, dated 27 July 2016, summarized 
as follows 
Change 
Rationale 
Change total number of doses from 23 to up 
to 24 throughout document 
Clarification and correction 
Change from AESI as exclusion criterion to 
AESI that meet MBGS205 discontinuation 
being the exclusion criterion 
No safety reason to require AESIs that do not meet 
study drug discontinuation criterion to be exclusion for 
extension study MBGS206 
Labelling section removal reference to 
placebo 
No placebo in MBGS206 
Clarification MBGS206 will be un blinded to 
sponsor and CRO when preceding study 
MBGS205 is un blinded.  
As a result of un blinding MBGS205 the patient 
allocation for MBGS206 will be available to sponsor 
and CRO. MBGS206 will be fully recruited by this 
time and with quantitative endpoint the risk to the 
study conduct is considered acceptable. Site and 
subjects will remain blinded. 
Increased technical guidance on DEXA 
scanning and requirement to utilise guidance 
within study DEXA imaging manual 
To reduce the variability in DEXA results that had 
been observed in MBGS205 
Removal of monoclonal antibodies as a 
prohibited medication 
No clinical or scientific reason to exclude these 
treatments, apart from those that affect bone that are 
covered in a separate exclusion criterion 
Removal of use of insulin as a prohibited 
medication. 
To 
enable 
recruitment 
of 
representative 
target 
population of obese men with 
type 2 diabetes requiring insulin. 
Removal of Cyp3A4 and Cyp2A6 modifying 
concomitant medications. 
BGS649 has been shown not to be a substrate or 
inducer of major Cytochrome (CYP) 450 enzymes and 
is metabolised very slowly by CYPs. Therefore, the 
potential of BGS649 drug-drug interactions is low. 
Clarification of worsening of lower limb 
oedema to exclude measurement artefacts and 
effects of restrictive clothing. 
To prevent inappropriate drug interruption for 
artefactual worsening of leg oedema. 




Mereo BioPharma 2 Ltd 
CONFIDENTIAL 
Protocol MBGS206 
Amended Protocol Version 2.0, 28 Mar 2017 
Page 4 of 72 
3 
GENERAL INFORMATION 
A 6 month, double-blind safety extension study of MBGS205 evaluating the effects of 
long term treatment with BGS649 on bone mineral density 
Protocol No.: 
MBGS206 
Date of the Protocol: 
27 July 2016 
Date and Number of Amendment(s): 
28 Mar 2017,  Amendment 1 
Sponsor: 
Mereo BioPharma 2 Ltd 
1 Cavendish Place 
London W1G 0QF 
Clinical Research Organisation: 
ICON Clinical Research Ltd 
South County Business Park 
Leopardstown 
Dublin 18 
Ireland 
Sponsor Signatory: 
Sponsor Medical Expert: 
Principal Investigator: 
Professor T. Hugh Jones 
Robert Hague Centre for Diabetes and Endocrinology 
Barnsley Hospital NHS Foundation Trust 
Gawber Road 
Barnsely S25 2EP 
Biostatistics: 


Mereo BioPharma 2 Ltd 
CONFIDENTIAL 
Protocol MBGS206 
Amended Protocol Version 2.0, 28 Mar 2017 
Page 5 of 72 
4 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
Mereo BioPharma 2 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
Volume: 
Page: 
(For National Authority Use Only) 
Name of Product: 
BGS649 
Name of Active Ingredient: 
4,4’-[fluoro-(1-H-1,2,4-triazol-1-
yl)methylene]bisbenzonitrile 
Title of Study: 
A 6 month double-blind safety extension study of MBGS205 evaluating the effects of long term treatment with 
BGS649 on bone mineral density. 
Principal Investigator: 
Professor Hugh Jones 
Study Centre(s): 
Approximately 50 sites 
Publication(s): 
None 
Planned Study Period: 
Oct 2016 to Oct 2017 
Development Phase: 
Phase II 
Objectives: 
Primary Objective 
The primary objective is to evaluate the effect of 12 months treatment with BGS649 on bone mineral density 
(6 months treatment during Study MBGS205). 
Secondary Objectives 
Safety: 
1.
To evaluate the effect of BGS649 after 12 months period of treatment with active study drug (6 months
treatment during Study MBGS205 and 6 months treatment during Study MBGS206) by dose group on: 
o
Bone turnover biomarkers
o
Bone mineral density and bone biomarkers by vitamin D status (Baseline vitamin D from
Study MBGS205)
o
Oestradiol levels
o
Testosterone outside upper limit of normal range
o
Prostate specific antigen and haematocrit
o
Blood pressure
o
Adverse events (AEs)
2.
To evaluate if there are associations between changes in bone mineral density after 12 months treatment
with BGS649 with end of treatment testosterone and oestradiol levels
3.
To collect safety data in subjects switching from placebo arm in Study MBGS205 and treated with
6 months active study drug in Study MBGS206.
Pharmacokinetic 
The pharmacokinetic (PK) objective is to determine BGS649 concentration by dose in seminal fluid and 
relationship to plasma PK at the end of treatment  
Efficacy  
1.
To follow the change of total testosterone, bioavailable testosterone, luteinising hormone (LH), and follicle
stimulating hormone (FSH) over a total of 12 months administration of BGS649 in those on active 
treatment in Study MBGS205 and a total of 6 months administration of BGS649 on subjects that were 
switched from placebo treatment during Study MBGS205 
2.
Evaluation of percentage of subjects with normalised testosterone after 12 months treatment with BGS649
in those on active treatment in Study MBGS205 and total of 6 months administration of BGS649 on 


Mereo BioPharma 2 Ltd 
CONFIDENTIAL 
Protocol MBGS206 
Amended Protocol Version 2.0, 28 Mar 2017 
Page 6 of 72 
Name of Sponsor/Company: 
Mereo BioPharma 2 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
Volume: 
Page: 
(For National Authority Use Only) 
Name of Product: 
BGS649 
Name of Active Ingredient: 
4,4’-[fluoro-(1-H-1,2,4-triazol-1-
yl)methylene]bisbenzonitrile 
subjects that were on placebo treatment during Study MBGS205 
Exploratory Efficacy Objectives 
1.
To evaluate the effect of 12 months treatment with BGS649 (6 months treatment in Study MBGS205 and 6
months treatment in Study MBGS206) on:
o
Cardiometabolic parameters, body composition, physical activity, grip strength, and sleep pattern; and
on sexual functioning, fatigue, and quality of life, assessed by patient reported outcomes (PROs)
o
The association between changes in PROs and changes in body composition, physical activity, grip
strength, and sleep
o
The association between changes in testosterone and changes in cardiometabolic parameters, body
composition, physical activity, grip strength, sleep, and PROs
2.
To evaluate the 6 month efficacy data on subjects on placebo arm in Study MBGS205 treated with active
study drug in Study MBGS206 (cardiometabolic parameters, body composition, physical activity, grip
strength, sleep, and PROs).
Methodology: 
This is a 6 months, active treatment, extension study, open to subjects who have completed full 24 weeks in 
Study MBGS205 (A Phase IIb multicentre, double-blind, dose-ranging, randomised, placebo-controlled study 
evaluating safety and efficacy of BGS649 in male obese subjects with hypogonadotropic hypogonadism [HH]). 
The main purpose of the study is to evaluate bone mineral density and other long term safety and efficacy 
parameters in subjects after 12 months exposure with BGS649, to better define the risk/benefit of BGS649 in the 
obese male HH patient. The study will also collect additional BGS649 safety and efficacy data on subjects that 
were randomised to placebo in Study MBGS205 and have 6 months active drug exposure in Study MBGS206. 
Informed Consent will be taken prior to study procedures being performed. Study participation will comprise of 
an Extension Study Baseline visit (Week 24 of Study MBGS205), 7 visits during the treatment period up to 
Week 48 (End of Treatment [EOT]), and a Follow-Up (FU) visit for safety performed at Week 60, 12 weeks 
after the Week 48/EOT visit. The End of Study is defined as the last visit of the last global subject. 
During the 24 week treatment period, subjects will take required dose weekly (± 1 day from the time schedule of 
regular planned dose) with water. 
Safety assessments will include bone mineral density (by dual energy X-ray absorptiometry [DEXA] scan), 
vital signs, physical examination, electrocardiograms (ECGs), haematology, blood chemistry and urinalysis, 
bone turnover markers, prostate-specific antigen (PSA), oestradiol, and recording of AEs, serious AEs (SAEs), 
AEs of special interest (AESIs), and concomitant medications.  
The safety of the study will also be periodically monitored through a data monitoring committee (DMC) and 
will include relevant subject data from Study MBGS205 and Study MBGS206.  
To ensure adequate safety monitoring, serum total testosterone levels will be evaluated at each visit by an 
independent unblinded physician, and if subject meets discontinuation criteria (total testosterone ≥ 1500 ng/dL 
[52 nmol/L] at any 2 consecutive time points throughout both studies MBGS205 and MBGS206), the subject 
will be discontinued from the treatment.  
Efficacy assessments will include measurement of total and calculated bioavailable testosterone, LH, FSH, 
body composition measurement including body mass index (BMI), waist and hip circumference and impedance, 
cardiometabolic parameters, physical activity and sleep pattern via the wearing of wrist monitors, and grip 
strength via a dynamometer, and sexual functioning and satisfaction, fatigue, and quality of life via PROs. 
Pharmacokinetics of BGS649 in plasma and seminal fluid will also be evaluated at 12 months of study drug 
exposure. Seminal fluid PK will be assessed (excluding subjects that are vasectomised or have vasectomy 
planned during the study period) at the Baseline visit (Week 24 of Study MBGS205) and Week 48 (EOT Visit 
7. Subjects that are discontinued early from the study drug will provide samples for seminal fluid PK at EOT
Visit 7, unless they are not able to provide this sample. Concomitantly with semen PK, plasma PK will be 
assessed to estimate plasma to semen BGS649 transference. 


Mereo BioPharma 2 Ltd 
CONFIDENTIAL 
Protocol MBGS206 
Amended Protocol Version 2.0, 28 Mar 2017 
Page 7 of 72 
Name of Sponsor/Company: 
Mereo BioPharma 2 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
Volume: 
Page: 
(For National Authority Use Only) 
Name of Product: 
BGS649 
Name of Active Ingredient: 
4,4’-[fluoro-(1-H-1,2,4-triazol-1-
yl)methylene]bisbenzonitrile 
Treatment allocation 
Subjects receiving active doses of BGS649 in Study MBGS205 will continue with the same dose in 
Study MBGS206. Subjects receiving placebo in Study MBGS205 will be randomised, using interactive response 
technology (IRT), on a 1:1:1 basis to each of the following active treatment arms: 
•
BGS649 
•
BGS649 
•
BGS649 
If one or more dosing arms are dropped during the conduct of Study MBGS205 these will not be progressed in 
Study MBGS206 and subjects switching from placebo will be randomly allocated to available dose arms.  
Number of Subjects: 
Enrolment will continue until 30 subjects from each of the previous active treatment arms in Study MBGS205 
have entered this study aiming for approximately 25 subjects completing each dose level with 48 weeks total 
exposure. Assuming about 17% dropout rate in the extension study. Subjects previously treated with placebo 
will be enrolled until target subject population is met in all active arms.  
Diagnosis and Main Criteria for Inclusion: 
Inclusion 
1.
Participating in Study MBGS205 and completion of the 24 week treatment period without meeting any
discontinuation criteria of Study MBGS205
2.
Agreement on the part of the subjects to use double-barrier contraception for vaginal sexual intercourse
with female partners of child bearing potential to prevent conception and foetal BGS649 exposure from
seminal fluid. To use single barrier protection (condom) to prevent semen exposure through non-vaginal
sexual intercourse with female partners of child bearing potential and refrain from sperm donation for the
duration of the study. All to be continued for at least 3 months following study drug discontinuation
3.
Ability to understand and comply with the requirements of the protocol/study, including understanding and
being able to give informed consent
4.
In opinion of the investigator has been compliant with the requirements of the Study MBGS205 protocol.
Exclusion 
1.
Development of clinically significant medical or psychiatric condition during Study MBGS205 that may
interfere with the study assessments or mask/mimic symptoms of hypogonadism, would prevent the subject
complying with the requirements of the protocol, or would make it unsafe for the subject to participate in
the study as per investigator judgment
2.
Development of hypothalamic or pituitary tumour (or inflammatory condition) or suspicion of pituitary or
hypothalamic tumour based on a clinical or laboratory evidence, e.g., elevated prolactin or other pituitary
hormone abnormality, symptoms/signs of tumour mass effect (unless there is documentation of a normal
magnetic resonance imaging scan of pituitary and hypothalamus within 3 months before Baseline)
3.
Meeting any of the discontinuation criteria of initial Study MBGS205
4.
Evidence of new significant prostatic disease in Study MBGS205
5.
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal
(ULN) or bilirubin ≥ 2 times the ULN (unless caused by Gilbert syndrome)
6.
Fragility fracture or bone mineral density T-score < -2.0
7.
Use of cardiac pacemaker or other medical electronic devices that can be affected by bio-impedance
assessment
8.
Planned treatment with prohibited medications (including self-prescribed)
9.
12-lead ECG abnormalities at Baseline including QTC by Fridericia’s correction method (QTCF) interval
> 450 ms
10. Intention to take part in study of other investigational product during the next 36 weeks.


Mereo BioPharma 2 Ltd 
CONFIDENTIAL 
Protocol MBGS206 
Amended Protocol Version 2.0, 28 Mar 2017 
Page 8 of 72 
Name of Sponsor/Company: 
Mereo BioPharma 2 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
Volume: 
Page: 
(For National Authority Use Only) 
Name of Product: 
BGS649 
Name of Active Ingredient: 
4,4’-[fluoro-(1-H-1,2,4-triazol-1-
yl)methylene]bisbenzonitrile 
Test Product, Dose and Mode of Administration: 
BGS649 is prepared 
 
Subjects will receive
 
 
Reference Therapy, Dose and Duration of Administration: 
None. 
Duration of Treatment in Study MBG206: 
Subjects will be treated for maximum of 24 weeks with BGS649, with a 12 week follow-up period after 
completion 
Study endpoints 
Primary  
1.
Percentage change in lumbar bone mineral density measured by DEXA (g/cm2) from Baseline in
Study MBGS205 to Week 48 in Study MBGS206 by dose group in subjects randomised to active treatment
in Study MBGS205.
Secondary 
Safety 
1.
In subjects that were randomised to active treatment in Study MBGS205 by dose group:
o
Percentage change in hip bone mineral density measured by DEXA (g/cm2) from Baseline in
Study MBGS205 to Week 48 in Study MBGS206
o
Percentage change in bone turnover markers (C-terminal telopeptide [CTx1], osteocalcin, bone alkaline
phosphatase, and procollagen type 1 N-propeptide [P1NP]) from Baseline in Study MBGS205 to
Week 48 in Study MBGS206
o
Proportion of subjects with T-scores ≤ -2.5 at Week 48
o
Percentage change in bone density and bone biomarkers adjusted for vitamin D deficiency from
Baseline in Study MBGS205 to Week 48 in Study MBGS206
o
Change of oestradiol (absolute and percentage) from Baseline in Study MBGS205 to Week 48
o
Proportion of subjects that overshoot testosterone (total testosterone above 1000 ng/dl [35 nmol/L],
from first dose of study drug in Study MBGS205 until study completion)
o
Change in PSA from Baseline in Study MBGS205 to Week 48 in Study MBGS206
o
Change in haematocrit from Baseline in Study MBGS205 to Week 48 in Study MBGS206
o
Change in blood pressure (systolic and diastolic) Baseline in Study MBGS205 to Week 48 in Study
MBGS206
o
Treatment emerged AE, SAE, and AESI (from first dose of study drug in Study MBGS205 until study
completion)
o
Relationship between change in bone mineral density from Baseline in Study MBGS205 to Week 48 in
Study MBGS206 and absolute levels of oestradiol and total testosterone at Week 48 in MBGS206
2.
In subjects that were randomised to placebo in Study MBGS205 by dose group:
o
Percentage change in hip bone mineral density measured by DEXA (g/cm2) from Baseline in
Study MBGS206 to Week 48
o
Percentage change in bone turnover markers (CTx1, osteocalcin, bone alkaline phosphatase, and P1NP)
from Baseline in Study MBGS206 to Week 48
o
Change of oestradiol (absolute and percentage) from Baseline in Study MBGS206 to Week 48
o
Proportion of subjects with T-scores ≤ -2.5 at Week 48 of Study MBGS206


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS206 
 
 
 
 
Amended Protocol Version 2.0, 28 Mar 2017 
 
Page 9 of 72 
 
Name of Sponsor/Company: 
Mereo BioPharma 2 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
BGS649 
Name of Active Ingredient: 
4,4’-[fluoro-(1-H-1,2,4-triazol-1-
yl)methylene]bisbenzonitrile 
o 
Proportion of subjects that overshoot testosterone (total testosterone above 1000 ng/dl [35 nmol/L] 
from first dose of study drug in Study MBGS206 until study completion) 
o 
Change in PSA from Baseline in Study MBGS206 to Week 48 
o 
Change in haematocrit from Baseline in Study MBGS206 to Week 48 
o 
Change in blood pressure (systolic and diastolic) Baseline in Study MBGS206 to Week 48 
o 
Treatment emerged AE, SAE, and AESI (from first dose of study drug in Study MBGS206 until study 
completion). 
Efficacy  
1. In subjects that were randomised to active treatment in Study MBGS205 by dose group: 
o 
Percentage of subjects that have normalisation of total testosterone at Week 48 in Study MBGS206 
o 
Change in total and bioavailable testosterone from Baseline in Study MBGS205 to Week 48 in Study 
MBGS206 
o 
Change of LH and FSH from Baseline in Study MBGS205 to Week 48 in Study MBGS206 
2. In subjects that were randomised to placebo in Study MBGS205 by dose group: 
o 
Percentage of subjects that have normalisation of total testosterone at Week 48 of Study MBGS206 
o 
Change in total and bioavailable testosterone from Extension Study Baseline to Week 48 in Study 
MBGS206 
o 
Change of LH and FSH from Extension Study Baseline to Week 48. in Study MBGS206 
Pharmacokinetics 
1. EOT plasma and semen concentration of BGS649 by dose group. 
Exploratory 
1. In subjects that were randomised to active treatment in Study MBGS205: 
o 
Change in exploratory parameters from Baseline in Study MBGS205 to Week 48 in Study MBGS206 
by dose group 
o 
Body composition (weight, BMI, waist and hip circumference, and parameters measured 
by bio-impedance) 
o 
Markers of cardiometabolic disease (blood pressure, lipid profile, HbA1c, glucose and 
insulin, hs-CRP, and homeostatic assessment of insulin resistance [HOMA-IR]) 
o 
Physical activity, sleeping pattern, and strength (measured by wrist worn monitors and 
grip strength measurement) 
o 
Total and domain scores on PRO measures (Sexual function (IIEF, PROMIS SexSF), 
Energy/fatigue (BFI, PROMIS Fatigue), SF-36 
o 
The relationship between changes in PROs and changes in body composition, physical activity, grip 
strength, and sleep  
o 
The relationship between changes in testosterone and changes in cardiometabolic parameters, body 
composition, physical activity, grip strength, sleep, and PROs. 
2. In subjects that were randomised to placebo in Study MBGS205: 
o 
Change in exploratory parameters from Baseline in Study MBGS206 to Week 48 in Study MBGS206 
by dose group 
o 
Body composition (weight, BMI, waist and hip circumference, and parameters measured 
by bio-impedance) 
o 
Markers of cardiometabolic disease (blood pressure, lipid profile, HbA1c, glucose and 
insulin, hs-CRP, and HOMA-IR) 
o 
Physical activity, sleeping pattern, and strength (measured by wrist worn monitors and 
grip strength measurement) 
o 
Total and domain scores on PRO measures (Sexual function (IIEF, PROMIS SexSF), 


Mereo BioPharma 2 Ltd 
CONFIDENTIAL 
Protocol MBGS206 
Amended Protocol Version 2.0, 28 Mar 2017 
Page 10 of 72 
Name of Sponsor/Company: 
Mereo BioPharma 2 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
Volume: 
Page: 
(For National Authority Use Only) 
Name of Product: 
BGS649 
Name of Active Ingredient: 
4,4’-[fluoro-(1-H-1,2,4-triazol-1-
yl)methylene]bisbenzonitrile 
Energy/fatigue (BFI, PROMIS Fatigue), SF-36 
Statistical Methods: 
Populations to be analysed: 
The intention to treat (ITT) population includes all subjects who: 
1.
Are randomised, and
2.
Receive at least 1 dose of study medication, and
3.
Provide a Baseline efficacy value and at least 1 available evaluation of efficacy post-Baseline.
The safety population includes all subjects who received at least 1 administration of the study medication. 
For the summary of semen concentration of BGS649, all subjects who received at least 1 administration of the 
study medication and have at least 1 quantifiable concentration will be included in the PK population. 
All safety endpoints will be analysed using the safety population. All efficacy endpoints will be analysed using 
the ITT population. 
Further safety and tolerability will be analysed using the safety population. 
Primary Statistical Hypothesis: The percentage decrease from Baseline in lumbar bone mineral density 
measured in g/cm2 by DEXA 
 
H0:  ≤ 3% 
H1:  > 3% 
The null hypothesis will be rejected for a dose group and the endpoint considered met if the lower bound of the 
2-sided 95% confidence interval for the percentage decrease from Baseline in lumber spine is greater than 3%.  
Assuming a 2-sided test at 
 significant level and a standard deviation of 
 to achieve 90% power 
N=25 subjects in each dose group would be needed to detect a 
 decrease from Baseline in bone mineral 
density at 48 weeks. 
Date of the Protocol:  Amended  Version 2.0, 28 Mar 2017 


Mereo BioPharma 2 Ltd 
CONFIDENTIAL 
Protocol MBGS206 
Amended Protocol Version 2.0, 28 Mar 2017 
Page 11 of 72 
5 
TABLE OF CONTENTS 
1 
TITLE PAGE ................................................................................................................. 1 
SUMMARY AND JUSTIFICATION OF CHANGES……………………………………….. 2 
2 
SPONSOR SIGNATURE PAGE .................................................................................. 3 
3 
GENERAL INFORMATION ........................................................................................ 4 
4 
STUDY SYNOPSIS ...................................................................................................... 5 
5 
TABLE OF CONTENTS ............................................................................................ 11 
5.1 
List of Tables .................................................................................................. 14 
5.2 
List of Figures................................................................................................. 14 
5.3 
List of Appendices and Supplements ............................................................. 14 
6 
LIST OF ABBREVIATIONS AND DEFINITONS OF TERMS ............................... 15 
7 
INTRODUCTION ....................................................................................................... 17 
7.1 
Background..................................................................................................... 17 
7.1.1 
Aromatase Inhibitors and Bone ........................................................ 18 
7.1.2 
Clinical Experience with BGS649 ................................................... 19 
7.2 
Rationale/Discussion ...................................................................................... 20 
7.2.1 
Rationale for bone density safety study. .......................................... 20 
8 
STUDY OBJECTIVES ............................................................................................... 22 
8.1 
Primary Objective ........................................................................................... 22 
8.2 
Secondary Objectives ..................................................................................... 22 
8.2.1 
Safety Objectives .............................................................................. 22 
8.2.2 
Pharmacokinetic Objective .............................................................. 22 
8.2.3 
Efficacy Objectives .......................................................................... 22 
8.2.4 
Exploratory Efficacy Objectives ...................................................... 23 
9 
INVESTIGATIONAL PLAN ...................................................................................... 24 
9.1 
Overall Study Design and Plan....................................................................... 24 
9.1.1 
Description ....................................................................................... 24 
9.1.2 
Schedule of Assessments ................................................................. 26 
9.2 
Discussion of Study Design............................................................................ 29 
9.2.1 
Risk/Benefit and Ethical Assessment ............................................... 29 
9.3 
Selection of Study Population ........................................................................ 30 
9.3.1 
Inclusion Criteria .............................................................................. 30 
9.3.2 
Exclusion Criteria ............................................................................. 30 
9.3.3 
Rescreening ...................................................................................... 31 
9.3.4 
Study Drug Interruption and Discontinuation .................................. 31 
9.3.5 
Withdrawal of Subjects from the Study ........................................... 33 


Mereo BioPharma 2 Ltd 
CONFIDENTIAL 
Protocol MBGS206 
Amended Protocol Version 2.0, 28 Mar 2017 
Page 12 of 72 
9.3.6 
Procedures for handling subjects incorrectly enrolled or 
randomised ....................................................................................... 34 
9.3.7 
Discontinuation of Study Sites ......................................................... 34 
9.3.8 
Discontinuation of Study .................................................................. 34 
9.3.9 
Lost to Follow-up ............................................................................. 34 
10 
TREATMENT OF SUBJECTS ................................................................................... 35 
10.1 
Identity of Study Treatment(s) ....................................................................... 35 
10.1.1 Administration of Study Treatment(s) ............................................. 35 
10.2 
Study Treatment Packaging and Labelling..................................................... 35 
10.2.1 Packaging ......................................................................................... 35 
10.2.2 Labelling ........................................................................................... 36 
10.2.3 Storage .............................................................................................. 36 
10.2.4 Blinding and Randomisation of Study Treatment(s) ........................ 36 
10.3 
Procedure for Breaking the Randomisation Code .......................................... 37 
10.4 
Subject Compliance ........................................................................................ 37 
10.5 
Study Treatment Accountability ..................................................................... 38 
10.6 
Contraception ................................................................................................. 38 
10.7 
Prohibited Therapy ......................................................................................... 38 
11 
ASSESSMENT OF EFFICACY ................................................................................. 39 
11.1 
Efficacy and Pharmacokinetic Variables........................................................ 39 
11.2 
Efficacy Assessments ..................................................................................... 40 
11.2.1 Male Hormonal Parameters .............................................................. 40 
11.2.2 Body Composition............................................................................ 40 
11.2.3 Cardiometabolic Parameters ............................................................ 42 
11.2.4 Patient Reported Outcomes .............................................................. 42 
11.2.5 Actigraphy Derived Activity and Sleep Parameters ........................ 43 
11.2.6 Grip Strength Measurement ............................................................. 44 
11.3 
Pharmacokinetic Assessments ........................................................................ 44 
12 
ASSESSMENT OF SAFETY...................................................................................... 45 
12.1 
Adverse Events ............................................................................................... 45 
12.1.1 Definitions ........................................................................................ 45 
12.1.2 Recording of Adverse Events ........................................................... 46 
12.1.3 Causal Assessment ........................................................................... 47 
12.1.4 Abnormal Laboratory Values/Vital Signs/Electrocardiograms ....... 48 
12.1.5 Overdose ........................................................................................... 48 
12.1.6 Partner Pregnancies .......................................................................... 49 
12.1.7 Adverse Events of Special Interest ................................................... 49 


Mereo BioPharma 2 Ltd 
CONFIDENTIAL 
Protocol MBGS206 
Amended Protocol Version 2.0, 28 Mar 2017 
Page 13 of 72 
12.1.8 Reporting of Serious Adverse Events and Adverse Events of 
Special Interest ................................................................................. 50 
12.2 
Safety Endpoints ............................................................................................. 50 
12.3 
Laboratory Assessments ................................................................................. 50 
12.3.1 
Clinical Laboratory Tests ................................................................. 51 
12.4 
DEXA Scan .................................................................................................... 51 
12.5 
Bone Turnover Markers ................................................................................. 52 
12.6 
Hormonal Parameters ..................................................................................... 52 
12.7 
Physical Examination ..................................................................................... 52 
12.8 
Vital Signs ...................................................................................................... 52 
12.9 
12-Lead ECG .................................................................................................. 53 
12.10 
24/7 Medical Emergency Coverage ............................................................... 53 
13 
STATISTICAL EVALUATION ................................................................................. 54 
13.1 
Sample Size and Power .................................................................................. 54 
13.2 
Randomisation ................................................................................................ 54 
13.3 
Analysis Sets .................................................................................................. 54 
13.3.1 
Intention to Treat .............................................................................. 54 
13.3.2 
Safety Population ............................................................................. 55 
13.3.3 
PK Population .................................................................................. 55 
13.4 
Endpoints ........................................................................................................ 55 
13.4.1 
Primary Endpoint ............................................................................. 55 
13.4.2 
Secondary Endpoints ........................................................................ 55 
13.4.2.1 Secondary Safety Endpoints .............................................. 55 
13.4.2.2 Secondary Efficacy Endpoints ........................................... 56 
13.4.2.3 Secondary Pharmacokinetic Endpoint ............................... 56 
13.4.2.4 Exploratory Endpoints ....................................................... 57 
13.5 
Description of Statistical Analyses ................................................................. 57 
13.5.1 
General Considerations ................................................................ ....57 
13.5.2 
Analysis of Primary Endpoint .......................................................... 58 
13.5.3 
Analysis of Secondary Endpoints ................................................ ....58 
13.5.3.1 Safety.............................................................................. ....58 
13.5.3.2 Efficacy .............................................................................. 59 
13.5.3.3 Pharmacokinetics ............................................................... 59 
13.5.4 
Analysis of Exploratory Endpoints .................................................. 59 
13.5.5 
Safety Analyses ................................................................................ 60 
13.5.6 
Analysis of Further Endpoints .......................................................... 61 


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14 
DIRECT ACCESS TO SOURCE DATA/NOTES ..................................................... 62 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 62 
15.1 
Conduct of the Study ...................................................................................... 62 
15.2 
Study Monitoring............................................................................................ 62 
16 
ETHICS ....................................................................................................................... 63 
16.1 
Independent Ethics Committee/Institutional Review Board .......................... 63 
16.2 
Written Informed Consent .............................................................................. 63 
16.3 
Data Monitoring Committee........................................................................... 63 
17 
DATA HANDLING AND RECORD KEEPING ....................................................... 64 
17.1 
Case Report Forms/Source Data Handling..................................................... 64 
17.2 
Retention of Essential Documents .................................................................. 64 
18 
FINANCING AND INSURANCE .............................................................................. 65 
19 
PUBLICATION POLICY ........................................................................................... 65 
20 
SIGNATURE OF INVESTIGATOR .......................................................................... 66 
21 
REFERENCE LIST ..................................................................................................... 67 
22 
APPENDICES ............................................................................................................. 69 
5.1 
List of Tables 
Table 9–1 
Schedule of Assessments ................................................................................... 27 
Table 10–1 
Study Treatments................................................................................................ 35 
5.2 
List of Figures 
Figure 9–1 
Study Design ...................................................................................................... 26 
5.3 
List of Appendices and Supplements 
Appendix I 
World Medical Association Declaration of Helsinki 
Appendix II: Patient Global Impression of Status items  


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6 
LIST OF ABBREVIATIONS AND DEFINITONS OF TERMS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BFI 
Brief Fatigue Inventory 
BMI 
body mass index 
CI 
confidence interval 
CTx1 
C-terminal telopeptide 
CYP 
Cytochrome 
CYP19 
aromatase 
D 
Day 
DBP 
diastolic blood pressure 
DEXA 
dual energy X-ray absorptiometry 
DMC 
Data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOT 
End of Treatment 
EUDRACT 
European Union Drug Regulatory Agency Clinical Trial 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
FU 
Follow-Up 
GCP 
Good Clinical Practice 
h 
hour 
HbA1c
glycosylated haemoglobin 
HDL 
high density lipoprotein 
HH 
hypogonadotropic hypogonadism 
HOMA-IR 
homeostatic assessment of insulin resistance 
hs-CRP 
high sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IIEF 
International Index of Erectile Function 
INR 
International Normalised Ratio 
IRB 
Institutional Review Board 


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IRT 
interactive response technology 
ITT 
intention to treat 
LDL 
low density lipoprotein 
LH 
luteinising hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
P1NP 
procollagen type 1 N-propeptide 
PGI-S 
Patient Global Impression of Status 
PK 
pharmacokinetics 
PRO 
patient reported outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PSA 
prostate-specific antigen 
QoL 
quality of life 
QTC 
corrected QT interval 
QTCF 
QTC by Fridericia’s correction method 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SexFS 
Sexual Function and Satisfaction 
SF-36 
36-item Short Form Health Survey 
SHBG 
sex hormone binding globulin 
SBP 
systolic blood pressure 
SD 
standard deviation 
T1/2 
half-life 
TEAE 
treatment emergent adverse event 
Tmax 
time at which maximum serum concentration is reached 
ULN 
upper limit of normal 
W 
week 
WBC 
white blood cell 


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7 
INTRODUCTION 
7.1 
Background 
Aromatase (CYP19) is highly expressed in adipose tissue, where it converts testosterone to 
oestradiol and androstenedione to oestrone. In human obesity, excess adipose tissue is 
associated with excess aromatase activity, resulting in higher levels of oestradiol in men and 
women. In obese men, the relative excess of oestradiol can feed back to the hypothalamic 
pituitary axis, supressing gonadotropin secretion and thereby suppressing testicular 
testosterone production and spermatogenesis. Severe obesity is associated with relative 
androgen deficiency in men and epidemiologic data support the hypothesis that excess 
adipose tissue contributes to the pathogenesis of hypogonadotropic hypogonadism (HH) in 
obese men (Hofstra et al 2008).  
There are many consequences of testosterone deficiency including decreased libido, erections 
and fertility, low bone mineral density, increased risk of fractures, decreased muscle mass 
and strength, fatigue, and impact on mood and cognition and loss of body hair 
(Bhasin et al 2006). Recent studies have also demonstrated that testosterone deficiency in 
older obese men is associated with metabolic abnormalities including insulin resistance, 
glucose intolerance, and lipid abnormalities, contributing to an increased incidence of 
metabolic syndrome and likely increased risk of cardiovascular disease (Kapoor et al 2006). 
BGS649 is a potent aromatase inhibitor and a derivative of the marketed drug letrozole 
(Femara). It was conceived as a long half-life (T1/2) aromatase inhibitor for the treatment of 
refractory endometriosis and is being evaluated in obese men with HH.  
The safety and efficacy (in terms of normalisation of serum testosterone levels) of BGS649 in 
male obese subjects with HH is currently being evaluated in the ongoing Study MBGS205.   
Use of aromatase inhibitors in women with breast cancer have been associated with reduction 
in bone mineral density and risk of fracture. This is attributed to the oestrogen lowering 
effects in post-menopausal women. The potential for BGS649 to affect bone in obese males 
with hypogonadism is expected to be less as oestrogen levels are similar to those in pre-
menopausal women and only 25% oestradiol reduction was observed after 12 weeks of 
BGS649 0.3 mg loading dose and 0.1 mg weekly. There may be other factors that reduce 
sensitivity to aromatase inhibition on bone in this population as bone mineral density 
increases with increasing BMI, and bone anabolic effects are expected with the normalisation 
of testosterone.  
Understanding any potential effect is a critical element to the risk/benefit profile of BGS649. 
Bone turnover biomarkers and bone mineral density are being assessed in MBGS205, 
however 6 months is too short duration to assess bone mineral density. Study MBGS206 will 
be a 6 month extension of Study MBGS205 to measure the effects of 12 months treatment 
with BGS649 on bone mineral density. 


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7.1.1 
Aromatase Inhibitors and Bone  
In the adult skeleton, bone remodelling is controlled by regulating the balance between the 
resorptive activity of osteoclasts and the bone-forming action of osteoblasts (Perez and 
Weilbaecher 2006). Normal bone turnover is maintained by a complex regulatory system 
involving both systemic and local factors. Oestrogen has suppressive, antiresorptive effects 
on osteoclasts during the process of bone remodelling; these effects are pleiotropic and 
largely indirect. Aromatase inhibitors block the peripheral conversion (aromatisation) of 
oestrogen from androgen precursors, thereby lowering tissue and circulating oestrogen levels.  
Treatment with aromatase inhibitors can decrease oestrogen levels and lead to excessive bone 
resorption. It has been associated with bone loss, decreased bone mineral density, and an 
increase in osteoporotic fractures. However, these effects have generally been observed in 
woman treated for breast cancer with high relative doses and long duration of treatment of the 
aromatase inhibitor and in post-menopausal women with low oestrogen levels (Mincey et al 
2006).  
Testosterone and oestradiol are critical for normal bone development and maintenance in men 
(Sinnesael et al 2011). However, there are limited data on aromatase inhibition in this 
population and none in the obesity-related HH population which is the target for BGS649 or 
with the lower levels of aromatase inhibition that is being developed within this dose-ranging 
study. 
Bone mineral density was investigated in two studies in older men with low testosterone 
levels (Dias et al 2015, Burnett-Bowie et al 2009). The effects of a transdermal testosterone 
gel, anastrozole (an aromatase inhibitor) 1 mg daily, or placebo on body composition, bone 
mass, muscle strength, and gait speed were evaluated for 12 months in 43 older men with low 
testosterone levels (Dias et al 2015). Both transdermal testosterone and anastrozole increased 
serum testosterone levels (>500 ng/dL, p < 0.05) compared with baseline, and testosterone 
levels remained stable throughout the study. At 12 months, the primary outcome of lumbar 
spine bone mineral density increased compared with baseline in the transdermal testosterone 
and placebo groups (p < 0.01), and remained stable in the anastrozole group. The reason for 
the increase in bone mineral density in the placebo group was unclear and expected to have 
driven the statistical significance of the change in bone mineral density of anastrozole which 
was assessed relative to placebo. The effects of anastrozole 1 mg daily or placebo on bone 
mineral density and bone turnover were evaluated in a 1-year study in 69 older men with 
borderline or low testosterone levels and hypogonadal symptoms (Burnett-Bowie et al 2009). 
The aromatase inhibitor increased testosterone levels and moderately decreased oestradiol 
levels. Posterior-anterior spine bone mineral density decreased in the anastrozole group 
compared with the placebo group (p = 0.0014); there were no significant effects on bone 
mineral density at other anatomical sites. Bone turnover markers were not affected by 
anastrozole therapy. Therefore, aromatisation of testosterone may play a role in bone mineral 
density in older men with low testosterone levels.  
Further understanding on the gonadal steroid-dependent effects on bone turnover and bone 
mineral density has come through investigation in healthy adult men aged 20-50 years 
(Finkelstein et al 2016). All volunteers were given goserelin acetate to suppress endogenous 


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gonadal steroid production. One cohort (198 men) were randomised to treatment with 
increasing concentrations of testosterone gel daily for 16 weeks. A second cohort (202 men) 
were randomised to receive these treatments together with anastrazole. A control group 
(37 men) were given placebo. The study supports other studies that a balance between 
oestrogen and testosterone is important. Although oestrogen may primarily regulate bone 
metabolism in adult men, in order to affect bone development, testosterone and oestradiol 
levels must decline substantially. Oestradiol levels above 10 pg/mL and testosterone levels 
above 200 ng/dL were generally sufficient to prevent increases in bone resorption and 
decreases in bone mineral density in men in this study, suggesting that in hypogonadism the 
elevation of testosterone in association with oestradiol above a threshold may enable 
maintenance or improvement of bone density.  
7.1.2 
Clinical Experience with BGS649 
To date, 54 post-menopausal and 52 pre-menopausal women of non-childbearing potential 
have been exposed to single doses of BGS649 up to 20 mg. BGS649 showed a dose-
dependent suppression of oestrone, which was maximal at 0.1 mg, and oestrone inhibition 
was sustained for more than 3 weeks after a single dose. There was no effect of BGS649 on 
cortisol metabolism, aldosterone synthesis, progesterone levels, androgen levels, urinary 17-
keto, or 17-hydroxysteroids. However, BGS649 at the highest single doses of 10 and 20mg 
showed small but clinically significant decrease in bone density limited to the lumbar spine at 
6 months. 
To date, BGS649 has also been administered to 21 obese men with HH (8 subjects were 
assigned to placebo) (Study CBGS649A2204). This first-in-man study was a 2-part study 
over 12 weeks (11 treatments); Part 1 was an open-label dose-finding study (weekly, 
individually titrated doses) and Part 2 used a fixed dose regimen 
 
. Overall, BGS649 treatment (n=21) resulted in 
normalisation and maintenance of serum total testosterone, with no evidence of total 
testosterone peaks above the upper limit of normal (ULN). Oestradiol levels were reduced by 
approximately 25-50%. There was no change in femoral neck bone mineral density and bone 
turnover markers after first or second part of the study. However, the second part of the study 
was underpowered and result not interpretable. 
Study MBGS205 is an ongoing Phase IIb multicentre, double-blind, dose-ranging, 
randomised, placebo-controlled study evaluating the safety and efficacy of BGS649 in male 
obese subjects with HH. The primary objective of the study is to demonstrate the efficacy of 
BGS649 to normalise testosterone (to within normal lab-specific reference range i.e., total 
testosterone levels 300-1000 ng/dL [10.4-35 nmol/L]) in ≥ 75% of a population of obese 
male subjects with HH after 24 weeks of double-blind treatment compared to placebo. As a 
part of safety objectives, study will evaluate effect of BGS649 on bone mineral density and 
bone turnover markers. 
A complete review of data obtained to date on BGS649 is presented in the most recent 
Investigator’s Brochure (IB) and Food and Drug Administration (FDA) guidelines have been 


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published on the use of testosterone replacement therapy (Testosterone Replacement 
Therapy, 2014). 
7.2 
Rationale/Discussion 
7.2.1 
Rationale for bone density safety study. 
Bone density decrease is a class effect of aromatase inhibitors via a mechanism of decreased 
oestrogenic production. BGS649 has been shown to decrease oestrogen by 25-50%, 
potentially 
affecting 
the 
bone 
formation 
process 
and 
leading 
to 
osteoporosis 
(Study CBGS649A2204). In a single dose study in post-menopausal women, BGS649 at the 
highest doses of 10 and 20 mg showed a small but clinically significant decrease in bone 
density limited to the lumbar spine at 6 months. In clinical studies to date there has been no 
consistent effect of BGS649 on bone resorption biomarkers and no effects of BGS649 on 
bone density were demonstrated at 12 weeks in the previous study in males with HH. 
However, the effects of long-term treatment with BGS649 in male obese subjects with HH 
have not been investigated.  
Men with hypogonadism have low testosterone that is associated with a decrease in bone 
mineral density. However, men with obesity related HH may have oestrogen levels similar to 
the levels in pre-menopausal women. In addition, obesity has protective effect on the bone 
mineral density so the risk associated with aromatase inhibitor treatment may be attenuated 
(Zhao et al 2007). 
Study MBGS206 will investigate the effect of BGS649 on bone mineral density after a 
12 month period of treatment with active study drug (6 months treatment during 
Study MBGS205). The overall 12 months exposure with BGS649 in the obese male HH 
patient should be an adequate duration of the aromatase inhibitor therapy to detect a change 
in bone mineral density to better define the risk/benefit of BGS649 in the obese male HH 
patient (Dias et al 2015; Burnett-Bowie et al 2009). The study is powered to detect a 3% 
decrease from Baseline in lumbar bone mineral density measured in g/cm2 by dual energy X-
ray absorptiometry (DEXA) at 48 weeks (Kacker et al 2014). 
Rational for other study considerations: 
The doses of BGS649
 and dosing schedule
 
 selected for use in Study MBGS205 were chosen based on results obtained in a 
previous study in obese male subjects with HH, which suggested that these doses were well 
tolerated and may normalise testosterone levels (Study CBGS649A2204). To assure 
12 months each dose arm study drug exposure, subjects will continue with the same active 
study drug assignment from Study MBGS205 to the Study MBGS206. To keep the study 
blinded and offer subjects receiving placebo the benefit of active arm treatment, the placebo 
subjects in Study MBGS205 will be randomised to one of the active treatment arms. If one or 
more dosing arms are dropped during the conduct of Study MBGS205, these will not be 
progressed in Study MBGS206. 
Aromatase inhibitors decrease oestrogen synthesis and increase pituitary luteinising hormone 
(LH) and follicle stimulating hormone (FSH) with a consequent stimulation of testosterone 


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production (de Boer et al 2005; Loves et al 2008). This increase in testosterone has multiple 
clinical effects, including: effect on insulin resistance, on body composition, strength and 
sexual and overall well-being. Therefore, additional safety, efficacy, and pharmacokinetic 
(PK) will be collected in subjects who completed the full 24 week treatment period in Study 
MBGS205. It is conceivable that up to 12 month exposure may be needed to demonstrate full 
treatment benefit in regards to positive effect on cardiometabolic parameters (Haider et al 
2010). In addition, the improvement in body composition may be also shown consistently 
only after 12 months treatment (Emmelot-Vonk et al 2008).    
Testosterone increase may lead to worsening certain parameters e.g. prostate-specific antigen 
(PSA), haematocrit. To ensure adequate safety monitoring, these parameters together with 
testosterone level will be monitored in the same way as in MBGS205 study (see Section 9.1.1 
for a detailed description) 
BGS649 has been shown to be present in semen. PK assessment of seminal fluid and plasma 
will be performed to determine the plasma/semen relationship to enable modelling of 
BGS649 semen concentration by dose in order to determine the potential transference of 
BGS649 to sexual partners.   
This study will be conducted in compliance with the protocol and with the International 
Conference on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP). 
 


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8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective is to evaluate the effect of 12 months treatment with BGS649 on bone 
mineral density (6 months treatment during Study MBGS205). 
8.2 
Secondary Objectives 
8.2.1 
Safety Objectives 
1. To evaluate the effect of BGS649 after 12 months period of treatment with active study 
drug (6 months treatment during Study MBGS205 and 6 months treatment during 
Study MBGS206) by dose group on: 
o Bone turnover biomarkers 
o Bone mineral density and bone biomarkers by vitamin D status (Baseline vitamin D 
from Study MBGS205)  
o Oestradiol levels  
o Testosterone outside upper limit of normal range  
o Prostate specific antigen and haematocrit 
o Blood pressure 
o Adverse events (AEs) 
2. To evaluate if any association between changes in bone mineral density after 12 months 
treatment with BGS649 with end of treatment testosterone and oestradiol levels  
3. To collect safety data in subjects switching from placebo arm in Study MBGS205 and 
treated with 6 months active study drug in Study MBGS206. 
8.2.2 
Pharmacokinetic Objective 
The PK objective is to determine BGS649 concentration by dose in seminal fluid and 
relationship to plasma PK at the end of treatment.  
8.2.3 
Efficacy Objectives 
1. To follow the change of total testosterone, bioavailable testosterone, LH, and FSH over a 
total of 12 months administration of BGS649 in those on active treatment in 
Study MBGS205 and a total of 6 months administration of BGS649 on subjects that were 
switched from placebo treatment during Study MBGS205 
2. Evaluation of percentage of subjects with normalised testosterone after 12 months 
treatment with BGS649 in those on active treatment in Study MBGS205 and total of 
6 months administration of BGS649 on subjects that were on placebo treatment during 
Study MBGS205 


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8.2.4 
Exploratory Efficacy Objectives 
1. To evaluate the effect of 12 months treatment with BGS649 (6 months treatment in Study 
MBGS205 and 6 months treatment in Study MBGS206) on: 
o 
Cardiometabolic parameters, body composition, physical activity, grip strength, and 
sleep pattern; and on sexual functioning, fatigue, and quality of life, assessed by 
patient reported outcomes (PROs) 
o 
The association between changes in PROs and changes in body composition, 
physical activity, grip strength, and sleep 
o 
The association between changes in testosterone and changes in cardiometabolic 
parameters, body composition, physical activity, grip strength, sleep, and PROs 
2. To evaluate the 6 month efficacy data on subjects on placebo arm in Study MBGS205 
treated with active study drug in Study MBGS206 (cardiometabolic parameters, body 
composition, physical activity, grip strength, sleep, and PROs). 


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
9.1.1 
Description 
This is a 6 month, active treatment, extension study, open to subjects who have completed the 
full 24 week treatment period in Study MBGS205 (a Phase IIb multicentre, double-blind, 
dose-ranging, randomised, placebo-controlled study evaluating safety and efficacy of 
BGS649 in male obese subjects with HH).  
The main purpose of this study is to evaluate bone mineral density in subjects after 12 months 
exposure with BGS649. The study will also collect additional BGS649 safety and efficacy 
data on subjects that were randomised to placebo in Study MBGS205 and have 6 months 
active drug exposure in Study MBGS206. The study design and schedule of assessments are 
summarised in Figure 9–1 and Table 9–1, respectively.  
Subjects that completed full 24 weeks treatment period of Study MBGS205 will be invited to 
participate. Informed consent will be taken prior to study procedures being performed. Study 
participation will comprise of the Extension Study Baseline visit (Week 24 of Study 
MBGS205), 7 visits during the treatment period up to Week 48 (End of Treatment [EOT]), 
and a Follow-Up (FU) visit for safety performed at Week 60, 12 weeks after the 
Week 48/EOT visit. The End of Study is defined as the last visit of the last global subject.  
Extension Study Baseline assessment: 
The Extension Study Baseline assessment will be performed on a same day as the EOT visit 
of Study MBGS205. As applicable, EOT assessments of Study MBGS205 will be used for 
Baseline assessments of Study MBGS206 and do not need to be repeated. The results of liver 
biochemistry, PSA, haematocrit, and electrocardiogram (ECG) assessments performed at the 
Baseline visit (EOT of MBGS205) may not be available for eligibility assessment, therefore 
results of these parameters from last valid visit of Study MBGS205 will be used to enable 
recruitment and dosing. This includes any of the parameters from last scheduled or 
unscheduled visit, measured not longer than 1 month before Baseline visit/EOT of 
MBGS205. Bone density from EOT assessment of MBGS205 will be used for eligibility 
evaluation for MBGS206. 
If results of liver biochemistry, renal function, PSA, haematocrit and ECG measured at 
Extension Study Baseline visit/EOT of MBGS205 are subsequently found to meet any study 
discontinuation criteria, the subject will be withdrawn.  
During the 24 week treatment period, subjects will take the required dose weekly (± 1 day 
from the time schedule of regular planned dose), starting with the first dose being taken at the 
baseline visit. The treatment period will consist of up to 24 weekly doses of BGS649. The 
capsule will be taken orally by the subject with water. Subjects receiving active doses of 
BGS649 in Study MBGS205 will continue with the same dose in Study MBGS206; this 
transfer will be handled by the interactive response technology (IRT) and the blind will be 


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maintained. Subjects receiving placebo in Study MBGS205 will be re-randomised, using 
IRT, on a 1:1:1 basis to each of the active treatment arms: 
o BGS649
capsules) 
o BGS649 
 
o BGS649 
. 
If one or more dosing arms are dropped during the conduct of Study MBGS205 these will not 
be progressed in Study MBGS206 and subjects switching from placebo will be randomly 
allocated to available dose arms. 
Details of the safety assessments to be performed are provided in Section 12.  
The safety of the study will also be periodically monitored through a data monitoring 
committee (DMC) and will include relevant subject data from Study MBGS205 and Study 
MBGS206.  
To ensure adequate safety monitoring, serum total testosterone levels will be evaluated at 
each visit by an independent unblinded physician (see Section 9.3.4 and Section 16.3), and if 
a subject meets the discontinuation criteria (total testosterone ≥ 1500 ng/dL [52 nmol/L] at 
any 2 consecutive time points throughout both studies the subject will be discontinued from 
the treatment. This would also include situation when first testosterone value that meets this 
threshold of ≥ 1500 ng/dL [52 nmol/L] was measured during MBGS205 and consecutive 
testosterone during study MBGS206.  
Details of the efficacy assessments to be performed are provided in Section 11. 
PK of BGS649 in seminal fluid will also be evaluated after 12 months of study drug 
exposure. Seminal fluid PK will be assessed (excluding subjects that are vasectomised or 
have vasectomy planned during the study period) at the Baseline visit (Week 24 of 
Study MBGS205) and End of Treatment (Visit 7). Subjects that are discontinued early from 
the study drug will provide samples for seminal fluid PK at the time of the End of Treatment 
visit, unless they are not able to provide this sample. Simultaneously with semen PK, plasma 
PK will be assessed to estimate plasma to semen BGS649 transference. 


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Figure 9–1 
Study Design 
 
 
 
 
 
DMC=data monitoring committee; W=week 
During the 24 week treatment period, 
 
 to total of up to 24 doses. The capsule will be taken orally by the subject with 
water. Subjects receiving active doses of BGS649 in Study MBGS205 will continue with the same dose in 
Study MBGS206 and the blind will be maintained at randomisation. Subjects receiving placebo in Study 
MBGS205 will be randomised on a 1:1:1 basis to each of the active treatment arms. If one or more dosing arms 
are dropped during the conduct of Study MBGS205 these will not be progressed in Study MBGS206 and 
subjects switching from placebo will be randomly allocated to available dose arms. The safety of the study will 
be monitored through a DMC and will include relevant subject data from Study MBGS205 and Study 
MBGS206. 
 
9.1.2 
Schedule of Assessments 
The schedule of assessments is presented in Table 9–1. 


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Table 9–1 
Schedule of Assessments 
 
 
 
Treatment Period 
Visit 
 
1 
2 
3 
4 
5 
6 
7 
(EOT) 
8 (FU) 
Week 
Assessments 
transferred 
from 
MBGS205  
MBGS206 
Baseline1 
W24 
W28 
(±2 D) 
W32 
(±2 D) 
W36 
(±2 D) 
W40 
(±2 D) 
W44 
(±2 D) 
W48 
(±2 D) 
W60 
(±2 D) 
Confirmation of written 
informed consent  
 
X 
 
 
 
 
 
 
 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
 
X 
 
 
 
 
 
 
 
Treatment allocation2 
 
X 
 
 
 
 
 
 
 
Full physical exam: 
general, prostate and 
breast exam 
X 
 
 
 
X 
 
 
X 
 
Limited physical 
exam 
 
 
X 
X 
 
X 
X 
 
X 
Blood pressure (SBP, 
DBP) and heart rate 
X 
 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
X 
 
 
X 
 
Clinical laboratory 
tests3: haematology, 
blood chemistry, and 
dipstick urinalysis4, 
eGFR by 
Cockcroft-Gault 
formula, PSA 
X 
 
X 
X 
X 
X 
X 
X 
X 
Cardiometabolic 
parameters3: HbA1c, 
fasting lipids (total 
cholesterol, LDL, HDL, 
triglycerides), fasting 
glucose and insulin, hs-
CRP, HOMA-IR 
X 
 
 
 
 
 
 
X 
 
Bone turnover 
markers5 
X 
 
 
 
X 
 
 
X 
 
Testosterone total6 
X 
 
X 
X 
X 
X 
X 
X 
X 
Testosterone 
bioavailable, oestradiol 
(total), SHBG, FSH, 
LH6 
X 
 
 
 
 
 
 
X 
 
Semen PK7 
X 
 
 
 
 
 
 
X 
 
Plasma PK7 
X 
 
 
 
 
 
  
X 
 
Weight, BMI hip and 
waist measurement 
X 
 
 
 
X 
 
 
X 
 
Body composition 
using bioimpedance8 
X 
 
 
 
X 
 
 
X 
 
Actigraphy9 
X 
 
 
 
 
 
 
X 
 
Grip strength 
X 
 
 
 
X 
 
 
X 
 
PROs: IIEF, BFI, SF-
36 QoL  
PROMIS: SexFS, 
Fatigue Short Form 
PGI-S10 
X 
 
 
 
X 
 
 
X 
 
DEXA11 
X 
 
 
 
 
 
 
X 
 
Study drug 
dispensation 
 
X 
X 
X 
X 
X 
X 
 
 
Study drug 
administration12 
 
 
 
Study drug 
accountability 
 
X 
 


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Page 28 of 72 
 
 
 
 
Treatment Period 
Visit 
 
1 
2 
3 
4 
5 
6 
7 
(EOT) 
8 (FU) 
Week 
Assessments 
transferred 
from 
MBGS205  
MBGS206 
Baseline1 
W24 
W28 
(±2 D) 
W32 
(±2 D) 
W36 
(±2 D) 
W40 
(±2 D) 
W44 
(±2 D) 
W48 
(±2 D) 
W60 
(±2 D) 
AE assessment13 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
1 
Baseline assessment will be performed on a same day as the EOT visit of Study MBGS205. As applicable, 
EOT assessments of Study MBGS205 will be used for Baseline assessments of Study MBGS206 and do not 
need to be repeated. The results of liver enzymes, PSA, haematocrit, and ECG assessments performed at the 
Baseline visit will not be available for eligibility assessment, therefore results of these parameters from last 
valid visit of Study MBGS205 will be used. This includes any of these parameters from last scheduled or 
unscheduled visit measure but no longer than 1 month before Baseline visit/EOT of MBGS205.  
2 
Only subjects receiving placebo in Study MBGS205 to be randomised. Subjects already on active in Study 
MBGS205 will maintain their treatment allocation 
3 
All blood samples are to be collected after 8 hours fasting, after ECG and vital sign measurements have 
been performed 
4 
A microscopic examination including RBC and WBC or urinary protein will be performed only when 
dipstick evaluation is positive for WBC and/or blood or protein 
5 
Bone turnover markers include CTx1, osteocalcin, bone alkaline phosphatase, and P1NP 
6 
Has to be collected before 11 am. If the sample was inadvertently taken after this time, a retest is allowed 
after a discussion with the Medical Monitor. 
7 
All subjects that are not vasectomised will be asked to provide a semen sample. Subjects that provided 
semen sample for PK will also have plasma for PK drawn at the assessment visit Semen sample collection 
is not required to be the same day as the assessment visit. Therefore, semen PK collection is allowed ± 48 
hours around the plasma PK attendance visits.  
8 
Subjects should come well hydrated, drinking water the night before and the morning before the impedance 
measurements 
9 
Activity wrist monitors will be collected from subjects at EOT visit of the Study MBGS205. If the activity 
wrist monitor was not performed before EOT of Study MBGS205 and collected at EOT Study MBGS205, 
it can be applied at the Baseline visit of current study and worn for 7 c consecutive days and collected at 
Visit 2. An activity wrist monitor will also be worn for 7 continuous days after Visit 7 (EOT) and collected 
at Visit 8 (FU) 
10 Some questionnaires will be new for some subjects and completed first time at the Baseline visit 
11 For subjects that discontinued early, EOT DEXA scan will be performed only if they reached minimum 
Week 36 (Visit 4) active treatment period. In order to accommodate scheduling, EOT DEXA can be 
performed within 5 days before the EOT visit or 5 days after the EOT Visit 
12 
 
13 AEs, SAEs, and AESIs collected from signature of informed consent 
 
 
 
 
 
 
 


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9.2 
Discussion of Study Design 
9.2.1 
Risk/Benefit and Ethical Assessment 
Refer to the most recent Investigator’s Brochure (IB) for a benefit/risk assessment of 
BGS649. 
Aromatase inhibitors decrease oestrogens, normalising LH, FSH, restoring physiologic 
hypothalamic, pituitary axis leading to normalisation in androgen levels. This is on-target 
pharmacology of aromatase inhibitors leading to benefit of treating symptoms of hypogonadism 
but also a clinical risk, as pharmacologic suppression of aromatase in men can cause androgens to 
rise above normal ranges (Loves et al 2008).  
The emerging pre-clinical profile of BGS649 predicts multiple beneficial effects on the 
pathophysiology of HH. It is expected that the benefits of BGS649 will be similar to those of 
testosterone (standard of care treatment), including improvement in serum testosterone levels and 
hypogonadal signs and symptoms. It may also potentially improve fertility via restoration of LH 
and FSH feedback loops (see Section 7.1 for further details).  
Acute consequences of elevated androgens are rare; however chronic testosterone elevation can 
lead to elevation of haematocrit, effect on prostate and elevation of PSA and cardiovascular 
effects. Chronic suppression of oestrogens can also lead to worsening of bone mineral density. 
The study examines all potential adverse effects by evaluating bone density and other safety 
parameters on subjects exposed for 12 months and 6 months to BGS649.  
Current study design allows 12 months benefit of study drug exposure (6 months from MBGS205 
and 6 months from current study). To keep the study blinded and offer subjects receiving 
placebo the benefit of active arm treatment, the placebo subjects in Study MBGS205 will be 
randomised to one of the active treatment arms. 
The most common side effects associated with BGS649 include headache, sweats, increased 
incidence of morning erections, nasal congestion, sore throat, cough, diarrhoea, musculoskeletal 
pain, insomnia and abnormal hair growth. Based on safety pharmacology studies in animals, 
BGS649 is not anticipated to cause cardiovascular, central nervous system or respiratory AEs. No 
significant corrected QT interval (QTC) or QTC by Fridericia’s correction method (QTCF) 
prolongation was observed in subjects across a wide range of doses up to 20 mg (see the IB). 
Therefore, a large therapeutic index is expected in humans. 
Based on the benefit/risk profile of BGS649 in obese male subjects with HH, BGS649 is 
expected to normalise testosterone levels with very few adverse effects leading to all benefits 
of testosterone normalisation. BGS649 is also expected to decrease oestradiol with the 
potential risk of a reduction in bone mineral density and increased risk of fracture in subjects 
(see Section 7). Therefore, subjects will not be enrolled in the study if they have history of 
fragility fracture. In order to prevent potential premature withdrawals because of bone density 
deterioration, subjects with T score in pre-osteoporotic range and lower (T-score < -2.0) will 
not be allowed to participate. In addition, subjects will be monitored throughout the study and 
must be permanently withdrawn from study treatment if they develop fragility fracture (see 


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Page 30 of 72 
 
Section 9.3.5). An independent, unblinded external DMC will periodically review 
accumulating safety data (see Section 16.3). 
9.3 
Selection of Study Population 
9.3.1 
Inclusion Criteria 
1. Participating in Study MBGS205 and completion of the 24 week treatment period without 
meeting any discontinuation criteria of Study MBGS205 
2. Agreement on the part of the subjects to use double-barrier contraception for vaginal 
sexual intercourse with female partners of child bearing potential to prevent conception 
and foetal BGS649 exposure from seminal fluid. To use single barrier protection 
(condom) to prevent semen exposure through non-vaginal sexual intercourse with female 
partners of child bearing potential and refrain from sperm donation for the duration of the 
study. All to be continued for at least 3 months following study drug discontinuation 
3. Ability to understand and comply with the requirements of the protocol/study, including 
understanding and being able to give informed consent 
4. In opinion of the investigator has been compliant with the requirements of the 
Study MBGS205 protocol. 
9.3.2 
Exclusion Criteria 
1. Development of clinically significant medical or psychiatric condition during 
Study MBGS205 that may interfere with the study assessments or mask/mimic symptoms 
of hypogonadism, would prevent the subject complying with the requirements of the 
protocol, or would make it unsafe for the subject to participate in the study as per 
investigator judgment 
2. Development of hypothalamic or pituitary tumour (or inflammatory condition) or 
suspicion of pituitary or hypothalamic tumour based on a clinical or laboratory evidence, 
e.g., elevated prolactin or other pituitary hormone abnormality, symptoms/signs of 
tumour mass effect (unless there is documentation of a normal magnetic resonance 
imaging scan of pituitary and hypothalamus within 3 months before Baseline) 
3. Meeting any of the discontinuation criteria of initial Study MBGS205 
4. Evidence of new significant prostatic disease in Study MBGS205 
5. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN 
or bilirubin ≥ 2 times the ULN (unless caused by Gilbert syndrome)  
6. Fragility fracture or bone mineral density T-score < -2.0  
7. Use of cardiac pacemaker or other medical electronic devices that can be affected by bio-
impedance assessment 
8. Planned treatment with prohibited medications (including self-prescribed) 
9. 12-lead ECG abnormalities at Baseline including QTCF interval > 450 ms 
10. Intention to take part in study of other investigational product during the next 36 weeks. 


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9.3.3 
Rescreening 
Not applicable. 
9.3.4 
Study Drug Interruption and Discontinuation 
Subjects may voluntarily discontinue investigational treatment for any reason at any time. 
At the time of study drug discontinuation, the subject should have (as soon as possible) an 
EOT visit with the assessments that are normally done at the Week 48 visit (EOT, Visit 7). 
This should take place within 7 days after discontinuation of study drug. The reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate electronic case report form (eCRF) page. All subjects who discontinue the study 
drug should enter the FU phase and attend the final follow up visit 12 weeks after EOT 
(FU, Visit 8).  
Subjects will in addition be asked to provide a plasma and semen sample for PK at EOT 
(Visit 7), unless they are not able to provide this sample. This applies also to a subject 
discontinued because of elevated testosterone as determined by an unblinded physician. The 
investigator and study staff must discuss with the subject, the subject’s continued 
participation in the study and request subjects to continue attending FU visits according to the 
study visit schedule.  
If the subject cannot, or is unwilling to attend the FU visits, the site staff should request 
maintenance of regular phone contact with the subject, or with a person pre-designated by the 
subject. This phone contact should preferably be performed according to the study visit 
schedule. Data concerning the subject’s health status, including information regarding 
new/concomitant treatments, AEs, AESIs (i.e., rash), and vital status will continue to be 
collected. 
The investigator must also contact the IRT to register the subject’s discontinuation from 
investigational treatment. 
If the subject temporarily discontinues study drug because of AE or SAE or other relevant 
issue, the investigator should attempt to restart it as soon as possible after circumstances 
allow and in agreement with the Medical Monitor. 
Investigational treatment MAY be permanently discontinued under the following 
circumstances: 
1. Significant worsening of lower extremity oedema 
2. Significant worsening of obstructive urinary symptoms 
Investigational treatment MUST be permanently discontinued under the following 
circumstances: 
3. If subject develops fragility fracture. 
4. Total testosterone ≥ 1500 ng/dL (52 nmol/L) at any 2 consecutive scheduled visits during 
and in between the both studies MBGS205 and MBGS206. This would also include 
situation when first testosterone value that meets this threshold of ≥ 1500 ng/dL 


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Page 32 of 72 
 
[52 nmol/L] was measured during MBGS205 and consecutive testosterone during 
Study MBGS206. 
5. Liver laboratory values of: 
o ALT or AST > 5 times the ULN  
If the increase in ALT or AST is associated with normal bilirubin and ALP, the medical 
evaluation of withdrawing a subject can be made on a repeat AST/ALT test taken within 
48 hours. (Repeated parameters should include: ALT, AST, alkaline phosphatase and total 
bilirubin). The subject should interrupt study drug until the repeat liver enzymes are available. 
If repeat liver parameters are all within the normal range, dosing may be continued. If not 
normalised the subject should be permanently discontinued. 
or 
o ALT or AST > 3 times the ULN and bilirubin total > 2 times ULN or International 
Normalised Ratio (INR) > 1.5 or the appearance of worsening fatigue, nausea, 
vomiting, right upper quadrant pain/tenderness, fever, rash, or eosinophilia 
o A hepatic event leading to subject discontinuation should be followed up until event 
resolution, or becomes not clinically significant 
6. Any of the following laboratory abnormalities: 
o Renal function values that require discontinuation: 
• 
Discontinue investigational treatment for a subject if individual serum creatinine 
increases ≥ 50% compared to Baseline (and is considered clinically significant), 
or in the event of treatment emergent proteinuria (albumin: creatinine ratio 
> 300 mg/g or > 30 mg/mmol; protein: creatinine ratio ≥ 500 mg/g or 
> 50 mg/mmol) (Creatinine can be repeated once within 7 days of initial alert. 
Study drug administration should be suspended during this time and resumed only 
if repeat creatinine is back to pre-alert level) 
• 
A renal event leading to subject discontinuation should be followed up until event 
resolution (serum creatinine within 10% of Baseline, protein-creatinine ratio 
within 50% of Baseline), stabilises or becomes not clinically significant, or is 
assessed as being chronic 
7. Subject missed 4 or more consecutive study drug dosing 
8. Development of prostate cancer or PSA increase more than 1.4 ng/mL above Baseline 
level in study MBGS205. It is recommended that in these cases subjects undergo urologic 
consultation 
9. Haematocrit > 54% (Haematocrit can be repeated once within 7 days of initial alert. 
Study drug administration should be suspended during this time and resumed only if 
repeat haematocrit is under 54%) 
10. Development of sleep apnoea 


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11. Development of cardiovascular event (significant arrhythmia acute myocardial infarction, 
brain stroke, transient ischemic attack, unstable angina, congestive heart failure) 
12. Emergence of the following AEs: 
o Absolute QTCF > 500 msec, or a rise of QTCF of ≥ 60 msec above Baseline confirmed 
by triplicate ECG measurements 
13. Pregnancy in female sexual partner of the male study subject, occurring after the start of 
study treatment 
14. Breast cancer. 
9.3.5 
Withdrawal of Subjects from the Study 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
Withdrawal of consent occurs when a subject does not want to participate in the study 
anymore and does not want to attend any further visits or assessments, have further 
study-related contact, or allow analysis of already obtained biologic material. 
If a subject withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Investigational treatments must 
be discontinued and no further assessments conducted. All study participation for that subject 
will cease and data to be collected at subsequent visits will be considered missing. 
All biological material that has not been analysed at the time of withdrawal may be used, 
unless consent for its use is withdrawn in writing. Further attempts to contact the subject are 
not allowed unless safety findings require communication or follow-up.  
Under the following circumstances the subject MUST be withdrawn from the study: 
1. Withdrawal of informed consent 
2. Any safety reasons, clinical AE, laboratory abnormality, or intercurrent illness which, in 
the opinion of the investigator or sponsor indicates that continued participation in the 
study is not in the best interest of the subject 
3. Exogenous testosterone use or additional monitoring of testosterone levels that 
inadvertently unblinds the subject’s study arm allocation 
4. Severe non-compliance to the protocol, as judged by the investigator and/or sponsor 
5. Treatment code or unblinding prematurely broken by the investigator 
6. Termination of the study by the sponsor 
7. Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness. 


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9.3.6 
Procedures for handling subjects incorrectly enrolled or randomised 
Subjects who fail to meet the inclusion/exclusion criteria must not be enrolled or randomised. 
If a subject not meeting the study criteria is randomised in error, a discussion must occur 
between the Medical Monitor and the investigator regarding whether to continue or 
discontinue the subject from the study. If agreement is reached, the subject should complete 
the study unless there are safety concerns or if the subject withdraws the consent.  
9.3.7 
Discontinuation of Study Sites  
Study site participation may be discontinued if Mereo BioPharma or designee, the 
investigator or Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of the 
study site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.  
9.3.8 
Discontinuation of Study  
The study may be discontinued if Mereo BioPharma or designee, including through DMC 
recommendation, judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulation, and GCP.  
9.3.9 
Lost to Follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. There should be three documented attempts to contact the subject. This includes 
follow-up with persons authorised by the subject. Lost to follow-up is defined by the inability 
to reach the subject after a minimum of 3 documented phone calls, faxes or emails, as well as 
a lack of response by the subject to 1 registered mail letter. All attempts should be 
documented in the subject’s medical records. If it is determined that the subject has died, the 
site will use permissible local methods to obtain the date and cause of death. 
If the investigator’s use of a third-party representative to assist in the FU visit of the study has 
been included in the subject’s informed consent, then the investigator may use a 
sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the FU visit of the study. 
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. If, after all attempts, 
the subject remains lost to follow-up, then the last known alive date as determined by the 
investigators should be reported and documented in the subject’s medical records. 


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10 
TREATMENT OF SUBJECTS 
10.1 
Identity of Study Treatment(s) 
Details of the study treatments are presented in Table 10–1. 
Table 10–1 
Study Treatments 
Drug Name 
BGS649 
BGS649 matched placebo 
Active ingredient 
BGS649 
Not applicable 
Strength(s) 
Not applicable 
Dosage Form 
 
  
 
 
Route of administration 
Oral 
Oral 
Mode of administration 
With water 
With water 
Dose 
 
Possible doses are: 
 
OR 
 
OR 
 
10.1.1 
Administration of Study Treatment(s) 
Subjects receiving active doses of BGS649 in Study MBGS205 will continue with the same 
dose in Study MBGS206 and the blind will be maintained. Subjects receiving placebo in 
Study MBGS205 will be randomised to receive BGS649 
 If one or 
more dosing arms are dropped during the conduct of Study MBGS205 these will not be 
progressed in Study MBGS206 and subjects switching from placebo will be randomly 
allocated to available dose arms. All doses should be taken orally by the subject, with water, 
on a 
 at approximately 
the same time. Treatment may be self-administered except at the Baseline visit of 
Study MBGS206 (Week 24 of Study MBGS205), when it must be taken by the subject at the 
study site. 
10.2 
Study Treatment Packaging and Labelling 
10.2.1 
Packaging 
Each study site will be supplied with investigational treatment 
and matching placebo, indistinguishable in appearance and taste) in three pack types
 
with packaging of identical appearance, consistent with Table 10–1. 
A unique medication number is printed on the label of each pack which corresponds to one of 
the treatment regimens. Investigator staff will identify the investigational treatment to 
dispense to the subject by contacting the IRT and obtaining the medication number(s). 
Records of subjects assigned medication numbers will be recorded in source documentation.  


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10.2.2 
Labelling 
Labels will comply with the legal requirements of each country and be printed in the local 
language. They will supply no information about the subjects. Packs are labelled for both 
MBGS205 and MBGS206. However, the IRT will not allow allocation of placebo packs to 
subjects in MBGS206. 
10.2.3 
Storage 
Based on available stability data, BGS649
 packaged in 
Aclar blisters, should be stored below 25°C. The storage conditions for the study drug will be 
described on the medication label. Until dispensed to the subjects, the study drug will be 
stored in a securely locked area, accessible to authorised personnel only. 
10.2.4 
Blinding and Randomisation of Study Treatment(s) 
Subjects receiving active doses of BGS649 in Study MBGS205 will continue with the same 
dose in Study MBGS206; this transfer will be handled by the IRT and the blind will be 
maintained.  
Subjects receiving placebo in Study MBGS205 will be re-randomised at the Baseline visit to 
receive one of the 3 treatment regimens 
 in a 1:1:1 
ratio. If one or more dosing arms are dropped during the conduct of Study MBGS205 these 
will not be progressed in Study MBGS206 and subjects switching from placebo will only be 
randomly allocated to available dose arms. 
The investigator or his/her delegate will contact the IRT after confirming that the subject 
fulfils all the inclusion/exclusion criteria. The IRT will assign a medication number to the 
subject, which will be used to link the subject to a treatment regimen and will specify a 
unique medication number on the label of investigational treatment to be dispensed to the 
subject. The randomisation number will not be communicated to the caller. 
The randomisation numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
A subject randomisation list will be produced by ICON Biostatistics using a validated system 
that automates the random assignment of subject numbers to randomisation numbers. These 
randomisation numbers are linked to the different treatment regimens, which in turn are 
linked to medication numbers. A separate medication list will be produced using a validated 
system that automates the random assignment of medication numbers to packs containing the 
investigational drug.  
Subjects, investigational staff, persons performing the assessments and data analysts (other 
than those described below) will remain blind to the identity of the treatments 
 from the time of randomisation until after database 
lock. The Sponsor and CRO personnel may be unblinded at the time of unblinding the 
MBGS205 study, in order to make development decisions. At this time, enrolment of 
MBGS206 will be completed and the opportunity to introduce a bias, minimal. In order to 
maintain the blind described above, testosterone, LH, FSH and oestradiol measurements will 


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be blinded to site and sponsor staff and monitoring will be performed by an independent 
unblinded physician. 
The blind will be maintained using the following methods: 
1. Randomisation data will be kept strictly confidential until the time of unblinding, and will 
not be accessible to anyone involved in the study 
2. The identity of the treatments will be concealed by the use of investigational treatment 
that is identical in packaging, labelling, schedule of administration and appearance. 
Should a situation arise where unblinding is required, the investigator at that site may 
perform immediate unblinding without the need for communication with the sponsor 
(see Section 10.3). 
10.3 
Procedure for Breaking the Randomisation Code 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
subject safely and efficaciously. Most often, investigational treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study subject who 
presents with an emergency condition. Emergency code breaks are performed using the IRT. 
When the investigator contacts the system to break a treatment code for a subject, he/she 
must provide the requested subject identifying information and confirm the necessity to break 
the treatment code for the subject. The investigator will then receive details of the 
investigational drug treatment for the specified subject and a fax or email confirming this 
information. The system will automatically inform the ICON site monitor, the medical 
monitor, and the ICON Project Manager that the code has been broken, but no treatment 
assignment will be communicated. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow 
access to the IRT in case of emergency. The investigator will inform the subject how to 
contact his/her backup in cases of emergency when he/she is unavailable. The investigator 
will provide the protocol number, investigational treatment name if available, subject 
number, and instructions for contacting the local entity which has responsibility for 
emergency code breaks to the subject in case an emergency treatment code break is required 
at a time when the investigator and backup are unavailable. 
10.4 
Subject Compliance 
Each time study medication is dispensed subjects will be informed about compliance. When 
study medication is returned, compliance will be assessed based on the subject’s interview 
and a count of the capsules. The investigator (or designee) will record the amount of study 
medication dispensed and returned at each visit, as well as document the reasons for 
non-compliance in the source document. The investigator will record the date and time of the 
study drug intake to the electronic data capture (EDC). The subject should be re-educated 
regarding treatment compliance and/or recording dose. A significant noncompliance with 
protocol or study drug will be communicated to the sponsor. 


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10.5 
Study Treatment Accountability 
Records shall be maintained of the delivery of study treatments to the study centres, the 
inventory at the study centres, the use of each subject and the return to the sponsor. 
These records shall include dates, quantities, batch numbers, expiry dates, and the unique 
code numbers assigned to the study medication and to the study subjects. 
The investigator shall be responsible for ensuring that the records adequately document that 
the subjects were provided the doses specified in the protocol and that all study medication 
received from the sponsor is reconciled. All study medication must be returned to the sponsor 
at the end of the study. 
10.6 
Contraception 
There is potential to transfer BGS649 to a female partner through seminal fluid, with 
resulting theoretical risk to embryo-foetal development. Therefore, sexually active study 
subjects must use a double barrier method during vaginal sexual intercourse with women of 
child bearing potential while taking the study drug and for 3 months after completing the 
study treatment, even if the female partner is using a highly effective contraception, and 
should not father a child in this period. Single barrier (condom) should be used for non-
vaginal penetrative intercourse with women of child bearing potential to prevent exposure of 
the partner to BGS649 through the semen and theoretical risk to an unborn child. This to be 
continued while taking the study drug and for 3 months after completing the study treatment. 
The subject should also not perform sperm donation while taking the study drug and for 3 
months after completing the study treatment. A condom, together with a spermicide cream is 
required to be used in order to reduce risk of conception and to prevent delivery of the drug 
via the seminal fluid.  
Seminal fluid samples will be collected after a minimum of 48 hours of sexual abstinence, 
therefore no sexual activity should be performed in this time period and no spermicidal cream 
used to avoid interference with seminal fluid evaluation.  
10.7 
Prohibited Therapy 
The following classes of medication listed below are not permitted to be taken during the 
conduct of the study starting from Baseline. Over the counter or ordered via the internet or 
prescribed medications that are known to influence production or efficacy of sex hormones, 
or with oestrogen/androgen-like or antioestrogen/antiandrogen-like properties e.g. 
o Opiates/Opioids including methadone for > 7 consecutive days during study duration 
o Chronic systemic steroid treatment or systemic steroids for > 5 consecutive days for 
intercurrent illness (inhaled and topical steroids are allowed) 
o Medications known to increase prolactin levels, e.g., antipsychotics  
o 5-α-reductase inhibitors, e.g., Finasteride 
o Spironolactone 
o Cimetidine 


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o Growth hormone 
o Testosterone, known testosterone enhancers, anabolic steroids, known active Fertility 
drugs and Oestrogens or selective oestrogen receptor modulators (SERMS) 
o Clomid 
o Bisphosphonates, Teriparatide, Denosumab (treatment with calcium and vitamin D for 
bone health is allowed at the discretion of the investigator) 
11 
ASSESSMENT OF EFFICACY 
11.1 
Efficacy and Pharmacokinetic Variables 
1. Total and bioavailable testosterone, SHBG, FSH, LH 
2. Body composition 
o Body weight and BMI 
o Waist circumference, hip circumference, and waist to hip ratio 
o Gynecomastia 
o Fat and muscle percentage (by impedance) 
3. Cardiometabolic parameters 
o Blood pressure (diastolic blood pressure [DBP] and systolic blood pressure [SBP]) 
and heart rate 
o Fasting lipid panel (total cholesterol, low density lipoprotein [LDL], high density 
lipoprotein [HDL], triglycerides) 
o Glycosylated haemoglobin (HbA1c) 
o Fasting glucose and insulin 
o High sensitivity C-reactive protein (hs-CRP) 
o Homeostatic assessment of insulin resistance (HOMA-IR) (see Section 11.2.3 for 
details) 
4. PRO measures 
o International Index of Erectile Function (IIEF) and Patient-Reported Outcomes 
Measurement Information System® (PROMIS®) Sexual Function and Satisfaction 
(SexFS): to assess improvement in erectile function 
o IIEF and PROMIS SexFS: to assess improvement in sexual desire and satisfaction 
with sex life 
o 36-item Short Form Health Survey (SF-36): to assess general quality of life (QoL)  
o Brief Fatigue Inventory (BFI), PROMIS Fatigue Short Form, and the SF-36 Vitality: 
to assess improvement in energy levels 


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o Patient Global Impression of Status (PGI-S) items: to assess the subjects’ overall 
impression of their current health status. 
5. Actigraphy derived activity and sleep parameters 
o Counts of sedentary, moderate, and vigorous activity 
o Sleep quality and duration 
6. Dynometry derived grip strength assessment 
7. PK semen analysis. Concomitantly with semen PK, plasma PK will be assessed to 
estimate plasma to semen BGS649 transference. 
Detail of assessment of the efficacy and PK variables are presented in Section 11.2 and 
Section 11.3, respectively. 
11.2 
Efficacy Assessments 
All efficacy assessments will be performed according to the schedule of assessments 
(Table 9–1). 
11.2.1 
Male Hormonal Parameters 
Testosterone 
Serum total testosterone and SHBG levels will be measured. Bioavailable testosterone will be 
calculated. 
Serum total testosterone and SHBG laboratory parameters have to be taken before 11 am. If 
there is evidence that a sample has been inadvertently taken after this time, a retest is allowed 
after discussion with medical monitor. 
Testosterone monitoring will be blinded to the subject, sponsor, and investigators and a 
decision about discontinuing BGS649/placebo will be made by an independent unblinded 
physician on a one to one basis after detailed evaluation of the subject (Section 9.3.4 and 
Section 16.3). The subject may be discontinued if meeting testosterone discontinuation 
criteria as per section 9.3.4. It is important that investigators do not monitor testosterone 
independently of the study protocol as this will have the potential to inadvertently unblind the 
protocol. A subject may be withdrawn from the study if there was unblinded testosterone 
monitoring in addition what is described in the protocol. 
Other Parameters 
LH, and FSH will be assessed. In order not to unblind treatment assignment, these parameters 
will be blinded. 
11.2.2 
Body Composition 
Body weight will be measured as part of the vital signs assessment (Section 12.8). 
BMI 
Body weight will be measured at the same time of day (± 30 minutes) at each assessment, 
before eating. Subjects should be instructed to wear similar clothing at each visit where 


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weight will be measured. Shoes and heavy accessories should be removed prior to 
measurement. Study staff should ensure that the same scale is used for the same subject at 
each assessment, and that the scales have been properly calibrated. 
Height was measured at Screening in Study MBGS205 to enable BMI determination. 
BMI is to be calculated from the height obtained at Screening in Study MBGS205. The BMI 
is calculated by dividing the measured subject weight by the square of the measured subject 
height, and is expressed in kg/m2. 
Waist Circumference/Hip Circumference 
Measurements will be performed to the nearest 0.1 cm. 
The waist measurement (in cm) will be taken by measuring the distance around the 
narrowest part of the waist or, if this is not apparent, by measuring at the mid-point between 
the lowest rib and the top of the hip bone (iliac crest). The hip measurement (in cm) will be 
taken by measuring the distance around the largest extension of the buttocks and at the level 
of the bony prominences felt in the front of the hips. 
The waist to hip ratio will be calculated by dividing the waist girth by the hip girth. 
Measurements will preferably be performed using a flexible tape measure (provided for the 
study) and a non-permanent pen for marking the skin. If a plastic or cloth tape is used, it 
should be regularly checked against a metal tape to ensure that it has not stretched with 
prolonged use. Measurements should be made with the measuring tape placed firmly against 
the skin, but not so tight that it is compressing the skin. The tape should be placed so that it is 
lying flat and horizontal on the skin, parallel to the floor. Subjects should be asked to relax 
and exhale before the measurements are read. 
Gynecomastia 
Breast examination will be performed by palpation by an investigator. The subject will be in 
a supine position with hands behind their head. Investigators will perform a thorough 
examination of the breasts, noting their size and consistency, presence of any nipple 
discharge or axillary lymphadenopathy. The purpose is to look for or monitor enlargement or 
irregularities of glandular breast tissue. The investigator will then document the findings and, 
if gynecomastia is present, will document size of glandular breast tissue in 
centimetres/inches. 
Body composition by bio-impedance 
Bioelectrical impedance analysis estimates body composition. Measuring electrical 
impedance or opposition to the flow of an electric current through body tissues will be used 
to estimate and calculate subcutaneous and visceral body fat and proportion of muscle during 
the study. 
The evaluation takes a few minutes. Subjects should be well hydrated (drinking water the 
night before and morning before assessment) and rested prior to the measurements as 
impedance is influenced by hydration and exercise. 


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11.2.3 
Cardiometabolic Parameters 
Blood pressure (SBP and DBP) will be measured as part of the vital signs analysis 
(Section 12.8). 
All blood samples are to be collected after 8 hours fasting, after ECG and vital sign 
measurements 
HbA1c, fasting lipids (total cholesterol, LDL, HDL, triglycerides), fasting glucose and insulin 
and hs-CRP will be measured. In addition, HOMA-IR will be calculated to estimate insulin 
resistance using the following formula: 
HOMA-IR = [glucose (nmol/L) * insulin (µU/mL)/22.5], where glucose and insulin must be 
fasting (Matthews et al 1985). 
11.2.4 
Patient Reported Outcomes 
The impact of BGS649 on various aspects of subject’s health-related quality of life will be 
assessed using the following questionnaires. Ideally, PROs are to be evaluated before any 
other study activity is performed. 
International Index of Erectile Function 
The IIEF is a 15-item self-administered questionnaire, providing a quantitative index of 
erectile dysfunction severity by examining the following 5 relevant areas of sexual function 
(Rosen et al 1997; Cappelleri et al 2000): 
1. Erectile function 
2. Orgasmic function 
3. Sexual desire 
4. Intercourse satisfaction 
5. Overall satisfaction. 
Patient-Reported Outcomes Measurement Information System® Sexual Function and 
Satisfaction PROMIS® SexFS 
The PROMIS SexFS PRO measure is an up to 19 item self-administered questionnaire 
compiled from relevant items in the PROMIS Sexual Function and Satisfaction domains 
(Flynn et al., 2013). The measure assesses global satisfaction with sex life (up to 7 items), 
erectile function (up to 6 items), interest in sexual activity (up to 4 items), and interfering 
factors (up to 2 items) in the last 30 days.   
PROMIS® Fatigue Short Form  
The PROMIS Fatigue Short Form measure is a 7-item self-administered questionnaire 
assessing the extent of fatigue and its impact on work and functioning in the last 7 days. 


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Brief Fatigue Inventory 
The BFI is a 9-item self-administered questionnaire, providing an assessment of the severity 
of fatigue and its impact on the subject’s ability to function at present and in the previous 
24 hours (Mendoza et al., 1999). 
36-Item Short Form Health Survey 
The SF-36 QoL questionnaire is a multidimensional instrument that evaluates quality of life. 
It consists of questions assigned to the following categories (McHorney et al., 1994): 
1. Vitality   
2. Physical functioning 
3. Bodily pain 
4. General health perceptions 
5. Physical role functioning 
6. Emotional role functioning 
7. Social role functioning 
8. Mental health. 
Patient Global Impression of Status items  
Three patient global impression items (physical function, mental function, and sex life) will 
be included to assess the subjects’ overall impression of their current health status and thus to 
evaluate the performance of the other PROs in this patient population. For full details of this 
assessment see Appendix II.  
11.2.5 
Actigraphy Derived Activity and Sleep Parameters 
The Actigraph Link is a portable device that measures gross motor movements featuring a 
validated 3-axis accelerometer and data filtering technology that captures and records 
continuous, high resolution physical activity and sleep/wake information. It is a large, 
water-resistant wrist watch worn on the non-dominant hand. 
Subjects will wear the monitor for 7 days consecutively after Visit 7, as described in the 
schedule of assessments (Table 9–1). 
Activity parameters 
Moderate and vigorous physical activity, sedentary bouts and activity counts will be 
measured. Software algorithms will be used to differentiate the amount of time spent at each 
of these activity levels. The cut-offs selected will be chosen to reflect the sedentary lifestyle 
of the subjects. 
Sleep parameters 
Time spent in sleep will be measured to enable assessment of sleep quality and duration. 


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11.2.6 
Grip Strength Measurement 
Grip strength assessment using a hand held dynamometer will be used as a surrogate measure 
of muscle strength. During this assessment, the subject will squeeze the device 3 times with 
each hand. An average of 3 measurements for each hand will be calculated and recorded. 
11.3 
Pharmacokinetic Assessments 
Semen Pharmacokinetic sampling 
Semen PK sampling for BGS649 will be performed at the following time points (excluding 
subjects that are vasectomised or have vasectomy planned during the study period), as 
defined in the schedule of assessments (Table 9–1): Baseline visit (Week 24 of 
Study MBGS205) and EOT (Visit 7).  
Subjects that are discontinued early from the study drug will provide samples for seminal 
fluid PK at EOT (Visit 7) unless they are not able to provide this sample. 
Semen samples for PK analysis will be centrifuged (1000 g × 10 minutes) and the separated 
seminal plasma will be stored at -20°C until samples are used. 
Plasma Pharmacokinetic Sampling 
Plasma PK sampling for BGS649 will be performed at the Baseline visit (Week 24 of 
Study MBGS205) and EOT (Visit 7) to estimate plasma to semen BGS649 transference. 


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12 
ASSESSMENT OF SAFETY 
The timing and frequency of safety assessments provided in Table 9–1. For the primary and 
secondary safety endpoints see Section 13.4.1 and Section 13.4.2, respectively. 
12.1 
Adverse Events 
12.1.1 
Definitions 
The definitions for AEs and SAEs are given below. It is of the utmost importance that all 
staff involved in the study are familiar with the content of this section. The principal 
investigator is responsible for ensuring this. 
Adverse Event 
An AE is defined as any untoward medical occurrence in a subject, or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign, symptom or disease temporally associated with the use of a medicinal (investigation) 
product, whether or not related to the medicinal (investigational) product. 
AEs/SAEs that resolve in Study MBGS205 will be recorded as a pre-existing condition/past 
medical or surgical history.  
AEs will be recorded if there is a worsening of the pre-existing condition during study 
conduct with regard to nature, severity, or frequency or when there is new relevant 
occurrence. AEs ongoing from Study MBGS205 will be captured as AEs and followed 
accordingly. 
An adverse drug reaction is an “untoward and unintended response to an investigational 
medicinal product related to any dose administered”. 
All AEs judged by either the reporting investigator or the sponsor as having a reasonable 
causal relationship to a medicinal product qualify as adverse drug reactions. The expression 
of “reasonable causal relationship” means to convey in general that there are facts or 
arguments which suggest a causal relationship. 
Serious Adverse Event 
An SAE is defined as, but is not limited to, one that: 
1. Results in death 
Death is not an AE in itself, but an outcome. The cause of the death is the AE which 
resulted in death. 
2. Is life-threatening 
Life-threatening means that the subject was at immediate risk of death at the time of the 
SAE; it does not refer to an SAE that hypothetically might have caused death if it had 
been more severe. 
3. Requires in-subject hospitalisation or prolongs existing hospitalisation 


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Hospitalisation is defined as at least 1 overnight formal admission into hospital, usually in 
order to perform additional tests, provide treatment which it is not possible to provide at 
home, and/or due to an unstable medical condition which requires specific monitoring of 
the subject. Pre-planned hospitalisations (known already prior to signing the ICF) will not 
be considered an SAE, unless any of the above criteria are fulfilled over the course of the 
hospitalisation due to unplanned complications. “Social” hospitalisation whereby it is 
administratively impossible to release the subject home is not necessarily an SAE. 
Complications that occur during hospitalisations are AEs. If the complication delays 
subject release from hospital, then the AE becomes an SAE. 
4. Results in persistent or significant disability/incapacity 
The term significant disability refers to any condition that impairs physical/physiological 
well-being to the extent that the subject is unable to function normally. Physical disability 
may include, but is not limited to, permanent disability of locomotion or motility, but also 
systemic permanent dysfunction including heart failure, liver insufficiency, or pulmonary 
fibrosis. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
Important medical events that may not result in death, be life-threatening or require 
hospitalisation may be considered as an SAE when, based on appropriate medical 
judgement, they may jeopardise the subject, or the subject may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Treatment Emergent Adverse Event 
Treatment emergent AEs (TEAEs) are defined as any AE occurring or worsening on or after 
the first dose of study medication administered during the study MBGS206 
Adverse Events of Special Interest 
Refer to Section 12.1.7. 
12.1.2 
Recording of Adverse Events 
For the purposes of this study, any detrimental change in the subject's condition, after signing 
the ICF and any unresolved AEs from MBGS205 up to 90 days after the last administration 
of study drug should be considered an AE. 
The following variables will be recorded for each AE:  verbatim/AE description and date for 
AE start and stop, severity, seriousness, causality rating, whether or not the AE caused the 
subject to discontinue, and the outcome. If the severity of the AE changes, a new AE must be 
recorded. 
SAEs and AEs will be recorded after signing of the informed consent. All AEs/SAEs have to 
be reported, whether or not considered causally related to the investigational product or to the 
study procedure(s). 


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All ongoing AEs/SAEs should be followed up until resolution or stabilisation or the last visit 
if in the investigator's opinion, the AE is unlikely to resolve due to the subject's underlying 
disease. 
At any time after the FU visit, if an investigator learns of an SAE that can be reasonably 
related to study drug, he/she should promptly notify the sponsor. 
Intensity 
The investigator will assess the intensity of AEs based on the following definitions: 
1. Mild (awareness of sign or symptom, but easily tolerated) 
2. Moderate (discomfort sufficient to cause interference with normal activities) 
3. Severe (incapacitating, with inability to perform normal activities). 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 12.1.8. 
An AE of severe intensity need not necessarily be considered serious. For example, nausea 
that persists for several hours may be considered severe nausea, but not an SAE. On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild 
stroke but would be an SAE. 
For an AE to be a suspected drug-related event there should be at least a reasonable 
possibility of a causal relationship between the study drug and the AE. 
12.1.3 
Causal Assessment 
The following “binary” decision choice will be used by the investigator to describe the 
causality assessment: 
o Reasonable possibility of relatedness 
o No reasonable possibility of relatedness 
The term “reasonable possibility of relatedness” is meant to convey, in general, that there is 
enough evidence or argument to suggest a causal relationship. The investigator should 
consider the following, before reaching a decision on causality assessment: 
o Time relationship between study drug intake and event’s onset 
o Dechallenge 
o Rechallenge 
o Medical history 
o Study treatment 
o Mechanism of action of study drug 
o Class effect 
o Concomitant treatments in use 


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o Withdrawal of study treatment 
o Lack of efficacy/worsening of existing condition 
o Erroneous treatment with study medication or concomitant medication 
o Protocol-related process 
Action taken with study drug due to the AE: 
o None 
o Drug permanently discontinued 
o Drug temporarily discontinued 
o Unknown/not applicable 
Other action taken: 
o Specific therapy/medication 
o Surgical medical procedure 
o (Prolonged) hospitalisation 
Outcome: 
Each single AE must be rated by choosing 1 of the following: 
o Recovered/resolved 
o Recovering/resolving 
o Not recovered/not resolved 
o Recovered with sequelae/resolved with sequelae 
o Fatal 
o Unknown. 
12.1.4 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms 
Laboratory/vital signs/ECG abnormalities should be reported as AE/SAEs if any 1 of the 
following criteria is met: 
1. The result is clinically significant or associated with signs/symptoms 
2. Requires additional diagnostic testing and/or interventions 
3. Leads to a change in dose, discontinuation or interruption of the study drug. 
Results of an abnormal test results without any of the above criteria do not constitute an AE. 
Any test result determined to be an error is not required to be reported as an AE. A repeat 
measurement is in that situation may be recommended. 
12.1.5 
Overdose 
A drug overdose is defined as the accidental or intentional use of a drug or medicine or an 
administration error in drug administration above 20mg as single dose or 2 or more doses 


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above 5mg/dose. Every overdose must be reported to ICON Pharmacovigilance and Safety 
Services within 24 hours of awareness, irrespective of whether the overdose was associated 
with an AE/SAE. 
12.1.6 
Partner Pregnancies 
Pregnancy outcomes must be collected for the female partners of the subjects who took study 
treatment in this study. Pregnancy itself is not regarded as an AE unless there is suspicion 
that the study drug may have interfered with the effectiveness of a contraceptive medication. 
If a pregnancy is reported for a subject’s partner, study drug will be immediately 
discontinued. The outcome of all pregnancies (spontaneous miscarriage, elective termination, 
normal birth or congenital abnormality) must be followed up and documented. Follow up 
should be performed up to delivery and examination of the new-born, after which a follow-up 
report should be sent with any new information regarding the pregnancy and the outcome of 
the birth. After study drug discontinuation, the subject should continue with all study 
schedule assessments, except study drug administration. The male study subject has to 
continue to wear a condom for at least 3 months after the last medication intake. Unprotected 
intercourse with his pregnant partner presents a risk of toxicity to the unborn child. 
All congenital abnormalities/birth defects should be classified as SAEs. Spontaneous 
miscarriages should also be reported and handled as SAEs. Elective abortions without 
complications should not be handled as SAEs, but should be reported as AEs.  
Pregnancies must be reported to ICON Pharmacovigilance and Safety Services using the 
reporting details and timelines provided in Section 12.1.8 within 24 hours of awareness. 
12.1.7 
Adverse Events of Special Interest 
Some AEs, despite their severity or outcome, will be expedited due to the relevance for 
subject safety or study drug safety profile. These AESIs should be reported as expedited 
within 24 hours of awareness to ICON Pharmacovigilance and Safety Services: 
1. Cardiovascular event (acute myocardial infarction, brain stroke, transient ischemic attack,
unstable angina, congestive heart failure)
2. Prostate cancer
3. Lower extremity oedema ≥ Grade 3(which is not due to local pressure /venostasis effects
such as may be caused by socks or other clothing).
4. Polycythaemia as measured by a haematocrit > 54%
5. Fragility fracture
6. Development of sleep apnoea
7. Development of osteoporosis as per DEXA measurement (T score ≤ -2.5)
8. Breast cancer.


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12.1.8 
Reporting of Serious Adverse Events and Adverse Events of Special Interest 
Investigators and other site personnel must inform ICON Pharmacovigilance and Safety 
Services of any SAE/AESI that occurs during the course of the study whether or not 
considered causally related to the investigational product or to the study procedure(s):  SAE 
from the time of informed consent until the 90 days after last dose of study drug, AESI from 
the time of randomisation until 90 days after last dose of study drug and within 24 hours of 
when he or she becomes aware of it. 
Follow-up information on SAEs/AESIs must also be reported by the investigator within the 
same time frames. 
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to ICON within 24 hours as described above. 
All SAEs/AESIs will also be recorded in the eCRF. The investigator is responsible for 
informing the Ethics Committee of the SAE/AESI as per local requirements. 
Paper SAE/AESI forms should be completed at the site and faxed/emailed to the relevant 
ICON Pharmacovigilance and Safety Services or e-mailed to the global email distribution list 
within 24 hrs of awareness of the event. 
SAE/AESI reports should be sent to: 
 
If the report is sent via email, then the completed and signed SAE/AESI or Pregnancy report 
form must be attached to the email. A notification email of the event describing it in the email 
text is not sufficient. 
Alternatively, the following fax number can be used for completed SAE/AESI reporting 
forms. 
 
There may be situations when an SAE/AESI has occurred and the investigator has minimal 
information to include in the initial SAE/AESI report. However, it is very important that the 
investigator always makes an assessment of causality for every event prior to transmission of 
the SAE/AESI report form. Minimum criteria are identifiable subject (number), a suspect 
product (i.e., study drug or concomitant medication), an identifiable reporting source 
(investigator/study site identification), and an event or outcome that can be identified as 
serious or as an AESI. The investigator may change his/her opinion of causality in the light of 
follow-up information, amending the SAE/AESI report form accordingly. The causality 
assessment is one of the criteria used when determining regulatory reporting requirements for 
SAEs. 
12.2 
Safety Endpoints 
12.3 
Laboratory Assessments 
Laboratory measurements for blood chemistry, PSA, haematology, urinalysis, and will be 
performed according to the schedule of assessments (Table 9–1). Specific details not 


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mentioned in this section (including shipping requirements) are included in the laboratory 
manual.  
All blood samples are to be collected after 8 hours fasting, after ECG and vital sign 
measurements. 
12.3.1 
Clinical Laboratory Tests 
Blood Chemistry 
Sodium, potassium, chloride, bicarbonate/CO2, blood urea nitrogen, creatinine, fasting 
glucose, albumin, alkaline phosphatase, AST, ALT, prothrombin time/INR, total bilirubin, 
total protein, calcium, lipid panel (total cholesterol, LDL, HDL, triglycerides), and PSA will 
be measured. 
Estimated glomerular filtration rate (eGFR) will be calculated based on Cockcroft-Gault 
formula: 
eGFR = ((140 - Age) / (SerumCreat)) * (Weight / 72) 
Haematology 
Haemoglobin, white blood cell (WBC) count with differentials (monocytes, eosinophils, 
basophils, neutrophils, lymphocytes) as an absolute value, red blood cell (RBC) count, and 
platelet count will be measured. 
Due to the potential for dehydration to affect haematocrit, subjects should come fully 
hydrated during the trial when the haematocrit is tested to ensure reliable results.  
Urinalysis 
Specific gravity, pH, semi-quantitative “dipstick” evaluation of glucose, protein, bilirubin, 
ketones, leukocytes, and blood will be measured. 
A microscopic examination including RBC and WBC will be performed only when dipstick 
evaluation is positive for WBC and/or blood or protein. A midstream urine sample (about 
30 mL) will be obtained, in order to avoid contamination with epithelial cells and sediments, 
and allow proper assessments. 
12.4 
DEXA Scan 
Bone density will be evaluated with standard procedure described in study imaging manual. 
All evaluations during the study for particular subject should, where possible, be performed 
on the same machine with particular attention to ensuring consistency in positioning patients.  
To assess the spine, the subject will be in supine position with legs supported on a padded 
box to flatten the pelvis and lower (lumbar) spine. To assess the hip, the foot is placed in a 
brace that rotates the hip inward. The detector will be slowly passed over the area separately 
for spine and hip, generating images. The duration of examination will be up to 30 minutes. 
DEXA T Score will be calculated based on actual measured bone density value. Both values 
will be evaluated for safety. 


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EOT DEXA scan: If the subject is discontinued from the treatment early, DEXA will be 
performed only if they reached minimum Week 36 (Visit 4) active treatment period. In order 
to accommodate scheduling, EOT DEXA can be performed within 5 days before the EOT 
visit 
12.5 
Bone Turnover Markers 
CTx1, osteocalcin, bone alkaline phosphatase, and P1NP will be measured. 
12.6 
Hormonal Parameters 
Total oestradiol. In order not to unblind treatment assignment, total oestradiol will be blinded. 
 
12.7 
Physical Examination 
The following examinations will be performed: 
1. Full evaluation and physical examination (general appearance, skin and body hair, neck 
[including thyroid]), eyes, ears, nose, throat, lungs, heart, abdomen, testicular 
examination, lymph nodes, lower extremities examination for oedema and basic nervous 
system evaluation) 
2. Digital prostate examination. In a case an abnormality on prostate examination is 
detected, or subject develops significant worsening of obstructive urinary symptoms, it is 
recommended to have full urologic evaluation 
3. Limited physical examination (cardiovascular system and lower extremities oedema) at 
all visits where a full physical examination is not scheduled. For lower extremities 
examination, subject will be sitting with their lower extremities in the dependent position. 
Lower extremities will be inspected and palpated to look for pitting oedema. 
The lower extremities examination findings will be graded as per standard medical practice 
on a 5-point scale:  0 - no oedema; +1 - barely detectable 2 mm depression, immediate 
rebound; +2 - a 4 mm deep oedema, few seconds to rebound; +3 – 6 mm deep oedema, 
10-12 seconds to rebound; or + 4 – 8 mm deep oedema, > 20 seconds to rebound; and 
recorded in the eCRF. 
Information about the physical examination must be present in the source documentation at 
the study site. Significant findings that are present prior to the start of the study drug 
treatment must be included in the relevant medical history/current medical conditions. 
12.8 
Vital Signs 
Blood pressure (SBP and DBP) and heart rate will be measured at all visits. 
Details on body weight measurement are provided in Section 11.3.2. Body weight taken at 
Baseline will be utilised for all PK calculations. 
Blood pressure (SBP and DBP, see Section 11.3.2) and pulse rate will be assessed after the 
subject has rested quietly in the supine position for at least 5 minutes. Three consecutive 


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recordings will be taken and the average value will be noted in the eCRF. Blood pressure will 
be assessed using the same arm each time. 
12.9 
12-Lead ECG 
The subject number and initials or date of birth, the date and actual time of the tracing, and 
the study code must appear on each page of the tracing. The ECGs should be performed at 
approximately the same time of day at each of the ECG assessments, after subject has been in 
supine position for 10 min. Tracings will be dated and signed by the person who interprets 
the ECG. 
The eCRFs will contain: 
1. Date and time of the ECG 
2. Heart rate 
3. PR interval 
4. QT interval (QTCF) 
5. QRS duration 
6. RR interval 
The overall interpretation will be collected with a yes/no statement to confirm if any 
clinically significant abnormalities are present, which need to be detailed further and reported 
as AE/SAE if appropriate. Original ECG tracings, appropriately signed, will be archived at 
the study site. 
12.10 
24/7 Medical Emergency Coverage 
In a study related emergency situation, when assigned Medical Monitors for a study cannot 
be reached by a caller, an on-call Physician can be reached 24 hours per day, 7 days per week 
via an ICON Call Centre: 
 
 
(Chargeable telephone number allowing a global reach from both landlines and mobile 
phones) 
o https://icophone.iconplc.com 
On this internet page, a list of country-specific toll-free telephone numbers is provided. 
It should be noted that not all countries globally have access to toll-free numbers as indicated 
on the “24/7 Medical Helpdesk” index. Countries without toll-free numbers need to dial the 
chargeable number as indicated above. Furthermore, toll-free numbers are not available from 
mobile phones. 


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13 
STATISTICAL EVALUATION 
13.1 
Sample Size and Power 
Primary Statistical Hypothesis: The percentage decrease from Baseline in lumbar bone 
mineral density measured in g/cm2 by DEXA within a dose group is greater than 
 
H0:  ≤ 3% 
H1:  > 3% 
The null hypothesis will be rejected for a dose group and the endpoint considered met if the 
lower bound of the 2-sided 95% confidence interval (CI) for the percentage decrease from 
Baseline in lumber spine is greater than 
.  
Assuming a 2-sided test at 5% significant level and a standard deviation (SD) of 
0.0439 g/cm2, to achieve 90% power N=25 subjects in each dose group would be needed to 
detect a 
decrease from Baseline in bone mineral density at 48 weeks. 
Enrolment will continue until 30 subjects from each of the previous active treatment arms in 
Study MBGS205 have entered this study. Subjects previously treated with placebo will be 
enrolled until target subject population is met in all active arms. 
13.2 
Randomisation 
Subjects that received active doses of BGS649 in Study MBGS205 will continue with the 
same dose in Study MBGS206. ICON Biostatistics will prepare the randomisation list, based 
on a randomisation scheme blocked by site. Each subject that received placebo in 
Study MBGS205 will be re-randomised to one of the 3 active doses defined in Section 9.1 in 
a 1:1:1 ratio.  
See Section 10.2.4 for further details of the Randomisation procedures to be applied. 
13.3 
Analysis Sets 
All safety endpoints will be analysed using the safety population. All efficacy endpoints will 
be analysed using the intention to treat (ITT) population.   
Further safety and tolerability data will be analysed using the safety population. 
PK data will be analysed using the PK population. 
13.3.1 
Intention to Treat  
The ITT population includes all subjects who:  
1. Are randomised, and  
2. Receive at least 1 dose of study medication, and  
3. Provide a Baseline efficacy value and at least 1 available evaluation of efficacy 
post-Baseline. 


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13.3.2 
Safety Population 
The safety population includes all subjects who received at least 1 administration of the study 
medication. 
13.3.3 
PK Population 
For the summary of semen concentration of BGS649, all subjects who received at least 
1 administration of the study medication and have at least 1 quantifiable concentration will be 
included in the PK population. 
13.4 
Endpoints 
13.4.1 
Primary Endpoint 
The primary endpoint is percentage change in lumbar bone mineral density measured by 
DEXA (g/cm2) from Baseline in Study MBGS205 to Week 48 in Study MBGS206 by dose 
group in subjects randomised to active treatment in Study MBGS205. 
The primary endpoint will be assessed using the safety population. 
13.4.2 
Secondary Endpoints 
13.4.2.1 
Secondary Safety Endpoints 
1. In subjects that were randomised to active treatment in Study MBGS205 by dose group: 
o Percentage change in hip bone mineral density measured by DEXA (g/cm2) from 
Baseline in Study MBGS205 to Week 48 in Study MBGS206 
o Percentage change in bone turnover markers (C-terminal telopeptide [CTx1], 
osteocalcin, bone alkaline phosphatase, and procollagen type 1 N-propeptide [P1NP]) 
from Baseline in Study MBGS205 to Week 48 in Study MBGS206  
o Proportion of subjects with T-scores ≤ -2.5 at Week 48 
o Percentage change in bone density and bone biomarkers adjusted for vitamin D 
deficiency from Baseline in Study MBGS205 to Week 48 in Study MBGS206 
o Change of oestradiol (absolute and percentage) to Week 48 
o Proportion of subjects that overshoot testosterone (total testosterone above 1000 ng/dl 
[35 nmol/L], from first dose of study drug in Study MBGS205 until study completion) 
o Change in PSA from Baseline in Study MBGS205 to Week 48 in Study MBGS206 
o Change in haematocrit from Baseline in Study MBGS205 to Week 48 in Study 
MBGS206 
o Change in blood pressure (systolic and diastolic) Baseline in Study MBGS205 to 
Week 48 in Study MBGS206 
o Treatment emerged AE, SAE, and AESI (from first dose of study drug in 
Study MBGS205 until study completion) 


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o Relationship between change in bone mineral density from Baseline in Study 
MBGS205 to Week 48 in Study MBGS206 and absolute levels of oestradiol and total 
testosterone at Week 48 in MBGS206 
2. In subjects that were randomised to placebo in Study MBGS205 by dose group: 
o Percentage change in hip bone mineral density measured by DEXA (g/cm2) from 
Baseline in Study MBGS206 to Week 48  
o Percentage change in bone turnover markers (CTx1, osteocalcin, bone alkaline 
phosphatase, and P1NP) from Baseline in Study MBGS206 to Week 48  
o Change of oestradiol (absolute and percentage) from Baseline in Study MBGS206 to 
Week 48  
o Proportion of subjects with T-scores ≤ -2.5 at Week 48 of Study MBGS206 
o Proportion of subjects that overshoot testosterone (total testosterone above 1000 ng/dl 
[35 nmol/L] from first dose of study drug in Study MBGS206 until study completion) 
o Change in PSA from Baseline in Study MBGS206 to Week 48  
o Change in haematocrit from Baseline in Study MBGS206 to Week 48 
o Change in blood pressure (systolic and diastolic) Baseline in Study MBGS206 to 
Week 48  
o Treatment emerged AE, SAE, and AESI (from first dose of study drug in 
Study MBGS206 until study completion). 
13.4.2.2 
Secondary Efficacy Endpoints 
1. In subjects that were randomised to active treatment in Study MBGS205 by dose group: 
o Percentage of subjects that have normalisation of total testosterone at Week 48 in 
Study MBGS206 
o Change in total and bioavailable testosterone from Baseline in Study MBGS205 to 
Week 48 in Study MBGS206 
o Change of LH and FSH from Baseline in Study MBGS205 to Week 48 in Study 
MBGS206 
2. In subjects that were randomised to placebo in Study MBGS205 by dose group: 
o Percentage of subjects that have normalisation of total testosterone at Week 48 of 
Study MBGS206 
o Change in total and bioavailable testosterone from Baseline to Week 48 in Study 
MBGS206 
o Change of LH and FSH from Baseline to Week 48 in Study MBGS206 
13.4.2.3 
Secondary Pharmacokinetic Endpoint 
1. EOT plasma and semen concentration of BGS649 by dose group. 


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13.4.2.4 
Exploratory Endpoints 
1. In subjects that were randomised to active treatment in Study MBGS205: 
o Change in exploratory parameters from Baseline in Study MBGS205 to Week 48 in 
Study MBGS206 by dose group 
o Body composition (weight, BMI, waist and hip circumference, and parameters 
measured by bio-impedance)  
o Markers of cardiometabolic disease (blood pressure, lipid profile, HbA1c, glucose 
and insulin, hs-CRP, and HOMA-IR) 
o Physical activity, sleeping pattern, and strength (measured by wrist worn monitors 
and grip strength measurement) 
o Total and domain scores on PRO measures (Sexual function (IIEF, PROMIS 
SexSF), Energy/fatigue (BFI, PROMIS Fatigue), SF-36 
o The relationship between changes in PROs and changes in body composition, 
physical activity, grip strength, and sleep  
o The relationship between changes in testosterone and changes in cardiometabolic 
parameters, body composition, physical activity, grip strength, sleep, and PROs. 
2. In subjects that were randomised to placebo in Study MBGS205: 
o Change in exploratory parameters from Baseline in Study MBGS206 to Week 48 in 
Study MBGS206 by dose group 
o Body composition (weight, BMI, waist and hip circumference, and parameters 
measured by bio-impedance)  
o Markers of cardiometabolic disease (blood pressure, lipid profile, HbA1c, glucose 
and insulin, hs-CRP, and HOMA-IR) 
o Physical activity, sleeping pattern, and strength (measured by wrist worn monitors 
and grip strength measurement) 
o Total and domain scores on PRO measures (Sexual function (IIEF, PROMIS 
SexSF), Energy/fatigue (BFI, PROMIS Fatigue), SF-36 
13.5 
Description of Statistical Analyses 
13.5.1 
General Considerations 
All analysis will be considered as exploratory analysis.  
At the time of unblinding of the MBGS205 study, ICON will also be unblinded to MBGS206 
treatment assignment. At this time analysis maybe conducted to support MBGS205 reporting. 
As all analysis will be considered exploratory there will be no adjustment for multiplicity.  
 


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The statistical evaluation will be performed by ICON using SAS®, Version 9.3 or later. Data 
will be analysed by either enumeration of subjects displaying distinctive characteristics 
within each treatment regimen or by descriptive statistical summaries such as means, SD, 
medians, and ranges for continuous measures. Categorical variables will be presented by the 
number of observations and absolute and relative (%) frequency. 
For efficacy data summary statistics (N, mean, SD, median minimum and maximum for 
continuous data, and N [%] for categorical data) will be presented at each visit. 
Similarly, changes from Baseline (or percentage change from Baseline if appropriate) will be 
summarised in a similar manner. 
The main population for efficacy analysis will be the ITT population. 
Unless stated otherwise, for subjects randomised to active treatment in Study MBGS205, 
change in the extension study MBGS206 will be measured against their Baseline assessments 
in Study MBGS205 for subjects randomised to placebo in Study MBGS205, unless stated 
otherwise, Baseline will be the last value prior to first dose of study medication in 
Study MBGS206. 
Data in summary tables will generally be presented on an Observed Cases basis. 
The analysis of the primary safety endpoint will be 1-sided test conducted at the 2.5% 
significance level. Unless stated otherwise, all other statistical tests will be 2-sided and 
conducted at the 5% level, and all quoted CIs will be 2-sided 95% CIs. All 3 treatment arms 
will be assessed by pairwise comparisons made. 
Full details of the statistical analysis will be given in a statistical analysis plan (SAP). 
13.5.2 
Analysis of Primary Endpoint 
The percentage change from Baseline in lumbar bone mineral density measured in g/cm2 by 
DEXA will be summarised by dose group and visit. A single sample 1-sided t-test conducted 
at the 2.5% significance level will be used to analyse percentage change from Baseline 
(MBGS205) at Week 48 (MBGS206) in each treatment arm to test the null hypothesis that 
the percentage decrease from Baseline is ≤ 3%. Only subjects that have a post-Baseline  
DEXA assessment in MBGS206 will be included in this analysis. 
The primary analysis will be performed using the safety population. 
13.5.3 
Analysis of Secondary Endpoints 
13.5.3.1 
Safety 
The analysis of secondary safety endpoints will be performed using the safety population. 
The percentage change from Baseline in hip bone mineral density measured in g/cm2 by 
DEXA will be summarised by treatment arm and visit. A single sample 1-sided t-test 
conducted at the 2.5% significance level will be used to analysis percentage change from 
Baseline (MBGS205) at Week 48 (MBGS206) in each treatment arm to test the null 
hypothesis that the percentage decrease from Baseline is ≤ 3%. Only subjects that have a 
post-Baseline DEXA assessment in MBGS206 will be included in this analysis. 


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The percentage change from Baseline in bone turnover markers, bone density, bone 
biomarkers and oestradiol (absolute and percentage) will be summarised by treatment arm 
and visit. A 95% CI will be presented for the mean change at each visit.  
The proportion of subject with a T-score ≤ -2.5 at Week 48 will be summarised by treatment 
arm and visit. A 95% CI will be presented for the proportion of subjects with a T-score 
≤ -2.5.  
The proportion of subjects with testosterone ≤ 1000 ng/dl (35 nmol/L) and > 1000 ng/dl 
(35 nmol/L) will be summarised by treatment arm and visit. 
TEAEs will be summarised per Section 13.5.5. For subjects randomised to active treatment in 
Study MBGS205 first dose is considered as the first dose in Study MBGS205. For subjects 
randomised to placebo in Study MBGS205 first dose is considered as the first dose in 
Study MBGS206. 
A more detailed description will be presented in the SAP. 
13.5.3.2 
Efficacy 
The analysis of the secondary efficacy endpoints will be performed using the ITT population.   
The proportion of subjects that have normalisation of testosterone at Week 48 will be 
summarised by treatment arm and visit. For each treatment arm an exact 2-sided binomial test 
conducted at the 5% significance level will be performed to test the null hypothesis that the 
proportion of normalised subjects is ≤ 75%. An alternative way of expressing this is that the 
null hypothesis will be rejected for a treatment group and the endpoint considered met if the 
lower bound of the 2-sided 95% CI for the proportion of subjects with testosterone 
normalisation is greater than 75%. 
The change from Baseline in total and bioavailable testosterone, LH, and FSH will be 
summarised by treatment arm and visit. A single sample 2-sided t-test conducted at the 5% 
significance level will be used to analyse the percentage change from Baseline at Week 48 
within each treatment arm. 
For subjects randomised to placebo in Study MBGS205, unless otherwise stated, the 
Extension Study Baseline (Week 24) will be used for analysis of efficacy endpoints to Week 
48. 
A more detailed description will be presented in the SAP. 
13.5.3.3 
Pharmacokinetics 
EOT and FU semen concentration of BGS649 will be summarised by dose group. 
13.5.4 
Analysis of Exploratory Endpoints 
The analysis of exploratory endpoints will be performed on the ITT population. 
Data will be summarised by treatment arm and visit. 
For each continuous parameter, the change from Baseline will be summarised by treatment 
arm and visit. A single sample 2-sided t-test conducted at the 5% significance level will be 


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used to analyse the change from Baseline at Week 48 within each treatment arm. In addition, 
the change from Baseline will be assessed with a mixed model repeated measure analysis, 
with treatment dose as a factor and the Baseline value as a covariate. The adjusted mean 
difference between treatment doses will be presented along with a 95% CI for the time-points 
of interest. 
For binary outcomes the proportion of subjects with a response will be summarised and 
compared between treatment regimens using Fisher’s Exact Test. 
Associations between changes in PROs and changes in body composition, physical activity, 
sleep, and grip strength will be assessed with correlation coefficients and with separate linear 
regression models in which changes in PRO measure total or subscale scores will be taken as 
the predictor variable, and Baseline score as a covariate. The associations between changes in 
testosterone and changes in PROs, body composition, physical activity, grip strength, and 
sleep will be assessed in the same way. Correlation coefficients, Beta coefficients, standard 
errors, and 95% CIs will be presented. 
A more detailed description will be presented in the SAP. 
13.5.5 
Safety Analyses 
The analysis of safety parameters will be based on the safety population. In general, missing 
safety data will not be replaced. A more detailed description will be presented in the SAP. 
Adverse Events 
AEs will be coded using the most recent version available of the Medical Dictionary for 
Regulatory Activities (MedDRA). Summaries will be by system organ class and preferred 
term. TEAEs are defined as any AE occurring or worsening on or after the first dose of study 
medication. Further details of this will be provided in a SAP. If a subject experiences the 
same preferred term multiple times, then the event will be counted only once and by the 
greatest severity. 
The frequency and incidence of TEAEs will be presented by system organ class and preferred 
term for each treatment regimen (number and percentage of subjects experiencing at least 
1 AE per preferred term as well as the number of observed events per preferred term). 
Separate tables will be presented by severity and by relationship. All AEs will be presented in 
full in a comprehensive listing including subject number, treatment regimen, severity, 
seriousness, action taken, outcome, relationship to treatment, onset/stop, and duration. Details 
of SAEs and AEs leading to withdrawal will be listed separately. 
Concomitant Medication 
Concomitant medication will be tabulated and summarised by treatment regimen. 
Physical Examination 
Physical examination results will be listed by subject and body system. 
Vital Signs 


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Vital signs will be summarised as actual values and change from Baseline by treatment 
regimen and visit. 
ECG 
The overall ECG interpretation will be summarised by presenting the number and percentage 
of subjects with “Normal”, “Abnormal, not clinically significant”, and “Abnormal, clinically 
significant”. 
ECG parameter values (e.g., QTCF) will be summarised as actual values and change from 
Baseline by treatment regimen and visit to end of treatment. 
Clinical Laboratory 
Descriptive statistics will be presented for quantitative laboratory parameters for each 
treatment regimen and time-point. Similarly, changes from Baseline will be summarised. 
Values outside the normal range will be categorised as H (above the normal range) or 
L (below the normal range) based on the laboratory’s reference range and these will be 
flagged in the listings of individual subject data. 
Withdrawals 
Subjects who withdraw from the study will be summarised by treatment regimen according to 
their reason for withdrawal. 
13.5.6 
Analysis of Further Endpoints 
Demographic data and subjects’ characteristics at Screening in Study MBGS205 will be 
listed and summarised using descriptive statistics. Formal statistical analysis will not be 
performed on Baseline demographic data. 
Medical history will be coded using MedDRA. An incidence table by body system and 
preferred term will be presented by treatment regimen. 
Compliance with study medication will be summarised descriptively by treatment arm. 


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14 
DIRECT ACCESS TO SOURCE DATA/NOTES 
The investigator/institution shall provide direct access to source data/documents for 
study-related monitoring, audits, IEC/ IRB review and regulatory inspection. 
15 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 
Conduct of the Study 
ICON shall implement and maintain quality control and quality assurance procedures with 
written standard operating procedures to ensure that the study is conducted and data are 
generated, documented, and reported in compliance with the protocol, ICH GCP, and 
applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of 
Helsinki (October 1996) and all revisions thereof (See Appendix I), and in accordance with 
FDA regulations (CFR, Sections 312.50 and 312.56) and with ICH GCP (CPMP 135/95). 
The investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate IEC/IRB, except when necessary to 
eliminate immediate hazards to the subject or when the change(s) involve(s) only logistical or 
administrative aspects of the study. Any deviations may result in the subject having to be 
withdrawn from the study.   
15.2 
Study Monitoring 
The investigator shall permit the ICON Site Monitor to review study data as frequently as 
deemed necessary to ensure that data are being recorded in an adequate manner and that 
protocol adherence is satisfactory. 
The investigator will provide access to medical records for the Monitor in order that entries in 
the eCRF may be verified. The investigator, as part of his/her responsibilities, is expected to 
co-operate with ICON in ensuring that the study adheres to GCP requirements. 
The investigator may not recruit subjects into the study until such time that a visit, or with the 
agreement of the sponsor, attendance at the investigator meeting, has been made by a 
sponsor/ICON monitor to conduct a detailed review of the protocol and eCRF. 


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16 
ETHICS 
16.1 
Independent Ethics Committee/Institutional Review Board 
Prior to the start of the study, the investigator is responsible for ensuring that the protocol and 
consent form have been reviewed and approved by a relevant IEC/IRB. The IEC/IRB shall be 
appropriately constituted and perform its functions in accordance with FDA ICH GCP and 
local requirements as applicable. 
The IEC/IRB shall approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, subject recruitment 
procedures (e.g., advertisements), written information to be provided to the subjects, IB, 
available safety information, information about payment and compensation available to 
subjects, the investigator's curriculum vitae and/or other evidence of qualifications, and any 
other documents requested by the IEC/IRB and Regulatory Authority (Competent Authority) 
as applicable. 
16.2 
Written Informed Consent 
The nature and purpose of the study shall be fully explained to each subject (or their legally 
responsible guardian). 
Written informed consent must be obtained from each subject (or guardian) prior to any study 
procedures being performed. The process of obtaining informed consent must be documented 
in the subject source documents. 
The consent documents to be used for the study shall include all the elements of informed 
consent in accordance with FDA, ICH GCP, and local requirements as applicable and be 
reviewed and approved by the appropriate IEC/IRB prior to use. 
16.3 
Data Monitoring Committee 
An independent, unblinded external DMC will periodically review accumulating safety data 
from MBGS205 and MBGS206. Full details of composition, operational aspects, and data to 
be reviewed and recommendation of the DMC will be provided in a separate DMC charter. 


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17 
DATA HANDLING AND RECORD KEEPING 
17.1 
Case Report Forms/Source Data Handling 
All required study data must be entered in the eCRF created for the study. This data 
collection tool is a validated EDC system that contains a system generated audit trail. Data 
required according to this protocol are recorded by investigational site personnel via data 
entry into the internet based EDC software system. The investigator shall ensure that all data 
from subject visits are promptly entered into the eCRFs in accordance with the specific 
instructions given. The investigator must sign each eCRF to verify the integrity of the data 
recorded. All internal ICON and external investigational site personnel seeking access to the 
eCRF are to do so according to the FDA guidance for industry on electronic source data in 
clinical investigations. At the end of the study all data captured electronically will be 
provided to the investigator on CD-ROM for archiving at the investigational site. 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to study start. If a central laboratory has been selected to 
conduct any or all tests, it is essential that all samples be analysed at that laboratory. 
The investigator must maintain source documents, such as laboratory reports, X-rays, ECGs, 
consultation reports, and complete medical history and physical examination reports. All 
information in the eCRF must be traceable to the source documents in the subject’s file. 
Data to be recorded directly on the eCRFs (i.e., no prior written or electronic record of data) 
and considered to be source data must be identified in the protocol. 
17.2 
Retention of Essential Documents 
The investigator/institution should maintain the study documents as specified in the ICH 
guidelines on GCP and as required by the applicable regulatory requirements. The 
investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and 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. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 


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18 
FINANCING AND INSURANCE 
The sponsor shall carry an insurance policy to cover compensation of subjects’ health injuries 
arising from the study. If a subject incurs a study-related injury, the subject may be treated 
(and other necessary measures taken) at the study site and/or another medical institution. If it 
is necessary to compensate for the treatment, the sponsor will cover the cost. The sponsor 
shall not impose on the subject the burden of proving the causal relation between the study 
and the injury. 
If any of the following is confirmed, the sponsor may refuse or restrict the payment of the 
compensation: 
1. A serious GCP or protocol deviation by the investigator or sub-investigator (except 
deviation medically necessary to avoid an immediate hazard to the study subjects) 
2. Intentional act or negligence on the part of the investigator or sub-investigator or 
malpractice thereby 
3. Injury caused by unlawful act or delinquency of a third party 
4. Injury caused by intentional act or negligence of the subject. 
If compensation becomes necessary for a study-related injury, the site will promptly notify 
the sponsor and will co-operate with the sponsor and its insurer (or their legal representatives) 
in their handling thereof. 
19 
PUBLICATION POLICY 
The sponsor shall retain the ownership of all data. When the study is complete the sponsor 
shall arrange the analysis and tabulation of data. A clinical study report shall then be 
prepared, which may be used for publication, presentation at scientific meetings, or 
submission to regulatory authorities. All proposed publications based on this study must be 
subject to the sponsor's approval requirements. 
The sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalisation of the study report, the results of this trial will be submitted for publication and/or 
posted in a publicly accessible database of clinical trial results. 


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20 
SIGNATURE OF INVESTIGATOR 
I agree to conduct the study outlined above in accordance with the terms and conditions of 
the protocol, ICH guidelines on GCP, and with applicable regulatory requirements. All 
information pertaining to the study shall be treated in a confidential manner. 
 
 
 
 
 
 
 
 
 
 
 
Date (day/month/year) 
 


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21 
REFERENCE LIST 
Bhatnagar AS, Häusler A, Schieweck K, et al (1990). Highly selective inhibition of estrogen 
biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem 
Molec Biol 37:1021–27. 
Burnett-Bowie SAM, McKay EA, Lee H, and Leder BZ (2009). Effects of Aromatase 
Inhibition on Bone Mineral Density and Bone Turnover in Older Men with Low Testosterone 
Levels. J Clin Endocrinol Metab, 94(12): 4785–4792. 
Cappelleri JC, Siegel RL, Osterloh IH, et al (2000). Relationship between patient 
self-assessment or erectile function and the erectile function domain of the International 
Index of Erectile Function. Urology, 56:477–481. 
de Boer H, Verschoor L, Ruinemans-Koerts J, et al (2005). Letrozole normalizes serum 
testosterone in severely obese men with hypogonadotropic hypogonadism. Diabetes Obes 
Metab, 7:211–215. 
Dias JP, Melvin D, Simonsick EM, et al (2016). Effects of aromatase inhibition vs. 
testosterone in older men with low testosterone: randomized-controlled trial. Andrology, 
4(1):33–40. 
Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al (2008). Effect of testosterone 
supplementation on functional mobility, cognition, and other parameters in older men: a 
randomized controlled trial. JAMA, 299(1):39–52. 
Finkelstein JS, Lee H, Leder BZ, et al (2016). Gonadal steroid-dependent effects on bone 
turnover and bone mineral density in men. J Clin Invest, 126(3):1114–11125. 
Flynn KE, Lin L, Cyranowski JM, et al (2013). Development of the NIH PROMIS ® Sexual 
Function and Satisfaction measures in patients with cancer. J Sex Med, 10(Suppl 1):43–52. 
Haider A, Gooren LJ, Padungtod P, and Saad F. Improvement of the metabolic syndrome and 
of non-alcoholic liver steatosis upon treatment of hypogonadal elderly men with parenteral 
testosterone undecanoate. Exp Clin Endocrinol Diabetes, 118(3):167–171. 
Hofstra J, Loves S, van Wageningen B, et al (2008). High prevalence of hypogonadotropic 
hypogonadism in men referred for obesity treatment. Neth J Med, 66:103–109. 
Investigator’s Brochure (IB). 
Kacker R, Conners W, Zade J, and Morgentaler A (2014). Bone mineral density and response 
to treatment in men younger than 50 years with testosterone deficiency and sexual 
dysfunction or infertility. J Urol, 191(4):1072–1076. 
Kapoor D, Aldred H, Clark S, et al (2006). Clinical and Biochemical Assessment of 
Hypogonadism in Men With Type 2 Diabetes. Diabetes Care, 30:911–917. 
Loves S, Ruinemans-Koerts J, and de Boer H (2008). Letrozole once a week normalizes 
serum testosterone in obesity-related male hypogonadism. Eur J Endocrinol, 158:741–747. 


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Matthews DR, Hosker JP, Rudenski AS, et al (1985). Homeostasis model assessment: insulin 
resistance and beta-cell function from fasting plasma glucose and insulin concentration in 
man. Diabetologia, 28:412–429. 
McHorney CA, Ware JE, Lu JFR, and Sherbourne CD. The MOS 36-Item Short-Form Health 
Survey (SF-36®): III. tests of data quality, scaling assumptions and reliability across diverse 
patient groups. Med Care1994, 32(4):40–66. 
Mendoza TR, Wang XS, Cleeland CS, et al (1999). The rapid assessment of fatigue severity 
in cancer patients: use of the Brief Fatigue Inventory. Cancer, 85(5):1186–1196. 
Mincey BA, Duh MS, Thomas SK, et al (2006). Risk of cancer treatment-associated bone 
loss and fractures among women with breast cancer receiving aromatase inhibitors. 
Clin Breast Cancer, 7(2):127–132. 
Perez EA and Weilbaecher K (2006). Aromatase inhibitors and bone loss. Oncology 
(Williston Park), 20(9):1029-139. 
Rosen RC, Riley A, Wagner G, et al (1997). The International Index of Erectile Function 
(IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology, 49:822–
830. 
Sinnesael M, Boonen S, Claessens F, et al (2011). Testosterone and the male skeleton: a dual 
mode of action. J Osteoporos, 2011:240328. 
Study CBGS649A2204 An open label dose finding study (part 1) followed by a parallel 
group, randomised, double blind study to evaluate the safety, tolerability and 
pharmacodynamics of 12 week BGS649 treatment (part 2) in obese, hypogonadotropic 
hypogonadal (OHH) men. 
Testosterone Replacement Therapy, 2014. Advisory Committee Industry Briefing Document. 
Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk 
Management Advisory Committee. 
Zhao LJ, Liu YJ, Liu PY, et al (2007). Relationship between obesity and osteoporosis. J Clin 
Endocrinol Metab, 92(5):1640–1646. 
 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS206 
 
 
 
Amended Protocol  Version 2.0, 28 Mar 2017 
 
Page 69 of 72 
 
22 
APPENDICES 
Appendix I:  World Medical Association Declaration of Helsinki, 2013 
 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS206 
 
 
 
Amended Protocol  Version 2.0, 28 Mar 2017 
 
Page 70 of 72 
 
 
 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS206 
 
 
 
Amended Protocol  Version 2.0, 28 Mar 2017 
 
Page 71 of 72 
 
 
 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS206 
 
 
 
Amended Protocol  Version 2.0, 28 Mar 2017 
 
Page 72 of 72 
 
 
Appendix II:  Patient Global Impression of Status items  
Three patient global impression items (physical function, mental function, and sex life) will 
be included to assess the subjects’ overall impression of their current health status and thus to 
evaluate the performance of the other PROs in this patient population.  
1. Overall, how much does your HH affect your physical function? Typical effects include 
low energy levels and difficulties in performing physical activities. 
a) Not at all 
b) A little bit 
c) Somewhat 
d) Quite a bit 
e) Very much 
2. Overall, how much does your HH affect your mental function? Typical effects include 
feelings of tiredness and problems with sleep, mood, and thoughts. 
a) Not at all 
b) A little bit 
c) Somewhat 
d) Quite a bit 
e) Very much 
3. Overall, how much does your HH affect your sex life? Typical effects include lack of 
sexual desire and erectile dysfunction. 
a) Not at all 
b) A little bit 
c) Somewhat 
d) Quite a bit 
e) Very much 
 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: MBGS206 
              Version: FINAL 1.0, Date: 20 November 2018
                                                                         Page 1 of 63
 
Protocol Title: 
A 6 month, double-blind safety extension study of MBGS205 
evaluating the effects of long term treatment with BGS649 on bone 
mineral density 
Protocol Number: 
MBGS206 
Protocol Version, Date 
Final V2.0, 28MAR2017 
ICON ID:  
3082/0023 
Document Version, Date: 
FINAL 1.0, 20 November 2018 
 
 
Prepared by: 
ICON Clinical Research Services 
 
On behalf of: 
Mereo BioPharma 2 Limited 
 
 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential.  
 
The recipients of the SAP must not disclose the confidential information 
contained within this document or any related information to other persons
without the permission of the sponsor. 
 
In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment which prevents unauthorized access to the document. 
 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
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Protocol Number: MBGS206 
              Version: FINAL 1.0, Date: 20 November 2018
                                                                         Page 2 of 63
 
 
 
Date  
(DDMMM YYYY) 
 
 
Date  
(DDMMMYYYY) 
 
 
 
 
 
 
 
Date  
(DDMMMYYYY) 
 
 




 
 
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SIGNATURE PAGE ....................................................................................................................... 2
REVISION HISTORY .................................................................................................................... 3
TABLE OF CONTENTS ................................................................................................................ 4
LIST OF ABBREVIATIONS ......................................................................................................... 5
1
INTRODUCTION ..................................................................................................................... 7
2
STUDY OBJECTIVES ............................................................................................................. 8
2.1
Primary objective(s) ......................................................................................................... 8
2.2
Secondary objective(s) ..................................................................................................... 8
2.3
Exploratory objective(s) ................................................................................................... 8
2.4
Safety objective(s) ............................................................................................................ 9
3
STUDY DESIGN .................................................................................................................... 10
3.1
General study design ...................................................................................................... 10
3.2
Randomisation and blinding ........................................................................................... 11
3.3
Study treatments and assessments .................................................................................. 12
4
STUDY ENDPOINTS ............................................................................................................. 15
4.1
Primary Endpoint ............................................................................................................ 15
4.2
Secondary Endpoints ...................................................................................................... 15
4.3
Exploratory endpoint(s) .................................................................................................. 17
5
SAMPLE SIZE AND POWER ............................................................................................... 18
6
ANALYSIS POPULATIONS ................................................................................................. 19
6.1
Intention-To-Treat population (ITT) .............................................................................. 19
6.2
Safety population (Safety) .............................................................................................. 19
6.3
PK population ................................................................................................................. 20
6.4
Other Populations Defined for Tables and Listings ....................................................... 20
6.5
Protocol Deviations/Violations and Exclusions from Analysis Sets .............................. 20
7
STATISTICAL CONSIDERATIONS AND ANALYSIS ...................................................... 21
7.1
Derived Variables ........................................................................................................... 21
7.2
Handling of missing data and outliers ............................................................................ 28
8
STATISTICAL METHODS.................................................................................................... 29
8.1
General statistical conventions ....................................................................................... 29
8.2
Subject disposition .......................................................................................................... 31
8.3
Protocol deviations ......................................................................................................... 31
8.4
Demographics and baseline characteristics .................................................................... 31
8.5
Extent of exposure .......................................................................................................... 32
8.6
Efficacy analyses ............................................................................................................ 33
8.7
Safety analyses ............................................................................................................... 39
8.8
Other analysis ................................................................................................................. 45
8.9
CSR ................................................................................................................................. 47
9
CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL ............................... 48
10 REFERENCES ........................................................................................................................ 49
11 APPENDICES ......................................................................................................................... 50
 
 


 
 
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The following abbreviations will be used within this SAP. 
 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BFI 
Brief Fatigue Inventory 
BMI 
Body mass Index 
BUN 
Blood Urea Nitrogen 
CDISC 
Clinical Data Interchange Standards Consortium 
CDS 
Clinical Data Services 
CRF 
Case Report Form 
CTx1
C-terminal telopeptide
DBP 
Diastolic blood pressure 
DEXA 
Dual Energy X-ray Absorptiometry 
DHT 
Dihydrotestosterone 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOT 
End of Treatment 
ET 
Early termination 
FSH 
Follicle Stimulating Hormone 
FT4  
Free thyroxine;  
HbA1c 
Glycosylated haemoglobin 
HDL 
High Density Lipoprotein 
HOMA-IR  
Homeostatic assessment of insulin resistance;  
hs-CRP 
High sensitivity C-reactive protein 
IIEF 
International index of erectile function; 
IRT  
Interactive Response Technology 
LDL 
Low Density Lipoprotein 
LH 
Luteinising hormone  
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMRC 
Modified Medical Research Council 
MMRM 
Mixed model repeated measure 
PGI-S 
Patient Global Impression of Status items 
PK 
pharmacokinetics 
P1NP  
Procollagen Type 1 N-Propeptide;  
PRO 
Patient reported outcomes 
PROMIS 
Patient-Reported Outcomes Measurement Information System, 
PROMIS SexFS 
PROMIS Sexual Function and Satisfaction 
PSA 
Prostate-specific antigen 
QoL 
Quality of life 
RBC 
Red Blood Cell 


 
 
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RR 
Respiratory Rate 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SHBG 
sex hormone binding globulin 
SI 
Standard International 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event  
TSH 
Thyroid Stimulating Hormone 
WBC 
White Blood Cell 
 


 
 
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1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations and data displays for study protocol MBGS206 Final V2.0 A 
6 month, double-blind safety extension study of MBGS205 evaluating the effects of long term 
treatment with BGS649 on bone mineral density
dated 28MAR2017. The table of contents and 
templates for the Tables, Figures and Listings (TFLs) will be produced in a separate document.  
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). 
The preparation of this SAP has been based on International Conference on Harmonisation (ICH) 
E9. 
All data analyses and generation of TFLs will be performed using SAS 9.4
 
Notes:  
This plan does not address the pharmacokinetic (PK) analyses for this study. These analyses will be 
described in a separate analysis plan and results from the PK modelling will be reported separately 
from the CSR. 
Throughout this document: 
 
medication (i.e does not include Placebo 
medication taken during study MBGS205. 
 
MBGS205 study medication refers to any medication (BGS649 or Placebo) taken during 
Study MBGS205 
 
MBGS206 study medication refers to any medication taken during Study MBGS206 
 
 
 
 


 
 
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2 
STUDY OBJECTIVES 
The study is designed to evaluate bone mineral density in subjects after 12 months exposure with 
BGS649 (6 months treatment during Study MBGS205 and 6 months treatment during Study 
MBGS206). The study will also collect additional BGS649 safety and efficacy data on subjects that 
were randomised to placebo in Study MBGS205 and have 6 months active drug exposure in Study 
MBGS206. 
2.1 
Primary objective(s) 
The primary objective is to evaluate the effect of 12 months treatment with BGS649 on bone 
mineral density (6 months treatment during Study MBGS205). 
2.2 
Secondary objective(s) 
The secondary objectives are: 
1. 
To follow the change of total testosterone, free and bioavailable testosterone, LH, and 
FSH over a total of 12 months administration of BGS649 in those on active treatment in 
Study MBGS205 and a total of 6 months administration of BGS649 on subjects that 
were switched from placebo treatment during Study MBGS205 
2. 
Evaluation of percentage of subjects with normalised testosterone after 12 months 
treatment with BGS649 in those on active treatment in Study MBGS205 and total of 6 
months administration of BGS649 on subjects that were on placebo treatment during 
Study MBGS205 
2.3 
Exploratory objective(s) 
The exploratory objectives are: 
1. 
To evaluate the effect of 12 months treatment with BGS649 (6 months treatment in 
Study MBGS205 and 6 months treatment in Study MBGS206) on: 
o 
Cardiometabolic parameters, body composition, physical activity, grip strength, 
and sleep pattern; and on sexual functioning, fatigue, and quality of life, assessed 
by patient reported outcomes (PROs) 
o 
The association between changes in PROs and changes in body composition, 
physical activity, grip strength, and sleep 
o 
The association between changes in testosterone and changes in cardiometabolic 
parameters, body composition, physical activity, grip strength, sleep, and PROs 
2. 
To evaluate the 6 month efficacy data on subjects on placebo arm in Study MBGS205 
treated with active study drug in Study MBGS206 (cardiometabolic parameters, body 
composition, physical activity, grip strength, sleep, and PROs). 


 
 
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2.4 
Safety objective(s) 
1. 
To evaluate the effect of BGS649 after 12 months period of treatment with active study 
drug (6 months treatment in Study MBGS205 and 6 months treatment in Study 
MBGS206) by dose group on: 
o 
Bone turnover biomarkers 
o 
Bone mineral density and bone biomarkers by vitamin D status (Baseline vitamin 
D from Study MBGS205) 
o 
Oestradiol levels 
o 
Testosterone outside upper limit of normal range 
o 
Prostate specific antigen  and haematocrit 
o 
Blood Pressure 
o 
Adverse events (AEs) 
2. 
To evaluate any association between changes in bone mineral density after 12 months 
treatment with BGS649 with end of treatment testosterone and oestradiol levels 
3. 
To collect safety data in subjects switching from placebo arm in Study MBGS205 and 
treated with 6 months active study drug in Study MBGS206 
 
 
 


 
 
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3 
STUDY DESIGN 
3.1 
General study design 
This is a 6 month, active treatment, extension study, open to subjects who have completed the full 
24 week treatment period in Study MBGS205 (a Phase IIb multicentre, double-blind, dose-ranging, 
randomised, placebo-controlled study evaluating safety and efficacy of BGS649 in male obese 
subjects with HH). 
Study participation will comprise of the Extension Study Baseline visit (Week 24 of Study 
MBGS205, where the Extension Study Baseline assessment will be performed on a same day as the 
EOT visit of Study MBGS205), 7 visits during the treatment period up to Week 48 (End of 
Treatment [EOT]), and a Follow-Up (FU) visit for safety performed at Week 60, 12 weeks after the 
Week 48/EOT visit. 
time schedule of regular planned dose), starting with the first dose being taken at the baseline visit. 
The capsules will be taken orally by the subject with water. Subjects receiving active doses of 
BGS649 in Study MBGS205 will continue with the same dose in Study MBGS206; this transfer 
will be handled by the interactive response technology (IRT) and the blind will be maintained. 
Subjects receiving placebo in Study MBGS205 will be re-randomised on a 1:1:1 basis to each of 
the active treatment arms: 
o 
BGS649
 
capsules) 
o 
BGS649 
 
o 
BGS649 
 
capsules). 
The planned interim analysis of MBGS205 determined that all active doses met efficacy and safety 
criteria and therefore all three doses
 were progressed into 
MBGS206. 
Enrolment will continue until 30 subjects from each of the previous active treatment arms in Study 
MBGS205 have entered this study. 
 
Figure 1: Study Flow Chart 


 
 
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DMC=Data Monitoring Committee;  
3.2 
Randomisation and blinding 
3.2.1 Randomisation 
Subjects receiving active doses of BGS649 in Study MBGS205 will continue with the same dose in 
Study MBGS206 and the blind will be maintained. Subjects receiving placebo in Study MBGS205 
will be randomised on a 1:1:1 basis to each of the active treatment arms. The IRT will assign a 
medication number to the subject, which will be used to link the subject to a treatment regimen and 
will specify a unique medication number on the label of investigational treatment to be dispensed 
to the subject. 
3.2.2 Blinding 
Subjects, investigational staff, persons performing the assessments and data analysts (with the 
exception of unblinded DMC staff/members) will remain blind to the identity of the treatments 
from the time of randomisation until completion of the 
randomisation phase of Study MBGS205.  In order to maintain the blind described above, 
testosterone, LH, FSH and estradiol measurements will be blinded to site and sponsor staff and 
monitoring will be performed by an independent unblinded physician. 
3.2.3 Unblinding 
Upon completion of the randomization phase of Study MBGS205 the blind will be broken and the 
primary efficacy analysis of Study MBGS205 completed. Given the study design, at this point the 
blind for MBGS206 will also be broken and the Sponsor and CRO personnel will be unblinded at 
the time of unblinding the MBBS205 study. However subjects, investigational staff, persons 
performing the assessments and data analysts (other than those described above) will remain blind 
to the identity of the treatments from the time of randomisation until after database lock. 
Emergency treatment code breaks should only be undertaken when it is essential to treat the subject 
safely and efficaciously. Emergency code breaks are performed using the IRT.  


 
 
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3.3 
Study treatments and assessments 
During the 24 week treatment period subjects in the BGS649 groups will take the required dose 
Subjects will receive 
three capsules per dose to deliver a total of 
 
 
 
Dose changes are not permitted during the treatment period. 
The maximum MBGS206 study duration from baseline to end of the safety follow-up period is 36 
weeks which yields to a maximum duration across both MBGS205 and MBGS206 of 60 weeks. 
A detailed description of procedures and assessments to be conducted during this study is 
summarised in the Schedule of Study Assessments in Table 1 below. 
 
Table 1: Schedule of Study Assessments 
 
 
 


 
 
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4 
STUDY ENDPOINTS 
4.1 
Primary Endpoint 
Percentage change in lumbar bone mineral density measured by DEXA (g/cm2) from Baseline in 
Study MBGS205 to Week 48 in Study MBGS206 by dose group in subjects randomised to active 
treatment. 
4.2 
Secondary Endpoints 
4.2.1 Secondary Safety Endpoints 
1. In subjects that were randomized to active treatment in Study MBGS205 by dose group: 
o 
Percentage change in hip (total and femoral neck) bone mineral density measured 
by DEXA (g/cm2) from Baseline in Study MBGS205 to Week 48 in Study 
MBGS206 
o 
Percentage change in bone turnover markers (C-terminal telopeptide [CTx1], 
osteocalcin, bone alkaline phosphatase, and procollagen type 1 N-propeptide 
[P1NP]) from Baseline in Study MBGS205 to Week 48 in Study MBGS206 
o 
Proportion of subjects with T-
-2.5 at Week 48 
o 
Percentage change in bone density and bone biomarkers adjusted for vitamin D 
deficiency from Baseline in Study MBGS205 to Week 48 in Study MBGS206 
o 
Change of oestradiol (absolute and percentage) from Baseline in Study 
MBGS205 to Week 48 
o 
Proportion of subjects that overshoot testosterone (total testosterone above 1000 
ng/dl [35 nmol/L], from first dose of study drug in Study MBGS205 until study 
completion) 
o 
Change in PSA from Baseline in Study MBGS205 to Week 48 in Study 
MBGS206 
o 
Change in haematocrit from Baseline in Study MBGS205 to Week 48 in Study 
MBGS206 
o 
Change in blood pressure (systolic and diastolic) Baseline in Study MBGS205 to 
Week 48 in Study MBGS206 
o 
Treatment emerged AE, SAE, and AESI (from first dose of study drug in Study 
MBGS205 until study completion) 
o 
Relationship between change in bone mineral density from Baseline in Study 
MBGS205 to Week 48 in Study MBGS206 and absolute levels of oestradiol and 
total testosterone at Week 48 in MBGS206 


 
 
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2. In subjects that were randomized to placebo in Study MBGS205 by dose group: 
o 
Percentage change in lumbar bone mineral density measured by DEXA (g/cm2) 
from Baseline in Study MBGS206 to Week 48 
o  
Percentage change in hip (total and femoral neck) bone mineral density measured 
by DEXA (g/cm2) from Baseline in Study MBGS206 to Week 48 
o 
Percentage change in bone turnover markers (CTx1, osteocalcin, bone alkaline 
phosphatase, and P1NP) from Baseline in Study MBGS206 to Week 48 
o 
Change of oestradiol (absolute and percentage) from Baseline in Study 
MBGS206 to Week 48 
o 
Proportion of subjects with T-
-2.5 at Week 48 of Study MBGS206 
o 
Proportion of subjects that overshoot testosterone (total testosterone above 1000 
ng/dl [35 nmol/L] from first dose of study drug in Study MBGS206 until study 
completion) 
o 
Change in PSA from Baseline in Study MBGS206 to Week 48 
o 
Change in haematocrit from Baseline in Study MBGS206 to Week 48 
o 
Change in blood pressure (systolic and diastolic) Baseline in Study MBGS206 to 
Week 48 
o 
Treatment emerged AE, SAE, and AESI (from first dose of study drug in Study 
MBGS206 until study completion). 
4.2.2 Secondary Efficacy Endpoints 
1. In subjects that were randomized to active treatment in Study MBGS205 by dose group: 
o 
Percentage of subjects that have normalisation of total testosterone at Week 48 in 
Study MBGS206 
o 
Change in total, free and bioavailable testosterone from Baseline in Study 
MBGS205 to Week 48 in Study MBGS206 
o 
Change of LH and FSH from Baseline in Study MBGS205 to Week 48 in Study 
MBGS206 
2. In subjects that were randomized to placebo in Study MBGS205 by dose group: 
o 
Percentage of subjects that have normalisation of total testosterone at Week 48 of 
Study MBGS206 
o 
Change in total, free and bioavailable testosterone from Extension Study Baseline 
to Week 48 in Study MBGS206 
o 
Change of LH and FSH from Extension Study Baseline to Week 48 in Study 


 
 
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MBGS206 
4.3 
Exploratory endpoint(s) 
1. In subjects that were randomized to active treatment in Study MBGS205 by dose group: 
o 
Change in exploratory parameters from Baseline in Study MBGS205 to Week 48 
in Study MBGS206 by dose group: 
o 
Body composition (weight, BMI, waist and hip circumference, and 
parameters measured by bio-impedance) 
o 
Markers of cardiometabolic disease (blood pressure, lipid profile, HbA1c, 
glucose and insulin, hs-CRP, and homeostatic assessment of insulin 
resistance [HOMA-IR]) 
o 
Physical activity, sleeping pattern, and strength (measured by wrist worn 
monitors and grip strength measurement) 
o 
Total and domain scores on PRO measures (Sexual function (IIEF, 
PROMIS SexSF), Energy/fatigue (BFI, PROMIS Fatigue), SF-36 
o 
The relationship between changes in PROs and changes in body composition, 
physical activity, grip strength, and sleep 
o 
The relationship between changes in testosterone and changes in cardiometabolic 
parameters, body composition, physical activity, grip strength, sleep, and PROs. 
2. In subjects that were randomized to placebo in Study MBGS205 by dose group: 
o 
Change in exploratory parameters from Baseline in Study MBGS206 to Week 48 
in Study MBGS206 by dose group: 
o 
Body composition (weight, BMI, waist and hip circumference, and 
parameters measured by bio-impedance) 
o 
Markers of cardiometabolic disease (blood pressure, lipid profile, HbA1c, 
glucose and insulin, hs-CRP, and homeostatic assessment of insulin 
resistance [HOMA-IR]) 
o 
Physical activity, sleeping pattern, and strength (measured by wrist worn 
monitors and grip strength measurement) 
o 
Total and domain scores on PRO measures (Sexual function (IIEF, 
PROMIS SexSF), Energy/fatigue (BFI, PROMIS Fatigue), SF-36 
 
 
 
 


 
 
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5 
SAMPLE SIZE AND POWER 
The statistical hypothesis is the percentage decrease from Baseline in MBGS205 to EOT in 
MBGS206 in lumbar bone mineral density measured in g/cm2 by DEXA within a dose group is 
greater than
: 
H1:   
The null hypothesis will be rejected for a dose group and the endpoint considered met if the lower 
bound of the 2-sided 95% confidence interval (CI) for the percentage decrease from Baseline in 
lumber spine is greater than 
. 
Assuming a 2-sided test at 
 significant level and a standard deviation (SD) of 
 g/cm2, to 
achieve 90% power N=
 subjects in each dose group would be needed to detect a
 decrease 
from Baseline in bone mineral density at 48 weeks. 
Enrolment will continue until 
 subjects from each of the previous active treatment arms in Study 
MBGS205 have entered this study. Subjects previously treated with placebo will be enrolled until 
target subject population is met in all active arms. 


 
 
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6 
ANALYSIS POPULATIONS 
All safety endpoints will be analysed using the safety population. All efficacy endpoints will be 
analysed using the intention to treat (ITT) population.  
Further safety and tolerability data will be analysed using the safety population. 
Pharmacokinetic data will be analysed using the PK population. 
6.1 
Intention-To-Treat population (ITT) 
The ITT population includes all subjects who: 
1. 
Are randomised, and 
2. 
Receive at least one dose of MBGS206 study medication, and 
3. 
Provide a baseline (see section 8.1.5 for full definition of baseline) primary endpoint 
safety value (lumbar spine) and at least 1 available evaluation of primary endpoint safety 
value (lumbar spine)  post- Baseline in MBGS206. 
Subjects will be analysed according to the treatment to which they were randomised. 
6.1.1 Modified Inention-To-Treat Population (MITT) 
The mITT population includes all subjects who are included in the ITT but were not enrolled from 
site 1156 
Subjects will be analysed according to the treatment to which they were randomised. 
6.2 
Safety population (Safety) 
The safety population includes all subjects who received at least one administration of MBGS206 
study medication. 
Subjects will be analysed according to the treatment actually received. Subjects who did not 
receive the treatment planned by the randomisation will be analysed according to the treatment 
received. 
6.2.1 Modified Safety Population (MSafety) 
The modified safety population includes all subjects who are included in the Safety Population but 
were not enrolled from site 1156. 
Subjects will be analysed according to the treatment actually received. Subjects who did not 
receive the treatment planned by the randomisation will be analysed according to the treatment 
received. 
6.3 
Completer Population (CP) 
The completer population includes all subjects in the safety population who completed the 
MBGS206 study and subsequently provided a Week 48 primary endpoint point assessment. 
Subjects will be analysed according to the treatment to which they received.  


 
 
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6.4 
PK population 
For the summary of semen concentration of BGS649, all subjects who received at least 1 
administration of MBGS206 study medication and have at least 1 quantifiable concentration will be 
included in the PK population. 
6.5 
Other Populations Defined for Tables and Listings 
For the purposes of tables and listings a further population will be utilized: 
 
Randomised population (all randomised subjects) 
6.6 
Protocol Deviations/Violations and Exclusions from Analysis Sets 
All violations and exclusions of subjects from analysis populations will be identified and 
documented at the Classification Meeting prior to study unblindin
data will be conducted using (but not limited to) the following sources of information: 
 
Supportive subject listings, provided by the ICON ahead of the Classification Meeting, 
based on data recorded on the eCRF. 
 
Protocol Deviation Logs, retrieved from Clinical Trial Management System (CTMS). 


 
 
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7 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
7.1 
Derived Variables 
7.1.1 General Variables 
Study Day 
Study day will be relative to the date of first active study medication (Study Day 1, either from 
MBGS205 or MBGS206) and calculated as:  
 
(assessment date  date of first dose of active study medication) + 1, for assessments on or 
after the date of first dose of active study medication date 
 
(assessment date  date of first dose of active study medication), for assessments prior to 
date of first dose of active study medication 
Follow-up time 
Follow-up time (days) will be calculated as:  
(date of last contact - date of first dose of MBGS206 study medication) + 1 
7.1.2 Definitions relative to demographic and other baseline characteristics 
Age 
Age at informed consent will be calculated as:  
Age (years) = (date of informed consent of MBGS205 - date of birth + 1) / 365.25 
Weight, height and BMI 
Weight, recorded in pounds on the eCRF, will be converted in kilograms (1 pound = 0.45359 kg). 
Height, recorded in inches on the eCRF, will be converted in centimeters (1 inch = 2.54 cm) 
(International System of Units). 
Body mass index (BMI) will be calculated in kg/m2 as: weight (kg)/(height (m))2. 
Temperature 
Temperature, recorded in Fahrenheit degrees on the eCRF, will be converted in Celsius degrees: 
Celsius degrees = (Fahrenheit degrees - 32) x (5/9) 
HH disease duration 
Duration of HH disease will be calculated in years as: 
(date of informed consent of MBGS205  date of initial diagnosis of HH  + 1) / 365.25 
7.1.3 Definitions relative to efficacy criteria 
7.1.3.1 Total Testosterone 
Testosterone Normalisation 


 
 
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A subject is deemed to have achieved testosterone normalisation if their total testosterone value is 
between 300-1000 ng/dL (10.4-35 nmol/L) inclusive.  
To allow for a potential 10-25% decrease in total testosterone that can occur due to diurnal 
variation in the afternoons (given current testing is restricted to mornings), a stricter secondary 
definition of normalisation will be used. A subject is deemed to have achieved the secondary 
definition of testosterone normalisation if their total testosterone value is between 350-1170 ng/dL 
(12.15-40.6 nmol/L) inclusive. The secondary definition boundaries were derived by averaging the 
testosterone value that a 25% decrease in would result in the primary definition boundary with the 
primary definition boundary itself.  
Testosterone Overshoot 
A subject is deemed to have testosterone overshoot if their total testosterone value is greater than 
1000 ng/dL (35 nmol/L). 
7.1.3.2 Body Composition 
Gynecomastia 
The size of glandular breast tissue, recorded in inches on the eCRF, will be converted in 
centimeters (1 inch = 2.54 cm). 
7.1.3.3 International Index of Erectile Function (IIEF) 
The IIEF is a 15-item self-administered questionnaire with each question being scored between 0-5 
(see Appendix A - International Index of Erectile Function (IIEF)for scoring conversion). 
Five sexual function domains will be derived by summing the scores of the associated questions 
(noted in parentheses below): 
1. Erectile function (1,2,3,4,5,15) 
2. Orgasmic Function (9,10) 
3. Sexual Desire (11,12) 
4. Intercourse Satisfaction (6,7,8) 
5. Overall Satisfaction (13,14) 
If at least one of the questions within a domain is missing then the domain will not be calculated. A 
higher score denotes a higher level of satisfaction/function 
In addition the erectile function domain scores will be classified into the below severity categories: 
 No Dysfunction (25-30) 
 Mild (22-24) 
 Moderate (11-21) 
 Severe (1-10) 


 
 
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The minimal meaningful difference in the change from baseline in the erectile function domain 
score is defined as a change in 2 points for subjects who are mild at baseline, 5 points for subjects 
who are moderate at baseline and 7 points for subjects who are severe at baseline.    
7.1.3.4 Patient-
 
The PROMIS SexFS PRO measure will be utilized by collecting a 10 item self-administered 
questionnaire compiled from relevant items in the PROMIS Sexual Function and Satisfaction 
domains (Flynn et al., 2013). Each question is scored between 0 and 5 (See Appendix B - 
Patient-
for scoring conversion) and three sexual 
function domains will be derived by summing the scores of the associated questions (noted in 
parentheses below) and converting to a standardised T-score (standardised to a scale with mean 50 
and Standard Deviation 10  See Appendix B for conversion tables): 
1. Interest in Sexual Activity (1,2) 
2. Erectile Function (3) 
3. Satisfaction with Sex Life (4,5,6,7,8) 
If at least one of the questions within a domain is missing then the domain will not be calculated. In 
addition if a subject answers any question within a domain with a score of 0 (indicating the subject 
has not had the item in question) then the domain will also not be calculated. 
Questions 9 and 10 (Interfering Factors) will be summarized by raw score as no calibration is 
available for interfering factors. 
7.1.3.5 
 
The PROMIS Fatigue Short Form measure is an 8-item self-administered questionnaire assessing 
the extent of fatigue and its impact on work and functioning in the last 7 days. Each question is 
scored between 1 and 5 (See Appendix C - 
Formfor scoring 
conversion) and a total raw score will be calculated by summing the values of the response to each 
question. A standardised T-Score will then be calculated by standardizing the raw total score to a 
scale with mean 50 and SD 10 (See Appendix C - 
Formfor 
conversion tables). 
If between 1 and 4 items (inclusive) have a missing response then the raw total score will be 
estimated from the non-missing responses using the below formula: 
 
Total Raw Score =    Sum of scores of items answered x 8    
                                      Number of items answered  
 
If the result is a fraction, round up to the nearest whole number. If greater than 4 items have a 


 
 
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missing response then the total raw score will not be calculated  
7.1.3.6 Brief Fatigue Inventory (BFI) 
The BFI is an 9-item self-administered questionnaire, providing an assessment of the severity of 
. A 
global fatigue score is calculated by deriving the mean score of each of the non-missing questions. 
If more than 4 questions have a missing response, then the global fatigue score will not be 
calculated 
 
7.1.3.7 36-Item Short Form Health Survey (SF-36) 
The SF-36 questionnaire is a multidimensional instrument that evaluates quality of life. It measures 
8 general health concepts or domains: Vitality, Physical Functioning, Bodily Pain, General Health 
Perceptions, Physical Role Functioning, Emotional Role Functioning, Social Role Functioning and 
Mental Health. These domains will also be summarised as physical and mental component scores. 
Please see  
 


 
 
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Appendix D - 36-Item Short Form Health Survey (SF-36)for detailed scoring of each 
domain and component scores. 
 
7.1.3.8 Patient Global Impression of Status items (PGI-S) 
their current health status and thus to evaluate the performance of the other PROs in this patient 
population. Each response will be converted to a numeric score for summarising using the below 
conversions: 
 
Response 
Score
Not at all 
1 
A little bit 
2 
Somewhat 
3 
Quite a bit 
4 
Very much
5 
 
7.1.3.9 Actigraphy Derived Activity and Sleep Parameters 
The Autograph Link is a portable device that measures gross motor movements featuring a 
validated 3-axis accelerometer and data filtering technology that captures and records continuous, 
high resolution physical activity and sleep/wake information.  
Subjects are instructed to wear the monitor for 7 days consecutively starting with the day of the 
scheduled Visit 1 (if not collected as part of the EOT assessment for MBGS205), and Visit 7 
(EOT). Only data collected during the specified visit windows (See Appendix E  Actigraphy 
Visit Windows) on days were the device had been worn for >=1152 minutes (i.e 80% daily 
compliance) and deemed (either algorithmically or hardware detected by the device) to have been 
collected while the device was being worn will be used. All evaluable data within the specified 
visit window will be used to derive each parameter at each visit. However if there are less than 3 
collected within the window the parameter will be set to missing.    
Activity Parameters 
The average number of minutes spent per day within each activity category below will be 
calculated for each visit: 
 
Sedentary 
 
Light 


 
 
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Lifestyle 
 
Moderate 
 
Vigorous 
 
Very Vigorous 
 
MVPA (Moderate to Very Vigorous Physical Activity) 
In addition the average daily total number of steps and total activity counts (across all 3 axis) will 
be calculated as well as the maximum daily total activity count across each visit. 
Sleep Parameters 
The average length of awakenings (minutes), number of awakenings, number of minutes asleep 
(minutes), number of minutes awake (minutes) and proportion of time spent asleep during the sleep 
period will be calculated per day for each scheduled visit. Sleep periods starting before 5am will be 
assigned to the previous day. 
7.1.3.10 Grip Strength 
Grip strength assessment using a hand held dynamometer will be used as a surrogate measure of 
muscle strength. During this assessment, the subject will squeeze the device three times with each 
hand. An average (mean) of three measurements for each hand will be calculated at each visit. 
7.1.3.11 Metabolic syndrome (APP III) Definition  
A subject will be deemed as meeting the definition of metabolic syndrome if they meet 3 out of 5 
the below criteria at the same visit: 
 Waist Circumference >102cm (>40inches) 
 Triglycerides > 150mg/dl (>1.69 mmol/L) 
 HDL Cholesterol <40mg/dl (<1.036 mmol/L) 
 Blood pressure >130mmHg (systolic) or >85mmHg (diastolic) 
 Glucose >110 mg/dl (>6.11 mmol/L) 
7.1.4 Definitions relative to safety parameters 
7.1.4.1 Adverse Event (AE) 
Treatment Emergent Adverse Event (TEAE) 
A Treatment Emergent AE (TEAE) is defined as an AE occurring or worsening on or after the first 
dose of active study medication (from either MBGS205 or MBGS206).  
TEAEs will also be split between AEs that start during the subject s active treatment period (for 
and 
those that start on or after the first day of the MBGS206 follow-up period. A further category of 
TEAEs that started in MBGS206 but prior to the MBGS206 follow up period will also be utilised 
for summary tables (TEAEs started in MBGS205 would be excluded from this category).  


 
 
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Duration of AEs 
The duration of an AE will be calculated as the resolution date minus the start date plus 1. 
7.1.4.2 Treatment Compliance 
Duration of Exposure 
The duration of Exposure to active study medication over both MBGS205 and MBGS206 (number 
of days) will be defined as: 
(date of last dose of active study medication  date of first dose of active study medication) + 1 
The duration of Exposure to MBGS206 study medication (number of days) will be defined as: 
(date of last dose of MBGS206 study medication 
 date of first dose of MBGS206 study 
medication) + 1 
Treatment Compliance 
Overall (MBGS205 and MBGS206) active treatment compliance will be defined as: 
MBGS206 treatment compliance will be defined as: 
7.1.4.3 Prior, Concomitant and Follow-up Medications/Procedures 
Medications and Procedures will be assigned as being prior to active study medication, 
concomitant with active study treatment or taken during the follow-up phase based on the start and 
stop dates of the medication and dosing dates. 
If the medication/procedure stop date is before the date of the first active study medication (for 
subjects randomised to Placebo in MBGS205, this includes medication/procedures starting in study 
MBGS205), the medication/procedure will be assigned as being prior to active study medication. 
Otherwise, the medication/procedure will be assigned as being concomitant with active study 
treatment (for subjects randomised to active in MBGS205, this includes medications/procedures 
starting in study MBGS205) unless the start date of the medication/procedure is after the 
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phase. 
In addition medications will be flagged as being concomitant during the MBGS206 treatment 
period (i.e medication started on or after the first dose of MBGS206 study medication but before 
the follow up period or was ongoing at MBGS206 baseline).   
7.1.4.4 Osteopenia and Osteoporosis 
DXA Scans assessments for each region (Spine and Hip) will be assigned into the below severity 
cateogories: 
 Normal: (T score >-1.0 ) 
 Osteopenia: (T Score between -1.0 and -2.5) 
 Osteoporosis: (T score < -2.5 or Z-Score (under 50 years) <-2.0) 
7.1.4.5 Potential 
 
bilirubin > 2 x ULN at the same visit. 
7.1.4.6 Estimate Glomerular Filtration Rate (eGFR) 
A derived calculation of eGFR will be calculated using the 4 variable Modification of Diet in Renal 
Disease (MDRD) equation (Lavey 1999 and 2000): 
 
eGFR (mL/min/1.73m2
-1.154 
-0.203 
 
 
 
This derivation will be used as a supporitve analysis to the eGFR as derived by the lab. 
7.2 
Handling of missing data and outliers 
7.2.1 Missing data analysis methods 
Unless specified, data in summary tables will be presented using Observed Case (OC) data and 
therefore no missing data will be imputed. 
For specified endpoints a last observation carried forward (LOCF) imputation will be utilised. In 
this approach subjects with a missing observed value at a visit will be imputed with the last non-
missing, post-baseline value. 
For each continuous exploratory endpoint, the change from Baseline will be assessed with a mixed 
model repeated measure (MMRM) analysis.  
For data listings, unless specified, all data will be presented as they have been recorded (e.g. 
missing and partial dates will not be replaced). 


 
 
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7.2.2 Handling of missing or incomplete data 
7.2.2.1 Partial dates of first HH diagnosis 
In order to calculate the HH disease duration (i.e. time since first HH diagnosis), the following 
rules will be applied for partial dates for first diagnosis of HH: 
 
if the day of the month is missing it is imputed to be the 15th 
 
if both the day and month are missing, they are imputed to be June 30th 
 
missing years will be left as missing. 
The above will be flagged and described as a footnote in the appropriate listings. 
7.2.2.2 Missing items within Questionnaire data 
The method of handling missing data for each questionnaire 
recommendation. Details can be found in Section 7.1.3. 
7.2.2.3 Missing or incomplete concomitant medication dates 
Should the start date for a medication/procedure be missing or incomplete to the extent that it could 
be before or after the time of start of MBGS206 study medication, then it will be assumed that the 
medication/procedure began after the start of MBGS206 study medication (i.e. reported as 
concomitant medication/procedure). Similarly, if it is not clear whether the medication/procedure 
start date was on or before, or after the Visit 7 date, then it will be assumed the 
medication/procedure began on or before the Visit 7 date (i.e. reported as a concomitant 
medication/procedure) (worst case approach). 
7.2.2.4 Definition of treatment-emergent AEs and handling of missing or 
incomplete dates 
In the event of an incomplete onset date, the event will be considered to be treatment-emergent 
unless the partial onset date information or complete or partial end date confirms onset or end prior 
to the first dose of active study medication date. 


 
 
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8 
STATISTICAL METHODS 
8.1 
General statistical conventions 
All statistical procedures will be completed using SAS version 9.4 or higher. 
8.1.1 Populations for analysis 
Demographic and baseline characteristics will be summarised by Safety, Completers and ITT 
populations, unless otherwise stated. 
Analyses of the primary endpoint and secondary safety BMD endpoints will be performed on ITT 
and completer population. Analysis of all other safety endpoints will use the safety population. 
The secondary efficacy endpoints and exploratory endpoints will be analysed using the ITT 
population. 
The safety and tolerability variables will be analysed using the Safety population. 
PK data will be analysed using the PK population. 
8.1.2 Treatment groups 
Statistics will be displayed for the following treatment regimens in the below order: 
 
BGS649 
  
 
BGS649 
  
 
BGS649
  
 
Active Total (Includes all continuous active groups where applicable) 
 
Placebo -> BGS649 
  
 
Placebo -> BGS649 
  
 
Placebo -> BGS649 
  
 
Plabebo-> Active Total (Includes all Placebo-> Active Groups where applicable) 
 
Overall Total (Includes all groups where applicable) 
8.1.3 Descriptive statistics 
Continuous variables will be summarised using descriptive statistics including number of non-
missing observations (n), arithmetic mean (Mean), median (Median), standard deviation (SD), 
minimum value (Min) , maximum value (Max) and number of missing observations (if any). One 
additional decimal point for mean and median and 2 additional decimal points for SD will be used.  
For categorical variables, summaries will include the number of non-missing observations (n) or 
the number of patients in the population (N) as applicable, the counts of subjects and percentages. 
Percentages will be rounded to one decimal place. The number of missing values will be presented 
as a separate category with no percentage, but only if any missing value is recorded in the data for 
that summary. 
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collected. 
8.1.4 Statistical significance 
Unless otherwise stated, all statistical testing will be two-sided and conducted at the significance 
(alpha) level of 0.05. Two-sided 95% confidence intervals (CIs) will be provided when relevant. 
Treatment regimens will be assessed by pairwise comparisons, and no adjustment for multiplicity 
will be made. 
8.1.5 Definition of Baseline 
For summary purposes, the baseline value is defined as the last non-missing value collected on or 
before the first active study treatment administration (from either Study MBGS205 or MBGS206). 
Therefore subjects randomised to active treatment in Study MBGS205, baseline will be the last 
value prior to first dose of study medication in Study MBGS205. For subjects randomised to 
placebo in Study MBGS205, baseline will be the last value prior to first dose of study medication 
in Study MBGS206 (expected to be from the MBGS206 baseline visit)..    
Change from Baseline is defined as (value at assessment date  baseline value). 
For DXA parameters, assessments at MBGS205 baseline can be taken up to 8 days after the 
Baseline Visit. As such baseline will be defined as the last non-missing value collected up to 8 days 
post the date of first dose of study medication for subjects randomised to active treatment in Study 
MBGS205). 
For selected renal parameters change from MBGS205 Screening and Baseline will be calculated. 
Change from Screening will be defined as (value at assessment date  screening value), where the 
screening value is defined as the last non-missing value collected at a Screening Visit (Day -28 to 
Day -1). 
8.1.6 Data re-allocation 
The following general rules to handle repeated assessments will be considered: 
 
12-lead ECG: 
 in case of multiple measurements associated to the same timepoint (e.g. triplicate 
ECGs), the average value will be considered for all post baseline HR, RR interval, 
PR interval, QRS duration, QT interval, QTcB interval and QTcF interval. 
8.1.7 Data listings 
All relevant subject data collected during the MBGS206 study, including those derived will be 
presented in individual subject data listings. Selected data from study MBGS205 will also be 
presented to aid in interpretation (e.g MBGS205 baseline)  All listings will be sorted by treatment 
regimen, investigational site, subject number, date/time and visit. The 
 age will be stated 
on each listing. Unless otherwise stated, data listings will be based on all subjects randomised. 
Unscheduled visit results will be included in date/time chronological order within subject listings, 
but will not be tabulated. 


 
 
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8.2 
Subject disposition 
All subjects who entered the extension study will be included in a summary of subject 
accountability. The number of subjects entering the extension study, the frequency and percentage 
of subjects randomised, in the Safety population, in the ITT population and in the PK population 
will be summarised by treatment regimen and overall.  
Subject disposition information will be summarised by treatment regimen and overall. The number 
of subjects completing and withdrawing from the treatment period (up to and including Visit 7) and 
the number of subjects completing and withdrawing from the study will be tabulated. Reasons for 
treatment discontinuation and discontinuation from the study will also be presented.  
The follow-up time will be summarised descriptively.  
8.3 
Protocol deviations 
The number of subjects excluded from ITT, Safety and PK populations and reasons for exclusion 
will be summarised by treatment regimen and overall. 
All protocol deviations identified during MBGS206 will be summarised descriptively by treatment 
regimen and overall. 
Summaries will be conducted on all subjects that were randomised  
8.4 
Demographics and baseline characteristics 
No formal comparison between treatment regimens on demographics and baseline characteristics 
will be conducted. 
8.4.1 Demographics 
Demographic variables captured at the start of study MBGS205 will be listed and summarised for 
subjects entering the extension study by treatment regimen and overall. This will include age, sex, 
race, weight, height and BMI. Separate summaries will be produced using the Safety and ITT 
populations. 
8.4.2 Baseline and disease characteristics 
Duration of HH disease (years) and the number of subjects receiving previous treatment and each 
item on the Androgen Deficiency Symptom Checklist captured at the start of study MBGS205 will 
be summarised descriptively by treatment regimen and overall. 
Total testosterone at initial diagnosis, first and second screening visits and the average testosterone 
over the first and second screening visits from study MBGS205 will be tabulated.  
In addition baseline total testosterone (absolute values and number of subjects above and below 
200 ng/dl), free testosterone (absolute values and number of subjects above and below 47 pg/mL), 
bioavailable testosterone (absolute values and number of subjects above and below 130 ng/dl), 
oestradiol, DHT, inhibin A, inhibin B, HBA1c, sex hormone binding globulin (SHBG), fasting 
lipid profile (total cholesterol, low density lipoprotein [LDL], triglycerides and HDL), Vitamin D, 


 
 
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IIEF domain scores, IIEF erectile function domain severity and PROMIS sexFS domains will be  
summarised descriptively by treatment regimen and overall.   
All Summaries will be produced using the Safety Population and ITT Population. 
8.4.3 Medical history  
A summary of all medical history captured from Study MBGS205 will be presented by Medical 
History Code (as per CRF), system organ class (SOC) and preferred term (PT), by treatment 
regimen and overall 
Version 19.1 or 
higher.  
In addition the number of subjects with an MRI of pituitary performed, the MRI finding (Normal, 
Abnormal NCS or Abnormal CS) and the number of subjects who have had a vasectomy will be 
summarised. 
All Summaries will be produced using the Safety Population. 
8.4.4 Prior, Concomitant and Follow-up medications 
All medications (taken across both MBGS205 and MBGS206) will be coded using the World 
Health Organization (WHO) Drug Dictionary (March 2016 or later) and will be summarised by 
Anatomical Therapeutic Chemical (ATC) classification level 4 and Preferred Name by treatment 
regimen and overall for the Safety population. 
Summaries of Prior medications to active study medication, concomitant to active study medication 
(i.e across both MBGS205 and MBGS206), concomitant to MBGS206 study medication and 
follow-up medications will be presented. 
8.4.5 Concomitant Procedures 
Concomitant procedures to active study medication (i.e across both MBGS205 and MBGS206) and 
concomitant procedures to MBGS206 study medication will be summarised by Procedure Name, 
treatment regimen and overall for the Safety population. 
8.5 
Extent of exposure 
8.5.1 Treatment duration 
Duration of treatment (in days) for active study medication and just MBGS206 study medication 
will be categorised in intervals and summarised descriptively by treatment regimen on the Safety 
population using descriptive statistics. 
8.5.2 Treatment compliance 
The overall treatment compliance (in %) of active study medication and just MBGS206 study 
medication will be presented by treatment regimen using the Safety population. The number of 
subjects with overall compliance <80% or >120% will be presented. 


 
 
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8.6 
Efficacy analyses 
This section addresses the analyses to be conducted on the secondary and exploratory efficacy 
endpoints. 
All definitions relative to efficacy and exploratory endpoints are detailed in Section 7.1.3. 
Analyses will be conducted separately for subjects that were randomised to active treatment and 
subjects that were randomised to placebo treatment in study MBGS205. 
8.6.1 Analysis methods 
For binary outcomes the proportion of subjects with a response will be summarised and compared 
  
For continuous parameters, the change from baseline will be summarised by treatment arm and 
visit. A single sample 2-sided t-test conducted at the 5% significance level will be used to analyse 
the change from baseline to Week 48 within each treatment arm. In addition, the change from 
baseline will be assessed with a mixed model repeated measure (MMRM) analysis. Analyses will 
include the fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well 
as the continuous, fixed covariates of the associated baseline value and baseline-by-visit 
interaction. An unstructured covariance matrix will be used to model the within-subject errors.  If 
the model with the unstructured covariance matrix fails to converge, other covariance structures, 
including Toeplitz, compound symmetry, and spatial power, will be considered. The denominator 
degrees of freedom will be calculated according to the Kenward-Roger method. Significance tests 
for treatment differences will be based on least-squares means.  
Associations between changes in PROs and changes in body composition, physical activity, sleep, 
and grip strength will be assessed with correlation coefficients and with separate linear regression 
models in which changes in PRO measure total or subscale scores will be taken as the predictor 
variable, and baseline score as a covariate. The associations between changes in testosterone and 
changes in PROs, body composition, physical activity, grip strength, and sleep will be assessed in 
the same way. Correlation coefficients, Beta coefficients, standard errors, and 95% CIs will be 
presented. 
8.6.1.1 Multiplicity 
Treatment regimens will be assessed by pairwise comparisons. No adjustment will be made for 
multiple comparisons and all analyses are considered exploratory. 
8.6.1.2 Treatment by centre interaction analysis (multi-centre study) 
No analysis will be made to assess the treatment-by-centre interaction. 
8.6.2 Analysis of primary endpoint 
The Primary Endpoint is defined as the change in lumbar bone density measured by DEXA from 
baseline in Study MBGS205 to Week 48 in Study MBGS206 by dose group in subjects randomised 
to active treatment in Study MBGS205. 


 
 
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DXA Scan assessments will only be performed at the EOT visit (for subjects that reached at least 
Week 36) and will be over-read by IMI. The DEXA over-read data will be used for the primary 
endpoint statistical analysis.  
Descriptive statistics (observed values, changes from baseline and percentage change from 
baseline) in lumbar bone mineral density will be presented for each treatment regimen and time-
point. A single sample 1-sided t-test conducted at the 2.5% significance level will be used to 
analyse percentage change from Baseline (MBGS205) to Week 48 (MBGS206) LOCF in each 
-
values and associated CI will be presented.  
Only subjects included in the safety population that have a post-Baseline DEXA assessment in 
MBGS206 and were randomised to active treatment in Study MBGS205 will be included in this 
analysis. The anlysis will be repeated for subjects included in the completer population.  
Observed and percentage change from baseline values at each visit will be presented in a line graph 
by treatment group. 
8.6.3 Analysis of secondary efficacy endpoint(s) 
All analysis of secondary efficacy endpoints will be performed on the ITT population. 
8.6.3.1 Testosterone Normalisation (Primary Definition) 
The number and proportion of subjects with normal testosterone levels (testosterone value is 
between 300-1000 ng/dL inclusive) will be summarised by treatment regimen at each visit using 
the total testosterone assessed by ICON central lab. Observed values and LOCF values will be 
presented. In addition, a P-value for the comparison between each dose will be provided using 
 
8.6.3.2 Testosterone Normalisation (Secondary Definition) 
The secondary definition of testosterone normalisation (350-1170 ng/dL inclusive) that allows a 
decrease in total testosterone due to diurnal variation will be analysed in the same manner as 
primary definition of testosterone normalisation.  
8.6.3.3 Change from Baseline in Total Testosterone 
A descriptive summary table will be presented for Total Testosterone values and percentage change 
from baseline in Total Testosterone values by treatment regimen and visit using both ICON central 
lab assessed testosterone. 
A single sample 2-sided t-test conducted at the 5% significance level will be used to analyse the 
percentage change from Baseline at Week 48 within each treatment arm. The p-value and 
associated confidence internal will be presented. 
In addition the percentage change from baseline in Total Testosterone up to Week 48 for subjects 
randomised to active in Study MBGS206 using the ICON central lab assessed values will be 
analysed using an MMRM model as described in Section 8.6.1. Least squares means and standard 


 
 
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errors will be presented for each visit, p-value and 2-sided 95% confidence interval for treatment 
differences will be presented for each visit. Significance tests will be based on least-squares means 
using a two-
   
A figure presenting the least square mean change from baseline in total testosterone at each visit by 
treatment regimen will also be provided. 
The above analyses will be repeated for subjects that were randomised to placebo in Study 
MBGS205 by analysing the change from MBGS206 baseline (Week 24) to Week 48.   
8.6.3.4 Proportion of subjects that Overshoot Testosterone 
The number and proportion of subjects that overshoot testosterone (total testosterone above 1000 
ng/dL [35 nmol/L]) at each visit and at least once during the study will be summarised similar to 
that of Testosterone normalisation. 
In addition the number and proportion of subjects whose maximum testosterone value falls into 
each of the below categories will be presented by visit and overall during the study: 
 
>1000 - <=1500ng/dl 
 
>1500  <1800 ng/dL 
 
=>1800 - <= 2500 ng/dL 
 
>2500 ng/dL 
8.6.3.5 Change from Baseline in Free and Bioavailable Testosterone 
Descriptive summary tables will be presented for Free and Bioavailable Testosterone values and 
change from baseline in Free and Bioavailable Testosterone by treatment regimen and visit. 
The change from baseline in Free and Bioavailable Testosterone will be analysed in the same 
manner as the change from baseline in total testosterone for subjects that were randomised to active 
treatment in study MBGS205 (see Section 8.6.3.3). For subjects that were randomised to placebo in 
study MBGS205, the change from baseline will be analysed using an ANCOVA model with 
treatment as a fixed effect and baseline value as a covariate. Least squares means and standard 
errors will be presented for each visit, p-value and 2-sided 95% confidence interval for treatment 
differences across all doses will be presented for each visit. Significance tests will be based on 
least-squares means using a two-
 
8.6.3.6 Change in LH and FSH 
Descriptive summary tables will be presented for LH and FSH values and change from baseline in 
LH and FSH by treatment regimen and visit. 
The change from baseline in LH and FSH up to Week 48 will be analysed in the same manner as 
the change from baseline in bioavailable testosterone (see Section 8.6.3.5). Analyses will be 
conducted separately for subjects that were randomised to active treatment (MMRM analysis) and 
subjects that were randomised to placebo (ANCOVA analysis) in study MBGS205. 


 
 
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A figure presenting the least square mean change from baseline in LH and FSH at each visit by 
treatment regimen will also be provided. 
8.6.4 Analysis of exploratory endpoint(s) 
The analysis of exploratory endpoints will be performed on the ITT population. 
8.6.4.1 Change in Body composition 
Descriptive summary tables will be presented for Body Weight, BMI, Waist Measurement, Hip 
Measurement and Waist to Hip Ratio values and change from baseline values by treatment regimen 
and visit.  
The number and proportion of subjects with gynecomastia will be summarised by treatment 
regimen at each visit. A P-value for the comparison of the presence of gynecomastia between each 
 A descriptive summary 
table for the size of glandular breast tissue will be presented for those subjects with gynecomastia. 
The change from baseline in each parameter up to Week 48 will be analysed via t-test and MMRM 
in the same manner as the change from baseline in total testosterone (see Section 8.6.3.3). Analyses 
will be conducted separately for subjects that were randomised to active treatment and subjects that 
were randomised to placebo treatment in study MBGS205. 
Descriptive summary tables will be presented for all body composition bio impedance parameters 
[Total Fat (kg and percentage), Visceral adipose tissue, Total fat free mass (kg and percentage) and 
Skeletal muscle mass whole body, right arm, right leg, left arm, left leg and torso] values and 
change from baseline values by treatment regimen and visit. 
The change from baseline in each parameter up to Week 48 will be analysed via t-test and MMRM 
in the same manner as the change from baseline in total testosterone (see Section 8.6.3.3). Analyses 
will be conducted separately for subjects that were randomised to active treatment and subjects that 
were randomised to placebo treatment in study MBGS205. 
A subgroup analysis of body composition parameters by baseline total testosterone (<200ng/dL vs 
>=200ng/dL) as assessed by ICON central labs will be conducted. Descriptive summaries and 
analysis up to Week 48 as described above will be presented. 
8.6.4.2 Changes in Cardiometabolic Disease Markers 
Descriptive summary tables will be presented for blood pressure (systolic and diastolic blood 
pressure), fasting lipid profile (total cholesterol, low density lipoprotein [LDL], triglycerides and 
HDL), HbA1c, fasting glucose, fasting insulin, high sensitivity C reactive protein (hs CRP) and 
HOMA-IR values and change from baseline values by treatment regimen and visit. 
The change from baseline in each parameter up to Week 48 will be analysed via t-test and MMRM 
in the same manner as the change from baseline in total testosterone (see Section 8.6.3.3). Analyses 
will be conducted separately for subjects that were randomised to active treatment and subjects that 
were randomised to placebo treatment in study MBGS205. 


 
 
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Non-fasting values of all lipid profile parameters, glucose and insulin will be excluded from both 
the descriptive summary and analysis. 
In addition the number and proportion of subjects who met the definition of metabolic syndrome 
will be summarised by treatment regimen at each visit (baseline and post-baseline). 
8.6.4.3 Change in physical activity, sleeping pattern and strength 
Physical Activity 
Descriptive summary tables will be presented for the average number of minutes spent per day over 
within each activity category, total daily steps, total daily activity counts and maximum daily 
activity counts by treatment regimen and visit. The change from baseline in the average number of 
minutes spent in moderate to very vigorous activity, total daily steps and total activity counts to 
Week 48 will be analysed in the same manner as the change from baseline in bioavailable 
testosterone (see Section 8.6.3.5). Analyses will be conducted separately for subjects that were 
randomised to active treatment (MMRM analysis) and subjects that were randomised to placebo 
(ANCOVA analysis) in study MBGS205. 
Sleeping Pattern 
Descriptive summary tables will be presented for each sleeping pattern parameter (The average 
length of awakenings [minutes], number of awakenings, number of minutes asleep [minutes], 
number of minutes awake [minutes] and proportion of time spent asleep during the sleep period) 
and associated change from baseline by treatment regimen and visit. The change from baseline in 
each parameter to Week 48 will be analysed in the same manner as the change from baseline in 
bioavailable testosterone (see Section 8.6.3.5). Analyses will be conducted separately for subjects 
that were randomised to active treatment (MMRM analysis) and subjects that were randomised to 
placebo (ANCOVA analysis) in study MBGS205. 
Grip Strength 
A descriptive summary table will be presented for the average grip strength and associated change 
from baseline by treatment regimen and visit. The change from baseline in average grip strength to 
Week 48 will be analysed via MMRM in the same manner as the change from baseline in total 
testosterone (see Section 8.6.3.3). Analyses will be conducted separately for subjects that were 
randomised to active treatment and subjects that were randomised to placebo treatment in study 
MBGS205. 
A subgroup analysis of the change from baseline in grip strength by baseline total testosterone 
(<200ng/dL vs >=200ng/dL) as assessed by ICON central labs will be conducted. Descriptive 
summaries and analysis up to Week 48 as decribed above will be presented. 
8.6.4.4 Change in PRO measures  
For some PRO Measures (PROMIS SexFS, PROMIS Fatigue Short Form and PGI-S), not all 
MBGS205 protocol versions mandated their collection. Thus for subjects originally enrolled into 


 
 
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study MBGS205 using protocol version 2.0 MBGS206, baseline will be the first time these 
measures were collected. To handle such cases, these subjects will be excluded from the change 
from MBGS205 baseline to Week 48 analysis (if randomised to active treatment in Study 
MBGS205), however will still be included in the descriptive summary tables. 
IIEF 
Descriptive summary tables will be presented for each of the 5 sexual function domain scores 
(Erectile function, Orgasmic function, Sexual desire, Intercourse satisfaction and Overall 
satisfaction) and change from baseline scores by treatment regimen and visit. 
The change from baseline in each sexual function domain score to Week 48 will be analysed via 
MMRM in the same manner as the change from baseline in total testosterone (see Section 8.6.3.3), 
however 90% confidence intervals (instead of 95%) will be presented for all inferences. Analyses 
will be conducted separately for subjects that were randomised to active treatment and subjects that 
were randomised to placebo treatment in study MBGS205. A figure presenting the least square 
mean change from baseline in each sexual function domain at each visit by treatment regimen will 
also be provided. 
The number and proportion of subjects achieving a minimal  meaningful difference in the change 
in IIEF erectile function domain score will be summarised by treatment regimen at each visit and 
overall. 
In addition the change from baseline in the IIEF domains will also be summarised and analysed as 
described above by erectile function baseline severity (No dysfunction, mild, moderate and severe), 
baseline total testosterone (<200ng/dL vs >=200ng/dL) as assessed by ICON central labs and end 
of treatment total testosterone (<300ng/dL, 300-500 ng/dL and >500ng/dL) as assessed by ICON 
central labs. 
PROMIS SexFS 
Descriptive summary tables will be presented for each of the 3 sexual function domains scores 
(Interest in Sexual Activity, Erectile Function, Satisfaction with Sex Life) 2 interfering factors raw 
scores and change from baseline scores (domain and interfering factor raw scores) by treatment 
regimen and visit. 
The change from baseline in each sexual function domain score to Week 48 will be analysed via 
MMRM in the same manner as the change from baseline in IIEF domain scores including subgroup 
analysis by baseline total testosterone (<200ng/dL vs >=200ng/dL) and end of treatment total 
testosterone (<300ng/dL, 300-500 ng/dL and >500ng/dL) as assessed by ICON central labs. 
PROMIS Fatigue Short Form 
A descriptive summary table will be presented for the PROMIS Fatigue Short Form standardised 
T-Score and change from baseline score by treatment regimen and visit. 


 
 
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The change from baseline to Week 48 will be analysed via MMRM in the same manner as the 
change from baseline in IIEF domain scores including subgroup analysis by baseline total 
testosterone (<200ng/dL vs >=200ng/dL) and end of treatment total testosterone (<300ng/dL, 300-
500 ng/dL and >500ng/dL) as assessed by ICON central labs. 
BFI 
A descriptive summary table will be presented for the global fatigue score and change from 
baseline score by treatment regimen and visit. 
The change from baseline to Week 48 will be analysed via MMRM in the same manner as the 
change from baseline in IIEF domain scores including subgroup analysis by baseline total 
testosterone (<200ng/dL vs >=200ng/dL) and end of treatment total testosterone (<300ng/dL, 300-
500 ng/dL and >500ng/dL) as assessed by ICON central labs. 
SF-36 
Descriptive summary tables will be presented for each of the 8 general health domain scores and 2 
component scores and change from baseline scores by treatment regimen and visit. 
The change from baseline in each domain and component score to Week 48 will be analysed via 
MMRM in the same manner as the change from baseline in IIEF domain scores including subgroup 
analysis by baseline total testosterone (<200ng/dL vs >=200ng/dL) and end of treatment total 
testosterone (<300ng/dL, 300-500 ng/dL and >500ng/dL) as assessed by ICON central labs.  
PGI-S 
Descriptive summary tables will be presented for each of the 3 status items and associated change 
from baseline scores by treatment regimen and visit. 
The change from baseline in each status item to Week 48 will be analysed via MMRM in the same 
manner as the change from baseline in IIEF domain scores including subgroup analysis by baseline 
total testosterone (<200ng/dL vs >=200ng/dL) and end of treatment total testosterone (<300ng/dL, 
300-500 ng/dL and >500ng/dL) as assessed by ICON central labs. 
8.7 
Safety analyses 
All definitions relative to safety endpoints are detailed in Section 7.1.4. 
All safety analyses will be based on the Safety population and will be performed for all safety 
endpoints specified below. 
8.7.1 DXA Scans 
DXA Scan assessments will only be performed at the EOT visit (for subjects that reached at least 
Week 36) and will be over-read by IMI. Both the site assessed and the over-read data will be used 
for all statistical analysis and utilise the visit windows specified in Appendix F. If multiple 
assessments are recorded within the window, the closet to the target date will be used for analysis. 


 
 
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Descriptive statistics (observed values, changes from baseline and percentage change from 
baseline) in hip (total and femoral neck) bone density will be presented. In addition descriptive 
statistics (observed values and changes from baseline) for the associated T-scores in both the 
lumbar spine and hip will be presented for each treatment regimen and time-point. 
A shift table of baseline severity categories (Normal, Osteopenia and Osteoporosis) to post baseline 
severities will be generated by treatment regimen and visit.  
Change from baseline in bone density (in both the lumbar spine and hip) to Week 48 for subject 
randomised to active treatment in Study MBGS205 will analysed via MMRM in the same manner 
as the change from baseline in total testosterone (see Section 8.6.3.3).  
Change from baseline in bone density (in both the lumbar spine and hip) to Week 48 for subjects 
randomised to placebo in Study MBGS205 will be analysed using an ANCOVA model with 
treatment as a fixed effect and the associated baseline value as a covariate. Least squares means 
and standard errors will be presented for each visit, p-value and 2-sided 95% confidence interval 
for treatment differences across all doses will be presented for each visit. Significance tests will be 
based on least-squares means using a two-
 
In addition subgroup descriptive summary tables of change in bone density by subjects with and 
without 25 hydroxy vitamin D deficiency at baseline (vitamin D deficiency is defined as 25 
hydroxy vitamin D < 30ng/ml) will be presented.  
8.7.2 Bone turnover markers 
Descriptive summary tables will be presented for all bone turnover marker (C-terminal telopeptide 
[CTx1] and procollagen type 1 N-propeptide [P1NP], osteocalcin and bone alkaline phosphatase) 
values, change from baseline and percentage change from baseline by treatment regimen and visit. 
The change from baseline and percentage change from baseline in each parameter up to Week 48 
will be analysed via MMRM in the same manner as the change from baseline in total testosterone 
(see Section 8.6.3.3). Analyses will be conducted separately for subjects that were randomised to 
active treatment and subjects that were randomised to placebo treatment in study MBGS205. 
Line graphs of absolute bone turnover marker parameters will be provided by treatment regimen 
and boxplots of observed values by treatment and visit will be generated for all bone turnover 
markers. 
In addition subgroup descriptive summary and analysis tables of bone turnover markers by subjects 
with and without 25 hydroxy vitamin D deficiency at baseline (vitamin D deficiency is defined as 
25 hydroxy vitamin D < 30ng/ml) will be presented.  
8.7.3 Oestradiol and testosterone/oestradiol ratio 
Descriptive summary tables will be presented for oestradiol and testosterone/oestradiol ratio values, 
change from baseline values and percentage change from baseline values by treatment regimen and 
visit. High sensitivity Oestradiol values collected during MBGS205  will summarised together with 


 
 
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the Oestradiol values assessed by the Central lab. 
The change and percentage change from baseline in each parameter up to Week 48 will be analysed 
in the same manner as the change from baseline in bioavailable testosterone (see Section 8.6.3.5). 
Analyses will be conducted separately for subjects that were randomised to active treatment 
(MMRM analysis) and subjects that were randomised to placebo (ANCOVA analysis) in study 
MBGS205. A figure of absolute oestradiol will be provided by treatment regimen.   
In addition the number and proportion of subjects with oestradiol values < 11 pg/mL will be 
summarised by treatment regimen at each visit. 
8.7.4 Adverse events 
All AEs will be classified by SOC and PT according to the MedDRA Version 19.1 or higher.  
Details for imputing missing or partial start dates of adverse events are described in Section 7.2.2.4. 
All AE summaries will be generated by active treatment period (across both MBGS205 and 
MBGS206), MBGS206 treatment period, MBGS206 follow-up period and overall (i.e including 
those that started in both the active treatment period and follow-up period). 
Notes: 
 
Two AEs with the same PT will be considered as two different events when calculating 
 
 
Where a subject has the same AE, based on preferred terminology, reported multiple 
times in the same category the subject will only be counted once at the preferred 
terminology level in AE frequency tables. 
 
Where a subject has multiple AEs within the same SOC in the same category, the 
subject will only be counted once at the SOC level in AE frequency tables. 
 
AEs where the intensity is missing will be assumed to be 
 
 
AEs where the causality is missing will be assumed to have Reasonable possibility of 
relatedness 
An overall summary of AEs will be provided. The total number of events and number and 
proportion of subjects experiencing any AEs, TEAEs, TEAEs of special interest, AEs related to 
study medication 
Reasonable possibility of relatedness , 
SAEs, SAEs related to study medication, severe AEs, AEs leading to permanent discontinuation of 
study treatment and AEs leading to death will be tabulated for each treatment regimen and overall. 
Additionally, TEAEs, TEAEs of special interest, related TEAEs, serious TEAEs, related SAEs, 
AEs leading to permanent discontinuation of study treatment and AEs leading to death will be 
summarised by SOC and PT for each treatment regimen and overall (number and percentage of 
subjects experiencing at least one AE per PT as well as the number of observed events per PT). All 
TEAEs will also be summarised separately by maximum intensity for each SOC and PT and by 
causality for each SOC and PT. 


 
 
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A table presenting the number and percentage of subjects with at least one AE and the number of 
AEs for the most common treatment-
treatment 
regimen) will be provided. PTs will be used for tabulation, sorted by decreasing overall frequency. 
All AEs will be presented in full in a comprehensive listing including subject number, treatment 
regimen, intensity, seriousness, actions taken, outcome, causality, onset/stop and duration. Details 
of all TEAEs of special interest, SAEs, AEs leading to permanent discontinuation of study 
treatment and AEs leading to death will be listed separately.  
8.7.5 Laboratory evaluations 
8.7.5.1 Clinical laboratory 
Haematology, blood chemistry, and urinalysis assessments will be conducted at each visit during 
the treatment phase and Week 60. 
The following laboratory parameters will be assessed: 
 
Blood chemistry 
 Sodium 
 Potassium 
 Chloride 
 Bicarbonate/CO2 
 Blood urea nitrogen 
 Creatinine 
 Fasting Glucose 
 Albumin 
 Alkaline phosphatase 
 AST 
 ALT 
 GGT 
 PT/INR 
 Total bilirubin 
 
Total protein 
 
Calcium 
 
Lipid panel (total cholesterol, LDL, HDL, triglycerides) 
 
PSA 
 eGFR (calculated based on Cockcroft-Gault formula) 
 eGFR (derived from 4-v MDRD) 
 
Haematology 
 Red Blood Cell Count [RBC] 
 White Blood Cell Count [WBC] 
 Neutrophils 
 Lymphocytes 


 
 
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 Monocytes 
 Eosinophils 
 Basophils 
 Haemoglobin 
 Haematocrit 
 Platelets 
 
Urinalysis 
 Specific gravity 
 pH 
 Protein 
 
Bilirubin 
 Glucose 
 Blood 
 
Ketones 
 Leukocytes 
For the purposes of summarisation in both the tables and listings, all clinical laboratory data will be 
reported in Standard International (SI) units.  
If a lab value is reported using a nonnumeric qualifier e.g., less than (<) a certain value, or greater 
than (>) a certain value, the given numeric value will be used in the summary statistics, ignoring 
the nonnumeric qualifier. 
Descriptive statistics will be presented for quantitative clinical laboratory parameters for each 
treatment regimen and time-point. Similarly, changes from baseline (and changes from screening 
for selected renal parameters; creatinine, urea, and glomerular filtration rate) will be summarised.  
The change from baseline in each renal parameter to Week 48 will also be analysed via MMRM in 
the same manner as the change from baseline in total testosterone (see Section 8.6.3.3). 
Values outside the normal range will be categorised as H (above the normal range) or L (below the 
data listings along with 
 
Qualitative urinalysis parameters (e.g protein, glucose and blood) will only be listed. 
8.7.5.2 Liver Function  
The number and proportion of subjects with laboratory values for liver function and enzymes of 
clinical concern as follows will be presented descriptively by treatment regimen: 
 


 
 
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Parameter
Level for clinical concern
ALT 
> 1.5 times the upper limit of the 
normal range (ULN) 
> 2xULN 
> 3xULN 
> 5xULN 
> 10xULN 
AST 
> 1.5xULN 
> 2xULN  
> 3xULN 
> 5xULN 
> 10xULN 
Bilirubin Total 
> 2xULN 
> 3xULN 
ALT/AST and Bilirubin Total 
ALT/AST> 3xULN and Bilirubin 
Total> 2xULN 
(assessments to occur at the same 
visit) 
 
8.7.6 Vital signs 
Vital sign assessments will be performed at each visit. 
Descriptive statistics (observed values and changes from baseline) will be presented for each 
treatment regimen and time-point for vital sign measurements (body temperature, pulse rate, 
systolic blood pressure, diastolic blood pressure, weight and BMI).  
The change from baseline in systolic and diastolic blood pressure to Week 48 will also be analysed 
via MMRM in the same manner as the change from baseline in total testosterone (see Section 
8.6.3.3). 
Boxplots of observed and change from baseline values by treatment and visit will also be generated 
for both systolic and diastolic blood pressure. 
In addition the number and percentage of subjects meeting each of the criteria below will be 
presented: 
 
Normal: SBP <120mm Hg and DBP < 80 mm Hg 
 
 
 
Hypertension S
 
 
 
 
 
SBP Change from baseline >=20 mmHg 
 
DBP Change from baseline >=10 mmHg 


 
 
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8.7.7 Physical examinations 
A full physical examination will be performed at Week 36 and Week 48 whereas a limited physical 
examination (cardiovascular system and lower extremities oedema only) will be performed at all 
other. 
The number and percentage of patients reporting an abnormal physical examination finding 
(Abnormal CS and Abnormal NCS) will be presented per body system for each treatment regimen 
and time-point.  
In addition the grade of pitting oedema will be summarised descriptively for each treatment 
regimen and time-point. 
8.7.8 Electrocardiograms 
12-Lead ECG assessments will be performed at Week 36 and Week 48. 
Descriptive statistics (observed values and changes from baseline) will be presented for the 12-lead 
ECG measurements for each treatment regimen and time-point for all ECG parameters (Heart Rate, 
PR interval, QT interval, RR interval, QRS duration and QTcF interval). In addition, the overall 
ECG interpretation will be summarised by presenting the number and percentage of subjects with 
 time-point.  
8.8 
Other analysis 
8.8.1 DMC 
An independent, unblinded external DMC will periodically review accumulating safety data.  This 
will include data evaluation of accumulating unblinded safety dat 
a of BGS649, testosterone monitoring assessment and performing the interim analysis. Full details 
of composition, operational aspects, and data to be reviewed and recommendation of the DMC is 
provided in a separate DMC charter and DMC SAP. 
8.8.1.1 Testosterone Monitoring 
To ensure adequate safety monitoring, serum total testosterone levels will be evaluated at each visit 
by an independent unblinded physician and if subject meets discontinuation criteria (total 
 ng/dL (52 nmol/L) at any 2 consecutive time points during the study), the 
subject will be discontinued from treatment. This would also include situation when first 
testosterone value that meets this 
/L] was measured during 
MBGS205 and consecutive testosterone during study MBGS206. 
8.8.1.2 Interim Analysis 
No interim analysis is planned for this study.  
8.8.2 PK analyses 
Plasma and Semen PK will be collected at Week 48/EOT only. 


 
 
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BGS649 PK plasma and semen concentrations will be summarised for the PK population by 
descriptive statistics by treatment regimen and time-point, including the geometric mean and 
coefficient of variation. 
8.8.3 Association Testing 
To determine any correlation between endpoints after 12 months active treatment, various 
association testing will be conducted using the ITT Population in subjects that were randomised to 
active treatment in Study MBGS205 at Week 48. For the below sets of endpoints separate linear 
regression models in which changes in PRO measure total or subscale scores will be taken as the 
predictor variable, associated PRO baseline score as a covariate and the endpoint to be tested 
against as the regressor variable. 
Correlation coefficients, coefficients of determination 
(R2 statistic) Beta coefficients, standard errors, and 95% CIs will be presented. In addition scatter 
graphs will be generated annotated with the coefficient of determination (R2 statistic): 
 
Change in PRO measures vs Change in Body Composition Parameters  
 
Change in PRO measures vs Change in Bio Impedance Parameters  
 
Change in PRO measures vs Change in Physical Activity Parameters  
 
Change in PRO measures vs Change in Grip Strength  
 
Change in PRO measures vs Change in Sleep Parameters 
 
Change in PRO measures vs Change in Oestradiol 
 
Change in PRO measures vs Change in Testosterone/oestradiol Ratio 
 
Similar association testing will be conducted on the below endpoints using total testosterone as the 
predictor variable: 
 
Change in Total Testosterone vs Change in Cardiometabolic parameters  
 
Change in Total Testosterone vs Change in Body Composition parameters  
 
Change in Total Testosterone vs Change in Bio Impedance Parameters  
 
Change in Total Testosterone vs Change in Physical Activity Parameters  
 
Change in Total Testosterone vs Change in Grip Strength  
 
Change in Total Testosterone vs Change in Sleep Parameters 
 
Change in Total Testosterone vs Change in PRO measures 
 
Association testing will also be conducted on the below 
 
Change in systolic blood pressure vs Total Testosterone, Oestradiol and 
Testosterone/Oestradiol ratio at Week 48 
 
Change in diastolic blood pressure vs Total Testosterone, Oestradiol and 
Testosterone/Oestradiol ratio at Week 48 
 
Change in Creatinine vs Blood Pressure (Absolute systolic and diastolic blood pressure)  at 
Week 48 
 
Change in Creatinine vs Change in Blood Pressure (Systolic and Diastolic blood pressure) 
at Week 48 


 
 
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8.8.4 Sensitivity Analysis of Site 1156 
To assess the impact of site 1156 on key endpoints the below analyses will be conducted utilising 
the modified populations (see section 6.0) which removes subjects enrolled from site 1156: 
  
- 
Analysis of Proportion of Subject Achieving Normalisation of Total Testosterone (300-
1000 ng/dl). Analysis will be conducted on the Central lab testosterone using LOCF 
imputation.  
- 
Summary of Change in LH and FSH 
- 
Summary of Vitals signs Parameters and Change from Baseline 
- 
Summary of Blood Pressure Categorisation 
- 
Summary of Body Composition 
8.9 
CSR 
The primary efficacy analysis will be performed when all data has been collected.  
 
 


 
 
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9 
CHANGES TO PLANNED ANALYSIS FROM STUDY 
PROTOCOL 
The below are changes to the study protocol analysis: 
The Percentage change in lumbar bone mineral density measured by DEXA (g/cm2)  from Baseline 
in Study MBGS206 to Week 48 for subjects that were randomised to placebo in Study MBGS205 
has been added as a secondary safety endpoint. This was inadvertently absent from the study 
protocol.  
Vitamin D deficiency is defined in the protocol as <20ng/ml. For all analyses Vitamin D deficiency 
has been defined as <30ng/ml. 
Following data integrity concerns at site 1156, sensitivity analyses were added to assess the impact 
of the site on key parameters. 
 
 
 


 
 
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10 
REFERENCES 
1. 
ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96  adopted 
March 1998). 
 
2. 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130:461-70. 
3. 
Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in 
the modification of diet in renal disease study equation for estimating glomerular 
filtration rate. Ann Intern Med. 2006; 145:247-54. 
4. 
Landon W. Trost and John P. Mulhall. Challenges in Testosterone Measurement, 
Data Interpretation, and Methodological Appraisal of Interventional Trials. J Sex 
Med. 2016 July ; 13(7): 1029 1046. 
 
 


 
 
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11 
APPENDICES 
Appendix A - International Index of Erectile Function (IIEF) 
Question 
Number 
Question 
Response 
Score
1 
Over the past 4 weeks how 
often were you able to get an 
erection during sexual 
activity? 
Almost always or always 
5 
Most times (much more than half the time) 
4 
Sometimes (about half the time) 
3 
A few times (much less than half the time) 
2 
Almost never or never 
1 
No sexual activity 
0 
2 
Over the past 4 weeks when 
you had erections with sexual 
stimulation, how often 
were your erections hard 
enough for penetration? 
Almost always or always 
5 
Most times (much more than half the time) 
4 
Sometimes (about half the time) 
3 
A few times (much less than half the time) 
2 
Almost never or never 
1 
No sexual stimulation 
0 
3 
Over the past 4 weeks when 
you attempted sexual 
intercourse how often were 
you able to penetrate (enter) 
your partner? 
Almost always or always 
5 
Most times (much more than half the time) 
4 
Sometimes (about half the time) 
3 
A few times (much less than half the time) 
2 
Almost never or never 
1 
Did not attempt intercourse 
0 
4 
Over the past 4 weeks during 
sexual intercourse how often 
were you able to maintain 
your erection after you had 
penetrated (entered) your 
partner? 
Almost always or always 
5 
Most times (much more than half the time) 
4 
Sometimes (about half the time) 
3 
A few times (much less than half the time) 
2 
Almost never or never 
1 
Did not attempt intercourse 
0 
5 
Over the past 4 weeks during 
sexual intercourse how 
difficult was it to maintain 
your erection to completion 
of intercourse? 
Not difficult 
5 
Slightly difficult 
4 
Difficult 
3 
Very difficult 
2 
Extremely difficult 
1 
Did not attempt intercourse 
0 
6 
Over the past 4 weeks how 
many times have you 
attempted sexual intercourse?
11+ attempts 
5 
7-10 attempts 
4 
5-6 attempts 
3 
3-4 attempts 
2 
1-2 attempts 
1 
No attempts 
0 
7 
Over the past 4 weeks when 
you attempted sexual 
intercourse how often was it 
satisfactory for you? 
Almost always or always 
5 
Most times (much more than half the time) 
4 
Sometimes (about half the time) 
3 
A few times (much less than half the time) 
2 
Almost never or never 
1 


 
 
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Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
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Did not attempt intercourse 
0 
8 
Over the past 4 weeks how 
much have you enjoyed 
sexual intercourse? 
Very highly enjoyable 
5 
Highly enjoyable 
4 
Fairly enjoyable 
3 
Not very enjoyable 
2 
Not enjoyable 
1 
No intercourse 
0 
9 
Over the past 4 weeks when 
you had sexual stimulation or 
intercourse how often did 
you ejaculate? 
Almost always or always 
5 
Most times (much more than half the time) 
4 
Sometimes (about half the time) 
3 
A few times (much less than half the time) 
2 
Almost never or never 
1 
No sexual stimulation or intercourse 
0 
10 
Over the past 4 weeks when 
you had sexual stimulation or 
intercourse how often 
did you have the feeling of 
orgasm with or without 
ejaculation? 
Almost always or always 
5 
Most times (much more than half the time) 
4 
Sometimes (about half the time) 
3 
A few times (much less than half the time) 
2 
Almost never or never 
1 
No sexual stimulation or intercourse 
0 
11 
Over the past 4 weeks how 
often have you felt sexual 
desire? 
Almost always or always 
5 
Most times (much more than half the time) 
4 
Sometimes (about half the time) 
3 
A few times (much less than half the time) 
2 
Almost never or never 
1 
12 
Over the past 4 weeks how 
would you rate your level of 
sexual desire? 
Very high 
5 
High 
4 
Moderate 
3 
Low 
2 
Very low or none at all 
1 
13 
Over the past 4 weeks how 
satisfied have you been with 
your overall sex life? 
Very satisfied 
5 
Moderately satisfied 
4 
About equally satisfied and dissatisfied 
3 
Moderately dissatisfied 
2 
Very dissatisfied 
1 
14 
Over the past 4 weeks how 
satisfied have you been with 
your sexual relationship 
with your partner? 
Very satisfied 
5 
Moderately satisfied 
4 
About equally satisfied and dissatisfied 
3 
Moderately dissatisfied 
2 
Very dissatisfied 
1 
15 
Over the past 4 weeks how 
would you rate your 
confidence that you could get 
and keep an erection? 
Very high 
5 
High 
4 
Moderate 
3 
Low 
2 
Very 
1 
 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
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Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
                                                                        Page 53 of 63
 
Appendix B - Patient-
 
Question 
Number 
Question 
Response 
Score
1 
How interested have you 
been in sexual activity? 
Very 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
2 
How often have you felt like 
you wanted to have sexual 
activity? 
Always 
5 
Often 
4 
Sometimes 
3 
Rarely 
2 
Never 
1 
3 
Please rate your ability to 
have an erection. 
Very good 
5 
Good 
4 
Fair 
3 
Poor 
2 
Very Poor 
1 
4 
How satisfied have you been 
with your sex life? 
Very 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
5 
How much pleasure has your 
sex life given you? 
A lot 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
None 
1 
6 
How often have you thought 
that your sex life is 
wonderful? 
Always 
5 
Often 
4 
Sometimes 
3 
Rarely 
2 
Never 
1 
7 
How satisfied have you been 
with your sexual 
relationship(s)? 
Very 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
Have not had a sexual relationship in last 
30 days 
0 
8 
When you have had sexual 
activity, how much have you 
enjoyed it? 
Very much 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
9 
How much has fatigue or 
lack of energy affected your 
Very Much 
5 
Quite a bit 
4 


 
 
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Statistical Analysis Plan 
Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
                                                                        Page 54 of 63
 
satisfaction with your sex 
life? 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
Have not had fatigue or lack of energy in 
the last 30 days 
0 
10 
How much has weight gain 
affected your satisfaction 
with your sex life? 
Very Much 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
Have not had weight gainin the last 30 days 
0 
 
T-Score Conversion Tables : 
 
1. 
Interest in Sexual Activity (1,2) 
 


 
 
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Statistical Analysis Plan 
Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
                                                                        Page 55 of 63
 
 
2. 
Erectile Function (3) 
 
3. 
Satisfaction with Sex Life (4,5,6,7,8) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
                                                                        Page 56 of 63
 
 
Appendix C - 
Form 
 
Question 
Number 
Question 
Response 
Score
1 
I feel fatigued 
Very much 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
2 
I have trouble starting things 
because I am tired 
Very much 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
3 
How run-down did you feel 
on average? 
Very much 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
4 
How fatigued were you on 
average? 
Very much 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
5 
How much were you 
bothered by your fatigue on 
average? 
Very much 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
6 
To what degree did your 
fatigue interfere with your 
physical functioning? 
Very much 
5 
Quite a bit 
4 
Somewhat 
3 
A little bit 
2 
Not at all 
1 
7 
How often did you have to 
push yourself to get things 
done because of your 
fatigue? 
Always 
5 
Often 
4 
Sometimes 
3 
Rarely 
2 
Never 
1 
8 
How often did you have 
trouble finishing things 
because of your fatigue? 
Always 
5 
Often 
4 
Sometimes 
3 
Rarely 
2 
Never 
1 
 


 
 
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Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
                                                                        Page 57 of 63
 
 
 
T-Score Conversion Table: 
 
 
 
 
Reference : https://www.assessmentcenter.net/ 
 
 


 
 
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Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
                                                                        Page 58 of 63
 
Appendix D - 36-Item Short Form Health Survey (SF-36) 
 
VARIABLE 
DERIVATION 
SF-36 PF scale score 
raw score = sum (items 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J) 
PF = (raw score -10 ) * 5 
PF_Z = (PF  82.62455) / 24.43176 
PF scale score = (PF_Z*10) + 50 
When calculating the raw score, if 5 or more of the items are non-missing 
then replace any missing values as follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores. 
Otherwise, if less than 5 of the items are non-missing then PF scale score is
missing. 
The response scale for each activity ranges from 1 to 3 where 1=limited a 
lot, 2=limited a little, and 3=not limited at all. 
A higher PF scale score indicates better physical functioning. 
SF-36 RP scale score 
raw score = sum (items 4A, 4B, 4C, and 4D ) 
RP = [(raw score -4)/16] * 100 
RP_Z = (RP  82.65109) / 26.19282 
RP scale score = (RP_Z * 10) + 50 
When calculating the raw score, if 2 or more of the items are non-missing 
then replace any missing values as follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator.  Substitute the mean for any 
missing scores. 
Otherwise, if less than 2 of the items are non-missing then RP scale score is
missing. 
The response scale for each item ranges from 1 to 5 where 1=All of the 
time, 2=Most of the time, 3=Some of the time, 4=A little of the time, and 
5=None of the time.   
 
A higher RP scale score indicates better role-physical functioning. 


 
 
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Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
                                                                        Page 59 of 63
 
SF-36 BP scale score 
raw score = sum (reversed item 7 and reversed item 8) 
BP = (raw score -2) * 10 
BP_Z = (BP  73.86999) / 24.00884 
BP scale score = (BP_Z * 10) + 50 
Reverse direction of Item 7 as follows: if =1, set to 6; if =2, set to 5.4;  
if =3, set to 4.2; if=4, set to 3.1; if=5, set to 2.2 if=6, set to 1. 
Reverse direction of item 8 as follows: 
if =1 and original value of item 7=1, set to 6; 
if =1 and original value of item 7>=2, set to 5; if=2, set to 4; 
if=3, set to 3; if=4, set to 2; if=5, set to 1. 
If item 7 is answered and item 8 is missing, set 8 = reversed 7 as defined 
above.  If 8 is answered and 7 is missing, set 7 as reverse item 8 as 
follows: 
if =1, set to 6; 
if =2, set to 4.75; if=3, set to 3.5; if=4, set to 2.25; 
if=5, set to 1. 
If 1 or more questions were answered, calculate BP scale score as defined 
above. If neither question was answered then BP scale score is missing. 
The scale for Question 7, amount of bodily pain, ranges from 1 to 6 where 
1=None, 2=Very mild, 3=mild, 4=Moderate, 5=Severe, and 6=Very severe.  
The scale for Question 8, the degree to which pain interfered with normal 
work, ranges from 1 to 5 where 1=Not at all, 2=A little bit, 3=Moderately, 
4=Quite a bit, and 5=Extremely.   
 
A higher BP scale score indicates lack of bodily pain. 
SF-36 GH scale score 
raw score = sum (reversed item 1, item 11A, reversed 11B, 
11C and reversed 11D) GH = (raw score -5) * 5 
GH_Z = (GH  70.78372) / 21.28902 
GH scale score = (GH_Z * 10) + 50 
Reverse direction of Item 1 as follows: 
if =1, set to 5; 
if =2, set to 4.4; if =3, set to 3.4; if=4, set to 2; if=5, set to 1. 
Reverse direction of item 11B and 11D by subtracting score from 6. 
When calculating the raw score, if 3 or more of the items are non-missing 
then replace any missing values as follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores. 
Otherwise, if less than 3 of the items are non-missing then GH scale score is
missing. 
Responses for Question 1, an assessment of self-perceived health status, 
range from 1 to 5 where 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 
5=Poor. Responses for the items in Question 11 range from 1 to 5 where 
1=Definitely true, 2=Mostly true, 3=
 know, 4=Mostly false, and 
5=Definitely false and reflect the subject  perception of their relative 
health and expectations of their future health status.   
 
A higher GH scale score indicates better general health perceptions. 


 
 
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Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
                                                                        Page 60 of 63
 
SF-36 VT scale score 
raw score = sum (reversed item 9a, reversed 9e, 9g and 9i) 
VT = [(raw score -4)/16] * 100 
VT_Z = (VT  58.41968) / 20.87823 
VT scale score = (VT_Z * 10) + 50 
Reverse direction of Items 9a and 9e by subtracting score from 6. 
When calculating the raw score, if 2 or more of the items are non-missing 
then replace any missing values as follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores. 
Otherwise, if less than 2 of the items are non-missing then VT scale score is
missing. 
The scale for these items ranges from 1 to 5 where 1=All of the time, 
2=Most of the time, 3=Some of the time, 4=A little of the time, and 5=None
of the time.   
A higher VT scale score indicates more vitality. 
SF-36 SF scale score 
raw score = sum (reversed 6 and 10) 
SF = [(raw score -2) / 8] * 100 
SF_Z = (SF  85.11568) / 23.24464 
SF scale score = (SF_Z * 10) + 50 
Reverse direction of score for item 6 by subtracting score from 6. 
When calculating the raw score, if 1 of the items is missing then substitute 
the missing score with the score on the non- missing item.  If both items are
missing then SF scale score is missing. 
Responses to Question 6, an assessment of the extent to which 
health/emotional problems interfered with social activities, range from 1 to 
5 where 1=Not at all, 2=Slightly, 3=Moderately, 4=Quite a bit, and 
5=Extremely.   
 
Responses to Question 10 reflect the amount of time that health/emotional 
problems interfered with social activities and range from 1 to 5 where 1=All
of the time, 2=Most of the time, 3=Some of the time, 4=A little of the time,
and 5=None of the time.   
 
A higher SF scale score indicates better social functioning. 


 
 
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Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
                                                                        Page 61 of 63
 
SF-36 RE scale score 
raw score = sum (items 5A, 5B, and 5C ) 
RE = [(raw score -3) / 12] * 100 
RE_Z = (RE  87.50009) / 22.01216 
RE scale score = (RE_Z * 10) + 50 
When calculating the raw score, if 2 or more of the items are non-missing 
then replace any missing values as follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores. 
Otherwise, if less than 2 of the items are non-missing then RE scale score is
missing. 
Responses to the items in Question 5 range from 1 to 5 where 1=All of the 
time, 2=Most of the time, 3=Some of the time, 4=A little of the time, and 
5=None of the time.   
 
A higher RE scale score indicates better role-emotional functioning. 
SF-36 MH scale score 
raw score = sum (items 9B, 9C, reversed 9D, 9F and reversed 9H) 
MH = (raw score - 5 ) * 5 
MH_Z = (MH  75.76034) / 18.04746 
MH scale score = (MH_Z * 10) + 50 
Reverse direction of scores for 9D and 9H, by subtracting score from 6. 
If 3 or more of the items are non-missing then replace any missing values as
follows: 
Calculate the mean of the answered questions, using the number of 
answered questions as the denominator. Substitute the mean for any 
missing scores. 
Otherwise, if less than 3 of the items are non-missing then MH scale score 
is missing. 
The scale for these items ranges from 1 to 5 where 1=All of the time, 
2=Most of the time, 3=Some of the time, 4=A little of the time, and 5=None
of the time.   
 
A higher MH scale score indicates better mental health. 
SF-36 PCS  score 
PCS score includes the 8 scales for GH, PF, RP, RE, SF, MH, BP, and VT.
PF1= (PF-82.62455)/24.43176; RP1=(RP-82.65109)/26.19282;  
BP1=(BP-73.86999)/24.00884; GH1 = (GH-70.78372)/21.28902;  
VT1= (VT-58.41968)/20.87823; SF1=(SF-85.11568)/23.24464;  
RE1= (RE-87.50009)/22.01216; MH1=(MH-75.76034)/18.04746; 
Raw Score = ((GH1*.24954)+(PF1* .42402)+(RP1*.35119)+  
(RE1*-.19206)+(SF1*-.00753)+(MH1*-.22069)+(BP1*.31754)+ 
(VT1*.02877)) 
PCS Summary Scale Score = (raw score *10) + 50 
Raw Score is missing if one of the component scale scores is missing. 


 
 
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Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
                                                                        Page 62 of 63
 
SF-36 MCS score 
MCS score includes the 8 scales for GH, PF, RP, RE, SF, MH, BP, and VT.
PF1= (PF-82.62455)/24.43176; RP1=(RP-82.65109)/26.19282;  
BP1=(BP-73.86999)/24.00884; GH1 = (GH-70.78372)/21.28902;  
VT1= (VT-58.41968)/20.87823; SF1=(SF-85.11568)/23.24464;  
RE1= (RE-87.50009)/22.01216; MH1=(MH-75.76034)/18.04746; 
Raw Score =((GH1*-.01571)+(PF1*-.22999)+(RP1*-.12329)+ 
(RE1*.43407)+(SF1*.26876)+(MH1*.48581)+(BP1*-.09731)+ 
(VT1*.23534)) 
MCS Summary Concept Score = (raw score *10) + 50 
Raw Score is missing if one of the component scale scores is missing. 
 
 
 


 
 
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Protocol Number: MBGS206 
               Version: FINAL 1.0, Date: 20 November 2018
                                                                        Page 63 of 63
 
Appendix E  Actigraphy Visit Windows 
For subjects randomised to active medication in MBGS205 
 
Visit 
Window Start 
Window End 
Baseline 
Day 1 
Day 7 
Week 12 
Day 56 
Day 112 
Week 24 
Day 140 
Day 196 
Week 48 
Day 308 
End of Study 
 
For subjects randomised to Placebo in MBGS205 
 
Visit 
Window Start 
Window End 
Baseline 
Day - 28 
Day 7 
Week 48 
Day 140 
End of Study 
 
 
Appendix F  DEXA Visit Windows  
For subjects randomised to active medication in MBGS205 
 
Visit  
Window Start  
Window End  
Target Day  
Baseline  
Day -28  
Day 8  
Day 1  
Week 24  
Day 140  
Day 196  
Day 168  
Week 48 
Day 308 
End of Study 
Day 336 
 
For subjects randomised to Placebo in MBGS205 
 
Visit 
Window Start 
Window End 
Target Day  
Baseline 
Day - 28 
Day 8 
Day 1  
Week 24 
Day 140 
End of Study 
Day 168