Clinical trial NCT02730169
Conditions: Hypogonadotropic Hypogonadism
Keywords: Hypogonadotropic hypogonadism testosterone
Sponsor: Mereo BioPharma
Start date: 2016-05-12; Completion date: 2018-05-19
Enrollment: 271 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of BGS649 in male obese subjects with hypogonadotropic hypogonadism. All subjects will be treated for a maximum of 24 weeks. Some subjects who complete 24 weeks of treatment will be invited to participate in a 6-month blinded safety extension study (Protocol MBGS206). The study is planned to enroll 268 subjects.

Detailed description:

Arms: arm 1: BGS649 0.1 mg weekly (1 BGS649 0.1 mg capsule and 2 indistinguishable placebo capsules) arm 2: BGS649 0.3 mg weekly (3 BGS649 0.1 mg capsules) arm 3: BGS649 1.0 mg weekly (1 BGS649 1.0 mg capsule and 2 indistinguishable placebo capsules) arm 4: Placebo weekly (3 indistinguishable placebo capsules)
Interventions: intervention 1: BGS649 intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules were taken weekly for a maximum of 24 weeks intervention 2: Capsules were taken weekly for a maximum of 24 weeks

Protocol documents:
Prot_000.pdf: 
Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 1 of 87 
 
 
 
 
1 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
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 
 
 
Protocol No.:  MBGS205 
EUDRACT/IND No.: 2015-005760-42 
Test Product: 
BGS649  
Indication: 
Hypogonadotropic hypogonadism 
Sponsor: 
Mereo BioPharma 2 Ltd 
Development Phase: 
Phase IIb 
Sponsor Signatory: 
Sponsor Medical Expert: 
Date of the Protocol: 
10 March 2017 
Version of the Protocol: 
Amended Protocol Version 6.0 
 
 
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 MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 2 of 87 
 
SUMMARY AND JUSTIFICATION OF CHANGES  
This amendment includes revisions to Protocol Version 5.0, dated 03 November 2016, 
summarized as follows 
Change 
Rationale 
Clarification that the primary efficacy analysis 
and study unblinding will be performed when 
all data from Visit 8 (week 24) has been 
collected. The full 12 week follow up safety 
data will be separately analysed. 
 
 
Limiting semen PK to Visit 8/EOT and 
removal of requirement for semen PK at Visits 
9, 10 and 11. 
 
Performing the MBGS205 efficacy 
analysis at the earliest point will enable 
ineffective doses in MBGS206 to be 
discontinued and prevent subjects from 
MBGS205 transitioning an ineffective 
arm of MBGS206.  
 
To reduce burden of semen sampling 
on patients,as adequate follow up 
samples will be obtained through 
previously recruited patients and 
through the extension study MBGS206. 
 
Screened subjects increased from 700 to 2000. 
 
Change in exclusion criterion to HbA1C from 
<8.5% to <10.5%. 
 
 
 
To reflect the screen failure rate. 
 
To reflect the target population which 
includes a number of patients with type 
2 diabetes and in light of no adverse 
effects on glucose control in >100 
patients within the current trial. 
 
Removal of monoclonal antibodies as 
exclusion criterion. 
 
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 exclusion 
criterion. 
 
To enable recruitment of representative 
target population of obese men with 
type 2 diabetes requiring insulin.  
Removal of exclusion critererion for new 
prescription or over-the-counter drug known to 
affect glucose homeostasis within the 4 weeks 
prior to first Screening Visit. 
Already covered in exclusion criterion 
7. 
Change of exclusion of any history of weight 
reduction surgery or procedures, to surgeries and 
procedures that have occurred in the 3 months 
prior to Screening. 
To enable inclusion of releavent 
patients in the target population. 
Ongoing significant weight effecta of 
surgeries prior to this time would be 
captured by weight loss or gain 
exclusion criterion 12. 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 3 of 87 
 
Removal of change in smoking habit exclusion 
criterion. 
Change in smoking not anticipated to 
affect study assessments or safety. 
Only SAEs to be collected during screening. 
No requirement to collects AEs prior to 
randomisation and dosing. 
Increase semen sample timing window at baseline 
to 48 hours before/after baseline visit. 
To increase flexibility of sampling date 
due to difficulty patients may have in 
providing sample and travel to 
specialist labs. 
Plasma PK limited to testing at Visit 5 (week 12) 
and Visit 8 (EOT). 
Adequate plasma PK data has now 
been collected to enable reduction in 
testing frequency to reduce burden on 
subject. 
Visits 9 and 10 changed to telephone follow up. 
Removal of requirement for semen PK 
at FU Visits 9 and 10 means these can 
be telephone only for assessment of 
AEs and concomitant medications. 
Window for Baseline DEXA scan increased to 
be allowed any time in screening period and 
up to Day 8 after randomisation. 
To overcome scheduling challenges 
with other assessments. 
Window for EOT DEXA scan increased to up 
to 14 days before EOT. 
To overcome scheduling challenges 
with other assessments and timelines to 
meet inclusion criteria for extension 
study MBGS206. 
Ability to retest inclusion/exclusion laboratory 
tests under specific circumstances of technical 
failure or defined abherent results on 
agreement with medical monitor. 
To prevent technical issues in 
laboratory measures inappropriately 
excluding subjects. 
Ability to rescreen if change in clinical status 
> 6 months after an initial screen failure if 
approved by medical monitor. 
To enable previously screen failed 
subjects to be recruited when there has 
been a change in clinical statusover 
time. 
Ability to rescreen if a subject previously 
failed due to a inclusion/exclusion or other 
study requirement than has been changed in 
subsequent protocols. 
To enable previously screen failed 
subjects to be recruited when there has 
been a  protocolised change in study 
requirements. 
Clarification of follow up visits for early drug 
termination. 
Clarification 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 4 of 87 
 
Removal of Cyp3A4 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 worseining of lower limb 
oedema to exclude measurement artifacts and 
effects of restrictive clothing. 
To prevent innapropriate drug 
interruption for artefactual worsening 
of leg oedema. 
DEXA scan information changed to require 
same machine to the be used for baseline and 
follow up scans and greater details on 
technical requirements, including 
measurement of both femoral neck and total 
hip,  requirement  to apply the guidance given 
within the study imaging manual and to retain 
the primary source data from the scan. 
DEXA scan procedures required to be 
tightened following variability of bone 
mineral density data from study to date. 




Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 6 of 87 
 
3 
GENERAL INFORMATION 
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 
Protocol No.: 
MBGS205 
Date of the Protocol: 
28 December 2015 
Date and Number of Amendment(s): 
09 March 2016, Amendment 1.0  
 
05 May 2016, Amendment 2.0 
 
26 September 2016, Amendment 3.0 
 
03 November 2016, Amendment 4.0 
 
10 March 2017, Amendment 5.0 
 
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 
 
UK 
 
Tel No.:  +44 (0) 1226 431896 
 
Fax No.:  +44 (0) 1226 434404 
 
 
 
 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 7 of 87 
 
Biostatistics: 
 
 
 
 
 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 8 of 87 
 
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 Phase IIb multicentre, double-blind, dose-ranging, randomised, placebo-controlled study evaluating safety 
and efficacy of BGS649 in male obese subjects with hypogonadotropic hypogonadism. 
Principal Investigator: 
Professor T. Hugh Jones 
Study Centre(s): 
It is planned that approximately 75 centres will be initiated for this study in approximately five countries.  
Publication(s): 
None 
Planned Study Period: 
Jan 2016 to Feb 2017 
Development Phase: 
Phase IIb 
Objectives: 
Primary Objectives 
The primary objective is to demonstrate the efficacy of BGS649 to normalise total testosterone levels 
(300-1000 ng/dL [10.4-35 nmol/L]) in ≥ 75% of subjects after 24 weeks of treatment. 
Secondary Objectives 
1. To follow the time-course of normalisation in total testosterone levels 
2. To demonstrate the efficacy of BGS649 to normalise total testosterone levels in ≥ 90% of subjects after 
24 weeks of treatment 
3. To evaluate the effect of BGS649 on luteinising hormone (LH) and follicle stimulating hormone (FSH)  
4. To further determine the pharmacokinetics (PK) of BGS649. 
Safety Objectives 
1. To evaluate safety and tolerability of BGS649 
Exploratory Objectives 
1. To evaluate the effect of BGS649 on oestradiol, DHT and inhibins (A and B) 
2. To evaluate the effect of BGS649 on testosterone/oestradiol ratio 
3. To investigate the effect on patient reported outcomes (PROs) following treatment with BGS649. PRO 
measures will be: 
o 
International Index of Erectile Function (IIEF) and PROMIS Sexual Function and Satisfaction 
(PROMIS 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. 
o 
Patient Global Impression of Status items (PGI-S): to assess the patients’ overall impression of their 
current health status. 
4. To determine any change in physical activity and sleeping pattern via wrist worn monitor 
5. To determine any change in grip strength, as measured by a dynamometer 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 9 of 87 
 
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 
6. To determine any associations between objective findings of improvement (e.g. testosterone, time in 
physical activity or sleep, and grip strength) and total and domain scores on PRO measures 
7. To determine body composition change: waist circumference, BMI, body composition (as measured by 
impedance), and gynecomastia 
8. To determine any associations between change in testosterone, body composition (as measured by BMI and 
waist circumference) and change in grip strength and wrist monitor data 
9. To determine any associations between change in testosterone, body composition (as measured by 
impedance) and change in grip strength and wrist monitor data 
10. To determine the effect of BGS649 on cardiometabolic parameters: systolic blood pressure (SBP) and 
diastolic blood pressure (DBP), lipid panel (total cholesterol, low density lipoprotein [LDL], triglycerides 
and HDL), glycosylated haemoglobin (HbA1c), fasting glucose and insulin, HOMA-IR  and high sensitivity 
C-reactive protein (hs-CRP) 
11. To determine any associations between testosterone, change in body composition and cardiometabolic 
parameters: SBP and DBP, lipid panel (total cholesterol, LDL, triglycerides and HDL), HbA1c, fasting 
glucose and insulin, HOMA-IR and hs-CRP 
12. To determine the change in bone mineral density (dual energy X-ray absorptiometry [DEXA] scan), bone 
turnover markers (C-terminal telopeptide [CTx1] and procollagen type 1 N-propeptide [P1NP], osteocalcin, 
bone alkaline phosphatase) 
13. To explore the effects of BGS649 on bone biomarkers on subjects with and without 25 hydroxy vitamin D 
deficiency (vitamin D deficiency is defined as 25 hydroxy vitamin D < 20ng/ml) 
14. To explore the relationship between BGS649 concentration and testosterone levels 
15. To determine the effects of BGS649 on semen parameters (semen volume, sperm count, concentration, 
motility and morphology) and to measure BGS649 concentrations in seminal fluid in subjects that provide 
semen samples 
16. To explore the relationship between LH/FSH change and improvement in semen analysis in subjects that 
provide semen samples. 
 
Methodology: 
This is a 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). 
The study will have three phases: 
1. A Screening Phase lasting up to 28 days, including Day -28 to Day -1 
2. A Randomisation Phase including the Baseline visit (Day 1) and the treatment period Day 1 to Visit 8 
(Week 24) 
3. A Safety Follow-Up Phase to Visit 11 (Week 36, follow-up [FU]). Visits 9 and 10 are telephone 
assessments 
Study participation will comprise up to 2 Screening Visits, 8 visits during the treatment period up to Week 24 
(End of Treatment [EOT]), FU Visits 9, 10 (telephone assessments)  and 11 (at Weeks 28, 32 and 36 
respectively) for safety performed to 12 weeks after Visit 8 (EOT). PK in seminal fluid will be performed at 
Visits 8 (EOT). A minimum of 25 subjects per arm will be offered a 6 month extension study (Protocol 
MBGS206), starting at Visit 8 (EOT). Subjects participating in the 6-month extension will have their last study 
visit at Visit 8 (EOT). The end of the study will be the last visit of the last subject. 
Eligible subjects will be randomised on Day 1 (Baseline) in a 1:1:1:1 ratio to one of the following treatment 
groups, consisting of three capsules per dose taken weekly: 
o 
BGS649
 
o 
BGS649
 
o 
BGS649
 
o 
BGS649 matching placebo 
 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 10 of 87 
 
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 
Once approximately 100 of the overall planned enrolled subjects have completed the Week 4 visit, an interim 
analysis will be performed by an independent data monitoring committee (DMC) who will review unblinded 
data and determine whether the criteria for normalisation of testosterone (testosterone within or above normal 
reference range for healthy adult males according to the Food and Drug Administration [FDA] criteria) were 
met. The DMC will establish whether an individual arm has met the criteria of ≥ 75% of subjects reaching the 
normalisation of testosterone, or whether in the opinion of the DMC following unblinded review that when the 
arm is fully recruited it is expected to achieve a ≥ 75% response at Week 24. Dosing arms which meet either of 
these criteria will be deemed effective. For dosing arms deemed ineffective, dosing will be stopped and no 
further randomisation to that arm will be performed. Subjects assigned to the ineffective or unsafe arm(s), as 
determined per the DMC, will be discontinued from the treatment, will attend Visit 8 (EOT) and will be 
followed-up for an additional 12 weeks (FU, Visit 11).  
The remainder of the randomisation will then continue in a 1:1:1 ratio of remaining active arms versus placebo 
to the following treatment groups: 
o 
BGS649
 
o 
BGS649 matching placebo. 
During the 24 week treatment period, subjects in the BGS649 groups and the matching placebo group will take 
the required dose weekly (± 1 day from the time schedule of regular planned dose) with water. 
Seminal Fluid Evaluation: 
Semen Quality 
To evaluate the effect of BGS649 treatment on sperm quality, semen analysis (sperm count, semen volume, 
concentration, motility, and morphology) will be performed. Subjects will be expected to successfully provide 
semen samples on three occasions during the Randomisation Phase. It is understandable that some subjects will 
not be able to provide semen samples.  
 
Semen PK 
An additional semen sample will be required at Visit 8 (EOT) in order to assess PK in seminal fluid to evaluate 
the concentration of BGS649.  
 
Any subjects who are vasectomised or have vasectomy planned during the study period, will be exempt from 
semen testing. 
 
If discontinued from the study drug earlier, subjects will directly undergo Visit 8 (EOT) and will be followed-up 
for an additional 12 weeks (safety FU, to Visit 11). 
 
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 testosterone is ≥ 
1500 ng/dL (52 nmol/L) at any 2 consecutive time points during the study), the subject will be discontinued 
from treatment. In addition, if one of the active BGS649 study arms presents with ≥ 2 subjects meeting this 
discontinuation criterion at any time point within the first 24 randomized subjects to that arm or > 15% subjects 
meet this criterion at any time point ≥ 25 randomized subjects,  then the arm will be evaluated by the 
independent DMC for potential dosing discontinuation based on FDA guidance (FDA Advisory Committee 
Industry Briefing Document Testosterone Replacement Therapy, Sept 2014). Subjects may be discontinued 
from the study arm and no further randomisation to that arm will be performed.  
Efficacy assessments will include measurement of total and calculated bioavailable testosterone, LH, FSH, 
inhibins A and B, dihydrotestosterone (DHT) and total oestradiol, body composition measurement including 
waist and hip circumference and impedance, cardiometabolic parameters, PROs, physical activity and sleep 
pattern via the wearing of wrist monitors, grip strength via a dynamometer and semen analysis. Safety 
assessments will include vital signs, physical examination, electrocardiograms (ECGs), haematology, blood 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 11 of 87 
 
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 
chemistry and urinalysis, bone turnover markers, DEXA, prostate-specific antigen (PSA), and recording of 
adverse events (AEs), serious AEs (SAEs), AEs of special interest (AESIs), and concomitant medications. 
Sparse plasma PK and semen PK will also be collected. 
Number of Subjects: 
It is planned to screen approximately 1000 subjects in order to enrol 268 subjects (67 subjects per arm). 
Diagnosis and Main Criteria for Inclusion: 
Inclusion 
1. Adult male subject aged 18 to 65 years inclusive 
2. BMI > 30 kg/m2 and < 50 kg/m2 
3. Serum total testosterone concentration below the normal range (serum total testosterone < 300 ng/dL 
[< 10.4 nmol/L]) in both of  two morning samples, taken before 11am, at least 3 days apart 
4. LH levels below the upper limit of normal (ULN) 
5. Oestradiol levels within or above the normal range of approved assay 
6. At least two symptoms of androgen deficiency present for at least 2 months prior to the first Screening 
Visit, with at least one of these being a sexual dysfunction 
7. 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 theoretical fetal risk of 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 
8. Ability to understand and comply with the requirements of the protocol/study, including understanding and 
being able to give informed consent. 
Exclusion 
1. Evidence of clinically significant endocrinopathy at Screening that may interfere with the study assessments 
or mask/mimic symptoms of hypogonadism e.g., growth hormone deficiency, adrenal deficiency, untreated 
hypothyroidism (primary hypothyroidism on replacement with normal thyroid stimulating hormone [TSH] 
level is allowed), or that may interfere with the evaluation of efficacy/safety parameters 
2. Other types of HH (e.g., Kallmann syndrome) or primary hypogonadism (e.g., cryptorchidism, or 
Klinefelter syndrome) 
3. Any other pituitary or hypothalamic disease, as based on one of the following: 
o 
Current or past hypothalamic or pituitary tumour  
o 
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, very low 
testosterone and LH (unless there is documentation of a normal magnetic resonance imaging scan of 
pituitary and hypothalamus within 3 months before first Screening Visit) 
o 
Hypothalamic or pituitary conditions, which may contribute to hypogonadism e.g., pituitary 
sarcoidosis, histiocytosis or tuberculosis 
4. Subject with prostate disease, as confirmed by the presence of one of the following: 
o 
History of prostate cancer 
o 
Elevated PSA levels ≥ 3 ng/mL at Screening 
o 
Subjects with a detectable prostate nodule or induration at Screening unless proven previously benign 
by a biopsy 
o 
Urologist confirmed symptomatic benign prostatic hyperplasia  
5. History of type 1 diabetes mellitus 
6. Current clinically symptomatic depression or current or past Bipolar disorder 
7. Uncontrolled ype 2 diabetes mellitus (HbA1c > 10.5% at Screening) or significant diabetic neuropathy. 


Mereo BioPharma 2 Ltd 
 
CONFIDENTIAL 
Protocol MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 12 of 87 
 
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 with type 2 diabetes can be included when both of the following conditions are met: 
o 
HbA1c ≤ 10.5 % at Screening, and: 
o 
Anti-diabetic medication regimen (excluding insulin) has been stable for ≥ 8 weeks before the first 
Screening visit 
8. Treatment with one or more of the following prescribed or over the counter medications in the six months 
prior to first Screening Visit: 
o 
Medications with known androgenic or estrogenic properties or known to affect production of sex 
hormones 
o 
 Injectable testosterone enhancement therapy 
o 
Fertility drugs 
o 
Growth hormone 
o 
Anabolic steroids 
o 
Long acting opiates 
9. Treatment with topical testosterone therapy in the two months prior to first Screening Visit 
10. Treatment with one of the following medications for either >7 consecutive days in the three months prior to 
first Screening Visit OR any treatment within 3weeks of first Screening Visit: 
o 
Testosterone lowering drugs e.g., spironolactone, cimetidine, 5α-reductase inhibitors 
o 
Short acting opioids/opiates including methadone 
o 
Medications known to increase prolactin levels, e.g., antipsychotics 
11. Treatment with the following medications: 
o 
Chronic systemic steroid treatment or systemic steroids for > 5 consecutive days for intercurrent illness 
within the 4 weeks prior to the first Screening visit (inhaled and topical steroids are allowed) 
o 
Clomid within 1 year before first Screening Visit 
o 
Bisphosphonates or other medication used to treat low bone density (denosumab, teriparatide) except 
calcium and vitamin D within 1 year before first Screening Visit 
12. Weight loss or weight gain (gain or loss > 5% body weight) OR weight reduction surgery or procedure 
within the 3 months prior to first Screening Visit  
13. Participation in any clinical trial using clinical investigational product intervention within 3 months before 
first Screening Visit or 5 half-lives of investigational product administration, whichever is longer 
14. Any clinically significant 12-lead ECG abnormalities at Screening including corrected QT interval by 
Fridericia’s correction method (QTCF) > 450 ms  
15. Medical history of Long QT syndrome 
16. History of thromboembolic disease 
17. Grade ≥3 lower extremity oedema 
18. Use of cardiac pacemaker or other medical electronic devices that can be affected by bioimpedance 
assessment 
19. Medical diagnosis of any of the following cardiovascular conditions within the 6 months prior to first 
Screening Visit: 
o 
Myocardial infarction or unstable angina 
o 
Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary intervention or carotid 
revascularisation procedure 
o 
Uncontrolled hypertension within the 3 months prior to first Screening Visit 
o 
Significant cardiac arrhythmia (as determined by the investigator) 
o 
Endovascular procedure or surgical intervention for peripheral vascular disease within the 3 months 
prior to first Screening Visit 
o 
Advanced ischemic heart disease 


Mereo BioPharma 2 Ltd 
 
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Protocol MBGS205 
 
 
 
 
Amended Protocol Version 6.0, 10 March 2017 
 
Page 13 of 87 
 
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 
Congestive heart failure (New York Heart Association [NYHA] III/IV) 
o 
Stroke or transient ischemic attack 
20. History of osteoporosis or fragility fractures or bone density below the expected range for age (for men < 50 
years old [Z score ≤ -2]) based on The International Society for Clinical Densitometry definition 
21. DEXA scan T-score less than -2.0 at Screening or within 6 months prior to first Screening Visit 
22. Significant acute or chronic renal or hepatic dysfunction or disease or infection (as determined by the 
investigator), including chronic active hepatitis B and C, or human immunodeficiency virus positivity 
23. Significant illness within the 2 weeks prior to the initial dose of study drug that could supress pituitary 
gonadal axis and decrease testosterone levels (as determined by the investigator) 
24. Untreated sleep apnoea 
25. Any of the following laboratory parameters at Screening: 
o 
Haematocrit above 50% 
o 
Abnormal prolactin (outside of reference range) 
o 
Abnormal TSH or free thyroxine (FT4) (outside of reference range) 
o 
Morning cortisol ≤ 5 mcg/dL 
o 
Fasting transferrin saturation > 50% 
o 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN or bilirubin ≥ 
2 times the ULN (unless caused by Gilbert syndrome)  
o 
Estimated glomerular filtration rate (eGFR) < 60 mL/min (calculated using the Cockcroft-Gault 
formula)  
26. History of cancer within last 5 years, with the exception of well treated basal cell or squamous cell 
carcinoma of the skin 
27. Any history of breast cancer 
28. Alcohol and/or drug abuse within the 12 months prior to the first Screening Visit 
29. Current/previously reported allergy to the study drug or the class of drug under investigation 
30. Documented history of significant psychiatric or medical disorder that 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. 
Test Product, Dose and Mode of Administration: 
Reference Therapy, Dose and Duration of Administration: 
Those subjects randomised to the placebo arm will be administered matching placebo capsules that are 
indistinguishable to the test product in appearance and taste but contain no active ingredient. 
All doses should be taken orally by the subject, with water, on a weekly basis (± 1 day from the time schedule of 
regular planned dose) at approximately the same time of the day. 
Duration of Treatment: 
All subjects will be treated with BGS649 or matched placebo for a maximum of 24 weekly doses (which 
provides 24 weeks therapeutic coverage due to long half-life of BGS649). Some subjects who complete 24 
weeks of treatment will be invited to participate in a 6-month blinded safety extension study (Protocol 
MBGS206). An interim analysis will be performed once approximately 100 of overall planned enrolled subjects 
have completed the Week 4 visit and any doses of BGS649 that did not lead to normalisation of testosterone or 
were considered unsafe will be identified and the dose arm terminated. 


Mereo BioPharma 2 Ltd 
 
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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 
Study endpoints 
Primary 
1. Normalisation of total testosterone levels in ≥ 75% of subjects at Week 24. 
Secondary 
1. Proportion of subjects that have normalisation of total testosterone at Week 24 
2. Proportion of subjects that overshoot testosterone (total testosterone above 1000 ng/dL [35 nmol/L]) at 
Week 24 
3. Normalisation of total testosterone in ≥ 90% subjects at Week 24 
4. Change of LH and FSH at 24 weeks 
5. Population PK analysis of plasma BGS649 concentrations 
6. PK analysis of semen BGS649 concentrations. 
Exploratory 
1. Change in oestradiol, inhibins (A and B) levels and DHT 
2. Change in testosterone/oestradiol ratio 
3. Body composition changes at Week 12 and Week 24 
4. Changes in markers of cardiometabolic disease: blood pressure, lipid profile, HbA1c, glucose and insulin, 
hs-CRP and HOMA-IR and association with change in body composition and testosterone level. 
5. Change in markers of bone turnover in those with and without 25-hydroxy vitamin D deficiency 
6. Change in total and domain scores on PRO measures (IIEF, PROMIS SexFS: to assess sexual function; 
BFI, PROMIS Fatigue Short Form, SF-36 - Vitality: to assess energy levels and fatigue; SF-36: to assess 
general quality of life (QoL); PGI-S: to assess the patients’ impression of their current health status)  over 
the 24-week period 
7. Association of objective findings of improvement (e.g. testosterone, time in physical activity or sleep and 
grip strength) and domain scores on PROs 
8. Change in physical activity, sleeping pattern and strength measured by wrist worn monitors and grip 
strength measurement at 12 and 24 weeks and association with body composition (as measured by BMI and 
waist circumference and impedance) and testosterone level. 
9. PK/pharmacodynamic (PD) relationship between BGS649 concentrations and testosterone levels 
10. For semen analysis: change in semen parameters throughout the study and association with LH/FSH level 
11. Change in bioavailable testosterone 
12. Time to first normal testosterone level. 
Safety 
1. Treatment emergent AEs (TEAEs)/SAEs (from first dose of study drug until 90 days after last treatment 
dose) 
2. Change in PSA during 24 week treatment duration 
3. Change in haematocrit during 24 week treatment duration 
4. Change in Bone Mineral Density (DEXA scan T-score and density in g/cm2) from Screening and bone 
turnover biomarkers at 24-weeks from Baseline 
5. Change in vital signs and clinical laboratory parameters, ECG  
6. Change in physical examination (including general, prostate, breast and oedema of the lower extremities). 
Statistical Methods: 
The Primary Endpoint will be considered to have been met for a dose if ≥ 75% of subjects in the ITT population 
have normalisation of total testosterone levels at Week 24 
 
Populations to be analysed: 
The intention to treat (ITT) population includes all subjects who: 


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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 
1. Are randomised, and 
2. Receive at least one dose of study medication, and 
3. Provide a Baseline and at least one post-Baseline testosterone value. 
The per-protocol (PP) population is a subset of the ITT population and includes all randomised subjects as 
randomised who have been treated according to the protocol and fulfil the following criteria: 
1. All inclusion/exclusion criteria satisfied 
2. Absence of relevant protocol violations with respect to factors likely to affect the efficacy of treatment 
where the nature of protocol violation will be defined before breaking the blind 
3. Adequate study medication compliance 
4. Adequate measurement of the primary variable. 
The safety population includes all subjects who received at least one administration of the study medication. 
For the nonlinear mixed effects modelling, all subjects who received at least one administration and have at least 
quantifiable concentration will be included in the PK population. 
All primary and secondary efficacy endpoints will be analysed using the ITT population. The PP population will 
be used only for the analysis of the primary endpoint to examine the robustness of the primary analyses. 
Safety and tolerability will be analysed using the safety population. 
Sample Size and Power: 
Sample size for the study is calculated using exact binomial methods for comparison of a single proportion 
to a performance goal of 75% normalisation. This assumes a one-sided test conducted at the 2.5% 
significance level, for which 67 subjects will be enrolled in each dose group of BGS649. 
If the true normalisation rate in a dose group of BGS649 is 90% then the power of the study is 85%. 
 
Version and Date of the Amended Protocol:  6.0,  10 March 2017 
 


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5 
TABLE OF CONTENTS 
1 
TITLE PAGE ................................................................................................................. 1 
SUMMARY AND JUSTIFICATION OF CHANGES .............................................................. 2 
2 
SPONSOR SIGNATURE PAGE .................................................................................. 5 
3 
GENERAL INFORMATION ........................................................................................ 6 
4 
STUDY SYNOPSIS ...................................................................................................... 8 
5 
TABLE OF CONTENTS ............................................................................................ 16 
5.1 
List of Tables .................................................................................................. 19 
5.2 
List of Figures................................................................................................. 19 
5.3 
List of Appendices and Supplements ............................................................. 19 
6 
LIST OF ABBREVIATIONS AND DEFINITONS OF TERMS ............................... 20 
7 
INTRODUCTION ....................................................................................................... 23 
7.1 
Background..................................................................................................... 23 
7.2 
Rationale ......................................................................................................... 24 
8 
STUDY OBJECTIVES ............................................................................................... 26 
8.1 
Primary Objectives ......................................................................................... 26 
8.2 
Secondary Objectives ..................................................................................... 26 
8.3 
Safety Objectives ............................................................................................ 26 
8.4 
Exploratory Objectives ................................................................................... 26 
9 
INVESTIGATIONAL PLAN ...................................................................................... 28 
9.1 
Overall Study Design and Plan....................................................................... 28 
9.1.1 
Description ................................................................................................. 28 
9.1.2 
Schedule of Assessments ........................................................................... 32 
9.2 
Discussion of Study Design............................................................................ 36 
9.2.1 
Risk/Benefit and Ethical Assessment ........................................................ 38 
9.3 
Selection of Study Population ........................................................................ 39 
9.3.1 
Inclusion Criteria ....................................................................................... 39 
9.3.2 
Exclusion Criteria ...................................................................................... 39 
9.3.3 
Rescreening ................................................................................................ 42 
9.3.4 
Retesting of  laboratory parameters ........................................................... 43 
9.3.5 
Early Termination ...................................................................................... 43 
9.3.6 
Withdrawal of Subjects from the Study ..................................................... 43 
9.3.7 
Study Drug Interruption and Discontinuation............................................ 44 
9.3.8 
Lost to Follow-up ...................................................................................... 46 
10 
TREATMENT OF SUBJECTS ................................................................................... 48 
10.1 
Identity of Study Treatment(s) ....................................................................... 48 
10.1.1 
Administration of Study Treatment(s) ....................................................... 48 
10.2 
Study Treatment Packaging and Labelling..................................................... 48 
10.2.1 
Packaging ................................................................................................... 48 


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10.2.2 
Labelling .................................................................................................... 49 
10.2.3 
Storage ....................................................................................................... 49 
10.2.4 
Blinding and Randomisation of Study Treatment(s) ................................. 49 
10.3 
Procedure for Breaking the Randomisation Code .......................................... 50 
10.4 
Subject Compliance ........................................................................................ 50 
10.5 
Study Treatment Accountability ..................................................................... 50 
10.6 
Contraception ................................................................................................. 51 
10.7 
Prohibited Therapy ......................................................................................... 51 
11 
ASSESSMENT OF EFFICACY ................................................................................. 53 
11.1 
Efficacy and Pharmacokinetic Variables........................................................ 53 
11.2 
Efficacy and Pharmacokinetic Endpoints ....................................................... 54 
11.3 
Efficacy Assessments ..................................................................................... 55 
11.3.1 
Male Hormonal Parameters ....................................................................... 55 
11.3.2 
Body Composition ..................................................................................... 55 
11.3.3 
Cardiometabolic Parameters ...................................................................... 56 
11.3.4 
Patient Reported Outcomes ....................................................................... 57 
11.3.5 
Actigraphy Derived Activity and Sleep Parameters .................................. 58 
11.3.6 
Grip Strength Measurement ....................................................................... 59 
11.3.7 
Semen Analysis ......................................................................................... 59 
11.4 
Pharmacokinetic Assessments ........................................................................ 59 
12 
ASSESSMENT OF SAFETY...................................................................................... 61 
12.1 
Adverse Events ............................................................................................... 61 
12.1.1 
Definitions ................................................................................................. 61 
12.1.2 
Recording of Adverse Events .................................................................... 62 
12.1.3 
Causal Assessment ..................................................................................... 63 
12.1.4 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms ................. 64 
12.1.5 
Overdose .................................................................................................... 64 
12.1.6 
Partner Pregnancies ................................................................................... 65 
12.1.7 
Adverse Events of Special Interest ............................................................ 65 
12.1.8 
Reporting of Serious Adverse Events and Adverse Events of Special 
Interest ....................................................................................................... 66 
12.2 
Safety Endpoints ............................................................................................. 66 
12.3 
Laboratory Assessments ................................................................................. 67 
12.3.1 
Clinical Laboratory Tests........................................................................... 67 
12.3.2 
Specialised Chemistry................................................................................ 67 
12.3.3 
Bone Turnover Markers ............................................................................. 68 
12.4 
DEXA Scan .................................................................................................... 68 
12.5 
Physical Examination ..................................................................................... 68 
12.6 
Vital Signs ...................................................................................................... 69 
12.7 
12-Lead ECG .................................................................................................. 69 


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12.8 
Androgen Deficiency Guidance ..................................................................... 69 
12.9 
24/7 Medical Emergency Coverage ............................................................... 70 
13 
STATISTICAL EVALUATION ................................................................................. 71 
13.1 
Sample Size and Power .................................................................................. 71 
13.2 
Randomisation ................................................................................................ 71 
13.3 
Analysis Sets .................................................................................................. 71 
13.3.1 
Intention to Treat (ITT) (Full Analysis Set) .............................................. 71 
13.3.2 
Per Protocol ............................................................................................... 71 
13.3.3 
Safety Population ....................................................................................... 72 
13.3.4 
PK Population ............................................................................................ 72 
13.4 
Endpoints ........................................................................................................ 72 
13.4.1 
Primary Efficacy Endpoint(s) .................................................................... 72 
13.4.2 
Secondary Efficacy Endpoint(s) ................................................................ 72 
13.4.3 
Pharmacokinetics ....................................................................................... 72 
13.4.4 
Exploratory Endpoints(s) ........................................................................... 72 
13.4.5 
Safety Endpoint(s) ..................................................................................... 72 
13.5 
Description of Statistical Analyses ................................................................. 73 
13.5.1 
General Considerations .............................................................................. 73 
13.5.2 
Analysis of Primary Endpoint.................................................................... 73 
13.5.3 
Analysis of Secondary Endpoints .............................................................. 73 
13.5.4 
Analysis of Exploratory Endpoints ............................................................ 74 
13.5.5 
Safety Analyses ......................................................................................... 74 
13.5.6 
Analysis of Further Endpoints ................................................................... 75 
13.6 
Interim Analysis ............................................................................................. 75 
13.7 
Interim Clinical Study Report ........................................................................ 76 
13.8 
Population Pharmacokinetic/Pharmacodynamic Modelling .......................... 76 
14 
DIRECT ACCESS TO SOURCE DATA/NOTES ..................................................... 77 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 77 
15.1 
Conduct of the Study ...................................................................................... 77 
15.2 
Study Monitoring............................................................................................ 77 
16 
ETHICS ....................................................................................................................... 78 
16.1 
Independent Ethics Committee/Institutional Review Board .......................... 78 
16.2 
Written Informed Consent .............................................................................. 78 
16.3 
Data Monitoring Committee........................................................................... 78 
17 
DATA HANDLING AND RECORD KEEPING ....................................................... 79 
17.1 
Case Report Forms/Source Data Handling..................................................... 79 
17.2 
Retention of Essential Documents .................................................................. 79 


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18 
FINANCING AND INSURANCE .............................................................................. 80 
19 
PUBLICATION POLICY ........................................................................................... 80 
20 
SIGNATURE OF INVESTIGATOR .......................................................................... 81 
21 
REFERENCE LIST ..................................................................................................... 82 
22 
APPENDICES ............................................................................................................. 84 
 
5.1 
List of Tables 
Table 9–1 
Schedule of Assessments ................................................................................... 33 
Table 10–1 
Study Treatments................................................................................................ 48 
 
5.2 
List of Figures 
Figure 9–1 
Study Design ...................................................................................................... 31 
 
5.3 
List of Appendices and Supplements 
Appendix I 
World Medical Association Declaration of Helsinki 
Appendix II 
Symptoms of Androgen Deficiency 


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6 
LIST OF ABBREVIATIONS AND DEFINITONS OF TERMS 
ACR 
albumin:creatinine ratio 
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 
CRF 
case report form 
CSR 
clinical study report 
CTx1 
C-terminal telopeptide 
CYP 
Cytochrome 
CYP19 
aromatase 
D 
Day 
DBP 
diastolic blood pressure 
DEXA 
dual energy X-ray absorptiometry 
DHT 
dihydrotestosterone 
DMC 
Data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ET 
early termination 
EOT 
End of Treatment 
EUDRACT 
European Union Drug Regulatory Agency Clinical Trial 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
FT4 
free thyroxine 
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 
IC50 
half maximal inhibitory concentration 


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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 
IRT 
interactive response technology 
ITT 
intention to treat 
LDL 
low density lipoprotein 
LH 
luteinising hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measure 
MSAP 
Modelling and Simulation Analysis Plan 
NED 
no-effect dose 
NYHA 
PGI-S 
New York Heart Association 
Patient Global Impression - Status 
PCR 
protein:creatinine ratio 
PD 
pharmacodynamics 
P1NP 
procollagen type 1 N-propeptide 
PK 
pharmacokinetics 
PP 
per-protocol 
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 
SARM 
selective androgen receptor modulator 
SERM 
selective oestrogen receptor modulator 
SHBG 
sex hormone binding globulin 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOP 
standard operating procedure 
TEAE 
treatment emergent adverse event 
Tmax 
time at which maximum serum concentration is reached 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 


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US 
United States  
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, which results 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 as well as 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. In one study in 160 men who were 
referred for medical or surgical treatment of obesity, HH was present in 36% subjects and the 
prevalence of HH rose linearly with increasing body mass index (BMI) (7.4% for a BMI of 
30-35 kg/m2 to 59.2% for a BMI > 50 kg/m2) (Hofstra et al 2008). Given the prevalence of 
obesity (which is expected to continue to increase) it is estimated that up to 1.5 million men 
in the United States (US) and 1 million men in Europe may have androgen deficiency due to 
obesity. 
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 T1/2 aromatase inhibitor for the treatment of refractory 
endometriosis and is being evaluated in obese men with HH. In vitro experiments with 
human placenta microsomal aromatase demonstrated a half maximal inhibitory concentration 
(IC50) for BGS649 inhibition of 6 nM, which is 100 to 300 times more potent than 
aminoglutethimide and in the same range of potency as letrozole, for which an IC50 of 
11.5 nM has been reported (Bhatnagar et al 1990). 
 
 
 
 
 
 
 


 
 
 
 
 
 
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To date, BGS649 has also been administered to 21 obese men with HH (8 subjects were 
assigned to placebo) and was found to be well tolerated without drug discontinuation or drug 
related serious adverse events (SAEs) (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 (0.3 mg loading 
dose followed by 10 weekly fixed doses of 0.1 mg). 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). There were few SAEs 
reported (only during Part 2 and not considered related to the study drug) and the most 
commonly reported adverse events (AEs) included spontaneous penile erection and headache. 
Oestradiol levels were reduced by approximately 25-50% on average and gonadotropin levels 
(follicle stimulating hormone [FSH] and luteinising hormone [LH]) were increased in 
subjects treated with BGS649 (no effect observed for subjects on placebo). At the time of the 
interim analysis of Part 1, new data (Jones et al 2011) indicated that the variances of the 
homeostatic assessment of insulin resistance (HOMA-IR) were larger than assumed in the 
original sample size calculations and this (along with the discovery of dosing errors) 
contributed to the decision for early termination of Part 2 of the study. 
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 
published on the use of testosterone replacement therapy (Testosterone Replacement 
Therapy, 2014). 
This dose-ranging study aims 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. Study CBGS649A2204 
demonstrated that testosterone levels normalised within 2 to 4 weeks of dosing. However, 
any impact of testosterone levels on the symptoms and signs of hypogonadism is expected to 
take longer. Therefore, this study evaluates the normalisation of testosterone levels as a 
primary endpoint, along with key secondary/exploratory endpoints of clinical efficacy after 
24 weeks. 
7.2 
Rationale 
This study will investigate the efficacy of different weekly oral doses of BGS649 
 
 versus matching placebo in normalising testosterone levels in ≥ 75% of a 
population of obese men with HH over a 24-week period. Subjects will be randomised to 
three treatment arms with doses of 
 of BGS649 or matching 
placebo. If any of the three active treatment arms is found to be ineffective at the time of 
interim analysis and is predicted not to reach at week 24 therapeutic range in > 75% of 
subjects, or is considered unsafe per the data monitoring committee (DMC), dosing for the 
ineffective or unsafe arm(s) will be stopped for ethical reasons (see Section 13.6). 


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Doses and administration schedules were chosen based on data obtained from a previous 
study where weekly administration of BGS649 was investigated. This was a 2-part clinical 
study in obese men with HH over 12 weeks (11 treatments). Part 1 was an open-label, dose 
finding study 
 assessing normalisation of testosterone levels. 
Part 2 included a loading dose of 
in the first week, followed by a maintenance dose of 
weekly. The majority of subjects recruited had normalisation and maintenance of 
serum total testosterone levels with no evidence of total testosterone peaks above the ULN. 
Oral androgen therapies are generally contraindicated because of the first pass hepatic effects 
which dramatically suppress high density lipoproteins (HDL), increase thrombogenic factors 
and often cause liver function abnormalities. These hepatic effects of androgens have so far 
limited the clinical utility of selective androgen receptor modulators (SARMs). Testosterone 
gels are currently widely used but require daily skin application and have a high potential for 
resulting in overshooting of testosterone levels above normal range and causing side effects 
such as elevated haematocrit and prostate-specific antigen (PSA), requiring dose titration. 
Thus, an oral therapy that normalises systemic testosterone, but does not significantly 
increase local hepatic exposure to androgens or require testosterone monitoring and dose 
titration is the therapeutic goal of testing BGS649 in men with HH. 
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 Objectives 
The primary objective is to demonstrate the efficacy of BGS649 to normalise total 
testosterone levels (300-1000 ng/dL [10.4-35 nmol/L]) in ≥ 75% of subjects after 24 weeks of 
treatment. 
8.2 
Secondary Objectives 
1. To follow the time-course of normalisation in total testosterone levels 
2. To demonstrate the efficacy of BGS649 to normalise total testosterone levels in ≥ 90% of 
subjects after 24 weeks of treatment 
3. To evaluate the effect of BGS649 on LH and FSH  
4. To further determine the pharmacokinetics (PK) of BGS649. 
8.3 
Safety Objectives 
1. To evaluate safety and tolerability of BGS649. 
8.4 
Exploratory Objectives 
1. To evaluate the effect of BGS649 on oestradiol, DHT and inhibins (A and B) 
2. To evaluate the effect of BGS649 on testosterone/oestradiol ratio 
3. To investigate the effect on patient reported outcomes (PROs) following treatment with 
BGS649. PRO measures will be: 
International Index of Erectile Function (IIEF) and PROMIS Sexual Function and 
Satisfaction (PROMIS 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. 
o 
Patient Global Impression of Status items (PGI-S): to assess the patients’ overall 
impression of their current health status. 
4. To determine any change in physical activity and sleeping pattern via wrist worn monitor 
5. To determine any change in grip strength, as measured by a dynamometer 
6. To determine any associations between objective findings of improvement (e.g. 
testosterone, time in physical activity or sleep, and grip strength) and total and domain 
scores on PRO measures 
7. To determine body composition change: waist circumference, BMI, body composition (as 
measured by impedance), and gynecomastia 
8. To determine any associations between change in testosterone, body fat (as measured by 
BMI and waist circumference) and change in grip strength and wrist monitor data 
9. To determine any associations between change in testosterone, body composition (as 
measured by impedance) and change in grip strength and wrist monitor data 


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10. To determine the effect of BGS649 on cardiometabolic parameters: systolic blood 
pressure (SBP) and diastolic blood pressure (DBP), lipid panel (total cholesterol, low 
density lipoprotein [LDL], triglycerides and HDL), glycosylated haemoglobin (HbA1c), 
fasting glucose and insulin, HOMA-IR  and high sensitivity C-reactive protein (hs-CRP) 
11. To determine any associations between testosterone, change in body composition and 
cardiometabolic parameters: SBP and DBP, lipid panel (total cholesterol, LDL, 
triglycerides and HDL), HbA1c, fasting glucose and insulin, HOMA-IR and hs-CRP 
12. To determine the change in bone mineral density (dual energy X-ray absorptiometry 
[DEXA] scan), bone turnover markers (C-terminal telopeptide [CTx1] and procollagen 
type 1 N-propeptide [P1NP], osteocalcin, bone alkaline phosphatase) 
13. To explore the effects of BGS649 on bone biomarkers on subjects with and without 
25 hydroxy vitamin D deficiency (vitamin D deficiency is defined as 25 hydroxy 
vitamin D < 20ng/ml) 
14. To explore the relationship between BGS649 concentration and testosterone levels 
15. To determine the effects of BGS649 on semen parameters (semen volume, sperm count, 
concentration, motility and morphology) and to measure BGS649 concentrations in 
seminal fluid in subjects that provide semen samples 
16. To explore the relationship between LH/FSH change and improvement in semen analysis 
in subjects that provide semen samples. 


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
9.1.1 
Description 
This is a phase IIb, multicentre, double-blind, randomised, placebo-controlled parallel-group 
36-week study evaluating safety and efficacy of BGS649 in male obese subjects with HH. 
The study will have three phases: 
1. A Screening Phase lasting up to 28 days (Screen Visit 1, Screen Visit 2), including Day -
28 to Day -1 
2. A Randomisation Phase including the Baseline visit (Day 1) and the treatment period 
Day 1 to Visit 8 (Week 24)  
3. A Safety Follow-Up Phase to Visit 11 (Week 36, follow up [FU]). Visits 9 and 10 are 
telephone assesments. 
Study participation will comprise up to 2 Screening Visits, 8 visits during the treatment 
period up to Week 24 (End of Treatment [EOT]), FU Visits 9, 10 (telephone assessment) and 
11 (at Weeks 28, 32 and 36 respectively) for safety performed to 12 weeks after Visit 8 
(EOT) (see schedule of assessments, Table 9–1). PK in seminal fluid will be performed at 
Visit 8. A minimum of 25 subjects per treatment arm will be invited to participate in a 
6-month extension study (Protocol MBGS206), starting at Visit 8 (EOT). This transfer will 
be handled by the interactive response technology (IRT) and the blind will be maintained. 
Subjects participating in the 6-month extension will have their last study visit at Visit 8 
(EOT) and will not participate in Visits 9, 10, and 11. The study design is summarised in 
Figure 9–1. The end of the study will be the last visit of the last subject. 
Subjects that agree to participate in the trial (informed consent form [ICF] process completed; 
subject has signed and dated ICF) will be screened (Screening Phase) and assessed against 
inclusion/exclusion criteria. Symptoms of androgen deficiency will be assessed based on the 
questionnaire provided (see Section 12.8) and all positive symptoms will be entered in the 
electronic case report form (eCRF).  
Testosterone levels to be taken before 11 am. If there is evidence that screening was failed 
due to a sample inadvertently being taken after this time, technical error (for example due to 
failure to meet storage conditions defined in laboratory manual) or clinically discrepant 
results (>100ng/dl difference between tests with one test being <200ng/dl),   a retest is 
allowed in discussion with the Medical Monitor. 
Due to the potential for dehydration to affect Haematocrit, subjects should be fully hydrated 
at the time of screening and during the trial when the haematocrit is tested, to ensure a 
reliable result both for study eligibility assessment and the ongoing monitoring (with respect 
to the haematocrit stopping criterion).  
Eligible subjects will be randomised on Day 1 (Baseline) in a 1:1:1:1 ratio to one of the 
following treatment groups, consisting of three capsules per dose taken weekly: 


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o 
o 
o 
Once approximately 100 of the overall planned enrolled subjects have completed the Week 4 
visit, an interim analysis will be performed by an independent DMC who will review 
unblinded data and determine whether the criteria for normalisation of testosterone 
(testosterone within or above normal reference range for healthy adult males according to 
FDA criteria) were met. The DMC will establish whether an individual arm has met the 
criteria of ≥ 75% of subjects reaching the normalisation of testosterone, or whether in the 
opinion of the DMC following unblinded review that when the arm is fully recruited it is 
expected to achieve a ≥ 75% response at Week 24 (see Section 13.6). Dosing arms which 
meet either of these criteria will be deemed effective. For dosing arms deemed to be 
ineffective, dosing will be stopped and no further randomisation to that arm will be 
performed. Subjects assigned to ineffective or unsafe arm(s), as determined per the DMC, 
will be discontinued from the study, will attend Visit 8 (EOT) and will be followed-up for an 
additional 12 weeks (FU, Visit 11) and will not be eligible for MBGS206 extension study. 
Recruitment will continue while the interim analysis is ongoing. 
The remainder of the randomisation will then continue in a 1:1:1 ratio of remaining active 
arms versus placebo to the following treatment groups:  
During the 24-week treatment period, subjects in the BGS649 groups and the matching 
placebo group will take the required dose weekly (± 1 day from the time schedule of regular 
planned dose).  The treatment period consists of 24 weekly doses providing therapeutic 
coverage to week 24 due to long half-life of BGS649. The capsule will be taken orally by the 
subject with water. 
Seminal Fluid Evaluation: 
Semen Quality 
To evaluate the effect of BGS649 treatment on semen quality, semen analysis (semen 
volume, sperm count, concentration, motility and morphology) will be performed. Subjects 
will be expected to successfully provide semen samples on three occasions during the 
Randomisation Phase. It is understandable that some subjects will not be able to provide 
semen samples.  
Semen 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 semen evaluation.  
Semen PK 


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Additional semen samples will be required at EOT in order to assess PK in seminal fluid to 
evaluate the concentration of BGS649 at steady state. Seminal fluid PK will be assessed at 
Visit 8 (EOT) (Section 11.3.7). For subjects that are discontinued early from the study drug, 
an EOT sample will be obtained.  
Any subjects who are vasectomised or have vasectomy planned during the study period, will 
be exempt. 
Semen samples at baseline be taken up to 48 hours before or after the Baseline Visit. During 
Randomisation Phase semen samples may be provided up to 48 hours before or after the 
Assessment visit.  
 
Testosterone Monitoring: 
To ensure adequate safety monitoring, serum total testosterone levels will be evaluated at 
each visit by an independent unblinded physician (see Section 9.3.6 and Section 16.3) and if 
subject meets discontinuation criteria (total testosterone is ≥ 1500 ng/dL (52 nmol/L) at any 2 
consecutive time points during the study), the subject will be discontinued from treatment. In 
addition, if one of the active BGS649 study arms presents with ≥ 2 subjects meeting this 
discontinuation criterion at any time point within the first 24 randomized subjects to that arm 
or > 15% subjects meet this criterion at any time point ≥ 25 randomized subjects, then the 
arm will be evaluated by the independent DMC for potential dosing discontinuation based on 
FDA guidance (FDA Advisory Committee Industry Briefing Document Testosterone 
Replacement Therapy, Sept 2014). Subjects may be discontinued from the study arm and no 
further randomisation to that arm will be performed.  
Efficacy and safety variables will be assessed according to the schedule of assessments in 
Table 9–1. Efficacy assessments will include measurement of total and calculated 
bioavailable testosterone, LH, FSH, inhibins A and B, dihydrotestosterone (DHT), and total 
oestradiol, body composition measurement including waist and hip circumference and 
impedance, cardiometabolic parameters, PROs, physical activity and sleep pattern via the 
wearing of wrist monitors, grip strength via a dynamometer and semen analysis. Safety 
assessments will include vital signs, physical examination, electrocardiograms (ECGs), 
haematology, blood chemistry and urinalysis, bone turnover markers, DEXA scan, PSA, and 
recording of AEs, SAEs, AEs of special interest (AESIs) and concomitant medications. 
Pharmacokinetic samples will be collected as follows (see Table 9–1): 
1. Plasma PK samples will be taken pre-dose and 1h post-dose at Visit 5. At Visit 8 (EOT; 
Week 24) it will be taken only once. 
2. Semen samples for seminal fluid PK will be taken at Visit 8 (EOT) 
The primary efficacy endpoint is the normalisation of total testosterone in ≥ 75% of subjects 
at Week 24. Secondary and exploratory efficacy endpoints are presented in Section 11.2, and 
safety endpoints in Section 12.2. 
 


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Figure 9–1 
Study Design 
 
 
 
 
D=day; DMC=Data Monitoring Committee; EOT= End of Treatment; IRT=interactive response technology; PK, pharmacokinetic; W=week 
1 
A minimum of 25 subjects per treatment arm will be invited to participate in a 6-month extension study (Protocol MBGS206), starting at Visit 8 (Week 24 EOT). This 
transfer will be handled by the IRT and the blind will be maintained. Subjects participating in the 6-month extension will have their last study visit at Visit 8 (Week 24 
EOT)  
2 
If one of the BGS649 study arms at Visit 3 (Week 4) fulfils discontinuation criteria as determined per DMC, the dosing for the ineffective or unsafe arm(s) will be 
stopped and no further randomisation to that arm will be performed. 
 


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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 
 
Screening Phase 
Randomisation Phase (Treatment Period) 
Follow-Up1 
Visit 
Screening (D -28 to D -1) 
1 
(Baseline) 
2 
3 
4 
5 
6 
7 
8 
(EOT) 
9 
10 
11 
(FU) 
Week/Day 
Screen 
Visit 1 
Screen Visit 2 
(Visit 1 + 
3-7 days) 
D 1  
D 8 
(±1 D) 
W4 
(±2 D) 
W8 
(±2 D) 
W12 
(±2 D) 
W16 
(±2D) 
W20 
(±2 D) 
W24 
(±2 D) 
W282 
(±2 D) 
W322 
(±2 D) 
W36 
(±2 D) 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Androgen deficiency symptom checklist 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Full general physical exam and 
prostate exam and breast exam 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
Limited physical exam3 
 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
Vital signs4; height (Visit 1 only)  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
12-Lead ECG 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
Specialised chemistry: morning cortisol, 
TSH, FT4, prolactin, iron, transferrin5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
25 hydroxy vitamin D 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests: haematology, 
blood chemistry, eGFR by 
Cockcroft-Gault formula, dipstick 
urinalysis6 and PSA7 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Cardiometabolic parameters 1:HbA1c, 
fasting lipids (total cholesterol, LDL, 
HDL, triglycerides)7 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
Cardiometabolic parameters 2: Fasting 
glucose and insulin, hs-CRP, HOMA-IR 
Bone turnover markers7,8 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Sex hormones 1: testosterone (total), 
oestradiol (total), LH 
X9, 11 
X9,10, 11 
X11 
X11 
X11 
X11 
X11 
X11 
X11 
X11 
 
 
X 
Bioavailable testosterone, SHBG 
 
 
X11 
X11 
X11 
X11 
X11 
X11 
X11 
X11 
 
 
X 
Sex hormones 2: FSH 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
DHT, inhibin A and B 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Semen quality analysis12 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Semen PK samples13 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Plasma PK samples14 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
Hip and waist measurement 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 


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Screening Phase 
Randomisation Phase (Treatment Period) 
Follow-Up1 
Visit 
Screening (D -28 to D -1) 
1 
(Baseline) 
2 
3 
4 
5 
6 
7 
8 
(EOT) 
9 
10 
11 
(FU) 
Week/Day 
Screen 
Visit 1 
Screen Visit 2 
(Visit 1 + 
3-7 days) 
D 1  
D 8 
(±1 D) 
W4 
(±2 D) 
W8 
(±2 D) 
W12 
(±2 D) 
W16 
(±2D) 
W20 
(±2 D) 
W24 
(±2 D) 
W282 
(±2 D) 
W322 
(±2 D) 
W36 
(±2 D) 
Body composition using bioimpedance15 
(by impedance) 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Actigraphy16 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Grip strength 
 
 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
PROs: IIEF, BFI, PROMIS SexFS, 
PROMIS Fatigue Short Form, PGI-S 
 
X17 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
PROs: SF-36  
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
DEXA 
X18 
 
 
 
 
 
X18 
 
 
 
Study treatment 
 
 
X 
Once weekly19 
 
 
 
 
Study drug dispensation 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Study drug accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AE assessment20 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
A minimum of 25 subjects per treatment arm will be invited to participate in a 6-month extension study (Protocol MBGS206), starting at Visit 8 (EOT). Subjects participating in the 
6-month extension will have their last study visit at Visit 8 (EOT)  
2 
Telephone Assessment Visit only 
3 
Limited physical examination (cardiovascular system and lower extremities oedema)  
4 
Vital signs assessment will include the measurement of SBP, DBP, pulse, oral temperature and body weight 
5 
Fasting transferrin  
6 
A microscopic examination including RBC and WBC will be performed only when dipstick evaluation is positive for WBC and/or blood or protein 
7 
All blood samples are to be collected after 8 hours fasting, after ECG and vital sign measurements 
8 
Bone turnover markers include CTx1, osteocalcin, bone alkaline phosphatase and P1NP 
9 
At Screening serum total testosterone concentration must be < 300 ng/dL (10.4 nmol/L) based on two morning samples, taken before 11 am at least 3 days apart. Laboratory parameters 
from screening visit 1 do not need to be received before screening visit 2 is take place 
10 Oestradiol and LH will not be measured at this visit 
11 Samples to be collected in the morning before 11 am pre-dose 
12 Semen quality analysis will include semen volume, sperm count, concentration,  motility and morphology. Sample collection is not required to be the same day as the assessment visit. 
Therefore sample collection is allowed within +/-48 hours the scheduled visit for Baseline and attendance Visits  during the treatment phase 
13 Semen samples for seminal fluid PK  is not required to be the same day as the assessment visit. Therefore semen PK collection is allowed +/- 48 hours around the attendance visits   
14 Samples will be taken at pre-dose and 1h post-dose for sparse plasma PK sampling at Visit 5 (week 12). Investigators should ensure that Visit 5 where plasma PK is measured coincides 
with the study drug dosing day. At EOT Visit 8 (Week 24), PK will be taken only once together with other laboratory assessments taken at that visit. 
15 Subjects should come well hydrated, drinking water the night before and the morning before the impedance measurements 


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16 Activity wrist monitors will be worn by subjects for 7 continuous days after Baseline visit and visit 5 and 7 continuous days before Visits 8 and 11, so that the monitors can be collected at 
Visit 8 from subjects transferring to the extension study and at Visit 11 from subjects completing FU visit. 
17 Screening PRO’s should be performed no more than 7 days before dosing and may be performed outside of the Screen Visit 2 to meet this timing if required 
18 Screening DEXA scan will be performed during screening and up to Day 8 after randomisatio. The End of treatment DEXA will be performed only in a case patient reached minimum visit 
5(w12) and it can be performed within 14 days before EOT to accommodate scheduling 
19 The administration of the study drug (BGS649/placebo) will be performed at the study site on Week 12 to allow measurement of PK at pre-dose and 1h post-dose 
20 SAEs collected from signature of informed consent and AEs, AESIs collected from  randomization. 


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9.2 
Discussion of Study Design 
This phase IIb, randomised, multi-centre, double-blind, parallel group, placebo-controlled 
24-week study design is considered suitable for the assessment of normalisation of serum 
testosterone levels, the effect on clinical symptoms and signs, and safety and tolerability in 
adult obese male subjects with HH. 
The assessment methods used to demonstrate the efficacy of BGS649 in normalising 
testosterone levels in ≥ 75% of subjects after 24 weeks of double-blind treatment are 
considered appropriate. For the primary efficacy endpoint, a clinically significant treatment 
effect is considered to be 75% of subjects attaining total testosterone levels within normal 
therapeutic range. This is in line with the current regulatory efficacy endpoint (FDA), where 
75% subjects with testosterone in the therapeutic range was the recommended target for 
clinical trials with hypogonadism (Testosterone Replacement Therapy, 2014). 
The doses of BGS649 selected for use in this study 
) are 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). However, to attempt to define a no-effect dose (NED), there will be an 
interim analysis conducted once approximately 100 of overall planned enrolled subjects have 
completed the Week 4 visit (see Section 13.6). If any of the initial three active treatment arms 
is found to be ineffective or unsafe, dosing for the ineffective or unsafe arm(s) will be 
stopped for ethical reasons. 
The selected dosing schedule (1 intake per week) was chosen based on the PK properties of 
BGS649, which indicate rapid absorption (time at which the maximum serum concentration 
is reached [Tmax] of 1h), extensive distribution and a prolonged elimination phase 
(elimination half-life of 21 days) (Study CBGS649A2204). Previous studies also indicated 
that a once weekly or monthly administration of BGS649 should provide continuous, stable 
levels of aromatase inhibition (Study CBGS649A2101). The treatment period of 24 weeks is 
considered to be a suitable length to allow demonstration of the primary objective on 
dose-finding for testosterone normalisation and clinical effects. 
Aromatase inhibitors decrease oestrogen synthesis and increase pituitary LH and FSH with a 
consequent stimulation of testosterone production (de Boer et al 2005; Loves et al 2008). 
This increase in testosterone has multiple clinical effects, including: 
1. Effect on insulin resistance with an improvement observed specifically in subjects with 
Baseline high insulin resistance (Cai et al 2014; Traish et al 2014). Therefore multiple 
cardiovascular risk markers and HOMA-IR as a marker for insulin resistance will be 
evaluated during this study. 
2. Effect on body composition leading to an increase in lean body mass and a decrease in 
total fat mass (Wang et al 2000). Therefore change in body composition will be 
evaluated. 


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3. Effect on sleep pattern, (Barrett-Connor et al.,2008) increase in strength and stamina and 
physical activity Therefore, sleep quality and duration, strength, stamina and physical 
activity will be evaluated   
4. Effect on sexual well-being leading to substantial improvements in erectile dysfunction 
and libido/sexual desire (Pexman-Fieth et al., 2014). Therefore, sexual functioning, 
including erectile function, will be evaluated via the International Index of Erectile 
Function (IIEF) PRO and via the Patient-Reported Outcomes Measurement Information 
System(®) Sexual Function and Satisfaction (PROMIS(®) SexFS) PRO (Flynn et al., 
2013) 
5. Effect on fatigue leading to substantial improvements in fatigue (Pexman-Fieth et al., 
2014). Therefore, levels of fatigue will be evaluated via the PROMIS Fatigue Short Form 
and Brief Fatigue Inventory (BFI) (Mendoza et al., 1999) and levels of vitality via the 
Short Form 36 (SF-36) Vitality domain 
6. Effect on overall well-being and health status is inconsistent, with open label but not 
randomised studies finding an improvement in mood and well-being (Spitzer et al, 2013). 
Therefore quality of life will be evaluated via the Short Form 36 (SF-36) (McHorney et 
al., 1994) and via Patient Global Impression of Status items (PGI-S)  
7. Total and domain scores on PRO measures will then be compared to objective 
measurement of functionality via actigraphy evaluating the time spent in sedentary, 
moderate and vigorous physical activity and sleep, and assessment of muscle strength by 
assessing grip strength. 
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 
hypogonadotropic hypogonadism. The planned study may be too short to detect a significant 
effect on bone density, as evaluated by DEXA scan, but bone formation and resorption 
markers will be monitored. However, there will be an extension study planned that will 
evaluate bone density by DEXA.  
An increase of LH and FSH stimulates spermatogenesis and in this way may improve 
fertility. However excessive testosterone exposure could lead to testicular atrophy and 
therefore this study will monitor semen parameters (Crosnoe et al 2013). It will be accepted 
that not all subject will be able to provide semen sample on all visits. Vasectomised subjects 
or those who have vasectomy planned during the study period will be exempt from this 
assessment. 


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BGS649 has been shown to be present in semen in a previous study (Study 
CBGS649A2204). PK assessment of seminal fluid will be performed to further monitor the 
levels of BGS649 present in the semen at the three doses used in this study. 
Aromatase inhibitors, such as BGS649 could theoretically cause androgens to rise above 
normal ranges, potentially leading to elevation of haematocrit, spermatogenesis suppression 
and worsening of other parameters. Such effects have not been observed in the previous 
human BGS649 study (Study CBGS649A2204) or other aromatase inhibitor studies 
(Saylam et al 2011) and therefore the likelihood of these effects being observed in this study 
is low due to a functioning feedback loop. However, to ensure adequate safety monitoring, 
testosterone levels will be monitored throughout the study by an unblinded independent 
physician. In the event of subjects presenting with total testosterone ≥ 1500 ng/dL 
(52 nmol/L) at any 2 consecutive time points, treatment will be discontinued 
(see Section 9.1.1).  
9.2.1 
Risk/Benefit and Ethical Assessment 
BGS649 is a highly specific and potent aromatase inhibitor, which is structurally related to 
letrozole (Femara), a currently marketed aromatase inhibitor.  
Oestrogens in men, together with testosterone, contribute to the regulation of LH and FSH 
levels and therefore an aromatase inhibitor such as BGS649 is expected to increase 
gonadotrophins and lead to an increase in androgen levels. This is both the on-target 
pharmacology of aromatase inhibitors, and a clinical risk, as pharmacologic suppression of 
aromatase in men can cause androgens to rise above normal ranges (Loves et al 2008). Acute 
consequences of elevated androgens are rare; however chronic testosterone elevation can lead 
to testicular atrophy via suppression of gonadotrophins, and suppression of spermatogenesis. 
Other effects of high testosterone include elevation of haematocrit, effect on prostate and 
elevation of PSA and cardiovascular effects. The measures which will be used in this study to 
monitor/avoid these risks are described in Section 9.2. 
Administration of BGS649 therefore presents a theoretical risk of impaired spermatogenesis 
and infertility, although this is regarded as generally reversible based on clinical experience 
with androgens and aromatase inhibitors, and on pre-clinical studies in dogs dosed with 
BGS649 (Study 1070172 and Study 1170689). The emerging pre-clinical profile of BGS649 
predicts multiple beneficial effects on the pathophysiology of HH. Administration of BGS649 
in men has not led to significantly elevated levels of testosterone. 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 9.2 for further details). 
Decrease in oestrogen is a risk factor for osteoporosis development in a postmenopausal 
woman. Administration of BGS649 in man leading to reduction of estradiol levels may 
therefore represent a risk potentially leading to decrease in bone density and development of 
osteoporosis.  


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BGS649 does not exhibit genotoxicity, and is not a substrate or inducer of major Cytochrome 
(CYP) 450 enzymes. It has shown 100-fold selectivity for CYP19 inhibition compared to 
other CYPs and has also shown minimal inhibition of CYP2A6, which is considered to be 
unlikely to be relevant at therapeutic drug concentrations. In addition, BGS649 is metabolised 
very slowly by CYPs. Therefore, the potential of BGS649 drug-drug interactions from a PK 
perspective is considered to be low. 
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 
). 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. This study compares 
the effect of different doses of BGS649 
 with a matched placebo in 
the normalisation of testosterone levels in obese male subjects with HH. 
9.3 
Selection of Study Population 
9.3.1 
Inclusion Criteria 
1. Adult male subject aged 18 to 65 years inclusive 
2    BMI > 30 kg/m2 and < 50 kg/m2 
3. Serum total testosterone concentration below the normal range (serum total testosterone 
< 300 ng/dL [< 10.4 nmol/L]) in both of two morning samples, taken before 11am,  at 
least 3 days apart 
4. LH levels below the ULN 
5. Oestradiol levels within or above the normal range of approved assay 
6. At least two symptoms of androgen deficiency present for at least 2 months prior to the 
first Screening Visit, with at least one of these being a sexual dysfunction (a full list is 
provided in Appendix II) 
7. 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 theoretical fetal risk of 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 
8. Ability to understand and comply with the requirements of the protocol/study, including 
understanding and being able to give informed consent. 
9.3.2 
Exclusion Criteria 
1. Evidence of clinically significant endocrinopathy at Screening that may interfere with the 
study assessments or mask/mimic symptoms of hypogonadism e.g., growth hormone 
deficiency, adrenal deficiency, untreated hypothyroidism (primary hypothyroidism on 


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replacement with normal thyroid stimulating hormone [TSH] level is allowed), or that 
may interfere with the evaluation of efficacy/safety parameters 
2. Other types of HH (e.g., Kallmann syndrome) or primary hypogonadism 
(e.g., cryptorchidism, or Klinefelter syndrome) 
3. Any other pituitary or hypothalamic disease, as based on one of the following: 
o Current or past hypothalamic or pituitary tumour 
o 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, very low testosterone and LH (unless there is 
documentation of a normal magnetic resonance imaging scan of pituitary and 
hypothalamus within 3 months before first Screening Visit) 
o Hypothalamic or pituitary conditions, which may contribute to hypogonadism 
e.g., pituitary sarcoidosis, histiocytosis or tuberculosis 
4. Subject with prostate disease, as confirmed by the presence of one of the following: 
o History of prostate cancer 
o Elevated PSA levels ≥ 3 ng/mL at Screening 
o Subjects with a detectable prostate nodule or induration at Screening unless proven 
previously benign by a biopsy 
o Urologist confirmed symptomatic benign prostatic hyperplasia 
5. History of type 1 diabetes mellitus 
6. Current clinically symptomatic  depression or current or past Bipolar disorder 
7. Uncontrolled type 2 diabetes mellitus (HbA1c > 10.5% at Screening) or significant 
diabetic neuropathy. Subjects with type 2 diabetes can be included when both of the 
following conditions are met: 
o HbA1c ≤ 10.5% at Screening, and: 
o Anti-diabetic medication regimen has been stable for ≥ 8 weeks before the first 
Screening visit 
8. Treatment with one or more of the following prescribed or over the counter medications 
in the six months prior to first Screening Visit: 
o Medications with known androgenic or estrogenic properties or  known to affect 
production of sex hormones 
o  Injectable testosterone enhancement therapy 
o Fertility drugs 
o Growth hormone 
o Anabolic steroids 
o Long acting opiates 


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9. Treatment with topical testosterone therapy in the two months prior to first Screening 
visit 
 
10. Treatment with one of the following medications  for either >7 consecutive days in the 
three months prior to first Screening Visit OR any treatment within 3 weeks of first 
Screening Visit: 
o Testosterone lowering drugs e.g., spironolactone, cimetidine, 5α-reductase inhibitors  
o Short acting opiates/opioids including methadone 
o Medications known to increase prolactin levels, e.g., antipsychotics 
11. Treatment with the following medications: 
o Chronic systemic steroid treatment or systemic steroids for > 5 consecutive days for 
intercurrent illness within the 4 weeks prior to the first Screening visit (inhaled and 
topical steroids are allowed) 
o Clomid within 1 year before first Screening Visit 
o Bisphosphonates or other medication used to treat low bone density (denosumab, 
teriparatide) except calcium and vitamin D within 1 year before first Screening Visit 
12. Weight loss or weight gain (gain or loss > 5% body weight) OR weight loss surgery or 
procedures within the 3 months prior to first Screening Visit  
13. Participation in any clinical trial using clinical investigational product intervention within 
3 months before first Screening Visit or 5 half-lives of investigational product 
administration, whichever is  longer 
14. Any clinically significant 12-lead ECG abnormalities at Screening including QTCF 
interval > 450 ms 
15. Medical history of Long QT syndrome 
16. History of thromboembolic disease 
17. Grade ≥3 lower extremity oedema 
18. Use of cardiac pacemaker or other medical electronic devices that can be affected by 
bioimpedance assessment 
19. Medical diagnosis of any of the following cardiovascular conditions within the 6 months 
prior to first Screening Visit: 
o Myocardial infarction or unstable angina 
o Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary 
intervention or carotid revascularisation procedure 
o Uncontrolled hypertension within the 3 months prior to first Screening Visit 
o Significant cardiac arrhythmia (as determined by the investigator) 
o Endovascular procedure or surgical intervention for peripheral vascular disease within 
the 3 months prior to first Screening Visit 
o Advanced ischemic heart disease 
o Congestive heart failure (New York Heart Association [NYHA] III/IV) 


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o Stroke or transient ischemic attack 
20. History of osteoporosis or fragility fractures or bone density below the expected range for 
age (for men < 50 years old ( Z score ≤ -2) based on The International Society for Clinical 
Densitometry definition 
21. DEXA scan T-Score less than -2.0 at Screening or within 6 months prior to first 
Screening Visit 
22. Significant acute and chronic renal or hepatic dysfunction or disease or infection (as 
determined by the investigator), including chronic active hepatitis B and C, or human 
immunodeficiency virus positivity 
23. Significant illness within the 2 weeks prior to the initial dose of study drug that could 
supress pituitary gonadal axis and decrease testosterone levels (as determined by the 
investigator) 
24. Untreated sleep apnoea 
25. Any of the following laboratory parameters at Screening: 
o Haematocrit above 50% 
o Abnormal prolactin (outside of reference range) 
o Abnormal TSH or free thyroxine (FT4) (outside of reference range) 
o Morning cortisol ≤ 5 mcg/dL 
o Fasting transferrin saturation > 50% 
o Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the 
ULN or bilirubin ≥ 2 times the ULN (unless caused by Gilbert syndrome) 
o Estimated glomerular filtration rate (eGFR) < 60 mL/min (calculated using the 
Cockcroft-Gault formula)  
26. History of cancer within last 5 years, with the exception of well treated basal cell or 
squamous cell carcinoma of the skin 
27. Any history of breast cancer 
28. Alcohol and/or drug abuse within the 12 months prior to the first Screening Visit 
29. Current/previously reported allergy to the study drug or the class of drug under 
investigation 
30. Documented history of significant psychiatric or medical disorder that 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.  
9.3.3 
Rescreening 
There are three categories of subjects that may be considered for rescreening: 
1.Subjects who met inclusion criteria 3 to 6 at Screening Visits 1, but who were not 
randomised or received study drug, may be rescreened at a later date.  
2.Subjects who failed screening due to an inclusion/exclusion criterion or other study 
requirement  that has been changed through a protocol amendment may also be rescreened  at 
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3. Subjects who failed inclusion criteria 3 to 6 at screening > 6 months previously, and where 
the clinical situation has changed so that in the investigators judgement they may now meet 
the criteria may also be rescreened. To include where there was screen failure on total 
testosterone inclusion criterion through clinically discrepant results (>100ng/dl difference 
between tests with one test being <200ng/dl). 
Prior to rescreening, every case has to be discussed and approved by Medical Monitor. 
Rescreening is allowed only one time per screened subject. Rescreened subjects will receive a 
new Screening number. Previous Screening numbers will not be reused. Rescreened subjects 
will need to repeat complete Screening assessment (except bone mineral density measured by 
DEXA if it still falls within 6 months of rescreening visit) starting with signing the ICF. 
9.3.4 
Retesting of  laboratory parameters 
 
Retesting of individual laboratory procedures may be permitted in the following 
circumstances 
• When there is obvious methodological issue (hemolysed sample, dilution or 
calculation error)  or sampling error documented at the site (sampling time is outside 
the window, incorrect procedure followed)  
• When a data point is considered aberrant,  including where there was screen failure on 
total testosterone inclusion criterion through clinically discrepant results (>100ng/dl 
difference between tests with one test being <200ng/dl). Also where the value  reported 
would be incompatible  with life or in a range clearly discrepant with  current medical 
status of the subject.  
 
In either of these instances, the investigator should get approval to repeat laboratory 
parameters from the medical monitor. The reason for re-test should be recorded by the 
Investigator in the patient’s source documentation. 
9.3.5 
Early Termination 
The study may be terminated at any time by the sponsor if serious side effects should occur, 
or per the DMC decision. In the event of an early termination of the study, the sponsor will 
inform the study investigators, institutions and all regulatory authorities. 
9.3.6 
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 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: 


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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. 
9.3.7 
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 24 visit (this should take 
place within 7 days of discontinuation of study drug). In addition subjects who discontinue 
the study drug are expected to complete the 12 week follow-up period (Visits 9, 10 and 11) to 
collect safety data. Subjects who have discontinue before Week 12 (Visit 5) are not required to 
have EOT DEXA scan measured The subjects will in addition provide semen sample for PK 
analysis at Visits 8 (EOT) , unless they are not able to provide the samples. This applies also 
to a subject discontinued because of elevated testosterone as determined by an unblinded 
physician and if the whole treatment arm is discontinued because of elevated testosterone 
level as determined by DMC. The investigator and study staff must discuss with the subject, 
the subject’s continued participation in the study and request subjects to continue attending 
follow-up visits according to the study visit schedule. A study arm may be discontinued from 
the treatment at the Week 4 visit as decided by DMC during interim analysis (see 
Section 9.1). Discontinued subjects will not be replaced. Those subjects will attend only 
Visit 8 (EOT) and will be followed at FU-Visit s 9, 10 and 11 (to 12 weeks after EOT). 
The only exception to this requirement is when a subject withdraws consent for all study 
procedures including post-treatment study follow-up or loses the ability to consent freely 
(i.e., is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or 
physical illness). 
If the subject cannot, or is unwilling to attend the follow-up 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. 


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If the subject decides to completely withdraw from the study (refuses any further study 
participation or contact) all study participation for that subject will cease and data to be 
collected at subsequent visits will be considered missing. 
The investigator must also contact the IRT to register the subject’s discontinuation from 
investigational treatment. 
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page. 
If the subject temporarily discontinue study drug because of AE or SAE or other relevant 
issue, investigator may restart if considered medically safe and in discussion with the Medical 
Monitor. 
Investigational treatment MAY be permanently discontinued under the following 
circumstances: 
1.  Significant worsening of lower extremity oedema (demonstrated by use of the same 
technique of evaluation for comparison over time and which is not due to local pressure 
/venostasis effects such as may be caused by socks or other clothing). 
2. 
Significant worsening of obstructive urinary symptoms 
Investigational treatment MUST be permanently discontinued under the following 
circumstances: 
3. Total testosterone ≥ 1500ng/dL (52 nmol/L) at any two consecutive scheduled visits 
during the study 
4. 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 patient 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 
5. Any of the following laboratory abnormalities: 
o Renal function values that require discontinuation: 


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• 
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 [ACR] 
>300 mg/g or >30 mg/mmol; protein:creatinine ratio [PCR] ≥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. 
6. Subject missed 4 or more consecutive study drug dosing. 
7. Development of prostate cancer or PSA increase more than 1.4 ng/ml above Screening 
level. It is recommended that in these cases subjects undergo urologic consultation. 
8. Haematocrit >54% (Hematocrit  can be  repeated once within 7 days of  initial alert. 
Study drug administration should be suspended during this time and resumed only 
if repeat hematocrit is under 54%) 
9. Development of sleep apnoea. 
10. Development of cardiovascular event (significant arrhythmia acute myocardial infarction, 
brain stroke, transient ischemic attack, unstable angina, congestive heart failure). 
11. Emergence of the following adverse events: 
o Absolute QTcF >500 msec, or a rise of QTcF of ≥ 60 msec above baseline confirmed 
by triplicate ECG measurements. 
12. Pregnancy in female sexual partner of the male study subject, occurring after the start of 
study treatment. 
13. Fragility bone fracture. 
14. Breast cancer. 
 
Procedures for handling patients incorrectly enrolled or randomized 
Subjects who fail to meet the inclusion/exclusion criteria must not be enrolled or randomized.  
If a subject not meeting the study criteria is randomized 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.  
 
9.3.8 
Lost to Follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. 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 three documented phone 
calls, faxes or emails, as well as a lack of response by the subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that 


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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 Follow-Up Phase 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 Follow-Up Phase 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 
c
 
Route of administration 
Oral 
Oral 
Mode of administration 
 With water 
 With water 
Dose 
10.1.1 
Administration of Study Treatment(s) 
 
 
 
 
 
10.2 
Study Treatment Packaging and Labelling 
10.2.1 
Packaging 
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. 
10.2.3 
Storage 
 
 
 
10.2.4 
Blinding and Randomisation of Study Treatment(s) 
At Visit 1 (Baseline) all eligible subjects will be randomised via the IRT to one of the four 
treatment regimens 
 in a 1:1:1:1 
ratio. After the interim analysis (see Section 13.6), if one or more of the BGS649 study arms 
is discontinued by the DMC, the dosing for that arm(s) will be stopped and no further 
randomisation to that arm will be performed. The remaining subjects will be randomised in a 
1:1:1 ratio into remaining active 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 database 
lock. In order to maintain the blind described above, testosterone measurements will be 
blinded to site and sponsor staff and monitoring will be performed by an independent 
unblinded physician. The interim analysis will be performed by an independent unblinded 
committee (see Section 16.3). 
The blind will be maintained using the following methods: 
1. Randomisation data will be kept strictly confidential until the time of blinding, and will 
not be accessible to anyone involved in the study 


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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 tablets. 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 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. 
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 


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received from the sponsor is reconciled. All study medication must be returned to the sponsor 
at the end of the study. 
10.6 
Contraception 
Semen 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 semen 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 Screening (for details of Screening criteria concerning 
medications, see Section 9.3.1 and Section 9.3.2): 
1. 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 
o Growth hormone 
o Testosterone, known testosterone enhancers, anabolic steroids, known active Fertility 
drugs and Oestrogens or selective oestrogen receptor modulators (SERMS) 


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o Clomid 
o Bisphosphonates, Teriparatide, Denosumab (treatment with calcium and vitamin D for 
bone health is allowed at the discretion of the investigator) 


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11 
ASSESSMENT OF EFFICACY 
11.1 
Efficacy and Pharmacokinetic Variables 
1. Total and bioavailable testosterone, LH, FSH, inhibins (A and B), oestradiol (total) 
2. Testosterone/oestradiol ratio 
3. 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) 
4. Cardiometabolic parameters 
o Blood pressure (DBP and SBP) 
o Fasting lipid panel (total cholesterol, LDL, HDL, triglycerides) 
o HbA1c 
o Fasting glucose and insulin 
o hs-CRP 
o HOMA-IR (see Section 11.3.3 for details) 
5. PRO measures 
o International Index of Erectile Function (IIEF) and PROMIS Sexual Function and 
Satisfaction (PROMIS 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. 
o Patient Global Impression of Status items (PGI-S): to assess the patients’ overall 
impression of their current health status. 
6. Actigraphy derived activity and sleep parameters 
o Counts of sedentary, moderate and vigorous activity 
o Sleep quality and duration 
7. Dynometry derived grip strength assessment 
8. Semen analysis  
o Sperm count 
o Sperm concentration 
o Volume of semen 


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o Sperm motility 
o Sperm morphology 
9. PK plasma analysis and PK semen analysis. 
Detail of assessment of the efficacy and PK variables are presented in Section 11.3 and 
Section 11.4, respectively. 
11.2 
Efficacy and Pharmacokinetic Endpoints 
Primary 
1. Normalisation of total testosterone levels in ≥ 75% of subjects at Week 24. 
Secondary 
1. Proportion of subjects that have normalisation of total testosterone to Week 24 
2. Proportion of subjects that overshoot testosterone (total testosterone above 1000 ng/dL 
[35 nmol/L]) to Week 24 
3. Normalisation of total testosterone in ≥ 90% subjects at Week 24 
4. Change of LH and FSH to 24 weeks 
5. Population PK analysis of plasma BGS649 concentrations 
6. PK analysis of semen BGS649 concentrations. 
Exploratory 
1.    Change in oestradiol, inhibins (A and B) levels and DHT 
2.   Change in testosterone/oestradiol ratio 
3.   Body composition changes at Week 12 and Week 24 
4.   Changes in markers of cardiometabolic disease: blood pressure, lipid profile, HbA1c, 
glucose and insulin, hs-CRP and HOMA-IR and association with change in body 
composition and testosterone level. 
5. Change in markers of bone turnover in those with and without 25-hydroxy vitamin D 
deficiency 
6. Change in total and domain scores on PRO measures (IIEF, PROMIS SexFS: to assess 
sexual function; BFI, PROMIS Fatigue Short Form, SF-36 - Vitality: to assess energy 
levels and fatigue; SF-36: to assess general quality of life (QoL); PGI-S: to assess the 
patients’ impression of their current health status)  over the 24-week period 
7. Association of objective findings of improvement (e.g. testosterone, time in physical 
activity or sleep and grip strength) and domain scores on PROs 
8. Change in physical activity, sleeping pattern and strength measured by wrist worn 
monitors and grip strength measurement at 12 and 24 weeks and association with body 
composition (as measured by BMI and waist circumference and impedance) and 
testosterone level. 
9. PK/pharmacodynamic 
(PD) 
relationship 
between 
BGS649 
concentrations 
and 
testosterone levels 
10. For semen analysis: change in semen parameters throughout the study and association 
with LH/FSH level 
11. Change in bioavailable testosterone 
12. Time to first normal testosterone level. 
 


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11.3 
Efficacy Assessments 
All efficacy assessments will be performed according to the schedule of assessments 
(Table 9–1). 
11.3.1 
Male Hormonal Parameters 
Testosterone 
Serum total testosterone and sex hormone binding globulin (SHBG) levels will be measured. 
Bioavailable testosterone will be calculated. 
All serum total testosterone and SHBG laboratory parameters are to be taken before 11 am. 
Samples are to be separated within an hour of being taking to prevent artificial increases in 
testosterone levels, and further stored and transported as described in the laboratory manual. 
If total testosterone is ≥ 1500ng/dL (52 nmol/L) at any 2 consecutive measurements (time 
points) during the study, the subject will be discontinued from treatment (see Section 9.3.6). 
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 10.2.4 and 
Section 16.3). 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, FSH, Inhibins A and B, total oestradiol and DHT will be assessed. 
11.3.2 
Body Composition 
Body weight will be measured as part of the vital signs assessment (Section 12.6). 
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 
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 will be measured at Screening to enable BMI determination. 
BMI is to be calculated from the height obtained at Screening. 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 taken to the nearest 0.1 cm. 


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The waist measurement (in cm) will be taken by measuring the circumference distance 
around the waist 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 bioimpedance 
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. 
11.3.3 
Cardiometabolic Parameters 
Blood pressure (SBP and DBP) will be measured as part of the vital signs analysis 
(Section 12.6). 
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). 


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Insulin use will be documented within the concomitant medications to enable the analysis of 
insulin and HOMA-IR to be appropriately performed to exclude the confounding effects of 
exogenous insulin use. 
11.3.4 
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 five 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 an 7-item self-administered questionnaire 
assessing the extent of fatigue and its impact on work and functioning in the last 7 days. 
Brief Fatigue Inventory 
The BFI is a 99-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 


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6. Emotional role functioning 
7. Social role functioning 
8. Mental health. 
Patient Global Impression of Status items (PGI-S) 
Three patient global impression items will be included to assess the patients’ 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 hypogonadotropic hypogonadism 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 hypogonadotropic hypogonadism 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 hypogonadotropic hypogonadism 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 
 
11.3.5 
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. It is a large, water-
resistant wrist watch worn on the non-dominant hand. 
Subjects will wear the monitor for 7 days consecutively starting with the day of the scheduled 
Visit 1, and 5 and 7 days consecutively before Visits 8 and 11, so that the monitors can be 
collected at Visit 8 from subjects transferring to the extension study and at Visit 11 from 
subject completing FU visit, as described in the schedule of assessments (Table 9–1). 


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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. 
11.3.6 
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 three times 
with each hand. An average of three measurements for each hand will be calculated and 
recorded. 
11.3.7 
Semen Analysis 
Subjects who are vasectomised or have vasectomy planned during the study period will be 
exempt from the semen analysis.  
Semen Quality 
Semen samples will be collected after a minimum of 48 hours of sexual abstinence based on 
WHO laboratory manual for the examination and processing of human semen. Condoms will 
not be used for collection as they may contain spermicide affecting quality of the specimen. 
The analysis will be performed at the study sites for the assessment of semen volume, sperm 
count, concentration, motility and morphology. Samples may be repeated up to two times at a 
scheduled time point due to individual variability in semen parameters. 
Semen PK 
Seminal fluid PK will also be performed at EOT to assess the concentration of BGS649 at 
steady state (see Section 11.4). . 
11.4 
Pharmacokinetic Assessments 
Sparse Plasma Pharmacokinetic Sampling 
PK sampling for BGS649 will be performed at the following time points, as defined in the 
schedule of assessments (Table 9–1): 
Visit 5 (Week 12). Pre-dose and 1h post-dose.  The investigator should ensure that the site 
visit when PK is taken coincides with the scheduled dosing visit.  
Visit 8 (EOT;Week 24) PK will be taken only once together with other laboratory 
assessments taken at that visit.  
It is important that the time that the last dose of study drug was taken prior to PK testing is 
recorded when PK is performed. 


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Semen Pharmacokinetic Sampling 
PK sampling for BGS649 will be performed as defined in the schedule of assessments 
(Table 9–1) at Visit 8 (EOT). 
Semen samples for PK analysis will be centrifuged (1000 g x 10 minutes) and the separated 
seminal plasma will be stored at -20°C until samples are used. 


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12 
ASSESSMENT OF SAFETY 
The timing and frequency of safety assessments provided in Table 9–1. 
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. 
Any relevant observations made at the Screening Visit (prior to signing the ICF) are to be 
recorded as pre-existing conditions. AE will only be recorded if there is a worsening of the 
pre-existing condition during study conduct with regard to nature, severity or frequency . 
Only SAEs will be collected during Screening Period (the time between signing the ICF and 
randomisation). From randomisation to Day 90 after last study drug administration all AEs 
will be reported. 
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 one 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. 
Adverse Events of Special Interest 
Refer to Section 12.1.7. 
12.1.2 
Recording of Adverse Events 
For the purposes of this study, only SAEs will be collected during Screening Period (the time 
between signing the ICF and randomisation).  
Any detrimental change in the subject's condition, after randomisation and 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 randomisation. SAEs only will be reported during the 
screening period (from signing of the informed consent to randomisation). All AEs/SAEs 


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have to be reported, whether or not considered causally related to the investigational product 
or to the study procedure(s). 
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 


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o Concomitant treatments in use 
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. 
Each single AE must be rated by choosing one 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 one 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. 
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 in an amount that is higher than is normally used. 


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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. Polycythemia as measured by a haematocrit > 54% 
5. Fragility fracture 
6. Development of sleep apnoea 
7. Development of osteoporosis or low mineral density as per DEXA measurement (T score 
≤ -2.5 for men ≥ 50 years or Z score ≤ -2 for men < 50 years of age) 
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 study drug dose, AESI from the 
time of randomisation until 90 days after last study drug dose 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: 
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 
1. TEAEs/SAEs (from first dose of study drug until 90 days after last treatment dose) 
2. Change in PSA during 24 week treatment duration 
3. Change in haematocrit during 24 week treatment duration 


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4. Change in Bone Mineral Density (DEXA scan T-score and density in g/cm2) from 
Screening and bone turnover biomarkers at 24-weeks from Baseline 
5. Change in vital signs and clinical laboratory parameters, ECG  
6. Change in physical examination (including general, prostate, breast and oedema of the 
lower extremities). 
12.3 
Laboratory Assessments 
Laboratory measurements for blood chemistry, PSA, haematology, urinalysis and specialised 
chemistry will be performed according to the schedule of assessments (Table 9–1). Specific 
details not 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, PT/INR, total bilirubin, total protein, 
calcium, lipid panel (total cholesterol, LDL, HDL, triglycerides) and PSA will be measured. 
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. 
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. 
12.3.2 
Specialised Chemistry 
The following laboratory parameters will be measured at Screening only, for assessment of 
exclusion criteria (see Section 9.3.2): 
1. Morning cortisol 
2. TSH  
3. FT4 


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4. Prolactin 
5. 25-hydroxy vitamin D (no exclusion criteria related to this parameter) 
6. Fasting transferrin saturation reported in % and calculated according to the formula: 
o Transferrin saturation = [Iron / (Transferrin × 1.4)] × 100 
12.3.3 
Bone Turnover Markers 
CTx1, osteocalcin, bone alkaline phosphatase and P1NP will be measured. 
12.4 
DEXA Scan 
Bone density will be evaluated with standard procedure. An overview is provided here. The 
study imaging manual contains more detailed guidance which should be followed. All 
evaluations during the study for particular subject will be performed on the same machine, 
wherever possible by the same technician. It is important that the same subject positioning is 
followed for each scan. Primary scan results need to be stored for central overread when 
required. 
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. Both femoral neck and total hip results will be reported.. 
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 density and T-score values will 
be evaluated for safety. 
12.5 
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 
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 2mm depression. Immediate 
rebound, +2- a 4mm deep oedema, few seconds to rebound, +3 - 6mm deep oedema. 10-12 
seconds to rebound to + 4- 8mm deep oedema, >20 seconds to rebound and recorded in the 
eCRF. Use of bony prominence such as the malleoli may reduce the artefactual pitting 
oedema that may occur above sites of constriction such as tight socks. 


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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 section 
of the CRF. Significant findings made after the start of study drug treatment, which meet the 
definition of an AE must be recorded in the AE CRF summary page. 
12.6 
Vital Signs 
Vital signs include measurement of oral temperature, SBP, DBP,  pulse and weight. Height 
will also be measured at Screening only, to enable BMI determination (Section 11.3.2). 
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 
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. 
12.7 
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 CRFs 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. 
12.8 
Androgen Deficiency Guidance 
All subjects will be assessed by an investigator at Screening for symptoms of androgen 
deficiency based on an androgen deficiency guidance document that will list all androgen 
deficiency symptoms (see Appendix II). All positive symptoms will be entered into the 
eCRF. 


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12.9 
24/7 Medical Emergency Coverage 
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 
Statistical Hypothesis: 
ICON Biostatistics will prepare the randomisation list, based on a randomisation scheme 
blocked by site. Until the outcome of the interim analysis is known, each subject will be 
assigned to one of four dosing regimens defined in Section 9.1 in a 1:1:1:1 ratio. This will be 
adjusted as per Section 9.1 depending on the outcome of the interim analysis. 
See Section 10.2.4 for further details of the Randomisation procedures to be applied. 
13.3 
Analysis Sets 
All primary and secondary efficacy endpoints will be analysed using the intention to treat 
(ITT) population. The per-protocol (PP) population will be used only for the analysis of the 
primary endpoint to examine the robustness of the primary analyses. 
Safety and tolerability will be analysed using the safety population. 
Pharmacokinetic data will be analysed using the PK population. 
13.3.1 
Intention to Treat (ITT) (Full Analysis Set) 
The ITT population includes all subjects who: 
1. Are randomised, and 
2. Receive at least one dose of study medication, and 
3. Provide a Baseline and at least one post-Baseline testosterone value. 
13.3.2 
Per Protocol 
The PP population is a subset of the ITT population and includes all randomised subjects as 
randomised who have been treated according to the protocol and fulfil the following criteria 
(to be further described in the statistical analysis plan [SAP]): 
1. All inclusion/exclusion criteria satisfied 


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2. Absence of relevant protocol violations with respect to factors likely to affect the efficacy 
of treatment where the nature of protocol violation will be defined before breaking the 
blind 
3. Adequate study medication compliance 
4. Adequate measurement of the primary variable. 
13.3.3 
Safety Population 
The safety population includes all subjects who received at least one administration of the 
study medication. 
13.3.4 
PK Population 
For the nonlinear mixed effects modelling, all subjects who received at least one 
administration and have at least quantifiable concentration will be included. 
13.4 
Endpoints 
13.4.1 
Primary Efficacy Endpoint(s) 
The primary efficacy endpoint is the normalisation of total testosterone levels in ≥ 75% of 
subjects at Week 24. 
13.4.2 
Secondary Efficacy Endpoint(s) 
Efficacy will be further assessed based on the secondary endpoints, as defined in 
Section 11.2. 
Further details and the time points for collection are given in Section 11.3 and in the 
Schedule of assessments (Table 9–1). A complete list of efficacy endpoints is given in 
Section 11.2. 
These secondary efficacy parameters will be assessed using the ITT population. 
13.4.3 
Pharmacokinetics 
Nonlinear mixed effects PK/PD models evaluating the relationship between BGS649 
exposure and testosterone levels. 
13.4.4 
Exploratory Endpoints(s) 
Exploratory endpoints are defined in Section 11.2. 
13.4.5 
Safety Endpoint(s) 
The following data will be collected for assessment of safety: 
1. AEs including SAEs and AESIs 
2. Vital signs and clinical laboratory parameters 
3. ECG 
4. Physical examination (including general, prostate, breast and oedema of the lower 
extremities) 
5. DEXA scan T-Score and density in g/cm2. 


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These safety parameters will be assessed using the safety population. A list of safety 
endpoints is given in Section 12.2. 
13.5 
Description of Statistical Analyses 
13.5.1 
General Considerations 
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, 
standard deviations (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 the Baseline value for a variable will be latest value take prior to first 
dose of study medication. 
Data in summary tables will generally be presented on an Observed Cases basis. 
Unless stated otherwise, all statistical tests will be two-sided and conducted at the 5% level, 
and all quoted CIs will be two-sided 95% CIs. All four treatment regimens will be assessed 
by pairwise comparisons, no adjustment for multiplicity will be made and all analyses will be 
considered as exploratory analyses. 
Full details of the statistical analysis will be given in a SAP. 
13.5.2 
Analysis of Primary Endpoint 
The Primary Endpoint will be considered to have been met for a dose if ≥ 75% of subjects in 
the ITT population have normalisation of total testosterone levels at Week 24 
The proportion of subjects with normal testosterone levels will be summarised by treatment 
regimen and visit. 
The primary analysis of efficacy will be performed with the ITT population. Additionally for 
exploring the robustness of the intent-to-treat results, a supportive analysis using the PP 
population will be carried out. 
As per section 13.7 the primary analysis will be conducted once all data up to Visit 8 has 
been collected. 
13.5.3 
Analysis of Secondary Endpoints 
The analysis of secondary efficacy endpoints will be performed on the ITT population. 
For the secondary efficacy endpoints data will be summarised by treatment regimen and visit. 


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For each continuous parameter, change from Baseline will be assessed with a mixed model 
repeated measure (MMRM) analysis, with treatment regimen as a factor and the Baseline 
value as a covariate. The adjusted mean difference between treatments 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. 
A more detailed description will be presented in the SAP. 
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 regimen and visit. 
For each continuous parameter, change from Baseline will be assessed with a MMRM 
analysis, with treatment regimen as a factor and the Baseline value as a covariate. The 
adjusted mean difference between treatments 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. 
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. 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 one 
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. 


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Vital Signs 
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. 
DEXA Scan  
DEXA scan T-Score and density in g/cm2 will be summarised as actual values and change 
from Screening at Week 24 and by treatment regimen. 
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 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 regimen. 
13.6 
Interim Analysis 
An interim analysis will be conducted once approximately 100 of overall planned subjects 
have completed the Week 4 visit. The analysis will be performed by an independent DMC 
who will review un-blinded data to identify: 
1. Any safety signals across the dose groups which would preclude further continuation of 
dosing 


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2. Whether an individual arm has met the criteria of ≥ 75% of subjects reaching the 
normalisation of testosterone (testosterone within or above normal reference range for 
healthy adult males according to the FDA) 
3. Whether in the opinion of the DMC following unblinded review that when the arm is 
fully recruited it is expected to achieve a ≥ 75% response at Week 24.  
Dosing arms which meet either criterion 2 or 3 will be deemed effective. For arms that are 
determined to be ineffective or unsafe, dosing will be stopped and no further randomisation 
to that arm will be performed.  
Subjects assigned to the ineffective or unsafe arm(s) will be discontinued from the treatment, 
will attend an EOT visit and will be followed-up for an additional 12 weeks (FU, Visit 11). 
While the interim analysis is being performed, dosing and recruitment of study subjects will 
continue. 
13.7 
Interim Clinical Study Report 
The primary efficacy analysis and study unblinding will be performed when all data up to 
Visit 8 (Week 24) has been collected. Given the study has been powered at Week 24 and 
there will not be multiple comparisons, there is no requirement to adjust the Type I error rate.   
An interim Clinical Study report (CSR) will be prepared based upon the results of this 
analysis. 
The safety data collected during the off treatment 12 week follow-up will be separately 
analysed and published in the full CSR. 
13.8 
Population Pharmacokinetic/Pharmacodynamic Modelling 
Nonlinear mixed effects modelling will be utilised to develop a population PK model for 
plasma BGS649 concentrations and to develop a PK/PD model linking BGS649 
concentrations to changes in testosterone levels. 
A separate Modelling and Simulation Analysis Plan (MSAP) will be prepared and results 
from the PK and PK/PD modelling will be reported separately from the clinical study report 
(CSR). 


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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, Independent Ethics Committee (IEC)/Institutional Review Board 
(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 (SOPs) 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 and render that subject non-evaluable. 
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.  T
 
 
. The 
DMC will in addition perform the interim analysis in order to determine any doses of 
BGS649 that did not lead to normalisation of testosterone (not reaching therapeutic range of 
testosterone > 300ng/dL). 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 electronic data capture (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 CRFs (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 CSR 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 
Bhasin S, Cunningham GR, Hayes FJ, et al (2006). Testosterone Therapy in Adult Men with 
Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. J Clin 
Endocrinol Metab, 91:1995–2010. 
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. 
Cai X, Tian Y, Wu T, et al (2014). Metabolic effects of testosterone replacement therapy on 
hypogonadal men with type 2 diabetes mellitus: a systematic review and meta-analysis of 
randomized controlled trials. Asian J Androl, 16(1):146–152. 
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. 
Ciconelli RM, Ferra MB, Santos W, et al (1999). Tradução para a língua portuguesa e 
validação do questionário genérico de avaliação de qualidade de vida SF-36 (Brasil SF-36). 
Rev Bras Reumatol, 39(3):143–150. 
Crosnoe LE, Grober E, Ohl D, et al (2013). Exogenous testosterone: a preventable cause of 
male infertility, Transl Androl Urol, 2(2):106–113. 
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. 
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). 
Jones TH, Arver S, Behre HM, et al (2011). Testosterone replacement in hypogonadal men 
with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Obes Metab, 
12(7):653–661. 
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. 
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, 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. 


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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. 
Pexman-Fieth C, Behre HM, Morales A, et al (2014). A 6-month observational study of 
energy, sexual desire and body proportions in hypogonadal men treated with a testosterone 
1% gel. Aging Male, 17(1):1–11. 
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. 
Saylam B, Efesoy O, Cayan S (2011) The effect of aromatase inhibitor letrozole on body 
mass index, serum hormones, and sperm parameters in infertile men. Fertil Steril, 95:809–
811. 
Study CBGS649A2101 A randomised, double-blind, placebo-controlled, parallel group, 
adaptive design, ascending single dose first-in-human study to explore the safety, tolerability, 
pharmacokinetics and pharmacodynamics of oral BGS649 in healthy premenopausal and 
postmenopausal female volunteers without childbearing potential. 
Study CBGS639A2204 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. 
Study 107012, see IB. 
Study 1170869, see IB. 
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. 
Traish AM, Haider A, Doros G, et al (2014). Long-term testosterone therapy in hypogonadal 
men ameliorates elements of the metabolic syndrome: an observational, long-term registry 
study. Int J Clin Pract, 68(3):314–329. 
Wang C, Swerdloff RS, Iranmanesh A, et al (2000). Testosterone Gel Study Group. 
Transdermal testosterone gel improves sexual function, mood, muscle strength and body 
composition parameters in hypogonadal men. J Clin Endocrinol Metab, 85(8):2839–2853. 
www.ncbi.nlm.nih.gov/pubmed/23387911 
www.nihpromis.org 
www.assessmentcenter.net/documents/PROMIS%20Fatigue%20Scoring%20Manual.pdf 
 
 


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22 
APPENDICES 
Appendix I: World Medical Association Declaration of Helsinki, 2013 
 


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Appendix II: Symptoms and Signs Suggestive of Androgen Deficiency 
The following list is symptoms and signs that are suggestive of androgen deficiency: 
o Reduced sexual desire (libido) and sexual activity 
o Decreased spontaneous erections 
o Reduced intensity of orgasm  
o Gynecomastia 
o Loss of body (axillary and pubic) hair (can be measured by reduced shaving)frequency 
o Very small (especially _5 ml) or shrinking testes 
o Infertility or documented oligospermia or azoospermia 
o Hot flushes 
o Decreased energy, motivation, initiative, and self-confidence 
o Feeling depressed  
o Mood swings 
o Poor concentration and memory 
o Sleep disturbance, increased sleepiness 
o Mild anemia (normochromic, normocytic, in the female range) 
o Reduced muscle bulk and strength 
o Increased body fat, body mass index 
o 
Diminished physical or work performance 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (SAP)
Statistical Analysis Plan
Protocol Number: MBGS205
                   Version: FINAL 2.0, Date: 07 June 2018
                                                                         Page 1 of 64
Protocol Title:
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
Protocol Number:
MBGS205
Protocol Version, Date
Final V6.0, 10 March 2017
ICON ID: 
3082/0005
Document Version, Date:
FINAL 2.0, 07 June 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)
Statistical Analysis Plan
Protocol Number: MBGS205
                   Version: FINAL 2.0, Date: 07 June 2018
                                                                         Page 2 of 64
SIGNATURE PAGE


Statistical Analysis Plan (SAP)
Statistical Analysis Plan
Protocol Number: MBGS205
                         Version: FINAL 2.0, Date: 07 June 2018
Page 3 of 64
REVISION HISTORY
Version/Date
Version name
Section
Changes implemented
1.0 / 28FEB2018
Initial approved 
version
N/A
N/A
1.1/ 01MAR2018
1.1
8.9
Clarified procedure for future analysis of primary analysis 
assessments if they are not available at time of the primary 
analysis.
2.0/  07JUN2018
2.0
7.1.3.9
Inclusion of “number of minutes worn” criteria for all  actigraph
derived parameters
8.4.2
Update of categorical cut-offs for free testosterone, bioavailable
testosterone, Oestradiol and Vitamin D.
8.6.4.1
Inclusion of the high sensitivity lab values for Oestradiol analysis
8.7.2.1
Added treatment comparison in change from baseline in renal 
parameters
8.7.3
Added treatment comparison in change from baseline in systolic 
and diastolic blood pressure
Added new table for blood pressure categorisation
8.7.6
Site recorded DEXA results will now be summarised in addition 
to the overread values
8.8.4
Additional Scatter graphs added for Oestradiol vs PRO Scores 
and Testosterone/oestradiol vs PRO Scores


Statistical Analysis Plan (SAP)
Statistical Analysis Plan
Protocol Number: MBGS205
                       Version: FINAL 2.0, Date: 07 June 2018
                                                                        Page 4 of 64
TABLE OF CONTENTS
SIGNATURE PAGE ...................................................................................................................... 2
REVISION HISTORY.................................................................................................................... 3
TABLE OF CONTENTS................................................................................................................ 4
LIST OF ABBREVIATIONS......................................................................................................... 6
1
INTRODUCTION .................................................................................................................... 8
2
STUDY OBJECTIVES............................................................................................................. 9
2.1
Primary objective(s)......................................................................................................... 9
2.2
Secondary objective(s)..................................................................................................... 9
2.3
Exploratory objective(s)................................................................................................... 9
2.4
Safety objective(s) ......................................................................................................... 10
3
STUDY DESIGN.................................................................................................................... 11
3.1
General study design...................................................................................................... 11
3.2
Randomisation and blinding .......................................................................................... 12
3.3
Study treatments and assessments ................................................................................. 13
4
STUDY ENDPOINTS............................................................................................................ 17
4.1
Primary efficacy endpoint(s).......................................................................................... 17
4.2
Secondary efficacy endpoint(s)...................................................................................... 17
4.3
Exploratory endpoint(s) ................................................................................................. 17
4.4
Safety endpoint(s) .......................................................................................................... 18
5
SAMPLE SIZE AND POWER............................................................................................... 19
6
ANALYSIS POPULATIONS ................................................................................................ 20
6.1
Intention-To-Treat population (ITT).............................................................................. 20
6.2
Safety population (Safety) ............................................................................................. 20
6.3
Per-Protocol population (PP)......................................................................................... 20
6.4
PK population ................................................................................................................ 20
6.5
Other Populations Defined for Tables and Listings....................................................... 20
6.6
Protocol Deviations/Violations and Exclusions from Analysis Sets............................. 21
7
STATISTICAL CONSIDERATIONS AND ANALYSIS ..................................................... 22
7.1
Derived Variables .......................................................................................................... 22
7.2
Handling of missing data and outliers ........................................................................... 28
8
STATISTICAL METHODS................................................................................................... 30
8.1
General statistical conventions ...................................................................................... 30
8.2
Subject disposition......................................................................................................... 31
8.3
Protocol deviations......................................................................................................... 32
8.4
Demographics and baseline characteristics ................................................................... 32
8.5
Extent of exposure ......................................................................................................... 33
8.6
Efficacy analyses ........................................................................................................... 33
8.7
Safety analyses............................................................................................................... 40
8.8
Other analysis................................................................................................................. 46
8.9
CSR................................................................................................................................ 49
9
CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL.............................. 50


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Protocol Number: MBGS205
                       Version: FINAL 2.0, Date: 07 June 2018
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10 REFERENCES ....................................................................................................................... 51
11 APPENDICES ........................................................................................................................ 52


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Protocol Number: MBGS205
                       Version: FINAL 2.0, Date: 07 June 2018
                                                                        Page 6 of 64
LIST OF ABBREVIATIONS
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


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                       Version: FINAL 2.0, Date: 07 June 2018
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PSA
Prostate-specific antigen
QoL
Quality of life
RBC
Red Blood Cell
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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Protocol Number: MBGS205
                       Version: FINAL 2.0, Date: 07 June 2018
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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 MBGS205 Final V6.0 “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” dated 10 March 
2017. 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® or higher.
Note: This plan does not address the pharmacokinetic (PK)/pharmacodynamics (PD) analyses or 
summarisation for this study. These analyses will be described in a separate analysis plan and results 
from the PK/PD modelling will be reported separately from the CSR.
Note: This plan does not include the PRO quantitative validation for the study. This will be reported 
separately from the CSR.
Note: This plan does not address the statistical analyses or summarisation for the extension study,
MBGS206. These analyses will be described in a separate analysis plan.


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Protocol Number: MBGS205
                       Version: FINAL 2.0, Date: 07 June 2018
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2
STUDY OBJECTIVES
The study is designed to investigate the efficacy, safety and tolerability of three different doses
regimens of BGS649 versus placebo in male obese subjects with hypogonadotropic hypogonadism.
2.1
Primary objective(s)
The primary objective is to demonstrate the efficacy of BGS649 to normalise total testosterone levels 
(300-1000 ng/dL [10.4-
2.2
Secondary objective(s)
The secondary objectives are:
1.
To follow the time-course of normalisation in total testosterone levels
2.
subjects after 24 weeks of treatment
3.
To evaluate the effect of BGS649 on LH and FSH
4.
To further determine the pharmacokinetics (PK) of BGS649.
2.3
Exploratory objective(s)
The exploratory objectives are:
1.
To evaluate the effect of BGS649 on oestradiol, DHT and inhibins (A and B)
2.
To evaluate the effect of BGS649 on testosterone/oestradiol ratio
3.
To investigate the effect on patient reported outcomes (PROs) following treatment with 
BGS649. PRO measures will be:
o
International Index of Erectile Function (IIEF) and PROMIS Sexual Function and 
Satisfaction (PROMIS 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.
o
Patient Global Impression of Status items (PGI-S): to assess the patients’ overall 
impression of their current health status.
4.
To determine any change in physical activity and sleeping pattern via wrist worn monitor


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                       Version: FINAL 2.0, Date: 07 June 2018
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5.
To determine any change in grip strength, as measured by a dynamometer
6.
To determine any associations between objective findings of improvement (e.g. 
testosterone, time in physical activity or sleep, and grip strength) and total and domain 
scores on PRO measures
7.
To determine body composition change: waist circumference, BMI, body composition (as 
measured by impedance), and gynecomastia
8.
To determine any associations between change in testosterone, body fat (as measured by 
BMI and waist circumference) and change in grip strength and wrist monitor data
9.
To determine any associations between change in testosterone, body composition (as 
measured by impedance) and change in grip strength and wrist monitor data
10.
To determine the effect of BGS649 on cardiometabolic parameters: systolic blood pressure 
(SBP) and diastolic blood pressure (DBP), lipid panel (total cholesterol, low density 
lipoprotein [LDL], triglycerides and HDL), glycosylated haemoglobin (HbA1c), fasting 
glucose and insulin, HOMA-IR  and high sensitivity C reactive protein (hs CRP)
11.
To determine any associations between testosterone, change in body composition and 
cardiometabolic parameters: SBP and DBP, lipid panel (total cholesterol, LDL,
triglycerides and HDL), HbA1c, fasting glucose and insulin, HOMA-IR and hs-CRP
12.
To determine the change in bone mineral density (dual energy X-ray absorptiometry 
[DEXA] scan), bone turnover markers (C-terminal telopeptide [CTx1] and procollagen
type 1 N-propeptide [P1NP], osteocalcin, bone alkaline phosphatase)
13.
To explore the effects of BGS649 on bone biomarkers on subjects with and without 25 
hydroxy vitamin D deficiency (vitamin D deficiency is defined as 25 hydroxy vitamin D < 
20ng/ml)
14.
To explore the relationship between BGS649 concentration and testosterone levels
15.
To determine the effects of BGS649 on semen parameters (semen volume, sperm count, 
concentration, motility and morphology) and to measure BGS649 concentrations in 
seminal fluid in subjects that provide semen samples
16.
To explore the relationship between LH/FSH change and improvement in semen analysis 
in subjects that provide semen samples.
2.4
Safety objective(s)
To evaluate the safety and tolerability of BGS649.


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                       Version: FINAL 2.0, Date: 07 June 2018
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3
STUDY DESIGN
3.1
General study design
This is a 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). The study will have three phases:
1.
A Screening Phase lasting up to 28 days, including Day -28 to Day -1
2.
A Randomisation Phase including the Baseline visit (Day 1) and the treatment period Day 
1 to Visit 8 (Week 24)
3.
A Safety Follow-Up Phase to Visit 11 (Week 36, follow-up [FU]). Visits 9 and 10 are 
telephone assessments
Study participation will comprise up to 2 Screening Visits, 8 visits during the treatment period up to 
Week 24 (End of Treatment [EOT]), FU Visits 9, 10 (telephone assessment) and 11 (at Weeks 28, 32 
and 36 respectively) for safety performed to 12 weeks after Visit 8 (EOT).
Eligible subjects will be randomised on Day 1 (Baseline) in a 1:1:1:1 ratio to one of the following 
treatment groups, consisting of 
o
BGS649
o
BGS649 
o
BGS649
o
BGS649 matching placebo 
.
Once approximately 100 of the overall planned enrolled subjects have completed the Week 4 visit, an 
interim analysis will be performed by an independent DMC who will determine whether the criteria 
for normalisation of testosterone (testosterone within or above normal reference range for healthy 
adult males according to FDA criteria) were met. Dosing arms which met this criterion will be 
deemed effective. For dosing arms deemed to be ineffective, dosing will be stopped and no further 
randomisation to that arm will be performed. See Section 8.8.1.2 for full details of the Interim 
Analysis.
A minimum of 25 subjects per treatment arm will be invited to participate in a 6 month extension 
study (Protocol MBGS206), starting at Visit 8 (EOT). Subjects participating in the 6 month extension 
will have their last study visit at Visit 8 (EOT) and will not participate in Visits 9, 10, and 11.
Figure 1: Study Flow Chart


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Protocol Number: MBGS205
                       Version: FINAL 2.0, Date: 07 June 2018
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D=day; DMC=Data Monitoring Committee; EOT= End of Treatment; IRT=interactive response technology; PK, 
pharmacokinetic; W=week
1 A minimum of 25 subjects per treatment arm will be invited to participate in a 6-month extension study 
(Protocol MBGS206), starting at Visit 8 (Week 24 EOT). This transfer will be handled by the IRT and the 
blind will be maintained. Subjects participating in the 6-month extension will have their last study visit at 
Visit 8 (Week 24 EOT) 
2 If one of the BGS649 study arms at Visit 3 (Week 4) fulfils discontinuation criteria as determined per 
DMC, the dosing for the ineffective or unsafe arm(s) will be stopped and no further randomisation to that 
arm will be performed.
3.2
Randomisation and blinding
3.2.1
Randomisation
This is a double-blind randomised study. At Visit 1 (Baseline) all eligible subjects will be randomised 
via the IRT to one of the four treatment regimens (BGS649 0.1 mg, 0.3 mg, and 1.0 mg and matched 
placebo) in a 1:1:1:1 ratio. After the interim analysis (see Section 8.8.1.2), if one or more of the 
BGS649 study arms is discontinued by the DMC, the dosing for that arm(s) will be stopped and no 
further randomisation to that arm will be performed. The remaining subjects will be randomised into 
the remaining active arms versus placebo (ineffective or unsafe dose will not continue). 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.


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Protocol Number: MBGS205
                       Version: FINAL 2.0, Date: 07 June 2018
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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. In order to maintain the blind described above, testosterone 
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 (final Week 24 or EOT data collected for the final 
subject) the blind will be broken and the primary efficacy analysis completed. The 12 week, off 
treatment, follow up safety data will be analyzed separately.
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. 
3.3
Study treatments and assessments
During the 24 week randomization phase, subjects in the BGS649 groups and the matching placebo 
group will take the required dose weekly (± 1 day from the time schedule of regular planned dose) 
with water. Subjects will receive three capsules per dose to deliver a total of 
 
 and two indistinguishable placebo capsules)
 
 or placebo 
 
Dose changes are not permitted during the randomization phase.
The maximum study duration from screening to end of the safety follow-up period is 40 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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Protocol Number: MBGS205
                         Version: FINAL 2.0, Date: 07 June 2018
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Screening Phase
Randomisation Phase (Treatment Period)
Follow-Up1
Visit
Screening (D -28 to D -1)
1
(Baseline
)
2
3
4
5
6
7
8
(EOT
)
9
10
11
(FU)
Week/Day
Screen
Visit 1
Screen Visit 2 
(Visit 1 + 
3-7 days)
D 1 
D 8
(±1 D)
W4 
(±2 D
)
W8 
(±2 D
)
W12 
(±2 D
)
W16 
(±2D)
W20 
(±2 D
)
W24 
(±2 D
)
W282
(±2 D
)
W322
(±2 D)
W36 
(±2 D
)
Written informed consent
X
Demographics
X
Medical/surgical history
X
Inclusion/exclusion criteria
X
Androgen deficiency symptom 
checklist
X
Randomisation
X
Full general physical exam and 
prostate exam and breast exam
X
X
X
Limited physical exam3
X
X
X
X
X
X
X
Vital signs4; height (Visit 1 only) 
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
Specialised chemistry: morning 
cortisol, TSH, FT4, prolactin, iron, 
transferrin5
X
25 hydroxy vitamin D
X
Clinical laboratory tests:
haematology, blood chemistry, eGFR 
by Cockcroft-Gault formula, dipstick 
urinalysis6 and PSA7
X
X
X
X
X
X
X
X
X
X
Cardiometabolic parameters 
1:HbA1c, fasting lipids (total 
cholesterol, LDL, HDL, 
triglycerides)7
X
X
X
X
X
Cardiometabolic parameters 2:
Fasting glucose and insulin, hs-CRP, 
HOMA-IR
Bone turnover markers7,8
X
X
X
X
Sex hormones 1: testosterone (total), 
oestradiol (total), LH
X9, 11
X9,10, 11
X11
X11
X11
X11
X11
X11
X11
X11
X
Bioavailable testosterone, SHBG
X11
X11
X11
X11
X11
X11
X11
X11
X
Sex hormones 2: FSH
X
X
X
X
X
X
X
X
X


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                         Version: FINAL 2.0, Date: 07 June 2018
Page 15 of 64
Screening Phase
Randomisation Phase (Treatment Period)
Follow-Up1
Visit
Screening (D -28 to D -1)
1
(Baseline
)
2
3
4
5
6
7
8
(EOT
)
9
10
11
(FU)
Week/Day
Screen
Visit 1
Screen Visit 2 
(Visit 1 + 
3-7 days)
D 1 
D 8
(±1 D)
W4 
(±2 D
)
W8 
(±2 D
)
W12 
(±2 D
)
W16 
(±2D)
W20 
(±2 D
)
W24 
(±2 D
)
W282
(±2 D
)
W322
(±2 D)
W36 
(±2 D
)
DHT, inhibin A and B
X
X
X
X
Semen quality analysis12
X
X
X
Semen PK samples13
X
Plasma PK samples14
X
X
Hip and waist measurement
X
X
X
Body composition using 
bioimpedance15 (by impedance)
X
X
X
Actigraphy16
X
X
X
X
Grip strength
X
X
X
X
X
X
PROs: IIEF, BFI, PROMIS SexFS,
PROMIS Fatigue Short Form, PGI-S
X17
X
X
X
X
X
X
PROs: SF-36 
X
X
X
X
DEXA
X18
X18
Study treatment
19
Study drug dispensation
Study drug accountability
X
X
X
X
X
X
X
AE assessment19
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
1
A minimum of 25 subjects per treatment arm will be invited to participate in a 6-month extension study (Protocol MBGS206), starting at Visit 8 (EOT). Subjects participating 
in the 6-month extension will have their last study visit at Visit 8 (EOT) 
2
Telephone Assessment Visit only
3
Limited physical examination (cardiovascular system and lower extremities oedema) 
4
Vital signs assessment will include the measurement of SBP, DBP, pulse, oral temperature and body weight
5
Fasting transferrin 
6
A microscopic examination including RBC and WBC will be performed only when dipstick evaluation is positive for WBC and/or blood
7
All blood samples are to be collected after 8 hours fasting, after ECG and vital sign measurements
8
Bone turnover markers include CTx1, osteocalcin, bone alkaline phosphatase and P1NP
9
At Screening serum total testosterone concentration must be < 300 ng/dL (10.4 nmol/L) based on two morning samples, taken before 11 am at least 3 days apart. Laboratory 
parameters from screening visit 1 do not need to be received before screening visit 2 is take place


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Page 16 of 64
10
Oestradiol and LH will not be measured at this visit
11
Samples to be collected in the morning before 11 am pre-dose
12
Semen quality analysis will include semen volume, sperm count, concentration, motility and morphology. Sample collection is not required to be the same day as the 
assessment visit. Therefore sample collection is allowed within +/-48 hours the scheduled visit for Baseline and attendance Visits  during the treatment phase
13
Semen samples for seminal fluid PK is not required to be the same day as the assessment visit. Therefore semen PK collection is allowed +/- 48 hours around the attendance 
visits  
14
Samples will be taken at pre-dose and 1h post-dose for sparse plasma PK sampling at Visit 5 (week 12). Investigators should ensure that Visit 5 where plasma PK is measured 
coincides with the study drug dosing day. At EOT Visit 8 (Week 24), PK will be taken only once together with other laboratory assessments taken at that visit.
15
Subjects should come well hydrated, drinking water the night before and the morning before the impedance measurements
16
Activity wrist monitors will be worn by subjects for 7 continuous days after Baseline visit and visit 5 and 7 continuous days before Visits 8 and 11, so that the monitors can be 
collected at Visit 8 from subjects transferring to the extension study and at Visit 11 from subjects completing FU visit.
17
Screening PRO’s should be performed no more than 7 days before dosing and may be performed outside of the Screen Visit 2 to meet this timing if required
18
Screening DEXA scan will be performed during screening and up to Day 8 after randomisation. The End of treatment DEXA will be performed only in a case patient reached 
minimum visit 5(w12) and it can be performed within 14 days before EOT to accommodate scheduling
19
The administration of the study drug (BGS649/placebo) will be performed at the study site on Week 12 to allow measurement of PK at pre-dose and 1h post-dose
20
SAEs collected from signature of informed consent and AEs, AESIs collected from randomization.


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                         Version: FINAL 2.0, Date: 07 June 2018
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4
STUDY ENDPOINTS
4.1
Primary efficacy endpoint(s)
The primary efficacy endpoint of this study is the n
75% of subjects at Week 24
4.2
Secondary efficacy endpoint(s)
The secondary efficacy endpoints of this study are:
1.
Proportion of subjects that have normalisation of total testosterone to Week 24
2.
Proportion of subjects that overshoot testosterone (total testosterone above 1000 ng/dL [35 
nmol/L]) to Week 24
3.
4.
Change of LH and FSH to 24 weeks
5.
Population PK analysis of plasma BGS649 concentrations
6.
PK analysis of semen BGS649 concentrations.
4.3
Exploratory endpoint(s)
The exploratory endpoints of this study are:
1.
Change in oestradiol, inhibins (A and B) levels and DHT
2.
Change in testosterone/oestradiol ratio
3.
Body composition changes at Week 12 and Week 24
4.
Changes in markers of cardiometabolic disease: blood pressure, lipid profile, HbA1c, 
glucose and insulin, hs-CRP and HOMA-IR and association with change in body 
composition and testosterone level.
5.
Change in markers of bone turnover in those with and without 25-hydroxy vitamin D 
deficiency
6.
Change in total and domain scores on PRO measures (IIEF, PROMIS SexFS: to assess 
sexual function; BFI, PROMIS Fatigue Short Form, SF-36 - Vitality: to assess energy 
levels and fatigue; SF-36: to assess general quality of life (QoL); PGI-S: to assess the 
patients’ impression of their current health status)  over the 24 week period
7.
Association of objective findings of improvement (e.g. testosterone, time in physical 
activity or sleep and grip strength) and domain scores on PROs
8.
Change in physical activity, sleeping pattern and strength measured by wrist worn monitors 
and grip strength measurement at 12 and 24 weeks and association with body composition 
(as measured by BMI and waist circumference and impedance) and testosterone level.
9.
PK/pharmacodynamic (PD) relationship between BGS649 concentrations and testosterone 
levels
10. For semen analysis: change in semen parameters throughout the study and association with 
LH/FSH level
11. Change in bioavailable testosterone


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12. Time to first normal testosterone level.
4.4
Safety endpoint(s)
The safety endpoints of this study are:
1.
TEAEs/SAEs (from first dose of study drug until 90 days after last treatment dose)
2.
Change in PSA during 24 week treatment duration
3.
Change in haematocrit during 24 week treatment duration
4.
Change in Bone Mineral Density (DEXA scan T-score and density in g/cm2) from 
Screening and bone turnover biomarkers at 24-weeks from Baseline
5.
Change in vital signs and clinical laboratory parameters, ECG 
6.
Change in physical examination (including general, prostate, breast and oedema of the 
lower extremities).


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                         Version: FINAL 2.0, Date: 07 June 2018
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5
SAMPLE SIZE AND POWER
The sample size for this study is calculated using exact binomial methods for comparison of a 
single proportion to a performance goal. 
The statistical hypothesis is the proportion of subjects that have normalisation of testosterone at 
Week 24 within a dose group is greater than the pre-specified performance goal of 75%:
H1:  Normalisation > 75%
The calculation assumes a one-sided test conducted at the 2.5% significance level, for which 67 
subjects will need to be randomised in each dose group of BGS649.
If the true normalisation rate in a dose group of BGS649 is 90% then the power of the study is 
85%.


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6
ANALYSIS POPULATIONS
All primary and secondary efficacy endpoints will be analysed using the intention to treat (ITT)
and per-protocol (PP) populations.
Safety and tolerability 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 study medication, and
3.
Provide a Baseline and at least one post-Baseline testosterone value.
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 the 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.
6.3
Per-Protocol population (PP)
The PP population is a subset of the ITT population and includes all randomised subjects who have 
been treated according to the protocol and fulfil the following criteria (to be further described in the 
classification meeting plan):
1.
Specific inclusion/exclusion criteria satisfied
2.
Absence of relevant protocol violations with respect to factors likely to affect the efficacy of 
treatment where the nature of protocol violation will be defined before breaking the blind
3.
Adequate study medication compliance
4.
Adequate measurement of the primary variable.
Subjects will be analysed according to the treatment to which they were randomised.
6.4
PK population
For the nonlinear mixed effects modelling, all subjects who are randomised and received at least 
one administration of the study medication and have at least 1 quantifiable plasma concentration 
(either plasma or semen) will be included.
Subjects will be analysed according to their 
randomised treatment.
6.5
Other Populations Defined for Tables and Listings
For the purposes of tables and listings a further two populations are utilized:


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All screened subjects ( for use of subject disposition only)
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 unblinding. The review of each subject’s 
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 study medication (Study Day 1) and calculated as: 
(assessment date – date of first dose of study medication) + 1, for assessments on or after 
the date of first dose of study medication date
(assessment date – date of first dose of study medication), for assessments prior to date of 
first dose of study medication
Follow-up time
Follow-up time (days) will be calculated as: 
(date of last contact - date of first dose of 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 - 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 – 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
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.


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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).
Time to first Testosterone Normalisation
Time to first Testosterone Normalisation is defined as the time (in days) from the date of first dose 
of study medication until the date of the first occurrence of testosterone normalisation during the 
treatment period.
Subjects who do not achieve testosterone normalisation will be censored at their final testosterone 
assessment during the treatment period (Up to Visit 8).
End of Treatment Testosterone
End of treatment testosterone is defined as the Week 24 total testosterone assessment for subjects 
that completed the treatment period. For subjects that discontinued the treatment period early, the 
last on-treatment testosterone assessment will be used as their end of treatment testosterone value.
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 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)


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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)
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-Reported Outcomes Measurement Information System(®) 
Sexual Function and Satisfaction (PROMIS(®) SexFS)
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 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
PROMIS(®) Fatigue Short Form
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 for 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 for conversion tables).
If between 1 and 4 items (inclusive) have a missing response then the raw total score will be 


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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 
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 
fatigue and its impact on the subject’s ability to function at present and in the previous 24 hours. 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 Appendix D for detailed scoring of each domain and component scores.
7.1.3.8
Patient Global Impression of Status items (PGI-S)
Three patient global impression items will be included to assess the patients’ overall impression of 
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


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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, and 5 and 7 days consecutively before Visits 8 and 11. Only data collected 
during the specified visit windows (See Appendix E) 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 evaluable days’ worth of data 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
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 Semen Parameters
Semen concentration will be assigned into the below categories:
Normal (>15 million sperm/mL)


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Oligospermia: Mild (10-15 million sperm/mL)
Oligospermia: Moderate (5-10 million sperm/mL)
Oligosperma: Severe (<5 million sperm/mL)
Azoospermia (complete absence of sperm)
In addition total motile count will be derived by the below formula:
Total Motile Count = Volume of Semen x Semen Concentration x percentage motile
7.1.3.12 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 study medication. For subjects that enter the extension study, only AE’s occurring prior to 
entering the extension study will be considered a TEAE and summarised. 
TEAEs will also be split between AEs that start during the treatment period and those that start on 
or after the first day of the follow-up period (for subjects not entering the extension study).
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 study medication (number of days) will be defined as:
(date of last dose of study medication – date of first dose of study medication) + 1
Treatment Compliance
Overall treatment compliance will be defined as:
100% x [Total Number of capsules dispensed – Total Number of capsules returned]
[(Duration of Exposure (weeks) x Number of capsules expected to be taken (3)]


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Where Duration of Exposure (weeks) = [duration of exposure (days) / 7] rounded up to the nearest 
integer to derive the number of weeks started medication.  
If either the duration of exposure is missing or the number of (Number of capsules dispensed –
Number of capsules returned) cannot be calculated then the compliance calculation will not be 
computed.
7.1.4.3
Prior, Concomitant and Follow-up Medications/Procedures
Medications and Procedures will be assigned as being prior to study treatment, concomitant with 
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 dose of study medication, the 
medication/procedure will be assigned as being prior to study treatment. Otherwise, the 
medication/procedure will be assigned as being concomitant with study treatment unless the start 
date of the medication/procedure is after the Visit 8 date, when it will then be classified as
occurring in the follow-up
phase.
For subjects that enter the extension study, only 
medications/procedures with a start date prior to entering the extension study will be categorised 
and summarised.
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 Hy’s Law Criteria
Subjects will be deemed as meeting potential Hy’s law Criteria if their ALT or AST > 3x ULN and 
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) = 175 (Serum Creatinine in µmol/l × 0.011312) -1.154 × (age)-0.203 ×
(0.742 if female) × (1.212 if African/American Black)
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.


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The primary endpoint will be performed using both a last observation carried forward (LOCF) 
imputation and non-responder imputation (NRI). For the LOCF approach, subjects with missing 
testosterone value at a visit will be imputed with the last non-missing, post-baseline testosterone 
value. This value will then be used to determine if the subject achieved normalisation at that visit. 
For the NRI approach, subjects with missing testosterone value at a visit will be deemed as not 
achieving testosterone normalisation at that visit.
For each continuous secondary 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).
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 will be based upon the author’s 
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 study medication, then it will be assumed that the 
medication/procedure began after the start of 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 8 date, then it will be assumed the medication/procedure began on or 
before the Visit 8 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 study medication date (or after the date entering the extension study for those 
that continue into the extension study).


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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, ITT and PP populations,
unless otherwise stated.
Analyses of the primary efficacy endpoint will be performed on the ITT population, and also on the 
PP population as a sensitivity analysis.
The secondary and exploratory efficacy 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
t regimens in the below order:
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.
Summary statistics will only be presented at each visit for which the parameter is scheduled to be 
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. 
All four treatment regimens will be assessed by pairwise comparisons, and no adjustment for 


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multiplicity will be made.
8.1.5
Definition of Baseline
For summary purposes, the baseline value will be defined as the last non-missing value collected 
prior to the first dose of study medication, unless other specified.
Change from Baseline is defined as (value at assessment date – baseline value).
For Actigraphy Derived Activity and Sleep Parameters, as data is not collected prior to 
administrating the study drug, data collected during the 7 days from Visit 1 will be considered 
baseline data for all associated analysis.
For Semen quality analysis/parameters, samples at baseline can be taken up to 48 hours after the 
Baseline Visit. As such baseline will be defined as the last non-missing value collected up to 48 
hours post the date of first dose of study medication.
For DXA parameters, assessments at baseline can be taken up to day 8 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 selected renal parameters change from Screening 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:
o
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.
Semen quality analysis/parameters:
o
in case of multiple measurements associated to the same timepoint as permitted by 
the protocol the average value will be considered for all post baseline semen 
parameters.
8.1.7
Data listings
All relevant subject data, including those derived, will be presented in individual subject data 
listings. All listings will be sorted by treatment regimen, investigational site, subject number, 
date/time and visit. The subject’s 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.
8.2
Subject disposition
All subjects who provided informed consent will be included in a summary of subject


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accountability. The number of subjects screened, the number of screen failures, the frequency and 
percentage of subjects randomised, in the Safety population, in the ITT population, in the PP
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 Randomisation Phase (up to and including Visit 
8), number of subjects entering the extension study 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. 
Finally, the reasons for screen failure as reported on the eCRF will be tabulated.
8.3
Protocol deviations
The number of subjects excluded from ITT, Safety, PP and PK populations and reasons for 
exclusion will be summarised by treatment regimen and overall.
All protocol deviations identified 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 will be listed and summarised by treatment regimen and overall. This will 
include age, sex, race, weight, height and BMI. Separate summaries will be produced using the 
Safety, ITT and PP 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 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 will be tabulated using the Safety, PP and ITT population.
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, 
IIEF domain scores, IIEF erectile function domain severity and PROMIS sexFS domains will be 
summarised descriptively by treatment regimen and overall.


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All Summaries will be produced using the Safety Population and PP Population unless stated.
8.4.3
Medical history
A summary of all medical history will be presented by Medical History Code (as per CRF), system 
organ class (SOC) and preferred term (PT), by treatment regimen and overall using Medical 
Dictionary for Regulatory Affairs® (MedDRA) Version 19.1 or higher. Separate summaries will be 
produced using the Safety and ITT populations. 
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
Prior, concomitant and follow-up medications will be coded using the World Health Organization 
(WHO) Drug Dictionary (March 2016 or later).
Prior, concomitant and follow-up medications will be summarised by Anatomical Therapeutic 
Chemical (ATC) classification level 4 and Preferred Name by treatment regimen and overall for the 
Safety population.
8.4.5
Concomitant Procedures
Concomitant procedures 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) will be categorised in intervals (1-28, 29-56, 57-84, 85-112, 113-
140, >140) and summarised descriptively by treatment regimen on the Safety population using 
descriptive statistics.
8.5.2
Treatment compliance
The overall treatment compliance (in %) will be presented by treatment regimen using the Safety
population. The number of subjects with overall compliance <80% or >120% will be presented
8.6
Efficacy analyses
This section addresses the analyses to be conducted on the primary, secondary and exploratory 
efficacy variables.
All definitions relative to efficacy and exploratory endpoints are detailed in Section 7.1.3.
8.6.1
Analysis methods
For binary outcomes the proportion of subjects with a response will be summarised and compared 
between treatment regimens using Fisher’s Exact Test.


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For all continuous outcomes, where appropriate, a mixed model repeated measure model (MMRM) 
analysis will be performed. 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 (individual BGS649 doses vs. 
Placebo and between BGS649 doses) will be based on least-squares means. 
8.6.1.1
Multiplicity
All four treatment regimens will be assessed by pairwise comparisons. No adjustment will be made 
for multiple comparisons.
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 efficacy endpoint(s)
ITT population have normalisation of total testosterone levels (testosterone value is between 300-
1000 ng/dL inclusive) at Week 24.
The number and proportion of subjects with normal testosterone levels will be summarised by 
treatment regimen at each visit using the total testosterone assessed by ICON central lab. The Week 
12 total testosterone values assessed by the GLP lab will also be presented. In addition, a P-value 
for the comparison between each dose will be provided using Fisher’s exact test.
Moreover, a bar chart will be presented per treatment regimen for the normalisation of testosterone
at each visit showing the percentage of subjects normalised and confidence intervals.
The primary analysis of efficacy will be performed with the ITT population using LOCF 
imputation. Additionally for exploring the robustness of the intent-to-treat results, a supportive 
analysis using the PP population using LOCF, ITT population using non-responder analysis 
(subjects with missing testosterone values will be deemed as not achieving testosterone 
normalisation) and ITT population using observed cases will be carried out.
8.6.3
Analysis of secondary efficacy endpoint(s)
All analysis of secondary efficacy endpoints will be performed on the ITT population and the PP 
Population (as required).
8.6.3.1
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 the 
primary efficacy endpoint.


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8.6.3.2
Change from Baseline in Total Testosterone
A descriptive summary table will be presented for Total Testosterone values and change from
baseline in Total Testosterone by treatment regimen and visit using both ICON central lab and GLP 
lab assessed testosterone.
Change and percentage change from baseline in Total Testosterone up to Week 24 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 errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences (BGS649 doses vs. Placebo) 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.
Change from baseline in Total Testosterone up to Week 12 using the GLP  lab assessed values 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 will be presented for each 
visit. Significance tests will be based on least-squares means using a two-
8.6.3.3
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 the primary endpoint.
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:
<=1500ng/dl
>1500 – <1800 ng/dL
=>1800 - <= 2500 ng/dL
>2500 ng/dL
8.6.3.4
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 24 will be analysed via MMRM in the same 
manner as the change from baseline in total testosterone (see Section 8.6.3.1).
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 oestradiol, inhibins (A and B) levels, DHT and 
testosterone/oestradiol ratio
Descriptive summary tables will be presented for oestradiol, inhibin A, inhibin B, DHT,
testosterone/oestradiol ratio and DHT/testosterone ratio values,change from baseline values and 


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percentage change from baseline values by treatment regimen and visit. High sensitivity Oestradiol 
values will summarised together with the Oestradiol values assessed by the Central lab.
The change and percentage change from baseline in each parameter up to Week 24 will be analysed 
via MMRM in the same manner as the change from baseline in total testosterone (see Section 
8.6.3.1). Additionally 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.
8.6.4.2
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 change from baseline in each parameter up to Week 24 will be analysed via MMRM in the 
same manner as the change from baseline in total testosterone (see Section 8.6.3.1).
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 
dose of BGS649 and placebo will be provided using Fisher’s exact test. A descriptive summary 
table for the size of glandular breast tissue will be presented for those subjects with gynecomastia.
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 24 will be analysed via MMRM in the 
same manner as the change from baseline in total testosterone (see Section 8.6.3.1).
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 24 as described above will be presented.
8.6.4.3
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 24 will be analysed via MMRM in the 
same manner as the change from baseline in total testosterone (see Section 8.6.3.1).
Non-fasting values of all lipid profile parameters, glucose and insulin will be excluded from both 
the descriptive summary and analysis.


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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).
8.6.4.4
Change in 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 24 
will be analysed via MMRM in the same manner as the change from baseline in total testosterone 
(see Section 8.6.3.1). Additionally 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. 
8.6.4.5
Change in PRO measures
For some PRO Measures (PROMIS SexFS, PROMIS Fatigue Short Form and PGI-S), not all 
protocol versions mandated their collection. Subjects originally enrolled using protocol versions 
2.0 were not required to collect these measures. To handle such cases, denominators used for 
analysis will only include the subjects mandated to collect the particular PRO. 
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 24 will be analysed via 
MMRM in the same manner as the change from baseline in total testosterone (see Section 8.6.3.1),
however 90% confidence intervals (instead of 95%) will be presented for all inferences.
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 


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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 and 2 interfering factor raw scores
to Week 24 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.
The change from baseline to Week 24 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 24 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 24 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 24 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.


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8.6.4.6
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 
the 7 days 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 within each activity category, total daily steps and total activity counts to 
Week 24 will be analysed via MMRM in the same manner as the change from baseline in total 
testosterone (see Section 8.6.3.1).
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 24 will be analysed via MMRM in the same manner as the change from 
baseline in total testosterone (see Section 8.6.3.1).
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 24 will be analysed via MMRM in the same manner as the change from baseline in total 
testosterone (see Section 8.6.3.1).
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 24 as described above will be presented.
8.6.4.7
Change in Semen Parameters
Descriptive summary tables will be presented for each semen parameter (semen volume, sperm 
count, concentration, motility percentage, total motile count and morphology percentage) and 
change from baseline scores by treatment regimen and visit.
The change from baseline in each semen parameter to Week 20 will be analysed via MMRM in the 
same manner as the change from baseline in total testosterone (see Section 8.6.3.1).
A subgroup analysis of the change from baseline in semen parameters by baseline assessment 
timing (prior to first dose of study medication vs after first dose of study medication) will be 
conducted. Descriptive summaries and analysis up to Week 20 as described above will be 
presented.
A shift table of change from baseline in sperm concentration categories to post baseline categories 
will be generated by treatment regimen and visit. 


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The number and proportion of subjects moving from azoospermia at baseline to oligospermia post 
baseline and oligospermia at baseline to normal post baseline will be summarised by treatment 
regimen at each visit and overall.
8.6.4.8
Change in Bioavailable testosterone and Free testosterone
Descriptive summary tables will be presented for bioavailable and free testosterone values and 
change from baseline values by treatment regimen and visit.
The change from baseline in bioavailable and free testosterone up to Week 24 will be analysed via 
MMRM in the same manner as the change from baseline in IIEF domain scores.
8.6.4.9
Time to first normal testosterone level
Time to first normal total testosterone level will be analysed using the Kaplan-Meier method. As 
per Section 7.1.3.1, subjects that did not achieve testosterone normalisation (300-1000 ng/dL) or 
who discontinued the treatment period before achieving it will be considered as “censored” 
subjects. The number of subjects are normalised at baseline will be presented but excluded from the 
analysis.
For the following time points: Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24 the 
number of subjects not having achieved a normal total testosterone value from baseline to the 
timepoint, the cumulative number of subjects who have achieved a normal total testosterone value 
at the end of the period and the probability of achieving a normal total testosterone level at the end 
of the period with the associate two-sided 95% CIs will be presented by treatment regimen. The 
point estimates and the relative two-sided 95% CIs will be presented by treatment regimen for the 
75th, 50th and 25th percentiles. A Kaplan-Meier plot will also be presented. Comparisons between 
treatment regimens will be performed by means of the log-rank test.
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 
variables specified below.
No statistical tests will be performed.
8.7.1
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 treatment period, follow-up period and overall (i.e 
including those that started in both the treatment period and follow-up period).
Notes:
Two AEs with the same PT will be considered as two different events when calculating 
the “number of events” in the tables. 


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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 “Severe”
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 (i.e where the investigator has recorded “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.
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. 
8.7.2
Laboratory evaluations
8.7.2.1
Clinical laboratory
Haematology, blood chemistry, and urinalysis assessments will be conducted at Screening, 
Baseline, each visit during the treatment phase and Week 36.
The following laboratory parameters will be assessed:
Blood chemistry
o
Sodium
o
Potassium
o
Chloride
o
Bicarbonate/CO2
o
Blood urea nitrogen


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o
Creatinine
o
Fasting Glucose
o
Albumin
o
Alkaline phosphatase
o
AST
o
ALT
o
GGT
o
PT/INR
o
Total bilirubin
o
Total protein
o
Calcium
o
Lipid panel (total cholesterol, LDL, HDL, triglycerides)
o
PSA
o
eGFR (calculated based on Cockcroft-Gault formula)
o
eGFR (derived from 4-v MDRD)
Haematology
o
Red Blood Cell Count [RBC]
o
White Blood Cell Count [WBC]
o
Neutrophils
o
Lymphocytes
o
Monocytes
o
Eosinophils
o
Basophils
o
Haemoglobin
o
Haematocrit
o
Platelets
Urinalysis
o
Specific gravity
o
pH
o
Protein
o
Bilirubin
o
Glucose
o
Blood
o
Ketones
o
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.


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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 24 will also be analysed via MMRM in 
the same manner as the change from baseline in total testosterone (see Section 8.6.3.1).
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 individual 
data listings along with the Investigator’s assessment.
In addition boxplots of observed values by treatment and visit will be generated for the below lab 
parameters:
o
Hematocrit
o
Hemoglobin
o
Creatinine
o
PSA
Qualitative urinalysis parameters (e.g protein, glucose and blood) will only be listed.
8.7.2.2
Specialised Chemistry
The following laboratory parameters will be measured at Screening and will be only be listed:
Morning cortisol
thyroid stimulating hormone (TSH)
free thyroxine (FT4)
Prolactin
25-hydroxy vitamin D
Fasting transferrin saturation
8.7.2.3
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)
8.7.3
Vital signs
Vital sign assessments will be performed at each visit in the Randomisation Phase and Week 36.
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 24 will also be analysed 
via MMRM in the same manner as the change from baseline in total testosterone (see Section 
8.6.3.1).
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
Elevated BP
Hypertension Stage 1
or
Hypertension Stage 2: S
SBP Change from baseline >=20 mmHg
DBP Change from baseline >=10 mmHg


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8.7.4
Physical examinations
A full physical examination will be performed at Screening, Week 12 and Week 24 whereas a 
limited physical examination (cardiovascular system and lower extremities oedema only) will be 
performed at all other visits during the randomisation phase and Week 36.
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.
8.7.5
Electrocardiograms
12-Lead ECG assessments will be performed at Screening, Baseline, Week 4, Week 8, Week 12, 
Week 24 and Week 36.
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 
-point. 
8.7.6
DXA Scan
DXA Scan assessments will be performed at screening (up to day 8 after randomisation) and Week 
24 and will be over-read by IMI. Both the site assessed and 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.
Descriptive statistics (observed values, changes from baseline and percentage change from 
baseline) for bone density in both the lumbar spine and hip (total and femoral neck) 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 24 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-
= .05. 
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 


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hydroxy vitamin D < 30ng/ml) will be presented. 
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 data 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. In addition, if one of the active BGS649 study arms 
2 subjects meeting this discontinuation criterion at any time point within the first 
24 randomized subjects to that arm or > 15% subjects meet this criterion at any time point 
25 randomized subjects, then the arm will be evaluated by an independent unblinded, external
DMC for potential dosing discontinuation based on FDA guidance (FDA Advisory Committee 
Industry Briefing Document Testosterone Replacement Therapy, Sept 2014). Subjects may be 
discontinued from the study arm and no further randomisation to that arm will be performed.
Any treatment arm discontinued due to this process will still be presented in summary tables 
however no formal analysis vs Placebo will be conducted.
8.8.1.2
Interim Analysis
An interim analysis was conducted once approximately 100 of overall planned subjects completed 
their Week 4 visit. The analysis was performed by the independent DMC who reviewed un-blinded 
data to identify:
1.
Any safety signals across the dose groups which would preclude further continuation of 
dosing
2.
75% of subjects reaching the 
normalisation of testosterone (testosterone within or above normal reference range for 
healthy adult males according to the FDA)
3.
Whether in the opinion of the DMC following unblinded review that when the arm is fully 
recruited it is e
75% response at Week 24. 
Dosing arms which met either criterion 2 or 3 were deemed to be effective. For arms that were
determined to be ineffective or unsafe, dosing was to be stopped and no further randomisation to 
that arm was performed. Subjects assigned to any ineffective or unsafe arm(s) were to be 
discontinued from the treatment, attend an EOT visit and followed-up for an additional 12 weeks 


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(FU, Visit 11). Any treatment arm discontinued due to this process would still be presented in 
summary tables however no formal analysis vs Placebo will be conducted.
Following the results of the Interim Analysis no dose arm was dropped from the study.
8.8.2
PK analyses
Pharmacokinetic samples will be collected as follows:
1.
Plasma PK samples will be taken pre-dose and 1h post-dose at Visit 5. At Visit 8 (EOT; 
Week 24) it will be taken only once.
2.
Semen samples for seminal fluid PK will be taken at Visit 8 (EOT)
This plan does not address the PK analyses of BGS649 (Nonlinear mixed effects modelling will be 
utilised to develop a population PK model for BGS649 plasma concentrations and to develop a 
PK/PD model linking BGS649 plasma concentrations to changes in testosterone levels). These 
analyses will be performed by ICON Pharmacokinetics, Pharmacodynamics, Modelling and 
Simulation Department and will be described in a separate analysis plan. Results from the PK/PD 
modelling will be reported separately from the CSR.
BGS649 PK plasma concentrations will be summarised for the PK population by descriptive 
statistics by treatment regimen and time-point, and including the geometric mean and coefficient of 
variation.
A graphical representation of the PK plasma concentrations distribution using mean plots (mean 
and SD) will be provided over time per treatment regimen for the PK population. All dose levels 
will be plotted on the same graph.
8.8.3
Subgroup analysis
To determine the impact of other baseline measures on the primary efficacy analysis the following 
covariates may be added to the analysis independently and subgroup analysis performed to test for 
significance:
Age
BMI
Other baseline parameters reviewed at the classification meeting
All parameters to be tested will be documented at the classification meeting prior to unblinding. 
8.8.4
Association Testing
To determine any correlation between endpoints at Week 24, various association testing will be 
conducted using the PP Population. For the below sets of endpoints scatter graphs will be generated 
annotated with the coefficient of determination (R2 statistic):
Total testosterone vs PRO scores (total and domain)
Total oestradiol vs PRO score (total and domain)


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Testosterone/oestradiol vs PRO scores (total and domain)
Activity parameters vs PRO scores (total and domain)
Sleep parameters vs PRO scores (total and domain)
Change in grip strength vs PRO scores (total and domain)
Change in total testosterone vs Change in Grip Strength
Change in BMI vs Change in Grip Strength
Change in waist Circumference vs Change in Grip Strength
Change in bio impedance parameters vs Change in Grip Strength
Total testosterone vs cardiometabolic parameters: SBP and DBP, lipid panel (total 
cholesterol, LDL, triglycerides and HDL), HbA1c, fasting glucose and insulin, HOMA-IR 
and hs-CRP
Change in BMI vs cardiometabolic parameters: SBP and DBP, lipid panel (total 
cholesterol, LDL, triglycerides and HDL), HbA1c, fasting glucose and insulin, HOMA-IR 
and hs-CRP
Change in waist circumference vs cardiometabolic parameters: SBP and DBP, lipid panel 
(total cholesterol, LDL, triglycerides and HDL), HbA1c, fasting glucose and insulin, 
HOMA-IR and hs-CRP
Change in semen parameters vs Change in LH and FSH levels
Change in semen parameters vs Change in oestradiol
Change in systolic blood pressure vs Total Testosterone, Oestradiol and 
Testosterone/Oestradiol ratio (at Week 12 and Week 24)
Change in diastolic blood pressure vs Total Testosterone, Oestradiol and 
Testosterone/Oestradiol ratio (at Week 12 and Week 24)
Change in Creatinine vs Blood Pressure (Absolute systolic and diastolic blood pressure) 
Change in Creatinine vs Change in Blood Pressure (Systolic and Diastolic blood pressure) 
8.8.4.1
PROMIS SexFS Domains Testing
End of treatment testosterone levels (<300ng/dL vs 300-500 ng/dL vs >500 ng/dL) will be tested 
against each PROMIS sexFS domain score (excluding the domain “interfering factors”) by a 
MMRM model. Analyses will include the fixed, categorical effects of end of treatment testosterone 
level, visit, and end of treatment testosterone level-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. The end of treatment 
testosterone factor effect p-value aswell as the Week 24 least square mean differences and 95% CI 
of the pairwise comparisons of each end of treatment testosterone level group will be presented.
This process will be repeated to test the association of baseline testosterone level (<200 ng/dL vs 
>200 ng/dL) against the change from baseline of each PROMIS sexFS Domain (excluding the 
domain “interfering factors”).              
8.8.4.2
IIEF Erectile Function Domain Testing
End of treatment testosterone levels (<300ng/dL vs 300-500 ng/dL vs >500 ng/dL) will be tested 


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against IIEF erectile function domain response of achieving a minimal meaningful difference at 
Week 24 by a logistic regression model. The end of treatment testosterone factor effect p-value 
aswell as the odds ratio and 95% CI of the pairwise comparison of each end of treatment 
testosterone level group will be presented.
This process will be repeated to test the association of baseline testosterone level (<200 ng/dL vs 
>200 ng/dL) against IIEF erectile function domain response of achieving a minimal meaningful 
difference.
8.9
CSR
The primary efficacy analysis and study unblinding will be performed when all data up to Visit 8 
(Week 24) has been collected. Given the study has been powered at Week 24 and there will not be 
multiple comparisons, there is no requirement to adjust the Type I error rate.  
The Clinical Study report (CSR) will be prepared based upon the results of this analysis.
The data collected during the off treatment 12 week follow-up will be separately analysed and 
published in an addendum to the CSR.
If for any reason a primary analysis assessment (Total Testosterone) is not available at the time of 
the primary analysis, such values will not be used for any future efficacy endpoint analysis at any 
stage (i.e they will continue to be assumed missing). However such values will be included for
future safety endpoints analysis (e.g Total Testosterone Overshoot).   


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9
CHANGES TO PLANNED ANALYSIS FROM 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.


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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
Did not attempt intercourse
0


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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


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Appendix B - Patient-Reported Outcomes Measurement Information System(®) 
Sexual Function and Satisfaction (PROMIS(®) SexFS)
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 
satisfaction with your sex 
Very Much
5
Quite a bit
4
Somewhat
3


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life?
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 gain in the last 30 
days
0
T-Score Conversion Tables :
1.
Interest in Sexual Activity (1,2)


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2.
Erectile Function (3)
3.
Satisfaction with Sex Life (4,5,6,7,8)
Satisfaction with Sex 
Life Tscore.xlsx


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Appendix C - PROMIS(®) Fatigue Short 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


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Never
1
T-Score Conversion Table :
Reference : https://www.assessmentcenter.net/


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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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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=Don’t know, 4=Mostly false, and
5=Definitely false and reflect the subject’s 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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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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SF-36 RE scale score
rawscore = 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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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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Appendix E – Actigraphy Visit Windows
Visit
Window Start
Window End
Baseline
Day 1
Day 7
Week 12
Day 56
Day 112
Week 24
Day 140
Day 196
Week 36
Day 224
End of Study
Where Day 1 is first dose of study medication
Appendix F – DEXA Visit Windows
Visit
Window Start
Window End
Target Day
Baseline
Day -28
Day 8
Day 1
Week 24
Day 140
Day 196
Day 168
Where Day 1 is first dose of study medication