Clinical trial NCT04467697
Conditions: Hypogonadism, Male
Sponsor: Marius Pharmaceuticals
Start date: 2018-09-18; Completion date: 2020-05-01
Enrollment: 155 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this six-month treatment study is

* to assess feasibility of a lower starting dose of SOV2012-F1 (daily dose of 400 mg \[200 mg with breakfast meal and 200mg with dinner meal\]) to titrate individual doses to further enhance efficacy and safety.
* To examine the blood pressure (BP) effects of Marius's oral testosterone undecanoate formulation, SOV2012-F1, using 24-hour ambulatory blood pressure monitoring (ABPM).

Detailed description:
This is the six-month treatment extension of Study MRS-TU-2019, which like Study MRS-TU-2019 (NCT03198728), is an open-label study. The MRS-TU-2019 ABPM Extension Study (MRS-TU-2019EXT; NCT04467697), will extend the participation for up to 170 MRS-TU-2019 subjects and to new subjects, for a target of 135 evaluable subjects reaching the 4-month ABPM assessment. All subjects were washed out from previous testosterone therapy if they were not naïve. The study used ABPM monitoring to assess baseline and change from baseline after 120 and 180 days of treatment. The percentage of participants within the normal range for testosterone was assessed after two titration cycles and a total of 90 days of treatment.

Arms: arm 1: Patients treated with SOV2012-F1, starting daily dose in MRS-TU-2019EXT is 400 mg - (200 mg with morning meal and 200 mg with evening meal). Dosing is titrated up to a maximum of 800 mg SOV2012-F1 per day (400 mg in the morning and 400 mg in the evening) or titrated down to a minimum of 100 mg SOV2012-F1 per day (100 mg in the morning) based on plasma T after 14 and 42 days of treatment, intermediate dose levels include total daily doses of 600 mg, 400 mg and 200 mg.
Interventions: intervention 1: SOV2012-F1
Intervention descriptions: intervention 1: Oral preparation of testosterone undecanoate (TU). Strengths of 100 mg TU, 150 mg TU and 200 mg TU

Protocol documents:
Prot_000.pdf: 
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A 12-Month, Randomized, Active-controlled, Open-label Study of the Efficacy 
and Safety of Oral Testosterone Undecanoate 
in Hypogonadal Men 
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SAP_001.pdf: 
Statistical Analysis Plan 
This document is proprietary and confidential to Marius Pharmaceuticals.
03.007A.03
 ........................................................................................... Page 1 of 193 
Sponsor Name:
Marius Pharmaceuticals
Protocol Number and Title:
MRS-TU-2019: A 12-Month, Randomized, 
Active-controlled, Open-label Study of the 
Efficacy and Safety of Oral Testosterone 
Undecanoate in Hypogonadal Men
and
MRS-TU-2019EXT: 
Ambulatory 
Blood 
Pressure Monitoring (ABPM) Extension Study
Protocol Versions and Dates:
Version 1.0 01MAR2017
Version 2.0 10MAY2017
Version 3.0 15JUN2017
Version 4.0 08AUG2017
Version 5.0 18AUG2017
Version 6.0 19JAN2018
Version 7.0 27JUN2018
Version 8.0 09OCT2018
Version 9.0 18FEB2019
INC Research Project Code:
1005416
Authors:
, Senior Biostatistician
 Biostatistician II
 Principal Biostatistician (INC 
Research/Syneos Health)
 (Marius)
 Research Scientist, Pharmacokinetics 
(INC Research/Syneos Health)


Statistical Analysis Plan
Marius Pharmaceuticals 
Protocols MRS-TU-2019 and MRS-TU-2019EXT
Final Version 5.0
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
 ................................................................................................... Page 2 of 193 
SAP Version:
Final Version 5.0
SAP Version Date: 
August 28, 2020
Notice of Confidential and Proprietary Information:
The information contained in this document is confidential belonging to Marius Pharmaceuticals. Acceptance of this 
document constitutes agreement by the recipient that no information contained herein will be published or disclosed 
without prior written authorization from an official of Marius Pharmaceuticals. However, this document may be 
disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. In the event of an 
actual or suspected breach of this obligation, Marius Pharmaceuticals LLC should be notified promptly.




Statistical Analysis Plan
Marius Pharmaceuticals 
Protocols MRS-TU-2019 and MRS-TU-2019EXT
Final Version 5.0
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
 ................................................................................................... Page 4 of 193 
TABLE OF CONTENTS
Contents
1. 
GLOSSARY OF ABBREVIATIONS ...............................................................10 
2. 
PURPOSE.......................................................................................................14 
2.1. 
Responsibilities ...............................................................................................................................14 
2.2. 
Timings of Analyses ........................................................................................................................14 
3. 
STUDY OBJECTIVES....................................................................................15 
3.1. 
MRS-TU-2019 Objectives ...............................................................................................................15 
3.1.1. 
Primary Objective..............................................................................................................15 
3.1.2. 
Secondary Objective.........................................................................................................15 
3.1.3. 
Exploratory Objectives ......................................................................................................15 
3.1.4. 
Safety Objectives ..............................................................................................................15 
3.2. 
MRS-TU-2019EXT Objectives........................................................................................................16 
3.2.1. 
Primary Objectives............................................................................................................16 
3.2.2. 
Secondary Objectives .......................................................................................................16 
3.2.3. 
Safety Objectives ..............................................................................................................17 
3.3. 
Brief Description.............................................................................................................................17 
3.3.1. 
MRS-TU-2019...................................................................................................................17 
3.3.2. 
MRS-TU-2019EXT............................................................................................................20 
3.4. 
Subject Selection.............................................................................................................................22 
3.4.1. 
Inclusion Criteria ...............................................................................................................22 
3.4.2. 
Exclusion Criteria ..............................................................................................................22 
3.5. 
Determination of Sample Size .........................................................................................................22 
3.5.1. 
MRS-TU-2019...................................................................................................................22 
3.5.2. 
MRS-TU-2019EXT............................................................................................................24 
3.6. 
Treatment Assignment & Blinding..................................................................................................24 
3.7. 
Administration of Study Drug.........................................................................................................24 
3.8. 
Study Procedures and Flowchart ....................................................................................................25 
3.8.1. 
MRS-TU-2019...................................................................................................................25 
3.8.2. 
MRS-TU-2019EXT............................................................................................................30 


Statistical Analysis Plan
Marius Pharmaceuticals 
Protocols MRS-TU-2019 and MRS-TU-2019EXT
Final Version 5.0
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
 ................................................................................................... Page 5 of 193 
4. 
ENDPOINTS...................................................................................................37 
4.1. 
MRS-TU-2019 Endpoints................................................................................................................37 
4.1.1. 
Primary Endpoint...............................................................................................................37 
4.1.2. 
Secondary Endpoints........................................................................................................37 
4.1.3. 
Exploratory Endpoints.......................................................................................................37 
4.1.4. 
Safety Endpoints...............................................................................................................38 
4.2. 
MRS-TU-2019EXT Endpoints ........................................................................................................39 
4.2.1. 
Primary Endpoints.............................................................................................................39 
4.2.2. 
Secondary Endpoints ........................................................................................................39 
4.2.3. 
Safety Endpoints ...............................................................................................................40 
4.3. 
Pharmacokinetic (PK) Endpoints....................................................................................................40 
5. 
ANALYSIS SETS............................................................................................42 
5.1. 
MRS-TU-2019 Analysis Sets ...........................................................................................................42 
5.1.1. 
Safety Set (SS) .................................................................................................................42 
5.1.2. 
Full Analysis Set (FAS) .....................................................................................................42 
5.1.3. 
Pharmacokinetic Set (PKS) ..............................................................................................42 
5.1.4. 
Efficacy Completers Set (ECS).........................................................................................42 
5.1.5. 
ACTH Completer Analysis Set (AAS) ...............................................................................43 
5.2. 
MRS-TU-2019EXT Analysis Sets....................................................................................................43 
5.2.1. 
Subject Sources................................................................................................................43 
5.2.2. 
Extension Treated Set (EXTS)..........................................................................................43 
5.2.3. 
Extension Pharmacokinetic (EXPK) Set ...........................................................................44 
5.2.4. 
Extension Serum (EXSE) Set ...........................................................................................44 
5.3. 
Overall Analysis Set........................................................................................................................44 
5.3.1. 
Overall Safety Set (OSS) ..................................................................................................44 
5.4. 
Protocol Deviations (PDs)................................................................................................................44 
5.4.1. 
Data Review Meeting (DRM) ............................................................................................44 
5.4.2. 
PDs General......................................................................................................................45 
5.4.3. 
Signficant Protocol Deviations: MRS-TU-2019.................................................................45 
5.4.4. 
Significant Protocol Deviations: MRS-TU-2019EXT.........................................................47 
5.4.5. 
Site 104.............................................................................................................................48 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................49 
6.1. 
General Methods.............................................................................................................................49 
6.2. 
Key Definitions ...............................................................................................................................49 
6.2.1. 
First Dose Date of Study Drug..........................................................................................49 
6.2.2. 
Last Dose Date of Study Drug ..........................................................................................50 


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6.2.3. 
Study Day..........................................................................................................................50 
6.2.4. 
Baseline ............................................................................................................................50 
6.2.5. 
Change from Baseline ......................................................................................................50 
6.2.6. 
Time 0 (Vital Signs)...........................................................................................................51 
6.2.7. 
MRS-TU-2019 End of Treatment and Day 365 Visit.........................................................51 
6.2.8. 
MRS-TU-2019EXT Enrolled..............................................................................................51 
6.3. 
Missing and Below the Limit of Quantification (BLQ) Data ............................................................51 
6.3.1. 
Missing ABPM Data ..........................................................................................................51 
6.3.2. 
Missing Data for Primary Endpoints..................................................................................51 
6.3.3. 
Missing Pharmacokinetic (PK) Data .................................................................................52 
6.3.4. 
Below the Limit of Quantification (BLQ) PK Concentration Data......................................52 
6.3.5. 
Missing Adverse Event (AE) Data.....................................................................................53 
6.3.6. 
Missing and Partial Medication Dates...............................................................................53 
6.3.7. 
Missing and Partial Diagnosis Dates ................................................................................54 
6.3.8. 
Missing and Partial Last Dose of Study Drug Dates.........................................................54 
6.4. 
Visit Windows.................................................................................................................................55 
6.5. 
Pooling of Centers...........................................................................................................................55 
6.6. 
Subgroups.......................................................................................................................................55 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION
57 
7.1. 
Subject Disposition and Withdrawals..............................................................................................57 
7.1.1. 
MRS-TU-2019...................................................................................................................57 
7.1.2. 
MRS-TU-2019EXT............................................................................................................57 
7.1.3. 
Overall...............................................................................................................................58 
7.2. 
Demographic and Other Baseline Characteristics ...........................................................................58 
7.2.1. 
MRS-TU-2019...................................................................................................................59 
7.2.2. 
MRS-TU-2019EXT............................................................................................................59 
7.2.3. 
Overall...............................................................................................................................60 
7.3. 
Baseline Disease Characteristics......................................................................................................60 
7.4. 
Medical History ..............................................................................................................................60 
7.5. 
Medication......................................................................................................................................61 
8. 
EFFICACY.....................................................................................................64 
8.1. 
Normal Range.................................................................................................................................64 
8.2. 
Primary MRS-TU-2019 Endpoint ...................................................................................................64 


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8.2.1. 
Multiple Imputation Analysis .............................................................................................64 
8.2.2. 
Sensitivity Analyses ..........................................................................................................64 
8.3. 
Primary MRS-TU-2019EXT Efficacy Endpoint ..............................................................................65 
8.3.1. 
Primary Analysis ...............................................................................................................65 
8.3.2. 
Sensitivity Analyses ..........................................................................................................65 
8.4. 
Exploratory MRS-TU-2019 Endpoints............................................................................................66 
8.4.1. 
International Prostate Symptom Score (I-PSS) ................................................................66 
8.4.2. 
Psychosexual Daily Questionnaire (PDQ) ........................................................................67 
8.4.3. 
Short Form Survey (SF-36)...............................................................................................68 
8.4.4. 
International Index of Erectile Function Questionnaire (IIEF)...........................................68 
8.4.5. 
Fasting Serum Glucose and Fasting Insulin Concentrations............................................72 
8.5. 
Multiple Imputation Methods .........................................................................................................72 
8.5.1. 
MRS-TU-2019 Imputation Procedure ...............................................................................72 
8.5.2. 
Analysis of Imputed Data..................................................................................................74 
9. 
ANALYSIS OF PHARMACOKINETICS (PK) ...............................................75 
9.1. 
Data Sets Analyzed .........................................................................................................................75 
9.2. 
Pharmacokinetic (PK) Sampling Schedule ......................................................................................75 
9.3. 
Pharmacokinetic (PK) Concentration Data .....................................................................................76 
9.3.1. 
Handling of Missing Data and Data Below the Limit of Quantification (BLQ)...................76 
9.3.2. 
Presentation of Pharmacokinetic (PK) Concentration Data..............................................76 
9.4. 
Pharmacokinetic (PK) Parameters..................................................................................................79 
9.4.1. 
Derivation of Pharmacokinetic (PK) Parameters ..............................................................79 
9.4.2. 
Presentation of Pharmacokinetic (PK) Parameters ..........................................................80 
9.5. 
MRS-TU-2019 SOV2012-F1 Titration Algorithm Evaluation..........................................................82 
9.6. 
MRS-TU-2019EXT SOV2012-F1 Titration Algorithm Evaluation for Sampling Time and matrix 
Effects 82 
9.6.1. 
Analysis of T Cavg Within the Normal Range After 90 Days of Treatment (Day 90E) vs. 
Visit 10E (Day 42E) Titration Time, ........................................................................................................82 
9.6.2. 
Plasma Projected Dose Adjustments................................................................................82 
9.6.3. 
Actual and Projected Titration Decisions ..........................................................................83 
9.6.4. 
Spearman’s Correlation Matrix of Projected Dose Adjustments.......................................83 
9.6.5. 
Adjustment of NaF/EDTA Titration Thresholds to Serum Basis .......................................83 
9.6.6. 
Final Dose as an Outcome Variable .................................................................................83 
9.7. 
Analysis of food effect .....................................................................................................................83 
10. SAFETY .........................................................................................................84 


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10.1. 
Extent of Exposure..........................................................................................................................84 
10.2. 
Treatment Compliance ...................................................................................................................86 
10.3. 
Ambulatory Blood Pressure Monitoring (ABPM)............................................................................88 
10.3.1. 
24-hour Average Ambulatory sBP ....................................................................................88 
10.3.2. 
Daytime and Nighttime Average Ambulatory sBP ............................................................90 
10.3.3. 
Censoring..........................................................................................................................91 
10.3.4. 
Other Ambulatory sBP Endpoints .....................................................................................91 
10.3.5. 
Effect of Dose on Average ABPM sBP .............................................................................91 
10.3.6. 
Cavg and Average ABPM sBP............................................................................................92 
10.3.7. 
Estimation of Treatment Effects on ABPM sBP After a Year of Treatment......................92 
10.3.8. 
Ambulatory dBP ................................................................................................................92 
10.3.9. 
Ambulatory Heart Rate (HR).............................................................................................92 
10.3.10. 
Ambulatory Mean Arterial Pressure (MAP).......................................................................93 
10.3.11. 
Ambulatory Pulse Pressure (PP) ......................................................................................94 
10.4. 
T Cmax .............................................................................................................................................94 
10.4.1. 
MRS-TU-2019...................................................................................................................94 
10.4.2. 
MRS-TU-2019EXT............................................................................................................94 
10.5. 
Adverse Events (AEs)......................................................................................................................95 
10.6. 
Laboratory Evaluations ..................................................................................................................98 
10.6.1. 
MRS-TU-2019...................................................................................................................99 
10.6.2. 
MRS-TU-2019EXT............................................................................................................99 
10.7. 
Liver Toxicity ...............................................................................................................................100 
10.8. 
Vital Signs.....................................................................................................................................100 
10.8.1. 
MRS-TU-2019.................................................................................................................100 
10.8.2. 
MRS-TU-2019EXT..........................................................................................................103 
10.9. 
Adrenocorticotropic Hormone (ACTH) sub-study ........................................................................105 
10.10. Other Safety Assessments..............................................................................................................106 
11. INTERIM ANALYSES .................................................................................107 
12. CHANGE FROM ANALYSIS PLANNED IN PROTOCOL...........................108 
13. REFERENCE LIST ......................................................................................111 
14. PROGRAMMING CONSIDERATIONS.......................................................112 


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14.1. 
General Considerations.................................................................................................................112 
14.2. 
Table, Listing, and Figure (TLF) Format......................................................................................112 
14.2.1. 
General ...........................................................................................................................112 
14.2.2. 
Headers...........................................................................................................................113 
14.2.3. 
Display Titles...................................................................................................................113 
14.2.4. 
Column Headers .............................................................................................................114 
14.2.5. 
Body of the Data Display ................................................................................................114 
14.2.6. 
Footnotes ........................................................................................................................116 
15. QUALITY CONTROL..................................................................................118 
16. APPENDICES...............................................................................................119 
16.1. 
index of Output.............................................................................................................................119 
16.1.1. 
Index of Tables................................................................................................................119 
16.1.2. 
Index of Figures ..............................................................................................................152 
16.1.3. 
Index of Listings ..............................................................................................................172 
16.2. 
Derivation of Titration Algorithm for SOV2012-F1 (Testosterone Undecanoate 200 mg) and 
optimization of titration cut-offs for extension study ..................................................................................175 
16.3. 
Handling of Data for Duplicate Subjects .......................................................................................188 
16.4. 
Outlier analysis for site 104...........................................................................................................189 
16.4.1. 
Objective .........................................................................................................................189 
16.4.2. 
Study Population.............................................................................................................190 
16.4.3. 
Sample Size....................................................................................................................190 
16.4.4. 
Data Analysis and Report ...............................................................................................190 
16.4.5. 
Results ............................................................................................................................191 










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2.
PURPOSE
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives.
2.1.
RESPONSIBILITIES
Pharstat Inc. will perform the final statistical analyses and are responsible for the production and quality 
control of all tables, figures and listings as outlined within this SAP. Final pharmacokinetic (PK) analysis 
will be carried out by Pharstat Inc. as outlined within this SAP.
2.2.
TIMINGS OF ANALYSES
An informal interim analysis of the primary and secondary efficacy data, PK, and safety was conducted 
after all subjects had completed the 90-day visit in MRS-TU-2019 or had terminated early from the efficacy 
period of the MRS-TU-2019 study. The final analysis of all study data will be conducted when all subjects 
complete their final post-treatment follow-up visit. In addition, Study MRS-TNR2019 (for normal range 
assessment) will have completed with topline results prior to any analyses under MRS-TU-2019EXT.


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3.
STUDY OBJECTIVES
3.1.
MRS-TU-2019 OBJECTIVES
3.1.1.
Primary Objective
The primary objective of the MRS-TU-2019 study is to determine the efficacy of oral SOV2012-F1 as 
measured by the percentage of male hypogonadal subjects with T Cavg within the normal range after 90 
days of treatment.
3.1.2.
Secondary Objective
This secondary objective has been updated to reflect FDA feedback:
The secondary objective of the MRS-TU-2019 study is to determine the percentage of SOV2012-F1–treated
subjects with T Cmax values (a) ≤1.5 x ULN; (b) 1.800 x ULN to 2.5 x ULN ; and (c) >2.5 x ULN  after 
90 days of treatment, where  the ULN is defined using the NaF/EDTA plasma and serum endogenous 
testosterone from study MRS-TNR2019.
3.1.3.
Exploratory Objectives
The exploratory objectives of the MRS-TU-2019 study are:
•
To determine the change from baseline in the following subject-reported outcomes by SOV2012-
F1–treated and AndroGel-treated subjects in International Prostate Symptom Score (I-PSS),
Psychosexual Daily Questionnaire (PDQ), Short Form Survey (SF-36), and IIEF after 52 weeks of 
treatment. 
•
To determine change from baseline in fasting serum glucose and fasting insulin concentrations in 
SOV2012-F1–treated and AndroGel-treated subjects after 52 weeks of treatment.
•
Assessment of bioanalytical sample stability for measurement of T and DHT in serum and plasma 
samples from subjects receiving testosterone undecanoate (TU) orally, including three types of 
plasma tubes (EDTA, NaF/EDTA, and lithium heparin).
3.1.4.
Safety Objectives
The safety objectives of the MRS-TU-2019 study are:
x
To determine the incidence of adverse events (AEs), serious AEs (SAEs), and AEs leading to 
study withdrawal in SOV2012-F1–treated subjects compared with AndroGel-treated subjects after 
52 weeks of treatment.


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x
To assess change from baseline in blood pressure (BP), liver function tests, hematology 
parameters, hormone levels, lipid profiles, and serum PSA in SOV2012-F1–treated and AndroGel-
treated subjects after 52 weeks of treatment.
x
To determine the effect of SOV2012-F1 on adrenal cortical function as assessed by measuring the 
cortisol response to synthetic adrenocorticotropic hormone (ACTH) at baseline and after 52 weeks 
of treatment in a subset of 30 SOV2012-F1 subjects and 15 AndroGel subjects.
3.2.
MRS-TU-2019EXT OBJECTIVES
3.2.1.
Primary Objectives
x
To assess change from baseline in 24-hour mean sBP measured by ambulatory BP monitoring 
(ABPM) after approximately 120 (±3) days of treatment, in SOV2012-F1–treated subjects.
x
To determine the response to a lower starting dose of oral SOV2012-F1 with up and down titration 
as appropriate, as measured by:
o
The percentage of SOV2012-F1–treated subjects with T Cavg within the normal range after 
90 days of treatment.
3.2.2.
Secondary Objectives
To determine the response to a lower starting dose (and revised titration thresholds) of oral SOV2012-F1 
with up and down titration as appropriate, as measured by:
x
This secondary objective has been updated to reflect FDA feedback:  To determine the 
percentage of SOV2012-F1–treated subjects with T Cmax values (a) ≤1.5 x ULN; (b) 1.800 x 
ULN to 2.5 x ULN; and (c) >2.5 x ULN after 90 days of treatment, where  the ULN is defined 
using the NaF/EDTA plasma and serum endogenous testosterone from study MRS-TNR2019.
x
To assess change from baseline in 24-hour mean sBP measured by ABPM after approximately 
180 (±3) days of treatment, in SOV2012-F1–treated subjects. To assess change from baseline in 
24-hour mean dBP measured by ABPM after 120 (±3) days and 180 (±3) days of treatment, in 
SOV2012-F1–treated subjects.
x
To assess change from baseline in 24-hour heart rate (HR) measured by ABPM, after 120 (±3) 
days and 180 (±3) days of treatment, in SOV2012-F1–treated subjects.
x
To assess change from baseline in BP and HR measured in clinic after 120 (±3) and 180 (±3) days 
of treatment, in SOV2012-F1–treated subjects.
x
To collect samples for bioanalysis to correlate endogenous T levels (following medication 
washout) obtained in serum and plasma tubes (NaF/EDTA).


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3.2.3.
Safety Objectives
x
To assess hematology parameters, hormone levels, lipid profiles, and serum PSA in SOV2012-
F1–treated subjects after 180 days of treatment.
x
To determine the incidence of AEs, SAEs, and AEs leading to study withdrawal in SOV2012-F1-
treated subjects after 180 days of treatment.
3.3.
BRIEF DESCRIPTION
3.3.1.
MRS-TU-2019
This study is a Phase 3, randomized, multicenter, open-label, active-controlled, efficacy and safety study in 
adult hypogonadal men. The study duration is 12 months (365 days), including a 90-day, open-label
efficacy period and a 9-month (275-day) safety evaluation period.
Eligible subjects will be randomized 2:1 (approximately 200 SOV2012-F1–treated subjects to 100 
AndroGel-treated subjects, respectively) and stratified by study center to receive SOV2012-F1 with 
morning and evening meals, or AndroGel, a commonly prescribed topical T replacement product. Both 
treatments will be continued for the 12-month study duration.
SOV2012-F1 will be started at a total daily dose of 600 mg (400 mg with the morning meal and 200 mg 
with the evening meal). The plasma T concentration between 3 to 5 hours after the morning dose at Visit 
4, Day 14 and Visit 6, Day 42 will determine the need, if any, to titrate the dose up or down by 200 mg at 
Visit 5, Day 28 and Visit 7, Day 56, respectively. The minimum dose of SOV2012-F1 will be 200 mg with 
the morning meal and no evening dose. The maximum dose of SOV2012-F1 will be 1000 mg (600 mg with 
the morning meal and 400 mg with the evening meal).
AndroGel will be applied at a starting dose of 40.5 mg QD. The serum T predose concentration (T Cpredose)
from a single blood draw at Day 14 and Day 42 will determine the need, if any, to titrate per the product 
information (Section 16.4 of study protocol) at Day 28 and Day 56, respectively. 
The final doses established in the efficacy period for SOV2012-F1 and AndroGel will be used at the start 
of the 9-month safety evaluation period. The dose of SOV2012-F1 may be up- or down-titrated on Day 180 
and Day 270 based on the plasma T concentration from a single blood draw within 3 to 5 hours after the 
morning dose on Day 166 and Day 256, respectively. Single blood draw serum T concentrations predose at 
Day 166 and Day 256 will be used for AndroGel dose titration at Day 180 and Day 270, respectively, per 
product information. 
To determine any effect of the phytosterols in SOV2012-F1 on adrenal cortical function, ACTH stimulation 
testing will be performed and the serum cortisol response to synthetic ACTH will be measured at baseline 
(Visit 3) and the End-of-Treatment visit in a subset of subjects. At randomization, 45 subjects (2:1 ratio of 
SOV2012-F1 to AndroGel subjects) will be enrolled to the ACTH sub-study to ensure 30 subjects are 
available for assessment at the End of Treatment (EOT) visit (Day 365). Synthetic ACTH1-24 (cosyntropin) 


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will be administered to these subjects intravenously at Time 0 and blood for serum cortisol will be obtained 
before and 30 and 60 minutes after cosyntropin administration.
The schema in Figure 1 and Figure 2 depict the plan described in the protocol for the SOV2012-F1 and 
the AndroGel groups, respectively.
If analysis of the Day 90 24-hour PK data reveals that a subject is on an incorrect dose, withdrawal or
titration of the subject may be appropriate in the following instances: 
x
A SOV2012-F1–treated subject has been previously down-titrated to 200 mg in the morning only, 
and T Cmax is >2500 ng/dL on Day 90: the subject will be withdrawn, as continuation in the study 
will expose the subject to repeated T Cmax values >2500 ng/dL.
x
A SOV2012-F1–treated subject has been up-titrated to 1000 mg, and T Cavg is below the normal 
range on Day 90: the subject may be withdrawn if, in the opinion of the investigator, continuation 
in the study would expose the subject to an investigational treatment without probability of 
successful treatment.
x
If a SOV2012-F1–treated subject has T Cavg below the normal range (2.5% percentile) on Day 90:
the subject may be dose-titrated at an unscheduled visit, if the efficacy period data suggests benefit 
to the subject and an acceptable safety profile.
Subjects who discontinue study drug will be asked to complete the procedures of an EOT visit.


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Figure 1: Overall Study Design, SOV2012-F1 Group
Abbreviations: a m. = morning; N = number of subjects; p.m. = evening; T3-5 = plasma T concentration measured between 3 and 5 
hours post-morning dose.
a The investigator and the sponsor will review the data for each individual, and the reason for not responding to treatment will be 
investigated. Assuming correct compliance with study drug, SOV2012-F1 may be increased to 600 mg a.m., 400 mg p m. at the 
investigator’s discretion, taking safety into consideration, or subjects may be discontinued from the study as non-responders. Data 
will be reported in the clinical study report (CSR).


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Figure 2: Overall Study Design, AndroGel Group
Abbreviations: D/C = discontinued; N = number of subjects; T = testosterone; T Cpredose = serum
testosterone predose concentration.
3.3.2.
MRS-TU-2019EXT
Study MRS-TU-2019EXT is a second study following MRS-TU-2019. One purpose is to further examine 
the BP effects of Marius’s oral TU formulation, SOV2012-F1, using 24-hour ABPM. Another primary 
objective will be to demonstrate the feasibility of using a lower starting dose of SOV2012-F1 (daily dose 
of 400 mg [200 mg with breakfast meal and 200mg with dinner meal]), revised titration thresholds and 
using strengths of 100, 150 and 200 mg TU to further enhance drug administration. To distinguish the two 
studies, study days and visits in MRS-TU-2019EXT are designated with ‘E’, e.g. Day 120E or Visit14E or 
V14E.
Eligible subjects will include up to approximately 170 men who complete the 52-week MRS-TU-2019
study and are willing to consent to participate in the MRS-TU-2019EXT study. Eligible men who have 


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consented to this MRS-TU-2019EXT study will be withdrawn from TRT for a minimum of 8 weeks 
following their conclusion of MRS-TU-2019. 
Continuing Subjects:
Subjects completing the MRS-TU-2019 study and going directly into 
MRS-TU-2019EXT complete the MRS-TU-2019EXT study defined 8-week washout and begin a total of 
180 days of treatment on SOV2012-F1.  These subjects have an initial ABPM assessment on Day 364/365 
of MRS-TU-2019.  
Late Entry Subjects: Subjects who completed Day 365 in MRS-TU-2019 prior to the start of MRS-TU-
2019EXT, may enroll in MRS-TU-2019EXT, bypassing the Day 364-365 ABPM assessment. These late 
entry subjects will still be required to have an 8-week washout period, beginning at time of consent. Any 
interim TRT between time of completion of MRS-TU-2019 and consent for MRS-TU-2019EXT, must be 
recorded in the electronic case report form (eCRF). These subjects must pass the ABPM evaluation at V7E/ 
Day 1E to continue in the ABPM MRS-TU-2019EXT study. 
Newly Enrolling Subjects: Enrollment of subjects naïve to MRS-TU-2019 or subjects who completed the 
MRS-TU-2019 study more than 8 weeks prior to the start of MRS-TU-2019EXT will be permitted at a few 
sites in order to maximize enrollment for MRS-TU-2019EXT, provided those subjects meet both the MRS-
TU-2019 and MRS-TU-2019EXT eligibility criteria. These subjects would be required to consent and then 
complete screening assessments of the Screening Visit 1 (EXT) and Screening Visit 2 (EXT), for 
assessments consistent with the MRS-TU-2019 protocol, prior to being enrolled into MRS-TU-2019EXT. 
See Table 4: Schedule of Assessments for ABPM MRS-TU-2019EXT Study Pre-treatment Period for 
Newly Enrolled Subjects (MRS-TU-2019 Naïve or Late Entry Subjects who Qualify for New Enrollment).
These subjects must pass the ABPM evaluation at V7E/ Day 1E to continue in the ABPM MRS-TU-
2019EXT study.
During the 180-day treatment period, subjects will be titrated up or down, if necessary, over the first 4 to 8 
weeks (28 to 56 days) of the treatment period using a refined dose-titration algorithm (Appendix 16.2).
Subjects will stay on their final dose from Day 28 or Day 56, through Day 180, the completion of the ABPM 
study. ABPM will be conducted 3-4 times during the MRS-TU-2019EXT study depending on whether the 
subject is a Continuing Subject, or is a Late Entry Subject, or a Newly Enrolled Subject. Continuing 
Subjects will have an ABPM at Day 364/365 (EOT) of MRS-TU-2019 study; all MRS-TU-2019EXT 
subjects will have ABPM assessments at Day 1E (prior to treatment), at Day 120E and at Day 180E of 
treatment. The Day 180E (6-month) visit will provide data on stabilization of ambulatory BP, following the 
Day 120E (4-month) data for ambulatory BP primary endpoint. Note that in this SAP, ambulatory refers to 
ABPM.
24-hr Serum T and DHT Sub-study:
At select centers, approximately 100 subjects will participate in a 24-hr serum T sample collection sub-
study conducted at Visit 12E. Subjects enrolled in the serum T sub-study should have serum T samples 
drawn at all PK timepoints: pre-morning dose and 1.5, 3, 4, 5, 6, 8, 12, 13.5, 15, 16, 17, 18, 20, and 24 
hours after a.m. dose.


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The following diagram illustrates the design for subjects moving from MRS-TU-2019 directly to MRS-
TU-2019EXT*:
*For Late Entry Subjects and New Subject Enrollees, a modified study entry schedule is provided. See Schedule of Assessments
(Table 3 to Table 5).
3.4.
SUBJECT SELECTION
3.4.1.
Inclusion Criteria 
See
Protocol
Section
7.3.2
for
MRS-TU-2019
and
Protocol
Appendix
16.12
Section G
for
MRS-TU-2019EXT.
3.4.2.
Exclusion Criteria 
See
Protocol Section 7.3.3 for MRS-TU-2019
and
Protocol Appendix 16.12 Section G
for
MRS-TU-2019EXT. 
3.5.
DETERMINATION OF SAMPLE SIZE
3.5.1.
MRS-TU-2019
To meet the criterion of the primary endpoint, the percentage of subjects with T Cavg within the normal 
range at Day 90 must be ≥75%, with the lower bound of the 95% CI ≥65%. Based on the results of the 
Phase 2b clinical study, Study SOV-TU-PK20131, approximately 86% of subjects may be expected to have 
a T Cavg within the normal range at Day 90. The 95% CI associated with different point estimate 
assumptions are shown in Table 1 below. To yield a conservative estimate of the required sample size, the 
true percentage of subjects with average concentration (Cavg) within the normal range is estimated at 75%.




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3.5.2.
MRS-TU-2019EXT
The estimated SD of the differences in the 24-hour mean sBP obtained at 90 days post-treatment and after 
8 weeks of drug washout is 10 mmHg (SD estimate obtained from Clarus Briefing Document4, p. 62).
Assuming that we will have approximately 135 evaluable subjects, this sample size of 135 subjects can
produce a two-sided 90% CI with a distance from the difference in means to the limits that is equal to 1.4 
mmHg when the estimated SD is 10 mmHg.
Furthermore, a sample size of 119 evaluable subjects achieves 90% power to detect non-inferiority using a 
one-sided one-sample t-test when the non-inferiority margin is 3.0 mmHg, the actual mean is 0, and the 
significance level (alpha) of the test is 0.025. Assuming a 10% unevaluable rate, 133 subjects would need 
to be enrolled to achieve 119 evaluable.
With respect to sample size justification of Cavg, please refer to Section 3.5.1. Since the intended number of 
evaluable subjects for the MRS-TU-2019EXT study is greater than the 125 targeted in the MRS-TU-2019
study, the MRS-TU-2019EXT study should have adequate number of subjects to achieve the objectives 
regarding the endpoints of Cavg and Cmax.
For the serum T and DHT sub-study, serum samples will be collected from approximately 100 subjects 
with respect to Day 90E within the MRS-TU-2019EXT study. This will be done using all consenting 
subjects within a subset of sites (sites to be chosen by the sponsor).
3.6.
TREATMENT ASSIGNMENT & BLINDING
Subjects eligible for MRS-TU-2019 will be randomized 2:1 (approximately 200 SOV2012-F1-treated 
subjects to 100 AndroGel-treated subjects, respectively) using an interactive web randomization system 
and stratified by study center to receive SOV2012-F1 or AndroGel. At randomization, 45 subjects (2:1 ratio 
of SOV2012-F1 to AndroGel subjects) will be enrolled into the ACTH sub-study. At Screening Visit 1, 
subjects will be offered the opportunity to participate in the ACTH stimulation sub-study. The informed 
consent form addendum for the ACTH sub-study will be signed by Visit 2.
In MRS-TU-2019EXT, all subjects will receive SOV2012-F1, starting at a total daily dose of 400 mg (200 
mg with the breakfast meal and 200 mg with the dinner meal) and titrated, if needed, according to the dose-
titration algorithm established for the MRS-TU-2019EXT study protocol (Appendix 16.2).
Blinding is not applicable (N/A); these are open-label studies.
3.7.
ADMINISTRATION OF STUDY DRUG
MRS-TU-2019 uses only SOV2012-F1 200 mg TU capsules, with a starting total daily dose of 600 mg
(400 mg with morning meal, 200 mg with evening meal). Subjects will be instructed to take the SOV2012-
F1 capsules with water 30 minutes after the start of their meal.


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MRS-TU-2019EXT uses three capsule strengths (100, 150 and 200 mg TU per capsule), with a starting 
total daily dose of 400 mg (200 mg with the breakfast meal and 200 mg with dinner meal). Subjects will be
instructed to take the SOV2012-F1 capsules with water 30 minutes after the start of their meal.
In Study MRS-TU-2019, subjects randomized to AndroGel will be instructed to apply the gel topically in 
the morning to the shoulders and upper arms, starting at 2 pump actuations (40.5 mg).
3.8.
STUDY PROCEDURES AND FLOWCHART
3.8.1.
MRS-TU-2019
The study consists of 2 screening visits, with screening lasting up to 21 days, 11 treatment visits, starting 
with Visit 3 (Day 1) and ending with the EOT visit (Day 365 or early withdrawal) and a follow-up visit (14 
days after EOT).
The schedule of assessments is shown in Table 2 below.


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Table 2: MRS-TU-2019 Schedule of Assessments
Assessment
Pre-
Treatment Period
Post-
treatment
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11 Visit
End of
Follow-Up
Day -21
Day -10
Day 1
Day 14
Day 28
Day 42
Day 56
Day 90
Day166
Day 180
Day 256 12
Treatment
(14 days
To
to
Baseline
(+/-2)b
(+/-2)
(+/-2)b
(+/-2)
(+/-3)a
(+/-3)
(+/-3)a
(+/-3)
Day
Day 365
[+/-3]
Day -11
Day -7
(within
270
(+/-3)a,*
After Last
10 days
(+/-3) a,
Or Early
Dose)
of Visit
Withdrawal
2)a
Informed consent
X
X
X
Inclusion/exclusion criteria
X
X
X
X
X
Randomization
X
Demographic data
X
Medical history
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examinationc
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
Urinalysise
X
Urine drug screenf
X
HIV, hepatitis screens
X
Biochemistryg
X
X
X
X
X
X
X
Endocrinologyh
X
X
X
Hematologyi
X
X
X
X
X
Total T, serum,
screening, all
Xj
Xj
Fasting insulin
X
X
X
X
X
X
Xx
Lipid panel (TC,
LDL, HDL, TGs)
Xz
X
X
X
X
X
X
PSA
X
X
X
X
X
ACTH stimulation testingy
Xy
Xy
Table continues on next page.


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Assessment
Pre-treatment
Screening
Treatment Period
Post-
treatment
Visit 1
Day -21
to
Day -11
Visit 2
Day -10
to
Day -7
Visit 3
Visit 4
Day 14
(+/-2)b
Visit 5
Day 28
(+/-2)
Visit 6
Day 42
(+/-2)b
Visit 7
Day 56
(+/-2)
Visit 8
Day 90
(+/-3)a
Visit 9
Day 166
(+/-3)
Visit 10
Day 180
(+/-3)a,
Visit
11
Day
256
Visit 12
End of
Follow-Up
(14 days
[+/-3]
after Last
Day 1
Baseline
(within
10 days
Day
270
(+/-3)a,
Treatment
Day 365
(+/-3) a,*
or Early
of Visit
(+/-3)
Withdrawal
Dose))
2)a
24-hour PK sampling,
SOV2012-F1 group,
plasma T, DHT
Xk
Xk
Xk,
24-hour PK sampling,
SOV2012-F1 group,
plasma TU, DHTU
X l
Single-draw PK,
SOV2012-F1 group,
plasma T, DHT
X
Xm
Xm
Xm
24-hour PK sampling,
AndroGel, serum T, DHT
Xn
Single-draw PK, 
AndroGel group, 
serum T, DHT
X
X
X
Xo
Xo
Xo
Blood draw for
bioanalytical stability
X
X
E2 (Single or 24-hour PK),
SOV2012-F1 and
X
X
Dose adjustmentsq
X
X
X
X
I-PSS
X
X
X
PDQ dispense
X
X
X
X
X
PDQ collect
X
X
X
X
X
IIEF
X
X
X
X
X
SF-36
X
X
X
ASA24 trainingr
X
Provide Subject Food Diary
X
Table continues on next page.


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Collect Food Diary
and enter into ASA24
X
Breakfast served
X
Xs
Xs
X
X
X
All meals served,
SOV2012-F1 groupt
X
X
X
All meals served,
AndroGel groupu
X
Adverse event reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study 
medications
Xv
X
X
X
X
X
Perform accountability 
checkw
X
X
X
X
X
X
Abbreviations: ACTH = adrenocorticotropic hormone; ALT = alanine aminotransferase; ASA24 = Automated Self-Administered 24-Hour Recall; AST = aspartate aminotransferase;
ALP = alkaline phosphatase; BP = blood pressure; BUN = blood urea nitrogen; DHT = dihydrotestosterone; DHTU = dihydrotestosterone undecanoate; dBP = diastolic BP;
E2 = estradiol; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HbA1c = glycosylated hemoglobin; HDL = high-density lipoproteins; HIV = human
immunodeficiency virus; IIEF = International Index of Erectile Function; I-PSS = International Prostate Symptom Score; LC-MS = liquid chromatography-mass
spectrometry;
LDH = lactate dehydrogenase; LDL = low-density lipoproteins; LH = luteinizing hormone; PDQ = Psychosexual Daily Questionnaire; PK = pharmacokinetic; PSA = prostate-
specific antigen; sBP = systolic BP; SF-36 = Short Form Survey; SHBG = sex hormone-binding globulin; T = testosterone; TC = total cholesterol; TGs = triglycerides; TSH = thyroid-
stimulating hormone; WBC = white blood cells.
Note: Subjects come to the clinic for study procedures from 7 a m. to 10 a m. except for SOV2012-F1–treated subjects on Day 166 and Day 256, when they will arrive at the
clinic
in time for a single blood draw within 3 to 5 hours after the morning dose.
a All subjects come to the clinic having fasted for at least 8 hours. Subjects should remain well hydrated during fasting and drink at least one glass of water (240 mL or 8 oz)
prior
to visit. Subjects should have completed 7-day PDQ questionnaire and all laboratory results should be available.
b SOV2012-F1–treated subjects come to the clinic having fasted for at least 8 hours. Subjects should remain well hydrated during fasting and drink at least one glass of water (240 mL
or 8 oz) prior to visit.
c Full physical examination must include administering an I-PSS questionnaire, assessment for the presence of gynecomastia, and digital rectal examination at Screening Visit
2,
Visit 8 (Day 90), and EOT (Day 365). At all other visits, subjects should undergo a symptom-directed physical examination.
d Vital signs include BP, HR, temperature, and weight. BP will be measured using a cuff appropriate to the subject’s arm size, in a standardized manner, i.e., after the subject has 
rested in the sitting position for at least 5 minutes. On all study visit days where BP is measured only once (V2) or predose (V3, V5, V7, V9-V12, EOT for both SOV2012-F1 and
AndroGel; V4 and V6 for AndroGel), BP measurement will be duplicated within 5 minutes. If the difference in 2 sBP and dBP
measurements is > 10 mmHg and > 5 mmHg,
respectively, a third BP measurement will be taken and results averaged. BP will be monitored at 4-hour intervals (0, 4, 8, 12,
16, 20, and 24 hours) over the 24-hour PK collection
period on V4, V6, and V8 for SOV2012-F1–treated subjects and on V8 for AndroGel-treated subjects (±5 minutes for all
timepoints).Other vital signs will be assessed at Time 0
only. The time-zero measurement of BP at V4, V6 and V8 may be taken up to 60 minutes prior to dosing.
e Urinalysis includes pH, glucose, ketones, blood, protein, microscopy, and specific gravity.
f Urine drug screen will include, cocaine, narcotics, benzodiazepines, tetrahydrocannabinol, barbiturates, and amphetamines.
g Biochemistry includes AST, ALP, ALT, total bilirubin (TB), creatinine, BUN, eGFR, LDH, glucose, total protein, albumin, sodium, potassium, calcium, and
phosphorus.
h Endocrinology consists of LH, FSH, SHBG, and TSH.
i Hematology includes hemoglobin, hematocrit, WBC, and platelets.
j Subjects must have 2 consecutive serum total T levels ≤281 ng/dL based on a blood sample obtained from 7 a m. to 10 a m., drawn on separate days, at least 3 days apart. Furthermore,
subjects must have at least 1 clinical feature consistent with male hypogonadism. At Visit 1, a sample for T is collected. At Visit 2, the
biochemistry sampling includes sample for
T.














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SD = symptom-directed; SF-36 = Short Form Survey; SHBG= sex hormone-binding globulin; T = testosterone;
TC = total cholesterol; TGs = triglycerides; TSH = thyroid-stimulating
hormone; TU = T undecanoate; WBC = white blood cells; WD = withdrawal
a.
Visit applies to the MRS-TU-2019EXT ABPM subjects only.
b.
All subjects come to the clinic having fasted for at least 8 hours. Subjects should remain well hydrated during fasting and drink at least one glass of water (240 mL
or 8 oz) prior to
visit. Subjects should have completed 7-day PDQ questionnaire and all laboratory results should be available.
c.
Full physical examination must include assessment for the presence of gynecomastia, and digital rectal examination at EOT in MRS-TU-2019 (EOT/Day 365),
Visit 7E (Day 1E),
and V16E (Day180) and at early withdrawal visit. At all other visits, subjects should undergo a symptom-directed (SD) physical examination.
d.
Vital signs include BP, HR, temperature, and weight. BP will be measured using a cuff appropriate to the subject’s arm size, in a standardized manner,
i.e., after the subject has
rested in the sitting position for at least 5 minutes. Beginning with Visit Day 365/V2E, BP at all visits during the MRS-TU-2019EXT, BP should
be obtained after the subject is seated
for at least 5 mins prior to measuring BP, and the arm should be extended and supported at the level of the heart (mid-chest height).
The BP should be obtained in triplicate, 1 min
(+5 min) apart in the sitting position with the arm supported at the heart level (mid-chest height). BP
should be measured in the dominant arm at all visits. Any subject with an
in-clinic, average BP > 140/90 at Visit 6E, should be withdrawn from further MRS-TU-2019EXT participation.
e.
Biochemistry includes AST, ALP, ALT, TB, creatinine, BUN, eGFR, LDH, glucose, total protein, albumin, sodium, potassium, calcium, and phosphorus. At
Visit 7/Day 1E the
laboratory samples will be obtained predose and fasted.
f.
Endocrinology consists of LH, FSH, SHBG, and TSH.
g.
Hematology includes hemoglobin, hematocrit, WBC, platelets, and HbA1c (except at Early Withdraw when no HbA1c will be analyzed).
h.
For early withdrawal subjects, fasting insulin is not collected.
i.
ACTH stimulation testing is performed as a sub-study in MRS-TU-2019 only (45 subjects enrolled for 30 completers, 2:1 ratio between SOV2012-F1 and
AndroGel™.)
j.
Visit 8E (Day 14E) and 10E (Day 42E) collect PK only at these timepoints as it is not an overnight visit in MRS-TU-2019EXT: PK samples are collected pre-morning dose and
1.5,
3, 4, 5, and 6 hours, after a m. dose of SOV2012-F1 (±5 mins for all timepoints). PK samples include plasma T and DHT, and serum T and DHT. The initial dose is administered
30 (±5)
mins after the start of breakfast meal.
k.
Visit12E (Day 90E) is a 24-hr confinement and will include the same timepoints as SOV2012-F1 confinement visit at 90 days in MRS-TU-2019: PK samples are collected pre-morning
dose and 1.5, 3, 4, 5, 6, 8, 12, 13.5, 15, 16, 17, 18, 20, and 24 hours after a m. dose of SOV2012-F1 (±5 mins for all timepoints). PK samples
include plasma T and DHT, plasma TU
and DHTU. The initial and 12-hr doses are administered 30 (±5) mins after the start of breakfast and dinner meals.
l.
PK samples on these days should be drawn after the morning dose of SOV2012-F1 between 3-5 hours (+10min) post-morning dose. PK samples include plasma T and DHT. For
early withdrawal subjects, no PK sample is collected.
m.
Dose adjustments, if needed, will be made on these days.
n.
Providing breakfast is optional after fasting laboratory samples at EOT / Day 365 / Visit 2E, and on Visit 7E / Day 1E. Breakfast (MRS-TU-2019 ASA-assigned meal type) is required
on Visits 1E, 6E, 13E and 15E, after applying ABPM cuff. Breakfast (ASA24-assigned) and lunch (normal fat or lunch of choice) are to be provided on Visit 8E and Visit 10E. Lunch
should be given approximately 4 hours after
morning dose.
o.
Provide all 3 meals. Breakfast and dinner should be based on subjects’ ASA24 records (all lunches are to be chosen from normal fat menu or subject may have selection
of choice)
and record meals, meal fat type, and the percentage of meal consumed (0, 25%, 50%, 75%, or 100%). Lunch should be given approximately 4 hours after
dose.
p.
Perform an accountability check for any remaining study drug.
q.
If both the initial and repeat 24-hr ABPM assessment session at V7E/ Day 1E, the subject should be withdrawn from MRS-TU-2019EXT study.
r.
If ABPM data download quality equals “fail” status, subject may repeat the ABPM evaluation within 2 days. The subject can be sent home with the ABPM cuff for another 24-hr 
period of collection and return at the completion of the repeat 24-hr recording session, in which case the V2E / D365 or V7E / D1E visit will be delayed (to occur up to 2 days later 
than planned, using the longer “+” window). At Visit 14E (day 120) and Visit 16E (Day 180), a repeat 24-hr assessment may be attempted a second time at the discretion of the 
Investigator. As a reminder, if a second repeat is scheduled the subject must fast the night before.
s.
Late entry MRS-TU-2019EXT subjects who do not qualify for new enrollment: Subjects who already completed D365 of the MRS-TU-2019 study prior to the start of 
MRS-TU-2019EXT, ,may provide informed consent and enter the EXT study after the D364-365 requirements. These subjects will still be required to begin an additional 8-week 
washout period from the time of consenting Visit 3E should occur 28 days (4 weeks) from time of consent. ABPM SUBJECT TRAINING SHOULD OCCUR IN THIS 
INSTANCE, ON V6E.


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t.
New Subject Enrollment for EXT (naïve to MRS-TU-2019): ASA Food Diary should be provided to new subjects at Screening Visit 1(EXT). Diary completion for 3 days of 
typical breakfast and dinner meals should be completed by Screening Visit 2(EXT) and entered into the ASA-24-hr system in order to enter diet data into eCRF to obtain diet 
assignment information needed for meal at V6E. Subjects who would otherwise be considered Late  Entry Subjects from MRS-TU-2019, and completed MRS-TU-2019
>8 weeks before start of MRS-TU-2019EXT, may be considered for new subject screening and enter the MRS-TU-2019EXT by way of the new enrollment subject pathway.
u.
24-hr serum T sub-study subjects should have serum T drawn at all 24-hr PK timepoints at V12E/D90E: pre-morning dose and 1.5, 3, 4, 5, 6, 8, 12, 13.5, 15, 16, 17, 18, 20, and 
24 hours after a.m. dose.


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4.
ENDPOINTS
4.1.
MRS-TU-2019 ENDPOINTS
4.1.1.
Primary Endpoint
The primary endpoint of the MRS-TU-2019 study is the percentage of SOV2012-F1–treated subjects with 
a 24-hour T Cavg within the normal range after 90 days of treatment.
Serum T Cavg values for those subjects randomly assigned to receive AndroGel will be summarized only.
4.1.2.
Secondary Endpoints
Other endpoints of the MRS-TU-2019 study are the percentage of SOV2012-F1-treated subjects at Day 90 
(Visit 8) with plasma T Cmax values that are:
x
≤1.5 x ULN;
x
1.8 x ULN to 2.5 x ULN; and 
x
>2.5 x ULN where the ULN is defined using the NaF/EDTA plasma and serum endogenous 
testosterone from study MRS-TNR-2019.
Serum T Cmax values for those subjects randomly assigned to receive AndroGel will be summarized using 
the following ranges (ng/dL):
x
≤1500;
x
1800 to 2500; and 
x
>2500.
These endpoints will be reported as safety endpoints.
4.1.3.
Exploratory Endpoints 
The exploratory efficacy endpoints of the MRS-TU-2019 study are:
x
Change from baseline in the following subject-reported outcomes by SOV2012-F1-treated and 
AndroGel-treated subjects, after 52 weeks of treatment: 


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o
I-PSS;
o
PDQ;
o
SF-36;
o
IIEF.
x
Change from baseline in fasting serum glucose and fasting insulin concentrations in SOV2012-
F1–treated and AndroGel-treated subjects after 52 weeks of treatment.
x
Stability of serum and plasma samples subjected to different processing times, processing 
temperatures, and sample collection tubes types.
4.1.4.
Safety Endpoints 
The safety endpoints for the MRS-TU-2019 study include the following:
x
Incidence of AEs, SAEs, drug-related AEs and AEs leading to study withdrawal in SOV2012-F1–
treated subjects compared with AndroGel-treated subjects after 52 weeks of treatment.
x
Observed and change from baseline in sBP and dBP and HR.
x
Safety biochemistry and hematology laboratory evaluations including but not limited to the 
following:
o
Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
total bilirubin (TB), alkaline phosphatase [ALP]).
o
Hematology parameters (hemoglobin).
o
Hormone levels (luteinizing hormone [LH], follicle-stimulating hormone [FSH], DHT, sex 
hormone–binding globulin [SHBG], and thyroid-stimulating hormone [TSH]).
o
Lipid profiles (high-density lipoproteins, low-density lipoproteins, total cholesterol, and 
triglycerides).
o
Serum PSA.
x
Serum cortisol response to intravenous administration of synthetic ACTH.


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4.2.
MRS-TU-2019EXT ENDPOINTS
4.2.1.
Primary Endpoints
The primary ABPM endpoint is the change from baseline in 24-hour average ambulatory sBP after 
approximately 120 (±3) days of treatment.
The primary efficacy endpoint, to determine the response to a lower starting dose of oral SOV2012-F1 with 
up and down titration as appropriate, is the percentage of SOV2012-F1-treated subjects with a plasma T Cavg
within the normal range after 90 days of treatment.
4.2.2.
Secondary Endpoints
Other endpoints are:
x
Percentage of subjects with T Cmax values after 90 days of treatment:
o
≤1.5 x ULN;
o
1.8 x ULN to 2.5 x ULN; and 
o
>2.5 x ULN where the ULN is defined using the NaF/EDTA plasma and serum endogenous 
testosterone from study MRS-TNR-2019.
x
Change from baseline in 24-hour average ambulatory sBP after approximately 180 (±3) days of
treatment.
x
Change from baseline in 7 a.m. to 10:30 p.m. -hour average ambulatory sBP (daytime) after 
approximately 120 (±3) days and 180 (±3) days of treatment.
x
Change from baseline in 11 p.m. to 6:30 a.m. -hour average ambulatory sBP (nighttime) after 
approximately 120 (±3) days and 180 (±3) days of treatment.
x
Change from baseline in 24-hour mean dBP measured by ABPM after 120 (±3) days and 180 (±3) 
days of treatment.
x
Change from baseline in 7 a.m. to 10:30 p.m. -hour average ambulatory dBP (daytime) after 
approximately 120 (±3) days and 180 (±3) days of treatment.
x
Change from baseline in 11 p.m. to 6:30 a.m. -hour average ambulatory dBP (nighttime) after 
approximately 120 (±3) days and 180 (±3) days of treatment.


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x
Change from baseline in 24-hour average ambulatory HR after approximately 120 (±3) days and 
180 (±3) days of treatment.
x
Change from baseline in 7 a.m. to 10:30 p.m. -hour average ambulatory HR (daytime) after 
approximately 120 (±3) days and 180 (±3) days of treatment.
x
Change from baseline in 11 p.m. to 6:30 a.m. -hour average ambulatory HR (nighttime) after 
approximately 120 (±3) days and 180 (±3) days of treatment.
x
Observed and change from baseline in half-hourly sBP, dBP, and HR after approximately 120 (±3) 
days and 180 (±3) days of treatment.
4.2.3.
Safety Endpoints
x
To determine the incidence of AEs, SAEs, and AEs leading to MRS-TU- 2019EXT study 
withdrawal.
x
Observed and change from baseline in BP and HR obtained in-clinic during the treatment period.
x
Observed, change from baseline, and percent change from baseline in the following laboratory 
parameters during the treatment period:
o
Liver function tests (ALT, AST, TB, ALP)
o
Hematology parameters (hemoglobin)
o
Hormone levels (LH, FSH, DHT, SHBG, and TSH)
o
Lipid profiles (high-density lipoproteins, low-density lipoproteins, total cholesterol, and 
triglycerides)
o
Serum PSA
4.3.
PHARMACOKINETIC (PK) ENDPOINTS
PK assessments include the concentration data and calculation of PK parameters for:
x
Plasma total T and DHT for SOV2012-F1 subjects measured at Days 14, 42, 90 and 90E in 
NaF/EDTA tubes.
x
Serum total T and DHT for SOV2012-F1 subjects measured at Day 90E.


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x
Plasma TU, DHT undecanoate (DHTU), and E2 for SOV2012-F1 subjects measured at Day 90 and
Day 90E in NaF/EDTA tubes.
x
Serum total T, DHT, and plasma E2 for AndroGel subjects measured at Day 90, if applicable.
PK Parameters:
x
Maximum concentration (Cmax)
x
Time to maximum concentration (Tmax)
x
Area under the concentration-time curve from Time 0 to 24 hours (AUC0-24)
x
Area under the concentration-time curve from Time 0 to 12 hours (AUC0-12)
x
Area under the concentration-time curve from Time 12 to 24 hours (AUC12-24)
x
Average concentration from Time 0 to 24 hours (Cavg)
x
Average concentration from Time 0 to 12 hours (Cavg0-12)
x
Average concentration from Time 12 to 24 hours (Cavg12-24)
x
DHT/T and E2/T ratios calculated on Cavg, AUC0-12, and AUC12-24
x
Calculated free T concentration at MRS-TU-2019 baseline, MRS-TU-2019EXT baseline, Day 90
and Day 90E (methods in Section 9.4.1)
Additional parameters may be calculated if deemed necessary and useful for data interpretation.


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5.
ANALYSIS SETS
For MRS-TU-2019, the Safety Set (SS), Full Analysis Set (FAS), Pharmacokinetic Set (PKS), and Efficacy 
Completers Set (ECS) were defined and finalized at a data review meeting (DRM) after data cleaning was
complete for the interim analysis. The ACTH Analysis Set (AAS) will be finalized at a DRM after data 
cleaning is complete for the final analysis.
For MRS-TU-2019EXT, the Extension Treated Set (EXTS), the Modified Extension Treated Set (mEXTS), 
the Extension Pharmacokinetic (EXPK) Set, the Extension Serum (EXSE) Set, and the Modified Extension 
Serum (mEXSE) Set will be defined and finalized at a DRM after data cleaning is complete for the final 
analysis.
The Overall Safety Set (OSS), which consists of subjects from both studies who took at least one dose of 
SOV2012-F1, will be finalized at a DRM after data cleaning is complete for the final analysis.
5.1.
MRS-TU-2019 ANALYSIS SETS
5.1.1.
Safety Set (SS)
The SS will include all subjects who took at least one dose of study drug (SOV2012-F1 or AndroGel) in 
MRS-TU-2019. Note that MRS-TU-2019 AE analyses will include the washout period before the first dose 
of SOV2012-F1 in MRS-TU-2019EXT for continuing subjects and late entry subjects.
5.1.2.
Full Analysis Set (FAS)
The FAS will include all subjects randomized into the study who received at least one dose of correctly 
assigned study drug. The primary analyses for the primary and secondary MRS-TU-2019 endpoints will be 
performed on the FAS.
5.1.3.
Pharmacokinetic Set (PKS)
The PKS will include all subjects in the study who received at least one dose of study drug and at least one 
evaluable PK profile within MRS-TU-2019 (calculable Cmax and Cavg) and no significant protocol deviations
(PDs).
5.1.4.
Efficacy Completers Set (ECS)
The ECS will include all subjects in the PKS who have evaluable Cavg and Cmax from the 24-hour PK 
assessment obtained at Visit 8, Day 90, and no significant PDs.


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5.1.5.
ACTH Completer Analysis Set (AAS)
The AAS will include all subjects randomized into the ACTH sub–study who received correctly assigned 
study drug (including synthetic ACTH1-24 [cosyntropin]) and who had serum cortisol results at Visit 3 and 
Day 365 (end of treatment).
5.2.
MRS-TU-2019EXT ANALYSIS SETS
5.2.1.
Subject Sources
Continuing
Subjects completing the MRS-TU-2019 study and going directly into MRS-TU-2019EXT, completing the 
MRS-TU-2019EXT study defined 8-week washout, and beginning a total of 180 days of treatment on 
SOV2012-F1. These subjects will have participated in a Day 364/365 (Visit 1E) ABPM assessment.
These subjects must have a successful ABPM assessment at Visit 6E/7E to continue in the study.
Late Entry
Subjects having a gap between completion of MRS-TU-2019 and entry into the MRS-TU-2019EXT 
study who will complete 8 weeks of washout from time of consent and then begin 180 days of treatment 
on SOV2012-F1.  These subjects completed Day 365 in MRS-TU-2019 prior to the start of MRS-TU-
2019EXT thus bypassing the Day 364/365 ABPM MRS-TU-2019EXT study assessment.
New Enrollment
These are subjects naïve to MRS-TU-2019 or subjects who have completed the MRS-TU-2019 study 
more than 8 weeks prior to the start of MRS-TU-2019EXT. These subjects would need to complete
Screening Visit 1 (EXT) and Screening Visit 2 (EXT) prior to being enrolled into MRS-TU-2019EXT.
5.2.2.
Extension Treated Set (EXTS)
The EXTS will include all subjects who took at least one dose of SOV2012-F1 within MRS-TU-2019EXT.
This analysis set will be used for all analyses related to the ambulatory BP, and the ambulatory HR.
Modified EXTS (mEXTS)
The modified EXTS consists of the EXTS excluding Site 104.  Reasons for excluding Site 104 are 
documented in Appendix 16.4. This analysis set will be used for the primary analysis of Cavg, and the
analysis of Cmax


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5.2.3.
Extension Pharmacokinetic (EXPK) Set
The EXPK Set consists of all subjects in the study who received at least one dose of SOV2012-F1, have 
at least 1 evaluable 24-hr PK profile within MRS-TU-2019EXT (calculable Cmax or Cavg) and no
significant protocol deviations. Site 104 is excluded from the EXPK Set. Reasons for excluding Site 104 
are documented in Appendix 16.4.
5.2.4.
Extension Serum (EXSE) Set
The EXSE population consists of all subjects in the study who consented to the serum substudy and took 
at least one dose of SOV2012-F1 within MRS-TU-2019EXT.
Modified EXSE (mEXSE)
The modified EXTS consists of the EXSE excluding Site 104.  Reasons for excluding Site 104 are 
documented in Appendix 16.4.
5.3.
OVERALL ANALYSIS SET
5.3.1.
Overall Safety Set (OSS) 
The OSS will include all subjects who took at least one dose of SOV2012-F1 in MRS-TU-2019 and/or 
MRS-TU-2019EXT. This analysis set will be used for pooled analysis of all subjects exposed to SOV2012-
F1.
5.4.
PROTOCOL DEVIATIONS (PDS)
PDs will be addressed during study monitoring on an ongoing basis. All PDs will be recorded in the clinical 
trial management system.
5.4.1.
Data Review Meeting (DRM)
A review of all PDs from MRS-TU-2019 and MRS-TU-2019EXT will be performed on an ongoing basis 
to categorize each one as significant (with a potential impact on the efficacy and/or PK evaluation) or not 
significant and identify the subjects that should be excluded from any of the relevant analysis sets. Each 
PD will be assigned as significant or not significant by the Study Management Team, in cooperation with
Data Management, Biostatistics, Medical Monitoring, and the Sponsor. These data will then be imported 
into SAS®.
All decisions made at the DRM will be documented in the DRM highlights. The final list of PDs including 
the decisions on analysis sets made in the meeting will be appended to the highlights. Approval of the DRM 


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highlights will be confirmed by the signatures of the Lead Biostatistician, the Project Leader and a Marius 
Pharmaceuticals representative.
5.4.2.
PDs General
x
A PD will be considered related to MRS-TU-2019 if it occurs at any time before Visit 1E (Day 364) 
for a continuing subject or if it occurs at any time before MRS-TU-2019EXT late entry consent for 
a late entry subject.
x
A PD will be considered related to MRS-TU-2019EXT if it occurs on or after Visit 1E (Day 364) 
for a continuing subject or if it occurs at or after MRS-TU-2019EXT late entry consent for a late 
entry subject. 
x
Missing and partial PD start dates will be reviewed to determine if relationship to study can be 
assigned.
x
All PDs will be listed for all subjects in the SS and EXTS, including their assignment of significant
or not significant. 
x
Significant PDs will be summarized by deviation type, for all subjects in the OSS and for all 
subjects who took SOV2012-F1 in both studies.
5.4.3.
Signficant Protocol Deviations: MRS-TU-2019
Examples of significant PDs leading to exclusion from the PKS and ECS are:
x
Taking prohibited 5 alpha-reductase inhibitors.
x
SOV2012-F1 subjects meeting Exclusion Criterion 10 (relevant gastrointestinal [GI] surgery).
x
Not completing a single confinement visit.
Additional significant PDs leading to exclusion from the PKS are:
x
SOV2012-F1 subjects with major PDs in dosing meal at both breakfast and dinner at all
3 confinement visits.
Additional significant PDs leading to exclusion from the ECS were:
x
SOV2012-F1 subjects with major PDs in dosing meal at both breakfast and dinner at Visit 8
(Day 90).


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Significant PDs leading to exclusion of the relevant 24-hour PK visit data only were:
x
Not receiving any study drug on a 24-hour PK visit.
x
Any use of Anabolic Steroid or Anti-androgens for more than 7 days or within 14 days before a 
24-hour PK visit.
x
Opioid, Spironolactone or oral ketoconazole use within 7 days before a 24-hour PK visit.
x
SOV2012-F1 subject missing a 3 to 5 hour sample in combination with missing a 15 to 17 hour 
sample at confinement Visit 4, 6, or 8.
x
AndroGel subject missing 2 samples out of the 2-hour, 4-hour and 8-hour samples at confinement 
Visit 8.
x
Use of GI medications/protein pump inhibitors within 48 hours before a 24-hour PK visit did not 
exclude the relevant 24-hour PK visit data.
Confinement-visit specific PK concentration data from subjects within the PKS and/or ECS will be 
programmatically excluded from summary tables, summary figures, and statistical analyses if the subject 
did not receive any study drug prior to the planned sampling of the concentration profile. 
Confinement-visit specific PK parameter data from subjects within the PKS and/or ECS will be 
programmatically excluded from summary tables, summary figures, and statistical analyses if the 
concentration profile was not evaluable per the outcome of the DRM or the subject did not receive any 
study drug prior to the planned sampling of the concentration profile.
No individual confinement-visit specific PK concentration or PK parameter data will be programmatically 
excluded from summary tables, summary figures, or statistical analyses for subjects within the FAS.
GI and urological surgery for SOV2012-F1 subjects were assessed on a case-by-case basis (whether having 
occurred prior to study entry or on study).
Prohibited natural supplements with hormonal effect did not exclude the subject from the PKS or ECS.
According to Quality Issue Summary Version 2.05 (regarding Site 141), the presence of extensive questions 
about source data, significant site compliance issues, and non-representative PK profiles for all four 
SOV2012-F1 subjects causes Marius to conclude that the PK data from this site are not valid.  All Site 141 
subjects (1411071, 1411092, 141951, and 141956) were excluded from the PKS and ECS.  They were
included in the SS and FAS where their PK data will be listed ,flagged, summarized and analyzed.


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5.4.4.
Significant Protocol Deviations: MRS-TU-2019EXT
Examples of significant PDs (but not limited to this list) leading to exclusion from the EXPK Set are:
x
Taking prohibited 5 alpha-reductase inhibitors within one month before Visit 7E, or within six 
months before Visit 7E in the case of dutasteride.
x
Meeting MRS-TU-2019 Exclusion Criterion 10 (relevant GI surgery).
x
Not completing Visit 12E.
x
Major PDs in dosing meal at both breakfast and dinner at Visit 12E.
Significant PDs leading to exclusion of the relevant 24-hour PK visit data only:
x
Not receiving any study drug at Visit 12E.
x
Any use of Anabolic Steroid or Anti-androgens for more than 7 days or within 14 days before Visit 
12E.
x
Opioid, Spironolactone or oral ketoconazole use within 7 days before Visit 12E.
x
Missing a 3 to 5 hour sample in combination with missing a 15 to 17 hour sample at Visit 12E.
Visit 12E PK concentration data from subjects within the EXPK Set will be programmatically excluded 
from summary tables, summary figures, and statistical analyses if the subject did not receive any study drug 
prior to the planned sampling of the concentration profile. 
Visit 12E PK parameter data from subjects within the EXPK Set will be programmatically excluded from 
summary tables, summary figures, and statistical analyses if the concentration profile is not evaluable per
the outcome of the DRM or the subject did not receive any study drug prior to the planned sampling of the 
concentration profile.
GI and urological surgery will be assessed on a case-by-case basis (whether having occurred prior to MRS-
TU-2019EXT study entry or on study).
These definitions will be discussed at the final DRM and therefore may be amended at that time. 


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5.4.5.
Site 104
During study management it was noted that significant protocol deviations occurred at Study Site 104 
during study MRS-TU-2019EXT resulting in exclusion of all subjects from the site for efficacy and Cmax
analysis. Two populations were created to exclude this site: mEXTS and mEXSE. The analysis set 
EXPK was also defined as excluding Site 104 subjects. Further details are described in Appendix 16.4.


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6.
GENERAL ASPECTS FOR STATISTICAL ANALYSIS
6.1.
GENERAL METHODS
All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.4 or higher. 
Unless otherwise stated, summaries presented in tables will be presented by randomized or assigned 
treatment group. Any MRS-TU-2019 subjects receiving a treatment they were not randomized to, will be
discussed in the CSR. Three subjects were randomized into the MRS-TU-2019 study twice in error and the 
handling of data for these subjects is described in Appendix 16.3.
Unless otherwise stated, summary statistics for continuous outcomes to be presented will include the 
number of non-missing observations (n), mean, SD, coefficient of variation (CV, %) calculated as 
100%*SD/mean, median, minimum value, and maximum value. Unless otherwise stated, means and 
medians will be presented with one more decimal than the observed values. SD values will be presented 
with 2 more decimals than the observed values. CV values will be presented to 1 decimal place.
Conventions for PK summaries are detailed separately in Section 9.4.2.
Categorical variables will be summarized using frequencies and percentages. Percentages will be calculated 
using the number of subjects in the analysis set or the number of subjects with a non-missing value for the 
assessment. The footnotes to the tables will note the method for calculating the percentages.
In general, subject listings will be provided for all data collected through MRS-TU-2019 and 
MRS-TU-2019EXT together. Exceptions will be for: subject disposition, where listings will be provided 
for screening and EOT separately for MRS-TU-2019 and MRS-TU-2019EXT. Listings for study drug 
administration, dose titration, exposure, and compliance, will be provided separately for MRS-TU-2019 
SOV2012-F1 treatment arm, MRS-TU-2019 AndroGel treatment arm, and MRS-TU-2019EXT. For PK
parameters and projected dose adjustments, listings will be provided separately for MRS-TU-2019 and
MRS-TU-2019EXT. In general, listings will be sorted by subject identifier, date of collection, and time of 
collection (if applicable).
6.2.
KEY DEFINITIONS
6.2.1.
First Dose Date of Study Drug
The first dose date of study drug in MRS-TU-2019 will be defined as the date of the first a.m. dose on 
Visit 3 Day 1. 
The first dose date of study drug in MRS-TU-2019EXT will be defined as the date of the first a.m. dose on 
Visit 7E Day 1E. 


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6.2.2.
Last Dose Date of Study Drug
The last dose date of study drug in MRS-TU-2019 will be recorded at the Early Withdrawal or EOT visit.
The last dose date of study drug in MRS-TU-2019EXT will be recorded at Visit 16E EOT or at Early 
Withdrawal Visit E.
Missing and partial last dose dates will be handled according to Section 6.3.8.
6.2.3.
Study Day 
Study day for MRS-TU-2019 only subjects, and for MRS-TU-2019EXT continuing subjects and late entry 
subjects up to and including Visit 6E, will be calculated using the first dose date (Section 6.2.1) of MRS-
TU-2019. For events/recordings of outcomes on or after the first dose date, the study day will be calculated 
as assessment date–first dose date+1. For events/recordings prior to the first dose date, the study day will 
be calculated as assessment date–first dose date. There will be no study Day 0.
Study day for MRS-TU-2019EXT will be calculated using the first dose date (Section 6.2.1) of MRS-TU-
2019EXT. For events/recordings of outcomes on or after the first dose date, the study day will be calculated 
as assessment date–first dose date+1. For events/recordings prior to the first dose date, the study day will 
be calculated as assessment date–first dose date. There will be no study Day 0. In the tables, listings and 
figures (TLFs), study day will be displayed as xxxE. 
6.2.4.
Baseline
For MRS-TU-2019 subjects, baseline will be defined as the last non-missing observation prior to the first 
dose of study drug at Visit 3 (Day 1). For in-clinic BP for MRS-TU-2019, baseline will be defined as the 
within subject mean of all Screening Visit 2 and Visit 3 (Day 1) individual observations.
For MRS-TU-2019EXT subjects, baseline will be defined as the last non-missing observation prior to the 
first dose of study drug at Visit 7E (Day 1E). For in-clinic BP, baseline will be defined as the within subject 
mean of all Visit 6E individual observations. Baseline for ABPM statistic values will be the statistic value
at Visit 7E (Day 1E). Baseline for hourly or half-hourly assessments will be time matched to the relative 
clock time at Visit 6E/7E.
6.2.5.
Change from Baseline 
Change from baseline = Post-baseline value – value at baseline.


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6.2.6.
Time 0 (Vital Signs)
For MRS-TU-2019, Time 0 is time of last recorded assessment(s) before morning dosing.
For MRS-TU-2019EXT ABPM visits, Time 0 is within 0.5 hour before placement of the ABPM cuff.  For 
non-ABPM visits, Time 0 is the last recorded assessment(s) before the morning dose.
6.2.7.
MRS-TU-2019 End of Treatment and Day 365 Visit
End of Treatment assessments, where subjects continue to take MRS-TU-2019 assigned treatment after 
study day 345 (≥345) will be assigned to the Day 365 visit, if the nominal Day 365 visit assessments are 
missing.
6.2.8.
MRS-TU-2019EXT Enrolled
A subject is defined as enrolled into the MRS-TU-2019EXT study when they have provided informed 
consent and been deemed to have passed all MRS-TU-2019 and MRS-TU-2019EXT inclusion and 
exclusion criteria.
6.3.
MISSING AND BELOW THE LIMIT OF QUANTIFICATION 
(BLQ) DATA
6.3.1.
Missing ABPM Data
Only quality accepted ABPM readings will be included in calculations, summaries and analyses; criteria 
constituting a failed/rejected set of ABPM 24-hr data are defined as any of the following:
x
More than 10 of the required 48 timepoints over 24 hours are missing/unreadable (>20%).
x
More than 2 consecutive hours of data missing (5 or more consecutive 30-min data points missing).
x
Less than 22 hours of recording time. 
Only timepoints with both a baseline (Section 6.2.4) and a post baseline quality accepted reading will be 
evaluated for changes from baseline. Only timepoints with both a Day 120E and a Day 180E quality 
accepted reading will be evaluated for Day 180E changes from Day 120E.
No imputation methods will be employed.
6.3.2.
Missing Data for Primary Endpoints
Following the parameter derivation of T Cavg according to Section 9.4.1, for the MRS-TU-2019 study, 
missing endpoint data will be imputed for the primary statistical analyses using a multiple imputation
approach as detailed in Section 8.5 when at least one post baseline 24 hour T Cavg is evaluable.


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For sensitivity analysis on the MRS-TU-2019 primary endpoint, worst-case scenario (WCS) imputations 
will be performed. Subjects with missing data at Visit 8 will be considered as treatment failures, i.e. they 
will be set to 24-hour T Cavg not within the normal range after 90 days of treatment. These analyses will be 
performed on the FAS.
For the primary analysis on the MRS-TU-2019EXT primary efficacy endpoint where there are no other 
post baseline Cavg values before Visit 12E (Day 90E), WCS imputations will be applied for the primary 
analysis. Subjects with missing data at Visit 12E will be considered as treatment failures, i.e. they will be
set to 24-hour T Cavg not within the normal range after 90 days of treatment. This analysis will be performed 
on the mEXTS and EXTS.
6.3.3.
Missing Pharmacokinetic (PK) Data
Missing PK concentration data will not be imputed for the purpose of calculating PK parameters for the
particular subject and visit. However, if there is a missing sample collection time, the nominal (scheduled) 
sample collection time will be used based on a case-by-case review by the pharmacokineticist. If PK
concentration data are missing, the pharmacokineticist will review on a case-by-case basis to determine if 
PK parameters should be calculated.
6.3.4.
Below the Limit of Quantification (BLQ) PK Concentration Data
When handling PK concentration data that are BLQ, the following rules will apply for the derivation of PK 
parameters:
x
BLQ concentration values for predose samples will be treated as zero.
x
Postdose BLQ values prior to the first quantifiable concentration will be assigned as the predose 
concentration.
x
Postdose BLQ values after the first quantifiable concentration will be treated as missing.
When handling PK concentration data that are BLQ, the following rules will apply for the calculation of 
summary statistics:
x
BLQ concentration values for predose samples will be treated as zero.
x
Postdose BLQ values prior to the first quantifiable concentration will be assigned as the predose 
concentration.
x
Postdose BLQ values after the first quantifiable concentration will be treated as zero.


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6.3.5.
Missing Adverse Event (AE) Data
Imputation of AE onset, when a missing or partial onset date has been recorded, will be performed using 
the following algorithm, designed to conservatively assign AEs to a study period.
x
If the onset date is entirely missing then the date of first dose of any study drug (Section 6.2.1) will
be imputed as the onset date.
x
If the year of onset only is provided and the year is the same as the year of first dose of any study
drug, then the date of first dose (Section 6.2.1) will be imputed as the onset date. This event would
be treatment-emergent. If the year of onset only is provided and the year is not the same as the year
of first dose, then the onset date will be imputed as the 1st of January of that year.
x
If only the month and year of onset are provided, and the month and year are equal to the month/
yearof first dose of any study drug, then the date of first dose (Section 6.2.1) will be imputed as the
onset date. In all other cases, the 1st day of the provided month/year of onset will imputed for the
onset date. Only if the provided month/year of onset is prior to the month/year of first dose would
an event not be considered treatment-emergent.
AEs with missing severity will be considered severe in the summaries. 
TEAEs with missing relationship to study drug will be considered to be probably related to study drug in
the summaries. 
If a partial onset date is provided, the imputed onset date will be utilized for determination whether the 
event was treatment-emergent. Partial onset dates will be presented as reported by the investigator in the 
listings. Similarly, AEs with missing severity or relationship will be presented as missing in the listings.
If date of death is missing, date of last contact will be used.
6.3.6.
Missing and Partial Medication Dates
In order to classify medications documented on the Prior and Concomitant Medications eCRF as prior or 
concomitant to a study or period, missing and partial medication dates will be handled as follows:
x
Missing medication start dates likely to be after the date of first dose of study drug in MRS-TU-
2019EXT (Section 6.2.1) will be imputed as the date of first dose of study drug in MRS-TU-
2019EXT. Otherwise, missing medication start dates likely to be after the date of first dose of study
drug in MRS-TU-2019 (Section 6.2.1) will be imputed as the date of first dose of study drug in
MRS-TU-2019.


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x
Missing end dates will be imputed as the date of last contact.
x
Incomplete medication start dates will be imputed using the earliest possible date implied by the
portions of the date provided. If the year is provided and not the month (regardless of the day),
January 1st of that year will be imputed as the start date. If the month and year are provided but not
the day, the 1st day of the provided month/year will be imputed as the start date.
Incomplete medication end dates will be imputed using the latest possible date implied by the portions of 
the date provided. If only the year is provided and not the month regardless of the day, December 31st of 
that year will be imputed as the end date. If the month and year are provided but not the day, the last day of
the provided month/year will be imputed as the end date. If any imputed end date would be after the 
subject’s date of last contact, then the medication end date will be imputed as the date of last contact.
6.3.7.
Missing and Partial Diagnosis Dates
In order to calculate the number of years since hypogonadism diagnosis, missing and partial diagnosis dates 
will be handled as follows:
Missing diagnosis dates will not be imputed.
Incomplete diagnosis dates will be imputed using the earliest possible date implied by the portions of the 
date provided. If only the year is provided and not month regardless of the day, January 1st of that year will 
be imputed as the start date. If the month and year are provided and not the day, the 1st day of the provided 
month/year will be imputed as the start date.
6.3.8.
Missing and Partial Last Dose of Study Drug Dates
In order to calculate the duration of exposure of study drug, missing and partial last dose dates (Section 
6.2.2) will be handled as follows: 
Missing last dose dates will be imputed as the date of the last scheduled treatment visit.
Incomplete last dose dates will be imputed using the latest possible date implied by the portions of the date 
provided. If only the year is provided, December 31st of that year will be imputed as the last dose date. If 
the month and year are provided, the last day of the provided month/year will be imputed as the last dose
date. If any imputed last dose date would be after the date of the subject’s last scheduled treatment visit,
then the last dose date will be imputed as the date of the last scheduled treatment visit.


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6.4.
VISIT WINDOWS
There are no plans to derive visit windows, visits will be used in the analyses as reported on the eCRF. For 
subjects with multiple screening attempts, only data from the most recent screening attempt will be 
included in summary statistics. Unscheduled PK and safety data (physical examination, vital signs, 
electrocardiogram [ECG], and laboratory evaluations) will not be summarized unless they are determined 
to be the last non-missing observations before the first dose of study drug (i.e. baseline [Section 6.2.4]). All 
data will be listed. 
The T levels determined from the T assays processed at Syneos Health (301D College road East, Princeton, 
NJ 08540, USA) will be considered the relevant T concentration. In a case where a PK visit is repeated due 
to loss of sample due to either human error or during transit, the T assay on the repeat PK samples will be 
considered the relevant T concentration.
PK samples taken far outside the protocol sampling window may be excluded from by-timepoint summary 
statistics; this will be decided by the pharmacokineticist.
6.5.
POOLING OF CENTERS
No pooling of centers is planned. No listings, tables or analyses are planned to be presented by center.
6.6.
SUBGROUPS
The MRS-TU-2019EXT analyses of Cavg and Cmax will be presented separately for the following 
subgroups:
x
Weight - ≤93 kg vs. >93 kg, as assessed at baseline (Section 6.2.4).
x
BMI - <30 kg/m2 vs. ≥30 kg/m2, as assessed at Screening Visit 2.
x
Age - ≤50 years vs. >50 years, as at date of informed consent.
x
Race – Asian, Black or African American, White, or Other.
x
Ethnicity.
x
Actual Day 90E Breakfast Diet Category
For MRS-TU-2019, Time 0 (Section 6.2.6) vital signs summaries will be presented for the following 
subgroups, where applicable, as detailed in Section 16:
x
Baseline Diabetic Status – with Diabetes Mellitus (baseline medical history of diabetes, or
HbA1c at Visit 3 greater than 6.5%) and without Diabetes Mellitus.


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x
Baseline Hypertensive Status – hypertensive at baseline (baseline sBP ≥130 mmHg or dBP ≥80
mmHg) and not hypertensive at baseline.
x
Baseline Hypertensive Treatment Status - with and without antihypertensive therapy at 
baseline, Visit 3 (Day 1).
x
Day 90 Hemoglobin Tertiles.  (Used for Day 90 In Clinic sBP)
x
Baseline Hypogonadal Status:
o
Primary hypogonadism (LH and FSH above the upper limit of normal [ULN]).
o
Secondary hypogonadism where serum LH is within the normal range or below the 
lower limit of normal [LLN] and/or FSH is within the normal range or below the LLN).
For MRS-TU-2019EXT, Time 0 vital signs summaries will be presented for the following subgroups, 
where applicable, as detailed in Section 16:
x
Baseline Diabetic Status – with Diabetes Mellitus (baseline medical history of diabetes, or 
HbA1c at Visit 7E greater than 6.5%) and without Diabetes Mellitus.
x
Baseline Hypertensive Status – hypertensive at baseline (in clinic baseline sBP ≥130 mmHg or 
dBP ≥80 mmHg) and not hypertensive at in clinic baseline.
x
Baseline Hypertensive Treatment Status - with and without antihypertensive therapy at 
baseline, Visit 7E (Day 1E).
x
Baseline Hypogonadal Status:
o
Primary hypogonadism (LH and FSH above the upper limit of normal [ULN]).
Secondary hypogonadism where serum LH is within the normal range or below the lower limit of normal 
[LLN] and/or FSH is within the normal range or below the LLN).
x
Baseline Statin Treatment Status – with and without statin treatment at baseline.
x
Age - ≤50 years vs. >50 years, as at date of informed consent.
For the MRS-TU-2019EXT study, as data permit (minimum of 5 subjects per subgroup), subgroup 
analyses of 24-hour, daytime and nighttime ambulatory sBP and dBP, and 24-hour ambulatory HR,
mean arterial pressure (MAP) and pulse pressure (PP), will be performed focusing on:
x
Baseline Diabetic Status  
x
Baseline Hypertensive Treatment Status
x
History of Hypertension
x
Day 90E Hemoglobin Tertiles.  (Used for Day 120E and Day 180E ABPM sBP)


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7.
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS
AND MEDICATION
7.1.
SUBJECT DISPOSITION AND WITHDRAWALS
7.1.1.
MRS-TU-2019
The total number and percentage of subjects who screen failed will be summarized along with the number 
and percentage randomized to each treatment group, for all screened subjects.
The number and percentage of subjects within each analysis set and reasons for exclusion from each 
analysis set will be summarized by treatment group and overall in terms of the number of subjects 
randomized and/or treated.
Subject disposition will be summarized for all screened subjects and for the SS, FAS, PKS, ECS, and AAS
by treatment group and overall. The summary table will show the frequency and percentage of subjects in 
each of the analysis sets who completed the study to Day 90, who completed the study to Day 365, who 
withdrew from the study before Day 90, who withdrew from the study between Day 90 and Day 365, and 
who withdrew from the study at any time before Day 365, along with the primary reason for discontinuation
of study drug, with percentages based on the number of subjects randomized in the analysis set.
Reasons for discontinuation of study drug will also be listed, including the date of last dose of study drug
(without imputation), date of last visit, and date of last follow-up.
Eligibility details (including date of screen failure and inclusion and/or exclusion criteria not met) and 
informed consent (protocol version, date informed consent signed, consent for ACTH sub-study, consent 
for BSSS, and consent for ABPM MRS-TU-2019EXT study) will be listed only, for all subjects screened.
Randomization details will also be listed, including the date of randomization and randomization number. 
Three subjects were randomized into the MRS-TU-2019 study twice in error and the handling of data for 
these subjects is described in Appendix 16.3.
7.1.2.
MRS-TU-2019EXT
The number and percentage of subjects who screen failed, out of all those screened, will be summarized by 
source group (MRS-TU-2019 treatment group or newly enrolled group) and overall, for all screened 
subjects. 
The number and percentage of subjects enrolled (Section 6.2.8), out of all those screened, overall and 
broken down by continuing subjects, late entry subjects who do not qualify as new enrollment subjects, and 


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newly enrolled subjects or late entry subjects who qualify for new enrollment, will be summarized by source 
group (MRS-TU-2019 treatment group or newly enrolled group) and overall, for all screened subjects. 
The number and percentage of subjects within each analysis set and reasons for exclusion from each 
analysis set will be summarized in terms of the number of subjects providing written informed consent for 
the ABPM MRS-TU-2019EXT study.
Subject disposition will be summarized for all screened subjects, for all MRS-TU-2019EXT enrolled 
subjects (Section 6.2.8), and for the EXTS, mEXTS, EXPK Set and EXSE and mEXSE Set by source
group (MRS-TU-2019 treatment group or newly enrolled group) and overall. The summary table will 
show the frequency and percentage of subjects in each of the analysis sets who enrolled (overall and 
broken down by continuing subjects, late entry subjects, and newly enrolled subjects), and who completed 
and withdrew from each relevant study period, along with the primary reason for discontinuation of study 
drug, with percentages based on the number of subjects enrolled in the analysis set. For MRS-
TU-2019EXT the summary table will show the frequency and percentage of subjects who completed and 
withdrew from each relevant study period ( to Day 90E, to Day 120E and to Day 180E). For MRS-
TU-2019  the summary table will show the frequency and percentage of subjects who completed and 
withdrew from each relevant study period (to Day 90, to Day 365). 
Reasons for discontinuation of study drug will also be listed, including the date of last dose of study drug 
(without imputation), date of last visit, and date of last follow-up. 
Eligibility details (including date of screen failure and inclusion and/or exclusion criteria not met) for all 
screened subjects and informed consent date for all subjects providing written informed consent for the 
MRS-TU-2019EXT study will be listed only.
7.1.3.
Overall
The number and percentage of subjects in the OSS and reasons for exclusion from the OSS will be 
summarized by source group (MRS-TU-2019 treatment group or MRS-TU-2019EXT newly enrolled 
group) and overall for all randomized or enrolled subjects and for all subjects who took SOV2012-F1 in 
both studies.
Subject disposition will be summarized for all subjects in the OSS and for all subjects who took SOV2012-
F1 in both studies.
7.2.
DEMOGRAPHIC AND OTHER BASELINE 
CHARACTERISTICS
All demography and baseline data will be listed. 


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Unless otherwise stated, percentages will be calculated out of the number of subjects in the analysis set. Three
subjects were randomized into the MRS-TU-2019 study twice in error and the handling of data for these 
subjects is described in Appendix 16.3.
7.2.1.
MRS-TU-2019
All demographic data will be summarized by treatment group and overall using descriptive statistics for 
the SS, FAS, PKS, ECS, and AAS.
Age (years) will be calculated as (date of informed consent-date of birth+1)/365.25 truncated to complete 
years and will be summarized as a continuous variable. Height and BMI are collected at Screening Visit 2 
and will be summarized as continuous variables. BMI category at Screening Visit 2 (<30 kg/m2 or ≥30 
kg/m2) will also be summarized by the number and percentage of subjects in each category. Diet category 
(low-, normal-, or high-fat breakfast) will be summarized by the number and percentage of subjects in each 
category using the Day 90 meal recorded in the CRF. The ASA 24 assigned diet category will also be 
summarized in the demography.
All remaining MRS-TU-2019 subgroup variables defined in Section 6.6 will be summarized by the 
number and percentage of subjects in each category. 
Demography will also be broken down by the subgroups diabetic status and baseline hypertensive status 
as defined in Section 6.6.
7.2.2.
MRS-TU-2019EXT
All demographic data will be summarized using descriptive statistics for the EXTS, mEXTS, EXPK,
EXSE, and mEXSE.
Age (years) will be calculated as (date of MRS-TU-2019EXT informed consent-date of birth+1)/365.25 
truncated to complete years and will be summarized as a continuous variable. Height and BMI are collected 
at Screening Visit 2 and will be summarized as continuous variables. BMI category at Screening Visit 2 
(<30 kg/m2 or ≥30 kg/m2) will also be summarized by the number and percentage of subjects in each 
category. Diet category (low-, normal-, or high-fat breakfast) will be summarized by the number and 
percentage of subjects in each category using the Day 90E meal recorded in the CRF.  The ASA 24 assigned 
diet category will also be summarized in the demography.
All remaining MRS-TU-2019EXT subgroup variables defined in Section 6.6 will be summarized by the 
number and percentage of subjects in each category. 


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7.2.3.
Overall
All demographic data will be summarized using descriptive statistics for all subjects in the OSS and for 
all subjects who took SOV2012-F1 in both studies.
Age (years) will be calculated as (date of baseline informed consent-date of birth+1)/365.25 truncated to 
complete years and will be summarized as a continuous variable. Height and BMI are collected at Screening 
Visit 2 and will be summarized as continuous variables. BMI category at Screening Visit 2 (<30 kg/m2 or 
≥30 kg/m2) will also be summarized by the number and percentage of subjects in each category.
7.3.
BASELINE DISEASE CHARACTERISTICS
Symptoms and signs suggestive of androgen deficiency, present or past, are collected at Screening Visit 1 
and will be summarized using descriptive statistics for categorical variables for the MRS-TU-2019 SS and 
the MRS-TU-2019EXT EXTS, and for all subjects in the OSS.
All data will be listed. Three subjects were randomized into the MRS-TU-2019 study twice in error and the 
handling of data for these subjects is described in Appendix 16.3.
7.4.
MEDICAL HISTORY
Descriptions of medical history findings will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) Version 20.0 or later. Details related to the subjects’ hypogonadism will be specifically 
recorded. Medical/surgical history recorded at Screening Visit 1, will be summarized by the number and 
percentage of subjects within each SOC and PT, for the MRS-TU-2019 SS and the AAS by treatment group
and overall; for the MRS-TU-2019EXT EXTS, mEXTS, EXPK, EXSE and mEXSE, and overall; for all 
subjects in the OSS; and for all subjects who took SOV2012-F1 in both studies. Subjects will be counted 
once per SOC and PT.
The number of years since hypogonadism diagnosis will be calculated as (date of informed consent –
diagnosis date + 1)/365.25 for MRS-TU-2019, as (date of MRS-TU-2019EXT informed consent –
diagnosis date + 1)/365.25 for MRS-TU-2019EXT, and as (date of baseline informed consent – diagnosis 
date + 1)/365.25 overall, and presented to 2 decimal places. Missing and partial diagnosis dates will be 
handled according to Section 6.3.7. The number of years since hypogonadism diagnosis will be summarized 
as a continuous variable for the MRS-TU-2019 SS, the FAS, the PKS, the ECS, and the AAS by treatment 
group and overall, for the EXTS, mEXTS EXPK Set, EXSE Set, and mEXSE Set overall, for all subjects 
in the OSS, and for all subjects who took SOV2012-F1 in both studies. Number and percentage of subjects 
with symptoms of hypogonadism and receiving prior TRT will also be summarized for the MRS-TU-2019 
SS, the FAS, the PKS, the ECS, and the AAS by treatment group and overall, for the EXTS, mEXTS, 
EXPK, EXSE and mEXSE overall, for all subjects in the OSS, and for all subjects who took SOV2012-F1
in both studies.


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Prior TRT recorded on the hypogonadism medical history eCRF will be coded using the World Health 
Organization (WHO) Drug B2 Format, 01MAR2017 version. The number and percentage of subjects 
receiving prior TRT as recorded at Screening Visit 1 will be summarized by ATC (Anatomical Therapeutic 
Chemical) Levels 2 and 4 for the MRT-TU-2019 SS, the FAS, the PKS, the ECS, and the AAS by treatment 
group and overall, for the EXTS, EXPK Set, and EXSE Set overall, for all subjects in the OSS, and for all 
subjects who took SOV2012-F1 in both studies. Subjects will be counted once per ATC class (Level 2) and 
PT (Level 4).
Medical history will also be listed for all subjects in the SS and the EXTS.
A disease or illness reported as medical history without a start date will be included in medical history 
without a date assigned. 
Medical history will be sorted by descending overall frequency, by SOC and PT in the summary table. 
Medical history data listings will be sorted by treatment group, subject number, start date, SOC, PT, and 
verbatim term.
Three subjects were randomized into the MRS-TU-2019 study twice in error and the handling of data for
these subjects is described in Appendix 16.3.
7.5.
MEDICATION
Medications documented on the Prior and Concomitant Medications eCRF will be coded using the WHO 
Drug B2 Format, 01MAR2017 version. MRS-TU-2019 prior medications will be defined as medications 
documented on the Prior and Concomitant Medications eCRF that were started and stopped before the first 
dose of any study drug in MRS-TU-2019 (Section 6.2.1).
MRS-TU-2019EXT prior medications will be defined as medications documented on the Prior and 
Concomitant Medications eCRF that were started and stopped before the first dose of any study drug in 
MRS-TU-2019EXT (Section 6.2.1).
Overall prior medications will be defined as medications documented on the Prior and Concomitant 
Medications eCRF that were started and stopped before the first dose of any study drug for the subject 
(Section 6.2.1).
MRS-TU-2019 concomitant medications will be defined as medications documented on the Prior and 
Concomitant Medications eCRF that were started after the first dose of any study drug in MRS-TU-2019
(Section 6.2.1), and before the first dose of any study drug in MRS-TU-2019EXT (Section 6.2.1) for
subjects taking part in MRS-TU-2019EXT, or started before the first dose of any study drug in MRS-TU-
2019 and continued on or after the first dose of any study drug in MRS-TU-2019.  


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MRS-TU-2019EXT concomitant medications will be defined as medications documented on the Prior and 
Concomitant Medications eCRF that were started after the first dose of study drug in MRS-TU-2019EXT
(Section 6.2.1) or started before the first dose of study drug in MRS-TU-2019EXT and continued on or after 
the first dose of study drug in MRS-TU-2019EXT. SOV2012-F1 concomitant medications will be defined 
as medications documented on the Prior and Concomitant Medications eCRF that were started after the first 
dose of SOV2012-F1 (Section 6.2.1) or started before the first dose of SOV2012-F1 and continued on or 
after the first dose of SOV2012-F1.
In order to classify medications documented on the Prior and Concomitant Medications eCRF as prior or 
concomitant to a study or period, missing and partial medication dates will be handled as detailed in Section 
6.3.6.
The number and percentage of subjects taking MRS-TU-2019 prior medications will be summarized overall 
and by ATC Levels 2 and 4 for all subjects in the SS, the FAS, the PKS, the ECS, and the AAS by treatment 
group and overall. The number and percentage of subjects taking MRS-TU-2019EXT prior medications 
will be summarized overall and by ATC Levels 2 and 4 for all subjects in the EXTS, mEXTS, EXPK,
EXSE, and mEXSE.
The number and percentage of subjects taking overall prior medications will be summarized overall and by 
ATC Levels 2 and 4 for all subjects in the OSS and for all subjects who took SOV2012-F1 in both studies.
The number and percentage of subjects taking MRS-TU-2019 concomitant medications will be summarized 
overall and by ATC Levels 2 and 4 for all subjects in the SS and AAS by treatment group and overall.
The number and percentage of subjects taking MRS-TU-2019EXT concomitant medications will be 
summarized overall and by ATC Levels 2 and 4 for all subjects in the EXTS, mEXTS, EXPK, EXSE, and 
mEXSE.
The number and percentage of subjects taking MRS-TU-2019EXT concomitant medications up to the 
Day 90E efficacy visit will be summarized overall and by ATC Levels 2 and 4 for all subjects in the EXTS,
mEXTS, EXPK, EXSE, and mEXSE.
The number and percentage of subjects taking SOV2012-F1 concomitant medications will be summarized 
overall and by ATC Levels 2 and 4 for all subjects in the OSS and for all subjects who took SOV2012-F1 
in both studies. 
Subjects will be counted once per ATC class (Level 2) and PT (Level 4). Prior and concomitant medications 
will be listed together for all subjects in the SS and EXTS, with MRS-TU-2019EXT prior medications,
MRS-TU-2019EXT concomitant medications started on or before the Day 90E visit, antihypertensive 
medications, and statin treatments being flagged. Prior TRT recorded on the hypogonadism medical history 
eCRF will be listed and summarized separately according to Section 7.4. The number and percentage of 


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subjects taking new antihypertensive therapy during the study that was not present at baseline, and the
number and percentage of subjects with dose increases in antihypertensive therapy by EOT, will be 
summarized for the EXTS using summary statistics for categorical data.
Three subjects were randomized into the MRS-TU-2019 study twice in error and the handling of data for
these subjects is described in Appendix 16.3.


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8.
EFFICACY
8.1.
NORMAL RANGE
The T and DHT normal ranges for NaF/EDTA plasma and serum samples to be used in these studies in the 
evaluation of SOV2012-F1 treated subjects will be determined from Study MRS-TNR2019. The normal 
range for subjects treated with Androgel is 300 to 1000 ng/dL.
8.2.
PRIMARY MRS-TU-2019 ENDPOINT  
Three subjects were randomized into the study twice in error and the handling of data for these 
subjects is described in Appendix 16.3.
8.2.1.
Multiple Imputation Analysis
Analysis of the primary endpoint will be performed using the FAS.
The primary endpoint is the percentage of SOV2012-F1–treated subjects with a 24-hour T Cavg (based on 
NaF/EDTA tube plasma samples) within the normal range after 90 days of treatment. The normal range is 
defined using the NaF/EDTA plasma endogenous testosterone from study MRS-TNR-2019.
The Cavg will be calculated per Section 9.4.1. Missing T Cavg values at Day 90 (Visit 8) in the FAS will be 
imputed using multiple imputation procedures, as described in Section 8.5. Multiple Imputation is only 
applied when there is at least one evaluable post baseline 24 hour T Cavg
A 95%, 2-sided, binomial CI for the percentage of subjects will be reported along with the estimated 
percentage itself. This CI will be calculated for each imputation generated from the multiple imputation 
procedure and results combined as described in Section 8.5.
Serum T Cavg values for those subjects randomly assigned to receive AndroGel will be summarized using 
summary statistics for continuous data only.
8.2.2.
Sensitivity Analyses
Sensitivity Analysis 1 will be performed on SOV2012-F1-treated subjects using the ECS with no
imputation of missing data.
Sensitivity Analysis 2 will be performed on SOV2012-F1-treated subjects using the FAS and WCS
imputation, as described in Section 6.3.2.


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8.3.
PRIMARY MRS-TU-2019EXT EFFICACY ENDPOINT
8.3.1.
Primary Analysis
The primary analysis of efficacy will be performed using the mEXTS.
The primary efficacy endpoint is the percentage of SOV2012-F1–treated subjects with a 24-hour plasma 
total T Cavg (based on NaF/EDTA tube plasma samples) within the normal range after 90 days of treatment
within the MRS-TU-2019EXT study. The normal range is defined using the NaF/EDTA plasma 
endogenous testosterone from study MRS-TNR-2019.
The Cavg will be calculated per Section 9.4.1. Missing T Cavg values at Day 90E (Visit 12E) in the mEXTS
will not be imputed using multiple imputation procedures, as there are no 24 hour pk profiles prior to Day 
90E.  Instead, missing values will be treated as failures (WCS).
A 95%, 2-sided, binomial CI ( Wald asymptotic confidence limits ) for the percentage of subjects will be 
reported along with the estimated percentage itself.
The MRS-TU-2019EXT study will have shown effectiveness of SOV2012-F1 if at least 75% of the mEXTS
has total T Cavg in the normal range and if the lower bound of the 2-sided 95% CI for that proportion is ≥ 
65%.
8.3.2.
Sensitivity Analyses
The following sensitivity analyses will be performed:
x
the EXTS and WCS imputation
x
using the EXPK with no imputation of missing data.
x
the mEXSE and WCS imputation using the serum and the NaF/EDTA plasma data from the Serum 
Substudy. The normal range is defined using the results from study MRS-TNR2019.
x
the EXSE and WCS imputation using the serum and the NaF/EDTA plasma data from the Serum 
Substudy. The normal range is defined using the results from study MRS-TNR2019.


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8.4.
EXPLORATORY MRS-TU-2019 ENDPOINTS 
Three subjects were randomized into the study twice in error and the handling of data for these subjects is 
described in Appendix 16.3.
8.4.1.
International Prostate Symptom Score (I-PSS)
The I-PSS is a validated questionnaire used to assess the severity and impact of urinary symptoms. It is 
based on the answers to 7 questions concerning urinary symptoms and one question concerning quality of 
life. Each question concerning urinary symptoms allows the subject to choose one out of 6 answers
indicating increasing severity of the particular symptom. The answers are assigned points from 0 to 5. The 
total score can therefore range from 0 to 35 (asymptomatic to very symptomatic).
The questions refer to the following urinary symptoms:
Questions
Symptom
1
Incomplete emptying
2
Frequency
3
Intermittency
4
Urgency
5
Weak Stream
6
Straining
7
Nocturia
Question 8 refers to the subject’s perceived quality of life. The answers to the single quality of life 
question range from “delighted” to “terrible” or 0 to 6.
If any question response is left unanswered, then the resultant score will be missing and the total score 
will not be calculated.
The observed values and the change from baseline (Section 6.2.4) values for each subject will be 
summarized by treatment group and visit for total score and quality of life due to urinary symptoms score.
Summaries will be completed separately for those who completed 52 weeks of treatment and those whose 
EOT assessment was completed at the time of early withdrawal, and for both groups together.


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I-PSS summaries will be presented for the FAS. All questionnaire data will also be listed.
8.4.2.
Psychosexual Daily Questionnaire (PDQ)
The PDQ will be used to assess the subject’s sexual function and mood changes. Weekly averages of the 
PDQ subscale scores recorded for 7 consecutive days prior to the collection visit will be calculated. For 
the sexual activity subscale score, the weekly value will be sum of the number of “any” responses 
(1 = Yes, 0 = No), as detailed below. Scores are calculated if diaries are completed on at least 3 of the 7
consecutive days. The subscales are given below.
x
Sexual desire 
x
Sexual enjoyment:
o
Enjoyment without a partner 
o
Enjoyment with a partner 
x
Mood 
o
Positive mood (Full of pep/energetic, Friendly, Well/good, and Alert) 
o
Negative mood (Angry, Irritable, Sad or Blue, Tired, and Nervous) 
x
Sexual activity score 
x
Sexual performance with erection: 
o
Percent full erection
o
Satisfaction with erection
The sexual desire subscale is assessed using a 0 – 7 Likert scale (None to Very High). 
The sexual enjoyment with and without a partner subscales are assessed using a 0 – 7 Likert Scale 
(0 = None, 7 Very high enjoyment/pleasure). The availability of a partner (yes or no) is also recorded, but 
not used in the scoring.
The positive mood subscale score will be determined using each day’s average response on the Likert 
Scale from 0 – 7 (0 = Not at all true – 7 = Very true) to the positive mood questions (alert, full of 
pep/energetic, friendly, well/good).
The negative mood subscale score will be determined using the same method as for the positive mood 
subscale score using the negative mood questions (angry, irritable, sad or blue, tired, nervous).
The weekly sexual activity subscale score will be determined using a count of the activities experienced 
over the complete assessment week, as indicated on the daily assessments (1 = experienced, 0 = did not 
experience), dividing by the number of days during the week where the daily questionnaire was 
completed, and then multiplying this ratio by 7 to get an activities per week value. 
The percent of full erection is assessed by checking on the scale of 0 – 100% in increments of 10%.


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Satisfaction with erection is assessed using a 0 – 7 Likert Scale (0 = not satisfactory – 7 = very 
satisfactory).
The observed and change from baseline (Section 6.2.4) weekly average values for each subject will be 
summarized by treatment group and visit for each subscale score. Summaries will be completed 
separately for those who completed 52 weeks of treatment and those whose EOT assessment was 
completed at the time of early withdrawal, and for both groups together.
PDQ summaries will be presented for the FAS. All questionnaire data will also be listed.
8.4.3.
Short Form Survey (SF-36)
SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. SF-36 will be scored 
according to the scorning manual for RAND 36-Item Health Survey (Version 1.0).”.
Observed values and the change from baseline (Section 6.2.4) values for each subject will be summarized 
by treatment group and visit for each domain score, the physical (PCS) and mental (MCS) component 
summary scores, and the total score.
Summaries will be completed separately for those who completed 52 weeks of treatment and those whose 
EOT assessment was completed at the time of early withdrawal, and for both groups together.
SF-36 summaries will be presented for the FAS. All questionnaire data will also be listed.
8.4.4.
International Index of Erectile Function Questionnaire (IIEF)
The IIEF is a widely used, multi-dimensional, self-administered investigation that has been found useful in 
the clinical assessment of erectile dysfunction and treatment outcomes in clinical trials. A score of 0-5 is 
awarded to the response given to each of the 15 questions that examine the 5 main domains of erectile 
function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction, as detailed in 
Table 6.
Observed values and change from baseline (Section 6.2.4) values for each subject will be summarized by 
treatment group and visit for each totaled domain score. Note that the original Spanish version of the 
questionnaire used in the study had incorrect responses available for Question 12, therefore Question 12 
was left blank in the eCRF for all subjects who used this version of the questionnaire. These data will not 
be imputed.
Summaries will be completed separately for those who completed 52 weeks of treatment and those whose 
EOT assessment was completed at the time of early withdrawal, and for both groups together.










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are still in the study and randomized to the same treatment group. Data will be imputed in 2 stages for 
SOV2012-F1 subjects.
Stage 1: Impute intermittent missing data for the SOV2012-F1 group
In a preliminary step, imputation based on the missing at random (MAR) assumption will be performed for 
intermittent missing data using the Markov chain Monte Carlo method in order to obtain monotone missing 
data patterns, and will be implemented with the SAS® PROC MI procedure with center, BMI at Screening 
Visit 2, age, race, and all visits with T Cavg data, included as terms in the imputation model. Race subgroups 
will be as defined in Section 6.6. Example SAS® code is as follows:
proc mi data=DATAIN nimpute=100 seed=543571857 out=MONOTONE;
var CENTER_X BMI AGE RACE_X VISIT4 VISIT6 VISIT8;
mcmc chain=multiple impute=monotone;
run;
where _X represents parameterized categorical variables.
Stage 2: Impute monotone missing data for the SOV2012-F1 group
1.
Take the monotonic data set and create a new data set DATA1 including all subjects at Visit 4 with
non-missing values or missing at Visit 4.
2.
Sort by imputation (from the 100 imputations above) and subject number.
3.
Impute data at Visit 4 in data set 1. Example SAS® code is as follows:
proc mi data=DATA1 out=VISIT4 seed=6784325 nimpute=1;
by _Imputation_;
class CENTER RACE;
var CENTER BMI AGE RACE VISIT4;
monotone regression;
run;
4.
To impute missing data for the subsequent Visit 6 repeat steps 1 – 3 using the data set output above: 
VISIT4 instead of monotone, resulting in an output data set VISIT6.
5.
Repeat for Visit 8.
For any visit, if there are no non-missing data for a center, then perform the above imputation once
excluding the centers with no non-missing data at the visit, and once for the whole analysis set without 
center included in the model. From the second imputation, take the data for the centers that had no non-
missing data at the visit and merge them back in with the data from the first imputation.


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8.5.2.
Analysis of Imputed Data
In order to analyze the data from the multiple imputation procedure the binomial CI at Day 90 will be 
calculated for each of the 100 imputations in Stage 2 above (Section 8.5.1, respectively), and then the results 
will be combined together to provide the final CI. This can be done as follows:
1.
Calculate the binomial CI for each imputation.
PROC FREQ DATA=imputed_overall;
TABLES responder / cl binomial CL=wald;
BY _Imputation_; 
ODS OUTPUT BINOMIAL=prop; 
RUN; 
2.
Reformat the data.
DATA prop; 
MERGE
prop(WHERE=(Label1=”Proportion”)
KEEP=_Imputation_ nValue1 Label1 
RENAME=(nValue1=prop)) 
prop(WHERE=(Label1=”ASE”)
KEEP=_Imputation_ nValue1 Label1 
RENAME=(nValue1=prop_se)); 
BY _Imputation_; 
RUN; 
3.
Combine the results using PROC MIANALYZE
PROC MIANALYZE DATA=prop; 
MODELEFFECTS prop;
STDERR prop_se;
ODS OUTPUT PARAMETERESTIMATES=mian_prop; 
RUN; 






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x
MRS-TU-2019 individual subject linear plasma T concentration-time plots by Day (24-hour PK 
only) for SOV2012-F1-treated subjects.
x
MRS-TU-2019 individual subject linear serum T concentration-time plots at Day 90 for AndroGel-
treated subjects.
x
MRS-TU-2019EXT individual subject linear plasma and serum T concentration-time plots by Day 
(6-hour and 24-hour PK only).
x
MRS-TU-2019EXT individual subject linear TU concentration-time plots at Day 90E.
x
Summary of MRS-TU-2019 concentration by treatment group at each timepoint (including 24-hour 
PK timepoints and other single timepoints) (n, number of values below BLQ [nBLQ], mean, SD, 
CV, minimum, median, maximum, geometric mean, and geometric CV).
x
Summary of MRS-TU-2019EXT concentration at each timepoint (including 24-hour PK timepoints 
and other single timepoints) (n, nBLQ, mean, SD, CV, minimum, median, maximum, geometric 
mean, and geometric CV).
x
Summary of MRS-TU-2019 T, DHT, and E2 concentration by dose by treatment group at each 
timepoint by Day (24-hour PK only) (n, nBLQ, mean, SD, CV, minimum, median, maximum,
geometric mean, and geometric CV).
x
Summary of MRS-TU-2019EXT T, DHT, and E2 concentration by dose at each timepoint by Day 
(6-hour and 24-hour PK only) (n, nBLQ, mean, SD, CV, minimum, median, maximum, geometric 
mean, and geometric CV).
x
MRS-TU-2019 mean ± SD concentration-time profiles by treatment group by Day (24-hour PK 
only) on a linear scale.
x
MRS-TU-2019 mean + SD concentration-time profiles by treatment group by Day (24-hour PK 
only) on a log-linear scale.
x
MRS-TU-2019EXT mean ± SD concentration-time profiles by Day (6-hour and 24-hour PK only) 
on a linear scale.
x
MRS-TU-2019EXT mean + SD concentration-time profiles by Day (6-hour and 24-hour PK only) 
on a log-linear scale.


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x
MRS-TU-2019EXT mean ± SD concentration-time profiles at Day 90E on a linear scale.
x
MRS-TU-2019EXT mean + SD concentration-time profiles at Day 90E on a log-linear scale.
x
MRS-TU-2019 mean ± SD T and DHT concentration-time profiles by dose by treatment group by 
Day (24-hour PK only) on a linear scale.
x
MRS-TU-2019 mean + SD T and DHT concentration-time profiles by dose by treatment group by 
Day (24-hour PK only) on a log-linear scale.
x
MRS-TU-2019EXT mean ± SD T and DHT concentration-time profiles by dose by Day (6-hour 
and 24-hour PK only) on a linear scale.
x
MRS-TU-2019EXT mean + SD T and DHT concentration-time profiles by dose by Day (6-hour 
and 24-hour PK only) on a log-linear scale.
x
Mean ± SD T concentration-time profiles for pre-morning dose at Days 1, 14, 42, and 90 by
treatment group on a linear scale.
x
Mean ± SD T concentration-time profiles for pre-morning dose at Days 1E, 14E, 42E, and 90E on 
a linear scale.
x
Mean ± SD T concentration-time profiles (12-hour PK on Day 90 and Day 90E only) by diet 
categories as determined by the breakfast meal received on that day (low-, normal-, or high-fat) on 
a linear scale for SOV2012-F1-treated subjects.
x
Mean ± SD T concentration-time profiles (12-24 hour PK on Day 90 and Day 90E only) by dinner 
fat categories as determined by the evening meal received on that day (low-, normal-, or high-fat) 
on a linear scale for SOV2012-F1-treated subjects.
ASA24 system record and SOV2012-F1 on-site meal record details will be listed.
Reporting precision for summaries of subject concentration data will be the same as that for the PK 
Parameters in Section 9.4.2.


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9.4.
PHARMACOKINETIC (PK) PARAMETERS 
9.4.1.
Derivation of Pharmacokinetic (PK) Parameters
Validated WinNonLin Version 6.4 (Certara, USA) will be used for PK parameter derivation. PK parameters 
detailed in Section 4.3 will be estimated using the concentrations with rules for BLQ and missing data (as 
detailed in Section 9.3.1) applied. The sampling time relative to dosing for predose samples will be treated 
as zero. Further details of PK parameter derivation (24-hour PK sampling only) are as follows: 
x
The Cmax and the corresponding Tmax will be read directly from the concentration-time plot
(observed data, not predicted data, excluding the pre-morning dose data). If the same Cmax is
recorded more than once during the treatment period, the earliest occurrence will be considered the
Tmax.
x
AUCs will be calculated non-compartmentally using the linear up/log down trapezoidal rule.
x
The Cavg will be calculated as AUC0-24divided by 24 hours. If AUC0-24is not calculable, and the last
timepoint (Tlast) is close to 24 hours (between 23 and 25 hours inclusive), then Cavg0-last calculated
as AUClast/Tlast will be used for Cavg.
x
DHT/T and E2/T ratios will be calculated based on ratios of Cavg, AUC0-12, and AUC12-24normalized
by molecular weight using following equations:
1)
DHT/T Cavg = [(DHT Cavg)*FWT]/[(T Cavg)*FWDHT]
2)
E2/T Cavg = [(E2 Cavg)*FWT]/[(T Cavg)*FWE2]
Where FWT = 288.42 g/mol; FWDHT = 290.44 g/mol; FWE2 = 272.38 g/mol
The same equations will be applied with the other parameters in replacement of Cavg for AUC0-
12, and AUC12-24 based ratios.
Free T concentrations at MRS-TU-2019 baseline (Section 6.2.4), MRS-TU-2019EXT baseline, and for 
Day 90 and Day 90E will be calculated using total T (pre-dose for Visit 3 and 7E, and Cavg from Day 90 
and Day 90E), SHBG, and albumin concentrations for each subject according to a validated FTV method6,7
with the following equation: 
FTV = (T–N*FTV)/(Kt(S–T+N*FTV))
FTV is then converted to ng/dL by multiplying by 28.842


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Where FTV = free T concentration (nmol/L), T = total T concentration (nmol/L), S = SHBG
concentration (nmol/L), Kt = (association constant of SHBG for T) = 0.597 L/nmol, N = (KaCa+1), 
Ka = 3.6*104 L/mol, Ca = albumin molar concentration (mol/L), and 28.842 is the conversion factor of 
nmol/L to ng/dL
For albumin, molar concentration conversion will be:
albumin concentration (g/L) divided by 69000 (g/mol) = xx (mol/L).
Free T calculations will be performed using Total T (pre-dose for Visit 3 and 7E, and Cavg from Day 90 
and Day 90E) from NaF/EDTA samples for MRS-TU-2019 and MRS-TU-2019EXT for the SOV2012-F1
treatment groups and from the serum samples for the AndroGel treatment group. Free T calculations will 
also be performed for both serum and NaF/EDTA samples from the MRS-TU-2019EXT Serum Substudy.
9.4.2.
Presentation of Pharmacokinetic (PK) Parameters 
Individual subject PK parameters will be listed for each analyte.
PK parameters will be summarized by treatment group for the PKS and summarized for the EXPK Set 
using descriptive statistics as detailed in Table 9.
The following tables will be provided for the PKS and EXPK Set using descriptive statistics as detailed in
Table 9:
x
Plasma 0-24, and 0-12 T Cavg and T Cmax on Day 90E by diet category as determined by the meal 
received on that day (low-, normal-, or high-fat breakfast) and overall.
x
Plasma 12-24 T Cavg and T Cmax on Day 90E by diet category as determined by the meal received 
on that day (low-, normal-, or high-fat dinner).
x
Plasma 0-24, and 0-12 T Cavg and T Cmax on Day 90 by diet category as determined by the meal 
received on that day (low-, normal-, or high-fat breakfast) and overall.
x
Plasma 12-24 T Cavg and T Cmax on Day 90 by diet category as determined by the meal received on 
that day (low-, normal-, or high-fat dinner).
x
Plasma 0-24 T Cavg and T Cmax on Day 90E by the subgroups detailed in Section 6.6 and overall.




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x
Histograms of plasma T Cavg and T Cmax respectively (24-hour PK on Day 90 and Day 90E only)
on a linear scale.
x
Box plots of plasma T Cavg and T Cmax respectively (0-12 and 12-24-hour PK on Day 90E only) by
diet categories (low-, normal-, or high-fat dinner or breakfast) as determined by the meal received
on that day on a linear scale.
x
Box plots of plasma T Cavg and T Cmax respectively (24-hour PK on Day 90E only) by the subgroups
detailed in Section 6.6 on a linear scale.
9.5.
MRS-TU-2019 SOV2012-F1 TITRATION ALGORITHM 
EVALUATION
An evaluation of the MRS-TU-2019 titration algorithm was performed at the interim analysis and the 
methods were detailed in Version 2.0 of this SAP. The evaluation is reported in Appendix 16.2 and was 
used to determine the titration algorithm for MRS-TU-2019EXT. 
9.6.
MRS-TU-2019EXT SOV2012-F1 TITRATION ALGORITHM 
EVALUATION FOR SAMPLING TIME AND MATRIX 
EFFECTS
9.6.1.
Analysis of T Cavg Within the Normal Range After 90 Days of Treatment 
(Day 90E) vs. Visit 10E (Day 42E) Titration Time,
The number and percentage of subjects with a 24-hour plasma total T Cavg for NaF/EDTA plasma and serum 
for the EXSE and mEXSE within and outside the normal range after 90 days of treatment within the 
MRS-TU-2019EXT study will be presented by the Visit 10E timepoint that was used to determine the 
need, if any, to up or down titrate the dose of SOV2012-F1.
9.6.2.
Plasma Projected Dose Adjustments
In order to make the claim that the window of the timepoints that were used to determine the need, if any, 
to up or down titrate the dose of SOV2012-F1 (3, 4, and 5 hours) using plasma T concentration, an 
analysis of projected dose adjustment (increase, decrease, or no change) at 3, 4, 5 and 6 hours at Visits 8E
(Day 14E) and 10E (Day 42E) will be performed. Each hour will be compared to the other hours to see if 
the decision to dose adjust is the same. The percentage and frequency of matches will be presented.


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9.6.3.
Actual and Projected Titration Decisions
For titration visits in MRS-TU-2019EXT ,plasma actual titration decisions and serum projected titration 
decisions (increase, decrease, no change) will be summarized by assessment hour (3, 4, and 5). Serum
projections will be programmatically determined using the range of 460 to 971 ng/dL
Plasma titration decisions are actual decision during clinical conduct using plasma titration thresholds of 
400 and 900 ng/dL.
9.6.4.
Spearman’s Correlation Matrix of Projected Dose Adjustments
For each of Visit 8E (Day 14E) and Visit 10E (Day 42E) and each timepoint (1.5, 3, 4, 5, and 6 hours), a
Spearman’s correlation matrix of projected dose adjustment (increase, decrease, or no change) will be 
presented for both NaF/EDTA plasma and serum.
9.6.5.
Adjustment of NaF/EDTA Titration Thresholds to Serum Basis
Using the EXPK Set, the relationship between serum T concentrations and plasma T concentrations using 
NaF/EDTA tubes will be evaluated for each of the titration visits (8E and 10E), at the 3, 4, 5, and 6 hour 
timepoints separately, through scatter plots. A simple regression line will be displayed on each plot with 
the estimate of the slope and the 95% CI and p-value for the estimate of the slope, along with the adjusted 
R-squared. Then hours combined for 3,4,5 and then hours combined for 4,5,6 and finally all hours combined 
combined will also be presented with regression line, adjusted R-squared, and slope estimates.
9.6.6.
Final Dose as an Outcome Variable
With baseline hypertensive status, diabetes, and baseline weight as factors a logistic regression will be
performed to assess the relationship to final dose in the EXTS set. Dose will fall into one of the following 
three categories: 800mg, 600mg, and ≤400mg. Odds ratios and 95% CIs will be provided for each of the 
factors.
9.7.
ANALYSIS OF FOOD EFFECT
For the following parameters (Cavg0-24, Cmax0-24, Cavg0-12, Cmax0-12, Cavg12-24, and Cmax12-24)
in both MRS-TU-2019 and MRS-TU-2019EXT, a food effect analysis will be performed comparing low 
and high fat meals to normal fat(reference).  Parameters will be natural log transformed prior to analysis.  
The difference in geometric least squares means and associated 90% confidence intervals will be back 
transformed to provide the ratio and associated 90% confidence interval.


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10.
SAFETY
General safety endpoints are detailed in Sections 4.1.4 and 4.2.3. General safety will be assessed on the 
basis of AE reports, clinical laboratory data, vital signs, and serum cortisol response to intravenous 
administration of synthetic ACTH. Other safety assessments are physical examinations and ECG. The SS 
will be used for all general MRS-TU-2019 safety analyses, except the ACTH analysis, which will be 
performed using the AAS. The EXTS will be used for all general MRS-TU-2019EXT safety analyses. The 
OSS will be used for overall safety analyses.
The safety objectives are to assess the safety data after 52 weeks of treatment in the MRS-TU-2019 study 
and after 180 days of treatment in the MRS-TU-2019EXT study; however, selected safety data were also 
presented at the Day 90 interim analysis as detailed in Version 2.0 of this SAP.
Vital signs will also be evaluated using ABPM. The primary ABPM endpoint is the change from baseline 
in 24-hour average ambulatory sBP after approximately 120 (±3) days of treatment in the MRS-TU-
2019EXT study and will be analyzed using the EXTS.
Also part of the safety evaluations, T Cmax after 90 days of treatment in the MRS-TU-2019 study will be
analyzed using the FAS. Other safety endpoints for the MRS-TU-2019EXT study are detailed in 
Section 4.2.2 and will be analyzed using the EXTS.
Three subjects were randomized into the MRS-TU-2019 study twice in error and the handling of data for
these subjects is described in Appendix 16.3.
10.1.
EXTENT OF EXPOSURE
Shift tables from dose level at the start of each scheduled dose adjustment visit to dose level at the end of 
the visit (i.e. after dose adjustment) will be presented by treatment group for MRS-TU-2019 and separately 
for MRS-TU-2019EXT. The final study drug dose level at the end of every scheduled study visit will also 
be summarized by treatment group for MRS-TU-2019 and separately for MRS-TU-2019EXT. Percentages 
will be calculated out of the number of subjects attending the visit.
Categorical summaries of number of titrations and final study drug dose level reached will be presented for 
MRS-TU-2019 by treatment received, and for MRS-TU-2019EXT overall.
Bar charts of the number of subjects at each dose at Visit 4 (Day 14), Visit 6 (Day 42), Visit 8 (Day 90)
and Visit 8E (Day 14E), Visit 10E (Day 42E) and Visit 12E (Day 90E)  will be presented by treatment 
group for MRS-TU-2019 and separately for MRS-TU-2019EXT.
Summary statistics of the average dose daily dose at Visit 4, Visit 6 and Visit 8 (Day 90) for MRS-TU-
2019 , and also for Visit 8E, Visit 10E and Visit 12E MRS-TU-2019EXT will be calculated.


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Duration of exposure to study drug in days will be summarized for MRS-TU-2019 by treatment received,
for MRS-TU-2019EXT overall, and for SOV2012-F1 overall for all subjects in the OSS and for all subjects 
who took SOV2012-F1 in both studies, and will be calculated as follows, where missing and partial last 
study drug administration dates will be handled according to Section 6.3.8:
x
For MRS-TU-2019, duration of exposure (days) = (last date study drug administration in 
MRS-TU-2019–first date study drug administration in MRS-TU-2019 +1).
x
For MRS-TU-2019EXT, duration of exposure (days) = (last date study drug administration in 
MRS-TU-2019EXT–first date study drug administration in MRS-TU-2019EXT +1).
x
For SOV2012-F1 overall for all subjects in the OSS, duration of exposure (days) = (last date 
SOV2012-F1 administration in MRS-TU-2019–first date SOV2012-F1 administration in
MRS-TU-2019 +1)+(last date SOV2012-F1 administration in MRS-TU-2019EXT–first date 
SOV2012-F1 administration in MRS-TU-2019EXT +1).
x
For all subjects who took SOV2012-F1 in both studies, duration of exposure (days) is the sum of 
exposure in MRS-TU-2019 and MRS-TU-2019EXT. .
Cumulative total dosage consumed will be summarized for MRS-TU-2019 by treatment received, for 
MRS-TU-2019EXT overall, and for SOV2012-F1 overall for all subjects in the OSS and for all subjects 
who took SOV2012-F1 in both studies, and will be calculated as follows:
x
For AndroGel-treated subjects, total dose consumed (g) = sum of (dispensed weight (g)-returned 
weight (g) for each bottle dispensed).
x
For SOV2012-F1-treated subjects in MRS-TU-2019, total dose consumed in MRS-TU-2019 will
be calculated 2 ways:
1)
Total dose consumed (g) = 0.2 g*total number of capsules reported as taken or missing in 
MRS-TU-2019.
2)
Total dose consumed (g) = 0.2 g*total number of capsules reported as taken in
MRS-TU-2019.
Where missing capsules are the total number of capsules not returned minus the number of capsules 
reported as taken.
x
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1)
Total dose consumed (g) = 0.1 g*total number of 100 mg capsules reported as taken or
missing in MRS-TU-2019EXT+0.15 g*total number of 150 mg capsules reported as taken
or missing in MRS-TU-2019EXT+0.2 g*total number of 200 mg capsules reported as
taken or missing in MRS-TU-2019EXT.
2)
Total dose consumed (g) = 0.1 g*total number of 100 mg capsules reported as taken in
MRS-TU-2019EXT+0.15 g*total number of 150 mg capsules reported as taken in
MRS-TU-2019EXT+0.2 g*total number of 200 mg capsules reported as taken in
MRS-TU-2019EXT.
x
For all subjects in the OSS, total dose of SOV2012-F1 consumed overall will be calculated 2 ways:
1)
Total dose consumed (g) = 0.2 g*total number of capsules reported as taken or missing in
MRS-TU-2019+0.1 g*total number of 100 mg capsules reported as taken or missing in
MRS-TU-2019EXT+0.15 g*total number of 150 mg capsules reported as taken or missing
in MRS-TU-2019EXT+0.2 g*total number of 200 mg capsules reported as taken or
missing in MRS-TU-2019EXT.
2)
Total dose consumed (g) = 0.2 g*total number of capsules reported as taken in
MRS-TU-2019+0.1 g*total number of 100 mg capsules reported as taken in
MRS-TU-2019EXT+0.15 g*total number of 150 mg capsules reported as taken in
MRS-TU-2019EXT+0.2 g*total number of 200 mg capsules reported as taken in
MRS-TU-2019EXT.
All data will be listed. Three subjects were randomized into the MRS-TU-2019 study twice in error and the 
handling of data for these subjects is described in Appendix 16.3.
10.2.
TREATMENT COMPLIANCE
Subject compliance with the dosing regimen will be assessed at Visit 5 (Day 28), Visit 7 (Day 56), Visit 8 
(Day 90), Visit 10 (Day 180), Visit 12 (Day 270), EOT, Visit 9E (Day 28E), Visit 11E (Day 56E), Visit 12E
(Day 90E), Visit 14E (Day 120E), Visit 16E (Day 180E), and Early Withdrawal Visit E.
Study drug compliance (%) will be calculated for each of these dosing compliance periods attended as 
100*the actual dose consumed divided by the expected dose, where:
x
For SOV2012-F1-treated subjects, actual dose consumed will be calculated 2 ways:
1)
Actual dose consumed = 0.1 g*number of 100 mg capsules reported as taken or
missing+0.15 g*number of 150 mg capsules reported as taken or missing+0.2 g*number


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of 200 mg capsules reported as taken or missing, i.e. assuming missing capsules were 
taken.
2)
Actual
dose 
consumed = 0.1 g*number 
of 
100 mg 
capsules 
reported 
as 
taken+0.15 g*number of 150 mg capsules reported as taken+0.2 g*number of 200 mg
capsules reported as taken, i.e. assuming missing capsules were not taken.
x
For AndroGel-treated subjects, actual dose consumed = 0.0162*(dispensed weight (g)-returned 
weight (g)).
x
Expected dose = scheduled number of days between compliance assessment visits*assigned dose 
level (g).
Overall study drug compliance (%) will be calculated separately for the MRS-TU-2019 study and the MRS-
TU-2019EXT study and overall for SOV2012-F1 as 100*the overall actual dose consumed in the study 
divided by the overall expected dose for the study, where:
x
Overall Actual Dose Consumed in the study = sum of actual dose consumed for each dosing 
compliance period attended in the study.
x
Overall Expected Dose for the study = sum of Expected Dose for each dosing compliance period 
attended in the study.
Study drug compliance to Day 90 (%) will be calculated as 100*the actual dose consumed to Day 90 divided 
by the expected dose to Day 90, where:
x
Actual Dose Consumed to Day 90 = sum of actual dose consumed for each dosing compliance 
period attended between Visits 3 and 8. 
x
Expected Dose to Day 90 = 28*assigned dose level (g) for Visit 3 to Visit 5 dosing compliance 
period+28*assigned dose level (g) for Visit 5 to Visit 7 dosing compliance period+34*assigned 
dose level (g) for Visit 7 to Visit 8 dosing compliance period.
MRS-TU-2019EXT Study drug compliance to Day 90E (%) will be calculated as 100*the actual dose 
consumed between Day 1E and Day 90E divided by the expected dose between Day 1E and Day 90E, 
where:
x
Actual Dose Consumed to Day 90E = sum of actual dose consumed for each dosing compliance 
period attended between Visits 7E and 12E. 


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x
Expected Dose to Day 90E = 28*assigned dose level (g) for Visit 7E to Visit 9E dosing compliance 
period+28*assigned 
dose 
level 
(g) 
for 
Visit 9E 
to 
Visit 11E
dosing 
compliance
period+34*assigned dose level (g) for Visit 11E to Visit 12E dosing compliance period.
Overall MRS-TU-2019 study drug compliance and study drug compliance to Day 90 will be summarized
for the SS, FAS, PKS, ECS, and AAS by treatment group using summary statistics for continuous data.
Overall MRS-TU-2019EXT study drug compliance and study drug compliance to Day 90E will be 
summarized for the EXTS, mEXTS, EXSE and mEXSE  and the EXPK using summary statistics for 
continuous data. Overall SOV2012-F1 compliance will be summarized for all subjects in the OSS and for 
all subjects who took SOV2012-F1 in both studies using summary statistics for continuous data. The 
number and percentage of subjects in each of the following categories of compliance for each of these 
periods and analysis sets will also be presented:
x
<80%.
x
80% to 120%.
x
>120%.
All calculated compliance data will be listed.
10.3.
AMBULATORY BLOOD PRESSURE MONITORING (ABPM)
ABPM analyses will be performed using the EXTS.
Missing data will be handled as described in Section 6.3.1.
10.3.1.
24-hour Average Ambulatory sBP
The 24-hour average ambulatory sBP and changes from baseline (Section 6.2.4) will be summarized by 
visit using summary statistics for continuous variables, including 95% CIs for the means.
To evaluate central tendency and outliers, a box plot of 24-hour average ambulatory sBP will be presented 
overlaying visit. A cumulative distribution curve of 24-hour average ambulatory sBP will be presented 
overlaying visit. 
In addition, a mixed model repeated measures analysis on the 24-hour average ambulatory sBP will be 
performed with subject as a random effect (all subjects with non-missing post-baseline results), and visit 
(7E, 14E and 16E), MRS-TU-2019 prior randomized treatment (SOV2012-F1, AndroGel, or None for 
MRS-TU-2019 naïve subjects), and baseline hypertensive treatment status as fixed effects. Additional 


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effects such as baseline diabetic status (Section 6.6) will be considered for inclusion. An unstructured 
covariance structure will be used to model the within-subject errors. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom. The least squares mean at each visit and the least 
squares mean for the difference between Day 120E and Day 1E with the associated 95% CIs will be 
provided. Goodness of fit will be evaluated. A sensitivity analysis will be performed only including subjects 
with non-missing results at all of Visits 7E, 14E and 16E (ABPM completers).
24-hour average change from baseline ambulatory sBP values will be categorized into 5 mmHg increments 
to ±20 mmHg and summarized by visit using summary statistics for categorical variables. A cumulative 
distribution curve of categorical change from baseline to Day 120E will be presented for 24-hour average 
ambulatory sBP. 
A shift table for categorical hypertension classification between baseline and maximum post-baseline 
values will be presented for visits 14E, 16E, and all data for 24-hour average ambulatory sBP. This summary 
will also be presented by baseline diabetic status. The hypertension classifications to be used are given in 
Table . 
Hourly and half-hourly ambulatory sBP time matched changes from baseline (Section 6.2.4) to Day 120E
will be calculated and listed with clock time and half-hourly elapsed time from ABPM recording start time.
Subjects may have started ABPM at different times at different visits and this calculation controls for 
diurnal variation by evaluating the 24 hours as a continuum with the justification of being at steady state.
Time matches will be made using windowing, where the closest quality accepted reading (including all 
automatic and manually initiated readings) at the baseline visit within 30 minutes will be selected as the 
baseline reading; if 2 readings are equidistant in time, the earlier will be selected. The time matched changes 
from baseline will then be grouped into half-hourly clock time intervals, based on the clock time of the 
post-baseline measurement, by averaging multiple observations for a subject within a single interval. Half-
hourly clock time intervals will initiate at exactly 7 a.m.
Half-hourly ambulatory sBP and time matched changes from baseline will be summarized using summary 
statistics for continuous variables in 2 ways, firstly by visit and half-hourly elapsed time from ABPM 
recording start time, and secondly by visit and half-hourly clock time intervals. Mean ± SD half-hourly 
ambulatory sBP and time matched changes from baseline will be graphically displayed by half-hourly 
elapsed time from ABPM recording start time overlaying visit and separately by half-hourly clock time 
intervals overlaying visit. For the summaries and plots by half-hourly elapsed time from ABPM recording 
start time, values based on manually initiated post-baseline readings will not be included. The window will 
be +/-0.25 nominal half hour increments and will be presented from zero to 23.5. 
These tables and figures will be repeated including only subjects with non-missing results at all of Visits 
7E, 14E and 16E (ABPM completers).


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10.3.2.
Daytime and Nighttime Average Ambulatory sBP
Daytime average ABPM values will be calculated from individual ABPM values between 7 a.m. and 
<11 p.m., nighttime average ABPM values will be calculated from individual ABPM values between 
11 p.m. and <7 a.m. Secondary analyses will be on daytime and nighttime average ambulatory sBP after 
approximately 120 (±3) days of treatment in the MRS-TU-2019EXT study. The average values and changes 
from baseline will be summarized by visit using summary statistics for continuous variables, including 95%
CIs for the means.
Box plots of daytime and nighttime average ambulatory sBP will be presented overlaying visit. Cumulative 
distribution curves of daytime and nighttime average ambulatory sBP will be presented overlaying visit. 
Mixed model repeated measures analyses on the daytime and nighttime average ambulatory sBP will be 
performed with subject as a random effect (all subjects with non-missing post-baseline results), and visit 
(7E, 14E and 16E), MRS-TU-2019 prior randomized treatment (SOV2012-F1, AndroGel, or None for 
MRS-TU-2019 naïve subjects), and baseline hypertensive treatment status  as fixed effects. Additional 
effects such as baseline diabetic status (Section 6.6) will be considered for inclusion. An unstructured 
covariance structure will be used to model the within-subject errors. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom. The least squares mean at each visit and the least 
squares mean for the difference between Day 120E and Day 1E with the associated 95% CIs will be 
provided for the daytime and nighttime average ambulatory sBP. Goodness of fit will be evaluated. A
sensitivity analysis will be performed only including subjects with non-missing valid results at all of Visits 
7E, 14E and 16E (ABPM completers). 
These summaries and analyses on the 24-hour, daytime and nighttime average ambulatory sBP will also be 
presented for the subgroups detailed in Section 6.6, as data permit (minimum of 5 subjects per subgroup).
Separate Forest plots of daytime average, nighttime average, and 24-hour average ambulatory sBP will be 
provided, each presenting the least squares mean differences between visits with 95% CIs, including results 
from both the analysis on all subjects with non-missing post-baseline results and the analysis on ABPM 
completers.
Daytime average change from baseline ambulatory sBP values will be categorized into 5 mmHg increments 
to ±20 mmHg and summarized by visit using summary statistics for categorical variables. A cumulative 
distribution curve of categorical change from baseline to Day 120E will be presented for 24-hour average 
ambulatory sBP.
A shift table for categorical hypertension classification between baseline and maximum post-baseline 
values will be presented for daytime average ambulatory sBP. This summary will also be presented by 
baseline diabetic status. The hypertension classifications to be used are given in Table .


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10.3.3.
Censoring
All tables and figures will be repeated censoring for antihypertensive therapy changes, where profiles that 
were collected on or after the date of addition of or an increase in dosage of antihypertensive medications 
will be excluded after first dose of study drug in MRS-TU-2019EXT (Section 6.2.1). Antihypertensive 
medication restarted after any interruption at the same antihypertensive dose will not be counted as an 
addition. Censoring will not be done for summaries focusing on the washout time between studies. 
10.3.4.
Other Ambulatory sBP Endpoints
Other endpoints for ambulatory sBP are:
x
Change from baseline in 24-hour average ambulatory sBP after approximately 180 (±3) days of
treatment
x
Change from baseline in daytime (Section 10.3.2) average ambulatory sBP after approximately 180
(±3) days of treatment.
x
Change from baseline in nighttime (Section 10.3.2) average ambulatory sBP after approximately
180 (±3) days of treatment.
x
Observed and change from baseline in half-hourly ambulatory sBP after approximately 180 (±3)
days of treatment.
Ambulatory sBP at Day 180E will be evaluated in a similar fashion to the primary ABPM endpoint of sBP 
at Day 120E. Additionally, in the mixed model repeated measures analyses, the least squares mean for the 
difference between Day 180E and Day 120E will be provided with the associated 95% CI.
10.3.5.
Effect of Dose on Average ABPM sBP
For Visit 14E (Day 120E) and Day 180E(Visit 16E), 24-hour  average systolic and daytime average 
systolic will be broken down by the subject’s dose.  Observed and change from baseline will be
summarized using summary statistics for continuous variables.  Box plots of the changes from baseline 
for each of the visits will overlay the dose groups.
Further exploratory ANCOVA using the EXTS may be performed to evaluate the impact of baseline 
covariates including weight, baseline diabetic status, baseline hypertensive treatment status, age and dose 
on changes in 24 hour ABPM.


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10.3.6.
Cavg and Average ABPM sBP
Using the EXPK Set, scatter plots of the observed and change from baseline ABPM Day 120E 24 hour 
average systolic blood pressure versus Day 90E 24 hour Cavg will be produced.  This will include an 
overlayed regression line with slope (95% CI) and adjusted R-square. This will also be done for the 
daytime average. 
10.3.7.
Estimation of Treatment Effects on ABPM sBP After a Year of Treatment 
In order to estimate 24-hour, daytime, and nighttime average ambulatory sBP changes after a year of 
treatment, the values at Day 365 (after a year of treatment) and Day 6E/7E (after at least 8 weeks washout 
and simulating baseline) for continuing SOV2012-F1 subjects will be summarized using summary statistics 
for continuous variables, including 95% CIs for the means. The difference in least squares means between 
the 2 visits (Day 365-Day 6E/7E) and associated 95% CI will be determined through a mixed model 
analysis to simulate change from baseline values. Baseline hypertensive treatment status, and baseline 
diabetic status (Section 6.6) will be considered for inclusion as fixed effects. An unstructured covariance 
structure will be used to model the within-subject errors. The Kenward Roger approximation will be used 
to estimate denominator degrees of freedom. Analysis will not be repeated for any washout censoring. 
10.3.8.
Ambulatory dBP
Ambulatory dBP will be evaluated in a similar fashion to the ambulatory sBP.
10.3.9.
Ambulatory Heart Rate (HR)
The 24-hour average ambulatory HR and changes from baseline will be summarized by visit using summary 
statistics for continuous variables, including 95% CIs for the means.
To evaluate central tendency and outliers, a box plot of 24-hour average ambulatory HR will be presented 
overlaying visit.
In addition, a mixed model repeated measures analysis on the 24-hour average ambulatory HR will be 
performed with subject as a random effect (all subjects with non-missing post-baseline results), and visit 
(7E, 14E and 16E), MRS-TU-2019 prior randomized treatment (SOV2012-F1, AndroGel, or None for MRS-
TU-2019 naïve subjects), and baseline hypertensive treatment status. Additional effects such as baseline 
diabetic status (Section 6.6) will be considered for inclusion. An unstructured covariance structure will be 
used to model the within-subject errors. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. The least squares mean at each visit and the least squares mean for the 
difference between Day 120E and Day 1E with the associated 95% CIs will be provided. Goodness of fit 
will be evaluated. 


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These summaries and analyses will also be presented for the subgroups detailed in Section 6.6, as data 
permit (minimum of 5 subjects per subgroup).
24-hour average change from baseline ambulatory HR values will be categorized into 5 bpm increments to 
±20 bpm and summarized by visit using summary statistics for categorical variables. 
Hourly and half-hourly ambulatory HR time matched changes from baseline (Section 6.2.4) to Day 120E
and Day 180E will be calculated and listed with clock time and half-hourly elapsed time from ABPM 
recording start time. Time matches will be made using windowing, where the closest quality accepted 
reading (including all automatic and manually initiated readings) at the baseline visit within 30 minutes 
will be selected as the baseline reading; if 2 readings are equidistant in time, the earlier will be selected. 
The time matched changes from baseline will then be grouped into half-hourly clock time intervals, based 
on the clock time of the post-baseline measurement, by averaging multiple observations for a subject within 
a single interval. Half-hourly clock time intervals will initiate at exactly 7 a.m.
Half-hourly ambulatory HR and time matched changes from baseline will be summarized using summary 
statistics for continuous variables in 2 ways, firstly by visit and half-hourly elapsed time from ABPM 
recording start time, and secondly by visit and half-hourly clock time intervals. Mean ± SD half-hourly 
ambulatory HR and time matched changes from baseline will be graphically displayed by half-hourly 
elapsed time from ABPM recording start time overlaying visit and separately by half-hourly clock time 
intervals overlaying visit. For the summaries and plots by half-hourly elapsed time from ABPM recording 
start time, values based on manually initiated post-baseline readings will not be included. The window will 
be +/-0.25 nominal half hour increments and will be presented from zero to 23.5. 
All tables and figures will be repeated censoring for antihypertensive therapy changes, where profiles that 
were collected on or after the date of addition of or an increase in dosage of antihypertensive medications 
will be excluded after first dose of study drug in MRS-TU-2019EXT (Section 6.2.1). Antihypertensive 
medication restarted after any interruption at the same antihypertensive dose will not be counted as an 
addition. 
10.3.10.
Ambulatory Mean Arterial Pressure (MAP)
Ambulatory MAP will be evaluated in a similar fashion to the ambulatory HR. In addition, a cumulative 
distribution curve of 24-hour average ambulatory MAP will be presented overlaying visit. A mixed model 
repeated measures sensitivity analysis will also be performed on ABPM completers.
A Forest plot of 24-hour average ambulatory MAP will be provided, presenting the least squares mean 
differences between visits with 95% CIs, including results from both the analysis on all subjects with non-
missing post-baseline results and the analysis on ABPM completers. 


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10.3.11.
Ambulatory Pulse Pressure (PP)
Ambulatory PP will be evaluated in a similar fashion to the ambulatory MAP. 
10.4.
T CMAX
10.4.1.
MRS-TU-2019
Analyses will be performed using the FAS.
Plasma T Cmax after 90 days of treatment will be evaluated by estimating the percentage of SOV2012-F1-
treated subjects at Visit 8, Day 90 with:
a) T Cmax≤1.5xULN.
b) T Cmax>1.8x ULN and ≤2.5 xULN.
c) T Cmax>2.5 xULN .
Where ULN is the upper limit of normal as determined from the MRS-TNR2019 study.
The T Cmax will be calculated per Section 9.4.1. Missing T Cmax values at Day 90 (Visit 8) in the FAS will 
not be imputed.
The FDA targets for these PK safety parameters are for a) to be ≥85% of subjects, b) to be <5% of subjects, 
and for c) to be no subjects.
Serum T Cmax values for those subjects randomly assigned to receive AndroGel will also be summarized
using the following ranges (units ng/dL)
a) T Cmax≤1500.
b) T Cmax>1800 and ≤2500.
c) T Cmax>2500 .
10.4.2.
MRS-TU-2019EXT
Analyses will be performed using the mEXTS.


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Plasma T Cmax after 90 days of treatment will be evaluated by estimating the percentages of SOV2012-F1–
treated subjects at Visit 12E, Day 90E with:
a) T Cmax≤1.5x ULN.
b) T Cmax>1.8x ULN and ≤2.5x ULN.
c) T Cmax>2.5 xULN .
Where ULN is the upper limit of normal as determined from the MRS-TNR2019 study
The T Cmax will be calculated per Section 9.4.1. Missing T Cmax values at Day 90E (Visit 12E) in the EXTS 
will not be imputed.
Similar analyses will be performed for the EXTS, ESXE, mEXSE and EXPK.
Serum Cmax values will use the following ranges:
a) T Cmax≤1500.
b) T Cmax>1800 and ≤2500.
c) T Cmax>2500  .
Subjects with Visit 12E Plasma T Cmax Over 1200 ng/dL will be listed separately.
10.5.
ADVERSE EVENTS (AES)
AEs will be coded using MedDRA Version 20.0 or later.
TEAE definitions:
x
An AE will be considered treatment-emergent if it begins or worsens in severity after the first dose 
of any study drug.
x
An AE will be considered MRS-TU-2019 treatment-emergent if it begins or worsens in severity 
after the first dose of randomized study drug, and before the first dose of any study drug in 
MRS-TU-2019EXT.
x
An AE will be considered MRS-TU-2019EXT treatment-emergent if it begins or worsens in
severity after the first dose of study drug in MRS-TU-2019EXT. 


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x
An AE will be considered SOV2012-F1 treatment-emergent if it begins or worsens in severity after 
the first dose of SOV2012-F1.
First dose dates of study drug are defined in Section 6.2.1. Partial AE start dates will be imputed as detailed 
in Section 6.3.5.
TEAEs will be summarized for both studies combined (SOV2012-F1 TEAEs only for all subjects in the 
OSS and for all subjects who took SOV2012-F1 in both studies), and separately for the MRS-TU-2019
study by MRS-TU-2019 treatment group and the MRS-TU-2019EXT study. TEAEs will be summarized 
by SOC and PT. Subjects will be counted once at the SOC level and once at each PT within the SOC level. 
Where applicable, summaries will include the number and percentage of subjects who report at least one
TEAE, the number and percentage of subjects reporting at least one TEAE in a SOC, the number and 
percentage of subjects reporting at least one TEAE in a PT, and the total number of events within a SOC 
and within a PT. Tables will be sorted by decreasing frequency (overall) of SOC, and then, within a SOC, 
descending frequency (overall) of PT.
Overall summary tables of TEAEs will be presented detailing the number and percentage of subjects, and 
number of events for the following categories:
x
At least one TEAE;
x
Serious TEAEs;
x
Treatment-related TEAEs;
x
Treatment-related serious TEAEs;
x
Severe TEAEs;
x
Treatment-related severe TEAEs;
x
TEAEs leading to discontinuation from study drug;
x
TEAEs resulting in death;
x
MACE;
x
TEAEs of Hypertension or BP Increased;
x
TEAEs of special interest (depression, anger, aggression and suicidality events).


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The incidence of TEAEs by SOC and PT will be presented for the following:
x
All TEAEs;
x
Serious TEAEs;
x
Treatment-related TEAEs;
x
TEAEs leading to discontinuation from study drug;
x
TEAEs of special interest (depression, anger, aggression and suicidality events).
Summaries of all TEAEs by maximum severity (mild, moderate, severe), SOC, and PT will be presented, 
where the maximum severity per subject will be counted at each level of summarization.
Relationships of ‘possible’ and ‘probable’ for AEs will be judged as being treatment-related for the 
summary tables. If the relationship to study drug is missing for TEAEs then the relationship will be counted 
as probably related to study drug for the summary tables. Similarly, missing severity for TEAEs will be 
counted as ‘Severe’.
MACE are defined as non-fatal myocardial infarction, non-fatal cerebrovascular accident, and death due to 
cardiovascular disease. MACE will be summarized for both studies combined (MACE on SOV2012-F1 
only for all subjects in the OSS and for all subjects who took SOV2012-F1 in both studies), and separately 
for the MRS-TU-2019 study by MRS-TU-2019 treatment group and the MRS-TU-2019EXT study. MACE 
summaries will be presented detailing the number and percentage of subjects, and number of events for the 
following categories:
x
At least one MACE.
x
Non-fatal myocardial infarction.
x
Non-fatal cerebrovascular accident.
x
Death due to cardiovascular disease.
Only TEAEs will be included in the AE summary tables, however all AEs will be included in the listings. 
In the listings, AE duration is calculated as date of adverse event stop – date of adverse event start + 1. 
MRS-TU-2019 TEAEs and MRS-TU-2019EXT TEAEs will be flagged in the listings. Additional listings 
will be provided for deaths, Serious TEAEs, TEAEs resulting in discontinuation from study drug, and
TEAEs of hypertension or BP increased.




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EOT, Visit 7E, Visit 12E, 
Visit 16E, Early 
Withdrawal Visit E
Conventional units will be used for all listings and summaries, unless otherwise stated.
Standard 
International units will also be included in the datasets.
All laboratory data will be listed, with abnormal results also listed separately. In addition, a listing will be 
presented for hemoglobin abnormal results and results of special concern, including and flagging 
hemoglobin results with increases from baseline (Section 6.2.4) of >0.5 g/dL. 
10.6.1.
MRS-TU-2019
Actual (observed) values and changes from baseline (Section 6.2.4) in continuous biochemistry, 
hematology, lipid panel, serum PSA, and endocrinology laboratory parameters will be summarized by
treatment group at each scheduled visit. The number and percentage of subjects with laboratory 
measurements (except serum PSA) outside of the normal reference range will also be summarized by
treatment group and visit. Shift tables from baseline to each scheduled visit will be used to evaluate changes 
in laboratory test values (except serum PSA) with respect to normal reference ranges (below, within, above
the normal reference range). 
Actual (observed) values and changes from baseline (Section 6.2.4) in HbA1c will be summarized by 
treatment group at each scheduled visit by baseline diabetic status (Section 6.6).
Subjects with serum PSA≥4.0 ng/mL or change from baseline in serum PSA>1.4 ng/mL will be listed and 
summarized using summary statistics for categorical variables, at any time and by visit.
Actual (observed) values in urinalysis and other laboratory parameters measured at screening only will be 
summarized by treatment group.
10.6.2.
MRS-TU-2019EXT
Actual (observed) values and changes from MRS-TU-2019EXT baseline (Section 6.2.4) in continuous 
biochemistry, hematology, lipid panel, serum PSA, and endocrinology laboratory parameters will be 
summarized by MRS-TU-2019EXT visit. The number and percentage of subjects with laboratory 
measurements (except serum PSA) outside of the normal reference range will also be summarized by visit. 
Shift tables from baseline to each scheduled visit will be used to evaluate changes in laboratory test values 
(except serum PSA) with respect to normal reference ranges (below, within, above the normal reference 
range). 


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Actual (observed) values and changes from MRS-TU-2019EXT baseline (Section 6.2.4) in HbA1c will be 
summarized by MRS-TU-2019EXT visit and baseline diabetic status (Section 6.6).
Subjects with serum PSA≥4.0 ng/mL or change from baseline in serum PSA>1.4 ng/mL will be listed and 
summarized using summary statistics for categorical variables, at any time and by visit. 
Actual (observed) values in urinalysis and other laboratory parameters measured at screening only will also
be summarized.
10.7.
LIVER TOXICITY
For MRS-TU-2019, the number and percentage of subjects in each treatment group with liver function tests 
(AST, ALT, and TB) greater than 1, 2, and 3 times the ULN at each study visit will be presented for the 
SS.
For MRS-TU-2019EXT, the number and percentage of subjects with liver function tests (AST, ALT, and 
TB) greater than 1, 2, and 3 times the ULN at each study visit will be presented for the EXTS.
Evaluation of drug-induced serious hepatotoxicity (eDISH) log-log plots of peak post-baseline TB (x ULN)
vs. peak post-baseline AST (x ULN), and vs. peak post-baseline ALT (x ULN) will be presented for MRS-
TU-2019 for the SS by treatment group, and eDISH log-log plots of peak post-baseline TB (x ULN) vs.
peak post-baseline AST (x ULN), and vs. peak post-baseline ALT (x ULN) will be presented for 
MRS-TU-2019EXT for the EXTS. Reference lines will be displayed to show the normal range, and will be 
displayed at 2 times the ULN for peak post-baseline TB and 3 times the ULN for peak post-baseline AST 
or ALT to divide the plot into labelled quadrants. The cholestasis quadrant is where TB>2 x ULN and AST 
or ALT<3 x ULN, Temple’s Corollary quadrant is where TB<2 x ULN and AST or ALT>3 x ULN, and 
Hy’s Law quadrant is where TB>2 x ULN and AST or ALT>3 x ULN.
Liver function tests (AST, ALT, and TB) will be listed and values greater than 2 and 3 times the ULN will 
be flagged. In addition, subjects whose peak data lie in the cholestasis quadrant, Temple’s Corollary 
quadrant, or Hy’s Law quadrant for AST and/or ALT will be flagged.
10.8.
VITAL SIGNS
10.8.1.
MRS-TU-2019
Time 0 (Section 6.2.6) vital sign measurements including sBP, dBP, HR, and weight, and changes from 
baseline (Section 6.2.4), will be summarized at each scheduled visit by treatment group using summary 
statistics for continuous variables, including 95% CIs for the means. For sBP and dBP, where multiple 






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These analyses may be repeated to include a confirmatory assessments at a separate visit following the 
elevation visit where the first assessment of an increase in hypertensive category was made in order to 
reflect clinical practice.  The two visits must be at least within the range of the hypertensive elevation 
category unless the confirmatory visit is not available, in which case the hypertensive category will reflect 
the elevation visit assessment.
Censoring
All tables and figures will be repeated censoring for antihypertensive therapy changes, where 
measurements that were collected on or after the date of addition of or an increase in dosage of 
antihypertensive medications will be excluded after first dose of study drug (Section 6.2.1).
Antihypertensive medication restarted after any interruption at the same antihypertensive dose will not be
counted as an addition. For sBP and dBP assessed at 4-hour intervals, the whole profile will be censored 
if any of the measurements were collected on or after the date of addition of or an increase in dosage of 
antihypertensive medications after first dose of study drug (Section 6.2.1).
All vital signs data recorded will be listed. BMI at each visit after Screening Visit 2 will be calculated as 
weight (kg)/(height at Screening Visit 2 [m])² and also listed.
Effect of Dose on Time 0 sBP
For Day 90 and Day 180 , Time 0 systolic blood pressure will be broken down by the subject’s dose.  
Observed and change from baseline will be summarized using summary statistics for continuous 
variables. 
10.8.2.
MRS-TU-2019EXT
Ambulatory BP, HR, MAP, and PP will be analyzed as detailed in Section 10.3.
Observed values collected in clinic (Time 0) vital sign measurements, including sBP, dBP, HR, and weight, 
and changes from baseline (Section 6.2.4), will be summarized by MRS-TU-2019EXT visit using summary 
statistics for continuous variables, including 95% CIs for the means. For sBP and dBP, where multiple 
readings are taken at one timepoint, the mean of those 3 readings will be calculated in the database, 
truncated to whole numbers, and used as the timepoint value in summaries and analyses. These summaries 
will also be presented for the subgroups detailed in Section 6.6, where applicable, as detailed in Section 16.
Mean ± SD sBP and dBP will be plotted at each scheduled visit, separately for observed and 
change from baseline values. To evaluate central tendency and outliers, box plots of sBP and 
dBP will be presented overlaying visit. Cumulative distribution curves of sBP and dBP will be 
presented overlaying visit.


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Hypertension
For sBP, dBP, and HR, shift tables for categorical hypertension classification between baseline 
and maximum post-baseline Time 0 (Section 6.2.6) values (using the mean value at timepoints 
where there are multiple readings) will be presented. In addition, the categorical hypertension 
classifications for each scheduled visit and the maximum post-baseline Time 0 values will be
summarized. These summaries will also be presented for the subgroups detailed in Section 6.6,
where applicable, as detailed in Section 16.
The hypertension classifications to be used are given in Table 13.
Kaplan-Meier plots for the time in days from baseline to the first occurrence of a Stage 1 hypertensive event
(date of first occurrence of Stage 1 hypertensive event-date of Visit 7E) will be presented. A Stage 1
hypertensive event will be defined if either Time 0 sBP or Time 0 dBP (using the mean values at timepoints 
where there are multiple readings) are classified as Stage 1 hypertension. This analysis will be limited to 
those subjects whose baseline hypertension status is normal or elevated. Subjects who do not experience 
Stage 1 hypertension during the study will be censored at the time of study early withdrawal. Kaplan-Meier 
plots for the time in days from baseline to the first occurrence of a Stage 2 hypertensive event (date of first 
occurrence of Stage 2 hypertensive event-date of Visit 7E) will also be presented. This analysis will be 
limited to those subjects whose baseline hypertension status is normal, elevated or Stage 1 hypertension.
These analyses may be repeated to include a confirmatory assessments at a separate visit following the 
elevation visit where the first assessment of an increase in hypertensive category was made in order to 
reflect clinical practice.  The two visits must be at least within the range of the hypertensive elevation 
category unless the confirmatory visit is not available, in which case the hypertensive category will reflect 
the elevation visit assessment.
ABPM versus In Clinic
Scatter Plots of Time 0 in-clinic sBP and dBP versus 24-Hour average ambulatory sBP and dBP 
and versus daytime average ambulatory sBP and dBP at Visits 6E/7E, 13E/14E, and 15E/16E 
will be presented to assess the utility of in-clinic BP monitoring. Scatter Plots of Time 0 in-clinic 
change from baseline in sBP and dBP versus 24-Hour average change from baseline in 
ambulatory sBP and dBP and versus daytime average change from baseline in ambulatory sBP 
and dBP at 13E/14E, and 15E/16E will also be presented. A simple regression line will be 
displayed on each plot with the estimate of the slope and the p-value for the estimate of the 
slope.


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ABPM versus Hemoglobin
Day 120E and Day 180E Scatter Plots of 24-Hour, Daytime and Nighttime average ambulatory sBP 
versus Day 90E hemoglobin will be presented. A simple regression line will be displayed on each plot 
with the estimate of the slope and the p value for the estimate of the slope. Similar analyses will be 
performed for the changes in sBP versus the changes in hemoglobin.
Washout
To determine the rate at which BP returns to steady state after discontinuation of TRT, sBP and dBP for 
continuing subjects will be summarized using summary statistics for continuous variables and presented as 
box plots by MRS-TU-2019 treatment group and overall for Visits 2E, 3E, 4E, 5E, and 6E.
Censoring
All tables and figures will be repeated censoring for antihypertensive therapy changes, where measurements 
that were collected on or after the date of addition of or an increase in dosage of antihypertensive 
medications will be excluded after first dose of study drug (Section 6.2.1). Antihypertensive medication 
restarted after any interruption at the same antihypertensive dose will not be counted as an addition. 
All vital signs data recorded will be listed. BMI at each visit after Screening Visit 2 will be 
calculated as weight (kg)/(height at Screening Visit 2 [m])² and also listed.
Effect of Dose on Time 0 sBP
For Day 120E and Day 180E , Time 0 systolic blood pressure will be broken down by the subject’s dose.  
Observed and change from baseline will be summarized using summary statistics for continuous 
variables.
10.9.
ADRENOCORTICOTROPIC HORMONE (ACTH) SUB-STUDY
The ACTH analysis will be performed using the AAS.
The maximum serum cortisol (from the 30 minute and 60 minute post-cosyntropin measurements) will be 
calculated and summarized at Day 1 and at Week 52 by treatment group.
The maximum serum cortisol will be analyzed separately for each treatment group using a mixed effects 
model with visit as a fixed effect, baseline (Day 1 pre-cosyntropin) serum cortisol as a continuous covariate,
and subject as a random effect. Differences in the least squares means of the comparisons between visits 
(Day 1 and Day 365) will be provided along with the 90% CIs.


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The model assumptions of normality and homogeneity of variance will be investigated. If either assumption 
is clearly not satisfied, the model will be repeated using a log transformation, and ratios of Day 365 to 
Day 1 will be provided along with the 90% CIs.
10.10.
OTHER SAFETY ASSESSMENTS
Physical examination data will be collected, as described in the Flowcharts in Section 3.8, and listed for all 
visits. Abnormal physical examination results will be listed separately. Abnormal physical examination 
results will be summarized using summary statistics for categorical variables by treatment group and visit 
for MRS-TU-2019 and by visit for MRS-TU-2019EXT.
12-Lead ECG data collected at Screening Visit 2, along with overall interpretation will be listed.


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11.
INTERIM ANALYSES
Interim analysis of the primary and secondary efficacy data, PK, and safety was planned for the 90-day 
efficacy period of the MRS-TU-2019 study to ensure all subjects were at the correct assigned dose. A high 
level of data cleaning was performed on the following data types: disposition, eligibility criteria, PDs,
demography, PK, extent of exposure, meal records. The efficacy analyses and all outputs included in the 
interim analysis delivery were detailed in Version 2.0 of this SAP. For PK/efficacy/titration algorithm data, 
only data to Day 90 for available analytes were included and these data were considered final. For all other 
data, all data up to the data cut were included.


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12.
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL
In the study protocol, MRS-TU-2019 is the original study described in the protocol body, and MRS-TU-
2019EXT is described in an appendix to the protocol. Following discussion with the FDA, efficacy and 
safety analysis for labeling will be performed using the MRS-TU-2019EXT study, and therefore the 
parameters for effectiveness of SOV2012-F1 in the MRS-TU-2019 study have been removed, serum T Cavg
and T Cmax values for those subjects randomly assigned to receive AndroGel will be summarized only, and, 
in general within each section of TLFs, MRS-TU-2019EXT outputs are presented first, followed by MRS-
TU-2019 outputs and then overall outputs.
Per FDA feedback, no multiple imputation methods will be used when there is not a post baseline 24 hour 
T Cavg  As a result, the imputation for the primary endpoint in MRS-TU-2019EXT is a Worst Case Scenario 
since there are no 24 hour profiles in the extension study prior to Day 90E.
The population for the primary analysis of efficacy has been changed to a modified Extension Treated Set 
(mEXTS) to exclude site 104.
The modified Extension Serum Set (mEXSE) was added to exclude site 104.
The Extension PK Population was further clarified to exclude site 104.
For the calculation of the 24-hour T Cavg, the AUC0-24 will now be divided by 24, instead of the actual 
number of hours between dosing and the 24-hour sample collection time, because the AUC0-24 is calculated 
for AUC from Time 0 to exact time 24 hours with interpolation or extrapolation. If AUC0-24 is not 
calculable, and the Tlast is close to 24 hours (between 23 and 25 hours inclusive), then Cavg0-last will now be 
used for Cavg.
The secondary T Cmax endpoint has been clarified to be a safety endpoint, rather than efficacy. Missing data 
will not be imputed and there will be no sensitivity analyses. The thresholds for SOV treated subjects will 
be set as (a) ≤1.5 x ULN; (b) 1.8 x ULN to 2.5 x ULN ; and (c) >2.5 x ULN  after 90 days of treatment, 
where the ULN is defined using the NaF/EDTA plasma and serum endogenous testosterone from study 
MRS-TNR-2019. Androgel thresholds will remain as (a) <=1500, (b) 1800 to 2500, and (c) >2500 ng/dL.
The AUC0-24 ratios of DHT to T, and E2 to T, will not be calculated as these will be the same as the Cavg
ratios of DHT to T, and E2 to T.
Sample size determination was updated to specify a non-inferiority test with a 3 mmHg upper boundary 
with respect to the 24-hour average in ambulatory sBP.
The MRS-TU-2019EXT secondary endpoints of maximum 24-hour sBP and dBP after approximately 120 
days (±3) and 180 days (±3) of treatment were removed.


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It has been clarified that ABPM analyses will be performed using 95% CIs.
Calculated ambulatory MAP and PP endpoints were added.
The SS was restricted to the MRS-TU-2019 study and the OSS was added for safety summaries across both 
studies with respect to SOV treated subjects. TEAEs will no longer be summarized separately for the 
washout period, instead, TEAE’s during washout will be attributed to MRS-TU-2019.
The Extension Efficacy Completers Set was removed as it was too similar to the EXPK and no longer 
required. The sensitivity analysis of the primary MRS-TU-2019EXT efficacy endpoint will be performed 
using the EXPK Set.
inVentiv Health Clinic was changed to Syneos Health to reflect the change in company name.
Prior and concomitant medications will be coded using the WHO Drug B2 Format 01MAR2017 version, 
instead of the September 2012 WHO Drug Dictionary.
I-PSS, PDQ, SF-36, and IIEF summaries will be presented for the FAS instead of the SS as the interest lies 
in the change from baseline data.
The definition of the AAS was expanded to include only subjects who received correctly assigned study 
drug (including synthetic ACTH1-24 [cosyntropin]) and who had serum cortisol results at both Visit 3 and 
Day 365.
The ACTH Analysis Set was renamed to the ACTH Completer Analysis Set
Study drug compliance cannot be calculated as the actual number divided by the expected number of doses, 
as the actual number of doses will not be collected. Instead, overall study drug compliance (%) will be 
calculated separately for the MRS-TU-2019 study and the MRS-TU-2019EXT study and overall for 
SOV2012-F1 as 100*the overall actual dose consumed in the study divided by the overall expected dose
for the study.
Mixed model repeated measures analyses on the 24-hour, daytime and nighttime average ambulatory vital 
signs will be performed instead of the more basic mixed model analyses suggested in the protocol.
The 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for defining 
hypertension replaced the previous definition. The analysis variable for the statistical analysis of the ACTH 
sub-study was changed, from the maximum increase from pre-cosyntropin administration, to the maximum 
serum cortisol. The change from baseline is not relevant, as a subject could have had a high baseline cortisol 
with little additional response to ACTH.


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The interim analysis was originally planned for the Day 90 efficacy data, but then adjusted to also include 
all PK and selected safety data.
EXPK and PKS updated to require that subjects should be also be dosed.


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13.
REFERENCE LIST
1.
SOV Therapeutics, Inc. Open-label, 4-part, Multiple-dose Study to Evaluate the Pharmacokinetic 
Profile, Safety, and Tolerability of Different Doses of Testosterone Undecanoate In Hypogonadal 
Subjects. Protocol SOV-TU-PK2013. On File. Morrisville, NC: SOV Therapeutics, Inc.; 25 
November 2015.
2.
End-of-Phase 2 Meeting. Pre-IND 118675; Testosterone Undecanoate (Oral) for the Treatment of 
Male Hypogonadism. SOV Therapeutics, Inc. 25 March 2015.
3.
Vestergaard P, Hoeck HC, Jakobsen PE, Laurberg P. Reproducibility of Growth Hormone and 
Cortisol Responses to the Insulin Tolerance Test and the Short ACTH Test in Normal Adults. 
Horm. Metab. Res. 1997;29:106-110.
4.
Oral testosterone undecanoate capsules (JATENZO™) for testosterone replacement therapy in 
hypogonadal men. Briefing document for Bone, Reproductive, and Urologic Drugs Advisory 
Committee. Advisory committee meeting date: 09 January 2018.
5.
Quality Issue Summary Version 2.0. Marius Pharmaceuticals: 03Aug2018.
6.
Vermeulen A, Verdonck L, Kaufman JM. A Critical Evaluation of Simple Methods for the 
Estimation of Free Testosterone in Serum. J. Clin. Endocrinol. & Metab. 1999;84(10):3666-3672.
7.
Södergard R, et al., Calculation of Free and Bound Fractions of Testosterone and Estradiol-17ß to 
Human Plasma Proteins at Body Temperature.  J. steroid  Biochem. 1982;16:801-810.
8.
Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma 
SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, 
Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. 
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the 
prevention, detection, evaluation, and management of high blood pressure in adults: a report of the 
American College of Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines. Hypertension. 2018;71:e13–e115. DOI: 10.1161/HYP.0000000000000065.


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14.
PROGRAMMING CONSIDERATIONS
All TLFs, and statistical analyses will be generated using SAS® for Windows, Release 9.4 (SAS® Institute 
Inc., Cary, NC, USA) or higher. Computer-generated TLF output will adhere to the following 
specifications.
PK parameters will be generated using WinNonLin Version 6.4 (Certara, USA).
14.1.
GENERAL CONSIDERATIONS
x
One SAS® program can create several outputs.
x
Each output will be stored in a separate file, named using the following convention:
o
T14-X-X-YY for tables.
o
F14-X-X-YY for figures.
o
L16-X-X-YY for listings.
Where X reflect the output numbering and YY is a mnemonic identifier for the type of output, e.g., DM 
for demography.
x
Individual output files will be delivered in Rich Text File (RTF) format. Outputs will be collated in pdf 
format, separately for tables, listings, and figures.
x
Numbering of TLFs will follow International Conference on Harmonization (ICH) E3 guidance
x
Default SAS® output for all statistical analyses will be provided in RTF format from the same programs 
as the respective tables. Each output file will be named similarly to the corresponding table. 
14.2.
Table, Listing, and Figure (TLF) Format
14.2.1.
General
x
All TLFs will be produced in landscape format on American letter size pages, unless otherwise 
specified.
x
All TLFs will be produced using the Courier New font, size 8
x
The data displays for all TLFs will have a minimum 1-inch blank margin on all 4 sides.
x
Headers and footers for figures will be in Courier New font, size 8.
x
Legends will be used for all figures with more than 1 variable, group, or item displayed.
x
TLFs will be in black and white (no color), unless otherwise specified


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x
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and subscripted 
text, will not be used in the TLFs, unless otherwise specified. On some occasions, superscripts 1, 2, or 
3 may be used (see below).
x
Only standard keyboard characters will be used in the TLFs. Special characters, such as non-printable 
control characters, printer-specific, or font-specific characters, will not be used. Hexadecimal-derived 
characters will be used, where possible, if they are appropriate to help display math symbols (e.g., μ). 
Certain subscripts and superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis.
x
Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, as 
appropriate.
14.2.2.
Headers
x
All output should have the following header at the top left of each page:
<Sponsor Name> Protocol XXX
x
All output should have Page n of N at the top or bottom right corner of each page. TLFs should be 
internally paginated in relation to the total length (i.e., the page number should appear sequentially as 
page n of N, where N is the total number of pages in the table).
x
The date output was generated should appear along with the program name as a footer on each page.
14.2.3.
Display Titles
Each TLF should be identified by the designation and a numeral, e.g., Table 14.1.1.1. ICH E3 numbering 
is strongly recommended but sponsor preferences should be obtained prior to final determination (see also 
template 03.007C “Table of Contents for Tables Listings and Figures in Statistical Analysis Plan”). A
decimal system (x.y and x.y.z) should be used to identify TLFs with related contents. The title is centered. 
The analysis set should be identified on the line immediately following the title. The title and table 
designation are single spaced. A solid line spanning the margins will separate the display titles from the 
column headers. There will be 1 blank line between the last title and the solid line.


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Table x.y.z
First Line of Title
Second Line of Title if Needed
(XXX Analysis Set)
14.2.4.
Column Headers
x
Column headings should be displayed immediately below the solid line described above in initial upper-
case characters. 
x
In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed by 
the treatment group columns and total column (if applicable). P-values may be presented under the total 
column or in separate p-value column (if applicable). Within-treatment comparisons may have p-values 
presented in a row beneath the summary statistics for that treatment.
x
For numeric variables, include “unit” in column or row heading when appropriate.
x
Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or in 
the row headings if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set.
x
The order of treatments in the tables and listings will be SOV2012-F1 first, followed by AndroGel, 
then a total column (if applicable).
14.2.5.
Body of the Data Display
General Conventions
Data in columns of a table or listing should be formatted as follows:
x
alphanumeric values are left-justified;
x
whole numbers (e.g., counts) are right-justified; and
x
numbers containing fractional portions are decimal aligned.
Table Conventions
Units will be included where available.
If the categories of a parameter are ordered, then all categories between the maximum and minimum 
category should be presented in the table, even if n=0 for all treatment groups in a given category that is
between the minimum and maximum level for that parameter. Where percentages are presented in these 
tables, zero percentages will not be presented and so any counts of 0 will be presented as 0 and not as 0 
(0%).


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If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the Study, etc.), 
then only those categories for which there is at least 1 subject represented in 1 or more groups should be 
included.
An Unknown or Missing category should be added to any parameter for which information is not available 
for 1 or more subjects.
Unless otherwise specified, the estimated mean and median for a set of values should be printed out to 1 
more significant digit than the original values, and SDs should be printed out to 2 more significant digits 
than the original values. The minimum and maximum should report the same significant digits as the 
original values. For example, for sBP:
N
XX
Mean
XXX.X
Std Dev
X.XX
Median
XXX.X
Minimum
XXX
Maximum
XXX
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. Any 
p-value less than 0.001 will be presented as <0.001. If the p-value should be less than 0.0001 then present 
as <0.0001. If the p-value is returned as >0.999 then present as >0.999
Percentage values should be printed to one decimal place, in parentheses with no spaces, one space after 
the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down to 0.0. A 
common convention is to display as ‘<0.1’, or as appropriate with additional decimal places. Unless 
otherwise noted, for all percentages, the number of subjects in the analysis set for the treatment group who 
have an observation will be the denominator. Percentages after zero counts should not be displayed and 
percentages equating to 100% should be presented as 100%, without any decimal places. 
Tabular display of data for medical history, prior / concomitant medications, and all tabular displays of AE
data should be presented by the body system, treatment class, or SOC with the highest occurrence in the 
active treatment group in decreasing order, assuming all terms are coded. Within the body system, drug 
class and SOC, medical history (by PT), drugs (by ATC1 code), and AEs (by PT) should be displayed in 
decreasing order. If incidence for more than 1 term is identical, they should then be sorted alphabetically.
Missing descriptive statistics or p-values which cannot be estimated should be reported as “-”.


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The percentage of subjects is normally calculated as a proportion of the number of subjects assessed in the 
relevant treatment group (or overall) for the analysis set presented. However, careful consideration is 
required in many instances due to the complicated nature of selecting the denominator, usually the 
appropriate number of subjects exposed. Describe details of this in footnotes or programming notes.
For categorical summaries (number and percentage of subjects) where a subject can be included in more 
than one category, describe in a footnote or programming note if the subject should be included in the 
summary statistics for all relevant categories or just 1 category and the criteria for selecting the criteria.
Where a category with a subheading (such as SOC) has to be split over more than one page, output the 
subheading followed by “(cont)” at the top of each subsequent page. The overall summary statistics for the 
subheading should only be output on the first relevant page.
Listing Conventions
x
Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time.
x
Missing data should be represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate.
x
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of 
dates should be represented on subject listings as dashes (--JUL2000). Dates that are missing because 
they are not applicable for the subject are output as “N/A”, unless otherwise specified.
x
All observed time values must be presented using a 24-hour clock HH:MM or HH:MM:SS format (e.g., 
11:26:45, or 11:26). Time will only be reported if it was measured as part of the study.
x
Units will be included where available
Figure Conventions
x
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis.
14.2.6.
Footnotes
x
A solid line spanning the margins will separate the body of the data display from the footnotes. 
x
All footnotes will be left justified with single-line spacing immediately below the solid line underneath 
the data display.


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x
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a reference
footnote. Each new footnote should start on a new line where possible.
x
Subject specific footnotes should be avoided, where possible.
x
Footnotes will be used sparingly and must add value to the table, figure, or data listing. If more than 
six lines of footnotes are planned, then a cover page may be used to display footnotes, and only those 
essential to comprehension of the data will be repeated on each page.
x
The last line of the footnote section will be a standard source line that indicates the name of the program 
used to produce the data display, date the program was run, and the listing source (i.e., ‘Program : 
myprogram.sas    Listing source: 16.x.y.z’).


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15.
QUALITY CONTROL
SAS® programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures or statistical analyses. An overview of the development of programs is detailed in Syneos Health 
Standard Operating Procedure (SOP) Developing Statistical Programs (3907).
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS® programs and 
output. Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS® programs produce the output by checking for their logic, efficiency and commenting and by 
review of the produced output.




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14.1.3.1.1.1
MRS-TU-2019EXT Subject Demographic and Baseline Characteristics by 
Baseline Diabetic Status
EXTS
14.1.3.1.1.2
MRS-TU-2019EXT Subject Demographic and Baseline Characteristics by 
Baseline Hypertensive Treatment Status
EXTS
14.1.3.1.1.3
MRS-TU-2019EXT Subject Demographic and Baseline Characteristics by 
Baseline Diabetic Status and Baseline Hypertensive Treatment Status
EXTS
14.1.3.1.2
MRS-TU-2019EXT Subject Demographic and Baseline Characteristics
mEXTS
14.1.3.1.3
MRS-TU-2019EXT Subject Demographic and Baseline Characteristics
EXPK
14.1.3.1.4
MRS-TU-2019EXT Subject Demographic and Baseline Characteristics
EXSE
14.1.3.1.5
MRS-TU-2019EXT Subject Demographic and Baseline Characteristics
mEXSE
14.1.3.1.6
MRS-TU-2019 Subject Demographic and Baseline Characteristics
SS
14.1.3.1.6.1
MRS-TU-2019 Subject Demographic and Baseline Characteristics by Baseline 
Diabetic Status
SS
14.1.3.1.6.2
MRS-TU-2019 Subject Demographic and Baseline Characteristics by Baseline 
Hypertensive Treatment Status
SS
14.1.3.1.6.3
MRS-TU-2019 Subject Demographic and Baseline Characteristics by Baseline 
Diabetic Status and Baseline Hypertensive Treatment Status
SS
14.1.3.1.7
MRS-TU-2019 Subject Demographic and Baseline Characteristics
FAS
14.1.3.1.8
MRS-TU-2019 Subject Demographic and Baseline Characteristics
PKS
14.1.3.1.9
MRS-TU-2019 Subject Demographic and Baseline Characteristics
ECS
14.1.3.1.10
MRS-TU-2019 Subject Demographic and Baseline Characteristics
AAS
14.1.3.1.11
MRS-TU-2019 and MRS-TU-2019EXT Subject Demographic and Baseline 
Characteristics
OSS
14.1.3.2.1
Symptoms and Signs Suggestive of Androgen Deficiency – Presenting or Past
EXTS
14.1.3.2.2
Symptoms and Signs Suggestive of Androgen Deficiency – Presenting or Past
SS
14.1.3.2.3
Symptoms and Signs Suggestive of Androgen Deficiency – Presenting or Past
OSS
14.1.3.3.1.1
Medical History – Hypogonadism
EXTS
14.1.3.3.1.2
Medical History – Hypogonadism
mEXTS
14.1.3.3.1.3
Medical History – Hypogonadism
EXPK
14.1.3.3.1.4
Medical History – Hypogonadism
EXSE


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14.1.3.3.1.5
Medical History – Hypogonadism
mEXSE
14.1.3.3.1.6
Medical History – Hypogonadism
SS
14.1.3.3.1.7
Medical History – Hypogonadism
FAS
14.1.3.3.1.8
Medical History – Hypogonadism
PKS
14.1.3.3.1.9
Medical History – Hypogonadism
ECS
14.1.3.3.1.10
Medical History – Hypogonadism
AAS
14.1.3.3.1.11
Medical History – Hypogonadism
OSS
14.1.3.3.2.1
Medical/Surgical History
EXTS
14.1.3.3.2.2
Medical/Surgical History
EXPK
14.1.3.3.2.3
Medical/Surgical History
EXSE
14.1.3.3.2.4
Medical/Surgical History
SS
14.1.3.3.2.5
Medical/Surgical History
AAS
14.1.3.3.2.6
Medical/Surgical History
OSS
14.1.4.1.1
MRS-TU-2019EXT Prior Medications
EXTS
14.1.4.1.2
MRS-TU-2019EXT Prior Medications
mEXTS
14.1.4.1.3
MRS-TU-2019EXT Prior Medications
EXPK
14.1.4.1.4
MRS-TU-2019EXT Prior Medications
EXSE
14.1.4.1.5
MRS-TU-2019EXT Prior Medications
mEXSE
14.1.4.1.6
MRS-TU-2019 Prior Medications
SS
14.1.4.1.7
MRS-TU-2019 Prior Medications
FAS
14.1.4.1.8
MRS-TU-2019 Prior Medications
PKS
14.1.4.1.9
MRS-TU-2019 Prior Medications
ECS
14.1.4.1.10
MRS-TU-2019 Prior Medications
AAS
14.1.4.1.11
Overall Prior Medications
OSS
14.1.4.2.1
MRS-TU-2019EXT Concomitant Medications
EXTS
14.1.4.2.2
MRS-TU-2019EXT Concomitant Medications
mEXTS
14.1.4.2.3
MRS-TU-2019EXT Concomitant Medications
EXPK
14.1.4.2.4
MRS-TU-2019EXT Concomitant Medications
EXSE
14.1.4.2.5
MRS-TU-2019EXT Concomitant Medications
mEXSE
14.1.4.2.6
MRS-TU-2019EXT Concomitant Medications Taken up to the Day 90E Efficacy 
Visit
EXTS
14.1.4.2.7
MRS-TU-2019EXT Concomitant Medications Taken up to the Day 90E Efficacy 
Visit
mEXTS
14.1.4.2.8
MRS-TU-2019EXT Concomitant Medications Taken up to the Day 90E Efficacy 
Visit
EXPK


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14.1.4.2.9
MRS-TU-2019EXT Concomitant Medications Taken up to the Day 90E Efficacy 
Visit
EXSE
14.1.4.2.10
MRS-TU-2019EXT Concomitant Medications Taken up to the Day 90E Efficacy 
Visit
mEXSE
14.1.4.2.11
MRS-TU-2019 Concomitant Medications
SS
14.1.4.2.12
MRS-TU-2019 Concomitant Medications
AAS
14.1.4.2.13
SOV2012-F1 Concomitant Medications
OSS
14.1.4.3.1
MRS-TU-2019EXT and MRS-TU-2019EXT Antihypertensive Medications
EXTS and SS
14.1.4.3.3
MRS-TU-2019EXT Treatment Emergent Antihypertensive Medications or 
Increases in Dose of Antihypertensive Medications
EXTS
14.1.4.3.4
MRS-TU-2019 Treatment Emergent Antihypertensive Medications or Increases 
in Dose of Antihypertensive Medications
SS
14.2.1.1.1
Primary MRS-TU-2019EXT Efficacy Parameter Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E) (Worst Case Scenario)  
mEXTS
14.2.1.1.2
Primary MRS-TU-2019EXT Efficacy Parameter Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E): Primary Efficacy Analysis 
(Worst Case Scenario)
EXTS
14.2.1.1.3.1
Primary MRS-TU-2019EXT Efficacy Parameter Serum T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E) (Worst-Case Scenario)
EXSE
14.2.1.1.3.2
Primary MRS-TU-2019EXT Efficacy Parameter Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E) (Worst-Case Scenario)
EXSE
14.2.1.1.4.1
Primary MRS-TU-2019EXT Efficacy  Parameter Serum T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E) (Worst-Case Scenario)
mEXSE
14.2.1.1.4.2
Primary MRS-TU-2019EXT Efficacy Parameter Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E) (Worst-Case Scenario)
mEXSE
14.2.1.1.5
Primary MRS-TU-2019EXT Efficacy Parameter  Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E)  (No Imputation)
EXPK


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14.2.1.1.6.1
Primary MRS-TU-2019EXT Efficacy Parameter  Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E): Subgroup Analysis 
Baseline by Weight Category(Worst Case Scenario) 
EXTS
14.2.1.1.6.2
Primary MRS-TU-2019EXT Efficacy Parameter  Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E): Subgroup Analysis by 
Age Category(Worst Case Scenario) 
EXTS
14.2.1.1.6.3
Primary MRS-TU-2019EXT Efficacy Parameter  Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E): Subgroup Analysis by 
BMI Category(Worst Case Scenario) 
EXTS
14.2.1.1.6.4
Primary MRS-TU-2019EXT Efficacy Parameter  Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E): Subgroup Analysis by 
Race Group(Worst Case Scenario) 
EXTS
14.2.1.1.7.1
Primary MRS-TU-2019EXT Efficacy Parameter  Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E): Subgroup Analysis by 
Weight Category(Worst Case Scenario)
mEXTS
14.2.1.1.7.2
Primary MRS-TU-2019EXT Efficacy Parameter  Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E): Subgroup Analysis by 
Age Category(Worst Case Scenario)
mEXTS
14.2.1.1.7.3
Primary MRS-TU-2019EXT Efficacy Parameter  Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E): Subgroup Analysis by 
BMI Category(Worst Case Scenario)
mEXTS
14.2.1.1.7.4
Primary MRS-TU-2019EXT Efficacy Parameter  Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E): Subgroup Analysis by 
Race Group (Worst Case Scenario)
mEXTS
14.2.1.1.7.5
Primary MRS-TU-2019EXT Efficacy Parameter Plasma T Cavg Within the 
Normal Range After 90 Days of Treatment (Day 90E): Subgroup Analysis by 
Actual Day 90E Breakfast Diet Category (Worst Case Scenario)
mEXTS
14.2.1.2
MRS-TU-2019EXT Pharmacokinetic Parameters
EXPK
14.2.1.2.1
MRS-TU-2019EXT Pharmacokinetic Parameters by Dose (Day 90)
EXPK
14.2.1.3.1
MRS-TU-2019 Summary of Observed and Change from Baseline in International 
Prostate Symptom Scores
FAS
14.2.1.3.2
MRS-TU-2019 Summary of Observed and Change from Baseline in 
Psychosexual Daily Questionnaire Scores
FAS
14.2.1.3.3
MRS-TU-2019 Summary of Observed and Change from Baseline in 36-Item 
Short Form Survey Instrument Scores
FAS


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14.2.1.3.4
MRS-TU-2019 Summary of Observed and Change from Baseline in International 
Index of Erectile Function Questionnaire Scores
FAS
14.2.1.4
MRS-TU-2019 Fasting Insulin and Fasting Serum Glucose: Summary by Visit 
and Change from Baseline
SS
14.2.2.1.1.1.1
MRS-TU-2019EXT Pharmacokinetic Concentrations (ng/dL) by Visit and 
Timepoint – SOV2012-F1 Group
EXPK
14.2.2.1.1.1.2
MRS-TU-2019EXT Pharmacokinetic Concentrations (ng/dL) by Visit,  
Timepoint and Diet – SOV2012-F1 Group
EXPK
14.2.2.1.1.1.3
MRS-TU-2019EXT Pharmacokinetic Concentrations (ng/dL) by Visit, Timepoint 
and Dose– SOV2012-F1 Group
EXPK
14.2.2.1.1.2.1
MRS-TU-2019EXT Pharmacokinetic Plasma T, DHT, and E2 Concentrations 
(ng/dL) by Visit,Timepoint and Dose – SOV2012-F1
EXPK
14.2.2.1.2.2
MRS-TU-2019EXT Pharmacokinetic Parameters – Plasma T Cavg and T Cmax 
on Visit 12E (Day 90E) by Actual Day90E Breakfast Diet Category
EXPK
14.2.2.1.2.2.1
MRS-TU-2019EXT Pharmacokinetic Parameters – Plasma T Cavg0-24 and
T Cmax0-24 on Visit 12E (Day 90E) Comparing  Actual Day90E Breakfast Diet 
Categories
EXPK
14.2.2.1.2.2.2
MRS-TU-2019EXT Pharmacokinetic Parameters – Plasma T Cavg0-12 and
T Cmax0-12 on Visit 12E (Day 90E) Comparing  Actual Day90E Breakfast Diet 
Categories
EXPK
14.2.2.1.2.2.3
MRS-TU-2019EXT Pharmacokinetic Parameters  - Listing of Plasma and Serum 
T Cavg0-24 and T Cmax0-24 on Visit 12E (Day 90E) for Low Fat Breakfast Diet 
Category Subjects  
EXPK
14.2.2.1.2.3
MRS-TU-2019EXT Pharmacokinetic Parameters – Plasma T Cavg12-24 and 
T Cmax on Visit 12E (Day 90E) by Actual Day 90E Dinner Diet Category
EXPK
14.2.2.1.2.3.1
MRS-TU-2019EXT Pharmacokinetic Parameters – Plasma T Cavg12-24 and
T Cmax12-24 on Visit 12E (Day 90E) Comparing Actual Day 90E Dinner Diet 
Categories
EXPK
14.2.2.1.2.4
MRS-TU-2019EXT Pharmacokinetic Parameters – Plasma T Cavg and T Cmax 
on Visit 12E (Day 90E) by Age Category
EXPK
14.2.2.1.2.6
MRS-TU-2019EXT Pharmacokinetic Parameters – Plasma T Cavg and T Cmax 
on Visit 12E (Day 90E) by Weight Category
EXPK
14.2.2.1.2.8
MRS-TU-2019EXT Pharmacokinetic Parameters – Plasma T Cavg and T Cmax 
on Visit 12E (Day 90E) by BMI Category
EXPK
14.2.2.1.2.10
MRS-TU-2019EXT Pharmacokinetic Parameters – Plasma T Cavg and T Cmax 
on Visit 12E (Day 90E) by Race
EXPK


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14.2.2.1.2.12
MRS-TU-2019EXT Pharmacokinetic Parameters – Plasma T Cavg and T Cmax 
on Visit 12E (Day 90E) by Ethnicity
EXPK
14.2.2.1.2.14
MRS-TU-2019EXT Pharmacokinetic Parameters – Plasma DHT Cavg and 
DHT Cmax on Visit 12E (Day 90E)
EXPK
14.2.2.1.3.1
MRS-TU-2019EXT Analysis of Plasma T Cavg Within the Normal Range After 
90 Days of Treatment (Day 90E) by Visit 10E (Day 42E) Titration Timepoint
EXPK
14.2.2.1.3.2
MRS-TU-2019EXT Analysis of Projected Dose Adjustments Using Plasma T 
Concentrations by Visit and Timepoint 
EXPK 
14.2.2.1.3.2.1
MRS-TU-2019EXT Overall Plasma T Projected Dose Adjustment Analysis by 
8E(Day 14E)  and 10E(Day 42E) and Timepoint
EXPK
14.2.2.1.3.3
MRS-TU-2019EXT Analysis of Projected Dose Adjustments Using Serum T 
Concentrations by Visit and Timepoint 
EXSE
14.2.2.1.3.3.1
MRS-TU-2019EXT Overall Serum T Projected Dose Adjustment Analysis by 
8E(Day 14E)  and 10E(Day 42E) and Timepoint
EXPK
14.2.2.1.3.4
MRS-TU-2019EXT Spearman’s Correlation Matrix of Projected Dose 
Adjustments Using Plasma T Concentrations by Visit and Timepoint
EXPK
14.2.2.1.3.5
MRS-TU-2019EXT Spearman’s Correlation Matrix of Projected Dose 
Adjustments Using Serum T Concentrations by Visit and Timepoint
EXPK-Serum
14.2.2.1.3.6
MRS-TU-2019EXT Logistic Analysis of Final Dose as an Outcome Variable  
EXTS
14.2.2.1.3.7
MRS-TU-2019EXT Listing of Titration Outcomes with Respect to Serum and 
Plasma Concentrations
EXTS
14.2.2.1.3.7.1
MRS-TU-2019EXT Summary of Titration Outcomes with Respect to Serum and 
Plasma Concentrations
EXTS
14.2.2.1.4.1
MRS-TU-2019EXT Pharmacokinetic Parameters – Serum and Plasma T Cavg 
and T Cmax on Visit 12E (Day 90E)
EXPK-Serum
14.2.2.1.4.2
MRS-TU-2019EXT Pharmacokinetic Parameters – Serum and Plasma T Cavg 
and T Cmax on Visit 12E (Day 90E)
mEXSE
14.2.2.1.4.3
MRS-TU-2019EXT Analysis of Serum and Plasma T Cavg Within the Normal 
Range After 90 Days of Treatment (Day 90E) by Visit 10E (Day 42E) Titration
Timepoint
EXSE
14.2.2.1.4.4
MRS-TU-2019EXT Analysis of Serum and Plasma T Cavg Within the Normal 
Range After 90 Days of Treatment (Day 90E) by Visit 10E (Day 42E) Titration 
Timepoint
mEXSE
14.2.2.2.1.1
Primary MRS-TU-2019 Parameter T Cavg Within the Normal Range After 90 
Days of Treatment (Day 90): Multiple Imputation Analysis
FAS


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14.2.2.2.1.2
Primary MRS-TU-2019 Parameter T Cavg Within the Normal Range After 90 
Days of Treatment (Day 90):  (No Imputation)
ECS - SOV2012-F1-Treated 
Subjects
14.2.2.2.1.3
Primary MRS-TU-2019 Parameter T Cavg Within the Normal Range After 90 
Days of Treatment (Day 90):  (Worst-Case Scenario )
FAS - SOV2012-F1-Treated 
Subjects
14.2.2.2.2.1.1
MRS-TU-2019 Pharmacokinetic Plasma Concentrations (ng/dL) by Visit and 
Timepoint – SOV2012-F1 Group
PKS
14.2.2.2.2.2.1
MRS-TU-2019 Pharmacokinetic Plasma T, DHT, and E2 Concentrations (ng/dL) 
by Visit and Timepoint by Dose – SOV2012-F1 Group
PKS
14.2.2.2.2.2.2
MRS-TU-2019 Pharmacokinetic Plasma T Concentrations (ng/dL) by Visit and 
Timepoint by Breakfast Diet Categogry – SOV2012-F1 Group
PKS
14.2.2.2.2.2.3
MRS-TU-2019 Pharmacokinetic Plasma T Concentrations (ng/dL) by Visit and 
Timepoint by Dinner Diet Categogry – SOV2012-F1 Group
PKS
14.2.2.2.3.1
MRS-TU-2019 Pharmacokinetic Parameters – SOV2012-F1 Group
PKS
14.2.2.2.3.1.1
MRS-TU-2019 Pharmacokinetic Parameters by Dose– SOV2012-F1 Group (Day 
90)
PKS
14.2.2.2.3.2
MRS-TU-2019  Pharmacokinetic Parameters – Plasma T Cavg and T Cmax on 
Visit 8 (Day 90) by Day 90 Breakfast Diet Category
PKS
14.2.2.2.3.2.1
MRS-TU-2019  Pharmacokinetic Parameters – Plasma T Cavg0-24 and T Cmax0-24
on Visit 8 (Day 90) Comparing Day 90 Breakfast Diet Categories
PKS
14.2.2.2.3.2.2
MRS-TU-2019  Pharmacokinetic Parameters – Plasma T Cavg0-12 and T Cmax0-12
on Visit 8 (Day 90) Comparing Day 90 Breakfast Diet Categories
PKS
14.2.2.2.3.2.3
MRS-TU-2019 Pharmacokinetic Parameters  - Listing of Plasma T Cavg0-24 and 
T Cmax0-24 on Visit 8 (Day 90) for Low Fat Breakfast Diet Category Subjects  
PKS
14.2.2.2.3.3
MRS-TU-2019EXT  Pharmacokinetic Parameters – Plasma T Cavg12-24 and 
T Cmax on Visit 8 (Day 90 ) by Day 90 Dinner Diet Category
PKS
14.2.2.2.3.3.1
MRS-TU-2019EXT  Pharmacokinetic Parameters – Plasma T Cavg12-24 and
T Cmax12-24 on Visit 8 (Day 90 ) Comparing Day 90 Dinner Diet Category
PKS
14.2.2.3.1.1
MRS-TU-2019 Pharmacokinetic Concentrations (ng/dL) at Visit 8 (Day 90) by
Timepoint – AndroGel Group
PKS
14.2.2.3.2.1
MRS-TU-2019 Pharmacokinetic Serum T, Serum DHT, and Plasma E2 
Concentrations (ng/dL) at Visit 8 (Day 90) by Timepoint by Dose – Androgel 
Group
PKS


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 Marius Pharmaceuticals  
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14.2.2.3.3
MRS-TU-2019 Pharmacokinetic Parameters – AndroGel Group
PKS
14.3.1.1.1
MRS-TU-2019EXT Treatment-Emergent Adverse Events –Overall Summary
EXTS
14.3.1.1.2
MRS-TU-2019EXT Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
EXTS
14.3.1.1.3
MRS-TU-2019EXT Treatment-Emergent Adverse Events by Frequency of 
Preferred Term 
EXTS
14.3.1.1.4
MRS-TU-2019EXT Serious Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
EXTS
14.3.1.1.5
MRS-TU-2019EXT Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, and Maximum Severity 
EXTS
14.3.1.1.6
MRS-TU-2019EXT Treatment-Related Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
EXTS
14.3.1.1.7
MRS-TU-2019EXT Treatment-Emergent Adverse Events Leading to Permanent 
Discontinuation of Study Drug by System Organ Class and Preferred Term 
EXTS
14.3.1.1.8
Summary of MRS-TU-2019EXT Major Adverse Cardiac Events
EXTS
14.3.1.1.9
MRS-TU-2019EXT Treatment-Emergent Adverse Events of Special Interest by 
System Organ Class and Preferred Term 
EXTS
14.3.1.2.1
MRS-TU-2019 Treatment-Emergent Adverse Events – Overall Summary
SS
14.3.1.2.2
MRS-TU-2019 Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
SS
14.3.1.2.3
MRS-TU-2019 Treatment-Emergent Adverse Events by Frequency of Preferred 
Term 
SS
14.3.1.2.4
MRS-TU-2019 Serious Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term
SS
14.3.1.2.5
MRS-TU-2019 Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Maximum Severity
SS
14.3.1.2.6
MRS-TU-2019 Treatment-Related Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term
SS
14.3.1.2.7
MRS-TU-2019 Treatment-Emergent Adverse Events Leading to Permanent 
Discontinuation of Study Drug by System Organ Class and Preferred Term
SS
14.3.1.2.8
MRS-TU-2019 Treatment-Emergent Adverse Events of Special Interest by 
System Organ Class and Preferred Term
SS


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 Marius Pharmaceuticals  
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14.3.1.2.9
Summary of MRS-TU-2019 Major Adverse Cardiac Events
SS
14.3.1.3.1
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events – Overall Summary
OSS
14.3.1.3.1.1
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events – Overall Summary by Baseline Age Category
OSS
14.3.1.3.1.2
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events – Overall Summary by Baseline Weight Category
OSS
14.3.1.3.1.3
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events – Overall Summary by Race
OSS
14.3.1.3.1.4
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events – Overall Summary by Baseline Diabetic Status
OSS
14.3.1.3.1.5
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events – Overall Summary by Baseline Hypertensive Treatment Status
OSS
14.3.1.3.2
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events by System Organ Class and Preferred Term
OSS
14.3.1.3.2.1
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events by System Organ Class and Preferred Term and Baseline Age 
Category
OSS
14.3.1.3.2.2
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events by System Organ Class and Preferred Term and Baseline Weight 
Category
OSS
14.3.1.3.2.3
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events by System Organ Class and Preferred Term and Race
OSS
14.3.1.3.2.4
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term and Baseline 
Diabetic Status
OSS
14.3.1.3.2.5
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events by System Organ Class and Preferred Term and Baseline 
Hypertensive Treatment Status
OSS


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 Marius Pharmaceuticals  
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Final Version 5.0
  
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14.3.1.3.3
MRS-TU-2019 and MRS-TU-2019EXT Treatment-Emergent Adverse Events by 
Frequency of Preferred Term 
OSS
14.3.1.3.3.1
MRS-TU-2019 and MRS-TU-2019EXT Treatment-Emergent Adverse Events by 
Frequency of Preferred Term and Baseline Age Category
OSS
14.3.1.3.3.2
MRS-TU-2019 and MRS-TU-2019EXT Treatment-Emergent Adverse Events by 
Frequency of Preferred Term and Baseline Weight Category
OSS
14.3.1.3.3.3
MRS-TU-2019 and MRS-TU-2019EXT Treatment-Emergent Adverse Events by 
Frequency of Preferred Term and Race
OSS
14.3.1.3.3.4
MRS-TU-2019 and MRS-TU-2019EXT Treatment-Emergent Adverse Events by 
Frequency of Preferred Term and Baseline Diabetic Status
OSS
14.3.1.3.3.5
MRS-TU-2019 and MRS-TU-2019EXT Treatment-Emergent Adverse Events by 
Frequency of Preferred Term and Baseline Hypertensive Treatment Status
OSS
14.3.1.3.4
MRS-TU-2019 and MRS-TU-2019EXT Serious SOV2012-F1 Treatment-
Emergent Adverse Events by System Organ Class and Preferred Term
OSS
14.3.1.3.5
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events by System Organ Class, Preferred Term, and Maximum Severity
OSS
14.3.1.3.5.1
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events by System Organ Class, Preferred Term, Maximum Severity and 
Baseline Age Cateogry
OSS
14.3.1.3.5.2
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events by System Organ Class, Preferred Term, Maximum Severity and 
Baseline Weight Category
OSS
14.3.1.3.5.3
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events by System Organ Class, Preferred Term, Maximum Severity and 
Race
OSS
14.3.1.3.5.4
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events by System Organ Class, Preferred Term, Maximum Severity and 
Baseline Diabaetic Status
OSS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
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14.3.1.3.5.5
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events by System Organ Class, Preferred Term, Maximum Severity and 
Baseline Hypertensive Treatment Status
OSS
14.3.1.3.6
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Related 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
OSS
14.3.1.3.6.1
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Related 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term 
and Baseline Age Category
OSS
14.3.1.3.6.2
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Related 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term 
and Baseline Weight Category
OSS
14.3.1.3.6.3
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Related 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term 
and Race
OSS
14.3.1.3.6.4
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Related 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term 
and Baseline Diabetic Status
OSS
14.3.1.3.6.5
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Related 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term 
and Baseline Hypertensive Treatment Status
OSS
14.3.1.3.7
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Events Leading to Permanent Discontinuation of Study Drug by System 
Organ Class and Preferred Term
OSS
14.3.1.3.8
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Treatment-Emergent 
Adverse Eventsof Special Interest by System Organ Class and Preferred Term
OSS
14.3.1.3.9
Summary of MRS-TU-2019 and MRS-TU-2019EXT Major Adverse Cardiac 
Events on SOV2012-F1
OSS
14.3.2.1
Deaths, Listing
SS and EXTS
14.3.2.2
Serious Treatment-Emergent Adverse Events, Listing
SS and EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
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14.3.2.3
Treatment-Emergent Adverse Events Leading to Permanent Discontinuation of 
Study Drug, Listing
SS and EXTS
14.3.2.4
Treatment-Emergent Adverse Events of Hypertension or Blood Pressure 
Increased, Listing
SS and EXTS
14.3.3
Narratives of Deaths, Other Serious, and Certain Other Significant Adverse 
Events
N/A
14.3.4.1.1.1.1.1
MRS-TU-2019EXT Hematology: Summary by Visit and Change from Baseline
EXTS
14.3.4.1.1.1.1.2
MRS-TU-2019EXT Hematology: Summary by Visit and %Change from 
Baseline
EXTS
14.3.4.1.1.1.2
MRS-TU-2019EXT Hematology: Laboratory Parameters Outside Normal 
Reference Range by Study Visit
EXTS
14.3.4.1.1.1.3
MRS-TU-2019EXT Hematology: Shift from Baseline Relative to the Normal 
Reference Range
EXTS
14.3.4.1.1.1.4
MRS-TU-2019EXT Hematology: HbA1c (%) by Visit and Baseline Diabetic 
Status
EXTS
14.3.4.1.1.1.5
HbA1c (%) at Screening
EXTS
14.3.4.1.1.2.1.1
MRS-TU-2019 Hematology: Summary by Visit and Change from Baseline
SS
14.3.4.1.1.2.1.2
MRS-TU-2019 Hematology: Summary by Visit and Percent Change from 
Baseline
SS
14.3.4.1.1.2.2
MRS-TU-2019 Hematology: Laboratory Parameters Outside Normal Reference 
Range by Study Visit
SS
14.3.4.1.1.2.3
MRS-TU-2019 Hematology: Shift from Baseline Relative to the Normal 
Reference Range
SS
14.3.4.1.1.2.4
MRS-TU-2019 Hematology: HbA1c (%) by Visit and Baseline Diabetic Status
SS
14.3.4.1.1.2.5
HbA1c (%) at Screening
SS
14.3.4.1.1.3.1
Hematology: Abnormal Laboratory Results, Listing
SS and EXTS
14.3.4.1.1.3.2
Hemoglobin: Abnormal Results and Results of Special Concern, Listing
SS and EXTS
14.3.4.1.2.1.1.1
MRS-TU-2019EXT Biochemistry: Summary by Visit and Change from Baseline
EXTS
14.3.4.1.2.1.1.2
MRS-TU-2019EXT Biochemistry: Summary by Visit and % Change from 
Baseline
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
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  .............................................................................................. Page 132 of 193 
14.3.4.1.2.1.2
MRS-TU-2019EXT Biochemistry: Laboratory Parameters Outside Normal 
Reference Range by Study Visit
EXTS
14.3.4.1.2.1.3
MRS-TU-2019EXT Biochemistry: Shift from Baseline Relative to the Normal 
Reference Range
EXTS
14.3.4.1.2.1.4
MRS-TU-2019EXT Biochemistry: Liver Function Tests Above Normal 
Reference Range by Study Visit
EXTS
14.3.4.1.2.2.1.1
MRS-TU-2019 Biochemistry: Summary by Visit and Change from Baseline
SS
14.3.4.1.2.2.1.2
MRS-TU-2019 Biochemistry: Summary by Visit and Percent Change from 
Baseline
SS
14.3.4.1.2.2.2
MRS-TU-2019 Biochemistry: Laboratory Parameters Outside Normal Reference 
Range by Study Visit
SS
14.3.4.1.2.2.3
MRS-TU-2019 Biochemistry: Shift from Baseline Relative to the Normal 
Reference Range
SS
14.3.4.1.2.2.4
MRS-TU-2019 Biochemistry: Liver Function Tests Above Normal Reference 
Range by Study Visit
SS
14.3.4.1.2.3.1
Biochemistry: Abnormal Laboratory Results, Listing
SS and EXTS
14.3.4.1.2.3.2
Biochemistry: Potential Liver Toxicity Events, Listing
SS and EXTS
14.3.4.1.3.1
MRS-TU-2019EXT Urinalysis: Screening Summary
EXTS
14.3.4.1.3.2
MRS-TU-2019 Urinalysis: Screening Summary
SS
14.3.4.1.3.3
Urinalysis: Abnormal Laboratory Results, Listing
SS and EXTS
14.3.4.1.4.1.1.1
MRS-TU-2019EXT Endocrinology: Summary by Visit and Change from 
Baseline
EXTS
14.3.4.1.4.1.1.2
MRS-TU-2019EXT Endocrinology: Summary by Visit and % Change from 
Baseline
EXTS
14.3.4.1.4.1.2
MRS-TU-2019EXT Endocrinology: Laboratory Parameters Outside Normal 
Reference Range by Study Visit
EXTS
14.3.4.1.4.1.3
MRS-TU-2019EXT Endocrinology: Shift from Baseline Relative to the Normal 
Reference Range
EXTS
14.3.4.1.4.2.1.1
MRS-TU-2019 Endocrinology: Summary by Visit and Change from Baseline
SS
14.3.4.1.4.2.1.2
MRS-TU-2019 Endocrinology: Summary by Visit and Percent Change from 
Baseline
SS
14.3.4.1.4.2.2
MRS-TU-2019 Endocrinology: Laboratory Parameters Outside Normal 
Reference Range by Study Visit
SS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 133 of 193 
14.3.4.1.4.2.3
MRS-TU-2019 Endocrinology: Shift from Baseline Relative to the Normal 
Reference Range
SS
14.3.4.1.4.3
Endocrinology: Abnormal Laboratory Results, Listing
SS and EXTS
14.3.4.1.5.1.1.1
MRS-TU-2019EXT Lipid Panel: Summary by Visit and Change from Baseline
EXTS
14.3.4.1.5.1.1.2
MRS-TU-2019EXT Lipid Panel: Summary by Visit and % Change from Baseline
EXTS
14.3.4.1.5.1.2
MRS-TU-2019EXT Lipid Panel: Laboratory Parameters Outside Normal 
Reference Range by Study Visit
EXTS
14.3.4.1.5.1.3
MRS-TU-2019EXT Lipid Panel: Shift from Baseline Relative to the Normal 
Reference Range
EXTS
14.3.4.1.5.2.1.1
MRS-TU-2019 Lipid Panel: Summary by Visit and Change from Baseline
SS
14.3.4.1.5.2.1.2
MRS-TU-2019 Lipid Panel: Summary by Visit and Percent Change from 
Baseline
SS
14.3.4.1.5.2.2
MRS-TU-2019 Lipid Panel: Laboratory Parameters Outside Normal Reference 
Range by Study Visit
SS
14.3.4.1.5.2.3
MRS-TU-2019 Lipid Panel: Shift from Baseline Relative to the Normal 
Reference Range
SS
14.3.4.1.5.3
Lipid Panel: Abnormal Laboratory Results, Listing
SS and EXTS
14.3.4.1.6.1.1.1
MRS-TU-2019EXT Serum PSA: Summary by Visit and Change from Baseline
EXTS
14.3.4.1.6.1.1.2
MRS-TU-2019EXT Serum PSA: Summary by Visit and % Change from 
Baseline
EXTS
14.3.4.1.6.1.2
MRS-TU-2019EXT Serum PSA: Summary of Percentage of Subjects with Serum 
PSA>=4 ng/mL and Percentage of Subjects with Change from Baseline in Serum 
PSA>1.4 ng/mL Anytime and by Visit
EXTS
14.3.4.1.6.2.1.1
MRS-TU-2019 Serum PSA: Summary by Visit and Change from Baseline
SS
14.3.4.1.6.2.1.2
MRS-TU-2019 Serum PSA: Summary by Visit and Percent Change from 
Baseline
SS
14.3.4.1.6.2.2
MRS-TU-2019 Serum PSA: Summary of Percentage of Subjects with Serum 
PSA>=4 ng/mL and Percentage of Subjects with Change from Baseline in Serum 
PSA>1.4 ng/mL Anytime and by Visit
SS
14.3.4.1.6.3
Serum PSA: Subjects with Serum PSA>=4 ng/mL or with Change from Baseline 
in Serum PSA>1.4 ng/mL, Listing
SS and EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 134 of 193 
14.3.4.1.7.1.1
Urine Drug Screen
EXTS
14.3.4.1.7.1.2
Urine Drug Screen
SS
14.3.4.1.7.2.1
Hepatitis/HIV Screening
EXTS
14.3.4.1.7.2.2
Hepatitis/HIV Screening
SS
14.3.4.2.1.1.1.1
MRS-TU-2019EXT Summary of Time 0 Vital Signs and Change from Baseline 
by Visit (All Data and Censored)
EXTS
14.3.4.2.1.1.2.1
MRS-TU-2019EXT Summary of Time 0 Vital Signs and Change from Baseline 
by Visit and Baseline Diabetic Status (All Data and Censored)
EXTS
14.3.4.2.1.1.2.2
MRS-TU-2019EXT Summary of Time 0 Vital Signs and Change from Baseline 
by Visit and Baseline Hypertensive Status (All Data and Censored)
EXTS
14.3.4.2.1.1.2.3
MRS-TU-2019EXT Summary of Time 0 Vital Signs and Change from Baseline 
by Visit and Baseline Hypertensive Treatment Status (All Data and Censored)
EXTS
14.3.4.2.1.1.2.4
MRS-TU-2019EXT Summary of Time 0 Vital Signs and Change from Baseline 
by Visit and Baseline Hypogonadal Status (All Data and Censored)
EXTS
14.3.4.2.1.1.2.5
MRS-TU-2019EXT Summary of Time 0 Vital Signs and Change from Baseline 
by Visit and Baseline Statin Treatment Status (All Data and Censored) 
EXTS
14.3.4.2.1.1.2.6
MRS-TU-2019EXT Summary of Time 0 Vital Signs and Change from Baseline 
by Visit and Age Group (All Data and Censored)
EXTS
14.3.4.2.1.1.2.7
MRS-TU-2019EXT Summary of Time 0 Vital Signs and Change from Baseline 
by Visit and Dose (All Data and Censored)
EXTS
14.3.4.2.1.2.1
MRS-TU-2019EXT Categorical Summary of Time 0 Vital Signs by Visit (All 
Data and Censored)
EXTS
14.3.4.2.1.2.2.1
MRS-TU-2019EXT Categorical Summary of Time 0 Vital Signs by Visit and 
Baseline Diabetic Status (All Data and Censored)
EXTS
14.3.4.2.1.2.2.2
MRS-TU-2019EXT Categorical Summary of Time 0 Vital Signs by Visit and 
Baseline Hypertensive Status (All Data and Censored)
EXTS
14.3.4.2.1.2.2.3
MRS-TU-2019EXT Categorical Summary of Time 0 Vital Signs by Visit and 
Baseline Hypertensive Treatment Status (All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 135 of 193 
14.3.4.2.1.2.2.4
MRS-TU-2019EXT Categorical Summary of Time 0 Vital Signs by Visit and 
Baseline Hypogonadal Status (All Data and Censored)
EXTS
14.3.4.2.1.2.2.6
MRS-TU-2019EXT Categorical Summary of Time 0 Vital Signs by Visit and 
Baseline Statin Treatment Status (All Data and Censored)
EXTS
14.3.4.2.1.2.2.7
MRS-TU-2019EXT Categorical Summary of Time 0 Vital Signs by Visit and 
Age Group (All Data and Censored)
EXTS
14.3.4.2.1.3.1
MRS-TU-2019EXT Time 0 Vital Signs: Shifts in Hypertension Classification 
between Baseline and  Post-baseline Value (All Data and Censored)
EXTS
14.3.4.2.1.3.1.1
MRS-TU-2019EXT Time 0 Vital Signs: Shifts in Hypertension Classification 
between Baseline and  Post-baseline Value Using Confirmatory Results (All Data 
and Censored)
EXTS
14.3.4.2.1.3.2.1
MRS-TU-2019EXT Time 0 Vital Signs: Shifts in Hypertension Classification 
between Baseline and Post-baseline Value by Baseline Diabetic Status (All Data 
and Censored)
EXTS
14.3.4.2.1.3.2.2
MRS-TU-2019EXT Time 0 Vital Signs: Shifts in Hypertension Classification 
between Baseline and Post-baseline Value by Baseline Hypertensive Status (All 
Data and Censored)
EXTS
14.3.4.2.1.3.2.3
MRS-TU-2019EXT Time 0 Vital Signs: Shifts in Hypertension Classification 
between Baseline and Post-baseline Value by Baseline Hypertensive Treatment 
Status (All Data and Censored)
EXTS
14.3.4.2.1.3.2.4
MRS-TU-2019EXT Time 0 Vital Signs: Shifts in Hypertension Classification 
between Baseline and  Post-baseline Value by Baseline Hypogonadal Status (All 
Data and Censored)
EXTS
14.3.4.2.1.3.2.6
MRS-TU-2019EXT Time 0 Vital Signs: Shifts in Hypertension Classification 
between Baseline and Maximum Post-baseline Value by Baseline Statin 
Treatment Status (All Data and Censored)
EXTS
14.3.4.2.1.3.2.7
MRS-TU-2019EXT Time 0 Vital Signs: Shifts in Hypertension Classification 
between Baseline and Maximum Post-baseline Value by Age Group (All Data 
and Censored)
EXTS
14.3.4.2.1.4.3
MRS-TU-2019EXT Concordance Analysis of Hypertension of In Clinic Time 0 
Blood Pressure versus 24 Hour Average ABPM 
EXTS
14.3.4.2.1.4.4
MRS-TU-2019EXT Concordance Analysis of Hypertension of In Clinic Time 0 
Blood Pressure versus Daytime Average ABPM 
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
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  .............................................................................................. Page 136 of 193 
14.3.4.2.1.7.1
MRS-TU-2019EXT Summary of Time 0 Blood Pressure by MRS-TU-2019
Treatment Group and Washout Visit (All Data )
All Continuing Subjects
14.3.4.2.2.1.1
MRS-TU-2019 Summary of Time 0 Vital Signs and Change from Baseline by 
Visit (All Data and Censored)
SS
14.3.4.2.2.1.2.1
MRS-TU-2019 Summary of Time 0 Vital Signs and Change from Baseline by 
Visit and Baseline Hypertensive Status (All Data and Censored)
SS
14.3.4.2.2.1.2.2
MRS-TU-2019 Summary of Time 0 Vital Signs and Change from Baseline by 
Visit and Baseline Hypertensive Treatment Status (All Data and Censored)
SS
14.3.4.2.2.1.2.3
MRS-TU-2019 Summary of Time 0 Vital Signs and Change from Baseline by 
Visit and Dose (All Data and Censored)
SS
14.3.4.2.2.3
MRS-TU-2019 Summary of  24-hour Mean Blood Pressure and Change from
Baseline by Visit (All Data and Censored)
SS
14.3.4.2.2.3.1
MRS-TU-2019 Summary of Day 90 24-hour Mean Blood Pressure and Change 
from Baseline by Day 90 Hgb Tertiles (All Data )
SS
14.3.4.2.2.4.1
MRS-TU-2019 Categorical Summary of Change from Baseline in 24-hour Mean 
Blood Pressure by Visit (All Data and Censored)
SS
14.3.4.2.2.5.1
MRS-TU-2019 Categorical Summary of Time 0 Vital Signs by Visit (All Data 
and Censored)
SS
14.3.4.2.2.5.2
MRS-TU-2019 Categorical Summary of Time 0 Vital Signs by Visit and 
Baseline Hypertensive Treatment Status (All Data and Censored)
SS
14.3.4.2.2.5.3
MRS-TU-2019 Time 0 Vital Signs: Shifts in Hypertension Classification 
between Baseline and Post-baseline Value (All Data and Censored)
SS
14.3.4.2.2.5.3.1
MRS-TU-2019 Time 0 Vital Signs: Shifts in Hypertension Classification 
between Baseline and Post-baseline Value with Confirmatory Results (All Data 
and Censored)
SS
14.3.4.3.1.1.1.1.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of 24-hour Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline by Visit (All Data and Censored)
EXTS
14.3.4.3.1.1.1.1.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Repeated Measures Analysis of 24-hour Average 
Ambulatory Systolic Blood Pressure (mmHg) (All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 137 of 193 
14.3.4.3.1.1.1.1.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Repeated Measures Analysis of 24-hour Average 
Ambulatory Systolic Blood Pressure (mmHg) (All Data and Censored): 
Sensitivity Analysis (ABPM Completers)
EXTS - ABPM Completers
14.3.4.3.1.1.1.2.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Daytime and Nighttime Average Ambulatory Systolic 
Blood Pressure (mmHg) and Change from Baseline by Visit (All Data and 
Censored)
EXTS
14.3.4.3.1.1.1.2.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Repeated Measures Analysis of Daytime Average 
Ambulatory Systolic Blood Pressure (mmHg) (All Data and Censored)
EXTS
14.3.4.3.1.1.1.2.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood
Pressure: Mixed Model Repeated Measures Analysis of Daytime Average 
Ambulatory Systolic Blood Pressure (mmHg) (All Data and Censored): 
Sensitivity Analysis (ABPM Completers)
EXTS - ABPM Completers
14.3.4.3.1.1.1.2.4
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Repeated Measures Analysis of Nighttime Average 
Ambulatory Systolic Blood Pressure (mmHg) (All Data and Censored)
EXTS
14.3.4.3.1.1.1.2.5
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Repeated Measures Analysis of Nighttime Average 
Ambulatory Systolic Blood Pressure (mmHg) (All Data and Censored): 
Sensitivity Analysis (ABPM Completers)
EXTS - ABPM Completers
14.3.4.3.1.2.1.1
MRS-TU-2019EXT Categorical Summary of 24-hour Average Ambulatory 
Systolic Blood Pressure by Visit (All Data and Censored) (Extension Treated Set)
EXTS
14.3.4.3.1.2.1.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Categorical Summary of Change from Baseline in 24-hour Average 
Ambulatory Systolic Blood Pressure (mmHg) by Visit (All Data and Censored)
EXTS
14.3.4.3.1.2.2.1
MRS-TU-2019EXT Categorical Summary of Daytime Average Ambulatory 
Systolic Blood Pressure by Visit (All Data and Censored) (Extension Treated Set)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 138 of 193 
14.3.4.3.1.2.2.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Categorical Summary of Change from Baseline in Daytime Average 
Ambulatory Systolic Blood Pressure (mmHg) by Visit (All Data and Censored)
EXTS
14.3.4.3.1.3.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Blood Pressure: 
Shifts in Hypertension Classification between Baseline
and Maximum Post-baseline Value in 24-Hour Average Ambulatory Blood 
Pressure (All Data and Censored) (All Data and Censored)
EXTS
14.3.4.3.1.3.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Blood Pressure: 
Shifts in Hypertension Classification between Baseline
and Maximum Post-baseline Value in 24-Hour Average Ambulatory Blood 
Pressure (All Data and Censored) by Baseline Diabetic Status (All Data and 
Censored)
EXTS
14.3.4.3.1.3.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory  Blood Pressure: 
Shifts in Hypertension Classification between Baseline and Maximum Post-
baseline Value in Daytime Average Ambulatory Systolic Blood Pressure 
(mmHg) (All Data and Censored)
EXTS
14.3.4.3.1.3.4
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory  Blood Pressure: 
Shifts in Hypertension Classification between Baseline and Post-baseline Value 
in Daytime Average Ambulatory Systolic Blood Pressure (mmHg) by Baseline 
Diabetic Status (All Data and Censored)
EXTS
14.3.4.3.1.4.1.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Half-Hourly Ambulatory Systolic Blood Pressure (mmHg) 
and Time Matched Changes from Baseline by Visit and Half-Hourly Elapsed 
Time From ABPM Start (All Data and Censored)
EXTS
14.3.4.3.1.4.1.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Half-Hourly Ambulatory Systolic Blood Pressure (mmHg) 
and Time Matched Changes from Baseline by Visit and Half-Hourly Elapsed 
Time From ABPM Start (All Data and Censored)
EXTS - ABPM Completers
14.3.4.3.1.4.2.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Blood Pressure: 
Summary of Half-Hourly Ambulatory Systolic Blood Pressure (mmHg) and 
Time Matched Changes from Baseline by Visit and Half-Hourly Clock Time 
Intervals (All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 139 of 193 
14.3.4.3.1.4.2.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Blood Pressure: 
Summary of Half-Hourly Ambulatory Systolic Blood Pressure (mmHg) and 
Time Matched Changes from Baseline by Visit and Half-Hourly Clock Time 
Intervals (All Data and Censored)
EXTS - ABPM Completers
14.3.4.3.1.4.3.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of 24-hour Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 120E and Day 180E by Total Daily
Dose  (All Data and Censored)
EXTS
14.3.4.3.1.4.3.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Daytime Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 120E and Day 180E by Total Daily 
Dose  (All Data and Censored)
EXTS
14.3.4.3.1.4.4.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of 24 Hour Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 120E by Day 90E Hemoglobin 
Tertiles  (All Data and Censored)
EXTS
14.3.4.3.1.4.4.1.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of 24 Hour Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 120E by Day 90E Hemoglobin 
Tertiles and by Baseline Hypertensive Treatment Status  (All Data and Censored)
EXTS
14.3.4.3.1.4.4.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Daytime Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 120E by Day 90E Hemoglobin 
Tertiles  (All Data and Censored)
EXTS
14.3.4.3.1.4.4.2.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Daytime Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 120E by Day 90E Hemoglobin 
Tertiles and by Baseline Hypertensive Treatment Status  (All Data and Censored)
EXTS
14.3.4.3.1.4.4.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Nighttime Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 120E by Day 90E Hemoglobin 
Tertiles  (All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 140 of 193 
14.3.4.3.1.4.4.3.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Nighttime Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 120E by Day 90E Hemoglobin 
Tertiles   and by Baseline Hypertensive Treatment Status(All Data and Cens 
ored)
EXTS
14.3.4.3.1.4.4.4
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of 24 Hour Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 180E by Day180E Hemoglobin 
Tertiles  (All Data and Censored)
EXTS
14.3.4.3.1.4.4.4.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of 24 Hour Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 180E by Day180E Hemoglobin 
Tertiles  and by Baseline Hypertensive Treatment Status (All Data and Censored)
EXTS
14.3.4.3.1.4.4.5
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Daytime Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 180E by Day 180E Hemoglobin 
Tertiles  (All Data and Censored)
EXTS
14.3.4.3.1.4.4.5.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Daytime Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 180E by Day 180E Hemoglobin 
Tertiles  and by Baseline Hypertensive Treatment Status (All Data and Censored)
EXTS
14.3.4.3.1.4.4.6
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood
Pressure: Summary of Nighttime Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 180E by Day 180E Hemoglobin 
Tertiles  (All Data and Censored)
EXTS
14.3.4.3.1.4.4.6.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Nighttime Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 180E by Day 180E Hemoglobin 
Tertiles and by Baseline Hypertensive Treatment Status(All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 141 of 193 
14.3.4.3.1.5.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Visit 2E (Day 365) and Visit 7E (Day 1E) 24-hour
Average Ambulatory Systolic Blood Pressure (mmHg) 
EXTS – Continuing Subjects
14.3.4.3.1.5.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Analysis of 24-hour Average Ambulatory Systolic Blood 
Pressure (mmHg) Comparing Visit 2E (Day 365) to Visit 7E (Day 1E)
EXTS – Continuing Subjects
14.3.4.3.1.5.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Visit 2E (Day 365) and Visit 7E (Day 1E) Daytime and 
Nighttime Average Ambulatory Systolic Blood Pressure (mmHg) 
EXTS – Continuing  Subjects
14.3.4.3.1.5.4
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Analysis of Daytime and Nighttime Average Ambulatory 
Systolic Blood Pressure (mmHg) Comparing Visit 2E (Day 365) to Visit 7E 
(Day 1E)
EXTS – Continuing  Subjects
14.3.4.3.1.4.5.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of 24 Hour Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 180E by Day 180E Hemoglobin 
Upper Limit of the Hgb Normal Range  (All Data and Censored)
EXTS
14.3.4.3.1.4.5.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Daytime Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 180E by Day 180E Hemoglobin 
Upper Limit of the Hgb Normal Range  (All Data and Censored)
EXTS
14.3.4.3.1.4.5.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Nighttime Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline at Day 180E by Day 180E Hemoglobin 
Upper Limit of the Hgb Normal Range  (All Data and Censored)
EXTS
14.3.4.3.1.6.1.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood
Pressure: Summary of 24-hour Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline by Visit and History of Hypertension (All 
Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 142 of 193 
14.3.4.3.1.6.1.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Repeated Measures Analysis of 24-hour Average 
Ambulatory Systolic Blood Pressure (mmHg) by History of Hypertension (All 
Data and Censored)
EXTS
14.3.4.3.1.6.1.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Daytime and Nighttime Average Ambulatory Systolic 
Blood Pressure (mmHg) and Change from Baseline by Visit and History of 
Hypertension (All Data and Censored)
EXTS
14.3.4.3.1.6.1.4
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood
Pressure: Mixed Model Repeated Measures Analysis of Daytime Average 
Ambulatory Systolic Blood Pressure (mmHg) by History of Hypertension (All
Data and Censored)
EXTS
14.3.4.3.1.6.1.5
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Repeated Measures Analysis of Nighttime Average 
Ambulatory Systolic Blood Pressure (mmHg) by History of Hypertension (All 
Data and Censored)
EXTS
14.3.4.3.1.6.2.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of 24-hour Average Ambulatory Systolic Blood Pressure 
(mmHg) and Change from Baseline by Visit and Baseline Diabetic Status (All 
Data and Censored)
EXTS
14.3.4.3.1.6.2.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Repeated Measures Analysis of 24-hour Average
Ambulatory Systolic Blood Pressure (mmHg) by Baseline Diabetic Status (All 
Data and Censored)
EXTS
14.3.4.3.1.6.2.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Summary of Daytime and Nighttime Average Ambulatory Systolic 
Blood Pressure (mmHg) and Change from Baseline by Visit and Baseline 
Diabetic Status (All Data and Censored)
EXTS
14.3.4.3.1.6.2.4
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Repeated Measures Analysis of Daytime Average 
Ambulatory Systolic Blood Pressure (mmHg) by Baseline Diabetic Status (All 
Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 143 of 193 
14.3.4.3.1.6.2.5
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: Mixed Model Repeated Measures Analysis of Nighttime Average 
Ambulatory Systolic Blood Pressure (mmHg) by Baseline Diabetic Status (All 
Data and Censored)
EXTS
14.3.4.3.1.6.2.6
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic Blood 
Pressure: ANCOVA of Change in 24-hour Average Ambulatory Systolic Blood 
Pressure (mmHg) as a Funtion of Baseline systolic Blood Pressure, Baseline 
Diabetic Status, Dose, Age,Weight, and Baseline Hypertensive Treatment Status 
by Visit 12E (Day 120E) and  14E (Day 180E)
EXTS
14.3.4.3.2.1.1.1.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of 24-hour Average Ambulatory Diastolic Blood Pressure (mmHg) and 
Change from Baseline by Visit (All Data and Censored)
EXTS
14.3.4.3.2.1.1.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Repeated Measures Analysis of in 24-hour Average Ambulatory 
Diastolic Blood Pressure (mmHg) (All Data and Censored)
EXTS
14.3.4.3.2.1.1.1.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Repeated Measures Analysis of 24-hour Average Ambulatory 
Diastolic Blood Pressure (mmHg) (All Data and Censored): Sensitivity Analysis 
(ABPM Completers)
EXTS - ABPM Completers
14.3.4.3.2.1.1.2.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of Daytime and Nighttime Average Ambulatory Diastolic Blood 
Pressure (mmHg) and Change from Baseline by Visit (All Data and Censored)
EXTS
14.3.4.3.2.1.1.2.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure:
Mixed Model Repeated Measures Analysis of Daytime Average Ambulatory 
Diastolic Blood Pressure (mmHg) (All Data and Censored)
EXTS
14.3.4.3.2.1.1.2.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Repeated Measures Analysis of Daytime Average Ambulatory 
Diastolic Blood Pressure (mmHg) (All Data and Censored): Sensitivity Analysis 
(ABPM Completers)
EXTS - ABPM Completers
14.3.4.3.2.1.1.2.4
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Repeated Measures Analysis of Nighttime Average Ambulatory 
Diastolic Blood Pressure (mmHg) (All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 144 of 193 
14.3.4.3.2.1.1.2.5
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Repeated Measures Analysis of Nighttime Average Ambulatory 
Diastolic Blood Pressure (mmHg) (All Data and Censored): Sensitivity Analysis 
(ABPM Completers)
EXTS - ABPM Completers
14.3.4.3.2.2.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Categorical Summary of Change from Baseline in 24-hour Average Ambulatory 
Diastolic Blood Pressure (mmHg) by Visit (All Data and Censored)
EXTS
14.3.4.3.2.2.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Categorical Summary of Change from Baseline in Daytime Average Ambulatory 
Diastolic Blood Pressure (mmHg) by Visit (All Data and Censored)
EXTS
14.3.4.3.2.4.1.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of Half-Hourly Ambulatory Diastolic Blood Pressure (mmHg) and 
Time Matched Changes from Baseline by Visit and Half-Hourly Elapsed Time 
From ABPM Start (All Data and Censored)
EXTS
14.3.4.3.2.4.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of Half-Hourly Ambulatory Diastolic Blood Pressure (mmHg) and 
Time Matched Changes from Baseline by Visit and Half-Hourly Elapsed Time 
From ABPM Start (All Data and Censored)
EXTS - ABPM Completers
14.3.4.3.2.4.2.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of Half-Hourly Ambulatory Diastolic Blood Pressure (mmHg) and 
Time Matched Changes from Baseline by Visit and Half-Hourly Clock Time 
Intervals (All Data and Censored)
EXTS
14.3.4.3.2.4.2.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of Half-Hourly Ambulatory Diastolic Blood Pressure (mmHg) and 
Time Matched Changes from Baseline by Visit and Half-Hourly Clock Time 
Intervals (All Data and Censored)
EXTS - ABPM Completers
14.3.4.3.2.5.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of Visit 2E (Day 365) and Visit 7E (Day 1E) 24-hour Average 
Ambulatory Diastolic Blood Pressure (mmHg) 
EXTS – Continuing 
SOV2012-F1 Subjects


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 145 of 193 
14.3.4.3.2.5.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Analysis of 24-hour Average Ambulatory Diastolic Blood Pressure 
(mmHg) Comparing Visit 2E (Day 365) to Visit 7E (Day 1E)
EXTS – Continuing 
SOV2012-F1 Subjects
14.3.4.3.2.5.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of Visit 2E (Day 365) and Visit 7E (Day 1E) Daytime and Nighttime 
Average Ambulatory Diastolic Blood Pressure (mmHg) 
EXTS – Continuing 
SOV2012-F1 Subjects
14.3.4.3.2.5.4
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Analysis of Daytime and Nighttime Average Ambulatory Diastolic 
Blood Pressure (mmHg) Comparing Visit 2E (Day 365) to Visit 7E (Day 1E)
EXTS – Continuing 
SOV2012-F1 Subjects
14.3.4.3.2.6.1.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of 24-hour Average Ambulatory Diastolic Blood Pressure (mmHg) and 
Change from Baseline by Visit and History of Hypertension (All Data and 
Censored)
EXTS
14.3.4.3.2.6.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Repeated Measures Analysis of 24-hour Average Ambulatory 
Diastolic Blood Pressure (mmHg) by History of Hypertension (All Data and 
Censored)
EXTS
14.3.4.3.2.6.1.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of Daytime and Nighttime Average Ambulatory Diastolic Blood 
Pressure (mmHg) and Change from Baseline by Visit and History of 
Hypertension (All Data and Censored)
EXTS
14.3.4.3.2.6.1.4
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Repeated Measures Analysis of Daytime Average Ambulatory 
Diastolic Blood Pressure (mmHg) by History of Hypertension (All Data and 
Censored)
EXTS
14.3.4.3.2.6.1.5
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Repeated Measures Analysis of Nighttime Average Ambulatory 
Diastolic Blood Pressure (mmHg) by History of Hypertension (All Data and 
Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 146 of 193 
14.3.4.3.2.6.2.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of 24-hour Average Ambulatory Diastolic Blood Pressure (mmHg) and 
Change from Baseline by Visit and Baseline Diabetic Status (All Data and 
Censored)
EXTS
14.3.4.3.2.6.2.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Repeated Measures Analysis of 24-hour Average Ambulatory 
Diastolic Blood Pressure (mmHg) by Baseline Diabetic Status (All Data and 
Censored)
EXTS
14.3.4.3.2.6.2.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Summary of Daytime and Nighttime Average Ambulatory Diastolic Blood 
Pressure (mmHg) and Change from Baseline by Visit and Baseline Diabetic 
Status (All Data and Censored)
EXTS
14.3.4.3.2.6.2.4
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Repeated Measures Analysis of Daytime Average Ambulatory 
Diastolic Blood Pressure (mmHg) by Baseline Diabetic Status (All Data and 
Censored)
EXTS
14.3.4.3.2.6.2.5
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood Pressure: 
Mixed Model Repeated Measures Analysis of Nighttime Average Ambulatory 
Diastolic Blood Pressure (mmHg) by Baseline Diabetic Status (All Data and 
Censored)
EXTS
14.3.4.3.3.1.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Summary of 24-
hour Average Ambulatory Heart Rate (bpm) and Change from Baseline by Visit 
(All Data and Censored)
EXTS
14.3.4.3.3.1.1.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate:
Categorical Summary of Change from Baseline in 24-hour Average Ambulatory
Heartrate (bpm) by Visit (All Data and Censored)
EXTS
14.3.4.3.3.1.1.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: 
Categorical Summary of Change from Baseline in Daytime Average Ambulatory 
Heartrate (bpm) by Visit (All Data and Censored)
EXTS
14.3.4.3.3.1.1.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: 
Categorical Summary of Change from Baseline in Nighttime Average 
Ambulatory Heartrate (bpm) by Visit (All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 147 of 193 
14.3.4.3.3.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Mixed Model 
Repeated Measures Analysis of 24-hour Average Ambulatory Heart Rate (bpm)
(All Data and Censored)
EXTS
14.3.4.3.3.2.1.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Summary of 
Half-Hourly Ambulatory Heart Rate (bpm) and Time Matched Changes from 
Baseline by Visit and Half-Hourly Elapsed Time From ABPM Start (All Data 
and Censored)
EXTS
14.3.4.3.3.2.2.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Summary of 
Half-Hourly Ambulatory Heart Rate (bpm) and Time Matched Changes from 
Baseline by Visit and Half-Hourly Clock Time Intervals (All Data and Censored)
EXTS
14.3.4.3.3.3.1.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Summary of 24-
hour Average Ambulatory Heart Rate (bpm) and Change from Baseline by Visit 
and History of Hypertension (All Data and Censored)
EXTS
14.3.4.3.3.3.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Mixed Model 
Repeated Measures Analysis of 24-hour Average Ambulatory Heart Rate (bpm) 
by History of Hypertension (All Data and Censored)
EXTS
14.3.4.3.3.3.2.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Summary of 24-
hour Average Ambulatory Heart Rate (bpm) and Change from Baseline by Visit 
and Baseline Diabetic Status (All Data and Censored)
EXTS
14.3.4.3.3.3.2.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Mixed Model 
Repeated Measures Analysis of 24-hour Average Ambulatory Heart Rate (bpm) 
by Baseline Diabetic Status (All Data and Censored)
EXTS
14.3.4.3.4.1.1.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial Pressure: 
Summary of 24-hour Average Ambulatory Mean Arterial Pressure (mmHg) and 
Change from Baseline by Visit (All Data and Censored)
EXTS
14.3.4.3.4.1.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial Pressure: 
Mixed Model Repeated Measures Analysis of 24-hour Average Ambulatory 
Mean Arterial Pressure (mmHg) (All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 148 of 193 
14.3.4.3.4.1.1.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial Pressure: 
Mixed Model Repeated Measures Analysis of 24-hour Average Ambulatory 
Mean Arterial Pressure (mmHg) (All Data and Censored): Sensitivity Analysis 
(ABPM Completers)
EXTS - ABPM Completers
14.3.4.3.4.2.1.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial Pressure: 
Summary of Half-Hourly Ambulatory Mean Arterial Pressure (mmHg) and Time 
Matched Changes from Baseline by Visit and Half-Hourly Elapsed Time From 
ABPM Start (All Data and Censored)
EXTS
14.3.4.3.4.2.2.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial Pressure: 
Summary of Half-Hourly Ambulatory Mean Arterial Pressure (mmHg) and Time 
Matched Changes from Baseline by Visit and Half-Hourly Clock Time Intervals 
(All Data and Censored)
EXTS
14.3.4.3.4.3.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial Pressure: 
Mixed Model Repeated Measures Analysis of 24-hour Average Ambulatory 
Mean Arterial Pressure (mmHg) by Baseline Hypertensive Treatment Status (All 
Data and Censored)
EXTS
14.3.4.3.4.3.2.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial Pressure: 
Summary of 24-hour Average Ambulatory Mean Arterial Pressure (mmHg) and 
Change from Baseline by Visit and Baseline Diabetic Status (All Data and
Censored)
EXTS
14.3.4.3.4.3.2.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial Pressure: 
Mixed Model Repeated Measures Analysis of 24-hour Average Ambulatory 
Mean Arterial Pressure (mmHg) by Baseline Diabetic Status (All Data and 
Censored)
EXTS
14.3.4.3.5.1.1.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: Summary of 
24-hour Average Ambulatory Pulse Pressure (mmHg) and Change from Baseline 
by Visit (All Data and Censored)
EXTS
14.3.4.3.5.1.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: Mixed Model 
Repeated Measures Analysis of 24-hour Average Ambulatory Pulse Pressure 
(mmHg) (All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 149 of 193 
14.3.4.3.5.1.1.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: Mixed Model 
Repeated Measures Analysis of 24-hour Average Ambulatory Pulse Pressure 
(mmHg) (All Data and Censored): Sensitivity Analysis (ABPM Completers)
EXTS - ABPM Completers
14.3.4.3.5.2.1.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: Summary of 
Half-Hourly Ambulatory Pulse Pressure (mmHg) and Time Matched Changes 
from Baseline by Visit and Half-Hourly Elapsed Time From ABPM Start (All 
Data and Censored)
EXTS
14.3.4.3.5.2.2.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: Summary of 
Half-Hourly Ambulatory Pulse Pressure (mmHg) and Time Matched Changes 
from Baseline by Visit and Half-Hourly Clock Time Intervals (All Data and 
Censored)
EXTS
14.3.4.3.5.3.1.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: Summary of 
24-hour Average Ambulatory Pulse Pressure (mmHg) and Change from Baseline 
by Visit and Baseline Hypertensive Treatment Status (All Data and Censored)
EXTS
14.3.4.3.5.3.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: Mixed Model 
Repeated Measures Analysis of 24-hour Average Ambulatory Pulse Pressure 
(mmHg) by Baseline Hypertensive Treatment Status (All Data and Censored)
EXTS
14.3.4.3.5.3.2.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: Summary of 
24-hour Average Ambulatory Pulse Pressure (mmHg) and Change from Baseline 
by Visit and Baseline Diabetic Status (All Data and Censored)
EXTS
14.3.4.3.5.3.2.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: Mixed Model 
Repeated Measures Analysis of 24-hour Average Ambulatory Pulse Pressure 
(mmHg) by Baseline Diabetic Status (All Data and Censored)
EXTS
14.3.4.4.1
MRS-TU-2019 ACTH Sub-study: Cortisol Response - Descriptive Statistics
AAS
14.3.4.4.2
MRS-TU-2019 ACTH Sub-study: Cortisol Response – Statistical Analysis
AAS
14.3.4.5.1.1
MRS-TU-2019EXT Abnormal Physical Examination Results by Visit
EXTS
14.3.4.5.1.2
MRS-TU-2019 Abnormal Physical Examination Results by Visit
SS
14.3.4.5.2
Physical Examination: Abnormal Results, Listing
SS and EXTS


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 Marius Pharmaceuticals  
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14.3.4.6.1.1
MRS-TU-2019EXT Safety Parameter Plasma T Cmax After 90 Days of 
Treatment (No Imputation)
EXTS
14.3.4.6.1.2
MRS-TU-2019EXT Safety Parameter Plasma T Cmax After 90 Days of 
Treatment (No Imputation)
mEXTS
14.3.4.6.1.3
MRS-TU-2019EXT Safety Parameter Plasma T Cmax After 90 Days of 
Treatment (No Imputation)
EXPK
14.3.4.6.1.4
MRS-TU-2019EXT Safety Parameter Plasma T Cmax After 90 Days of 
Treatment(No Imputation)
EXSE
14.3.4.6.1.5
MRS-TU-2019EXT Safety Parameter Plasma T Cmax After 90 Days of 
Treatment(No Imputation)
mEXSE
14.3.4.6.1.6.1
MRS-TU-2019EXT Safety Parameter Plasma T Cmax After 90 Days of 
Treatment by Baseline Weight Category (No Imputation)
mEXTS
14.3.4.6.1.6.2
MRS-TU-2019EXT Safety Parameter Plasma T Cmax After 90 Days of 
Treatment by Baseline BMI Category (No Imputation)
mEXTS
14.3.4.6.1.6.3
MRS-TU-2019EXT Safety Parameter Plasma T Cmax After 90 Days of 
Treatment by Age Category (No Imputation)
mEXTS
14.3.4.6.1.6.4
MRS-TU-2019EXT Safety Parameter Plasma T Cmax After 90 Days of 
Treatment by Race  (No Imputation)
mEXTS
14.3.4.6.1.6.5
MRS-TU-2019EXT Safety Parameter Plasma T Cmax After 90 Days of 
Treatment by Ethnicity (No Imputation)
mEXTS
14.3.4.6.1.7
MRS-TU-2019EXT Safety Parameter Serum T Cmax After 90 Days of 
Treatment(No Imputation)
EXSE
14.3.4.6.1.8
MRS-TU-2019EXT Safety Parameter Serum T Cmax After 90 Days of
Treatment(No Imputation)
mEXSE
14.3.4.6.1.9
MRS-TU-2019EXT Listing of Subjects with Visit 12E Plasma  T Cmax Over 
1200 ng/dL
EXTS
14.3.4.6.2.1
MRS-TU-2019 Safety Parameter T Cmax After 90 Days of SOV2012-F1
Treatment (No Imputation)
FAS
14.3.4.6.2.2
MRS-TU-2019 Safety Parameter T Cmax After 90 Days of Androgel Treatment 
(No Imputation)
FAS
14.3.4.7.1.1
Overall Study Drug Exposure – MRS-TU-2019EXT
EXTS
14.3.4.7.1.2
Study Drug Exposure by Titration Visit - MRS-TU-2019EXT
EXTS
14.3.4.7.1.3
Final Study Drug Dose by Visit - MRS-TU-2019EXT
EXTS
14.3.4.7.2.1
Overall Study Drug Exposure – MRS-TU-2019
SS


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 Marius Pharmaceuticals  
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14.3.4.7.2.2.1
Study Drug Exposure by Titration Visit - MRS-TU-2019 SOV2012-F1 Group
SS
14.3.4.7.2.2.2
Final Study Drug Dose by Visit - MRS-TU-2019 SOV2012-F1 Group
SS
14.3.4.7.2.3.1
Study Drug Exposure by Titration Visit - MRS-TU-2019 AndroGel Group
SS
14.3.4.7.2.3.2
Final Study Drug Dose by Visit - MRS-TU-2019 AndroGel Group
SS
14.3.4.7.3
Overall SOV2012-F1 Exposure – MRS-TU-2019 and MRS-TU-2019EXT
OSS
14.3.4.7.3.1
Study Drug Exposure by Dose 
OSS
14.3.4.7.3.2
Categorical Assessment of Study Drug Exposure by Dose  
OSS
14.3.4.8.1
MRS-TU-2019EXT Study Drug Compliance
EXTS
14.3.4.8.2
MRS-TU-2019EXT Study Drug Compliance
EXPK
14.3.4.8.3
MRS-TU-2019 Study Drug Compliance
SS
14.3.4.8.4
MRS-TU-2019 Study Drug Compliance
FAS
14.3.4.8.5
MRS-TU-2019 Study Drug Compliance
PKS
14.3.4.8.6
MRS-TU-2019 Study Drug Compliance
ECS
14.3.4.8.7
MRS-TU-2019 Study Drug Compliance
AAS
14.3.4.8.8
MRS-TU-2019 and MRS-TU-2019EXT SOV2012-F1 Compliance
OSS




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 Marius Pharmaceuticals  
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14.2.2.1.1.2.6
MRS-TU-2019EXT Mean (+/- SD) Pharmacokinetic Plasma T 12-24
Hour Concentration Curves (ng/dL) at Visit 12E (Day 90E) 
Overlaying Dinner Fat Category – Linear Scale
EXPK
14.2.2.1.1.2.7
MRS-TU-2019EXT Mean (+/- SD) Pharmacokinetic   Concentration 
Curves (ng/dL) at Visit 8E (Day 14E) Overlaying Plasma and Serum 
- Linear Scale
mEXSE
14.2.2.1.1.2.8
MRS-TU-2019EXT Mean (+/- SD) Pharmacokinetic Plasma 
Concentration Curves (ng/dL) at Visit 10E (Day 42E)Overlaying 
Plasma and Serum  - Linear Scale
mEXSE
14.2.2.1.1.2.9
MRS-TU-2019EXT Mean (+/- SD) Pharmacokinetic Plasma 
Concentration Curves (ng/dL) at Visit 12E (Day 90E) Overlaying 
Plasma and Serum  - Linear Scale
mEXSE
16.2.5.3.2.1.1
MRS-TU-2019EXT Individual Pharmacokinetic Plasma and Serum 
T Concentration Curves (ng/dL) Overlaying Visit by Subject - Linear 
Scale
EXPK
16.2.5.3.2.1.2
MRS-TU-2019EXT Individual Pharmacokinetic TU Concentration 
Curves (ng/dL) at Visit 12E (Day 90E) by Subject - Linear Scale
EXPK
16.2.5.3.2.1.3
MRS-TU-2019EXT Individual Pharmacokinetic Plasma and Serum T 
Concentration Curves (ng/dL) (Overlayed) ) by Subject and Visit 
(Visit 8E, Visit 10E and Visit 12E)- Linear Scale
EXTS
14.2.2.1.2.1
MRS-TU-2019EXT Distributions of Plasma T Cavg and T Cmax on 
Visit 12E (Day 90E) – Linear Scale
EXPK
14.2.2.1.2.3
MRS-TU-2019EXT Box Plots of Plasma T Cavg0-12 and T Cmax0-
12 Overlaying Actual Day 90E Breakfast Diet on Visit 12E (Day 
90E) – Linear Scale
EXPK
14.2.2.1.2.4
MRS-TU-2019EXT Box Plots of Plasma T Cavg12-24 and T 
Cmax12-24 Overlaying Actual Day 90E Dinner Diet on Visit 12E 
(Day 90E) – Linear Scale
EXPK
14.2.2.1.2.5
MRS-TU-2019EXT Box Plots of Plasma T Cavg and T Cmax 
Overlaying Age Category on Visit 12E (Day 90E) – Linear Scale
EXPK


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
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14.2.2.1.2.7
MRS-TU-2019EXT Box Plots of Plasma T Cavg and T Cmax 
Overlaying Weight Category on Visit 12E (Day 90E) – Linear Scale
EXPK
14.2.2.1.2.9
MRS-TU-2019EXT Box Plots of Plasma T Cavg and T Cmax 
Overlaying BMI Category on Visit 12E (Day 90E) – Linear Scale
EXPK
14.2.2.1.2.11
MRS-TU-2019EXT Box Plots of Plasma T Cavg and T Cmax 
Overlaying Race on Visit 12E (Day 90E) – Linear Scale
EXPK
14.2.2.1.2.13
MRS-TU-2019EXT Box Plots of Plasma T Cavg and T Cmax 
Overlaying Ethnicity on Visit 12E (Day 90E) – Linear Scale
EXPK
14.2.2.1.4.1
Scatter Plots of MRS-TU-2019EXT Serum T Concentration vs. 
Plasma T Concentration by Titration Visit and Timepoint
EXPK
14.2.2.1.4.2
Scatter Plot of MRS-TU-2019EXT Serum T Concentration vs.
Plasma T Concentration- Combines Visit 8E - Day 14E, Visit 10E -
Day 42E and Visit 12E - Day 90E.
EXPK
14.2.2.1.4.3
Scatter Plot of MRS-TU-2019EXT Serum T Concentration vs. 
Plasma T Concentration- Hours 3, 4, 5 and 6.
EXPK
14.2.2.1.4.4
Scatter Plot of MRS-TU-2019EXT Serum T Concentration vs. 
Plasma T Concentration- Hours 3, 4, 5 and 6.
EXPK
14.2.2.1.4.5
Scatter Plot of MRS-TU-2019EXT Serum T Concentration vs. 
Plasma T Concentration- Hours 3, 4, and 5 Combining Visits 8E and 
10E
EXPK
14.2.2.1.4.5.1
Scatter Plot of MRS-TU-2019EXT Serum T Concentration vs. 
Plasma T Concentration (Log-Log)- Hours 3, 4, and 5.
EXPK
14.2.2.1.4.5.2
Scatter Plot of MRS-TU-2019EXT Serum T Concentration vs. 
Plasma T Concentration - Plasma Concentration Data <900 ng/dL-
Hours 3, 4, and 5.
EXPK
14.2.2.1.4.5.3
Scatter Plot of MRS-TU-2019EXT Serum T Concentration vs. 
Plasma T Concentration - Plasma Concentration Data >=900 ng/dL-
Hours 3, 4, and 5.
EXPK


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 Marius Pharmaceuticals  
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Final Version 5.0
  
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14.2.2.1.4.6
Scatter Plot of MRS-TU-2019EXT Serum T Concentration vs. 
Plasma T Concentration- Hours 3, 4, and 5 Visit 12E
EXPK
14.2.2.2.2.1.2
MRS-TU-2019 Mean (+/- SD) Pharmacokinetic Plasma 
Concentration Curves (ng/dL) for SOV2012-F1 Group Overlaying 
Visit by Analyte - Linear Scale
PKS
14.2.2.2.2.1.3
MRS-TU-2019 Mean (+ SD) Pharmacokinetic Plasma Concentration 
Curves (ng/dL) for SOV2012-F1 Group Overlaying Visit by Analyte 
– Log-Linear Scale
PKS
14.2.2.2.2.2.2
MRS-TU-2019 Mean (+/- SD) Pharmacokinetic Plasma T and DHT 
Concentration Curves (ng/dL) Overlaying Dose for SOV2012-F1
Group by Visit - Linear Scale
PKS
14.2.2.2.2.2.3
MRS-TU-2019 Mean (+ SD) Pharmacokinetic Plasma T and DHT 
Concentration Curves (ng/dL) Overlaying Dose for SOV2012-F1
Group by Visit – Log-Linear Scale
PKS
14.2.2.2.2.2.4
MRS-TU-2019 Mean (+/- SD) Pharmacokinetic Plasma T Pre-
Morning Dose Concentration Curve (ng/dL) for SOV2012-F1 Group 
- Linear Scale
PKS
14.2.2.2.2.2.5
MRS-TU-2019 Mean (+/- SD) Pharmacokinetic Plasma T 12-hour 
Concentration Curves (ng/dL) at Visit 8 (Day 90) Overlaying 
Breakfast Diet Category for SOV2012-F1 Group – Linear Scale
PKS
14.2.2.2.2.2.6
MRS-TU-2019 Mean (+/- SD) Pharmacokinetic Plasma T 12-24
Hour Concentration Curves (ng/dL) at Visit 8 (Day 90) Overlaying 
Dinner Fat Category for SOV2012-F1 Group – Linear Scale
PKS
16.2.5.3.2.2
MRS-TU-2019 Individual Pharmacokinetic Plasma T Concentration 
Curves (ng/dL) for SOV2012-F1 Group Overlaying Visit by Subject 
- Linear Scale
PKS
14.2.2.2.3.2
MRS-TU-2019 Distributions of Plasma T Cavg and T Cmax for 
SOV2012-F1 Group on Visit 8 (Day 90) – Linear Scale
PKS
14.2.2.3.1.2
MRS-TU-2019 Mean (+/- SD) Pharmacokinetic Concentration 
Curves (ng/dL) at Visit 8 (Day 90) for AndroGel Group by Analyte -
Linear Scale
PKS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
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14.2.2.3.1.3
MRS-TU-2019 Mean (+ SD) Pharmacokinetic Concentration Curves 
(ng/dL) at Visit 8 (Day 90) for AndroGel Group by Analyte – Log-
Linear Scale
PKS
14.2.2.3.2.2
MRS-TU-2019 Mean (+/- SD) Pharmacokinetic Serum T and DHT 
Concentration Curves (ng/dL) at Visit 8 (Day 90) Overlaying Dose 
for AndroGel Group - Linear Scale
PKS
14.2.2.3.2.3
MRS-TU-2019 Mean (+ SD) Pharmacokinetic Serum T and DHT 
Concentration Curves (ng/dL) at Visit 8 (Day 90) Overlaying Dose 
for AndroGel Group – Log-Linear Scale
PKS
14.2.2.3.2.4
MRS-TU-2019 Mean (+/- SD) Pharmacokinetic Serum T Pre-
Morning Dose Concentration Curve (ng/dL) for AndroGel Group -
Linear Scale
PKS
16.2.5.3.2.3
MRS-TU-2019 Individual Pharmacokinetic Serum T Concentration 
Curves (ng/dL) at Visit 8 (Day 90) for AndroGel Group by Subject -
Linear Scale
PKS
14.3.4.1.2.1.5
eDISH Plot of MRS-TU-2019EXT Peak Post-baseline Total 
Bilirubin vs. Peak Post-baseline AST – Log-Log Scale
EXTS
14.3.4.1.2.1.6
eDISH Plot of MRS-TU-2019EXT Peak Post-baseline Total 
Bilirubin vs. Peak Post-baseline ALT – Log-Log Scale
EXTS
14.3.4.1.2.2.5
eDISH Plot of MRS-TU-2019 Peak Post-baseline Total Bilirubin vs. 
Peak Post-baseline AST by Treatment Group – Log-Log Scale
SS
14.3.4.1.2.2.6
eDISH Plot of MRS-TU-2020 Peak Post-baseline Total Bilirubin vs. 
Peak Post-baseline ALT by Treatment Group – Log-Log Scale
SS
14.3.4.1.5.1.1
MRS-TU-2019EXT Lipid Panel: Mean (+/- SE) Triglyceride and 
LDL Profiles  
EXTS
14.3.4.1.5.1.2
MRS-TU-2019EXT Lipid Panel: Mean (+/- SE) Triglyceride and 
LDL Profiles  
SS
14.3.4.2.1.1.1.2
MRS-TU-2019EXT Mean (+/- SE) Morning Time 0  In Clinic 
Predose Blood Pressure Profiles (All Data and Censored)
EXTS


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 Marius Pharmaceuticals  
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Final Version 5.0
  
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14.3.4.2.1.1.1.3
MRS-TU-2019EXT Mean (+/- SE) Change from Baseline In Clinic 
Time 0 Blood Pressure Profiles (All Data and Censored)
EXTS
14.3.4.2.1.1.1.4
MRS-TU-2019EXT Box Plot of Time 0 Systolic Blood Pressure 
Overlaying Visit (All Data and Censored)
EXTS
14.3.4.2.1.1.1.5
MRS-TU-2019EXT Box Plot of  Time 0  In Clinic Diastolic Blood 
Pressure Overlaying Visit (All Data and Censored)
EXTS
14.3.4.2.1.1.1.6
MRS-TU-2019EXT Cumulative Distribution Curve of  Time 0 In 
Clinic Blood Pressure Overlaying Visit (All Data and Censored)
EXTS
14.3.4.2.1.4.1
MRS-TU-2019EXT Kaplan Meier Plot of the Days from Baseline to 
the First Occurrence of Stage 1 Hypertensive Event  (All Data and 
Censored)
EXTS
14.3.4.2.1.4.2
MRS-TU-2019EXT Kaplan Meier Plot of the Days from Baseline to 
the First Occurrence of Stage 2 Hypertensive Event  (All Data and 
Censored)
EXTS
14.3.4.2.1.4.3
MRS-TU-2019EXT Kaplan Meier Plot of the Days from Baseline to 
the First Occurrence of Stage 1 Hypertensive Event  with 
Confirmatory Events (All Data and Censored)
EXTS
14.3.4.2.1.4.4
MRS-TU-2019EXT Kaplan Meier Plot of the Days from Baseline to 
the First Occurrence of Stage 2 Hypertensive Event with 
Confirmatory Events (All Data and Censored)
EXTS
14.3.4.2.1.4.5
MRS-TU-2019EXT SOV Kaplan Meier Plot of the Days from 
Baseline to the First Occurrence of Stage 1 Hypertensive Event  with 
Confirmatory Events Overlaying Baseline Hypertensive Status (All 
Data and Censored)
EXTS
14.3.4.2.1.4.6
MRS-TU-2019EXT Kaplan Meier Plot of the Days from Baseline to 
the First Occurrence of Stage 2 Hypertensive Event  with 
Confirmatory Events Overlaying Baseline Hypertensive Status (All 
Data and Censored)
EXTS
14.3.4.2.1.5.1.1
MRS-TU-2019EXT Scatter Plot of Time 0  In Clinic Systolic Blood 
Pressure at Visit 6E versus 24-Hour Average Ambulatory Systolic 
Blood Pressure at Visit 7E (Day 1E) (All Data and Censored)
EXTS


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 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
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14.3.4.2.1.5.1.2
MRS-TU-2019EXT Scatter Plot of Time 0  In Clinic  Systolic Blood 
Pressure at Visit 6E versus Daytime Average Ambulatory Systolic 
Blood Pressure at Visit 7E (All Data and Censored)
EXTS
14.3.4.2.1.5.2.1
MRS-TU-2019EXT Scatter Plot of Time 0  In Clinic Systolic Blood 
Pressure at Visit 13E versus 24-Hour Average Ambulatory Systolic 
Blood Pressure at Visit 14E (All Data and Censored)
EXTS
14.3.4.2.1.5.2.2
MRS-TU-2019EXT Scatter Plot of Time 0 In Clinic  Systolic Blood 
Pressure at Visit 13E versus Daytime Average Ambulatory Systolic 
Blood Pressure at Visit 14E (All Data and Censored)
EXTS
14.3.4.2.1.5.3.1
MRS-TU-2019EXT Scatter Plot of  Time 0 In Clinic Systolic Blood 
Pressure at Visit 15E versus 24-Hour Average Ambulatory Systolic 
Blood Pressure at Visit 16E (All Data and Censored)
EXTS
14.3.4.2.1.5.3.2
MRS-TU-2019EXT Scatter Plot of Time 0 In Clinic  Systolic Blood 
Pressure at Visit 15E versus Daytime Average Ambulatory Systolic 
Blood Pressure at Visit 16E (All Data and Censored)
EXTS
14.3.4.2.1.5.4.1
MRS-TU-2019EXT Scatter Plot of Time 0  In Clinic  Diastolic Blood 
Pressure at Visit 6E versus 24-Hour Average Ambulatory Diastolic 
Blood Pressure at Visit 7E (All Data and Censored)
EXTS
14.3.4.2.1.5.4.2
MRS-TU-2019EXT Scatter Plot of Time 0 In Clinic   Diastolic Blood 
Pressure at Visit 6E versus Daytime Average Ambulatory Diastolic 
Blood Pressure at Visit 7E (All Data and Censored)
EXTS
14.3.4.2.1.5.5.1
MRS-TU-2019EXT Scatter Plot of In Clinic Time 0  Diastolic Blood 
Pressure at Visit 13E versus 24-Hour Average Ambulatory Diastolic 
Blood Pressure at Visit 14E (All Data and Censored)
EXTS
14.3.4.2.1.5.5.2
MRS-TU-2019EXT Scatter Plot of Time 0  In Clinic  Diastolic Blood 
Pressure at Visit 13E versus Daytime Average Ambulatory Diastolic 
Blood Pressure at Visit 14E (All Data and Censored)
EXTS
14.3.4.2.1.5.6.1
MRS-TU-2019EXT Scatter Plot of Time 0 In Clinic  Diastolic Blood 
Pressure at Visit 15E versus 24-Hour Average Ambulatory Diastolic 
Blood Pressure at Visit 16E (All Data and Censored)
EXTS


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 Marius Pharmaceuticals  
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Final Version 5.0
  
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14.3.4.2.1.5.6.2
MRS-TU-2019EXT Scatter Plot of Time 0 In Clinic  Diastolic Blood 
Pressure at Visit 15E versus Daytime Average Ambulatory Diastolic 
Blood Pressure at Visit 16E (All Data and Censored)
EXTS
14.3.4.2.1.6.1.1
MRS-TU-2019EXT Scatter Plot of Change from Baseline Time 0  In 
Clinic  Systolic Blood Pressure at Visit 13E versus 24-Hour Average 
Change from Baseline in Ambulatory Systolic Blood Pressure at 
Visit 14E (All Data and Censored)
EXTS
14.3.4.2.1.6.1.2
MRS-TU-2019EXT Scatter Plot of Change from Baseline Time 0  In 
Clinic Systolic Blood Pressure at Visit 13E versus Daytime Average 
Change from Baseline in Ambulatory Systolic Blood Pressure at 
Visit 14E (All Data and Censored)
EXTS
14.3.4.2.1.6.2.1
MRS-TU-2019EXT Scatter Plot of Change from Baseline Time 0  In 
Clinic Systolic Blood Pressure at Visit 15E versus 24-Hour Average 
Change from Baseline in Ambulatory Systolic Blood Pressure at 
Visit 16E (All Data and Censored)
EXTS
14.3.4.2.1.6.2.2
MRS-TU-2019EXT Scatter Plot of Change from Baseline Time 0  In 
Clinic Systolic Blood Pressure at Visit 15E versus Daytime Average 
Change from Baseline in Ambulatory Systolic Blood Pressure at 
Visit 16E (All Data and Censored)
EXTS
14.3.4.2.1.6.3.1
MRS-TU-2019EXT Scatter Plot of Change from Baseline Time 0  In 
Clinic Diastolic Blood Pressure at Visit 13E versus 24-Hour Average 
Change from Baseline in Ambulatory Diastolic Blood Pressure at 
Visit 14E (All Data and Censored)
EXTS
14.3.4.2.1.6.3.2
MRS-TU-2019EXT Scatter Plot of Change from Baseline Time 0  In 
Clinic Diastolic Blood Pressure at Visit 13E versus Daytime Average 
Change from Baseline in Ambulatory Diastolic Blood Pressure at 
Visit 14E (All Data and Censored)
EXTS
14.3.4.2.1.6.4.1
MRS-TU-2019EXT Scatter Plot of Change from Baseline Time 0  In 
Clinic Diastolic Blood Pressure at Visit 15E versus 24-Hour Average 
Change from Baseline in Ambulatory Diastolic Blood Pressure at 
Visit 16E (All Data and Censored)
EXTS
14.3.4.2.1.6.4.2
MRS-TU-2019EXT Scatter Plot of Change from Baseline Time 0  In 
Clinic Diastolic Blood Pressure at Visit 15E versus Daytime Average 
Change from Baseline in Ambulatory Diastolic Blood Pressure at 
Visit 16E (All Data and Censored)
EXTS


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 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
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14.3.4.2.1.7.2
MRS-TU-2019EXT Box Plot of Time 0 In Clinic Systolic Blood 
Pressure by MRS-TU-2019 Treatment Group Overlaying Washout 
Visit (All Data and Censored)
All Continuing SOV 
Subjects
14.3.4.2.1.7.3
MRS-TU-2019EXT Box Plot of Time 0 Diastolic Blood Pressure by 
MRS-TU-2019 Treatment Group Overlaying Washout Visit (All Data 
and Censored)
All Continuing SOV 
Subjects
14.3.4.2.2.2.1
MRS-TU-2019 Mean (+/- SE) Time 0 In Clinic Fasting Blood 
Pressure Profiles Overlaying Treatment Group (All Data and 
Censored)
SS
14.3.4.2.2.2.2
MRS-TU-2019 Mean (+/- SE Change from Baseline Time 0 In Clinic 
Fasting Blood Pressure Profiles Overlaying Treatment Group (All 
Data and Censored)
SS
14.3.4.2.2.2.3
MRS-TU-2019 Mean (+/- SE) Change from Baseline Time 0 In 
Clinic Vital Signs for Fasting Visits Overlaying Baseline 
Hypertension Classification by Treatment Group (All Data and 
Censored)
SS
14.3.4.2.2.4.2.1
Cumulative Distribution Curve of Change from Baseline in 24-Hour
Mean In Clinic Systolic Blood Pressure Overlaying Visit for MRS-
TU-2019 SOV2012-F1 Group (All Data and Censored)
SS
14.3.4.2.2.4.2.2
Histogram of Categorical Change from Baseline to Visit 4 (Day 14) 
in 24-Hour Mean In Clinic Systolic Blood Pressure for MRS-TU-
2019 SOV2012-F1 Group (All Data and Censored)
SS
14.3.4.2.2.4.2.3
Histogram of Categorical Change from Baseline to Visit 6 (Day 42) 
in 24-Hour Mean In Clinic Systolic Blood Pressure for MRS-TU-
2019 SOV2012-F1 Group (All Data and Censored)
SS
14.3.4.2.2.4.2.4
Histogram of Categorical Change from Baseline to Visit 8 (Day 90) 
in 24-Hour Mean In Clinic Systolic Blood Pressure for MRS-TU-
2019 Overlaying Treatment Group  (All Data and Censored)
SS
14.3.4.2.2.4.2.5
Cumulative Distribution Curve of Change from Baseline  in 24-Hour 
Mean In Clinic Diastolic Blood Pressure Overlaying Visitfor MRS-
TU-2019 SOV2012-F1 Group (All Data and Censored)
SS
14.3.4.2.2.4.2.6
Histogram of Categorical Change from Baseline to Visit 4 (Day 14) 
in 24-Hour Mean In Clinic Diastolic Blood Pressure for MRS-TU-
2019 SOV2012-F1 Group (All Data and Censored)
SS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 161 of 193 
14.3.4.2.2.4.2.7
Histogram of Categorical Change from Baseline to Visit 6 (Day 42) 
in 24-Hour Mean In Clinic Diastolic Blood Pressure for MRS-TU-
2019 SOV2012-F1 Group (All Data and Censored)
SS
14.3.4.2.2.4.2.8
Histogram of Categorical Change from Baseline to Visit 8 (Day 90) 
in 24-Hour Mean In Clinic Diastolic Blood Pressure for MRS-TU-
2019 Overlaying Treatment Group  (All Data and Censored)
SS
14.3.4.2.2.6.1
MRS-TU-2019 Kaplan Meier Plot of the Days from Baseline to the 
First Occurrence of Stage 1 Hypertensive Event by Treatment Group
(All Data and Censored)
SS
14.3.4.2.2.6.2
MRS-TU-2019 Kaplan Meier Plot of the Days from Baseline to the 
First Occurrence of Stage 2 Hypertensive Event by Treatment Group 
(All Data and Censored)
SS
14.3.4.2.2.6.3
MRS-TU-2019 Kaplan Meier Plot of the Days from Baseline to the 
First Occurrence of Stage 1 Hypertensive Event with Confirmatory 
Events by Treatment Group (All Data and Censored)
SS
14.3.4.2.2.6.4
MRS-TU-2019 Kaplan Meier Plot of the Days from Baseline to the 
First Occurrence of Stage 2 Hypertensive Event with Confirmatory 
Events by Treatment Group (All Data and Censored)
SS
14.3.4.2.2.6.5
MRS-TU-2019   Kaplan Meier Plot of the Days from Baseline to the 
First Occurrence of Stage 1 Hypertensive Event  with Confirmatory 
Events Overlaying Baseline Hypertensive Status in SOV2012-F1
Treated Subjects (All Data and Censored)
SS
14.3.4.2.1.6.6
MRS-TU-2019  Kaplan Meier Plot of the Days from Baseline to the 
First Occurrence of Stage 2 Hypertensive Event  with Confirmatory 
Events Overlaying Baseline Hypertensive Status in SOV2012-F1
Treated Subjects(All Data and Censored)
SS
14.3.4.2.1.6.7
MRS-TU-2019   Kaplan Meier Plot of the Days from Baseline to the 
First Occurrence of Stage 1 Hypertensive Event  with Confirmatory 
Events Overlaying Baseline Hypertensive Status in Androgel Treated 
Subjects (All Data and Censored)
SS
14.3.4.2.1.6.8
MRS-TU-2019  Kaplan Meier Plot of the Days from Baseline to the 
First Occurrence of Stage 2 Hypertensive Event  with Confirmatory 
Events Overlaying Baseline Hypertensive Status in Androgel Treated 
Subjects(All Data and Censored)
SS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 162 of 193 
14.3.4.2.2.7.1
Plot of In Clinic Mean Systolic Blood Pressure and Mean Plasma T 
Concentration vs. Time for MRS-TU-2019 SOV2012-F1 Group by 
Visit (All Data and Censored)
PKS
14.3.4.2.2.7.2
Plot of In Clinic Mean Diastolic Blood Pressure and Mean Plasma T 
Concentration vs. Time for MRS-TU-2019 SOV2012-F1 Group by 
Visit (All Data and Censored)
PKS
14.3.4.2.2.7.3
Plot of In Clinic Mean Heart Rate and Mean Plasma T Concentration 
vs. Time for MRS-TU-2019 SOV2012-F1 Group by Visit (All Data 
and Censored)
PKS
14.3.4.2.2.7.4
Plot of In Clinic Mean Systolic Blood Pressure and Mean Plasma T 
Concentration vs. Time at Visit 8 (Day 90) for MRS-TU-2019
AndroGel Group (All Data and Censored)
PKS
14.3.4.2.2.7.5
Plot of In Clinic Mean Diastolic Blood Pressure and Mean Plasma T 
Concentration vs. Time at Visit 8 (Day 90) for MRS-TU-2019
AndroGel Group (All Data and Censored)
PKS
14.3.4.2.2.7.6
Plot of Mean Heart Rate and Mean Plasma T Concentration vs. Time 
at Visit 8 (Day 90) for MRS-TU-2019 AndroGel (All Data and 
Censored)
PKS
14.3.4.3.1.1.2.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic
Blood Pressure: Box Plot of 24-hour Average Ambulatory Systolic 
Blood Pressure Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.1.1.2.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Box Plot of Daytime Average Ambulatory Systolic 
Blood Pressure Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.1.1.2.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Box Plot of Nighttime Average Ambulatory Systolic 
Blood Pressure Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.1.1.3.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Cumulative Distribution Curve of 24-hour Average 
Ambulatory Systolic Blood Pressure Overlaying Visit (All Data and 
Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 163 of 193 
14.3.4.3.1.1.3.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Cumulative Distribution Curve of Daytime Average 
Ambulatory Systolic Blood Pressure Overlaying Visit (All Data and 
Censored)
EXTS
14.3.4.3.1.1.3.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Cumulative Distribution Curve of Nighttime 
Average Ambulatory Systolic Blood Pressure Overlaying Visit (All 
Data and Censored)
EXTS
14.3.4.3.1.1.4.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Forest Plot of Least Squares Mean Differences (95% 
CIs) Between Visits in 24-hour Average Ambulatory Systolic Blood 
Pressure (mmHg) (All Data and Censored)
EXTS
14.3.4.3.1.1.4.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Forest Plot of Least Squares Mean Differences (95% 
CIs) Between Visits in Daytime Average Ambulatory Systolic Blood 
Pressure (mmHg) (All Data and Censored)
EXTS
14.3.4.3.1.1.4.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Forest Plot of Least Squares Mean Differences (95% 
CIs) Between Visits in Nighttime Average Ambulatory Systolic
Blood Pressure (mmHg) (All Data and Censored)
EXTS
14.3.4.3.1.2.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Cumulative Distribution Curve of  Categorical 
Change from Baseline Overlaying Visit 14E (Day 120E) and Visit 
16E (Day 180E) in 24-hour Average Ambulatory Systolic Blood 
Pressure (All Data and Censored)
EXTS
14.3.4.3.1.2.4
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Histogram of Categorical Change from Baseline to 
Visit 14E (Day 120E) in 24-hour Average Ambulatory Systolic 
Blood Pressure (All Data and Censored)
EXTS
14.3.4.3.1.2.5
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Histogram of Categorical Change from Baseline to 
Visit 16E (Day 180E) in 24-hour Average Ambulatory Systolic 
Blood Pressure (All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 164 of 193 
14.3.4.3.1.4.1.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic
Blood Pressure: Mean  Half-Hourly Ambulatory Systolic Blood 
Pressure by Half-Hourly Elapsed Time From ABPM Start Overlaying 
Visit (All Data and Censored)
EXTS
14.3.4.3.1.4.1.4
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Mean  Half-Hourly Ambulatory Systolic Blood 
Pressure by Half-Hourly Elapsed Time From ABPM Start Overlaying 
Visit (All Data and Censored)
EXTS - ABPM 
Completers
14.3.4.3.1.4.1.5
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Mean  Half-Hourly Time Matched Changes from
Baseline in Ambulatory Systolic Blood Pressure by Half-Hourly 
Elapsed Time From ABPM Start Overlaying Visit (All Data and 
Censored)
EXTS
14.3.4.3.1.4.1.6
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Mean   Half-Hourly Time Matched Changes from 
Baseline in Ambulatory Systolic Blood Pressure by Half-Hourly 
Elapsed Time From ABPM Start Overlaying Visit (All Data and 
Censored)
EXTS - ABPM 
Completers
14.3.4.3.1.4.2.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Mean   Half-Hourly Ambulatory Systolic Blood 
Pressure by Half-Hourly Clock Time Intervals Overlaying Visit (All 
Data and Censored)
EXTS
14.3.4.3.1.4.2.4
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic
Blood Pressure: Mean Half-Hourly Ambulatory Systolic Blood 
Pressure by Half-Hourly Clock Time Intervals Overlaying Visit (All 
Data and Censored)
EXTS - ABPM 
Completers
14.3.4.3.1.4.2.5
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Mean   Half-Hourly Time Matched Changes from 
Baseline in Ambulatory Systolic Blood Pressure by Half-Hourly 
Clock Time Intervals Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.1.4.2.6
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic
Blood Pressure: Mean  Half-Hourly Time Matched Changes from 
Baseline in Ambulatory Systolic Blood Pressure by Half-Hourly 
Clock Time Intervals Overlaying Visit (All Data and Censored)
EXTS - ABPM 
Completers


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 165 of 193 
14.3.4.3.1.4.3.1
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Box Plot of 24-hour Average Ambulatory Systolic 
Blood Pressure Overlaying Dose- Visit 14E (All Data and Censored)
EXTS
14.3.4.3.1.4.3.2
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Box Plot of 24-hour Average Ambulatory Systolic 
Blood Pressure Overlaying Dose- Visit 16E (All Data and Censored)
EXTS
14.3.4.3.1.4.3.3
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Box Plot of Daytime Average Ambulatory Systolic
Blood Pressure Overlaying Dose- Visit 14E (All Data and Censored)
EXTS
14.3.4.3.1.4.3.4
Primary MRS-TU-2019EXT ABPM Parameter Ambulatory Systolic 
Blood Pressure: Box Plot of Daytime Average Ambulatory Systolic 
Blood Pressure Overlaying Dose- Visit 16E (All Data and Censored)
EXTS
14.3.4.3.2.1.2.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Box Plot of 24-hour Average Ambulatory Diastolic Blood 
Pressure Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.2.1.2.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Box Plot of Daytime Average Ambulatory Diastolic Blood 
Pressure Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.2.1.2.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Box Plot of Nighttime Average Ambulatory Diastolic 
Blood Pressure Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.2.1.3.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Cumulative Distribution Curve of 24-hour Average 
Ambulatory Diastolic Blood Pressure Overlaying Visit (All Data and 
Censored)
EXTS
14.3.4.3.2.1.3.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Cumulative Distribution Curve of Daytime Average 
Ambulatory Diastolic Blood Pressure Overlaying Visit (All Data and 
Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 166 of 193 
14.3.4.3.2.1.3.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Cumulative Distribution Curve of Nighttime Average 
Ambulatory Diastolic Blood Pressure Overlaying Visit (All Data and 
Censored)
EXTS
14.3.4.3.2.1.4.1
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Forest Plot of Least Squares Mean Differences (95% CIs) 
Between Visits in 24-hour Average Ambulatory Diastolic Blood 
Pressure (mmHg) (All Data and Censored)
EXTS
14.3.4.3.2.1.4.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Forest Plot of Least Squares Mean Differences (95% CIs)
Between Visits in Daytime Average Ambulatory Diastolic Blood 
Pressure (mmHg) (All Data and Censored)
EXTS
14.3.4.3.2.1.4.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Forest Plot of Least Squares Mean Differences (95% CIs) 
Between Visits in Nighttime Average Ambulatory Diastolic Blood 
Pressure (mmHg) (All Data and Censored)
EXTS
14.3.4.3.2.2.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure:Cumulative Distribution Curve of Change from Baseline 
Overlaying Visit 14E (Day 120E) and Visit 16E (Day 180E) in 
24-hour Average Ambulatory Diastolic Blood Pressure (All Data and 
Censored)
EXTS
14.3.4.3.2.2.4
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Histogram of Categorical Change from Baseline to 
Visit 14E (Day 120E) in 24-hour Average Ambulatory Diastolic 
Blood Pressure (All Data and Censored)
EXTS
14.3.4.3.2.2.5
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Histogram of Categorical Change from Baseline to 
Visit 16E (Day 180E) in 24-hour Average Ambulatory Diastolic 
Blood Pressure (All Data and Censored)
EXTS
14.3.4.3.2.4.1.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Mean   Half-Hourly Ambulatory Diastolic Blood Pressure 
by Half-Hourly Elapsed Time From ABPM Start Overlaying Visit 
(All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 167 of 193 
14.3.4.3.2.4.1.4
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Mean  Half-Hourly Ambulatory Diastolic Blood Pressure 
by Half-Hourly Elapsed Time From ABPM Start Overlaying Visit
(All Data and Censored)
EXTS - ABPM 
Completers
14.3.4.3.2.4.1.5
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Mean   Half-Hourly Time Matched Changes from Baseline 
in Ambulatory Diastolic Blood Pressure by Half-Hourly Elapsed 
Time From ABPM Start Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.2.4.1.6
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Mean  Half-Hourly Time Matched Changes from Baseline 
in Ambulatory Diastolic Blood Pressure by Half-Hourly Elapsed 
Time From ABPM Start Overlaying Visit (All Data and Censored)
EXTS - ABPM 
Completers
14.3.4.3.2.4.2.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Mean  Half-Hourly Ambulatory Diastolic Blood Pressure 
by Half-Hourly Clock Time Intervals Overlaying Visit (All Data and 
Censored)
EXTS
14.3.4.3.2.4.2.4
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Mean   Half-Hourly Ambulatory Diastolic Blood Pressure 
by Half-Hourly Clock Time Intervals Overlaying Visit (All Data and 
Censored)
EXTS - ABPM 
Completers
14.3.4.3.2.4.2.5
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Mean   Half-Hourly Time Matched Changes from Baseline 
in Ambulatory Diastolic Blood Pressure by Half-Hourly Clock Time 
Intervals Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.2.4.2.6
MRS-TU-2019EXT ABPM Parameter Ambulatory Diastolic Blood 
Pressure: Mean  Half-Hourly Time Matched Changes from Baseline 
in Ambulatory Diastolic Blood Pressure by Half-Hourly Clock Time 
Intervals Overlaying Visit (All Data and Censored)
EXTS - ABPM 
Completers
14.3.4.3.3.1.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Box 
Plot of 24-hour Average Ambulatory Heart Rate Overlaying Visit 
(All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 168 of 193 
14.3.4.3.3.1.4
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: 
Forest Plot of Least Squares Mean Differences (95% CIs) Between 
Visits in 24-hour Average Ambulatory Heart Rate (bpm) (All Data 
and Censored)
EXTS
14.3.4.3.3.2.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Mean  
Half-Hourly Ambulatory Heart Rate by Half-Hourly Elapsed Time 
From ABPM Start Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.3.2.1.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Mean  
Half-Hourly Time Matched Changes from Baseline in Ambulatory 
Heart Rate by Half-Hourly Elapsed Time From ABPM Start 
Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.3.2.2.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Mean  
Half-Hourly Ambulatory Heart Rate by Half-Hourly Clock Time 
Intervals Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.3.2.2.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Heart Rate: Mean 
Half-Hourly Time Matched Changes from Baseline in Ambulatory 
Heart Rate by Half-Hourly Clock Time Intervals Overlaying Visit
(All Data and Censored)
EXTS
14.3.4.3.4.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial 
Pressure: Box Plot of 24-hour Average Ambulatory Mean Arterial 
Pressure Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.4.1.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial 
Pressure: Cumulative Distribution Curve of 24-hour Average 
Ambulatory Mean Arterial Pressure Overlaying Visit (All Data and 
Censored)
EXTS
14.3.4.3.4.1.4
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial 
Pressure: Forest Plot of Least Squares Mean Differences (95% CIs) 
Between Visits in 24-hour Average Ambulatory Mean Arterial 
Pressure (mmHg) (All Data and Censored)
EXTS
14.3.4.3.4.2.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial 
Pressure: Mean  Half-Hourly Ambulatory Mean Arterial Pressure by 
Half-Hourly Elapsed Time From ABPM Start Overlaying Visit (All 
Data and Censored)
EXTS
14.3.4.3.4.2.1.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial 
Pressure: Mean Half-Hourly Time Matched Changes from Baseline 
in Ambulatory Mean Arterial Pressure by Half-Hourly Elapsed Time 
From ABPM Start Overlaying Visit (All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 169 of 193 
14.3.4.3.4.2.2.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial 
Pressure: Mean Half-Hourly Ambulatory Mean Arterial Pressure by 
Half-Hourly Clock Time Intervals Overlaying Visit (All Data and 
Censored)
EXTS
14.3.4.3.4.2.2.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Mean Arterial 
Pressure: Mean  Half-Hourly Time Matched Changes from Baseline 
in Ambulatory Mean Arterial Pressure by Half-Hourly Clock Time 
Intervals Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.5.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: 
Box Plot of 24-hour Average Ambulatory Pulse Pressure Overlaying 
Visit (All Data and Censored)
EXTS
14.3.4.3.5.1.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: 
Cumulative Distribution Curve of 24-hour Average Ambulatory 
Pulse Pressure Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.5.1.4
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: 
Forest Plot of Least Squares Mean Differences (95% CIs) Between 
Visits in 24-hour Average Ambulatory Pulse Pressure (mmHg) (All
Data and Censored)
EXTS
14.3.4.3.5.2.1.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: 
Mean  Half-Hourly Ambulatory Pulse Pressure by Half-Hourly 
Elapsed Time From ABPM Start Overlaying Visit (All Data and 
Censored)
EXTS
14.3.4.3.5.2.1.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: 
Mean Half-Hourly Time Matched Changes from Baseline in 
Ambulatory Pulse Pressure by Half-Hourly Elapsed Time From 
ABPM Start Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.5.2.2.2
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: 
Mean  Half-Hourly Ambulatory Pulse Pressure by Half-Hourly Clock 
Time Intervals Overlaying Visit (All Data and Censored)
EXTS
14.3.4.3.5.2.2.3
MRS-TU-2019EXT ABPM Parameter Ambulatory Pulse Pressure: 
Mean  Half-Hourly Time Matched Changes from Baseline in 
Ambulatory Pulse Pressure by Half-Hourly Clock Time Intervals 
Overlaying Visit (All Data and Censored)
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 170 of 193 
14.3.4.3.5.4.1
MRS-TU-2019EXT Scatter Plot of ABPM Day 120E 24 Hour 
Average Systolic Blood Pressure versus Day 90E  In Clinic 24 Hour 
Cavg (All Data and Censored)
EXPK
14.3.4.3.5.4.2
MRS-TU-2019EXT Scatter Plot of ABPM  Day 120E 24 Hour 
Average Systolic Blood Pressure Change from Baseline versus Day 
90E In Clinic 24 Hour Cavg (All Data and Censored)
EXPK
14.3.4.3.5.4.3
MRS-TU-2019EXT Scatter Plot of ABPM Day 120E Daytime 
Average Systolic Blood Pressure versus Day 90E  24 Hour Cavg (All 
Data and Censored)
EXPK
14.3.4.3.5.4.4
MRS-TU-2019EXT Scatter Plot of ABPM  Day 120E Daytime 
Average Systolic Blood Pressure Change from Baseline versus Day 
90E  In Clinic 24 Hour Cavg (All Data and Censored)
EXPK
14.3.4.3.5.4.5.1.1
MRS-TU-2019EXT Scatter Plot of  Day 120E ABPM 24 Hour 
Average Systolic Blood Pressure versus Day 90E  Hemoglobin (All 
Data )
EXTS
14.3.4.3.5.4.5.1.2
MRS-TU-2019EXT Scatter Plot of  Day 120E ABPM Daytime 
Average Systolic Blood Pressure versus Day 90E  Hemoglobin (All 
Data )
EXTS
14.3.4.3.5.4.5.1.3
MRS-TU-2019EXT Scatter Plot of  Day 120E ABPM Nighttime 
Average Systolic Blood Pressure versus Day 90E  Hemoglobin (All 
Data )
EXTS
14.3.4.3.5.4.5.2.1
MRS-TU-2019EXT Scatter Plot of  Day 180E ABPM 24 Hour 
Average Systolic Blood Pressure versus Day 180E  Hemoglobin (All 
Data )
EXTS
14.3.4.3.5.4.5.2.2
MRS-TU-2019EXT Scatter Plot of  Day 180E ABPM Daytime 
Average Systolic Blood Pressure versus Day 180E  Hemoglobin (All 
Data )
EXTS
14.3.4.3.5.4.5.2.3
MRS-TU-2019EXT Scatter Plot of  Day 180E ABPM Nighttime 
Average Systolic Blood Pressure versus Day 180E  Hemoglobin (All 
Data )
EXTS
14.3.4.3.5.4.6.1.1
MRS-TU-2019EXT Scatter Plot of Day 120E  ABPM  24 Hour 
Average Systolic Blood Pressure Change from Baseline versus Day
90E  Hemoglobin Change from Baseline (All Data )
EXTS


Statistical Analysis Plan 
 Marius Pharmaceuticals  
Protocols MRS-TU-2019 and MRS-TU-2019EXT 
Final Version 5.0
  
This document is proprietary and confidential to Marius Pharmaceuticals, LLC.
  .............................................................................................. Page 171 of 193 
14.3.4.3.5.4.6.1.2
MRS-TU-2019EXT Scatter Plot of Day 120E  ABPM  Daytime 
Average Systolic Blood Pressure Change from Baseline versus Day 
90E  Hemoglobin Change from Baseline (All Data )
EXTS
14.3.4.3.5.4.6.1.3
MRS-TU-2019EXT Scatter Plot of Day 120E  ABPM  Nighttime 
Average Systolic Blood Pressure Change from Baseline versus Day 
90E  Hemoglobin Change from Baseline (All Data )
EXTS
14.3.4.3.5.4.6.2.1
MRS-TU-2019EXT Scatter Plot of Day 180E  ABPM 24 Hour 
Average Systolic Blood Pressure Change from Baseline versus Day 
180E  Hemoglobin Change from Baseline (All Data )
EXTS
14.3.4.3.5.4.6.2.2
MRS-TU-2019EXT Scatter Plot of Day 180E  ABPM  Daytime 
Average Systolic Blood Pressure Change from Baseline versus Day 
180E  Hemoglobin Change from Baseline (All Data )
EXTS
14.3.4.7.1.4
Final Dose of SOV2012-F1 at Visit 12E (Day 90E) –
MRS-TU-2019EXT
EXTS
14.3.4.7.2.2.3
Final Study Drug Dose at Visit 8 (Day 90) – MRS-TU-2019
SOV2012-F1 Group
SS
14.3.4.7.2.3.3
Final Study Drug Dose at Visit 8 (Day 90) – MRS-TU-2019
AndroGel Group
SS
14.3.4.3.5.4.6.2.3
MRS-TU-2019EXT Scatter Plot of Day 180E  ABPM  Nighttime 
Average Systolic Blood Pressure Change from Baseline versus Day 
180E  Hemoglobin Change from Baseline (All Data )
EXTS


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16.1.3.
Index of Listings
Listing Number
Name
Analysis Set
16.2.1.1
Subject Disposition at MRS-TU-2019EXT End of 
Screening
All Subjects Providing Written Informed 
Consent for MRS-TU-2019EXT
16.2.1.2
Subject Disposition at MRS-TU-2019EXT End of 
Treatment
EXTS
16.2.1.3
Subject Disposition at MRS-TU-2019 End of 
Screening
All MRS-TU-2019 Screened Subjects
16.2.1.4 
Subject Disposition at MRS-TU-2019 End of 
Treatment
SS
16.2.1.5
Subject Disposition at Bioanalytical Sub-study End of 
Screening
All Subjects Providing Written Informed 
Consent for BSSS
16.2.2.1
Protocol Deviations
SS and EXTS
16.2.3.1
Inclusion Criteria Not Met
All Screened Subjects
16.2.3.2
Exclusion Criteria Met
All Screened Subjects
16.2.3.3
Analysis Sets
All Subjects Randomized and/or Treated  in 
MRS-TU-2019 and/or Enrolled in MRS-TU-
2019EXT
16.2.4.1
Baseline and Demographic Characteristics
All Screened Subjects
16.2.4.1.1
Subgroup Listing
SS
16.2.4.1.2
Subgroup Listing
EXTS
16.2.4.2.1
Medical/Surgical History
SS and EXTS
16.2.4.2.2
Medical History - Hypogonadism
SS and EXTS
16.2.4.3.1
Symptoms and Signs Suggestive of Androgen 
Deficiency – Presenting or Past
SS and EXTS
16.2.4.3.2
Automated Self-Administered 24-Hour Recall System 
Record
SS and EXTS
16.2.4.4
Prior and Concomitant Medications
SS and EXTS
16.2.5.1.1.1
Study Drug Administration – MRS-TU-2019EXT
SOV2012-F1
EXTS – MRS-TU-2019 AndroGel Subjects 
and Newly Enrolled Subjects 


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16.2.5.1.1.2
Study Drug Administration for MRS-TU-2019 and
MRS-TU-2019EXT – MRS-TU-2019 SOV2012-F1
Group
SS
16.2.5.1.1.3
Study Drug Administration - AndroGel
SS
16.2.5.1.2.1
Study Dose Titration and Drug Exposure – MRS-TU-
2019EXT SOV2012-F1
EXTS – MRS-TU-2019 AndroGel Subjects 
and Newly Enrolled Subjects
16.2.5.1.2.2
Study Dose Titration and Drug Exposure for MRS-
TU-2019 and MRS-TU-2019EXT – MRS-TU-2019 
SOV2012-F1 Group
SS
16.2.5.1.2.3
Study Dose Titration and Drug Exposure - AndroGel
SS
16.2.5.1.3
SOV2012-F1 on Site Meal Record
OSS
16.2.5.2.1
MRS-TU-2019EXT Study Drug Compliance -
SOV2012-F1
EXTS
16.2.5.2.2
MRS-TU-2019 Study Drug Compliance - SOV2012-
F1 Group
SS
16.2.5.2.3
MRS-TU-2019 Study Drug Compliance - AndroGel 
Group
SS
16.2.5.3.1
Pharmacokinetic Concentrations
SS and EXTS
16.2.5.3.2.1
MRS-TU-2019EXT Pharmacokinetic Parameters -
SOV2012-F1 Group
EXTS
16.2.5.3.2.2
MRS-TU-2019EXT Pharmacokinetic Parameters 
DHT/T and E2/T Ratio - SOV2012-F1 Group
EXTS
16.2.5.3.3.1
MRS-TU-2019 Pharmacokinetic Parameters -
SOV2012-F1 Group
SS
16.2.5.3.3.2
MRS-TU-2019 Pharmacokinetic Parameters DHT/T 
and E2/T Ratio - SOV2012-F1 Group
SS
16.2.5.3.3.3
MRS-TU-2019 Pharmacokinetic Parameters -
AndroGel Group
SS
16.2.5.3.3.4
MRS-TU-2019 Pharmacokinetic Parameters DHT/T 
and E2/T Ratio - AndroGel Group
SS
16.2.5.3.4
MRS-TU-2019EXT Projected Dose Adjustments
SS
16.2.5.3.5
Blood Draw for Bioanalytical Stability
All Subjects Providing Written Informed
Consent for BSSS
16.2.6.1
Primary Efficacy Endpoint
SS and EXTS


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16.2.6.2
International Prostate Symptom Score
SS
16.2.6.3
Psychosexual Daily Questionnaire
SS
16.2.6.4
36-Item Short Form Survey Instrument
SS
16.2.6.5
International Index of Erectile Function Questionnaire
SS
16.2.6.6
Fasting Insulin and Fasting Serum Glucose
SS
16.2.7.1
All Adverse Events
SS and EXTS
16.2.8.1.1
Laboratory Reference Ranges
N/A
16.2.8.1.2
Hematology
SS and EXTS
16.2.8.1.3
Biochemistry
SS and EXTS
16.2.8.1.4
Urinalysis
SS and EXTS
16.2.8.1.5
Endocrinology: LH, FSH, SHBG and TSH 
Concentrations
SS and EXTS
16.2.8.1.6
Lipid Panel: TC, LDL, HDL and TGs
SS and EXTS
16.2.8.1.7
Serum PSA
SS and EXTS
16.2.8.1.8
Screening Total Serum Testosterone
All Screened Subjects
16.2.8.1.9
Urine Drug Screen
SS and EXTS
16.2.8.1.10
Hepatitis/HIV Screening
SS and EXTS
16.2.8.2.1.1
Vital Signs Collected at Screening and Predose
SS and EXTS
16.2.8.2.1.2
Blood Pressure Collected at 4-hr Intervals During the 
24-hour Pharmacokinetic Collection Period
SS
16.2.8.2.1.3
Vital Signs and Change from Baesline by Visit and 
Timepoint
SS and EXTS
16.2.8.2.1.4
Vital Sign Hypertension Classification
SS and EXTS
16.2.8.2.1.5.1
ABPM Data Collection
All MRS-TU-2019 Enrolled Subjects
16.2.8.2.1.5.2
Ambulatory Blood Pressure Monitoring 
All MRS-TU-2019 Enrolled Subjects
16.2.8.2.1.6
Ambulatory Blood Pressure Monitoring - 24 
hour/daytime/Nighttime Average
EXTS
16.2.8.2.1.7
Ambulatory Blood Pressure Monitoring Time from 7 
AM Part 1
EXTS
16.2.8.2.1.8
Ambulatory Blood Pressure Monitoring Time from 7 
AM Part 2
EXTS


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16.2.8.2.1.9
Ambulatory Blood Pressure Monitoring Time from 
ABPM Start Part 1
EXTS
16.2.8.2.1.10
Ambulatory Blood Pressure Monitoring Time from 
ABPM Start Part 2
EXTS
16.2.8.2.1.11
Ambulatory Blood Pressure Monitoring Hypertension 
Classification
EXTS
16.2.8.2.2
T Cmax Endpoints
SS and EXTS
16.2.8.2.3
12-Lead Electrocardiogram
SS and EXTS
16.2.8.2.4
Physical Examination
SS and EXTS
16.2.8.2.5
ACTH Stimulation Testing
AAS
16.2.
DERIVATION OF TITRATION ALGORITHM FOR SOV2012-F1
(TESTOSTERONE UNDECANOATE 200 MG) AND 
OPTIMIZATION OF TITRATION CUT-OFFS FOR 
EXTENSION STUDY
Introduction:
To minimize unnecessary exposure to higher than needed testosterone concentrations at the 
initiation of therapy, the MRS-TU-2019EXT (ABPM) study started all subjects on a lower 
starting dose of 400 mg daily (200mg a.m. dose, 200mg p.m. dose) than the 600 mg daily dose 
used in the MRS-TU-2019 study (400mg a.m. dose, 200mg p.m. dose).  Visit 4 and Visit 6 refer 
to the PK visits used to determine dose adjustments at Visits 5 and 7 in MRS-TU-2019.  Note 
that in MRS-TU-2019EXT, the PK data for dose titration is obtained at Visits 8E and 10E, with 
dose titration occurring at Visits 9E and 11E.
Methods:
Marius has carried out PK modeling and concordance simulations based on the 90-day efficacy 
results from MRS-TU-2019 (total 196 observed subjects data) for determining the optimum 
sampling window for titration decision. 


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Nonparametric superposition method was performed for modeling and simulation using a
validated Phoenix WinNonLin software ver6.4 (Certara, NJ, USA). For the 196 observed data 
from Phase III MRS-TU-2019 study, morning (0-12 hour) and evening (12-24 hour) PK 
concentrations were used separately to model and simulate PK profiles for lower starting dose in 
morning (200mg a.m.) or evening 200mg p.m. at Visit 4; and simulated morning concentrations 
were combined with evening concentrations to obtain simulated 24-hour PK profile. In total 138 
subjects’ data were converged on nonparametric superposition approach, and used for further 
simulations. An increment/decrement scale of 100mg/100mg were applied for the two 
opportunities of dose titrations at visit 5 (visit 9E in MRS-TU2019EXT) and visit 7 (visit 11E in 
MRS-TU2019EXT), respectively.
Trials with various cutoff combinations for up- and down-titrations were simulated, including 
cutoffs of 235, 300, 350, 400 and 450 ng/dL for up-titration as well as 800, 900, 1000, and 1120 
ng/dL for down-titration. With simulated profiles for visit 4, each simulated subject 
concentrations at a randomly selected postdose timepoint (from C3, or C4 or C5; randomization 
code generated in excel) was evaluated to make titration decisions. 
Subsequently, visit 6 PK concentrations were simulated based on the doses after titrations from 
visit 4, and the same rules (cutoffs) for titration decisions were applied again on simulated visit 
6. After second opportunity for up-, down-, or no-titration on simulated visit 6 results, visit 8 PK 
concentrations were in turn simulated to generate PK profiles for efficacy phase. The primary 
and secondary efficacy endpoints as well as the performance of titration algorithm (titration
concordance analysis) were evaluated based on simulated results from visit 4 (first titration visit), 
visit 6 (second titration visit), and visit 8 (efficacy phase). (Refer to Section 4.1 for primary and 
secondary efficacy endpoints; and Section 9.5 for titration algorithm concordance analysis).  
While the MRS-TU-2019 study used a window from 3 to 5 hours post-morning dose, the 
simulations also tested the effect of sampling 6 hours post-dose. After the identification of best 
titration cutoffs (400-900 ng/dL) for 200mg a.m./200mg p.m. starting dose, the same approaches 
were also utilized for modeling and simulations to test randomly selected C4, or C5 or C6 for 
titration decisions based on 400-900 ng/dL cutoffs. The primary and secondary efficacy 
endpoints as well as the concordance analysis were also analyzed.
Results:
These simulations used a normal range of 252 to 840 ng/dL (derived from a serum normal range 
of 300 to 1000 ng/dL with a factor of 0.84 for NaF/EDTA plasma samples). 
1) New cutoffs for titration decisions 








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A correlation was explored using scatterplots and linear regression (with regression coefficient) 
on Cmax vs. each timepoint of Cx on Phase III MRS-TU2019 study data (Figure 3). Table 19
summarizing regression coefficient indicates that there is a strong correlation (0.7~0.9) between 
Cmax and Cx from 3-5 h for Visit 4 and 6, and a moderate correlation (~0.5) between Cmax and Cx
for 6 h for Visit 4 and 6; while a poor correlation (<0.5) between Cmax and Cx for 0, 1.5, 8 and 12 
h for Visit 4 and 6. These correlation analysis suggested that 3-6 h postdose (but not 0, 1.5, 8 and 
12 h) may be suitable as the single blood draw window for making titration decisions.
Figure 3
Scatterplots of Cmax vs. Cx on Phase III MRS-TU-2019 study data
Cmax vs. C0
Cmax vs. C1.5


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Cmax vs. C3
Cmax vs. C4


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Cmax vs. C5
Cmax vs. C6


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Cmax vs. C8
Cmax vs. C12


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Table 17
Regression coefficient (R) for Cmax vs. Cx.
Cx
Correlation (R) at Visit 4
Correlation (R) at Visit 6
0h
0.18
0.07
1.5h
0.34
0.33
3h
0.72
0.86
4h
0.78
0.90
5h
0.69
0.67
6h
0.53
0.45
8h
0.46
0.18
12h
0.40
0.08
Concordance analysis on simulated data 3-6 hours postdose window


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Concordance analysis results are shown in Table 20 for C3, C4, C5, and C6 at visit 4 or visit 6 
respectively. The total concordance at visit 4 were approximately 82, 92 and 90% for C3, C4, 
and C5 respectively, while 73% for C6.  At visit 6, total concordance was only about 51% for C6 
while those for C3, C4, C5 were at 71-83%. These results confirm that the 3-5 h window is 
optimum. 
Cell definitions are given below the table. Note that Cells I and VI are omitted from the table, as 
there are no subjects in these categories. Numeric concordance records the percent of titration 
decisions based on Cx which are the same as if the decision was based on Cavg. Effective 
concordance records the percent of titration decisions where the titration based on Cx is incorrect with 
respect to Cavg, but the resulting Cavg remains within the normal range. 


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Table 20
Concordance Analysis (Cavg vs Cx) for MRS-TU-2019 for Time Post-Dose.
Time of T-
Concentration
Numeric 
Concordance (NC)
Effective
Concordance (EC)
Total
Concordance
(NC+EC)
Cells A+B+C
Cell II
Cell III
Cell IV
Cell V
Visit 4 (T-measurement for first dose titration opportunity)
C3h
67.4
0
9.4
3.6
1.4
81.9
C4h
76.1
0
13.0
0.7
2.2
92.0
C5h
76.1
0
13.0
0
0.7
89.9
C6h
62.3
0
10.9
0
0
73.2
Visit 6 (T-measurement for second dose titration opportunity)
C3h
61.6
0
7.2
1.4
0.7
71.0
C4h
70.3
0
10.9
0.7
1.4
83.3
C5h
63.0
0
10.9
0.7
0.7
75.3
C6h
44.9
0
6.5
0
0
51.4
The cells used for the concordance calculation as defined as: 
Cell A: T-concentration < up-titration threshold and Cavg < lower limit of normal range. 
Cell B: T-concentration between titration thresholds and Cavg within normal range. 
Cell C: T-concentration > down-titration threshold and Cavg > upper limit of normal range. 
Cell I: T-concentration < up-titration threshold and Cavg > upper limit of normal range. No subjects are 
found in this category and the cell is not included in concordance results. 
Cell II: T-concentration between titration thresholds and Cavg > upper limit of normal range 
Cell III: T-concentration < up-titration threshold and Cavg within normal range 


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Cell IV: T-concentration between titration thresholds and Cavg < lower limit of normal range 
Cell V: T-concentration > down-titration threshold and Cavg within normal range 
Cell VI: T-concentration > down-titration threshold and Cavg < lower limit of normal range. No subjects 
are found in this category and the cell is not included in concordance results.
Conclusions:
Modeling and simulations based on Phase III MRS-TU2019 study data demonstrates that the 400-900
ng/dL up- and down-titration cutoffs are appropriate for 200mg a.m./200mg a.m. starting dose. 
Concordance analysis on simulated data identifies 3-5 h postdose as the appropriate window for single 
blood draw to make titration decisions.  These titration thresholds and starting dose are used in MRS-TU-
2019EXT.




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Efficacy Completers Set
n/a
Include
Extension Treated Set
n/a
Include
Overall Safety Set
n/a
Include
x
Subject ‘C’: Subject identifier 107274 and Subject identifier 1391174
Under the first randomization (SOV2012-f1 under Subject Identifier 107274), Subject ‘C’ received study 
drug but was lost to follow-up prior to any post baseline assessments. He enrolled at a different site about 
four months later and completed MRS-TU-2019 as Subject Identifier 1391174. As Subject ‘C’ was given 
study treatment under Subject Identifier 107274, he was deemed eligible for some study populations 
under this identifier. Subject ‘C’ was also included in most analysis sets under Subject Identifier 1381174.
Subject identifier 1381174 also participated in MRS-TU-2018EXT: 
Population
107274
1391174
Safety Set
Include
Include
Full Analysis Set
Include*
Include
Pharmacokinetic Set
Exclude
Include
Efficacy Completers Set
Exclude
Include
Extension Treated Set
n/a
Include
Overall Safety Set
Exclude**
Include
*Because Subject Identifier 107274 did not have any post baseline pk profiles, it will be treated as an efficacy failure.
**This exclusion is considered a conservative approach as Subject Identifier 107274 did not report any AEs.
Subject ‘C’ will be the only dual randomized subject with two subject identifiers being summarized in 
tables and figures in MRS-TU-2019.
All data from these six subject identifiers will be listed.
16.4.
OUTLIER ANALYSIS FOR SITE 104
16.4.1. Objective
The objective of this analysis is to develop an algorithm to identify outlier profiles that may indicate a 
process deviation.
Marius obtained at Day 90E 24-hr serum PK samples (for the MRS-TU-2019EXT Serum Substudy) in 
addition to the 24-hr NaF/EDTA plasma PK samples. Upon inspection of the data, the ratio of the 
NaF/EDTA plasma to serum values seemed anomalous .  Marius has previously examined these ratios, 


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such as in the Phase 2b study SOV-TU-PK2013 to understand the implications of using serum samples 
for TRT titration with SOV2012-F1.  
Laboratory and clinical data (e.g. SOV-TU-PK2013) have long shown that in properly acquired and 
handled samples, the serum value will generally equal or exceed the NaF/EDTA plasma value, especially 
at timepoints drawn during peak T or peak TU concentrations.  For Site 104, this ratio was consistently 
inverted over much (or all) of the PK timepoints for a substantial number of subjects.  These sets of 
observations prompted the outlier analysis.
16.4.2. Study Population
16.4.3. Sample Size
Data is provided by 103 subjects.
16.4.4. Data Analysis and Report
Analysis Population
This analysis utilizes all subjects with serum and plasma NaF/EDTA results from the serum substudy.
Statistical Analysis Methods
All serum and plasma results are natural log transformed prior to analysis.   
Within each subject and visit, the difference between plasma and serum is taken: Diff=plasma-serum. The 
distribution of this difference in natural log values is characterized by producing mean, median, and 
standard deviations.  
Each of these differences is evaluated for an outlier status by determining if it is outside the upper range 
as defined by 1.96*std which is in the upper 2.5 %.  Only the upper range is used since the expectation 
(the ‘null’ hypothesis) is that the serum would be greater than or equal to the plasma. 
H0: plasma <=serum.
Ha: plasma >serum
Next, then the number of individual outliers is counted within a profile to determine if a profile is in of 
itself an outlier. 
If the number of outliers within a profile (15 assessments within a profile) is required to be 4 or more, the 
outlier probability as determined by the hypergeometric distribution is 0.0003.  If the number of outliers 
within a profile (15 assessments within a profile) is required to be 3 or more, the outlier probability as 
determined by the hypergeometric distribution is 0.005.