Clinical trial NCT03452488
Conditions: Sarcopenia Gait Disorders in Old Age Muscle Weakness
Keywords: Sarcopenia Sarcopenic Obesity 6-minute walking distance 400 meters walking test BIO101 Short Physical Performance Battery Appendicular lean mass
Sponsor: Biophytis
Start date: 2017-02-07; Completion date: 2020-04-26
Enrollment: 233 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of the study is to evaluate the effect of two daily doses of BIO101 versus placebo on mobility function as measured by gait speed using the 400MW test. The absolute change from baseline in meters/second observed in each treatment group at 6 Month was compared to the placebo group. Due to the Covid pandemic \>50% of data at endpoint was missing, which may have affected the ability of the study to deliver the expected results. Additionally, although the planned duration of treatment was 6 months, it was extended up to 9 months for some participants as a result of the pandemic.

Detailed description:
The aim of this phase 2 double-blind, placebo-controlled, randomized interventional clinical trial (SARA-INT) is to evaluate the safety and efficacy of BIO-101 175 mg b.i.d. and 350 mg b.i.d. 9 months oral administration to participants suffering from age-related sarcopenia, including sarcopenic obesity, aged ≥65 years and at risk of mobility disability. There are 3-arms (2 doses versus placebo). This comparative clinical trial evaluated the effects up to 9 month treatment duration, based on the hypothesis that physical function of sarcopenic, older participants with an initial degree of mobility disability (SPPB) may be improved by BIO101.

Included participants were randomized in a 1:1:1 ratio, to one of the 3 arms of treatment in a blinded manner. The randomization was stratified by gender and by center. Based on absence of long-term toxicology data, the investigational drug exposure was initially capped at 6 months.

Arms: arm 1: Placebo was taken orally, two capsules twice daily (BID), 12 hours apart, up to 9 months. arm 2: BIO101 was taken orally, two capsules BID, 12 hours apart, up to 9 months. arm 3: BIO101 was taken orally, two capsules BID, 12 hours apart, up to 9 months.
Interventions: intervention 1: BIO101 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral capsules intervention 2: Oral capsules

Protocol documents:
Prot_000.pdf: 
The confidential information in this document is provided to you as an investigator, potential investigator or 
consultant for review by you, your staff and applicable Independent Ethics Committee or Review Board. It is 
understood that the information will not be disclosed to others without written authorisation from Biophytis S.A. 
 
 
 
Safety and efficacy of BIO-101 175 mg b.i.d. and 350 mg b.i.d. 
26-week oral administration to patients suffering from age-
related SARcopenia, including sarcopenic obesity, Aged ≥ 65 
years and at risk of mobility disability.  
A double-blind, placebo- controlled, randomized INTerventional 
clinical trial (SARA-INT). 
Protocol Number:  
BIO101-CL03 
National Clinical Trial (NCT) Identified Number: NCT03452488 
Phase:  
2 
Principal Investigator:  
 
 
 
 
 
 
 
Sponsor:  
BIOPHYTIS S.A. 
 
14 Avenue de l’Opéra 
 
75001 Paris France 
 
Tel. 
 
 
Sponsor Signatories:  
 
 
Clinical Development Director, Biophytis S.A 
 
 
 
Chief Medical Officer, Biophytis S.A 
Sponsor Medical Expert:  
 
Funded by:  
BIOPHYTIS S.A. 
Version Number:  
1.2.11, FINAL VERSION 
Date:  
20 APRIL 2020 
 


SARA-INT 
 
Addendeum 1 to the version 1.2.11,  
Biophytis Protocol: BIO101-CL03 
 
20 April 2020 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
Page II 
Summary of Changes from Previous Versions:  
Affected Section(s) 
Summary of Revisions Made 
Rationale 
3. Objectives and 
Endpoints 
400MW gait speed became the 
primary endpoint (replacing 6MWD) 
(starting on version 1.1.1) 
European Medicines Agency 
Scientific Advice (June 22, 2017) 
5. Study Population 
Low ALM (ALM <19.75kg in men and 
<15.02kg in women by DEXA scan) 
criterion added as an alternative 
sarcopenia cut-off point  
(starting on version 1.1.1) 
European Medicines Agency 
Scientific Advice (June 22, 2017) 
Protocol Template 
NIH-FDA Clinical Trial Protocol 
Template – v1.0 7 Apr 2017  
(starting on version 1.1.1) 
Updated standard 
Statement of 
Compliance 
EU adaptation  
(starting on version 1.1.2) 
EU coordinator signature added 
1.1 Synopsis 
2.2 Background  
5.2 Exclusion Criteria 
Adding one exclusion criterion, non-
clinical safety data update 
(starting on version 1.2.0) 
US FDA Regulatory considerations 
based on non-clinical safety data 
(STUDY MAY PROCEED OCT 31 
2017) 
1.1 Synopsis 
1.3 Schedule of 
Activities 
4.1 Overall Design 
Adding one investigation at baseline 
and Month6 visit, exposure capped at 
26 weeks 
Idem 
1.1 Synopsis 
1.3 Schedule of 
Activities 
2.3.1 Known 
potential risks 4.1 
Overall Design,  
7.1 Discontinuation 
of Study Intervention   
8.2 Safety and Other 
Assessments 
Safety: 1) Adding blood sampling for 
(haematology) and biochemistry at 
M1 and M3 visits; 2) Adding 
biochemistry parameters (D0, M1, M3 
and M6); 3) Defining stopping rules 
based on ULN; 4) Adding PK sampling 
at M1, M3 and M6  
(starting on version 1.2.2) 
Idem and FAMHP CTA NOV 28 2017  
8.1 Efficacy 
Assessment  
Option to add grip fatigue resistance 
sub-test  
(starting on version 1.2.2) 
Clarification 
6.2.2 Formulation, 
Appearance, 
Packaging and 
Labeling 
Modified description of the 
Therapeutic Unit 
Manufacturer’s requirements  
1.1 Synopsis 
Number of investigation centers 
Updated recruitment estimation 
per center  


SARA-INT 
 
Addendeum 1 to the version 1.2.11,  
Biophytis Protocol: BIO101-CL03 
 
20 April 2020 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
Page III 
1.3 Schedule of 
Activities 
Adding PK sampling at baseline (D1)  
 (starting on version 1.2.3) 
Editorial changes following FAMHP 
email 05 DEC 2017  
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
 will generate the randomization 
list and details are given on blinding of 
ICT staff and Sponsor staff. 
(starting on version 1.2.5) 
Decreasing (unintended) un-
blinding risks  
8.1 Efficacy 
Assessment 
Modified instructions and added 
reference to the use of the script for 
conducting the 400MW 
(starting on version 1.2.6) 
Correction and clarification of the 
test description  
8.3.4 Time Period 
and Frequency for 
Event Assessment 
and Follow-Up 
Possibility to order a blood sampling 
for PK analyses after a SAE 
(starting on version 1.2.5) 
Clarification of an implicit 
procedure 
8.3.6 Serious 
Adverse Events 
Reporting 
Cancelled: direct reporting to the 
Sponsor; SAE to be reported to the 
CRO 
 
(starting on version 1.2.5) 
Streamlining and simplifying of SAE 
reporting to a single recipient  
10.1.5 Key Roles and 
Study Governance 
Key role added: Bioanalytics for 
BIO101 plasma quantification center  
(starting on version 1.2.6) 
Identifying the responsible party for 
product quantification 
10.1.5 Key Roles and 
Study Governance 
Precision given on one of the tasks of 
the Adjudication Committee 
(starting on version 1.2.6) 
Detailing a procedure 
10.1.5 Key Roles and 
Study Governance 
Investigators/Sites list updated 
(starting on version 1.2.9) 
Based on administrative status 
1.1 Synopsis 
5.3. Exclusion 
Criteria 
Exclusion criteria “Febrile Illness 
within 7 days” removed 
(starting on version 1.2.9) 
Redundancy with temporary 
exclusion criteria 
1.1 Synopsis 
5.2 Non-inclusion 
criteria 
Non-inclusion criteria for French 
subjects added 
(starting on version 1.2.9) 
French CPP requirement 
10.1.5 Key Roles and 
Study Governance 
Key role added: Biostatistics for DSMB 
reviews  
(starting on version 1.2.9) 
Identifying the responsible for 
statistical analyses for DSMB 
reviews 
1.3 Schedule of 
Activities 
 
Maximum delay between screening 
tests and randomization date added 
(starting on version 1.2.9) 
Clarification 
4.1. Overall design 
 
PK Sub-Study timepoints of blood 
collection added 
Clarification 


SARA-INT 
 
Addendeum 1 to the version 1.2.11,  
Biophytis Protocol: BIO101-CL03 
 
20 April 2020 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
Page IV 
(starting on version 1.2.9) 
1.1 Synopsis 
2.1 Study rationale 
5.1 Inclusion criteria 
Definition of community dwelling 
subjects added 
(updated on version 1.2.10) 
Clarification 
10.1.5 Key roles and 
study governance 
Investigators/Sites list updated 
(updated on version 1.2.10) 
Based on administrative status 
10.1.6 Safety 
Oversight 
 
DSMB will meet quarterly (instead of 
at least – semi-annually at a 
minimum), for safety data review 
(efficacy review suppressed), every 3 
calendar months once the 25th patient 
is randomized (and not the first one) 
(starting on version 1.2.9) 
Clarification 
8.1 Efficacy 
Assessments 
Stair Climb Power 
Test (SCPT) 
 
Number of steps changed from 9 to 
10 with a 20 cm step height 
(harmonization of stair climb power 
test  assessment with literature/study 
scripts) 
(starting on version 1.2.10) 
Clarification 
1.1 Synopsis 
5.3 Exclusion Criteria 
 
Correction of a discrepancy of an 
exclusion criterion (occurrence of a 
safety concern during 6 MWT while 
the assessment is done after 
randomization).  
(starting on version 1.2.10) 
Clarification 
1.1 Synopsis 
1.2 Schema 
4.1 Overall Design 
5 Study Population 
9.2 Sample Size 
Determination 
Change in sample size from 334 to 
231 
(starting on version 1.2.10) 
New statistical analysis based on 
SARA-OBS study population 
preliminary analysis 
1.1 Synopsis 
3 Objectives and 
Endpoints 
9.4.1 General 
Approach 
9.4.3 Analysis of 
Secondary Endpoint 
(s) 
Removal of the chair stand sub-score 
of the SPPB as a key secondary 
endpoint 
(starting on version 1.2.10) 
Decreasing potential data 
inaccuracies since the SPPB is not 
assessed at baseline 
1.1 Synopsis 
3 Objectives and 
Endpoints 
9.4.1 General 
Approach 
9.4.3 Analysis of 
Secondary Endpoint 
(s) 
Handgrip strength test added as a key 
secondary endpoint 
(starting on version 1.2.10) 
Based on the importance of a 
strength assessment  
1.1 Synopsis 
3 Objectives and 
Endpoints 
8.1 Efficacy 
Assessments 
9.2 Sample Size 
Determination 
Change of the minimum clinically 
significant benefit set for the primary 
endpoint from gait speed of 0.05 m/s 
to 0.1 m/s 
(starting on version 1.2.10) 
Preliminary analysis of SARA-OBS 
study population determined a 
decline of 0.05 m/s at baseline vs. 
at month 6. This change allows an 
increase of up to 0.1 m/s for the 
expected difference between 
treatment groups  


SARA-INT 
 
Addendeum 1 to the version 1.2.11,  
Biophytis Protocol: BIO101-CL03 
 
20 April 2020 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
Page V 
1.1 Synopsis 
9.2 Sample Size 
Determination 
Rate of non-evaluable withdrawals or 
lost to follow-up increased from 5 to 
10% 
(starting on version 1.2.10) 
A larger percentage of withdrawals 
and lost-to-follow ups was observed 
in the trial so far 
1.1 Synopsis 
4.1 Overall Design 
9.4.6 Planned 
Interim Analysis 
Interim analysis modified to a formal 
unblinded interim analysis design 
(starting on version 1.2.10) 
Based on the increase of the 
expected difference between 
treatment arms for the primary 
endpoint 
1.1 Synopsis 
3 Objectives and 
Endpoints 
 
Safety follow-up phone call added six 
weeks after the end of the treatment 
intake  
(starting on version 1.2.10) 
DSMB recommendation 
8.3.8 Events of 
Special Interests 
Orthostatic hypotension added as an 
AE of special interest 
(starting on version 1.2.10) 
New AE reported in the study that 
requires more vigilance 
1.1 Synopsis 
5 Study Population 
9.4.7 Subgroup 
Analyses 
Definitions of sub-populations 
(starting on version 1.2.10) 
Clarification 
1.3 Synopsis 
Addition of questions for diabetes  
(starting on version 1.2.10) 
DSMB recommendation 
2.2 Background 
Rationale for the study population 
(starting on version 1.2.10) 
Clarification 
2.3.1 Known 
Potential Risks 
Addition of potential risks for 20E 
(starting on version 1.2.10) 
Information update 
2.3.2 Known 
Potential Benefits 
Addition of potential benefit of 20E 
(starting on version 1.2.10) 
Information update 
5.3 Exclusion Criteria 
and Temporary 
Exclusion Criteria 
5.5 Screen Failures 
Relocation of temporary exclusion 
criteria 
(starting on version 1.2.10) 
Clarification 
8.3.5 Adverse Events 
Reporting 
Specified the condition for AE 
reporting 
(starting on version 1.2.10) 
Clarification 
9.3 Populations for 
Analyses 
Population analysis criteria 
specification 
(starting on version 1.2.10) 
Clarification 
5.6 Strategies for 
Recruitment and 
Retention 
Addition of strategies 
(starting on version 1.2.10) 
Information update 
6.2.1 Acquisition and 
Accountability 
Change of distribution company 
(starting on version 1.2.10) 
Information update 
1.3 Schedule of 
Activities 
8.1 Efficacy 
Assessments 
Change of the timing to perform the 
400MW test during screening from 
Day 0 to 48 hrs prior to randomization 
(starting on version 1.2.10) 
To provide more time for the 400 
MW test to be performed 
6.5 Concomitant 
Therapy 
Removal of the protocol deviation due 
to the need to use an excluded 
medication during the study period  
The investigator has to treat any 
new symptoms or AEs based on the 
patient’s best interest and it is up to 
the investigator’s discretion if the 
participant should stay in the study  
1.1 Synopsis 
 
 
 
Information update 


SARA-INT 
 
Addendeum 1 to the version 1.2.11,  
Biophytis Protocol: BIO101-CL03 
 
20 April 2020 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
Page VI 
2.2 The 
Investigational 
Product 
5.3 Exclusion Criteria 
and Temporary 
Exclusion Criteria 
6.1.1 Study 
Intervention 
Description 
6.5 Concomitant 
Therapy 
 
 
1.1 Synopsis 
Measures taken to mitigate the 
COVID-19 outbreak 
(starting on version 1.2.11) 
Base on guidance of international 
and national agencies and the 
DSMB recommendation, measures 
taken to ensure the safety of the 
participants and mitigate the risk on 
the scientific integrity of the study 
1.1 synopsis 
Interim Analysis postponed; Increased 
population analyzed 
(starting on version 1.2.11) 
SDV not available on site due to 
COVID-19 restrictions. Increased 
population analyzed for the Interim 
analysis to take into account the 
data collected during and after the 
COVID-19 outbreak 
1.1 synopsis 
5. Study population 
Correction to 20% for the non-
evaluable withdrawals or lost to 
follow-up 
(starting on version 1.2.11) 
clarification 
1.2. Schedule of 
Acivity 
SoA updated 
(starting on version 1.2.11) 
Update of schedule of activity based 
on the measures, measures taken to 
ensure the safety of the participants 
and mitigate the risk on the 
scientific integrity of the study 
2.2 Background 
Addition of a 39-week toxicology 
study in dog 
(starting on version 1.2.11) 
update 
2.2 Background 
Scientific rationale updated for the 
measures taken to mitigate 
(starting on version 1.2.11) 
Based on new evidences and 
mitigation of measures taken during 
the COVID-19 outbreak 
2.3.4 Assessment of 
potential risks during 
the COVID-19 
pandemic 
Assessment of potential risks due to 
COVID-19 outbreak and actions taken 
(starting on version 1.2.11) 
Addition du to COVID-19 outbreak 
4.1 Overall design 
4.2 scientific 
rationale for Study 
Design 
Extension of the period of study 
intervention 
(starting on version 1.2.11) 
Mitigation for the scientific integrity 
of the study 
4.1 Overall design 
9.2 sample size 
determination 
9.4.7 Planned 
interim analysis 
Postponement of the Interim Analysis 
(starting on version 1.2.11) 
Due to COVID-19 outbreak 
restrictions 


SARA-INT 
 
Addendeum 1 to the version 1.2.11,  
Biophytis Protocol: BIO101-CL03 
 
20 April 2020 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
Page VII 
4.2 scientific 
rationale for Study 
Design 
Modification of assessments 
(starting on version 1.2.11) 
Due to COVID-19 outbreak 
restrictions 
4.4 End of study 
definition 
End of intervention updated 
(starting on version 1.2.11) 
clarification 
6.2.5 Shipment 
Addition of IP home delivery 
(starting on version 1.2.11) 
Mitigation of the COVID-19 
outbreak restrictions 
6.4 study 
intervention 
compliance 
Addition of IP return from participants 
home 
(starting on version 1.2.11) 
Mitigation of the COVID-19 
outbreak restrictions 
7.4 Participant 
discontinuation 
during the COVID-19 
Addition of collection of a reason for 
participant discontinuation 
(starting on version 1.2.11) 
Record of the impact of the 
situation on analyses and conduct 
of the trial 
8.2 safety and other 
assessments   
Modification of the safety monitoring 
of participants  
(starting on version 1.2.11) 
Mitigation of the COVID-19 
outbreak restrictions 
9.4.4 impact of the 
COVID-19 outbreak 
Updated strategy for the final 
statistical analysis 
(starting on version 1.2.11) 
Addition due to the situation 
restrictions  
10.1.1.1 consent and 
other information 
documents provided 
to participants 
Letter of information and addendum 
to the ICF provided to participants 
(starting on version 1.2.11) 
Addition due to th modification of 
the protocol design during the 
outbreak 
10.1.5 Key roles & 
study governance 
Additional role and schedule of 
meeting for the DSMB 
(starting on version 1.2.11) 
Safety surveillance during the 
COVID-19 outbreak 
10.1.7 Clinical 
monitoring 
Adaptation of the monitoring  
(starting on version 1.2.11) 
Mitigation of the COVID-19 
outbreak restrictions 
10.1.10 Protocol 
deviation 
Addition Identification of protocol 
deviations (starting on version 1.2.11) 
Mitigation of the COVID-19 
outbreak 


  
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
Page VIII 
Table of Contents 
SPONSOR SIGNATURE PAGE ............................................................................................................. 1 
STATEMENT OF COMPLIANCE ........................................................................................................... 2 
1 
PROTOCOL SUMMARY ............................................................................................................. 3 
1.1 
Synopsis .............................................................................................................................. 3 
1.2 
Schema ............................................................................................................................. 11 
1.3 
Schedule of Activities (SoA) ........................................................................................... 12 
2 
INTRODUCTION ........................................................................................................................ 17 
2.1 
Study Rationale ................................................................................................................ 17 
2.2 
Background....................................................................................................................... 22 
The Investigational Product 22 
Scientific Rationale for designing SARA-INT clinical trial ......................................................... 26 
2.3 
Risk/Benefit Assessment ................................................................................................ 28 
2.3.1 
Known Potential Risks ................................................................................. 28 
2.3.2 
Known Potential Benefits ............................................................................ 29 
2.3.3 
Assessment of Potential Risks and Benefits ............................................ 30 
2.3.4 
Assessment of potential risks and benefits during the COVID-19 
pandemic 
30 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................ 31 
4 
STUDY DESIGN ......................................................................................................................... 34 
4.1 
Overall Design .................................................................................................................. 34 
4.2 
Scientific Rationale for Study Design............................................................................ 35 
4.3 
Justification for Dose ....................................................................................................... 37 
4.4 
End of Study Definition ................................................................................................... 37 
5 
STUDY POPULATION .............................................................................................................. 37 
5.1 
Inclusion Criteria .............................................................................................................. 38 
5.2 
NON-Inclusion Criteria .................................................................................................... 38 
5.3 
Exclusion Criteria and Temporary exclusion criteria .................................................. 38 
5.4 
Lifestyle Considerations .................................................................................................. 40 
5.5 
Screen Failures ................................................................................................................ 40 
5.6 
Strategies for Recruitment and Retention .................................................................... 40 
6 
STUDY INTERVENTION .......................................................................................................... 41 
6.1 
Study Intervention(s) Administration ............................................................................. 41 
6.1.1 
Study Intervention Description ................................................................... 41 
6.1.2 
Dosing and Administration .......................................................................... 41 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 42 
6.2.1 
Acquisition and accountability .................................................................... 42 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .............................. 42 
6.2.3 
Product Storage and Stability ..................................................................... 44 
6.2.4 
Preparation .................................................................................................... 44 
6.2.5 
SHIPMENT .................................................................................................... 44 
6.3 
Measures to Minimize Bias: Randomization and Blinding ......................................... 45 
6.4 
Study Intervention Compliance ...................................................................................... 47 
6.5 
Concomitant Therapy ...................................................................................................... 47 
6.5.1 
Rescue Medicine .......................................................................................... 47 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................. 48 
7.1 
Discontinuation of Study Intervention ........................................................................... 48 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................. 48 
7.3 
Lost to Follow-Up ............................................................................................................. 49 
7.4 
Participant discontinuation during the COVID-19 .......................................................... 49 


  
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Page IX 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................................... 50 
8.1 
Efficacy Assessments ..................................................................................................... 50 
8.2 
Safety and Other Assessments ..................................................................................... 57 
8.3 
Adverse Events and Serious Adverse Events ............................................................. 60 
8.3.1 
Definition of Adverse Events (AE) ............................................................. 60 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................ 60 
8.3.3 
Classification of an Adverse Event ............................................................ 60 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ..... 61 
8.3.5 
Adverse Event Reporting ............................................................................ 62 
8.3.6 
Serious Adverse Event Reporting ............................................................. 62 
8.3.7 
Reporting Events to Participants ............................................................... 63 
8.3.8 
Events of Special Interest ........................................................................... 63 
8.3.9 
Reporting of Pregnancy .............................................................................. 63 
8.4 
Unanticipated Problems .................................................................................................. 64 
8.4.1 
Definition of Unanticipated Problems (UP) ............................................... 64 
8.4.2 
Unanticipated Problem Reporting .............................................................. 64 
8.4.3 
Reporting Unanticipated Problems to Participants ................................. 65 
9 
STATISTICAL CONSIDERATIONS ........................................................................................ 65 
9.1 
Statistical Hypotheses ..................................................................................................... 65 
9.2 
Sample Size Determination ............................................................................................ 65 
9.3 
Populations for Analyses ................................................................................................ 66 
9.4 
Statistical Analyses.......................................................................................................... 66 
9.4.1 
General Approach ........................................................................................ 66 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ........................................... 67 
9.4.3 
Analysis of the Secondary Endpoint(s) ..................................................... 68 
9.4.4 
impact of the COVID-19 outbreak ............................................................. 68 
9.4.5 
Safety Analyses ............................................................................................ 69 
9.4.6 
Baseline Descriptive Statistics ................................................................... 69 
9.4.7 
Planned Interim Analysis ............................................................................ 69 
9.4.8 
SubGroup Analyses ..................................................................................... 70 
9.4.9 
Tabulation of Individual participant Data .................................................. 70 
 
 ................................................................................... 71 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............ 71 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ......................................... 71 
10.1.1 
Informed Consent Process ......................................................................... 71 
10.1.2 
Study Discontinuation and Closure ........................................................... 72 
10.1.3 
Confidentiality and Privacy ......................................................................... 73 
10.1.4 
Future Use of Stored Specimens and Data ............................................. 73 
10.1.5 
Key Roles and Study Governance ............................................................ 74 
10.1.6 
Safety Oversight ........................................................................................... 78 
10.1.7 
Clinical Monitoring ........................................................................................ 79 
10.1.8 
Quality Assurance and Quality Control ..................................................... 80 
10.1.9 
Data Handling and Record Keeping .......................................................... 80 
10.1.10 
Protocol Deviations ...................................................................................... 82 
10.1.11 
Publication and Data Sharing Policy ......................................................... 82 
10.1.12 
Conflict of Interest Policy ............................................................................ 83 
10.2 
Additional Considerations ............................................................................................... 83 
10.3 
Abbreviations .................................................................................................................... 84 
10.4 
Protocol Amendment History ......................................................................................... 87 
11 
REFERENCES ........................................................................................................................... 88 


SARA-INT 
 
Version 1.2.11,  
Biophytis Protocol: BIO101-CL03 
 
20 April 2020 
Biophytis for SARA 
CONFIDENTIAL 
Page 1 of 91 
SPONSOR SIGNATURE PAGE 
PROTOCOL TITLE:  
Safety and efficacy of BIO-101 175 mg b.i.d. and 350 mg b.i.d. 26-week 
oral administration to patients suffering from age-related SARcopenia, 
including sarcopenic obesity, Aged ≥ 65 years and at risk of mobility 
disability.  
A double-blind, placebo-controlled, randomized INTerventional Clinical 
Trial (SARA-INT) 
PROTOCOL NUMBER: 
BIO101-CL03 
SPONSOR: 
Biophytis S.A. 
 
 
 
 
 
 
Date (day/month/year) 
 
 
 
 
 
Date (day/month/year) 
 
 
20 April 2020
April 20, 2020




SARA-INT 
 
Version 1.2.11,  
Biophytis Protocol: BIO101-CL03 
 
20 April 2020 
Biophytis for SARA 
CONFIDENTIAL 
Page 3 of 91 
1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Safety and efficacy of BIO-101 175 mg b.i.d. and 350 mg b.i.d. 26-week 
oral administration to patients suffering from age-related SARcopenia, 
including sarcopenic obesity, Aged ≥ 65 years and at risk of mobility 
disability. 
A 
double-blind, 
placebo- 
controlled, 
randomized 
INTerventional clinical trial (SARA-INT). 
Study Description: 
SARA-INT is a three-arm, interventional, phase 2, randomized, double- 
blind, placebo-controlled clinical trial. It will be conducted in the 
European Union (EU) and in the United States (US). 
231 community dwelling older adults (men or women ≥ 65 years), living 
independently at home (homes are any living communities that may or 
may not offer optional services for the convenience of the residents. 
Older adults living in nursing homes or in medicalized residences where 
caretaker services are mandatory are not eligible), able to walk outside 
from time to time, reporting a loss of physical functions and considered 
at risk of mobility disability, were selected to perform the Short Physical 
Performance Battery1 (SPPB) test.  
Those with SPPB scores ≤ 8 were selected to perform a body composition 
analysis with a dual-energy X-ray absorptiometry (DEXA) scan. (DEXA 
scans performed no more than 8 weeks before the date of randomization 
will be acceptable, and in that case, should not be repeated up to the end 
of the study visit). Participants with appendicular lean mass (ALM) 
adjusted for body mass index (BMI), or ALM/BMI < 0.789 in men and < 
0.512 in women, or ALM <19.75kg in men and <15.02kg in women, 
corresponding to the operational definition of sarcopenia based on the 
criteria of the Foundation of National Health Institute (FNIH)2, were 
definitively included and randomized if other inclusion/exclusion criteria 
are also satisfied.  
The study plan is divided into: a) screening and randomization phase and 
b) treatment and evaluation phase. The recruitment lasts approximately 
24 months. The investigational phase initially comprises three main visits 
for measurement of drug efficacy, pharmacokinetics (when appropriate) 
and safety parameters: 1) the inclusion visit, 2) the 3-month evaluation 
and 3) the 6-month final evaluation visit. Additionally, three 
communications (visit and phone calls) were planned for safety 
measures only: 1) an on-site visit at 1-month after randomization, 2) a 
telephone call at 5-month after randomization, and 3) a telephone call 6 
weeks post drug intervention (i.e. after M6 visit) or after the end-of-
intervention visit.  
The primary outcome is the change from baseline in gait speed, in meters 
per second (m/s), between the treatment groups versus placebo based 
on the 400 meters walking (400MW) test.  
The Short Form Health Survey (SF-36) and two other patients reported 
outcomes (PROs) will be completed by the participants on inclusion day 
(Day 0), at the month 3 (M3) visit and the month 6 (M6) or end-of-
intervention visit. The Physical Function Domain (PF-10) sub-score of the 
SF36 at M6 will be tested as a key secondary outcome at M6. 


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Additionally, the change from baseline of muscle strength measured by 
the handgrip strength test will be used as another key secondary 
outcome. Additionally, the SPPB will be evaluated at each visit and the 6 
Minute Walk Test (6MWT) will also be administered during the two main 
visits (Day 0 and M6) and considered as part of the secondary criteria at 
M6.  
At any time, participants complaining of meaningfully worsening of 
physical functions may be invited to an unscheduled visit for further 
assessment for consideration of their continued participation in the 
study.  
The statistical analyses will describe the demographic and functional 
characteristics of the three treatment groups at baseline, and compare 
the evolution (change in each treatment group versus placebo group) of 
the primary, key secondary, secondary and exploratory endpoints. The 
evolutions of efficacy parameters will also be analyzed according to 
specific variables or class of variables, e.g. gender, age, initial SPPB score, 
ALM, ALM/BMI and etc, in view of identifying a subpopulation at high risk 
of worsening and/or to show the homogeneity of the treatment effect 
across subgroups. 
 A predefined subgroup efficacy analysis will also be performed on a 
number of pre-identified, at-high risk of worsening, subpopulations: 
• 
Low gait speed 
• 
Sarcopenic obesity 
• 
Study participants with a chair stand sub-score of ≤2 of the SPPB 
• 
Study participants who experience a deterioration in their 
ALM/BMI, as measured by the DEXA scan in the M6 visit and 
compared to the baseline measurement 
Subgroup analyses will be provided through a forest-plot approach. 
Objectives: 
 
General Objectives:  
1. To evaluate the safety and efficacy of two doses of BIO101 (175 
mg b.i.d. and 350 mg b.i.d.) orally administered for 26 weeks 
versus placebo in a population of community dwelling older men 
and women (aged ≥ 65 years) living at home and at risk of 
mobility disability.  
2. To estimate treatment effect on improvement of physical 
function after a six-month treatment versus placebo in the target 
population. 
3. To estimate treatment effect on reduced risk of mobility 
disability after a six-month treatment versus placebo in the 
target population.  
Primary Objective:  
 
• 
To evaluate the effect of two daily doses of BIO101 versus 
placebo on mobility function as measured by gait speed using 
the 400MW test. The absolute change from baseline in m/s 
observed in each treatment group at M6 will be compared to the 
placebo group. A minimum clinically significant benefit is set at 
0.05 m/s in the mean difference between groups from M6 


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compared to baseline. The preliminary data from the SARA 
observational study (SARA-OBS) suggests that the untreated 
population naturally experienced a deterioration of 0.05 meter 
per second, when compared at M6 to baseline. Taken together, 
this increases the expected difference between treatment and 
placebo groups to 0.1 meter per second at M6 – corresponding 
to what is considered a clinically significant difference.  
Key Secondary Objectives:  
a. To compare the change from baseline of a standardized patient 
reported outcome (PRO): the PF-10 sub-score of the SF-36. A 
minimum clinically significant benefit is set at 2-point difference 
of the change at M6 from baseline versus placebo in the mean 
difference between groups. 
b. To compare the change from baseline to month 6 of the muscle 
strength using the handgrip strength test. A minimum clinically 
significant benefit is set at 2 kg difference of the change at M6 
from baseline versus placebo in the mean difference between 
groups.  
Other Secondary Objectives:  
a. To compare appendicular lean body mass and body composition 
versus placebo, and specifically ALM. 
b. To compare muscle strength using the knee extension test and the 
stair climb power test (SCPT) versus placebo. 
c. To compare the rate of successful patients who completed the 
400MW test after the 6-month treatment versus placebo. 
d. To assess the overall score change on the SPPB as a cumulative 
expression of a physically frail status. 
e. To compare the repeated chair stand test as a sub-score of the 
SPPB assessment versus placebo. 
f. To compare the distance walked during the 6MWT versus placebo.  
g. To compare the change from the baseline using the SarQol auto-
evaluation questionnaire versus placebo. 
 
 
 
 
 
 
 
 
 
 
 
Endpoints: 
Primary Endpoint: 
Gait speed measured during the 400MW test: the change from baseline 
to month 6 will be compared between groups of treatment (each dose 
versus placebo). 


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Key Secondary Endpoints:  
PF-10 sub-score of the SF-36: the change from baseline to month 6 will 
be compared between groups of treatment (each dose versus placebo). 
Muscle strength as measured by the handgrip test: the change from 
baseline to month 6 will be compared between groups of treatment 
(each dose versus placebo). Additionally, a responder analysis will be 
performed with a responder definition of “study participant with an 
improvement of gait speed at 400MW test greater or equal to 0.1 m/s 
versus baseline”, at an individual level. 
A further responder analysis will be performed with a responder 
definition of “study participant with an improvement of PF10 greater or 
equal to 2 points versus baseline”, at an individual level.  
Other secondary Endpoints:  
Change from baseline of ALM and other parameters of body composition 
by DEXA; the rate of success to complete 400MW test after a 6-month 
treatment versus placebo; change from baseline of muscle strength as 
measured by knee extension and SCPT; change from baseline of the total 
SPPB score and of the sub-score of the repeated chair stands test; change 
from baseline of the SarQol auto-evaluation questionnaire. 
  
 
 
 
 
 
  
 
 
 
 
 
 
Study Population: 
231 community dwelling older adults (men or women ≥ 65 years) and 
reporting a loss of physical function over the last six-twelve months and 
considered at risk of mobility disability will be included in the randomized 
interventional clinical trial SARA-INT (with 64 patients per treatment 
group) with a treatment period of 26 weeks. 39 additional participants 
will be randomized to allow 20% of non-evaluable withdrawals or lost to 
follow-up for a total of  231 older adults included in the US and the EU. 
An unblinded ‘promising zone’ interim analysis will take place, based on 
the complete efficacy data from half of the randomized participants who 
completed the trial, to determine if there will be a need to increase the 
sample size. 
A predefined subgroup efficacy analysis will also be performed in a 
number of pre-identified, at-high risk of worsening subpopulations:  


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• 
Low gait speed 
• 
Sarcopenic obesity 
• 
Study participants with a chair stand sub-score of ≤2 of the SPPB 
• 
Study participants who experience a deterioration in their 
ALM/BMI, as measured by the DEXA scan, in the M6 visit 
compared to the baseline measurement 
 
Subgroup analyses on these populations will be performed in order to 
better characterize treatment benefit in patients at increasing risk of 
mobility disability. Results will be presented in forest-plot graphs, for the 
primary and the  two key secondary endpoints.  
Inclusion criteria: 
1. Provision of signed and dated informed consent form (ICF) 
2. Stated willingness to comply with all study procedures and 
availability for the duration of the study  
3. Male or female aged ≥ 65 years, living in the community 
(living at home, able to walk outside from time to time. Homes 
can include any living community that may or may not offer 
optional services for the convenience of the residents. Older 
adults living in nursing homes or in medicalized residences 
where caretaker services are mandatory are not eligible) and 
reporting a loss of physical function over the last 6-12 
months 
4. SPPB score ≤ 8 
5. ALM/BMI < 0.789 in men and <0.512 in women, or ALM < 
19.75kg in men and < 15.02kg in women, as measured by 
DEXA scan 
6. Ability to take oral medication and be willing to adhere to the 
study intervention regimen (see section 6) 
7. Agreement to adhere to the outlined Lifestyle Considerations 
(see section 5.4) throughout the study duration 
8. In the US, women and members of minority groups should not 
be excluded, in accordance with the NIH Policy on Inclusion of 
Women and Minorities as Participants In Research Involving 
Human Subjects.  
Non-inclusion criteria 
1. In France, non-affiliation to compulsory French social security 
scheme (beneficiary or right-holder)  
2. In France, being under tutelage or legal guardianship  
Exclusion criteria 


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1. Current use of anabolic drugs (e.g. testosterone); current use 
of Erythropoietin; current use of corticosteroid agents (except 
local administration route, like eye drops or dermatologic 
formulations)  
2. Non-menopaused women (however, ongoing hormonal 
replacement hormonal treatment is not an exclusion 
criterion) 
3. Known allergic reactions to sourcing components of the 
investigational drug (i.e. 
;
 
  
 
4. Treatment with another investigational drug or other 
interventions within three months 
5. Unable to understand and perform the functional tests, as 
judged by the Investigator 
6. Inability to perform the 400MW test within 15 minutes 
7. Clinical conditions: 
a. Current diagnosis of major psychiatric disorders.  
b. Alcohol abuse or dependence 
c. Severe arthritis 
d. Cancer requiring active treatment (cancer previously 
treated with chemotherapy and/or radiotherapy and 
participants currently on remission is not an exclusion 
criterion) 
e. Lung disease requiring regular use of supplemental 
oxygen 
f. Inflammatory conditions requiring regular use of oral 
or parenteral corticosteroid agents 
g. Severe cardiovascular disease (including New York 
Heart Association [NYHA] class III or IV congestive 
heart failure, clinically significant valvular disease, 
history of cardiac arrest, presence of an implantable 
defibrillator, or uncontrolled angina) 
h. Parkinson’s disease or other progressive neurological 
disorder 
i. Renal disease requiring dialysis, or known renal 
insufficiency (moderate or severe reduction of 
eGFR≤30 ml/min/1.73 m2, based on Cockroft & Gault 
formula)  
j. Chest pain, severe shortness of breath, or occurrence 
of other safety concerns during the baseline 
functional tests such as the 400MW test   


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k. History 
or 
active 
signs 
or 
symptoms 
of 
gallbladder/biliary disease (e.g. previous episodes of 
cholestasis/biliary tract obstruction, cholelithiasis, 
cholecystitis, 
etc.). 
Of 
note, 
history 
of 
cholecystectomy and no active biliary signs or 
symptoms, is not an exclusion criterion. 
8. Current physical/rehabilitation therapy (except for passive 
physical therapy. However, this should not be initiated the 
week before an evaluation visit and once started, it should be 
maintained over the study duration). 
Phase: 
Phase 2 – with therapeutic intervention 
Description of 
Sites/Facilities 
Enrolling Participants: 
 
23 clinical investigation sites in the US and in Europe  
Description of Study 
Intervention: 
Oral treatment with BIO101 dosing of 350 mg b.i.d. or 175 mg b.i.d. or 
placebo (identical capsules).  
The BIO101 active principle ingredient is 20 hydroxyecdysone (20E), 
 
 
 
 
he study drug is packaged in individual 
blisters containing capsules and contained in an elderly- friendly weekly 
paper box for a monthly kit. 
 
COVID-19 pandemic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Due to the coronavirus disease 2019 (COVID-19) outbreak, the 
implementation of clinical protocol is affected, including but not limited 
to the scheduled site visit for safety and/or efficacy, site visit for 
monitoring, investigational product delivery, collection of adverse 
events and concomitant medication. Following GCP guidance to the 
situation of the public health emergencies, the core consensus 
guidelines for clinical trial management and the study DSMB 
recommendation, below measures have been taken:  
- No additional activity of prescreening, screening and randomization will 
be performed during the COVID-19 outbreak. Because of the potential 
impact of the COVID-19 outbreak leading to the withdrawals and lost-to-
follow ups from the study, these activities may resume after the COVID-
19 outbreak.  
- the complete assessment and tests per protocol requiring on-site 
visits have been suspended. every investigational visit within the 
protocol will now be performed remotely (e.g. by phone) for all 
participants still active in the study by the investigational site staff. 
These calls will be used to continue monitoring the health status of 
the participants by collecting information on Concomitant 
Medication (CM) and Adverse Events (AE). In addition, study 
questionnaires will be administered and study drug intake will also 
continue to be monitored following the same schedule.  


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Study Duration: 
- Study drugs will continue to be dispensed and provided to participants 
through direct shipping from study site to the participants’ home after 
the site investigator/staff(s) have completed reviewing all relevant 
safety study assessment results from the calls.  
- An updated strategy for the final analysis will be implemented, to 
account for the missing data on safety and efficacy which will have 
impact on the final analysis. The planned interim analysis is postponed 
to a time after the restrictions are lifted. Both updated are described in 
a new version of the Statistical analysis Plan. 
- As certain assessments/tests cannot be conducted per protocol, the 
investigator/site staff(s) should evaluate the overall risk/benefit, and 
contact the sponsor related staff(s) promptly should there be any safety 
concerns in order to reach agreement on how to proceed. This may 
require ad hoc safety assessments (e.g. safety blood draw, 
communication with participant’s HCP). Additional checks should be 
performed as soon as the conditions allow it or at the end of the 
outbreak restrictions based on the national/federal, state and local 
governance.  
- An extension for treatment of 3 additional months is proposed for those 
participants missing the efficacy assessments at Month 6 visit/End-of-
intervention. This would allow for the addition of data on safety and 
efficacy for the final analysis. 
 
 
 
 
 
 
  
 
 
33-35 months 
 
Participant Duration: 
 
Up to 39 weeks + screening (1-8 weeks) + follow-up at 6 weeks post study 
conclusion 
 
 


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1.2 
SCHEMA 
Flow diagram  
 
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
Visit Day0 
Time Point  
 
 
Visit M1 
Time Point  
 
Visit M3 
Time Point  
 
Visit M5 
Time Point 
 
 
Visit M6 
Time Point 
 
 
 
 
 
Visit M7.5 
Time Point 
 
 
 
 
 
Visit M9 
Time Point 
 
 
 
 
 
Visit M10.5 
Time Point 
 
 
 
Estimated Total N: 2,300 Obtain informed consent. Screen potential participants by 
inclusion and exclusion criteria; obtain history, documents, perform SPPB and DEXA.  
Perform baseline assessments. 
refer to Section 1.3, Schedule of Activities (SoA) 
Start to administer study intervention (on Day1).  
Telephone interview:  
assess safety and if needed anticipate Final assessment 
Follow-up assessments of study endpoints and safety 
refer to Section 1.3, SoA 
Arm 3 
N: 77
Arm 1 
N: 77
Assess AE and safety. Continue study intervention  
Randomize 
Arm 2 
N: 77  
Telephone interview:  
assess safety six weeks after the end of 
the treatment intake and, if needed, set 
up an unscheduled medical visit 
Final Assessments 
refer to Section 
1.3, SoA
 
Follow-up assessments of study endpoints 
and safety 
refer to Section 1.3.  SoA  
 
Telephone interview:  
assess safety and if needed anticipate 
Final assessment 
Final Assessments 
refer to Section 
1.3. SoA  
Telephone interview:  
assess safety six weeks after the end of 
the treatment intake and, if needed, set 
up an unscheduled medical visit 


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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
During the COVID-19 outbreak, no additional activity of prescreening, screening and 
randomization will be performed based on GCP guidance on the situation of the public health 
emergencies, the core consensus 
guidelines for clinical trial management and the DSMB 
recommendation, during the COVID-19 outbreak. For all active participants in the study, 
measures are as follows: 
• 
Screening activities listed below are being put on hold: 
• 
Activities can be performed only after the participant has signed the ICFs 
• 
SPPB should be performed prior to DEXA and ultrasound scans 
• 
DEXA can be conducted only after the medical history, concomitant medications, 
physical exam, and SPPB inclusion criteria are met 
• 
DEXA results can be collected for the study if a DEXA scan was conducted for a 
non-study related purpose within 8 weeks prior to the randomization date 
• 
Gallbladder ultrasound can be conducted, only if the medical history, concomitant 
medications, physical exam, SPPB and DEXA exclusion criteria are met 
• 
The 400MW test must be the last activity performed during the screening period 
and within 48 hours of randomization. This last screening assessment can be 
performed on the same day as the baseline visit, but it must be performed before 
randomization and baseline assessments occur  
• 
Randomization is being put on hold: 
• 
Randomization can occur only after all screening assessments results are 
available, specifically blood tests results for safety reasons 
• 
Baseline (Day 0) is being put on hold: 
• 
All baseline assessments are performed only after randomization 
• 
Extra blood sampling will be performed for participants partaking in the 
Population PK (Pop-PK) sub-study at Day 1 
• 
M1 Visit is replaced by a telephone call 
• 
Safety focused phone call after the first month of investigational treatment 
• 
M3 visit is replaced by a telephone call 
• 
Intermediate phone call for safety and fora reduced number of efficacy 
measurements (ePRO) 
• 
M5 Phone call 
• 
Safety focused phone call after 5 months of investigational treatment 
 
• 
M6 (end-of-intervention visit) visit is replaced by a telephone call 
• 
phone call for safety and fora reduced number of efficacy measurements (ePRO) 
• 
M7.5 Phone call 
• 
Safety focused phone call after 7.5 months of investigational treatment 
• 
M9 visit  
• 
M9 visit must be scheduled 39 weeks after Day 0. This end of intervention visit can 
be scheduled before M9 in case of patient withdrawal or based on modification of 
public health emergencies and the core consensus guidelines for clinical trial 
management.  
• All safety and efficacy measurements previously listed for the M6/end-of-
intervention visit are to be performed. 


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• 
M10.5 phone call  
• 
Post study intervention phone call 6 weeks after the end of intervention visit to 
follow up on safety parameters    


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Screening 
Randomization
& Baseline Visit 
M1 
Visit 
M3, M5, M6, M7.7 and M9 Visits 
Post study Intervention 
Phone Call 
Weeks 
-8 – 0 
Day 0 
4 
12 
21 
26  
 
32 
39  
(or End of 
intervention) 
45 (6 weeks after end 
of intervention) 
Visit Window 
n.a. 
n.a. 
+/-3 
days 
+/- 1 
week 
+/- 1 
week 
- 1 week 
+/- 1 
week 
 8 weeks 
+/- 1 week 
Telephone call  
  
 
X 
X 
X 
X 
X 
 
X 
Informed 
consent, including 
secondary 
research  
X (before any 
study activity) 
 
 
 
 
 
 
 
 
Informed consent 
(2) for biobank 
and DNA tests 
X (before any 
study activity) 
 
 
 
 
 
 
 
 
New informed 
consent, including 
secondary 
research 
 
 
X£ 
X£ 
X£ 
X£ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X (4 weeks) 
 
 
 
 
 
 
 
 
Medical history 
X (4 weeks) 
 
 
 
 
 
 
 
 
Concomitant 
medication 
review 
X  
 
X 
X 
 
X 
 
X 
 
Physical exam & 
Anthropometry 
X 
X 
 
 
 
 
 
X 
 
Safety 
measurements 
including vital 
signs and weight 
 
X 
 
 
 
 
 
X 
 
SPPB 
X (4 weeks) 
 
 
 
 
 
 
X 
 
ECG  
X (1 week) 
 
 
 
 
 
 
 
 




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Date of each next visit should be calculated back on Day 0 visit (baseline) in order to not exceed the total duration of 26 weeks of treatment (capped exposure). 
*Actimetry is continuously recorded from Day 0 to M6. 
£ Reconsent based on the COVID-19 outbreak and the next planned visit of the participant 
1 Biochemistry: sodium, potassium, chloride, bicarbonate, urea, uric acid creatinine, albumin, glucose, cholesterol (total cholesterol, LDL, HDL fractions), triglycerides, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, bone-specific alkaline phosphatase, lipase, amylase, gamma glutamyl aminotransferase, bilirubin (total, indirect, 
direct), creatine phosphokinase and mb-creatine phosphokinase, lactate dehydrogenase, total protein, and eGFR calculation; 
2 Hematology: haemoglobin, HbA1c, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with differential, platelet count, mean corpuscular haemoglobin, mean corpuscular 
haemoglobin concentration, mean corpuscular volume; Coagulation: 
activated partial thromboplastin time, prothrombin time, and international normalized ratio. 
3 Urinalysis: a midstream urine sample will be collected for urinalysis by dipstick for glucose, protein, and occult blood. 
 
 
Collect used 
treatment & 
record 
compliance to 
study 
intervention 
 
 
X 
X 
  
X 
 
X 
 
Actimetry* 
 
Provided 
X 
X 
 
 
 
collected 
 
General safety 
questions 
 
 
X 
X 
X 
X 
X 
 
X 
AEs review and 
evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
Diabetes/ 
prediabetes 
questions 
 
 
 
 
 
 
X 
 
X 
POP-PK sampling 
(optional) 
 
X (1 day after 
Day 0) 
 
 
 
 
 
X 
 
eCRF completion 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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2 
INTRODUCTION 
2.1 
STUDY RATIONALE  
We aim to perform this phase 2, interventional study in Europe and USA in order to evaluate the 
clinical benefits, safety and tolerability of the investigational drug, BIO101. BIO101 will be 
administered orally for a six-month (26 weeks) duration to community dwelling men and women 
aged ≥ 65 years (living at home and able to walk outside from time to time. Homes can include 
living communities that may or may not offer optional services for the convenience of the 
residents. Older adults living in nursing homes or in medicalized residences where caretaker 
services are mandatory are not eligible) suffering from age-related sarcopenia (including 
sarcopenic obesity) and at risk of mobility disability.  
This double-blind, placebo-controlled clinical trial will collect and analyze data on physical 
performance and body composition and will specifically focus on the change of one functional 
measurement: the gait speed measured during the 400MW test plus the change on a highly 
standardized PRO, the PF-10 sub-score of the SF-36 auto-evaluation questionnaire  Together, they 
will estimate the efficacy of BIO101 in preventing mobility disability in the target population.  
TARGET INDICATION 
Age-related sarcopenia is a geriatric condition characterized by a progressive loss of muscle mass 
and muscle function, with development beginning at the fifth decade and contributing to an 
increased risk of falls and fractures later in life3. Sarcopenia occurrence increases with age and 
may lead to mobility disability and physical dependence of the older person. In October 2016, the 
Center for Disease Control and Prevention established an ICD-10-CM code, M62.84, for age-
related sarcopenia therefore, providing its recognition for a separate reporting and data 
collection4. According to the Aging in Motion coalition, this new code designation for the disease 
has the potential to affect sarcopenia research and treatment in a number of ways, including the 
allowance for clearer establishment of clinical guidelines for diagnosis and treatment of 
sarcopenia and opening new avenues for development of novel therapeutics by researchers and 
approval by the United States Food and Drug Administration (FDA). Of note, the FDA organized a 
public consultation meeting to gather the point of view of patients suffering from sarcopenia in 
April 20175. 
 
Depending on the definition used, sarcopenia prevalence in 60-70 years old is reported as 5 to 
13% while the prevalence for people >80 years old ranges from 11 to 50%. The number of people 
around the world aged ≥60 years was estimated at 600 million in the year 2000, a figure that is 
expected to rise to 1.2 billion by 2025 and 2 billion by 2050. Even with a conservative estimate of 
prevalence, sarcopenia affects >50 million people today and will affect >200 million in the next 40 
years6. According to the World Health Organization (WHO) in 2009, the estimated direct 
healthcare cost attributable to sarcopenia in the United States of America in 2000 was $18.5 
billion USD. 
 
Many definitions can be considered for sarcopenia diagnosis. First, the European Working Group 
on Sarcopenia in Older People (EWGSOP) defined sarcopenia as a low muscle mass index in 


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participants (moderate sarcopenia is 8.51-10.75 kg/m2 in men, and 5.76-6.75 kg/m2 in women) 
with a walking speed of <0.8 m/s, or a normal walking speed and low muscle strength (<20 kg for 
women and <30 kg for men)7. Subsequently, the FNIH developed a data-driven definition based 
on a meta-analysis of 11 clinical studies and 26,725 participants (mean age of 75.2±6.1 years in 
men and 78.6±5.9 years in women). This definition takes into account the prevalence of low gait 
speed (≤0.8m/sec) and weakness (grip strength of <26 kg for men and <16 kg for women) in older 
individuals (≥ 65years) and is defined by low lean mass expressed as ALM <19.75kg in men and 
<15.02kg in women, or as ALM adjusted for body mass index (BMI), ALM/BMI, <0.789 for men 
and <0.512 for women2. This last definition of sarcopenia integrating the BMI was derived from a 
sensitivity analysis, and it allows for better appraisal of obese (sarcopenic) individuals. In fact, 
sarcopenic obesity (SO) represents a subgroup of sarcopenia characterized by the loss of muscle 
mass and function and a concomitant increase of fat mass. It is mainly affecting older obese 
individuals. A higher rate of functional decline has been reported in participants with SO. Indeed, 
lipid infiltration in muscle tissues seems to exacerbate sarcopenia, since accumulation of lipids 
prevents incorporation of amino acids, reduces protein synthesis and induces a chronic 
inflammation in the muscle8-10. The progressively increasing cohort of older people with SO are at 
particular risk of negative health impact such as loss of independence, increased disability and 
increased morbidity and mortality11.  
 
Establishing a consensus definition of SO is challenging since most of previous studies specifically 
focused on body composition (gain of fat mass and loss of muscle mass) and not on physical 
function10. The problem of the SO definition is also revealed by its wide range of prevalence (4-
84% in men and 4-94% in women depending on body composition measurement methods 
used)12. The lack of a consensus definition as well as the imprecision in its prevalence hampers SO 
recognition as a specific geriatric condition and has also led to its under-diagnosis. Thus, despite 
SO’s high relevance, appropriate clinical studies including both body composition and physical 
function measurements will contribute to better understanding of SO’s prevalence and clinical 
importance in the ageing population. In that regard, the definition of Batsis et al.13 that integrates 
the cut-off points for sarcopenia by the FNIH and a percentage of body fat mass of >25% in men 
and >35% in women, will be applied in this study.  
 
The pathogenesis of SO, adapted from Donini et al.,14 is described in Figure 1. 
 


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Figure 1: Pathogenesis of Sarcopenic Obesity 
 
In the LIFE clinical trial, it has been shown that in older adults with a sedentary lifestyle and low 
SPPB score at baseline, the Physical Activity (intervention) group had better lower extremity 
performance (SPPB score), compared with the Health Education group, over the course of the 
trial15. These effects were more pronounced in lower functioning participants (SPPB <8)16, with 
the greater benefit and difference between groups visible at as early as 6 months. The observed 
benefit was mostly explained by the chair stand component of the SPPB, while the balance test 
and the 4-meter gait speed were only slightly modified. 
 
In Europe, the SPRINT-T clinical trial has started to test the effects of a multicomponent treatment 
strategy (focused on structured physical activity as well) in 1,500 physically frail older participants 
(the frailty status being operationalized by SPPB ≤9 or ≤7) and sarcopenia (defined by low 
ALM/BMI or low ALM, according to the two subsets of criteria by the FNIH. In fact, the ALM and 
ALM/BMI cut-off points identified two relatively distinct subsets of sarcopenic individuals as only 
16% of patients do actually meet both definitions17. This clinical trial population is theoretically 
expected to be at higher risk of mobility disability than the LIFE population because of the dual 
initial diagnosis of physical frailty (based on low function) and sarcopenia (based on body 
composition by DEXA scans). 
 
The SARA-INT clinical trial population is intended to include those at risk of further loss of muscle 
functions even in the medium term (6 months), based on the very low physical performance at 
baseline (SPPB ≤ 8) and the coexisting sarcopenia criteria based on DEXA measurements. 
 
Sarcopenia management requires not only acting on muscle mass but also on the muscle 
functions in order to prevent subsequent disabilities. Physical performance is mainly measured 
through the SPPB, grip strength, or walking tests like the 400MW test or the 6MWT. 
 


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Several strategies were developed for the management of sarcopenia and/or SO18.These include 
monoclonal antibodies targeting myostatin, a negative regulator of muscle growth, or its 
receptor. Many products of different classes of molecules have been tested over the past decade 
in clinical studies of sarcopenic participants: 
 
• 
Molecule substrates of protein synthesis which are amino acids or their metabolites 
(leucine, beta-hydroxy-beta-methylbutyrate, citrulline, ornithine), as well as rapidly 
digested proteins such as whey. 
• 
Anabolic hormones like testosterone or selective androgen receptor modulators (SARMs), 
growth hormone, IGF-1, vitamin D, ghrelin or progranulin. 
• 
Myostatin inhibitors (monoclonal antibodies, soluble receptors). 
• 
Molecules targeting the renin-angiotensin system (RAS) such as angiotensin converting 
enzyme (ACE) inhibitors, angiotensin II antagonists and angiotensin 1-7 (or agonists 
thereof). 
• 
Some beta blockers (inhibitors of β-adrenergic receptors), e.g. espindolol19. 
• 
Various natural substances such as polyphenols (resveratrol, isoflavones), triterpenes 
(ursolic and oleanolic acid), or phytosteroids (brassinosteroids, phytoecdysones). 
 
Pharmaceutical companies had developed drug candidates based on the above technologies, 
especially on the use of therapeutic antibodies that inhibit myostatin. They also tested other 
strategies, in particular the use of testosterone in combination with aromatase inhibitors or 
receptor SARMs, but the development of these drug candidates was stopped in Phase 2 because 
of side effects and associated cancer risks. Moreover, SARMs have shown no advantage over 
testosterone.17. Finally, clinical research centers specialized in aging have tested the benefit of 
ACE inhibitors to increase muscle quality and mobility of elderly patients treated for hypertension, 
and the initial results were promising20. 
 
Regarding clinical research on myostatin inhibition for targeting sarcopenia, two main strategies 
are used, either blocking the myostatin receptor (activin A/B) or directly blocking myostatin and 
therefore preventing its interaction with its receptor. Three products have completed Phase 2 
studies. These are bimagrumab developed by Novartis, LY2495655 by Ely Lilly, and REGN1033 by 
Regeneron. 
 
 using their Troponin activator (CK-2127107), continue to target 
sarcopenia as well. The latter study with the troponin activator was terminated due to a lack of 
efficacy determined during interim analysis.  
Bimagrumab 
 is a human monoclonal antibody that binds to 
myostatin receptor. The phase 2 clinical trial in patients with sarcopenia showed no change in 
bimagrumab treated group versus placebo. Only a subsequent analysis of the clinical data 
revealed that sarcopenic participants with slow walking speed showed statistically significant 
improvements in gait speed and in the 6MWT compared to placebo21. However, these results 
from very limited cohorts did raise concerns regarding correlation between muscle size and 
function22. 


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The anti-myostatin antibody, LY2495655, in a phase 2 study on older, weak fallers for 24 weeks23, 
induced a significant difference in appendicular lean body mass of 0.43 kg (95% CI 0.192 to 0.660; 
p<0.0001) but did not show any significant difference compared to placebo with regards to 
physical performance (stair climbing, chair rise with arms and fast gait speed).  
REGN1033 or Trevogrumab a fully human mAb targeting myostatin was studied in sarcopenia, 
including disuse atrophy, chronic disease, changes in food and nutritional intake. The treatment 
induced an increase of total lean body mass of 2.29 % compared with placebo at the highest dose. 
However, this gain was not translated to statistically significant improvements over the placebo 
group in strength and function assessments including the 6MWT24. Clinical studies with REGN1033 
seem to be discontinued.  
To our knowledge, none of the products has concomitantly showed in Phase 2 meaningful effects 
on lean body mass and physical function. There is still an unmet need for new drugs for 
sarcopenia. Along with drug treatment, an ideal management would likely combine daily physical 
exercise to help strengthen muscle mass, adequate nutrition to avoid protein deficiency and drug 
therapy to limit the cardiovascular risk. 
 
Biophytis has developed BIO101 as an investigational drug candidate for treating age-related 
sarcopenia, including sarcopenic obesity, and prevent mobility disability in at-risk older adults. 
The overall clinical development of this innovative oral treatment currently conducted by 
Biophytis in age-related sarcopenia and SO is called “SARA” which stands for SARcopenia and 
sarcopenic obesity in patients Aged ≥ 65 years. 
 
SARA clinical development program includes 3 steps:  
 
1. SARA-PK: a phase 1 clinical trial evaluating the safety and pharmacokinetics of BIO101 
administered by oral route in young and older healthy volunteers (completed). 
 
2. SARA-OBS: an observational trial characterizing sarcopenia, including sarcopenic obesity, 
in community-dwelling older adults complaining about a loss of physical function and 
considered at risk of mobility disability. This is a 6-month observational study without any 
therapeutic intervention (completed). 
 
3. SARA-INT: a phase 2 double-blind, placebo-controlled clinical trial evaluating the safety 
and efficacy of two oral doses of BIO101 in study participants ≥ 65 years complaining of a 
loss of physical function, suffering from sarcopenia, and considered at risk of mobility 
disability. 
 
The SARA program is supported and hosted by SARA-Data, an innovative platform for a novel 
approach of clinical trials management. This includes an electronic Case Report Form (eCRF)  
electronically administered Patient Reported Outcomesas well as a continuous physical activityy 
recorded through a wearable actimetry device. All of this is performed within a different-source-
data integrated environment25. 
 
 


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2.2 
BACKGROUND  
THE INVESTIGATIONAL PRODUCT 
BIO101 active ingredient is 20-hydroxyecdysone (20E) 
 
 
The investigational product is formulated as 175 mg oral capsules, contained
 
  
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
According to the FDA guidance for estimating starting doses in initial clinical trials (2005), 
 
 
 
On this basis, the starting dose of 100 mg and the range of doses from 100 to 1,400 mg/day were 
selected for the single ascending doses of BIO101 phase 1, first-in-human study in young and 
elderly healthy volunteers.  
 
 
 
 


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Based on these new evidences, an extended treatment of 3 additional months for participants 
missing the efficacy assessments at Month 6 visit is proposed. This would allow for additional data 
on safety and efficacy for the final analysis. 
Based on all the data presented above, the 700 mg dose was set as the maximum daily dose 
 
 
 
 
The safety and pharmacokinetics of BIO101 were evaluated in SARA-PK, a phase 1, double-blind, 
placebo-controlled, randomized clinical trial combining a single oral administration in both young 
and older healthy volunteers and a 14-day multiple oral administration in older healthy 
volunteers, with the overarching objective of SARA-PK was to establish the range of oral doses 
suitable to be administered and evaluated in phase 2 clinical trials. The two clinical parts of the 
study started on August 2016 and were completed on December 201627.  


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In the Single Administration Dose (SAD) part, 2 cohorts of young healthy volunteers (18-55 years) 
in fasting state were dosed at 100, 350, 700 and 1,400 mg/day and one cohort of elderly healthy 
volunteers (65-85 years) was tested at 1,400 mg/day. Food effect was evaluated at 700 mg by 
comparing safety and pharmacokinetics in fed and fasted administration in the same cohort of 
young healthy volunteers (18-55 years). Age effect was evaluated at 1,400 mg/day by comparing 
safety and pharmacokinetics in the young healthy volunteer group to the elderly healthy 
volunteer group (65-85 years).  
 
No serious adverse events (SAEs) were observed up to 1,400 mg/day in young or elderly cohorts. 
Adverse events (AEs) were mild and were reported at the doses of 350 mg and 1,400 mg in the 
young study participants and at 1,400 mg for the elderly study participants. Most frequently 
reported AEs were gastrointestinal disorders, nervous system disorders (headache) and musculo-
skeletal-and-connective tissue disorders. No meaningful treatment-emergent laboratory, ECG or 
vital sign abnormalities were reported.  
 
After a single administration in fasted conditions, BIO101 was rapidly absorbed with a median 
time to Cmax between 2 and 3.5 hours. BIO101 plasma concentrations increased less than dose 
proportionally between 100 and 700 mg, and dose proportionally between 700 and 1,400 mg. 
After single (fasted) oral administration of 100, 350, 700 and 1400 mg it was observed a Cmax of 
141, 317, 399 and 710 ng/mL, respectively. The AUC was 797, 1,946, 2,658 and 4,283 ng.h/mL 
respectively. The mean half-life was short; between 2.4 and 4.9 hours. 
No age effect was observed on the pharmacokinetic profile of BIO101; the comparison of young 
healthy volunteers and elderly healthy volunteers at 1,400 mg/day in SAD did not show a 
meaningful difference in the Cmax (710 vs 552 ng/mL) or in the AUC (4,283 vs 3,630 ng.h/mL).  
In addition, no food effect was observed on the pharmacokinetic profile of BIO101; the 
comparison of healthy young volunteers dosed at 700 mg in fasted or fed conditions did not show 
a meaningful difference in the Cmax (399 ng/mL vs to 505 ng/mL) or in the AUC (2658 vs 3294 
ng.h/mL). It was therefore decided to use the fed condition in the Multiple Ascending Doses 
(MAD) part. 
Overall, BIO101 was well tolerated in doses ranging from 100 to 1,400 mg in a single oral 
administration. Cmax observed at 350 mg and 700 mg/day (399 and 505 ng/mL respectively) 
corresponds to the 
 
 
 
Both doses of 350 mg and 700 mg were therefore retained to be tested in the 14-day MAD part 
under fed condition.  
 
Based on the relatively short half-life observed under single administration conditions, it was 
decided to compare, sequentially, 350 mg once a day and 350 mg b.i.d. Subsequently, based on 
the good safety profile observed, a higher dose was also tested at 450 mg b.i.d. 
 
In the MAD part, three cohorts of elderly healthy volunteers (65-85 years) were administered 350 
mg q.d., 350 mg b.i.d. and 450 mg b.i.d. during 14 days. No SAEs were observed. Reported AEs 
were either mild or moderate (the latest limited to 450 mg b.i.d.). The highest number of study 


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participants with treatment related AEs was reported in the cohort of 450 mg b.i.d., in 5 study 
participants. Treatment related AEs were reported in at most 1 subject each in the 350 mg q.d. 
and the 350 mg b.i.d. cohorts. None of the observed treatment-emergent laboratory, ECG or vital 
sign abnormalities were considered clinically significant and none were reported as AEs. Overall, 
350 q.d. and 350 b.i.d. were equally safe.  
 
Administration of 350 mg q.d. generated a Cmax of 346 ng/mL on day 1 and 388 ng/mL on day 
14. From day 2 to day 12, the mean pre-dose concentrations ranged from 7.33 ng/mL to 7.73 
ng/mL. At 350 mg b.i.d., Cmax corresponded to 453 ng/mL on day 1, and 506 ng/mL on day 14. 
From day 2 to day 12, the mean pre-dose concentrations ranged from 105 to 126 ng/mL. After 
repeated daily administrations of 350 mg for 14 days (i.e., on Day 14), BIO101 Cmax and AUC0-τ 
were higher (increase of about 30% for Cmax and 16% for AUC0-τ), on average, in study 
participants administered 350 b.i.d. (506 ng/mL; 2768 ng.h/mL) than those administered q.d. (388 
ng/mL; 2389 ng.h/mL). The b.i.d. administration was therefore selected as it allowed continuous 
pre-dose plasma concentrations close to the pharmacologically active dose of 140 ng/mL during 
the whole 14-day MAD period.  
Administration of 450 mg b.i.d. generated a Cmax of 524 ng/mL on day 1 and 560 ng/mL on day 
14. From day 2 to day 12, the pre-dose concentrations ranged from 109 ng/mL to 151 ng/mL. 
AUC0- τ was 2,429 ng.h/mL on day 1 and 3,203 ng.h/mL on day 14.   
No accumulation of BIO101 was observed after q.d. administration of 350 mg BIO101 for 14 days 
(mean Rac= 1.14) whereas a slight accumulation was observed after b.i.d. administrations of 
BIO101 at 350 mg and 450 mg for 14 days (mean Rac= 1.31 in both panels). 
Median Tmax was the same (i.e., 3 h) in all dose groups and after the first and last doses. Mean 
BIO101 half-life was short with values approx. 2.8 and 4.4 h in all cohorts. At 350 mg and 450 mg 
b.i.d., after the day 14 morning administration, mean Cmax and AUC0-τ increased by about 1.11-
fold and 1.16-fold for a 1.29-fold dose increase (from 350 mg to 450 mg), so less than dose-
proportionally. Based on the above results, no clinically meaningful accumulation is expected over 
the 26-week administration. 
Based on the pharmacokinetic parameters, both 350 mg and 450 mg did show interesting profiles. 
On this basis, the b.i.d. administration was confirmed to be used for the next development phase 
of BIO101.  
 
 
 
 
 
 
 
 
  
 
 
 


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In conclusion, 
 the 
administration of 350 mg b.i.d. was selected as the highest dose to be tested in the phase 2 study. 
This dose was well tolerated as it generated few numbers of AEs with mild severity. The dose of 
350 mg b.i.d generated a Cmax of 346 ng/mL 
 
 
 The dose of 175 mg b.i.d. was selected as a 
second dose for the phase 2 study. This dose being lower than 350 mg b.i.d., is anticipated to be 
safe and well tolerated. The 175 mg b.i.d. was not evaluated during the MAD part. 
 
 
 
 
Refer to the Investigator’s Brochure (IB) for more details. 
  
SCIENTIFIC RATIONALE FOR DESIGNING SARA-INT CLINICAL TRIAL 
Study population 
SARA-INT will enroll older persons living at home and encountering objective limitation of physical 
functions as defined by a low score at SPPB (SPPB≤8). A similar reasoning has been applied to the 
SPRINT-T16 clinical trial (SPPB≤9 with a quota of patients scoring ≤7), an approach consistent with 
recent recommendations by the European regulators (ICFSR Philadelphia, 2016). According to 
published data, lower performers are in a state of disease in which therapeutic interventions such 
as a structured physical activity can produce a significant improvement on various parameters like 
gait speed or chair stand. We have therefore targeted participants that combine objective criteria 
for sarcopenia, as measured by DEXA, with evidence of reduced mobility. 
The main difference, between SARA-INT and SPRINT-T, is that SPRINT-T tests the impact of 
exercise. It is possible, that individuals who improve with exercise only, will not require an 
addition of a drug intervention. This is why, in this study, we are including only participants with 
an SPPB score of ≤8, and excluding those with a score of 9, like those who were included in the 
SPRINT-T study and were considered to be potentially more stable, and may respond well to 
exercise treatment only. 
Study Endpoints 
Designing and implementing an adapted set of investigations to accurately and efficiently 
describe the progressive decline of physical function in at-risk older individuals is also a challenge. 
In fact, there is no final consensus on the most sensitive and specific primary endpoints, even 
though there is a general convergence on low gait speed as the key physical function related to 
an increased risk for mobility disability, falls, loss of independence and mortality28,29. 
The LIFE study, and its preparatory LIFE-P clinical trial, extensively evaluated the 400MW test in a 
population of community dwelling men and women aged 70-89 years with a sedentary lifestyle 


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and an SPPB ≤ 9. The 400MW test was used as a dichotomous test, with failure being defined as 
the inability to walk 400 meters without sitting and without help within 15 minutes. The incident 
rate of failure in the LIFE control group (n= 817) with no specific therapeutic intervention, was 
35.5% (290 out of 817 study participants) and permanent mobility disability occurred in 19.8% 
over a mean follow-up duration of 2.6 years. Interestingly, majority of mobility disability events 
were observed in the subgroup with SPPB <8, with 177 out of 378 study participants or 46.8% 
with incident disability15. Transition rate from success to failure with the 400MW test over 
6 months had been 6.9% in LIFE-P. However, this outcome was more efficient as compared to the 
4-meter walk, or the SPPB itself30. 
The 6MWT has been initially validated and extensively used mostly in respiratory and 
cardiovascular conditions31. This test can be analyzed as a continuous variable, although a 
threshold value of 50 m improvement has been used as a dichotomous test.  
However, in a recent clinical trial on the effects of testosterone treatment in older men aged ≥ 65 
years, relatively stable values of 6MWT were observed over 6 months in the control group 
(n=196), as well as in the active treatment group (n=191), and there was no significant difference 
between the two groups32. Several reasons can be considered to explain the lower than expected 
effect of the tested intervention, among these: a) the selection of a relatively preserved 
population in terms of motor function (i.e. gait speed≤1.2 m/s) and b) the choice of a minimum 
clinically important difference of 50 m (although this threshold was previously validated in 
different patients populations, e.g. total and knee arthroplasty or chronic lung disease; see 
methods in Snyder et al, 2014 ClinTrials33). 
The LIFE study used the 400MW test as a dichotomous variable and a proxy for mobility disability. 
The same methodological approach was adopted in the case of SPRINT-T. Overall, the choice of 
this kind of primary endpoint is particularly onerous in terms of study and intervention duration; 
LIFE participants were treated for two and a half years and SPRINT-T has an expected treatment 
duration of two years  in order to detect a meaningful difference between treatment groups15. 
Santanasto et al performed additional prespecified analyses on LIFE results with the objective of 
identifying earlier changes that could anticipate later mobility disability or possibly focus on 
functional improvement and stabilization of muscle functions16. Interestingly, both the gait speed 
measured during the 400MW test and the chair stand sub-score of SPPB did show a visible and 
statistically significant improvement at six months, followed by a relative stabilization or decline. 
In general, gait speed decline has been strongly correlated to major outcomes like incident 
mobility disability, hospitalizations and lower life expectancy. 
For these reasons, it was decided to define the 400MW test gait speed as the primary endpoint 
for SARA-INT.  
In terms of PROs, both the US FDA and the European Medicine Agency (EMA) recently emphasized 
the importance of accompanying physical function objective measurements by an auto-
evaluation questionnaire to estimate the corresponding improvement in the daily life activities 
(ICFSR Philadelphia, 2016; FDA Patient-Focused Drug Development Public Meeting for Sarcopenia 
April 6, 2017). The SF-36 is one of the most widely used, validated measures of health-related 


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quality of life and has been shown to discriminate between study participants with different 
chronic conditions and between study participants with different severity levels of the same 
disease34,35. The SF-36 has also demonstrated sensitivity to significant treatment effects in a 
variety of patient populations. Population-based normative data on the SF-36 is available for the 
US and other countries as well. 
This instrument addresses health concepts that are relevant to the patient's perspectives. There 
is no single overall score for the SF-36, instead, it generates 8 subscales and two summary scores. 
The PF-10, which measures the role limitations due to physical problems, will be a key secondary 
endpoint for SARA-INT. PF-10 has been tested in numerous clinical trials and is considered a 
simple and effective measure of mobility disability and for epidemiological studies36. Climbing one 
flight of stairs (no change versus decline of two levels, two-point difference) or walking a block 
(no change versus two levels decline) exemplifies a substantial meaningful change, as appreciated 
by patients33,36.  
Data from the recently completed SARA-OBS study could be used to corroborate these 
hypotheses. 
COVID-19 pandemic 
Safety of study patients and investigators should be the priority during COVID-19 outbreak. Only 
ePROs (SF36, SARQoL, TSD-OC and Pat-D will be assessed during this period until further guidance. 
An extension of the treatment period for a total period of 9 months of intervention will enable 
the full assessment of the safety and efficacy of the investigational product for a significant part 
of the population randomized in this study, while staying in compliance with good clinical practice 
(GCP), and minimizing risks to trial integrity during the COVID-19 pandemic.  
 
2.3 
RISK/BENEFIT ASSESSMENT  
 
2.3.1 
KNOWN POTENTIAL RISKS  
Potential risks are related to the long-term administration of an investigational drug to 
participants suffering from multiple chronic diseases.  
 
 
 
 
 
 
 
 
 
 
 


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BIO101 was well tolerated in healthy elderly volunteers receiving up to 450 mg b.i.d. for 14 days. 
Based on non-clinical safety (26-week studies 
, safety 
pharmacology and phase 1 results, both immediate and long-ranging risks can be considered as 
low.  
The active ingredient in BIO101, 20E, may become a restricted substance, which is not allowed to 
be used in sport competitions. The reason is that there is a tendency to use it as an anabolic agent. 
Since BIO101 contains a high concentration of 20E at a dose that is much higher than the one that 
appears in nutritional supplements, there is concern that non-sarcopenic individuals may want to 
use BIO101 illicitly. Participants in this study will be warned and instructed to not allow anyone to 
gain access to their medication and to use only according to the medication instructions provided 
in the drug kits. 
In addition, 
 its 
putative mechanism of action through activation of the MAS receptor and potential impact on 
the renin–angiotensin–aldosterone system (RAS) requires attention. A special surveillance and 
precaution will be taken with events that could theoretically indicate presence of orthostatic 
hypotension (OTH), including dizziness and presyncope related to orthostatic changes and actual 
measurements. In addition, events that comply with the clinical definition of OTH (i.e. decrease 
in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg 
within three minutes of standing when compared with blood pressure from the sitting or supine 
position)  will require special attention even without symptoms. 
There are limited risks linked to the execution of the functional tests, e.g. falling during a test. The 
investigational site staff will put in place adapted surveillance, adequate prevention including 
cancellation or postponing of a planned test, and adapted emergency care in order to prevent, 
limit and appropriately and timely treat possible adverse events.  
All AEs will be reported as per standard pharmacovigilance procedures (Section 8.4). 
 
2.3.2 
KNOWN POTENTIAL BENEFITS  


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The potential benefit of BIO101 has been demonstrated in several in-vitro and in-vivo studies, as 
described in the investigator’s brochure and mentioned in section 2.2. This justifies testing the 
potential benefit of this drug in participants with age-related sarcopenia. 
Elderly participants suffering from initial loss of physical function are expected to improve their 
motor ability based on observed BIO101 non-clinical effects on muscles and muscle cells. 
All patients will undergo several nonspecific exams that could contribute to earlier diagnosis of 
unknown diseases. 
A further potential and indirect benefit is that all participants will be closely followed-up with their 
physical activities continuously reported through the wearable actimetry device and this could 
allow earlier diagnosis of a concomitant condition or of worsening of the mobility impairment. 
 
2.3.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Overall, potential benefits of participating in the study are expected to outweigh the potential 
risks.  
Immediate and long-term risks are considered low based on phase 1 safety evidence and non-
clinical studies. The scientific information collected during this clinical trial will allow the 
assessment of the safety and efficacy of a novel drug that could be useful in the future to prevent 
the consequences of a geriatric condition like age-related sarcopenia.  
2.3.4 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS DURING THE COVID-19 
PANDEMIC 
 
The main risk for participants is the exposure to COVID-19 virus and infection if clinical visits continued. 
The measure taken on March 20th 2020, therefore, was to cancel all on-site visits for participants active 
in the study.  
As a consequence of this measure, it is impossible to conduct most of the safety and efficacy 
assessments, putting the completeness of the data that is collected during the study at risk. The lack 
of information from participants during this period may hamper the global analysis of the full dataset 
of the study, to the extent that the whole study may become nullified. To mitigate this risk, and based 
on the safety profile of recently available pre-clinical data, an extension of the participation of these 
subjects under treatment is proposed up to a total of 9 months of intervention. This will allow the 
collection of safety and efficacy data at the end of the COVID-19 outbreak based on the updated 
projections from national/federal, state and local governments on the restrictive measures for travel 
and daily activities of participants and trial staff.  
All study activities are impacted by the restrictions on physical interactions (such as physical distancing 
and stay-at-home orders) due to the COVID-19 outbreak, which could lead to an early termination of 
participation of individuals in the study. The sponsor will rely on the contingency plans of each vendor 








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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
 
 
 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
 
SARA-INT is a 3-arm (2 doses versus placebo), randomized, double-blind, placebo-controlled 
parallel design phase 2 clinical trial. This comparative clinical trial evaluates the effects of a 6-
month treatment duration, based on the hypothesis that physical function of sarcopenic, older 
patients with an initial degree of mobility disability (SPPB≤8) will be meaningfully improved after 
6 months of oral treatment with BIO101 (in at least one of the two tested doses) with respect to 
placebo. 
 
SARA-INT is a multi-site study that aims to enroll 231 community dwelling, older adults (men or 
women ≥ 65 years), reporting a loss of physical function over the previous 6-12 months, and at 
risk of mobility disability, to undergo screening tests for inclusion in the study. Included 
participants will be randomized in a 1:1:1 ratio, for one of the 3 arms of treatment in a blinded 
manner. The randomization will be stratified by gender and by center. Bias are minimized by the 
use of identical therapeutic units whose number is automatically assigned via an eCRF embedded 
algorithm after the Investigator confirms randomization of a participant. All included participants 
will complete the inclusion visit and start a 6 to 9-month treatment and observation, with the 
main evaluation at the end of the study duration. Based on non-clinical safety considerations, the 
investigational drug exposure is capped at 39 weeks. The complete Schedule of Activities is 
provided in Section 1.3. 
 
An interim analysis will take place however, the number of completers, based on which it will be 
conducted, will be determined once restrictions are lifted and it is clear, how many participants 
dropped out before the end-of-study assessments. 
 
 
   
 
 
 
 
 
 
  
 
 
 


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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Study population 
As stated in the introduction, we are including older adults who are still living independently in 
the community and who have encountered objective limitation of physical function as defined by 
a low SPPB score (SPPB≤8). A similar reasoning was applied to the SPRINT-T17 clinical trial (SPPB≤9 
with a quota of patients scoring ≤7) which is an approach consistent with recent 
recommendations by the European regulators (ICFSR, Philadelphia, 2016). In fact, prespecified 
analyses from the LIFE study clearly showed a better response in lower performers and raised the 
possibility of limited benefits in treating more robust individuals as compared to the lower 
functioning individuals. 
Study Endpoints 
Designing and implementing an adapted set of investigations to accurately and efficiently 
describe the progressive decline of physical function in at-risk older individuals is a challenge. 
There is currently no consensus on what is the most sensitive and specific primary endpoint, 
however, there is a general convergence on low gait speed being the key physical function related 
to an increased risk for mobility disability, falls, loss of independence and mortality. 
The LIFE study, and its preparatory LIFE-P clinical trial, extensively evaluated the 400MW test in a 
population of community dwelling men and women aged 70-89 years old with a sedentary 
lifestyle and an SPPB ≤ 9. The 400MW was used as a dichotomous test with failure being defined 
as the inability to walk 400 meters without sitting and without help within 15 minutes. The 
incident rate of failure in the LIFE control group (n= 817) with no specific therapeutic intervention 
was 35.5% (290 out of817 study participants), and permanent mobility disability occurred in 
19.8% over a mean follow-up duration of 2.6 years. An interesting fact is that the majority of 
mobility disability events were observed in the subgroup with SPPB<8, in 177 out of 378 study 
participants or 46.8%, for incident disability15. Transition rate from success to failure with the 
400MW test over 6 months was 6.9% in LIFE-P. However, this outcome was more efficient as 
compared to the 4-meter walk, or the SPPB itself30. 
The 6MWT was initially validated and extensively used mostly in respiratory and cardiovascular 
conditions31. This test can be analyzed as a continuous variable, although a threshold value of 50 
m improvement has been used as a dichotomous variable.  
However, in a recent clinical trial on the effects of testosterone treatment in old men aged ≥ 65 
years, relatively stable values for the 6MWT were observed over 6 months in the control group 
(n=196) and in the active treatment group (n=191) with no significant differences between the 
two groups32. Several reasons can be considered to explain this lower-than-expected effect of the 
tested intervention: a) the selection of a relatively preserved population in terms of motor 
function (i.e. gait speed≤1.2 m/s) and b) the choice of a minimum clinically important difference 
of 50 m although this threshold was previously validated in different patient populations that 
included those with total and knee arthroplasty or chronic lung disease (see methods in Snyder 
et al, 2014 ClinTrials33). The LIFE study used the 400MW test as a dichotomous test and as a proxy 


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for mobility disability. The same methodological approach was adopted in the case of SPRINT-T. 
Overall, the choice of this kind of primary endpoint can be particularly onerous in terms of study 
and intervention duration: LIFE participants were treated for two and a half years and the 
expected treatment duration for SPRINT-T is two years  in order to detect a meaningful difference 
between treatment groups. 
Therefore, Santanasto et al16 performed additional prespecified analyses on LIFE results with the 
objective of identifying earlier changes that could anticipate later mobility disability or possibly 
focus on functional improvement and stabilization of muscle functions. 
Interestingly, both the gait speed measured during the 400MW test and the chair stand sub-score 
of the SPPB showed a visible and statistically significant improvement at six months, followed by 
relative stabilization or decline. In general, gait speed decline has been strongly correlated to 
major outcomes like incident mobility disability, hospitalizations and lowered life expectancy. 
For these reasons, the 400MW test gait speed was chosen as the primary endpoint for SARA-INT.  
In terms of PROs, both the US FDA and the EMA recently emphasized the importance of 
accompanying physical function objective measurements by an auto-evaluation questionnaire 
estimating the corresponding improvement in the daily life activities (ICFSR Philadelphia, 2016; 
FDA Patient-Focused Drug Development Public Meeting for Sarcopenia April 6, 2017). The SF-36 
is one of the most widely used, validated measures of health-related quality of life and has been 
shown to discriminate between subjects with different chronic conditions and between subjects 
with different severity levels of the same disease35. The SF-36 has also demonstrated sensitivity 
to significant treatment effects in a variety of patient populations. Population-based normative 
data on the SF-36 is available for the United States and other countries as well. 
This instrument addresses health concepts that are relevant to the patient's perspective. There is 
no single overall score for the SF-36, instead, it generates 8 subscales and two summary scores. 
The PF-10 sub-score that measures role limitations due to physical problems, will be the key 
secondary endpoint for SARA-INT. PF-10 has been tested in numerous clinical trials and is 
considered as a simple yet effective measure of mobility disability and also for epidemiological 
studies36. Climbing one flight of stairs (no change versus decline of two levels, two-point 
difference) or walking a block (no change versus two levels decline) exemplifies a substantial 
meaningful change, as appreciated by patients33,36.  
Data from the recently completed SARA-OBS study could be useful to corroborate these 
hypotheses. 
COVID-19 pandemic 
Safety of study patients and investigators should be the priority during COVID-19 outbreak. Only 
ePROs (SF36, SARQoL, TSD-OC and Pat-D will be assessed during this period until further guidance. 
An extension of the treatment period for a total period of 9 months will enable the full assessment 
of the safety and efficacy of the investigational product for a significant part of the population 
randomized in this study, while staying in compliance with good clinical practice (GCP) and 
minimizing risks to trial integrity during the COVID-19 pandemic.  


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4.3 
JUSTIFICATION FOR DOSE 
 
Based on the pharmacokinetics and safety parameters of the SARA-PK phase 1 MAD part, the 
administration of 350 mg b.i.d. was selected as the highest dose to be tested in the phase 2b 
study. This dose was well tolerated as it generated few numbers of AEs with mild severity. The 
dose of 350 mg b.i.d. generated a Cmax of 346 ng/mL 
 of 
BIO101 
 
 The dose of 175 mg b.i.d. was selected 
as a second dose for the phase 2 study. This dose, being lower than 350 mg b.i.d., is anticipated 
to be safe and well tolerated. The 175 mg b.i.d. was not evaluated during the MAD part. 
 
 
 
 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last on-site visit that includes all the safety and efficacy assessments and 
the post-intervention phone call or the last scheduled procedure for an end-of-study visit as 
shown in the SoA, Section 1.3. 
 
The end of the study is defined as a completion of the last visit or procedure shown in the SoA in 
the trial globally. 
 
5 
STUDY POPULATION 
231 community dwelling older adults (men or women ≥ 65 years) living at home and reporting a 
loss of physical functions over the last six-twelve months and considered at risk of mobility 
disability will be included in this randomized, interventional clinical trial, with 64 patients per 
treatment group and a treatment period of 26 to 39 weeks. 39 additional participants will be 
randomized to allow a 20% of non-evaluable withdrawals or lost to follow-up for a total of 231 
older adults included in the US and the EU. 
It is expected, that due to COVID-19 related restrictions, that the number of non-evaluable 
withdrawals will be higher than 20%. However, reassessment of the sample size, will take place, 
as a part of the interim analysis, that will take place after restrictions are lifted. 
A predefined subgroup efficacy analysis will also be performed in a number of pre-identified, at-
  
 
 
 
 
 
 
 
 


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5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study  
3. Male or female aged ≥ 65 years, living in the community (living at home, able to walk 
outside from time to time. Homes can include living communities that may or may not 
offer optional services for the convenience of the residents. Older adults living in nursing 
homes or in medicalized residences where caretaker services are mandatory are not 
eligible) and reporting a loss of physical functions over the last 6-12 months 
4. SPPB score ≤ 8 
5. ALM/BMI < 0.789 in men and 0.512 in women, or ALM < 19.75kg in men and <15.02kg 
in women, as measured by DEXA scan 
6. Ability to take oral medication and willingness to adhere to the study intervention regimen 
(see section 6) 
7. Agreement to adhere to the Lifestyle Considerations (see section 5.4) throughout the 
study duration 
8. In the US, women and members of minority groups should not be excluded, in accordance 
with the NIH Policy on Inclusion of Women and Minorities as Participants In Research 
Involving Human Subjects  
 
5.2 
NON-INCLUSION CRITERIA 
An individual who meets any of the following criteria will not be included in this study: 
 
1. In France, non-affiliation to compulsory French social security scheme (beneficiary or 
right-holder)  
 
2. In France, being under tutelage or legal guardianship  
 
5.3 
EXCLUSION CRITERIA AND TEMPORARY EXCLUSION CRITERIA 
An individual who meets any of the following exclusion criteria will not be eligible to participate 
in this study. An individual who meets any of the following temporary exclusion criteria may be 
re-screened after 3 months. 
Exclusion criteria: 


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1. Current use of anabolic drugs (e.g. testosterone); current use of Erythropoietin; current 
use of corticosteroid agents (except for local administration routes, such as eye drops or 
dermatologic formulations)  
2. Non-menopaused women (however, ongoing hormonal replacement treatment is not an 
exclusion criterion if started at least 3 months before screening) 
3. Known allergic reactions to sourcing components of the investigational drug 
 
 
4. Treatment with another investigational drug or other interventions within three months 
5. Unable to understand and perform the functional tests, as judged by the Investigator 
6. Inability to complete the 400MW test within 15 minutes 
7. Clinical conditions: 
a. Current diagnosis of major psychiatric disorders  
b. Alcohol abuse or dependence 
c. Severe arthritis 
d. Cancer requiring active treatment (study participants with cancer previously 
treated with chemotherapy and/or radiotherapy, or study participants currently 
on remission is not an exclusion criterion) 
e. Lung disease requiring regular use of supplemental oxygen 
f. Inflammatory conditions requiring regular use of oral or parenteral corticosteroid 
agents 
g. Severe cardiovascular disease (including New York Heart Association [NYHA] class 
III or IV congestive heart failure, clinically significant valvular disease, history of 
cardiac arrest, presence of an implantable defibrillator, or uncontrolled angina) 
h. Parkinson’s disease or other progressive neurological disorder 
i. 
Renal disease requiring dialysis, or known renal insufficiency (moderate or severe 
reduction in eGFR≤30 ml/min/1.73 m2, using Cockroft & Gault (CG) formula)  
j. Chest pain, severe shortness of breath, or occurrence of other safety concerns 
during the baseline functional test (the 400MW test)   
k. History or active signs or symptoms of gallbladder/biliary disease (e.g. previous 
episodes of cholestasis/biliary tract obstruction, cholelithiasis, cholecystitis, etc.). 
Of note, history of cholecystectomy and no active biliary signs or symptoms, is 
not an exclusion criterion 
8. Current physical/rehabilitation therapy (except for passive physical therapy. However, 
this should not be initiated the week before an evaluation visit and once started, it should 
be maintained over the study duration) 
Temporary exclusion criteria: 
1. Uncontrolled hypertension (systolic blood pressure >200mmHg or diastolic blood pressure 
>110 mmHg) 
2. Uncontrolled diabetes with recent weight loss, diabetic coma, or frequent hypoglycemia 


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3. Stroke, hip fracture, hip or knee replacement, or spinal surgery in the past 6 months 
4. Heart arrhythmic disorder, e.g. third-degree heart block, uncontrolled arrhythmia, new Q 
waves within the past 6 months or ST-segment depression (>3mm) on the ECG. Of note, a 
current pace-maker implant is not an exclusion criterion 
5. Myocardial infarction, major heart surgery (e.g., valve replacement or bypass surgery), 
deep vein thrombosis, or pulmonary embolus in the past 6 months 
6. Febrile illness within 7 days 
7. Recent introduction of hormone replacement therapy in menopaused women (less than 3 
months before screening) 
 
 
5.4 
LIFESTYLE CONSIDERATIONS 
During the SARA-INT 6-month treatment phase, all participants are asked to avoid a sedentary 
lifestyle and to try to perform at least 30 minutes of physical activity per day, at least 5 days per 
week. Physical activities can consist of walking, going for groceries, gardening, housekeeping, and 
light exercise (at home or outdoors) but only if the participant is already used to performing them 
on a routine basis.  
Of note, walking and other physical exercise will be automatically recorded via a wearable 
actimetry device for later analyses. With this aim, all participants will be requested to wear the 
actimetry device most of the time as a wrist watch, including at night. They are expected to 
remove it only during showers and/or baths.  
A structured physical exercise program should not be started during the study treatment phase. 
During this study, participants are also asked to maintain a healthy diet and to avoid excessive or 
low food intake. A brochure reminding participants of simple rules for a healthy, nutritional diet 
will be provided to all participants.  
5.5 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomized into the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAEs. 
Individuals who do not meet the criteria for participation in this trial (screen failures) because of 
a temporary exclusion criterion may be re-screened after 3 months. These re-screened 
participants should be assigned the same participant number from the initial screening. 
Investigational sites are allowed to rescreen a participant who had borderline results for an 
eligibility criterium (i.e. SPPB=9) 6 to 12 months after their first screening, if the subject complains 
from a decline in his.hr physical abilities. These rescreened participants should be assigned with 
a new participant number compared to the first screening. Participants can only be screened 
twice.  
5.6 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Mass mailings, posters or videos in the hospital/clinic waiting rooms, presentation of the 
SARA-INT study in local newspapers, on TV, radio broadcasting or on social media by the PI and 


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Investigators are all strategies that will be considered, made available and implemented/adapted 
according to the local policies and regulations. In addition, app-based tools could also be utilized. 
A dedicated website to present the study to the general public is available online 
(https://mysara.eu/#/) and could be referenced by institutional websites. 
Transportation vouchers could be provided to participants according to local policies and 
legislation. 
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
The investigational product BIO101 is prepared in accordance with Good Manufacturing Practice 
(GMP) as required by Good Clinical Practice (GCP). 
The BIO101 active principle ingredient is 20E, 
 
 
   
 
 
 
 
 
 
Placebo was prepared in accordance with GMP as required by the current GCP 
 
  
A Certificate of Analysis (CoA) is included in the CMC IMPD (Chemistry, Manufacturing and 
Controls Investigational Medicinal Product Dossier). 
6.1.2 
DOSING AND ADMINISTRATION 
Three doses are tested in this study: 175 mg b.i.d. of BIO101, 350 mg b.i.d. of BIO101 or placebo 
b.i.d. A rationale for the doses selected of the study drug is provided in section 4.3. 
Administered daily dose is the same throughout the whole treatment period. 
All therapeutic units (175 mg BIO101 b.i.d. or 350 mg BIO101 b.i.d. or placebo b.i.d.) are identical 
in compliance with the double-blind process. 
Study participants are instructed by the investigator or the investigation center staff to start the 
treatment the day after randomization; e. g. if the participant is randomized on Friday, he/she will 
start the investigational treatment on Saturday morning. 
Each administration is made of two capsules, to be taken by oral route, swallowed with water or 
fruit juice or other common soft drinks. Capsules should be taken twice a day: once in the morning 
and once in the evening. Those can be taken with a meal such as breakfast or dinner, 


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approximately 12 hours apart. If the participant forgets or is not able to take the capsules at the 
appointed time, he/she should be instructed not to make up for the missed pills; i.e. to not take 
more capsules later in the day or the day after. 
The four capsules to be taken daily is the same across the entire 6-month treatment period. 
Important note: Date of each next visit should be calculated back on Day 0 visit (baseline) in order 
to not exceed the total duration of 26 weeks of treatment. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
In the US, all Therapeutic Units (TUs) will be distributed to the clinical centers by 
 
 
will ensure all logistical steps including 
repository, physical management of TU packages and TU delivery to investigation centers in the US. 
In Europe, all TUs will be distributed to the clinical centers by 
 
). 
 will ensure all logistical steps including repository, physical 
management of TU packages and TU delivery to EU investigation centers. 
The order to deliver the initial stock and further reorders of individual investigation centers will be 
given by the contract research organization, 
 according to the center’s actual enrollment rate. 
 
Return of expired TUs or unused TUs will be ordered by Biophytis. 
Detailed information on TU handling will be provided in a Manual of Procedures (MOP). 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
BIO101 is formulated as a 
 capsule that includes 175 mg of the active principle ingredient, 
20E, 
 
 Placebo is manufactured as an identical size 1 opaque capsule containing 
  
Capsules containing BIO101 and placebo are opaque and identical in appearance. The matching 
placebo capsule 
 Stability was tested 
following ICH regulations. In order to be fully compliant, the drug substance and the excipients 
are controlled according to the FDA and European pharmacopeia. 
The study drug is packaged in 
 
 The study drug was labelled according to local law and regulatory requirements. All 
TUs had to be stored as specified at delivery and in the original packaging. In case of a deviation 
in storage conditions, the clinical site cannot dispense the affected study drug and have to notify 
Biophytis right away. Utmost care will be taken to correctly dispense the study drugs as assigned 
by the randomization system embedded within the eCRF. 
TUs are made up of 
 The 
 is called a kit. Each kit is individually 
numbered.  
Each 
box, 
 contains 
capsules, which is presented in 
 columns. 
 
 


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 The actual capsule combinations correspond to daily doses of 175 mg b.i.d., 350 mg 
b.i.d. or placebo. 
The box is conceived to be elderly friendly (US and EU), and child proof (for US only). Each 
individual study participant will receive a total of 
 over the 6-month period, released to 
the study participant according to the timeline of the study: 
 at randomization /baseline visit; 
 at the Month 1 visit , and 
 at the Month 3 visit. 
Detailed information on TU dispensing will be provided in a MOP. 
 
 


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A representative labeling of the drug product is presented below: 
 
 
Clinical Study Number: BIO101-CL03 
 
Study treatment: “BIO101, or placebo” 
 
Batch Number: #  
 
 capsules of BIO101 (175mg capsule) or placebo, per box 
 Oral route, 4 capsules per day (two on the morning and two on the evening) 
 
To be swallowed entirely without opening the capsules 
 
Expiration Date: # 
 
Kit Number: # 
 
Patient ID (to be completed at the center before supplying the patient) 
Investigator Name (to be completed at the center before supplying the patient) 
Visit Number (to be completed at the center before supplying the patient) 
Date dispensed (to be completed at the center before supplying the patient) 
 
Store at 
 away from light and humidity 
CAUTION: New Drug--Limited by Federal (or United States) law to investigational use 
Drug for investigational use – keep out of the reach of children 
Please return non-used capsules and empty boxes to your center at the end of the study 
 
 
Sponsor: Biophytis, 14 avenue de l’Opéra – 75001 Paris – FRANCE  
 telephone: 
 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
Based on the available stability data of the Drug Product, Biophytis currently certifies a shelf life 
of 
 at room temperature and protection from light and humidity. For more 
details please also see the IMPD. 
 
6.2.4 PREPARATION 
 
All treatment packages are delivered ready to be given directly to the participants. No further 
preparation is needed by the study Staff. 
 
Study participants should be instructed to take 4 capsules per day everyday in a specific order: 
the first two 
 in the morning and the second two 
 in the evening. 
 
If a dosing administration is skipped, study participants should start a 
 the day after and 
should not take the skipped capsules. 
Important note: Date of each next visit should be calculated back on Day 0 visit (baseline) in 
order not exceeding the total duration of 26 weeks treatment (capped exposure) 
6.2.5 SHIPMENT 
 


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Following GCP guidance on the situation of the public health emergencies, the core consensus 
guidelines for clinical trial management and the study DSMB recommendation, the safety of 
study patients and investigators is the priority during this COVID-19 outbreak. No on-site visit 
is allowed during the COVID-19 outbreak. Therefore, during this period and until further 
guidance, participants will receive their IPs at home with direct shipping/delivery from the study 
sites. The boxes are shipped to the participants’ homes only after the site investigator/staff(s) 
have completed reviewing of all relevant safety study assessment resultsfrom the the 
scheduled calls. Shipment to the participant’s homes are carried out based on a predefined and 
specific process to guarantee the proper shipment conditions that ensure study drug integrity. 
For intake of the drug, all participants have already been educated during previous on-site visits 
by the study staff and will already know the proper method and schedule for drug intake. 
 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Randomization will be stratified by center and by gender. Randomization is performed online at 
the time of the inclusion visit for each study participant fulfilling all the inclusion and non-inclusion 
criteria, according to the appropriate ratio. The randomization procedure is embedded within the 
eCRF, which is based on the 
 by 
 a 
21CFR Part 11 compliant system. 
Each treatment kit will show a pre-printed kit number affixed on the primary, secondary and 
tertiary containers. The kit number will be assigned via the eCRF after a patient qualifies and is 
randomized. Neither the Investigator, the staff or the Sponsor will be aware of the treatment that 
corresponds to the kit number. The assigned treatment cannot be retrieved from the system 
unless a specified unblinding procedure is engaged by the investigator. Unblinding can only occur 
when it is deemed necessary by the responsible physician of the investigation center in the 
context of a severe or serious adverse event. 
The randomization list will be provided by 
 to the manufacturer and to the eCRF identified 
responsible person. The randomization list will not be available to the Sponsor staff, study 
participants, investigators, monitors or employees of the clinical site involved in the management 
of the study before unblinding of the data (after database lock), except in case of emergency.  
The Clinical Research Organization (CRO) team from 
 performing the data management and 
statistical activities will receive a copy of the randomization list after database lock. 
A specific unblinding procedure will be made available in the eCRF for the investigator to perform 
emergency unblinding of a given patient for documented reasons. An unblinding procedure can 
only be engaged in an emergency situation where the Investigator considers it essential to know 
what treatment the subject was receiving. The monitor shall be notified promptly if unblinding is 
performed. It is recommended that the Investigator contacts the 
 medical monitor before 
unblinding, if possible. The investigator will document the date, time, and reason for the 
unblinding in the patient’s medical records. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access to 
the remote system in case of emergency. The investigator will inform the subject how to contact 
his/her backup in case of emergencies when he/she is unavailable. 
Should the code be (intentionally or unintentionally) broken by the Investigator or by a clinical 
staff, whether the subject could remain in the study or not should be judged by the Investigator 


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according to the subject’s best interest. The event will be immediately reported to the Sponsor 
and to 
 and dealt with as a major protocol deviation. 
The subject’s clinical data will not be analyzed in the per protocol set. 
 
 


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6.4 
STUDY INTERVENTION COMPLIANCE 
 
During the COVID-19 outbreak, all participants will be asked to send back all used and unused 
boxes containing the investigational study drug. These returns are carried out based on the same 
predefined and specific process as the one applied for the shipment from site to participants home. 
Adherence to the protocol will be assessed by the Investigator staff by counting the full and empty 
blisters.  
 
A participant study drug log will be completed (to be kept in the source documents) and recorded 
into the eCRF. An algorithm will automatically calculate the adherence based on visit dates. 
 
6.5 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by 
a properly authorized/licensed clinician. Medications to be reported in the CRF are concomitant 
prescription medications, over-the-counter medications and supplements. 
The following medications are not allowed during the study: 
1. Anabolic drugs e.g. testosterone, growth hormone, etc. (replacement hormonal 
treatment for menopause is allowed if started at least 3 months before 
randomization without dose changing)  
2. Anabolic supplements, e.g. branched-chain amino acids, anabolic treatments, or 
treatments containing 20E 
3. Herbal treatments containing  
 
 
4. Erythropoietin 
5. Corticosteroid agents chronically administered per oral or parenteral route 
(except local administration route such as eye drops or dermatologic 
formulations; except emergency parenteral administration for acute conditions 
like asthma, allergic reactions, etc.) 
6. Chemotherapy 
7. Radiotherapy 
8. Androgen suppressant treatments (e.g. finasteride); estrogen suppressant 
treatments (e.g. tamoxifen) 
Should a participant need or report the use of these drugs during the study due to 
treatment for an AE, the physician will make the decision to withdraw or to keep the 
patient in the study according to the patient’s best health interest.  
 
6.5.1 RESCUE MEDICINE 
 
There is no specific rescue medicine for BIO101. Standard medical measures should be taken in 
case of an accidental or deliberate overdose of BIO101. 
 
 


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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
The Investigator should discontinue study intervention and specifically ensure that a participant 
stops taking the investigational drug if the bioanalytical results at Month 1 or Month 3 shows the 
following changes: 
1. Confirmed 3-fold or greater elevations above the Upper Limits of Normal (ULN) of 
 
 
 
 
 
 
These stopping rules for discontinuation are established based on 
 
 
. 
 
Discontinuation from investigational oral treatment does not mean discontinuation from the 
study, and remaining study procedures should be completed as indicated by the study protocol. 
If a clinically significant finding is identified (including, but not limited to, changes from baseline) 
after enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an AE. 
 
The data to be collected at the time of study intervention discontinuation will include the 
following: 
• 
AE complete follow-up (if the treatment is stopped following an AE) 
• 
Last investigational medication administration date and time 
 
The physician can decide to re-introduce the investigational treatment if it was stopped because 
of a concomitant acute condition he/she considers unrelated to the treatment. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participating in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
 
• 
Pregnancy: however, in principle, only menopaused women are eligible in this protocol 
• 
Significant study intervention non-compliance  
• 
If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive oral treatment for more than 4 weeks 


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The list above is provided as considerations to guide the investigators and the decision to 
discontinue or withdraw a participant is up to the investigator’s discretion. A study participant is 
allowed to continue in the study, given his/her own choice, even if he/she needs to stop the study 
drug intervention.  
The reason for participant discontinuation or withdrawal from the study will be recorded in the 
eCRF. Based on the number of study participants enrolled in each center, study participants who 
signed the informed consent form and are randomized but do not receive the study intervention 
may be replaced. Study participants who signed the informed consent form were randomized and 
received the study intervention, but subsequently withdrew, or are withdrawn or discontinued 
from the study, will not be replaced. 
In any case, each subject needs to be randomized via the eCRF procedure, and already assigned 
TUs cannot be manually assigned to a new participant. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for all remaining 
scheduled visits and is unable to be contacted by the investigation site staff.  
The following minimum actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site will attempt to contact the participant (and at default his/her proxy when 
available) and reschedule the missed visit within 2 weeks. The site will counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if 
the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (a minimum of 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• 
If previously agreed by the participant, the study staff can decide to visit him/her at home 
in order to collect important medical information, and if applicable, perform a minimum 
functional assessment (i.e. SPPB).  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
7.4 
PARTICIPANT DISCONTINUATION DURING THE COVID-19 
During the COVID-19 pandemic, participants may not be willing to continue their participation in 
the SARA-INT study. Consent withdrawal due to the COVID-19 outbreak will be identified and 
recorded specifically in the eCRF.  
 


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8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
The following tests will be used in SARA-INT. The specific timing of procedures/evaluations to be 
done at each study visit can be found in Section 1.3, Schedule of Activities. 
Cumulative Illness Rating Scale (CIRS) 
The Cumulative Illness Rating Scale (CIRS)38,39 rates 13, conceptually valid, body systems 
(supporting content validity) on a five-point (pathophysiologic) severity scale. It has been slightly 
adapted to form the CIRS-G (CIRS geriatric), for which guidelines to enhance reliability have been 
formulated. Criterion validity has been confirmed by showing high correlation coefficients when 
comparing CIRS scores based on autopsy (the gold standard) with those based on health histories 
and chart reviews40,41. The CIRS was correlated with four other measures of comorbidity. Three 
out of five correlation coefficients exceeded 0.40, supporting concurrent validity. There is little 
evidence to support predictive validity. Small to fair positive correlations in the anticipated 
directions have been found for other variables, such as medication usage, ADL, IADL, and age, 
supporting construct validity41. Interrater and test-retest reliability are good. 
In the present protocol, the CIRS is compiled by a medical doctor, on the basis of the physical 
examination and patient’s clinical history. It will provide an estimation at baseline of the overall 
burden of disease. 
Short Physical Performance Battery (SPPB) 
In SARA-INT (and in SARA-OBS), the low physical performance is assessed first and defined by a 
low score as SPPB≤ 8. It is imperative to perform the SPPB at the beginning of the screening 
period, ahead of the DEXA or the ultrasound scans. The SPPB is a series of tests designed to 
examine physical movements1. The first test examines balance (without the assistance of a cane 
or walker) with the feet placed in 3 different orientations. The second test examines gait speed 
and the third test involves standing from a chair a number of times to test leg strength.  
The SPPB, originally developed for the Established Populations for the Epidemiologic Study of the 
Elderly (EPESE), is a brief performance battery based on timed short distance walk, repeated chair 
stands and balance test1, 29. The battery is administered by trained examiners. The measurement 
goal for this battery is to assess lower extremity functional limitations, which indicates functional 
abilities and is a strong measure of risk for future disability. This test takes about 10-15 minutes 
to administer and can be done in the home or the clinic setting. The battery has an excellent safety 
record. It has been administered to over 20,000 people in various studies and no serious injuries 
are known to have occurred. The components of the battery are as follows: 
- 
Walking speed. Walking speed is assessed by asking the participants to walk at their 
usual pace over a 4 m course. Participants are instructed to stand with both feet 
touching the starting line and to start walking after a specific verbal command. 


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Participants are allowed to use walking aids (cane, walker, or other walking aid) if 
necessary, but not the assistance of another person. Timing begins when the foot starts 
to move across the starting line and the time in seconds needed to complete the entire 
distance is recorded. The faster of two walks is used to compute walking speed. 
- 
Chair stands. The repeated chair stands test is performed using a straight-backed chair, 
which is placed with its back against a wall. Participants are first asked to stand once 
from a sitting position without using their arms. If they are able to perform the task, 
they are then asked to stand up and sit down five times, as quickly as possible. The time 
to complete the task is recorded. 
- 
Standing balance. For the test of standing balance, participants are asked to maintain 
balance in three positions, characterized by a progressive narrowing of the base 
support: with feet together (side by side position), the heel of one foot beside the big 
toe of the other foot (semi tandem position), and the heel of one foot in front of and 
touching the toes of the other foot (tandem position). For each of the three positions, 
participants are timed to a maximum of 10 seconds. Scores are summed for the 
measure of balance for a range of 0 to 30 seconds. 
- 
Summary performance score. Each of the three performance measured is assigned a 
score ranging from 0 to 4, with 4 indicating the highest level of performance and 0 the 
inability to complete the test. For the test of balance, participants are assigned a score 
of 1 if they can hold a side-by-side standing position for 10 seconds but are unable to 
hold a semi-tandem position for 10 seconds; a score of 2 is assigned if they can hold a 
semi-tandem position for 10 seconds, but are unable to hold a full-tandem position for 
3 seconds; a score of 3 is assigned if they can stand in a full-tandem position for 
3 seconds but less than 10 seconds; a score of 4 is assigned if they can stand in a 
full tandem position for 10 seconds. 
Four categories are computed for walking speed and chair stands, according to cut-off 
points that are based on quartiles of the time to perform each task assessed in the 
EPESE. The time of the faster of two walks is scored as follows: > 8.7 sec = 1; 6.21 to 
8.70 sec = 2; 4.82 to 6.20 sec = 3; < 4.82 sec = 4; a score of 0 is assigned to participants 
unable to perform the test. The time required to perform five chair stands is scored as 
follows: ≥ 16.70 sec = 1; 13.70 to 16.69 sec = 2; 11.20 to 13.69 sec = 3; ≤ 11.19 = 4. A 
score of 0 is assigned to participants unable to perform the task. A summary score 
ranging from 0 (worst performers) to 12 (best performers) is calculated by adding sub-
scores from the walking speed, chair stands and balance tests.  
The SPPB test will be performed during screening, at M3 and then at M6 or the end-of-study visit. 
During screening, it will allow evaluation of the patients’ lower extremities physical function 
impairment and to measure loss of physical function. 
The instructions for performing the SPPB test as well as for how to score each component will be 
standardized through the participating centers before the beginning of the study. 


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Dual Energy X-ray Absorptiometry (DEXA) 
In SARA-INT, the definition of the muscle mass component of sarcopenia is based on the 
operational criteria proposed by the FNIH initiative2. FNIH reports triggered a re-appraisal of 
existing operational definitions of sarcopenia, such as the one from the EWGSOP, that were 
mostly based on experts’ consensus. The new findings of the FNIH relied on a meta-analysis of 
eleven clinical trials with men and women ≥ 65 years. Applying the Classification and Regression 
Tree (CaRT) statistical model allowed for testing of several variables that best predicted low gait 
speed and weakness which are the two functional consequences of age-related sarcopenia.  
The FNIH project report recommended two alternative gender-specific measures to be used to 
define low muscle mass2. The first FNIH definition, ALM-to- BMI ratio or ALM/BMI, is the one 
recommended by the FNIH project, while the second definition using the ALM alone is proposed 
as an alternative.  
DEXA scan examination should be performed during the later phase of the screening period after 
the SPPB assessment. This should be performed only if most of the screening procedures, with 
the exception of the ultrasound and the 400MW test, have passed the inclusion criteria. 
DEXA is a simple, quick and non-invasive examination. DEXA scans can provide accurate 
measurements of body composition, recording fat and lean mass distribution throughout the 
entire body. Radiation exposure for the participant is relatively low, approx. 0.0042 mSv for an 
adult scanned on the Hologic Discovery A device42.  
DEXA exams will be standardized through the study participating centers. 
400 Meter Walk (400MW) Test 
The 400MW test is a measure of how long it takes a participant to walk a distance of 400 meters. 
In addition, the need for each participant to stop and rest (yes/no) and the ability to complete the 
test at all (yes/no) are factored in as variables. Since the gait speed measured during the 400MW 
test is defined as the primary endpoint, it is imperative to perform the 400MW test as the last 
test during the screening period, on Day 0 (prior to randomization) or within 48 hrs of Day 0, in 
order to ensure data accuracy. 
The test will be performed at the study centers. Study participants will receive instructions to walk 
400 m on a 20 m walking course (20 laps of 20 m) following a 2-min warm-up with standard 
encouragement from the study team. Instructions will be to walk at the usual pace. (For precise 
instructions and to obtain the script to be followed, please refer to the study handbook and/or 
the SARA portal digital version of the instructions and script). 
Non-disabled participants are defined as participants who are able to walk 400 m within 15 
minutes without sitting, leaning against the wall, or assistance of another person or walker. 
During the study, the onset of major mobility disability will be defined as the inability to complete 
the 400 m walk within 15 min without sitting, leaning against the wall, or assistance of another 
person or walker, and will be the primary study outcome assessed. 


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The time needed to perform the 400 m walk as well as whether or not the study participant 
performed the test without any assistance (i.e. successful test or onset of mobility disability) will 
be reported in the eCRF. 
The inability to complete the 400MW test during the screening period is an exclusion criterion. 
If the participant is unable to complete the 400 m, the actual distance reached and the time spent 
before suspending the test will be reported.  
The instructions to perform the test as well as to evaluate it (including timing) will be standardized 
throughout the study center teams. 
The choice of gait speed measured using the 400MWtest as a primary outcome in SARA-INT is 
justified by its prevalent use in similar study populations (LIFE-P30, LIFE15, SPRINT-T17, VIVE2, etc.). 
Gait speed, a continuous variable, is well adapted to a phase 2 study for assessing dose ranges. 
Specifically, Santanasto et al16, have demonstrated the sensitivity of the test to a 6-month 
structured physical activity regimen versus an educational intervention in the LIFE study 
population. 
This test also provides a dichotomous result (i.e., capacity/incapacity to complete the task) that 
accurately reflects a specific and clinically relevant condition, which is mobility disability1. The 
ability to walk 400 m is a proxy for mobility within the community and independent living16. As 
opposed to walking tests aimed at measuring the reserve capabilities of an individual (e.g. 6MWT), 
the 400MW test is very safe and does not need to be performed as fast as possible. On the other 
hand, the relatively long distance walked allows identification of those individuals with mobility 
limitation but who may appear to be well functioning during shorter tests (e.g., 4 meters). The 
15-minute time limit of the 400MW test is indeed there to differentiate the mobility efficiency of 
the individual. The inability to complete the 400MW test has already been used as the defining 
criterion for mobility disability in major clinical trials, in particular the LIFE-P and full-scale 
projects15,30. It has been demonstrated that the capacity of the 400MWtest to predict major 
negative health-related events (including disability and mortality) is independent of 
comorbidities.  
A difference of change from baseline of 0.1 m/s is determined to be the minimal clinically 
meaningful change between treatment groups based on preliminary analysis of the SARA-OBS 
participants, and a change of 0.1 m/sec will also be considered as a substantial clinically 
meaningful change to patients, according to Perera et al, 200636. 
6 Minute Walking Test (6MWT) 
The 6MWT is a test for functional exercise capacity and involves measuring the distance a 
participant can cover within the allotted time of 6 minutes.  
The 6MWT has gained importance in the assessment of functional exercise capacity in patients 
with chronic respiratory disease. It has been used in many studies with elderly people. The 6MWT 
has proved to be reliable, inexpensive, safe and easy to apply43,44. In addition, it correlates well 
with important outcomes including death45,46. Considerable variability was observed in the 


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distance walked in the 6MWT in studies performed by healthy volunteers46,47. The study 
performed with healthy elderly study participants aged 50-85 years47 showed that the 6MWT 
distance ranged from 383 to 820 m. On average, the distance was 631 ± 93 m. An important part 
of the variability in 6MWT was explained by height, gender, age and weight as dependent 
variables.  
The rationale behind the choice of 6MWT is guided by several points. First, this is a continuous 
assay that can be used to evaluate the percentage of decline over a period of time as well as the 
average speed in 6 minutes. Second, walking tests and endurance tests share many characteristics 
in common and there is a good correlation between the 6MWT and the VO2max46,48,49. Third, 
from a functional point of view, the 6MWT can be used to assess the physical fitness and exercise 
capacity of individuals with poor physical condition, heart disease or advanced age as described 
in several studies1,49. 
The 6MWT should be performed indoors in a long (approximately 100 m), flat, straight, enclosed 
corridor with a hard surface. The walking course could be 30 m in length; with length marked 
every 3 m. The turnaround point should be marked with a cone and a starting line should be 
marked with brightly colored tape. 
The test should be stopped at the onset of any of the following: 
• 
Chest pain 
• 
Intolerable dyspnea 
• 
Leg cramps 
• 
Staggering 
• 
Diaphoresis 
• 
Pale/ashen appearance 
Further information on required equipment, patient preparation, measurements and safety 
issues are available in the Guideline for the Six-Minute Walk Test31. The distance walked in the 
6MWT will be measured at Day 0 and at M6 and will be reported in the eCRF.  
Repeated negative results in similar population studies, however, failed to validate the use of the 
6MWT as a primary endpoint in sarcopenia. For these reasons, we will apply it as a secondary 
endpoint and a benchmark towards previously investigational treatments. 
Stair Climb Power Test (SCPT) 
Locomotion on stairs is among the most challenging and hazardous activities of daily living for 
older individuals. This is evidenced by the reports that stair falls account for more than 10% of 
fatal fall accidents50. Moreover, stairs require greater range of motion from the joints of the lower 
limb and greater muscle strength, with the demands on the joints and muscles differing between 
stair ascent and descent. Stairs are a more advanced activity of daily living and thereby may 
demonstrate functional difficulties more readily than walking tests51. All the features render the 
ability to climb one of the key markers of functional independence in older adults52. However, 
there is still a great need for a better characterization for stair negotiation (stair climbing and 
descent) as this activity has been identified as a major limitation in functional assessment in 


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several reviews53. Stairs also have the benefit of being able to measure multiple systems and 
highlight the limiting factors between the musculoskeletal, neurological, and cardiorespiratory 
systems. This makes the test even more valuable for assessing elderly or frail populations who 
may have multiple limitations. Stairs are currently increasingly being used in clinical practice as 
both an assessment tool and as part of exercise programs54. The benefit of the SCPT is that stairs 
are readily available, convenient, and cheap to use. The SCPT has been considered as a clinically 
relevant measure of leg power impairment as the results are consistent with more complex 
techniques for measuring leg power (double leg press at 40 and 70% of the one-repetition 
maximum) and performance (SPPB with components of gait speed, chair stand time and standing 
balance)54.  
The SCPT measures the ability to ascend and descend stairs and tests lower body strength and 
balance and measures time (in seconds) taken to ascend and descend a flight of stairs (10 steps 
with a 20 cm step height; a handrail is recommended). Step heights should be suitable (between 
16 and 20 cm). Measurements will be performed at Day 0 and at the M6 visit, and will be recorded 
in the eCRF. 
Handgrip Strength Test 
Handgrip strength will be measured using a Jamar dynamometer handle. The width of the 
dynamometer will be adjusted for each participant separately for optimal fit. Participants will be 
instructed to stand upright and with the dynamometer beside them but not against their body. 
Strength will be measured 3 times for both hands and will be recorded in kilograms. The highest 
value of all 3 attempts will be kept for further analysis. If the participant reports current flare-up 
of pain in the dominant wrist or hand, or has undergone fusion, arthroplasty, tendon repair, 
synovectomy, or other related surgery of the dominant hand or wrist in the past 3 months, it is 
o.k.to have only the other hand tested. The same dynamometer will be used in all study centers 
and it should be calibrated regularly. 
Handgrip strength is a commonly used measure of upper body skeletal muscle function and has 
been widely used as a general indicator of frailty with predictive validity for both mortality and 
functional limitation55,56.  Other than possible temporary discomfort during the test itself, there 
are no known risks for the participant.  
The isometric handgrip test will be performed at Day 0 and at M6 visit or the end-of-intervention 
visit. 
At Day 0 it will allow the evaluation of the patients’ strength or weakness and characterization of 
loss of muscle strength in the context of low physical performance and sarcopenia. 
The instructions to perform the test as well as how to score each component will be standardized 
through the study centers before the beginning of the study. 
Knee Extension Test (optional according to center feasibility) 
Strength can be measured isometrically or isokinetically, the latter being a closer reflection of 
muscle function in everyday activity. Isometric strength testing of maximal voluntary contractions 


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can be measured with relatively simple custom-made equipment. It is usually measured as the 
force applied to the ankle, with the subject seated in an adjustable straight-back chair, the lower 
leg unsupported and the knee flexed to 90°57. 
The knee extension measurement will be performed using protocols described in several 
publications57, and using preferably the Biodex System isokinetic dynamometer. Isometric knee 
extension torque will be measured with a knee extension dynamometer chair. The participants 
will be positioned in an upright position, with straps to affix the hips to the chair and the ankle to 
a force or torque transducer at the knee angle of 90°. Lever arm length will be recorded as the 
distance between the knee axis of rotation and the middle of the pad. After 3 warm-up trials at 
50 and 90% of self-perceived maximal strength, 3 trials will be conducted to measure maximal 
voluntary contraction (MVC) force of the knee extension muscle. For each attempt, maximal force 
or torque will be recorded by the transducer and saved on the computer. Each assay will be 
separated by a 1 minute rest period. Knee extension torque will be obtained either directly or by 
multiplying recorded peak force with the lever arm length. The assay with the highest torque 
output will be taken for analyses. 
PATIENT REPORTED OUTCOMES: 
Short Form-36 (SF-36) 
The SF-36 is one of the most widely used, validated measures of health-related quality of life and 
has been shown to discriminate between study participants with different chronic conditions and 
between study participants with different severity levels of the same disease34,35. The SF-36 has 
also demonstrated sensitivity to significant treatment effects in a variety of patient populations. 
Population-based normative data on the SF-36 is available for the United States and other 
countries as well. 
This instrument addresses health concepts that are relevant to the patient's perspective. There is 
no single overall score for the SF-36, instead, it generates 8 subscales and two summary scores. 
The 8 subscales are: physical functioning, role limitations due to physical problems, bodily pain, 
general health perceptions, vitality, social functioning, role-limitations due to emotional 
problems, and mental health. The two summary scores are the physical component summary and 
the mental component summary. Each scale is directly transformed into a 0-100 scale on the 
assumption that each question carries equal weight. The lower the score, the more disability; the 
higher the score the, less disability (i.e., a score of zero is equivalent to maximum disability and a 
score of 100 is equivalent to no disability). 
The physical function sub-score of PF-10, role limitations due to physical problems, will be a key 
secondary endpoint of SARA-INT. PF-10 has been tested in numerous clinical trials and is 
considered a simple and effective measure of mobility disability and is also often used in 
epidemiological studies (Syddall, 200935). Climbing one flight of stairs (no change versus decline 
of two levels) with a 2-point difference) or walking a block (no change versus two levels decline) 
exemplifies a substantial meaningful change, as appreciated by patients (Perera, 200636).  


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In SARA-INT, SF-36 will be auto-administered, either electronically or by filling out a paper booklet 
manually as provided by the clinical center . 
Pepper Assessment Tool for Disability (PAT-D) 
The Pepper Assessment Tool for Disability (PAT-D) is a disability questionnaire that was developed 
to assess difficulty with functioning in both discrete tasks and social/role functioning. The PAT-D 
has been widely used in randomized controlled trials and observational studies in a variety of 
chronic health conditions58. There are three domains: mobility, activities of daily living, and 
instrumental activities of daily living. This questionnaire asks respondents how much difficulty 
they have had with a range of activities in the past month due to their health. For each item, 
respondents answer on a 5-point Likert-type scale whether they experience: (1) no difficulty, (2) 
a little difficulty, (3) some difficulty, (4) a lot of difficulty, or (5) unable to do. For each item there 
is also a ‘not applicable’ option if the respondent usually did not do that activity for reasons other 
than disability. The PAT-D produces a score for each of the three domains as well as a total score, 
with higher scores indicating greater disability. 
This questionnaire will be administered by the clinical center personnel at Day 0 and M6.  
Sarcopenia Quality of Life (SarQoL) 
The SarQoL is a sarcopenia-specific, self-administered, quality of life questionnaire designed for 
community-dwelling elderly study participants aged 65 years and older59. The questionnaire will 
be provided to study participants in the appropriate language. The questionnaire contains 22 
questions, which takes approximately 10 minutes to complete. The questionnaire covers 7 
domains: physical and mental health; locomotion; body composition; functionality; activities of 
daily living; leisure activities; and fears. Most questions are answered on a 4 point Likert scale. 
This questionnaire will be auto-administered, electronically or filling a paper booklet provided at 
the clinical centre. 
Test SIO Disabilità Obesità Correlata (TSD-OC) 
The TSD-OC is considered a reliable and valid instrument for measuring self-reported disability in 
obese subjects60. The questionnaire is a set of multiple questions in 7 dimensions to measure pain; 
stiffness; function and autonomy in daily activities, housework, outdoor activities, occupational 
activities, and social life. Each question is scored by the subject from 0 (best) to 10 (worst). Each 
dimension score is calculated and then all dimension scores are added together for a total TSD-
OC score. 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Several procedures and evaluations in SARA-INT clinical protocol will be performed to monitor 
the study intervention’s safety. Some of those are necessary for other purposes (e.g., screening, 
eligibility, and enrollment).  
• 
Physical examination: a standard medical exam of all organ systems to detect possible 
concomitant conditions that could represent an exclusion criterion (e.g. food ulcer, lower 
limbs arterial insufficiency, severe respiratory condition, etc.) 


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• 
Anthropometry: includes height and weight, subcutaneous tissue thickness (with the help 
of a plicometer) and various circumference measurements  
• 
Short Form -Mini Nutritional Assessment (SF-MNA): this is a 6-question short form of the 
MNA that can be completed in 5 minutes or less. The MNA has been validated in 
international studies with a broad range of HCPs in a variety of settings. Currently, this 
instrument is administered by healthcare professionals to determine patients’ nutritional 
status (Huhmann et al, 2013)61  
• 
Vital signs (pulse and blood pressure) are measured at screening, M1, M3 and M6 (or end-
of-study) visits. These are measured twice, in lying or sitting and standing positions   
• 
Electrocardiograms (ECGs): this is performed for screening purposes only. It will be read 
locally, in order to exclude any underlying cardiac diseases that could represent an 
exclusion criteria. Meaningful abnormalities will be reported on the eCRF. The original will 
be kept in the source documents. This should be conducted prior to the start of any 
physical functional assessments (e.g. the 400MW test) for the safety of the study 
participants 
• 
Radiographic or other imaging assessments: 1) DEXA scan in SARA-INT is mostly devoted 
to assess body composition in terms of appendicular lean body mass, at screening visit 
and M6 (or end-of-study visit). DEXA scans could be performed up to 8 weeks before 
randomization and enrollment. 2) Gallbladder ultrasound: this is required during 
screening to exclude previous or active hepatobiliary diseases (e.g. cholestasis/biliary 
tract obstruction, cholelithiasis, cholecystitis, etc.), and is repeated at the end of the 
treatment (M6 visit) to assess any emergent hepatobiliary abnormalities  
• 
Biological specimen collection and laboratory evaluations: Blood samples will be 
collected by venepuncture or via indwelling cannula at screening, M1, M3 and at M6 visits 
for biochemistry and analyses. In case of previous abnormalities or new symptoms, a 
blood sample can be collected at M5 
a. Hematology: hemoglobin, HbA1c, hematocrit, red blood cell (RBC) count, white 
blood cell (WBC) count with differential, platelet count, mean corpuscular 
haemoglobin, mean corpuscular haemoglobin concentration, mean corpuscular 
volume 
b. Biochemistry: sodium, potassium, chloride, bicarbonate, urea, uric acid 
creatinine, albumin, glucose, cholesterol (total cholesterol, LDL, HDL fractions), 
triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase, bone-specific alkaline phosphatase, lipase, amylase, gamma 
glutamyl 
aminotransferase, 
bilirubin 
(total, 
indirect, 
direct), 
creatine 
phosphokinase and mb-creatine phosphokinase, lactate dehydrogenase, total 
protein, and GFR estimation based on Cockroft & Gault calculation 
c. Coagulation: activated partial thromboplastin time, prothrombin time, and 
international normalized ratio. 
d. Urine analysis: A midstream urine sample will be collected for urinalysis by 
dipstick for glucose, protein, and occult blood 


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All study analyses will be performed by a centralized laboratory. The Investigator must 
review the laboratory report, document this review, and record any changes occurred 
during the study. Laboratory values outside the normal ranges will be flagged and their 
clinical relevance will be assessed by the Investigator. See also Exclusion criteria based 
on lab results and stopping rules in Section 5.3 Exclusion criteria and temporary exclusion 
criteria and Section 7.1 discontinuation of study intervention, respectively. 
 
 
 
  
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
• 
Counseling procedures, including any dietary or activity considerations: see section 5.4 
Lifestyle considerations 
• 
Assessment of study intervention adherence: see Study Intervention Compliance, section 
6.4 
• 
Administration of the PROs: see Efficacy Assessments, Section 8.1 
• 
Assessment of AEs: At each visit, participants will be explicitly asked to report any new 
symptoms or any newly observed abnormality since the previous study visit. An 
unsolicited AE is one reported without any prompting or in response to a general question 
such as “Have you noticed anything different since you started the study, since you began 
the study intervention and etc.”. A solicited AE is one that is specifically solicited such as 
“Have you noticed any falls since you started the study medication?”. Ongoing AEs/SAEs 
will be followed up until resolution or clinical stabilization. See also Section 8.3.4, Time 
Period and Frequency for Event Assessment and Follow-Up. 
Participants will be provided with the results of their ECG and laboratory analyses.  
Due to the COVID-19 situation and safety concerns over viral transmission, every 
investigational visit within the protocol is now be performed remotely (e.g. by phone) for 
all participants still active in the study by the investigational site staff. The 
investigational site will continue to monitor the health status of the participants by 
collecting information on general health status, Concomitant Medication and Adverse 
Events.  
M7.5 and M10.5 phone calls include a pre-diabetic questionnaire as recommended by 


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the DSMB committee.  
 
  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An AE is considered "serious" if, in the view of either the investigator or sponsor, it results in any 
of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation 
of existing hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For AEs not included in the protocol-defined grading system, the following guidelines will be 
used to describe severity: 
• 
Mild – Events that require minimal or no treatment and do not interfere with the study 
participant’s daily activities  
• 
Moderate – Events that result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning  
• 
Severe – Events that interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious” 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All AEs must have their relationship to the study intervention assessed by the clinician who 
examines and evaluates the study participant based on the temporal relationship between the 
occurrence of the AE and the study drug administration and based on his/her clinical judgment. 
The degree of certainty about any causality will be graded using the categories below. In a clinical 
trial, the study product must always be suspected.  
 


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• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (de-challenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory re-challenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the study intervention, is unlikely 
to be attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (de-challenge). Re-challenge information is not 
required to fulfill this definition. 
• Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “potentially 
related” soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
 
For any reported AE, the study investigator will report the relationship to study intervention in 
the eCRF. 
 
8.3.3.3 EXPECTEDNESS  
The DSMB will be responsible for determining whether an AE is expected or unexpected. An AE 
will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study intervention. 
The expectedness determination will take place during periodic reviews, or exceptional reviews, 
as needed. 
8.3.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits, 
during interviews of a study participant presenting for medical care, or upon review by a study 
monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate report form. Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by 


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those with the training and authority to make a diagnosis), and time of resolution/stabilization of 
the event. All AEs occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
A SAE follow-up includes a prompt blood sampling for PK analyses, if deemed applicable by the 
Investigator or by his/her staff. Any medical condition that is present at the time that the study 
participant is screened will be considered as baseline and not reported as an AE. However, if the 
study participant’s condition deteriorates while performing any physical assessments at any time 
after signing the ICF (including the screening period), it will be recorded as an AE. Unanticipated 
problems (UPs) will be recorded in the data collection system throughout the study. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
The PI will record all reportable events with start dates occurring any time after informed consent 
is obtained until the last day of study participation. At each study visit, the investigator will inquire 
about the occurrence of AEs/SAEs since the last visit. Events will be followed for outcome 
information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
For the purposes of this study, AEs will be recorded from the time of informed consent until the 
completion of the study or at the end-of-study visit. However, AEs occurring prior to 
randomization will not be included in the analysis of the reports of events so it will not be part of 
the risk-benefit assessment in relation to the study intervention. 
All ongoing AEs should be followed up for 30 days after the end-of-study visit. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
The study clinician will immediately report to the sponsor of any SAEs, whether or not considered 
study intervention related, including those listed in the protocol or investigator brochure, and 
must include an assessment of whether there is a reasonable possibility that the study 
intervention caused the event. Study endpoints that are SAEs (e.g. all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g. death from anaphylaxis). In that case, the 
investigator must immediately report the event to the sponsor. 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event 
to be chronic or the participant is stable. Other supporting documentation of the event may be 
requested by the Data Coordinating Center (DCC)/study sponsor and should be provided as soon 
as possible. 
The study sponsor will be responsible for notifying the FDA of any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible, but in no case later than 7 calendar 




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8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
Unexpected in terms of nature, severity, or frequency given: 
• The research procedures that are described in the protocol-related documents, such as 
the IEC/IRB-approved research protocol and informed consent document 
• The characteristics of the participant population being studied 
• The event is related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research) 
• The suggestion that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized 
This study will use the OHRP definition of UP. 
 In this study, in which tests an investigational drug in older adults, and applies well established 
diagnostic tests and procedures, all precautions will be taken for prompt detection and reporting 
of UPs. 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report all medically relevant UPs to 
. 
 will report to the lead 
principal investigator (PI), Sponsor, the DSMB and the reviewing IRB. 
The UP report will include the following information: 
 
• Protocol identification information including protocol title and number, PI’s name, and 
the IRB project number 
• A detailed description of the event, incident, experience, or outcome  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP  
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
 
• UPs that are SAEs will be reported to the IRB and to the DCC/study sponsor within 24 h of 
the investigator becoming aware of the event  
• Any other UPs will be reported to the IRB and to the study sponsor within 7 days of the 
investigator becoming aware of the problem  


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• All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and 
the OHRP within 15 days of the IRB’s receipt of the report of the problem from the 
investigator 
 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Not applicable 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
The main hypothesis to be tested in this study is the superiority of at least one dose of active 
versus placebo on the change from baseline of the 400 m gait speed criterion after 6 months of 
treatment. 
In order to deal with the multiplicity issue due to the two doses, a Hochberg procedure will be 
used for testing the main hypothesis.  
Full details of the analysis and the procedure will be given in the statistical analyses plan (SAP) of 
the study. 
 
9.2 
SAMPLE SIZE DETERMINATION 
Originally, the sample size was calculated for a comparison test at a 0.05 two-sided significance 
level, a power of 80%, to detect a difference of 0.05 m/s (minimal clinically important difference) 
between active groups and placebo on the change from baseline in the 400 m gait speed at 6 
months, with a standard deviation of 0.13 (estimated from the VIVE2 trial, Fielding et al, 201762).  
After analysis of the preliminary data from our observational trial data (SARA-OBS, with approx. 
105 completers), the following were learned: 
• 
During the 6 months follow-up, this study population deteriorated as suggested by a 
decreased gait speed of 0.05 meter per second on the 400MW test, with a standard 
deviation of the change from baseline of 0.2 
• 
The expected effect of BIO101 remains at 0.05 meter per second, as the change from 
baseline  
• 
Together, this new information allows an increase of up to 0.1 m/s to be considered as a 
minimal clinically important difference of changes at the M6 visit from baseline between 
the treatment groups. Under these assumptions, a number of 64 patients/group is 
needed, giving a new sample-size of 192 patients for 3 arms, with a standard deviation of 
0.20 (estimated from SARA-OBS preliminary data). 


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Taking into consideration this increased expected difference between treatment arms, a formal 
interim analysis will be performed by the DSMB when half subjects reach their month 6 visit (See 
section 9.4.6). Once half study participants complete their End-of intervention study visit, an 
unblinded ‘promising zone’ interim analysis will take place and determine if there is a need to 
increase the sample size based on the complete efficacy data. 
Based on current calculation and given a limited 20% provision for premature withdrawals or lost-
to-follow up, a total number of 231 participants will be included in the study.  
It is expected, that due to COVID-19 related restrictions, that the number of non-evaluable 
withdrawals will be higher than 20%. However, reassessment of the sample size, will take place, 
as a part of the interim analysis, that will take place after restrictions are lifted. 
 
9.3 
POPULATIONS FOR ANALYSES 
The following analysis populations will be considered: 
- 
The safety population consists of all patients randomized in the study for whom there is any 
evidence that they used study medication and for whom any follow-up information is 
available. 
- 
The Full Analysis Set (FAS) population consists of randomized study participants, potentially 
excluding a few  participants who failed to take at least one dose of trial medication and had 
a very early withdrawal (first week after randomization) definitely not related to study 
medication and lacked any post randomization data (CPMP/ICH/363/96).  
- 
The Per Protocol (PP) population will exclude FAS patients with major protocol deviations that 
are related to drug administration (e.g. a long interruption period, see section 7.1) that may 
impact the efficacy analysis. The exclusion of patients from the PP population will be 
determined in a blinded data review meeting that will be held prior to the disclosure of the 
randomization list. Reason(s) for exclusion will be provided for each patient. 
The safety population (all the included patients having taken the product at least once) will be the 
set for the safety analyses. 
Concerning the main endpoint and the key secondary endpoints, the FAS population will be the 
population of interest (main population). However, for sensitivity purpose, the corresponding 
analyses (mixed models and logistic regression models) will also be fitted on the PP population. 
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
The SAP will be finalized & signed-off before database lock and unblinding. 
All inferential tests will be two-tailed and with a 5% alpha risk, unless otherwise specified. 
Descriptive statistics (mean, standard deviation, 95% confidence interval for mean, minimum, 
median, maximum, and number of observations and missing cases) will be used for quantitative 
variables, and frequencies and percentages will be used for categorical variables. The descriptions 
will be broken down by treatment group. 


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A Hochberg procedure will be used to deal with the multiplicity concern on the main endpoint 
and the key secondary endpoints. Other multiplicity concerns (relative to secondary endpoints) 
are kept under control by the pre-specification of key-secondary endpoints and a low number of 
secondary endpoints and analyses. 
Due to the quantitative form of the endpoints (gait speed PF10 and handgrip strength test) and 
the large number of patients, the normal assumption for the residuals of the mixed models will 
be assumed. However, if found necessary, additional non-parametric approach could be added 
and detailed in the SAP of the study.  
The covariates included in the models are the stratification factors (gender and center) and the 
baseline score of the parameter if available. No interactions will be included by default in the 
models, however, in case of interesting findings in the subgroup analyses, further analyses would 
be conducted. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
A Mixed Effect Model Repeat Measurement (MMRM) model with fixed factors in treatment, in 
centers, the baseline score and the stratification factor (gender) will produce an estimate of the 
contrast at M6 in the change from baseline of the 400MW test gait speed between each active 
arm and the placebo group (after adjustment by the Hochberg procedure).  
The MMRM model will give a correct estimation in presence of missing data, under the Missing 
at Random (MAR) assumption. This analysis will provide an estimand of the efficacy of the tested 
product in the population that stayed in the study for the entire 6 months. Additional sensitivity 
analyses may be added in the SAP during the blind-review meeting if the number of missing data 
is important (more than 10%). 
The same model will be also fitted in the Per Protocol population to give an estimand of the 
efficacy of the product in the population with good compliance. 
Alternative methods to adjudicate missing data for the primary endpoint like the Bayesian 
Multiple Imputation (MI) methods could be considered and adopted before to finalize the SAP. 
Chen at al (2017) demonstrated the interest of applying Bayesian MI method to 400MW non-
completers in the LIFE study63.  
Additionally, a responder analysis will be provided, using a logistic regression (with the same fixed 
factors as the mixed model) to model the chance to be a responder for the 400MW test 
(improvement of 0.1 m/s or more). The odds ratio of each active group versus placebo will be 
provided with a 95% confidence interval (CI). 
 


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9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The key secondary endpoints (handgrip strength and PF-10 sub-score of the SF-36) will be 
analyzed with the same strategy as the primary endpoint (i.e. using a repeated measures mixed 
model to estimate the contrast at M6 of the difference of each active group versus placebo). 
Missing data will not be replaced in these analyses but the MMRM model on observed data is 
known to perform well under a MAR hypothesis.  
Additional sensitivity analyses may be added in the SAP during the blind-review meeting if the 
number of missing data is important (more than 10%). 
Concerning the responder endpoints:  
1. for the PF-10 sub-score of the SF-36, a responder analysis will be performed with a 
responder definition of “patient with an improvement of PF-10 greater or equal to 2 
points versus baseline”, at an individual level. 
2. for the handgrip strength test: a responder definition is equal to the minimal 
significant benefit set at least 2 kg of improvement versus baseline, at an 
individual level.  
The rate of responders (according to the predefined definitions provided in the corresponding 
endpoint sections) will be provided in each group of treatment at M3 and M6 visits for the PF-10 
sub-score and at the M6 visit only for the handgrip strength test. Participants without any 
assessment for a parameter at a visit will be considered as non-responder for the corresponding 
parameter. 
A logistic regression model with treatment group, gender and center as fixed effects will be used 
to compare each active group versus placebo at M6. The odds-ratio comparing groups will be 
provided as well as its 95% confidence interval. The multiplicity issue due to the two doses of 
active treatment will be addressed using the Hochberg procedure. 
The other secondary and exploratory endpoints will be analyzed only in the FAS population. 
Details and exploratory endpoints analyses will be provided in the SAP.  
9.4.4 IMPACT OF THE COVID-19 OUTBREAK 
 
Due to the COVID-19 outbreak, an updated strategy for the final analysis will be 
implemented, to account for the missing data on safety and efficacy which will have impact on 
the final analysis This will include sensitivity analyses comprising before/during/after COVID_19 
outbreak. This will be detailed in an updated version of the SAP.  
In addition, sample-size reassessment, will take place, based on an interim analysis, which will 
take place once the COVID-19 restriction is lifted, to account for additional non-evaluable 
withdrawals and other considerations, based on reduced activity of participants due to 
restrictions. 


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9.4.5 SAFETY ANALYSES 
Safety variables will be summarized/analyzed by groups of treatment, on the Safety population. 
Vital signs, biochemistry and hematology parameters will be described by descriptive statistics, 
for the entire period of the study and at each timepoint. 
Usual tables (by SOC and preferred term) will be produced for AEs (falls, injurious falls and 
orthostatic hypotension will be tabulated separately) after coding with the MEDRA terms. 
 
 
9.4.6 BASELINE DESCRIPTIVE STATISTICS 
 
The disposition of study participants at each visit will be described, by treatment groups and overall, 
as well as the number of premature discontinuations and their main reasons. 
Demographic and baseline characteristics of the patients will be presented overall and by 
treatment arms with descriptive statistics (mean, standard deviation, median, range and number 
of missing cases for quantitative parameters and percentages and number of missing cases for 
the qualitative parameters). 
Compliance will also be described and compared by treatment groups. Details of the calculations 
will be provided in the SAP of the study. 
 
9.4.7 PLANNED INTERIM ANALYSIS  
 
The primary endpoint is the gait speed measured during the 400MW test. The group-sequential 
design consists in  one interim analysis, which was originally planned to take place when 50 
participants have finished their participation. Due to the COVID-19 restrictions, this analysis is 
postponed. The timing of this analysis will be defined once restrictions are lifted and will take into 
account, COVID-19 related non-evaluable withdrawals and reduction of activity.  
The sample size increase will use the ‘promising -zone’ method of Mehta and Pocock (Mehta, 
2011)64 for an interim analysis. This approach ensures that the sample size is only increased in 
case the interim results are promising, in which case the overall type-I error is not inflated by use 
of the conventional Wald statistic. More specifically, this ‘promising zone’ is defined in terms of 
the conditional probability of rejecting the null-hypothesis at final analysis, given the estimated 
difference at interim (‘conditional power’) and assuming that this estimated difference is the true 
underlying difference. Depending on the conditional power (CP) at interim analysis, we consider 
three different zones and anticipated actions: 
1. 
Unfavorable zone 
The interim results are so disappointing that it is not worth to increase the sample size to retrieve 
CP and the original sample size is retained. This zone will be defined for a sample size 
reassessment at 50% information fraction and a maximal increase in sample size 100 additional 


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participants. Note that in case the observed gait speed difference at interim below the threshold 
defined in the SAP, the study would stop for futility. 
2. 
Promising zone:  
If the CP is below the originally planned 0.80, the sample size will be increased to the maximal 
sample size of 330.  
3. Favorable zone 
The conditional power is at least 0.80. In this zone, the interim results are sufficiently favorable 
for the trial to continue to the original sample size without the need to adaptively increase the 
trial size.  
The DSMB will be responsible for reviewing accumulated safety and efficacy data at intervals 
throughout the study.  
In particular, the DSMB will evaluate the results of a formal pre-planned interim futility analysis 
and sample size reassessment. The DSMB will recommend to the Sponsor whether to continue, 
modify or stop the clinical trial based on futility but also on safety issues or other considerations 
not related to efficacy or safety. In case the study continues and the original sample size is 
retained, the DSMB will not communicate to anyone whether this is due to unfavorable or 
favorable results.  
 
9.4.8 SUBGROUP ANALYSES 
A predefined subgroup efficacy analysis will be performed in a number of pre-identified, at-high 
risk of worsening, subpopulations:  
• 
Low gait speed 
• 
Sarcopenic obesity 
• 
Study participants with a chair stand sub-score of ≤2 of the SPPB 
• 
Study participants who experience a deterioration in their ALM/BMI as measured by the 
DEXA scan in the M6 visit compared to the baseline measurement 
  
The subgroup analyses based on these factors will be performed in order to better characterize 
treatment benefits in patients with increased risk of mobility disability. Results will be presented 
in forest-plots graphs, for both the primary endpoint and the 2 key secondary endpoints. 
Parameters of low gait speed (4-meter walk with a gait speed <0.8 m/s) and sarcopenic obesity 
(having a percentage of body fat mass of >25% in men and >35% in women) will be used as 
stratification factors, as well as important demographics or baseline characteristics such as 
gender, age, country, etc. 
 
9.4.9 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual data listings will be provided in the annex 16 of the study report. 
 


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9.4.10 EXPLORATORY ANALYSES 
Exploratory analyses description will be provided in the final statistical plan. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
The investigator will ensure that this study is conducted in full conformity with applicable 
regulations, the Declaration of Helsinki, GCP and ICH E6.  
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing the study intervention, study procedures, and risks in detail are given 
to the participant and a written documentation of informed consent is required prior to start of 
intervention/administration of study intervention. The following consent materials are submitted 
with this protocol. 
 
I. 
General Informed Consent for participating in SARA-INT clinical trial and secondary 
research on data  
II. 
Separate Informed Consent for Biobank sample storage and DNA tests 
III. 
Separate Informed consent for the Population PK sub-study.  
 
Due to the COVID-19 outbreak, the following measures have been taken:  
IV. 
A specific letter of information has been sent to every participant still active in the study, 
providing the measures taken during the COVID-19 outbreak and all related modifications 
of their participations (e.g. replacement of on-site visits by phone calls, IP home delivery).   
V. 
An addendum to the general informed consent during the COVID pandemic has been 
provided. 
Participant will consent to an addendum to the current version of the ICF, that includes the 
modification of the schedule of activity, the IP delivery, and the option of an extension of the 
treatment period for an additional 3 months, with the entire treatment period totaling up to 9 
months. To avoid any on-site visit for the reconsent, investigational sites will contact the trial 
participants via phone or video-calls to obtain oral consents supplemented with email/mail 
confirmation. Any consent obtained this way will be documented and confirmed by way of normal 
consent procedures with signatures at the earliest opportunity when the trial participants will be 
back at the regular sites.  
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreement to participate in 
this study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB-approved and participants will be asked to read and review the 
document. The investigator will explain the research study to the participant and answer any 


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questions that may arise. A verbal explanation will be provided in terms suited to the participant’s 
comprehension of the purposes, procedures, and potential risks of the study and of their rights 
as research participants. Participants will have the opportunity to carefully review the written 
consent form and ask questions prior to signing. Participants should have the opportunity to 
discuss the study with their family or surrogates or time to think prior to agreeing to participate. 
Participants will sign the informed consent document prior to any procedures being done 
specifically for the study. Participants must be informed that participation is voluntary and that 
they may withdraw from the study at any time, without prejudice. A copy of the informed consent 
document will be given to the participants for their records. The informed consent process will be 
conducted and documented in the source document (including the date), along with the 
participant’s signed signature on the form, before the participant can undergo any study-specific 
procedures. The rights and welfare of the participants will be protected by emphasizing that the 
quality of their medical care will not be adversely affected if they decline to participate in this 
study. 
 
The nature and purpose of the trial shall be fully explained to each patient in a form 
understandable to them; the investigator must confirm that the participant is able to understand 
the language of the ICF and Subject Information. The process of obtaining informed consent will 
be in compliance with relevant regulatory guidance, ICH requirements and local laws. The consent 
documents to be used for the trial shall be reviewed and approved by the appropriate IEC/IRB 
prior to use. 
Signed and dated informed consent must be obtained from each study participant prior to any 
trial procedures being performed. The investigator or investigator’s designee will provide 
background information on the trial, including the benefits and risks of study participation, scope 
of the study, procedures to be done at each visit, and responsibility of the subject (e.g. attendance 
at each visit, completion of all surveys/questionnaires). The investigator or investigator’s designee 
will also encourage the prospective subject to ask questions about the trial and will provide the 
prospective subject with opportunity to consider whether or not to participate. 
Original signed and dated ICFs must be filed in the investigator’s site file at the site. A copy of the 
signed and dated consent with original signatures must also be provided to the subject, or to 
his/her legal guardian (should this becomes applicable over the study duration). 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigators, funding agency, the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) sponsor and regulatory authorities. If the study is prematurely terminated or 
suspended, the PI will promptly inform study participants, EC/IRB, and sponsor and will provide 
the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
  
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• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping   
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
• 
Sponsor’s decision based on not meeting realistic timelines and resources allocated to the 
clinical trial 
 
Study may resume once concerns about safety, protocol compliance, and data quality were 
addressed, and satisfy the sponsor, IRB and/or the FDA. 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor and their agents. This confidentiality is extended to cover testing of biological 
samples. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
The study monitor, other authorized representatives of the sponsor, or representatives of the IEC 
or IRB may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for 
the participants in this study. The clinical study site will permit access to such records.  
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IEC/IRBs and institutional regulations.  
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the SARA Clinical Data Platform at Biophytis. This 
will not include the participant’s contact or identifying information. Rather, individual participants 
and their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites and by Biophytis research staff will be 
secured and password protected. At the end of the study, all study databases will be de-identified 
and archived at Biophytis. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study (including DEXA raw data and actimetry records) will be analyzed and 
stored by the Sponsor. After the study is completed, the de-identified, archived data could be 
made available on demand based on previous agreement for use by other researchers or 
Consortia including those outside of the study. Permission to use and transmit de-identified data 
for secondary research will be included in the main ICF.  
 


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With the participant’s approval and as approved by the local IRBs, de-identified biological samples 
will be stored at the Sponsor premises or at an independent Biobank (according to local 
legislation) with the same goal as the sharing of data. These samples could be used to research 
the causes of sarcopenia or sarcopenic obesity, its complications and other conditions for which 
individuals with sarcopenia or sarcopenic obesity are at increased risk, and to improve treatment. 
The third part will also be provided with a code-link that will allow linking the biological specimens 
with the phenotypic data from each participant, maintaining the blinding of the identity of the 
participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
 
When the study is completed, access to study data and/or samples will be provided through the 
Sponsor or the mandated Biobank. 
With the participant’s approval and as approved by local IRBs, genetic material from de-identified  
samples collected under this protocol may be used to study sarcopenia and sarcopenic obesity. 
DNA material will be kept for secondary research. 
Storage: Access to stored samples will be limited. Samples and data will be stored using codes 
assigned by the investigators. Data will be kept in password-protected computers. During the 
study, only investigators and laboratory personnel will have access to the samples. Both 
investigators and Biophytis/Biophytis representatives will have access to de-identified data.  
Disposition at the completion of the study: all stored samples will be sent to a central storage 
facility. Study participants who request destruction of samples will be notified of compliance with 
such request and all supporting details will be maintained for tracking.  
See also Section 10.1.3, Confidentiality and Privacy and Section 10.1.9, Data Handling and 
Record Keeping, for further information on future use of study records. 
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Role  
Individual/Company 
Name 
Contact Address 
Principal Investigator 
 
 
 
 
 
Investigators/Sites (US) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Investigators/Sites (Belgium) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EU Clinical Coordinator 
 
 
 
 
 
 
Sponsor 
Biophytis S.A. 
14 Avenue de L’Opera 
75001 Paris, France 
Clinical Research Organization 
 
 
 
Information and Communication 
Technology (ICT) 
 
 
  
  
  
            
eCRF and ePROs, online 
randomization  
 
 
Centralized Laboratory and 
Biobank for Biochemistry, 
Hematology and Biomarkers 
 
  
 
  
Centralized Laboratory and 
Biobank  
 
 
 
 


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Bioanalytics and BIO101 plasma 
quantification 
 
 
Biostatistics for DSMB reviews 
 
  
 
Therapeutic Units: 
Manufacturing, Primary 
packaging, technical 
release, stability warehouse 
 
 
 
Therapeutic Units distribution in 
the USAOrganization 
 
. 
 
 
The overall organizational structure of the SARA-INT Clinical Trial will be organized and managed 
through the following bodies:  
- SARA Managing Board (on behalf of the Sponsor) 
- Steering Committee (independent) 
- Plenum: all the study investigators (independent) 
- Data Safety Monitoring Board (independent) 
- Independent Scientific Advisory Board 
This governance structure is meant to guarantee a high level of the scientific quality of SARA-INT. 
The SARA Managing Board 
The Managing Board is composed by two Biophytis representatives and the Principal Investigator. 
Main responsibilities include: 
- Making and implementing strategic decisions as advised by the independent Committees 
- Coordinating and optimizing the study resources 
- Monitoring the progress of the SARA-INT activities with respect to its objectives 
- Identifying possible issues and proactively proposing solutions  
- Coordinating communication activities 
It is envisioned that the Board will meet regularly, at least once every 3 months. 
Any member of the Managing Board may participate in meetings of the Managing Board by 
teleconference, video-conference or any other technology that enables everyone participating in 
the meeting to communicate interactively and effectively with each other and as a group. 
For major changes, the Managing Board will consult the Plenum, the SDMB, and the other leaders 
as applicable. 
 
The Steering Committee 
The Steering Committee is composed of four Members who are representatives of the two 
participating regions, the EU and US. The Steering Committee is chaired by the
 
 
 
are the EU representatives.  
The Biophytis Chief Medical Officer will act as Secretary of the Steering Committee. The Steering 
Committee will be able to invite other experts from Biophytis and Biophytis subcontractors, e.g. 


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clinical operations, clinical development, etc. as deemed necessary for the purpose of the 
meetings. 
The Plenum 
The Plenum consists of all SARA-INT Investigators and will be chaired by the Coordinator. The 
Plenum can be asked to meet and advise on topics and issues related to the good implementation 
of the clinical operations, their possible improvements and/or opportune changes.  
The Plenum will meet at least once a year to conduct a general project review and project outlook 
and will meet via teleconference in case an urgent decision has to be undertaken based on their 
advice. 
The Data Safety Monitoring Board (DSMB) 
The DSMB is periodically reviewing all safety data and raise alerts in case of negative or dangerous 
findings. Members of the DSMB will be selected based on their expertise by the SARA managing 
Board. 
During the COVID-19 outbreak, the DSMB is meeting at least every other week to review its 
recommendation based on update of guidance from the national health agencies and local status. 
The Adjudication Committee 
The committee will specifically adjudicate the primary end -point, i.e. the 400MW test, in those 
cases where patients either did not show up or were not able to be tested after 6 months of 
treatment. Adjudication will be based on the medical dossier and, when available, on the results 
to a proxy of the 400MW test, e.g. the walking speed of the 4-meter test of SPPB, (for rules of 
conversion see MCDermott, 200758) with a comprehensive individual case objective evaluation. 
Precise rules will be endorsed by the adjudication committee at the first meeting and will then 
made available in the study handbook and its digital version on SARA portal. 
Any effort will be undertaken to contact and evaluate patients temporarily lost to follow-up, 
including home visits where feasible. 
The Scientific Advisory Board (SAB) 
This is an independent advisory committee, able to advise and discuss the overall study conduct 
and scientific basis in view of ongoing progress of knowledge within the scientific community. The 
SAB will meet yearly and may ask DSMB questions and recommend specific actions to the other 
governance committees. 
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a DSMB composed of individuals with the 
appropriate expertise, including geriatrics, gerontology, clinical trial methodology, human and 
clinical nutrition, internal medicine, bioethics, data privacy and ethics of information 
technologies, information and communication technologies applied to health (e-health). 
Members of the DSMB should be independent from the study conduct and free of conflict of 
interest, or measures should be in place to minimize perceived conflict of interest. The DSMB will 
meet quarterly to assess safety data of all study participants enrolled in the study. The DMSB will 
operate under the rules of an approved charter that will be written and reviewed at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. The DSMB will provide its input to the Study Managing Board and 
will answer questions from the Steering Committee and the Scientific Advisory Board. 


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 the DSMB will review 
bioanalytical data and other relevant safety data each 3 calendar months once the 25th patient is 
randomized and starts the investigational drug administration. The DSMB can trigger interim PK 
analysis of collected blood samples by a third party in order to avoid the unblinding of the study.  
 
 
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
ICH GCP, and with applicable regulatory requirement(s).  
 
• Monitoring for this study will be performed by 
 staff 
• On-site monitoring will be complemented by centralized remote monitoring. The first on-
site visit will take place no later than 4 weeks after the start of clinical activities. Frequency 
will be adapted according to the center inclusion rate. Training on the study procedures, 
including the use of eCRF will be provided jointly by 
and 
before 
study start. Targeted review of critical data and targeted data verification of endpoints, 
safety and other key data variables will be specified in the Clinical Monitoring Plan (CMP) 
• The Sponsor will be provided copies of monitoring reports within 10 days of visit 
• Details of clinical site monitoring are documented in a CMP. The CMP describes in detail 
who will conduct the monitoring, at what frequency the monitoring will be done, at what 
level of detail monitoring will be performed, and the distribution of monitoring reports 
• Independent audits could be conducted by the Sponsor or a mandated sub-contractor to 
ensure monitoring practices are performed consistently across all participating sites and 
that monitors are following the CMP 
Planned Sponsor audits are postponed during the COVID-19 outbreak and will resume once 
permitted under national, local and/or organizational social distancing restrictions.  
The investigator shall permit the Site Monitor to review study data as frequently as deemed 
necessary to ensure that data are being recorded in an adequate manner and that protocol 
adherence is satisfactory. 
The investigator shall access medical records for the Monitor so that the entries in the eCRF may 
be verified. The investigator, as part of his/her responsibilities, is expected to cooperate with 
 
in ensuring that the study adheres to GCP requirements. 
The investigator may not start recruiting study participants into the study until a sponsor/
 
monitor has conducted a visit to give a detailed review of the protocol and the eCRF. Alternatively, 
with the agreement of the sponsor, attendance at the investigator meeting can be in lieu of an 
on-site visit by the sponsor or CRO.  
During the COVID-19 outbreak, no on-site visit is allowed. Remote monitoring is allowed when 
the system is CRFpart11 compliant. When no compliant system allows a full remote monitoring 
visit, alternative oversight is put in place, including the remote review of eCRF entries, collection 
of the list of participants who signed ICFs, protocol deviations with the identification of the COVID-


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19 outbreak reason, and collection of the list of document items that will require onsite follow-
up during the next onsite MV.  
 All the monitoring visits will resume once external visitors are allowed on investigational sites.  
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Biophytis shall implement and maintain quality control and quality assurance procedures with 
written standard operating procedures (SOPs) to ensure that the study is conducted and that the 
data are generated, documented and reported in compliance with the protocol, ICH GCP and 
applicable regulatory requirements. Specifically, for clinical operations, the SOPs of the CRO in 
charge, 
 will be applied. 
This study shall be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 1996) and all revisions thereof, and in accordance with FDA regulations (CFR, Sections 
312.50 and 312.56) and with ICH GCP (CPMP 135/95). 
The investigator should not deviate from the protocol without a formal protocol amendment 
approved by an appropriate IEC/IRB, except when necessary to eliminate immediate hazards to 
the subject or when the change(s) involve(s) only logistical or administrative aspects of the study. 
Any deviations may result in the subject having to be withdrawn from the study and render that 
subject non-evaluable. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat and legible manner to ensure accurate 
interpretation of data. Source data are all informational, original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation 
of the trial. Electronic source data are data initially recorded in electronic form. Examples of 
source data include, but are not limited to: hospital records, clinical and office charts, laboratory 
notes, memoranda, participants’ memory aids or evaluation checklists, pharmacy dispensing 
records, audio recordings of counseling sessions, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and participant files and records 
kept at the pharmacy, at the laboratories, and medico-technical departments involved in the 
clinical trial. It is acceptable to use CRFs as source documents. If this is the case, it should be stated 
in this section what data will be collected on CRFs and what data will be collected from other 
sources.  
It is not acceptable for the CRF to be the only record of a participant’s inclusion in the study. Study 
participation should be captured in a participant’s medical record. This is to ensure that anyone 
who would access the patient medical record has adequate knowledge that the patient is 
participating in a clinical trial. 
Hardcopies of the study visit worksheets will be made available (as printable version of eCRF) and 
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recording data for each participant enrolled in the study. Data recorded in the eCRF derived from 
source documents should be consistent with the data recorded on the source documents.  
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into a proprietary eCRF, a 21 CFR Part 11-compliant data 
capture system provided by the Sponsor ICT subcontractors. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
To obtain a high level of readability and easy data exchange between different systems, and to 
make statistical analysis easy, the following standards and dictionary will be used. 
1. CDISC (Clinical Data Interchange Standards Consortium) CDISC ODM v.1.3.2.  
2. CDISC (Clinical Data Interchange Standards Consortium) SDTM v.1.4 or more recent 
versions as applicable 
3. MedDRA: Medical Dictionary for Regulatory Activities   
4. WHO-DD: World Health Organization Drug Dictionary 
This study will use a dedicated Information and Communication Technology (ICT) centralized 
infrastructure for clinical data capture, different data source integration (e.g., DEXA scan results, 
actimetry), PROs electronic entry, and secure data storage. 
The collected information will be initially handled and stored by 
 and 
subsequently transferred and stored at Biophytis’s SARA Clinical Data Platform. 
The SARA Clinical Data Platform will allow to securely keep and access anonymized clinical data 
for the purpose of the clinical trial remote monitoring, managing, validation and result analyses. 
The investigator shall be provided with standardized eCRF and shall ensure that all data from 
participant visits are promptly entered into the eCRF in accordance with the specific instructions 
given. The investigator must electronically sign each eCRF to verify the integrity of the data 
recorded. Further details will be provided in the MOP. 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to study start. If a central laboratory has been selected to 
conduct any or all tests, it is essential that all samples be analyzed at that laboratory. 
The investigator must maintain source documents, such as laboratory reports, X-rays, ECGs, 
consultation reports, and complete medical history and physical examination reports. 
For patients that are not able to use an electronic device (desktop, laptop, tablet or analogous 
device), a printed booklet will be made available to complete the PROs foreseen at the protocol. 
The PRO booklets should be considered to be a source data. 
After the end of SARA-INT clinical trial, SARA Clinical Data Platform will continue operations and 
allow secondary research on the collected data. 
 
10.1.9.2 STUDY RECORDS RETENTION  
The investigator/institution should maintain the study documents as specified in the ICH 
guidelines of GCP and as required by the applicable regulatory requirements. The 


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investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal discontinuation 
of clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to 
when these documents no longer need to be retained. 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol or the GCP. Further 
details about the handling of protocol deviations will be included in the MOP.  
 The noncompliance may be either on the part of the participant, the investigator, or the study 
site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
No changes from the final approved and signed protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB and local competent 
authorities as applicable, except when necessary to address immediate safety concerns to the 
patients or when the change involves only non-substantial logistics or administration. Each 
investigator and the sponsor will sign the protocol amendment. 
It is the responsibility of the Investigator to use continuous vigilance to identify and report all 
deviations to Biophytis and the local IRC/IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IEC/IRB requirements. 
The sponsor expects that the COVID-19 situation will introduce more protocol deviations than 
normal. All protocol deviations will be accurately recorded and identified as deviations that 
incurred due to the COVID-19 outbreak and as reasons why the procedures were not 
performed according to protocol. They will be assessed and reported in the clinical study report, 
following ICH E3. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
The sponsor shall retain the ownership of all data. When the study is complete, the sponsor shall 
arrange the analysis and tabulation of data. A clinical study report shall then be prepared, which 
may be used for publication, presentation at scientific meetings or submission to regulatory 


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authorities. All proposed publications based on this study must be subject to the sponsor's 
approval requirements. 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate for their participation in the trial. The study 
leadership, in conjunction with Biophytis, will establish policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest. 
10.2 ADDITIONAL CONSIDERATIONS 
The investigator will ensure that this study is conducted in full conformity with applicable 
regulations, the Declaration of Helsinki, GCP and ICH E6. 
Prior to the start of the study, the investigator is responsible for ensuring that the protocol and 
consent form have been reviewed and approved by a relevant IEC and IRB. The IEC and IRB shall 
be appropriately constituted and perform its functions in accordance with the FDA, ICH GCP and 
local requirements as applicable. 
The IEC and IRB shall approve all protocol amendments (except for logistical or administrative 
changes), including but not limited to: written informed consent documents and document 
updates, participant recruitment procedures (e.g., advertisements), written information to be 
provided to the participants, available safety information, information about payment and 
compensation available to participants, the investigator's curriculum vitae and/or other evidence 
of qualifications and any other documents requested by the IEC, IRB and Regulatory Authority 
(Competent Authority) as applicable. 
 


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10.3 ABBREVIATIONS 
 
20E 
20-hydroxyecdysone 
400MW 
400-meter walk test 
6MWT 
6-minute (distance) walk test 
ACE 
Angiotensin Conversion Enzyme 
AE  
Adverse Event  
ALM 
Appendicular Lean body Mass 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA  
Analysis of Covariance  
AST 
Aspartate Aminotransferase 
BFM 
Body Fat Mass 
BMI 
Body Mass Index 
CFR  
Code of Federal Regulations  
CIOMS  
Council for International Organizations of Medical Science  
CIRS 
Cumulative Illness Rating Scale 
CLIA  
Clinical Laboratory Improvement Amendments  
CMP  
Clinical Monitoring Plan  
CMS  
Centers for Medicare and Medicaid Services 
CRF 
Case Report Form  
COA 
Certificate of Analysis 
COVID-19 
COronaVIrus Disease 2019 
CRO  
Contract Research Organization  
DCC  
Data Coordinating Center  
DEXA 
Dual-energy x-ray absorptiometry 
DHHS  
Department of Health and Human Services  
DSMB  
Data Safety Monitoring Board  
eCRF  
Electronic Case Report Forms  
EPESE 
Established Populations for the Epidemiologic Study of the Elderly 
EU 
European Union 
FAS 
Full Analysis Set 
FDA  
Food and Drug Administration  
FDAAA  
Food and Drug Administration Amendments Act of 2007  
FFR  
Federal Financial Report  
FNIH 
Foundation of NIH 
GCP  
Good Clinical Practice  
GLP  
Good Laboratory Practices  
GMP  
Good Manufacturing Practices  
GWAS  
Genome-Wide Association Studies  
HbA1c 
Glycated Hemoglobin A1c 
HIPAA  
Health Insurance Portability and Accountability Act  


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IB  
Investigator’s Brochure  
ICD-10 
International Classification of Diseases- 10th Edition 
ICH  
International Conference on Harmonisation  
ICH E6  
International Conference on Harmonisation Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance  
ICMJE  
International Committee of Medical Journal Editors  
ICT 
Information and Communication Technology 
IDE  
Investigational Device Exemption  
IGF-1 
Insulin-like growth factor 1 
IL-6  
Interleukin 6 
IND  
Investigational New Drug Application  
IRB  
Investigational Review Board  
ISO  
International Organization for Standardization  
LIFE 
Lifestyle Interventions and Independence for Elders 
LIFE-P 
Lifestyle Interventions and Independence for Elders- Pilot study 
LSMEANS  
Least-squares Means  
MAD 
Multiple Ascending Dose (phase1) 
MedDRA  
Medical Dictionary for Regulatory Activities  
MI 
Multiple Imputation 
MMRM 
Mixed Model for Repeated Measures 
MOP  
Manual of Procedures  
MSDS  
Material Safety Data Sheet  
NIH  
National Institutes of Health  
NIH IC  
NIH Institute & Center  
NYHA 
New York Heart Association (class of congestive heart failure) 
OHRP  
Office for Human Research Protections  
OHT 
Orthostatic Hypotension 
PAT-D 
Pepper Assessment Tool for Disability 
PF-10 
10 item Physical Function domain at SF-36 
PI  
Principal Investigator  
PRO 
Patient Reported Outcome 
QA  
Quality Assurance  
QC  
Quality Control  
SAD 
Single Ascending Dose (phase1) 
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SARA 
SARcopenia and sarcopenic obesity in patients Aged ≥ 65 years 
SARA-OBS 
SARA OBServational Study “Characterizing SARcopenia and sarcopenic obesity in patients 
Aged 65 years and over, at risk of mobility disability.” 
SARA-PK 
SARA Pharmaco-Kinetics phase1 study 
SARA-POP-PK 
Phase2 population PK sub-study 
SARM 
Selective Androgen Receptor Modulator 
SarQoL 
Sarcopenia Quality of Life (questionnaire) 


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SF-36 
Short Form-36 (quality of life questionnaire)  
SF-MNA 
Short Form Mini-Nutritional Assessment 
SO 
Sarcopenic Obesity 
SOA 
Schedule of Activities 
SCPT 
Stair Climb Power Test  
SOC  
System Organ Class  
SOP  
Standard Operating Procedure  
SMC  
Safety Monitoring Committee  
SPPB 
Short Physical Performance Battery  
TSD-OC 
Test SIO Disabilità Obesità Correlata (obesity disability questionnaire) 
TU 
Therapeutic Unit (individual patient packaged and labelled treatment) 
ULN 
Upper Limit of Normal 
UP  
Unanticipated Problem  
US 
United States 
WHO 
World Health Organisation 
 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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