A Double-blind, Placebo Controlled, Randomized INTerventional Clinical Trial (SARA-INT)

SARA-INT is a three- arm interventional, phase 2, randomized, double blind placebo controlled
clinical trial. It will be conducted in the EU (Belgium, France and Italy) and in the US.

334 community dwelling older adults (men or women≥65 years) reporting loss of physical
function and considered at risk of mobility disability, will be selected to perform SPPB
(Short Physical Performance Battery)1 tests. Those with SPPB scores ≤ 8 will be selected to
perform body composition analysis with 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 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 according to the criteria of FNIH, will be definitively included and
randomized if other inclusion/exclusion criteria are also satisfied.

The overarching objective of SARA-INT clinical trial is to evaluate the efficacy and safety
of BIO101 26-week oral administration on the prevention of mobility disability in at-risk,
community dwelling older adults (≥65 years) reporting loss of physical function over the
previous year, and in particular:

1. To estimate treatment effect improvement on physical function after six-month treatment
versus placebo in the target population.

2. To estimate treatment effect on decrease of risk of mobility disability after six-month
treatment versus placebo in the target population.

The primary objective of SARA-INT is to evaluate the effects of two daily doses of BIO101
versus placebo on mobility function as measured by the gait speed during the 400MW test

The first key secondary objective is to evaluate the effect of BIO101 on physical function
from the patient's perspective using an adapted patient reported outcome (PRO).

The second key objective is to assess on a simplified function test, i.e. raising from a
chair, a minimal clinically significant benefit on mobility.

SARA-INT other secondary objectives are: To assess changes in body composition and
specifically on appendicular lean body mass, which is an expression of sarcopenia; To
estimate the change of 400MW test as a dichotomous variable, for possible use in further
studies; To estimate the effect on muscular strength; To assess the overall change on SPPB as
cumulative expression of a physically frail status; To estimate the effect on a sarcopenia
specific PRO, in view of future studies.

SARA-INT exploratory objectives are:

1. To compare plasma and/or urinary levels of putative biomarkers of sarcopenia and of drug
activity, and calculate their correlation with physical function changes over the study
duration.

2. To compare change from baseline of the estimated cumulative daily activity as
continuously recorded via a connected wearable actimeter device.

A selection of physical activity indexes (by actimetry) will be described and a correlation
with primary and key secondary outcome will be tested.

The study plan is divided in a) screening and randomization phase; and b) treatment and
evaluation phase. The recruitment is estimated to last 6 months. The investigational phase
will comprise three main visits, the inclusion visit, the 3-month evaluation and the 6-month
final evaluation visit, plus an intermediate visit after 1-month focused on safety
assessment. Telephone interviews will be conducted at 5 months.

Inclusion 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 and living in the community, reporting loss of
physical function over the last 6-12 months

4. Short Physical Performance Battery (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.

7. Agreement to adhere to Lifestyle Considerations throughout study duration

8. In the US, women and members of minority groups must be included in accordance with
the NIH Policy on Inclusion of Women and Minorities as Participants In Research
Involving Human Subjects.

Exclusion Criteria:

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-menopausal women (however ongoing replacement hormonal treatment is not an
exclusion criterion)

3. Known allergic reactions to components of the investigational drug (i.e. stemmacantha
carthamoides leaves and roots).

4. Febrile illness within 7 days

5. Treatment with another investigational drug or other intervention within three months

6. Unable to understand and perform the functional tests, as judged by the Investigator

7. Inability to perform the 400MW test within 15 minutes

8. Clinical conditions:

1. Current diagnosis of major psychiatric disorders.

2. Alcohol abuse or dependence

3. Severe arthritis

4. Cancer requiring active treatment (cancer treated with chemotherapy, or
radiotherapy and currently on remission is not an exclusion criterion)

5. Lung disease requiring regular use of supplemental oxygen

6. Inflammatory conditions requiring regular use of oral or parenteral
corticosteroid agents

7. 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)

8. Parkinson's disease or other progressive neurological disorder

9. Renal disease requiring dialysis, or known renal insufficiency (moderate or
severe reduction in GFR≤30 ml/min/1.73 m2)

10. Chest pain, severe shortness of breath, or occurrence of other safety concerns
during the baseline functional tests 400-meter walk test or 6MWT

11. 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.

9. 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).