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

Safety and Efficacy of BIO-101 Oral Administration to Patients Suffering From Age-related SARcopenia, Including Sarcopenic Obesity, Aged ≥65 Years and at Risk of Mobility Disability (SARA-INT)

SARA-INT is a phase 2 interventional study performed in Europe and USA aimed to evaluate the clinical benefits, safety and tolerability of the investigational drug BIO101 administered orally for a six-month (26 weeks) duration to older patients, community dwelling men and women aged ≥65 years, suffering from age-related sarcopenia (including sarcopenic obesity), and at risk of mobility disability. The double-blind, placebo controlled clinical trial will collect and analyse 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 of a highly standardised patient reported outcome (PRO), the physical function domain PF-10 at the SF-36 auto-evaluation questionnaire, in order to estimate the efficacy of BIO101 administered over 26 weeks, in preventing mobility disability in the target population.

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: To estimate treatment effect improvement on physical function after six-month treatment versus placebo in the target population. 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: 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. 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 and c) post-treatment follow-up. The recruitment is estimated to last 24 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 and 6 weeks after the end of treatment.

Sarcopenia, Sarcopenic Obesity, 6-minute walking distance, 400 meters walking test, Patient Reported Outcomes, BIO101, SPPB, ALM; ALM/BMI

Each treatment kit will show a preprinted kit number affixed on the primary, secondary and tertiary container. The kit number will be assigned via the eCRF after a patient is qualified and is randomised. Nor the Investigator and his staff, either 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 specific unblinding procedure is engaged by the investigator when this is judged necessary by the responsible physician of the investigator center in the context of a severe or serious adverse event.

4 capsules taken twice a day: in the morning and in the evening with the meal approximately at 12-hour distance for 26 weeks. Component : Microcrystalline cellulose, Colloidal anhydrous silica

4 capsules taken twice a day (2 placebo and 2 experimental study drug) in the morning and in the evening with the meal approximately at 12-hour distance for 26 weeks. Study Drug Component : 251 mg per capsule including 175 mg of active principle 20-hydroxyecdysone (20E) containing also the following compendial excipients: colloidal silica, microcrystalline cellulose and magnesium stearate.

4 capsules taken twice a day (4 experimental study drug) in the morning and in the evening with the meal approximately at 12-hour distance for 26 weeks. Study Drug Component : 251 mg per capsule including 175 mg of active principle 20E containing also the following compendial excipients: colloidal silica, microcrystalline cellulose and magnesium stearate.

Oral capsules containing the BIO101 active principle is 20-hydroxyecdysone (20E) at 97%. Component : 251 mg per capsule including 175 mg of active principle 20E containing also the following compendial excipients: colloidal silica, microcrystalline cellulose and magnesium stearate.

The 400MWT is a measure of how long it takes a participant to walk a distance of 400 m. it is express in m/s

The change from baseline to month 6 will be compared between groups of treatment (each dose versus placebo).

Electronically self administrated or filling a paper booklet Patient Reported Outcome SF-36 will be assessed through a SF-36 questionnaire. The physical function score (PF-10), role limitations due to physical problems.

The change from baseline to month 6 will be compared between groups of treatment (each dose versus placebo)

Body composition especially Lean Body Mass in kg measured using DEXA. This will allow definition of the appendicular Lean Body mass

The change from baseline to month 6 will be compared between groups of treatment (each dose versus placebo)

Body composition especially Fat Mass will be measured in kg. This will allow definition of the body Fat mass

The change from baseline to month 6 will be compared between groups of treatment (each dose versus placebo)

The change from baseline to month 6 will be compared between groups of treatment (each dose versus placebo)

The grip strength will be measured using the appropriate dynamometer. Strength in kg will be measured 3 times for both hands and the highest value will be kept for further analysis.

The ability to ascend and descend stairs (9 stairs of 20 cm height) will be assessed in a specific period of time

Physical performance tests corresponding to standing balance, walking speed and chair stand will be assessed

Electronically self administrated or filling a paper booklet Patient Reported Outcome SarQoL will be assessed through the SarQoL. The SarQoL® is composed of 22 questions including in total 55 items rated on a 4-point Likert scale. The questionnaire is scored, through a scoring algorithm, on 100 points, with higher scores reflecting a better quality of life.

The change from baseline to month 6 will be compared between groups of treatment (each dose versus placebo)

The continuous physical activity of the volunteers will be recorded using a specific device during the 6-month study period.

Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged ≥ 65 years and living in the community, reporting loss of physical function over the last 6-12 months Short Physical Performance Battery (SPPB) score ≤ 8 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 Ability to take oral medication and be willing to adhere to the study intervention regimen. Agreement to adhere to Lifestyle Considerations throughout study duration 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: 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) Non-menopausal women (however ongoing replacement hormonal treatment is not an exclusion criterion) Known allergic reactions to components of the investigational drug (i.e. stemmacantha carthamoides leaves and roots). Febrile illness within 7 days Treatment with another investigational drug or other intervention within three months Unable to understand and perform the functional tests, as judged by the Investigator Inability to perform the 400MW test within 15 minutes Clinical conditions: Current diagnosis of major psychiatric disorders. Alcohol abuse or dependence Severe arthritis Cancer requiring active treatment (cancer treated with chemotherapy, or radiotherapy and currently on remission is not an exclusion criterion) Lung disease requiring regular use of supplemental oxygen Inflammatory conditions requiring regular use of oral or parenteral corticosteroid agents 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) Parkinson's disease or other progressive neurological disorder Renal disease requiring dialysis, or known renal insufficiency (moderate or severe reduction in GFR≤30 ml/min/1.73 m2) Chest pain, severe shortness of breath, or occurrence of other safety concerns during the baseline functional tests 400-meter walk test or 6MWT 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. 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).