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

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.

• BIO101 (Drug), also known as 20 hydroxyecdysone (20E): Oral capsules
• Placebo (Drug): Oral capsules

Primary outcomes

• Change From Baseline to 6 Months in Gait Speed for 400 Meter Walking (MW) Test [Baseline and 6 Months]: Gait speed was measured using the 400 MW test, which measured how long it took the participant to walk a distance of 400 meters. Missing data imputed using adjusted Bayesian Multiple Imputation (MI) methods for Non-Completers who failed to perform the Test feasibility and Multiple Imputation for participants who without data on on-Site visit. Data up to 9 months was used where 6 months data were unavailable for participants enrolled during the COVID-19 pandemic.

Secondary outcomes

• Change From Baseline to 6 Months in Short Form-36 (SF-36) 10 Item Physical Function Domain (PF-10) Sub-score [Baseline and 6 Months]: The Physical Function Domain (PF-10) of the SF-36 assesses an individual's perceived physical functioning and limitations in various activities. It consists of ten items that ask about a person's ability to perform different physical activities and tasks. Scores on the PF-10 range from 0 to 100 where 100 indicates no physical limitations. Missing data imputed using adjusted Bayesian MI methods. Data up to 9 month was used where 6 month data were unavailable for participants enrolled during the COVID-19 pandemic.
• Change From Baseline to 6 Months in Handgrip Strength Test [Baseline and 6 Months]: Handgrip strength was a commonly used measure of upper body skeletal muscle function and had been widely used as a general indicator of frailty with predictive validity for both mortality and functional limitations. Participants were instructed to stand upright and with the dynamometer beside them but not against their body. Strength was measured three times for both hands. The highest value of all 3 attempts was kept for further analysis. Grip strength was measured in the dominant hand using a hydraulic grip strength dynamometer. Data up to month 9 was used where 6 month data were unavailable for participants enrolled during the COVID-19 pandemic.
• Change From Baseline to 6 Months in Appendicular Lean Body Mass (ALM) Based on Dual-energy X-ray Absorptiometry (DEXA) Measurements [Baseline and 6 Months]: DEXA scans provided accurate measurements of body composition, recording fat and lean mass distribution throughout the entire body. Foundation of National Health Institute (FNIH) project report recommended ALM alone was used to measure gender-specific low muscle mass. Data up to month 9 was used where 6 month data were unavailable for participants enrolled during the COVID-19 pandemic.
• Rate of Response for Completing 400 MW Test After 6 Months [Baseline and 6 Months]: A responder was defined as an improvement (increase) of 0.1 m/s or more in 400MW gait speed test compared to baseline. A non-responder was defined as a participant that was not a responder. Participants with a missing value at the visit and/or missing baseline value were considered as non-responders. Data up to month 9 was used where 6 month data were unavailable for participants enrolled during the COVID-19 pandemic.
• Change From Baseline to 6 Months in Muscle Strength Based on Knee Extension [Baseline and 6 Months]: Isometric knee extension torque was measured with a knee extension dynamometer chair. The participants were 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 was recorded as the distance between the knee axis of rotation and the middle of the pad. Knee extension was measured using the maximum peak torque measurement Newton meter (Nm) for 60°/s, 90°/s and 180°/s for the tested leg (either right or left). The Knee extension torque was obtained either directly or by multiplying recorded peak force with the lever arm length. The assay with the highest torque output was taken for analyses. Data up to month 9 was used where 6 month data were unavailable for participants enrolled during the COVID-19 pandemic.
• Change From Baseline to 6 Months in Time for Five Chair Stands as Part of the Short Physical Performance Battery (SPPB) Assessment [Baseline and 6 Months]: The SPPB was a series of tests designed to examine physical movements. The chair stands tests involved standing from a chair a number of times to test leg strength. Each performance measures were assigned a score ranging from 0 to 4, with 4 indicating the highest level of performance and 0 the inability to complete the test. The time to complete the task was recorded. The time required to perform five chair stands was 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 was assigned to participants unable to perform the task. A summary score ranging from 0 (worst performers) to 12 (best performers) was calculated by adding sub scores from the chair stands test. Data up to month 9 was used where 6 month data were unavailable for participants enrolled during the COVID-19 pandemic.
• Change From Baseline to 6 Months in Distance in the 6-Minute Walk Test (6MWT) [Baseline and 6 Months]: The 6MWT was a test for functional exercise capacity and involved measuring the distance a participant could cover within the allotted time of 6 minutes. Data up to month 9 was used where 6 month data were unavailable for participants enrolled during the COVID-19 pandemic.
• Change From Baseline to 6 Months in Pepper Assessment Tool for Disability (PAT-D) for Obese Participants [Baseline and 6 Months]: The PAT-D was a disability questionnaire which asked respondents how much difficulty they had with a range of activities with functioning. PAT-D scores range from 1 (worst) to 5 (best). Data up to month 9 was used where 6 month data were unavailable for participants enrolled during the COVID-19 pandemic.
• Change From Baseline to 6 Months in SPPB Total Score [Baseline and 6 Months]: The SPPB was a series of tests designed to examine physical movements. Results of the SPPB included total gait speed score, total balance test score, and total chair stand score. The first tests examined balance (without the assistance of a cane or walker) with the feet in three different orientations, the second test examined gait speed, and the third tests involved standing from a Chair a number of times to test leg strength. A score of 0 was assigned to participants unable to perform the task. A summary score ranging from 0 (worst performers) to 12 (best performers) was calculated by adding sub scores from the walking speed, chair stands and balance tests. Data up to month 9 was used where 6 month data were unavailable for participants enrolled during the COVID-19 pandemic.
• Change From Baseline to 6 Months in Sarcopenia Quality of Life (SarQoL) Auto-Evaluation Questionnaire [Baseline and 6 Months]: The SarQoL was a sarcopenia-specific, self-administered, quality of life questionnaire designed for community-dwelling elderly study participants aged 65 years and older. The questionnaire contained 22 questions, which took approximately 10 minutes to complete. The questionnaire covered 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. The total scoring of the SarQoL questionnaire ranges from 0 (worst imaginable health) to 100 (best imaginable health). A higher score reflected a higher quality of life. Data up to month 9 was used where 6 month data were unavailable for participants enrolled during the COVID-19 pandemic.
• Change From Baseline to 6 Months in Stair Climb Power Test (SCPT) [Baseline and 6 Months]: The SCPT measured 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 was recommended). Step heights should have been suitable (between 16 and 20 cm). Data up to month 9 was used where 6 month data were unavailable for participants enrolled during the COVID-19 pandemic.

Sex: All, ages: 65 Years to any

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 participants.

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-menopaused women (however ongoing replacement hormonal treatment is not an exclusion criterion)
3. Known allergic reactions to components of the investigational drug.
4. Treatment with another investigational drug or other intervention 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:

   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.
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).

Participant flow

Outcome results

• Change From Baseline to 6 Months in Gait Speed for 400 Meter Walking (MW) Test (Primary), Least squares mean, Meter/Second (m/s): Placebo 0.0093 (-0.0369 to 0.0556); 175mg BIO101 0.0457 (-0.0014 to 0.0927); 350mg BIO101 0.0478 (0.0050 to 0.0907) (p 0.2437)
• Change From Baseline to 6 Months in Short Form-36 (SF-36) 10 Item Physical Function Domain (PF-10) Sub-score (Secondary), Least squares mean, score on a scale: Placebo 7.3 (2.4 to 12.3); 175mg BIO101 7.1 (1.9 to 12.3); 350mg BIO101 7.1 (2.2 to 12.1) (p 0.9408)
• Change From Baseline to 6 Months in Handgrip Strength Test (Secondary), Least squares mean, kilograms (Kg): Placebo -0.709 (-2.902 to 1.484); 175mg BIO101 -1.601 (-3.935 to 0.733); 350mg BIO101 0.590 (-1.533 to 2.712) (p 0.5200)
• Change From Baseline to 6 Months in Appendicular Lean Body Mass (ALM) Based on Dual-energy X-ray Absorptiometry (DEXA) Measurements (Secondary), Least squares mean, Kg: Placebo -0.276 (-0.911 to 0.359); 175mg BIO101 -0.283 (-0.944 to 0.378); 350mg BIO101 0.068 (-0.496 to 0.632) (p 0.9859)
• Rate of Response for Completing 400 MW Test After 6 Months (Secondary), Count of participants, Participants: Placebo 4; 175mg BIO101 9; 350mg BIO101 11 (p 0.1219)
• Change From Baseline to 6 Months in Muscle Strength Based on Knee Extension (Secondary), Least squares mean, Newton meter (Nm): Placebo 0.484 (-18.088 to 19.056); 175mg BIO101 -1.092 (-21.833 to 19.649); 350mg BIO101 -4.515 (-17.889 to 8.858) (p 0.8917)
• Change From Baseline to 6 Months in Time for Five Chair Stands as Part of the Short Physical Performance Battery (SPPB) Assessment (Secondary), Least squares mean, Seconds: Placebo -3.857 (-6.024 to -1.690); 175mg BIO101 -2.572 (-4.721 to -0.422); 350mg BIO101 -1.206 (-3.135 to 0.724) (p 0.3762)
• Change From Baseline to 6 Months in Distance in the 6-Minute Walk Test (6MWT) (Secondary), Least squares mean, Meters: Placebo -9.879 (-37.089 to 17.330); 175mg BIO101 -7.166 (-36.559 to 22.228); 350mg BIO101 15.728 (-10.981 to 42.436) (p 0.8824)
• Change From Baseline to 6 Months in Pepper Assessment Tool for Disability (PAT-D) for Obese Participants (Secondary), Least squares mean, score on a scale: Placebo -0.27 (-0.42 to -0.13); 175mg BIO101 -0.08 (-0.24 to 0.08); 350mg BIO101 -0.17 (-0.31 to -0.03) (p 0.0511)
• Change From Baseline to 6 Months in SPPB Total Score (Secondary), Least squares mean, score on a scale: Placebo 1.1 (0.5 to 1.6); 175mg BIO101 1.00 (0.4 to 1.5); 350mg BIO101 0.9 (0.3 to 1.5) (p 0.8084)
• Change From Baseline to 6 Months in Sarcopenia Quality of Life (SarQoL) Auto-Evaluation Questionnaire (Secondary), Least squares mean, score on a scale: Placebo 8.05 (4.95 to 11.14); 175mg BIO101 5.60 (2.43 to 8.78); 350mg BIO101 5.83 (2.79 to 8.87) (p 0.2312)
• Change From Baseline to 6 Months in Stair Climb Power Test (SCPT) (Secondary), Least squares mean, Seconds: Placebo 39.9 (-46.4 to 126.3); 175mg BIO101 32.4 (-65.4 to 130.3); 350mg BIO101 88.5 (5.1 to 171.8) (p 0.8934)

Adverse events

Time frame: Adverse events (AEs) were collected from the time of informed consent until the completion of the study or at the end-of-study visit (up to maximum of 9 months). All ongoing AEs were followed for an additional 30 days after the end-of-study visit.

Serious adverse events by term

Other adverse events by term

156 more terms not shown.

Limitations and caveats: Due to the coronavirus disease 2019 (COVID-19) outbreak, the implementation of the clinical protocol was affected, including but not limited to the scheduled site visit for safety and/or efficacy, site visits for monitoring, investigational product delivery, collection of adverse events (AEs) and concomitant medications. This led to >50% loss of efficacy data for the primary endpoint and other performance assessments.

• Study Protocol (PDF, 2020-04-20)
• Statistical Analysis Plan (PDF, 2021-06-04)

• Rob Van Maanen, Study director, Biophytis