Testing the Efficacy, Safety, and PK of 20E in Patients With Obesity Who Are Starting Treatment With the GLP-1 Agonist Semaglutide for Weight Loss.

A Phase 2, Double-blind, Randomized, Placebo-controlled Multicenter Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of 20-hydroxyecdysone (20E) in Reducing the Muscle Strength Loss From the GLP1 Agonist Semaglutide in Combination With Dieting in Obese and Overweight Adult Patients (OBA).

The goal of this clinical trial is to learn if BIO101 treatment can improve the muscle strength of participants males and females, aged 18 to 84 years old, suffering from obesity (BMI≥30) or overweight (BMI ≥ 27) with one or more sequelae (e.g., hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease, but excluding diabetes), and treated with semaglutide, a GLP1 agonist for 21 weeks. The main questions it aims to answer are:

• Is BIO101 administered orally improving muscle strength, as measured with knee extension strength (using isokinetic dynamometry)?
• Is BIO101 administration leading to additional medical problems for patients suffering from obesity or overweight with sequelae and treated with semaglutide? After the end of the study (after last patient did the last visit at the clinic), researchers will compare the BIO101-treated arm to the placebo control arm to see if the candidate drug has an effect on muscle strength, physical function, lean body mass and health related quality of life compared to placebo. BIO101 is the candidate drug and placebo is a look-alike substance that does not contain any active drug

Participants will be asked to:

• Take 2 pills every morning and every evening of BIO101 or placebo orally for 21 weeks.
• Simultaneously, take semaglutide for 21 weeks while being on caloric restriction, following the doctor recommendation and approved prescribing information for semaglutide, with dose increasing up to at least a dose level of 1.7 mg and a maximum dose level of 2.4 mg.
• Come to investigational site at screening, baseline, week 6, 13, 21 and week 33 (12 weeks after the end of treatment) for checkups and tests.
• Answer to phone calls at week 25 and 29 as well (4 and 8 weeks after the end of treatment) on global health status and quality of life.

Inclusion Criteria:

• Willing to participate and able to sign an ICF
• BMI ≥30 or BMI ≥27 with one or more weight-associated co-morbidities (e.g. hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease)
• Start of treatment with semaglutide for weight loss at Day 3 after the start of the study treatment
• Willing to maintain a diet with an average intake of at least 1 gr/kg body weight protein daily
• Willing to maintain sufficient exercise, i.e. at least 150 minutes per week moderate-vigorous exercise
• Body weight stable (within a 5 kg range) in the 3 months prior to enrolment
• Female participants should be at least 12 months post-menopausal) or surgically sterile OR have a negative urine pregnancy test at screening and be willing to use a contraceptive method from screening to 90 days after last dose.
• Based on Semaglutide long half-life, participants should consent to use a contraception method 3 months after administration of the last dose intake of semaglutide.

Exclusion Criteria:

• Participant not able to take medications by mouth (as capsules)
• Use of disallowed concomitant medications or herbal products: Any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides, Cyanotis vaga, or Cyanotis arachnoidea are not allowed and any other anabolic products, GH/IGF-1 products, spironolactone, metformin, chemotherapeutic agents, antidepressants, and systemic glucocorticoids within three months prior to study enrollment or strong inhibitors of the Organic Anion Transporting Polypeptide (OATP1B3) e.g. rifampicin and cyclosporine. Use of muscle strength-supporting food supplements
• Any known hypersensitivity to any of the active substances (20E), and its excipients (the study medication) and the active substance and the excipients of semaglutide.
• History or present cholelithiasis or cholecystectomy from medical history or sludge or stones observed on gallbladder ultrasound or any other method.
• Presence of contra-indications to semaglutide per current semaglutide Prescribing Information / Summary of Product Characteristics
• Current diabetes (both insulin dependent and T2DM)
• A history of chronic pancreatitis or acute pancreatitis
• Previous surgical obesity treatment or planned obesity surgery during the study period
• Use of anti-obesity (weight-loss) medication or use of any GLP-1 RA for diabetes within 90 days before enrollment
• BMI >40
• Uncontrolled hypertension (RR above 150/100 mmHg)
• NYHA Class III or IV CHF
• History of stroke, myocardial infarction, life-threatening arrhythmia, or coronary revascularization within 6 months prior to screening
• Clinically significant liver disease, ALT/AST >5x ULN, or total bilirubin > 2x ULN, unless the patient has known Gilbert's syndrome
• Neuromuscular disorder or CK >5x ULN
• Autoimmune/inflammatory disorders that may cause muscle wasting
• Use of antipsychotics, amphetamines, or any other treatments that can affect weight
• Clinically significant ECG abnormalities
• History of major depressive disorder within the last 2 years
• Any lifetime history of suicide attempt
• History of any suicidal behavior in the last month
• History of other severe psychiatric disorders, e.g., schizophrenia, bipolar disorder
• Baseline PHQ-9 score ≥15 or any suicidal ideation of level 4 or level 5 on the Columbia-Suicide Severity Rating Scale
• History or current gastroparesis (from medical history)
• Patients with obesity due to other endocrinologic disorders
• eGFR ≤60 mL/min/1.73 m2, based on Cockcroft & Gault formula OR Participant requiring renal dialysis
• Patients with clinically Recognized Eating Disorders
• Patients with clinically significant, uncontrolled hyperthyroidism or hypothyroidism, or those with newly diagnosed thyroid disease within the past 3 months.