| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Duchenne Muscular Dystrophy regardless the genotype |
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| E.1.1.1 | Medical condition in easily understood language |
| Duchenne Muscular Dystrophy regardless the genotype |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052655 |
| E.1.2 | Term | Duchenne muscular dystrophy gene carrier |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1
To evaluate the safety, tolerability and PK profile of BIO101 and its main metabolites after a single dose (Day 1) and after multiple doses at Day 7, 14 and 56
Part 2
To evaluate the safety, tolerability, and efficacy on respiratory function, of BIO101 following 48 weeks double blind dosing, in a small population (48 participants)
Part 3
To evaluate the safety, tolerability, and efficacy on respiratory function of BIO101 following 48 weeks double blind dosing, in a large population (100-200 participants) |
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| E.2.2 | Secondary objectives of the trial |
Part 2
Population PK analysis to characterize the PK of BIO101 following 48 weeks double blind dosing
To determine the number of new participants to enroll into confirmatory Part 3
Part 3
To further evaluate efficacy of BIO101 versus placebo and external controls on strength and respiratory function of participants according to their initial disease status
To evaluate the safety and tolerability of BIO101 versus placebo
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part 1
1. Genetically confirmed DMD
2. Age 12 and above at screening
3. Non-ambulant patients (The non-ambulatory patient is defined as non-ambulant for at least 6 months with inability to walk 10 meters without assistance, by another person or device)
4. FVC ≤80% and >45% of predicted value based on most recent assessment noted in the patient's medical record and subsequently confirmed at Screening and at Baseline and who, in the opinion of the investigator are in the respiratory function decline phase.
5. Stable cardiac function, defined as:
• No clinically important ECG abnormalities.
• Echocardiography left ventricular ejection fraction (LVEF) at screening >50%.
6. If clinically indicated, approved concomitant treatment for DMD is allowed (e.g., Eteplirsen [Exondys 51™], Golodirsen [Vyondys 53™], Ataluren [Translarna™])
7. On or off corticosteroid therapy
• If on steroids, including but not limited to Prednisone/ Prednisolone and Deflazacort [Emflaza®]:
o At a minimum dose of 0.3 mg/Kg/day prednisone equivalent
o Deflazacort approximately 0.9 mg/Kg/Day
o As long as the treatment is stable (i.e., unchanged and with no significant side effects) for at least 3 months.
o As long as the treatment is stable (i.e., unchanged and with no significant side effects) for at least 3 months.
• Participants who were treated with corticosteroids and stopped (for any reason) will wait for 3 months until they can be eligible for inclusion.
• Steroid treatment is expected to remain stable during study, except for adjustment for weight.
8. Participants on antihypertensive, lipid lowering, and/or thyroid replacement therapies, carnitine, creatineare eligible only if they are on a stable dose for at least 1 month prior to screening.
9. Stable hepatic function:
• Gamma-glutamyl transferase (GGT) ≤ upper limit of normal (ULN)
• Total bilirubin < 2×ULN
• GLDH < 2×ULN
• Alkaline phosphatase ≤ULN
• Serum albumin ≥ lower limit of normal (LLN)
10. Ability to provide reliable and reproducible repeat PEF within 15% of the first assessment (i.e. Baseline vs. Screening)
11. Ability to provide reliable and reproducible repeat FVC within 15% of the first assessment (i.e. Baseline vs. Screening)
12. Willing and able to participate and comply with all study procedures.
• For participants aged <18: Parent or legal guardians will sign an informed consent prior to start of screening procedures and patient will sign an informed ascent.
• For participants aged 18 and about – patient will sign an informed consent.
13. Must be accompanied, during the whole study activities, by a parent, guardian or a caregiver, who is 18 years or older.
14. Sexually active participants must use double contraception (e.g. the male uses a condom and the female uses an oral contraceptive pills)
15. For France only: Being affiliated with a European Social Security.
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| E.4 | Principal exclusion criteria |
Participants will not be eligible to participate in any part of this study (Part 1, Part 2, or Part 3) if one or more of the following is/are met:
1. Any serious medical/surgical or psychiatric condition/illness that in the opinion of the Investigator would jeopardize participant’s safety or would interfere with the study assessments/results.
2. History or active signs or symptoms of gallbladder/biliary disease (e.g., previous episodes of cholestasis/biliary tract obstruction, cholelithiasis, cholecystitis). Of note, history of cholecystectomy and no active biliary signs or symptoms, is not an exclusion criterion.
3. Any known allergies to products likely to be used in the study (e.g., antiseptics, anesthetics), known hypersensitivity to any of the ingredients, or excipients of the study drug.
4.Participation in other investigational study within 30 days or 5 half lives (whichever is longer) prior to randomization.
5. Patients undergoing Idebenone (Raxone ®)
6. Intellectual disability or behavioral problem such that he cannot comply with study procedures.
7. Patients who require daytime invasive ventilatory assistance(defined as use of any assisted ventilation while awake).
8. 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)
9. Asthma, bronchiolitis/COPD, bronchiectasis, emphysema, pneumonia or the presence of any other non-DMD respiratory illness that affects PEF.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF % predictive) at Week 48 (assessed by hospital-based spirometry measurements)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Efficacy:
Change From Baseline in Forced Vital Capacity (FVC% predictive) at Week 48 (assessed by hospital-based spirometry measurements)
Safety:
Type, frequency, intensity, timing, and relationship to study drug of:
• Adverse events (AEs), discontinuations due to AEs, serious AEs (SAEs), deaths
• 12-lead triplicate electrocardiograms (ECGs)
• Local Clinical laboratory tests
• Physical examination and vital signs
• Anthropometry
Pharmacokinetics:
• Non-compartmental PK parameters including maximum concentration (Cmax), time to Cmax (tmax), area under the curve (AUC) and other parameters for participants at Part 1:
o On Day 1 (pre-treatment)
o On Day 7, 14 and 56
• Population PK parameters including apparent clearance and volume of distribution (for participants of parts 2 and Part 3)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| 3 part adaptive seamless Phase 1-3 study |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the date of the last visit of the last participant in the study.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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