E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
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 | 10041582 |
E.1.2 | Term | Spinal muscular atrophy |
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 A: To evaluate the safety and tolerability of single ascending doses of BIIB115 administered via IT bolus injection to HVs Part B: To evaluate the safety and tolerability of multiple ascending doses of BIIB115 administered via IT bolus injection participants with SMA who previously received onasemnogene abeparvovec |
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E.2.2 | Secondary objectives of the trial |
Part A: To evaluate the single dose PK of BIIB115 administered via IT bolus injection to HVs Part B: To evaluate the PK of multiple ascending doses of BIIB115 administered via IT bolus injection to pediatric SMA participants who previously received onasemnogene abeparvovec |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part A: 1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with applicable privacy regulations. 2. Males aged 18 to 55 years inclusive, at the time of informed consent. 3. Have a body mass index between 18 and 30 kg/m2, inclusive. 4. All participants must practice highly effective contraception as described in Section 12.5 of the protocol. 5. Must be in good health as determined by the Investigator, based on medical history and Screening evaluations. Part B: - Age 0.5 to 12 years old, inclusive, at the time of informed consent - Weight ≥7 kg at the time of informed consent - Genetic diagnosis of SMA (5q SMA homozygous survival motor neuron 1 (SMN1)gene deletion or mutation or compound heterozygous mutation)- Survival motor neuron 2 (SMN2) copy number ≥1 - Must have received IV onasemnogene abeparvovec per the approved label or per guidelines including the steroid regimen and monitoring specified therein - Treatment with onasemnogene abeparvovec ≥180 days prior to first BIIB115 dose - Potential for improvement due to suboptimal clinical status secondary to SMA, as determined by the Investigator
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E.4 | Principal exclusion criteria |
Part A: 1. Any reason, anatomical or otherwise (including abnormal hematology/coagulation) that presents increase of risk of complication from multiple LP procedures required for dosing and CSF collection, per the investigator discretion. 2. History of any clinically significant cardiac, endocrine, gastrointestinal, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, or renal disease, or other major disease, as determined by the Investigator. 3. History of severe allergic or anaphylactic reactions, or of any allergic reactions that in the opinion of the Investigator are likely to be exacerbated by any component of the study treatment including LP procedures. 4. History of, or ongoing malignancy, carcinoma in situ, or high grade dysplasia (with the exception of no more than 1 basal cell carcinoma or squamous cell carcinoma that was completely excised and cured at least 12 months prior to randomization). 5. Systolic blood pressure > 150 mmHg or < 90 mmHg after resting in a supine or semi recumbent position for at least 5 minutes at screening or prior to dosing. 6. Clinically significant 12-lead electrocardiogram abnormalities. 7. Confirmed demonstration of corrected QT interval, using Fridericia’s correction method, of > 450 ms. 8. Plans to undergo elective procedures or surgeries at any time after signing the ICF through the follow-up visit. 9. History of a suicide attempt within 5 years prior to screening or suicidal ideation in the past 6 months 10. History of, or positive test result at Screening for, human immunodeficiency virus. 11. History of hepatitis C infection or positive test result at Screening for hepatitis C virus antibody. 12. Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or total hepatitis B core antibody [anti-HBc]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive hepatitis B surface antibody [anti-HBs]) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study. 13. Chronic, recurrent, or serious infection (e.g., pneumonia, septicemia), as determined by the Investigator, within 90 days prior to Screening or between Screening and Day -1. 14. • Any value for ALT, AST, bilirubin, or serum creatinine that is above the ULN at Screening or Baseline. • Any value of hemoglobin that is < 7.45 mmol/L (approx. < 12 g/dL) at Screening or Baseline. • Any value for platelets that is below the lower limit of normal at Screening or Baseline. • Any value out of normal range for absolute or differential WBC counts at screening or Baseline. 15. Current enrollment or a plan to enroll in any interventional clinical study of a drug, biologic, or device, in which an investigational treatment or approved therapy for investigational use is administered within 3 months (or 5 half lives of the agent, whichever is longer) prior to randomization. 16. Use of any prescription medication, over-the-counter oral medication that is known to alter hepatic or renal clearance (excluding acetaminophen/paracetamol), or nutraceutical (e.g., St. John’s wort, ginseng, ginkgo biloba) within 28 days prior to Day -1; use of other over-the-counter oral medication, vitamins, dietary supplements, or antacids within 14 days prior to Day -1; and an unwillingness or inability to refrain from this use during study participation, unless specifically permitted elsewhere within this protocol.
Part B: - Severe or serious AEs related to onasemnogene abeparvovec therapy that are ongoing during Screening - Interval of <180 days between onasemnogene abeparvovec therapy and first BIIB115 dose XML File Identifier: fkkPE/OBkhdN8MDY8UvuBX6zAlA= Page 10/27 - Ongoing steroid treatment following onasemnogene abeparvovec at time of screening - History of drug induced liver injury or liver failure per Hy's law definition - History of thrombotic micrangiopathy - Treatment with any SMN2-splicing modifier (nusinersen or risdiplam) after receiving onasemnogene abeparvovec. Treatment with nusinersen <12 months from the first dose of BIIB115. - Any reason, anatomical or otherwise (including abnormal hematology/coagulation),that presents increase of risk of complication from the LP procedures, CSF circulation, or safety assessments, including a history of hydrocephalus or implanted shunt for CSF drainage - Permanent ventilation, defined as tracheostomy or ≥16 hours ventilation/day continuously for ≥21 days in the absence of an acute reversible event |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A: Incidence of AEs/ SAEs Part B: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: Day -1 - EOT Part B: Up to Day 720 |
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E.5.2 | Secondary end point(s) |
Part A: • CSF BIIB115 Concentration • CSF PK Parameters: - t½ • Serum BIIB115 Concentration • Serum PK Parameters: - t½ - AUC0-last - AUC∞ - Cmax - Tmax Part B: 1. Concentration of BIIB115 in Cerebral Spinal Fluid (CSF) 2. Concentration of BIIB115 in Serum 3. Terminal Elimination Half-Life (t½) of BIIB115 in Serum 4. Area Under the Concentration-Time Curve from Time 0 to Last Measurable Concentration (AUC0-last) of BIIB115 in Serum 5. Area Under the Concentration-Time Curve from Time 0 to Infinity (AUCinf) of BIIB115 in Serum 6. Maximum Observed Concentration (Cmax) of BIIB115 in Serum 7. Time to Reach Maximum Observed Concentration (Tmax) of BIIB115 in Serum |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: Day -1 - EOT Part B: 1. Days 1 and 360 2. Day 1 to Day 720 3. Day 1 to Day 720 4. Day 1 to Day 720 5. Day 1 to Day 720 6. Day 1 to Day 720 7. Day 1 to Day 720 |
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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 | No |
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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Israel |
Belgium |
France |
Germany |
Italy |
Netherlands |
Poland |
Portugal |
Spain |
United Kingdom |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 3 |