E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis (ALS) associated with SOD1 gene mutation |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10077024 |
E.1.2 | Term | Familial amyotrophic lateral sclerosis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002026 |
E.1.2 | Term | Amyotrophic lateral sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052653 |
E.1.2 | Term | Amyotrophic lateral sclerosis 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 |
The primary objective of this study is to evaluate the efficacy of tofersen in presymptomatic adult carriers of a superoxide dismutase 1 (SOD1) mutation with elevated neurofilament (NF).
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate the safety and tolerability of tofersen and to evaluate the effect of tofersen on pharmacodynamics (PD)/treatment response biomarkers when initiated prior to versus at the time of emergence of clinically manifest amyotrophic lateral sclerosis (ALS). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Key Part A Inclusion Criteria: - Participants should have a protocol-defined rapidly progressive SOD1 mutation, confirmed by a central reader, or a SOD1 mutation that is approved for inclusion by an external mutation adjudication committee. - Participants with plasma NfL level less than the protocol-defined threshold. - Participants who are clinically presymptomatic for ALS (i.e., must not have clinically manifest ALS). |
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E.4 | Principal exclusion criteria |
Key Part A Exclusion Criteria: - History or positive test result at screening for human immunodeficiency virus (HIV). The requirement for testing at Screening may be omitted if it is not permitted by local regulations. - Current hepatitis C infection (defined as positive Hepatitis C Virus (HCV) antibody and detectable HCV RNA). Participants with positive HCV antibody and undetectable HCV Ribonucleic Acid (RNA) are eligible to participate in the study (United States Centers for Disease Control and Prevention). - Current hepatitis B infection (defined as positive for hepatitis B surface antigen (HBsAg) and/or anti-Hepatitis B Core antibody (HBc)). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive antihepatitis B surface antibody (HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti- HBs) are eligible to participate in the study. - History of systemic hypersensitivity reaction to tofersen, the excipients contained in the formulation, and if appropriate, any diagnostic agents to be administered during the study. - History of confounding neuromuscular or neurological disorder that is expected to have a progressive (i.e., worsening) course during the study, and/or is expected to be associated with elevations in NF, in the opinion of the Investigator. - Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that if not managed optimally could place a participant at an increased risk for intraoperative or postoperative bleeding. - Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression ≤ 90 days of Screening, which in the opinion of the Investigator would interfere with the study procedures. - Treatment with riluzole, edaravone and/or sodium phenylbutyrate/taurursodiol (also known as ursodoxicoltaurine). If the participant has been on riluzole, edaravone and/or sodium phenylbutyrate/taurursodiol, the medication(s) must be discontinued for at least 5 half-lives prior to screening. - Use of-label treatments for ALS. - Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering RNA, stem cell therapy, or gene therapy is allowed. - Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet or anticoagulant medication (e.g., clopidogrel) that cannot be safely continued or held for an LP procedure, if necessary, according to local or institutional guidelines and/or Investigator determination. - Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment, biological agent, device, or approved therapy for investigational use. Participation in a noninterventional study focused on ALS natural history may be allowed at the discretion of the Investigator.
NOTE: Other protocol defined Inclusion/Exclusion criteria will apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Parts B and C: Percentage of Participants with Emergence of Clinically Manifested ALS Within 24 Months of Part B Baseline
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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) |
1. Parts B and C: Time to Emergence of Clinically Manifest ALS. 2. Parts B and C: Change in ALS Functional Rating Scale (ALSFRS-R) Total Score. The ALSFRS-R measures 4 functional domains: respiratory, bulbar function, gross motor skills, and fine motor skills. There are 12 questions, each scored from 0 to 4, for a total possible score of 48, with higher scores representing better function. 3. Parts B and C: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC) 4. Parts B and C: Percentage of Participants with Outcome as Death or Permanent Ventilation Based on time to Death or Permanent Ventilation Analysis. Permanent ventilation is defined as ≥ 22 hours of invasive or non-invasive mechanical ventilation per day for ≥ 21 consecutive days. 5. Parts B and C: Percentage of Participants with Outcome as Deaths Based on Time to Death Analysis 6. Parts B, C and D: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Treatment Period 7. Parts B, C and D: Change from Baseline in Plasma NfL Concentrations 8. Parts B, C and D: Change in Total Cerebrospinal Fluid (CFL) SOD1 Concentrations |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part B, C: Up to 5.6 years Part D: Up to 2 years
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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 | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
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) | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Part A: Natural History Run-in: blood draws approx. every 28 days to access NfL levels |
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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 | 4 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
Brazil |
Canada |
Japan |
Korea, Republic of |
United Kingdom |
United States |
France |
Germany |
Italy |
Poland |
Spain |
Sweden |
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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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The end of study is last protocol-specified contact with the last participant. |
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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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |