E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis (ALS), motor neuron disease |
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E.1.1.1 | Medical condition in easily understood language |
ALS, motor neuron disease |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
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.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of ravulizumab compared with placebo on amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) score in adult patients with amyotrophic lateral sclerosis (ALS) |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of ravulizumab compared with placebo on ventilation assistance-free survival (VAFS) in adult patients with ALS
To evaluate the effect of ravulizumab compared with placebo on respiratory function in adult patients with ALS
To evaluate the safety of ravulizumab compared with placebo in adult patients with ALS
To evaluate the effect of ravulizumab compared with placebo on muscle strength in adult patients with ALS
To evaluate the effect of ravulizumab compared with placebo on neurofilament light chain (NfL) concentrations in adult patients with ALS
To characterize the pharmacokinetics (PK) of ravulizumab in adult patients with ALS
To characterize the pharmacodynamics (PD) of ravulizumab in adult patients with ALS
To characterize the immunogenicity of ravulizumab in adult patients with ALS |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 18 years of age or older, at the time of signing the informed consent. 2. A diagnosis of ALS, defined as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the revised World Federation of Neurology El Escorial criteria. Patients diagnosed with either sporadic or familial ALS are eligible for enrollment. 3. ALS onset, defined as time of onset of first muscle weakness (eg, limb weakness, dysarthria, dysphagia, shortness of breath), ≤ 36 months from the Screening Visit. 4. Prestudy ALSFRS-R progression between disease onset and screening of -0.3 points per month or worse (calculated by ALSFRS-R total score decline from 48 divided by the months since onset of ALS symptoms). 5. Upright SVC ≥ 65% predicted at Screening. 6. Vaccinated against N. meningitidis within 3 years prior to, or at the time of, initiating ravulizumab. Patients who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine must receive appropriate prophylactic antibiotics until 2 weeks after the vaccination. 7. Patients who enter the trial receiving standard of care for ALS (ie, riluzole and/or edaravone), either in combination or monotherapy, must be on a stable dosing regimen of adequate duration prior to screening with no plan to discontinue or to change the dose during the study period as follows: -If a patient who enters the study is receiving riluzole, the patient must have been on a stable dose of riluzole for ≥ 30 days prior to Day 1. -If a patient who enters the study is receiving edaravone, the patient must have initiated edaravone ≥ 60 days (2 treatment cycles) prior to Day 1. Note: Patients who are naïve to ALS therapies or have not taken approved ALS therapies for at least 30 days before screening are allowed to enroll. 8. Body weight ≥ 40 kg at Screening. 9. Male and/or female -Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 10. Capable of giving written or verbal informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
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E.4 | Principal exclusion criteria |
1. History of N. meningitidis infection. 2. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titer). 3. History of unexplained infections. 4. Active systemic bacterial, viral, or fungal infection within 14 days prior to study drug administration on Day 1. 5. Presence of fever ≥ 38°C (100.4°F) within 7 days prior to study drug administration on Day 1. 6. Hypersensitivity to murine proteins or to 1 of the excipients of ravulizumab. 7. Dependence on invasive or non-invasive mechanical ventilation. Dependence on mechanical ventilation is defined as being unable to lie flat (supine) without it, unable to sleep without it, or daytime use > 6 hours per day for > 3 days per week. Non-invasive ventilation for sleep apnea is allowed subject to discussion with Medical Monitor. 8. Any medical condition that, in the opinion of the Investigator, might interfere with the patient’s participation in the trial, poses any added risk for the patient, or confounds the assessment of the patient. 9. The presence of unstable psychiatric disease or dementia that might interfere with the patient’s participation in the trial, poses any added risk for the patient, or confounds the assessment of the patient. 10. History of drug and/or alcohol abuse (according to Diagnostic and Statistical Manual of Mental Disorders) within 1 year of screening that would limit patient participation in the study as determined by the Investigator. 11. History of Parkinson’s disease, myasthenia gravis, multiple sclerosis, or any other neurological disorder that may confound the diagnosis or assessment of the patient as determined by the Investigator. 12. Previously or currently treated with a complement inhibitor. 13. Use of IV immunoglobulin (IVIg) within 3 weeks prior to screening. 14. Has a diaphragm pacing system (DPS) at study entry or anticipate DPS placement during the course of the study. 15. Participation in any other investigational product study or exposure to an investigational drug or device within 30 days of screening or 5 half-lives of the study drug, whichever is greater or any prior exposure to gene therapy. 16. Receipt of stem cell transplant therapy as an investigational treatment for ALS < 90 days from the date of last transplant. 17. Pregnant, breastfeeding, or intending to conceive during the course of the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in ALSFRS-R total score |
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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) |
Time to the earliest occurrence of 1 of the following events during the 50-week Randomized Controlled Period: • All-cause mortality • First use of non-invasive ventilation (NIV) for ≥ 22 hours per day for ≥ 10 consecutive days • First use of permanent assisted ventilation (PAV) for ≥ 22 hours per day for ≥ 7 consecutive days • Change from baseline in percent (%) predicted slow vital capacity (SVC) at Week 50 • Incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and TEAEs leading to study drug discontinuation • Percent change in combined muscle megascore from baseline at Week 50 as assessed by handheld dynamometry (HHD) • Change from baseline in NfL concentrations in serum at Week 50 • Change in serum ravulizumab concentration over the study duration • Change in serum free complement component 5 (C5) concentration over the study duration • Presence and titer of antidrug antibodies (ADAs) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 50; throughout the study |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarker characterization, immunogenicity |
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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 |
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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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
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 |
Belgium |
Canada |
Denmark |
France |
Germany |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Poland |
Spain |
Sweden |
Switzerland |
United Kingdom |
United States |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |