Primary objective: 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).Secondary objectives:1. To…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from baseline in ALSFRS-R total score at Week 50.
Secondary outcome
1. 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
2. Change from baseline in percent (%) predicted slow vital capacity (SVC) at
Week 50.
3. Incidence of treatment-emergent adverse events (TEAEs), treatment-emergent
serious adverse events (TESAEs), and TEAEs leading to study drug
discontinuation.
4. Percent change in combined muscle megascore from baseline at Week 50 as
assessed by handheld dynamometry (HHD).
5. Change from baseline in NfL concentrations in serum at Week 50.
6. Change in serum ravulizumab concentration over the study duration.
7. Change in serum free complement component 5 (C5) concentration over the
study duration.
8. Presence and titer of antidrug antibodies (ADAs).
Background summary
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease
characterized by progressive degeneration of upper and lower motor neurons
leading to severe disability and eventually death. Currently, riluzole and
edaravone are the only available medications approved for the treatment of ALS
that may slow disease progression.
The pathogenesis of ALS is largely unknown, but immune dysregulation and
neuroinflammation have been implicated as potential mediators of disease. The
therapeutic rationale for complement component 5 (C5) inhibition in ALS is
supported by evidence of dysregulation of the complement system in tissue from
patients with ALS. Furthermore, functional and survival benefits of C5
signaling blockade have been demonstrated in animal models of ALS. Ravulizumab
(Ultomiris®) is a recombinant, humanized monoclonal antibody with high
specificity for human C5. Ravulizumab has been shown to achieve immediate,
complete, and sustained inhibition of terminal complement in adult patients
with paroxysmal nocturnal hemoglobinuria (approved in the US, European Union,
and Japan) and in pediatric and adult patients with atypical hemolytic uremic
syndrome (approved in the US). It is expected that the same dosing regimen will
also achieve comparable inhibition of complement-mediated damage in patients
with ALS, which may slow ALS disease progression.
Study objective
Primary objective: 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).
Secondary objectives:
1. To evaluate the effect of ravulizumab compared with placebo on ventilation
assistance-free survival (VAFS) in adult patients with ALS.
2. To evaluate the effect of ravulizumab compared with placebo on respiratory
function in adult patients with ALS.
3. To evaluate the safety of ravulizumab compared with placebo in adult
patients with ALS.
4. To evaluate the effect of ravulizumab compared with placebo on muscle
strength in adult patients with ALS.
5. To evaluate the effect of ravulizumab compared with placebo on neurofilament
light chain (NfL) concentrations in adult patients with ALS.
6. To characterize the pharmacokinetics (PK) of ravulizumab in adult patients
with ALS.
7. To characterize the pharmacodynamics (PD) of ravulizumab in adult patients
with ALS.
8. To characterize the immunogenicity of ravulizumab in adult patients with
ALS.
Study design
Study ALXN1210-ALS-308 is a Phase 3, double-blind, randomized,
placebo-controlled, parallel group, multicenter study to evaluate the efficacy
and safety of ravulizumab in adult patients with ALS. There are 3 periods in
this study: Screening Period, Randomized Controlled Period, and Open-Label
Extension Period.
Intervention
Eligible patients will be randomized in a 2:1 ratio to receive weight-based
intravenous (IV) infusion of ravulizumab or matching placebo until Week 50
during the double-blind Randomized Controlled Period. Randomization will be
stratified based on the site of ALS muscle weakness onset (bulbar vs other) and
background ALS treatment (riluzole and/or edaravone vs neither ALS therapy).
For each patient, the Randomized Controlled Period ends and the Open-Label
Extension Period starts when the patient has completed the Week 50 visit
assessments. Regardless of prior treatment allocation, all patients will
receive ravulizumab treatment during the Open-Label Extension Period. The
Open-Label Extension Period will continue for up to 2 years, or until
ravulizumab is approved and/or available (in accordance with country-specific
regulations), whichever occurs first.
Study burden and risks
Based on clinical trial experience and cumulative clinical trial safety data of
ravulizumab in PNH and aHUS, ravulizumab has been demonstrated to be well
tolerated and safe, and exposure to ravulizumab in humans has not raised any
unexpected safety concerns. Ravulizumab functions by blocking terminal
complement; therefore, patients have increased susceptibility to serious
infections, in particular Neisseria meningitidis. Specific risk
mitigation measures in place are described in Section 8.1.2 of the protocol. As
with any therapeutic protein, administration of ravulizumab may lead to the
development of antidrug antibodies (ADAs). Monitoring of immunogenicity is
planned, as described in Section 8.9 of the protocol. Administration of any
investigational product may result in infusion reactions. Management of
potential infusion reactions is described in Section 10.13 of the protocol.
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a
poor prognosis, rapid progression, and limited treatment options for which
discovery of new therapies is important to address unmet medical need. Clinical
research provides the best modality to identify effective treatments with the
potential to slow disease progression and improve survival which are of
critical importance to patients with ALS and their providers. Although the
efficacy of ravulizumab has not been previously studied in patients with ALS,
it represents an appropriate candidate for investigation due to its plausible
mechanism of action in ALS and reliable pharmacokinetic (PK) and
pharmacodynamic (PD) properties as well as the demonstrable functional benefit
of complement inhibition in ALS animal models and in the treatment of other
neuroinflammatory conditions. The scientific and therapeutic hypothesis for the
potential benefit in ALS is discussed in Section 2.2.2 of the protocol.
Given the severity of ALS, collective consideration of the unmet medical need
and plausible mechanism of action with the expected safety profile and
mitigation measures in place provides support for initiation of a Phase 3
clinical trial with ravulizumab.
More detailed information about the known and expected benefits and risks is
provided in the Investigator*s Brochure.
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Age
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.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004619-30-NL |
| ClinicalTrials.gov | NCT04248465 |
| CCMO | NL72466.056.20 |