HEALEY ALS Platform Trial - Master Protocol

Study Overview
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Brief Summary
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The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS.

Detailed Description
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The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS. This trial is designed as a perpetual platform trial. This means that there is a single Master Protocol dictating the conduct of the trial. In this trial, multiple investigational products for ALS will be tested simultaneously or sequentially. Each investigational product will be tested in a regimen. Each regimen consists of a placebo-controlled trial, meaning that the active investigational product and matching placebo will be tested in each regimen. The additional details that govern the testing of each investigational product will be summarized in separate regimen-specific appendices (RSAs). Each regimen will have a separate ClinicalTrials.gov posting, which will include specific information about the regimen. All regimen-specific outcome measures will be detailed in each regimen posting. Participants will have an equal chance to be randomized to all regimens that are active at the time of screening. Once randomized to a regimen, participants will be randomized in a 3:1 ratio to either study drug or placebo. The following regimens are active in the trial: Regimen A - Zilucoplan Regimen B - Verdiperstat Regimen C - CNM-Au8 Regimen D - Priodopidine Regimen E - SLS-005 Trehalose Regimen F - ABBV-CLS-7262 Regimen G - DNL343 New regimens will be continuously added as new investigational products become available. The HEALEY ALS Platform Trial will enroll additional participants as each new regimen is available.

Official Title
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HEALEY ALS Platform Trial

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Zilucoplan
* Drug: Verdiperstat
* Drug: CNM-Au8
* Drug: Pridopidine
* Drug: SLS-005 Trehalose
* Drug: ABBV-CLS-7262
* Drug: DNL343


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sporadic or familial ALS diagnosed as clinically possible, probable, lab-supported probable, or definite ALS defined by revised El Escorial criteria. Age 18 years or older. Capable of providing informed consent and complying with study procedures, in the SI's opinion. Time since onset of weakness due to ALS ≤ 36 months at the time of the Master Protocol Screening Visit. Vital Capacity ≥ 50% of predicted capacity for age, height, and sex at the time of the Master Protocol Screening Visit measured by Slow Vital Capacity (SVC), or, if required due to pandemic-related restrictions, Forced Vital Capacity (FVC). Participants must either not take riluzole or be on a stable dose of riluzole for ≥ 30 days prior to the Master Protocol Screening Visit. Riluzole-naïve participants are permitted in the study. Participants must either not take edaravone or have completed at least one cycle of edaravone prior to the Master Protocol Screening Visit. Edaravone-naïve participants are permitted in the study. Participants must have the ability to swallow pills and liquids at the time of the Master Protocol Screening Visit and, in the SI's opinion, have the ability to swallow for the duration of the study. Geographically accessible to the site. Participants must either not take Relyvrio/Albrioza or have started Relyvrio/Albrioza ≥ 30 days prior to the Master Protocol Screening Visit Exclusion Criteria: Clinically significant unstable medical condition (other than ALS) that would pose a risk to the participant, according to SI's judgment (e.g., cardiovascular instability, systemic infection, untreated thyroid dysfunction, or clinically significant laboratory abnormality or EKG changes). Lab abnormalities include, but are not limited to: Hemoglobin < 10 g/dL, White Blood Cells < 3.0 x 103/mm3, Neutrophils, Absolute ≤ 1000/mm3, Eosinophilia (absolute eosinophil count of ≥ 500 eosinophils per microliter), low platelet counts (< 150 x 109 per liter), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN), eGFR < 30 mL/min/1.73m2, thyroid-stimulating hormone (TSH) levels >10 mIU/L or <0.01 mIU/L. Presence of unstable psychiatric disease, cognitive impairment, dementia or substance abuse that would impair ability of the participant to provide informed consent, in the SI's opinion. Active cancer or history of cancer, except for the following: basal cell carcinoma or successfully treated squamous cell carcinoma of the skin, cervical carcinoma in situ, prostatic carcinoma in situ, or other malignancies curatively treated and with no evidence of disease recurrence for at least 3 years. Use of investigational treatments for ALS (off-label use or active participation in a clinical trial) within 5 half-lives (if known) or 30 days (whichever is longer) prior to the Master Protocol Screening Visit. Exposure at any time to any gene therapies under investigation for the treatment of ALS (off-label use or investigational). If female, breastfeeding, known to be pregnant, planning to become pregnant during the study, or of child-bearing potential and unwilling to use effective contraception for the duration of the trial and for 3 months, or longer as specified in each RSA, after discontinuing study treatment. If male of reproductive capacity, unwilling to use effective contraception for the duration of the trial and for 3 months, or longer as specified in each RSA, after discontinuing study treatment. Anything that would place the participant at increased risk or preclude the participant's full compliance with or completion of the study, in the SI's opinion. If a participant is being re-screened, the disqualifying condition has not been resolved, or the mandatory wash-out duration has not occurred.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: As new investigational products become available, additional regimens will be added to the HEALEY ALS Platform Trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A - Zilucoplan<br>Participants are randomized to receive either active zilucoplan or matching placebo. | Drug: Zilucoplan<br>* Drug: Zilucoplan Administration: Subcutaneous injection Dose: Minimum of .0.22 mg/kg daily to a maximum dose of 0.42 mg/kg daily, dependent on weight<br>|
| Experimental: Regimen B - Verdiperstat<br>Participants are randomized to receive either active verdiperstat or matching placebo. | Drug: Verdiperstat<br>* Drug: Verdiperstat Administration: Oral Dose: 600mg twice daily<br>|
| Experimental: Regimen C - CNM-Au8<br>Participants are randomized to receive either active CNM-Au8 or matching placebo. | Drug: CNM-Au8<br>* Drug: CNM-Au8 Administration: Oral Dose: 30 mg or 60 mg daily<br>|
| Experimental: Regimen D - Pridopidine<br>Participants are randomized to receive either active Pridopidine or matching placebo. | Drug: Pridopidine<br>* Drug: Pridopidine Administration: Oral Dose: 45mg twice daily<br>|
| Experimental: Regimen E - SLS-005 Trehalose<br>Participants are randomized to receive either active SLS-005 Trehalose or matching placebo. | Drug: SLS-005 Trehalose<br>* Drug: SLS-005 Trehalose Administration: Infusion Dose: 0.75 g/kg weekly<br>|
| Experimental: Regimen F- ABBV-CLS-7262<br>Participants are randomized to receive either active ABBV-CLS-7262 or matching placebo. | Drug: ABBV-CLS-7262<br>* Drug: ABBV-CLS-7162 Administration: Oral Dose: Dose 1 or Dose 2<br>|
| Experimental: Regimen G - DNL343<br>Participants are randomized to receive either active DNL343 or matching placebo. | Drug: DNL343<br>* Drug: DNL343 Administration: Oral Dose: Once per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Progression | Change in disease severity over time as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Each type of function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0. Patients with higher scores have more physical function. | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory Function | Change in respiratory function over time as measured by Slow Vital Capacity (SVC). | 24 Weeks | 
| Muscle Strength | Change in muscle strength over time as measured isometrically using hand-held dynamometry (HHD). | 24 Weeks | 
| Survival | Comparison of rate of occurrence between groups. | 24 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALS, Placebo-Controlled, Double-Blind, Master Protocol, Lou Gehrig's Disease