HEALEY ALS Platform Trial - Regimen G DNL343

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.

Regimen G will evaluate the safety and efficacy of a single study drug, DNL343, in participants with ALS.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: DNL343; Drug: Matching Placebo

Detailed Description

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. The HEALEY ALS Platform Trial Master Protocol is registered as NCT04297683. Once a participant enrolls into the Master Protocol and meets all eligibility criteria, the participant will be eligible to be randomized into any currently enrolling regimen. All participants will have an equal chance of being randomized to any currently enrolling regimen.

If a participant is randomized to Regimen G DNL343, the participant will complete a screening visit to assess additional Regimen G eligibility criteria. Once Regimen G eligibility criteria are confirmed, participants will complete a baseline assessment and be randomized in a 3:1 ratio to either active DNL343 or matching placebo.

Regimen G will enroll by invitation, as participants may not choose to enroll in Regimen G. Participants must first enroll into the Master Protocol and be eligible to participate in the Master Protocol before being able to be randomly assigned to Regimen G.

For a list of enrolling sites, please see the HEALEY ALS Platform Trial Master Protocol under NCT04297683.

• Study Type: Interventional
• Enrollment (Actual): 249
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Healey Center for ALS at Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• No additional inclusion criteria beyond the inclusion criteria specified in the Master Protocol (NCT NCT04297683).

Exclusion Criteria:

• The following exclusion criteria are in addition to the exclusion criteria specified in the Master Protocol (NCT NCT04297683).

  1. Diagnosis of epilepsy or seizure within 6 months of randomization
  2. Hypersensitivity to DNL343 or any of the excipients contained within the DNL343 drug product
  3. The concomitant use of prescription or over-the-counter (OTC) medications that are inducers of certain cytochrome P450 enzymes, substrates of certain cytochrome P450 enzymes, or substrates of certain drug transporters.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Matching Placebo	Drug: Matching Placebo; Matching placebo is administered orally once daily per day for 24 weeks.
Experimental: DNL343	Drug: DNL343; DNL343 is administered orally once daily per day for 24 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Progression as Assessed by the ALSFRS-R-Slope	Change in disease severity as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) total score using a Bayesian repeated measures model that accounts for loss to follow-up due to mortality. Each of 12 questions assessing distinct functional ability is scored from 4(normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0. Participants with higher scores have more physical function. Note that only participants who survived to their Week 24 visit contribute to the estimate.	Baseline to 24 Weeks
Mortality Event Rate	The Mortality Rate, presented as mean deaths per month, was estimated from a Bayesian shared-parametric model that assumed exponentially distributed survival times. Mortality is defined as death or death equivalent. A participant is determined to meet the criteria of death equivalent if permanent assisted ventilation (PAV) is used for more than 22 hours per day for more than seven days in a row.	Baseline to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ALSFRS-R Total Score	Change in ALSFRS-R total score over time. 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. Participants with higher scores have more physical function.	Baseline to 24 Weeks
Combined Assessment of Function and Survival (CAFS)	Combined assessment of function and survival (CAFS) ranks participants' clinical outcomes based on survival time and change in the functional score. Each participant's outcome is compared to every other participant's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS rank score indicates a better group outcome. The survival outcome is death or death-equivalent, where a participant is determined to meet the criteria of death equivalent if permanent assisted ventilation (PAV) is used for more than 22 hours per day for more than seven days in a row. The functional outcome is the ALS Functional Rating Scale-Revised (ALSFRS-R) score with a maximum total score of 48 and a minimum total score of 0. Participants with higher scores have more physical function.	Baseline to 24 Weeks
Respiratory Function	Change in respiratory function over time as assessed by slow vital capacity (SVC)	Baseline to 24 Weeks
Upper Limb Muscle Strength	Change in upper limb muscle strength over time as measured isometrically using hand-held dynamometry and grip strength, calculated as the average percent change from baseline of the following muscles/maneuvers: shoulder flexion, elbow flexion, elbow extension, wrist extension, abductor pollicis brevis contraction, abductor digiti minimi contraction, first dorsal interosseous contraction, and grip strength. Note that only those with measurable strength at baseline were included.	24 weeks
Number of Participants With Death or Permanent Assisted Ventilation (PAV)	The number of participants who died or met the criterion for a death equivalent from the date of their baseline visit to the end of the Week 24 visit window (generally 175 days after baseline). The death equivalent criterion is use of permanent assisted ventilation (PAV) for more than 22 hours per day for more than 7 days in a row.	Baseline to 24 weeks
Number of Participants Who Experience Death	The number of participants who died from the date of their baseline visit to the end of the Week 24 visit window (generally 175 days after baseline).	Baseline to 24 weeks
Disease Progression Biomarker	Change in log-transformed serum neurofilament light protein (NfL) concentration from baseline to Week 24	Baseline to 24 weeks

Collaborators and Investigators

• Sponsor: Merit E. Cudkowicz, MD
• Collaborators: Denali Therapeutics Inc.
• Investigators: Principal Investigator: Merit Cudkowicz, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2023
• Primary Completion (Actual): October 29, 2024
• Study Completion (Actual): October 29, 2024

Study Registration Dates

• First Submitted: April 24, 2023
• First Submitted That Met QC Criteria: April 24, 2023
• First Posted (Actual): May 6, 2023

Study Record Updates

• Last Update Posted (Actual): January 28, 2026
• Last Update Submitted That Met QC Criteria: January 9, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: ALS; Double-Blind; Placebo-Controlled; Lou Gehrig's Disease; Regimen Specific Appendix; DNL343; Denali Therapeutics
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Nutritional and Metabolic Diseases; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: 2019P003518G

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No