Amyotrophic Lateral SclerosisPhase 2/3NCT05842941

HEALEY ALS Platform Trial - Regimen G DNL343

A Phase 2/3 study testing DNL343 in people with Amyotrophic Lateral Sclerosis, run by Merit E. Cudkowicz, MD at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 100 years
Conditions the study is for: Amyotrophic Lateral Sclerosis
What is being tested?: DNL343
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 249 participants
Where: 1 siteUnited States
Study dates: 24 May 2023to 29 Oct 2024
Phase: Phase 2/3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 100 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

The following exclusion criteria are in addition to the exclusion criteria specified in the Master Protocol (NCT NCT04297683).
Diagnosis of epilepsy or seizure within 6 months of randomization
Hypersensitivity to DNL343 or any of the excipients contained within the DNL343 drug product
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.

Trial locations and contacts

1 site in 1 country.

United States1 site

Healey Center for ALS at Massachusetts General Hospital
Boston, Massachusetts, 02114

Other trials in United States

About this study

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.

Read the 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.

Conditions: Amyotrophic Lateral Sclerosis
Being tested: DNL343, Matching Placebo
Keywords: ALS, Placebo-Controlled, Double-Blind, Regimen Specific Appendix, Lou Gehrig's Disease, DNL343, Denali Therapeutics
Medical subject headings: Amyotrophic Lateral Sclerosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

DNL343Drug
DNL343 is administered orally once daily per day for 24 weeks.
Matching PlaceboDrug
Matching placebo is administered orally once daily per day for 24 weeks.

Study groups in NCT05842941
Study group	Role	What they receive
DNL343	Experimental	Not described Receives: Drug: DNL343
Matching Placebo	Placebo comparator	Not described Receives: Drug: Matching Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: Baseline to 24 weeks

Secondary outcomes (7)

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.
Measured: 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.
Measured: Baseline to 24 Weeks
Respiratory Function
Change in respiratory function over time as assessed by slow vital capacity (SVC)
Measured: 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.
Measured: 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.
Measured: 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).
Measured: Baseline to 24 weeks
Disease Progression Biomarker
Change in log-transformed serum neurofilament light protein (NfL) concentration from baseline to Week 24
Measured: Baseline to 24 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

24 May 202329 Oct 2024

First posted6 May 2023
Study start24 May 2023
Primary completion29 Oct 2024
Study completion29 Oct 2024

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Amyotrophic Lateral SclerosisStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2/3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 249 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT05842941
Sponsor's protocol ID: 2019P003518G
Status last verified: Dec 2025
First submitted: 24 Apr 2023
Last updated: 28 Jan 2026
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

Publications

Paganoni S, Chibnik LB, Quintana M, Macklin EA, Detry MA, Vestrucci M, Paulon G, McGlothlin A, Wang J, Walk D, Elman L, Chase M, Heyd L, Harkey B, Sherman AV, Shefner J, Berry JD, Scirocco E, Giacomelli E, Yu H, Kittle G, Hall M, Ho D, Jawdat O, Ladha S, Locatelli E, Rivner M, Felice K, Katz J, Ajroud-Driss S, Fee D, Miller T, Rosow L, Quick A, Heitzman D, Foster LA, Maragakis NJ, Goutman SA, Rosenfeld J, Benatar M, Swenson A, Connors RD, Shroff S, Bedlack R, McIlduff CE, Chen IA, Fernandes JAM, Walsh A, Peltier A, Ilieva H, Diaz F, Kushlaf H, Beydoun SR, Myers B, Arcila-Londono X, Heiman-Patterson T, Elliott M, Whitesell J, Al-Lahham T, Elliott M, Olney N, Baer M, Jackson C, Young E, Caress J, Weiss MD, Kuenzler R, Nayar S, Kasarskis EJ, Simmons Z, Gibson S, Owegi MA, Goyal NA, Wymer JP, Gwathmey KG, Erickson A, Gursoy N, Alameda G, Bodkin C, Wu A, Martinez-Thompson J, Twydell PT, Andrews J, Bayat E, Rezania K, Usman U, McCluskey L, Kovvuru S, Jennings D, Garza-Meilandt A, Maciuca R, Cohen IV, Tamuly D, Eren E, Cudkowicz ME, Babu S; HEALEY ALS Platform Trial Study Group. DNL343 and Disease Progression in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA Netw Open. 2026 Sep 1;9(9):e2634809. doi: 10.1001/jamanetworkopen.2026.34809.
PubMed 42771346

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Amyotrophic Lateral Sclerosis trials

Study at a glance

From the registry record, last updated by the sponsor on 28 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: HEALEY ALS Platform Trial - Regimen G DNL343
ClinicalTrials.gov ID: NCT05842941
Acronym / sponsor ID: 2019P003518G
Conditions: Amyotrophic Lateral Sclerosis
Keywords: ALS, Placebo-Controlled, Double-Blind, Regimen Specific Appendix, Lou Gehrig's Disease, DNL343, Denali Therapeutics
Phase: Phase 2/3
Study type: Interventional
Recruitment status: Completed
Enrolment: 249 participants (actual)
Lead sponsor: Merit E. Cudkowicz, MDUniversity, hospital or other
Collaborators: Denali Therapeutics Inc.
Study start: 24 May 2023 (actual)
Primary completion: 29 Oct 2024 (actual)
Study completion: 29 Oct 2024 (actual)
First posted: 6 May 2023 (actual)
Results: Posted 28 Jan 2026

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Detailed description

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

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
DNL343	Experimental	Drug: DNL343
Matching Placebo	Placebo comparator	Drug: Matching Placebo

Who may qualify

Ages: 18 to 100 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (1 listed)

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

Key exclusion criteria (4 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
DNL343DNL343 is administered orally once daily per day for 24 weeks.	Drug	DNL343
Matching PlaceboMatching placebo is administered orally once daily per day for 24 weeks.	Drug	Matching Placebo

Primary outcome

Disease Progression as Assessed by the ALSFRS-R-Slope
Time frame: Baseline to 24 Weeks
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.
Mortality Event Rate
Time frame: Baseline to 24 weeks
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.

7 secondary outcomes

ALSFRS-R Total Score
Time frame: Baseline to 24 Weeks
Combined Assessment of Function and Survival (CAFS)
Time frame: Baseline to 24 Weeks
Respiratory Function
Time frame: Baseline to 24 Weeks
Upper Limb Muscle Strength
Time frame: 24 weeks
Number of Participants With Death or Permanent Assisted Ventilation (PAV)
Time frame: Baseline to 24 weeks
Number of Participants Who Experience Death
Time frame: Baseline to 24 weeks
Disease Progression Biomarker
Time frame: Baseline to 24 weeks

Results and safety

Results posted to the registry on 28 Jan 2026, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
DNL343	186	156
Matching Placebo	63	55

Primary outcome: Disease Progression as Assessed by the ALSFRS-R-Slope

Time frame: Baseline to 24 Weeks. Mean (Standard Deviation). Unit: Percent change

Measure	DNL343 n = 186	Matching Placebo n = 139
Value	-0.88 (0.062)	-0.84 (0.081)

DNL343 vs Matching Placebo: Disease Rate Ratio: 1.06 (95% CI 0.840 to 1.351), Bayesian shared-parameter model

Population analysed: Outcome measure data was analyzed using the Efficacy Concurrent-controls Set (ECC), which included concurrent shared placebos from other regimens if randomized within 180 days of the first and last randomization for the applicable regimen, excluding any shared placebos also include in the focal regimen, as pre-specified in the Regimen Statistical Analysis Plan. Regimen F (NCT#05740813) and Regimen G (NCT#05842941) contributed placebo participants into the shared placebo cohort used for analysis.

Primary outcome: Mortality Event Rate

Time frame: Baseline to 24 weeks. Mean (Standard Deviation). Unit: Events per month

Measure	DNL343 n = 186	Matching Placebo n = 139
Value	0.007 (0.0021)	0.007 (0.0020)

7 secondary outcomes are reported in the full results.

Adverse events

Time frame: Up to 35 weeks after participant signed Master Protocol consent. For safety analyses, the analysis populations include all anticipated and unanticipated safety events (i.e. Deaths, Serious Adverse Events, and Other Adverse Events) due to any cause, that occurred or worsened on or after treatment initiation to either the final safety visit, the date of death, the date of last study contact, or the date of first dose of study drug during participation in the ATE period.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
DNL343	28 of 186 (15.1%)	149 of 186 (80.1%)	6 of 186
Matching Placebo	10 of 63 (15.9%)	43 of 63 (68.3%)	3 of 63

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 28 Jan 2026.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 42771346Paganoni S, Chibnik LB, Quintana M, Macklin EA, Detry MA, Vestrucci M, Paulon G, McGlothlin A, Wang J, Walk D, Elman L, Chase M, Heyd L, Harkey B, Sherman AV, Shefner J, Berry JD, Scirocco E, Giacomelli E, Yu H, Kittle G, Hall M, Ho D, Jawdat O, Ladha S, Locatelli E, Rivner M, Felice K, Katz J, Ajroud-Driss S, Fee D, Miller T, Rosow L, Quick A, Heitzman D, Foster LA, Maragakis NJ, Goutman SA, Rosenfeld J, Benatar M, Swenson A, Connors RD, Shroff S, Bedlack R, McIlduff CE, Chen IA, Fernandes JAM, Walsh A, Peltier A, Ilieva H, Diaz F, Kushlaf H, Beydoun SR, Myers B, Arcila-Londono X, Heiman-Patterson T, Elliott M, Whitesell J, Al-Lahham T, Elliott M, Olney N, Baer M, Jackson C, Young E, Caress J, Weiss MD, Kuenzler R, Nayar S, Kasarskis EJ, Simmons Z, Gibson S, Owegi MA, Goyal NA, Wymer JP, Gwathmey KG, Erickson A, Gursoy N, Alameda G, Bodkin C, Wu A, Martinez-Thompson J, Twydell PT, Andrews J, Bayat E, Rezania K, Usman U, McCluskey L, Kovvuru S, Jennings D, Garza-Meilandt A, Maciuca R, Cohen IV, Tamuly D, Eren E, Cudkowicz ME, Babu S; HEALEY ALS Platform Trial Study Group. DNL343 and Disease Progression in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA Netw Open. 2026 Sep 1;9(9):e2634809. doi: 10.1001/jamanetworkopen.2026.34809.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Merit Cudkowicz, MD principal investigator

Massachusetts General Hospital

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing DNL343 in people with Amyotrophic Lateral Sclerosis, run by Merit E. Cudkowicz, MD at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Jan 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Disease Progression as Assessed by the ALSFRS-R-Slope (time frame: Baseline to 24 Weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05842941, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jan 2026.