History of Changes for Study: NCT04615923

HEALEY ALS Platform Trial - Regimen D Pridopidine

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Study Record Versions

Version	Submitted Date	Changes
1	October 29, 2020	None (earliest Version on record)
2	December 25, 2020	Recruitment Status, Study Status, Contacts/Locations and Oversight
3	January 22, 2022	Recruitment Status and Study Status
4	April 27, 2022	Study Status
5	August 15, 2022	Study Status and Study Design
6	September 18, 2022	Study Status
7	May 15, 2023	Study Status
8	June 30, 2023	Quality Control Review has not concluded Returned: July 24, 2023 Recruitment Status, Outcome Measures, Study Status, Document Section
9	August 12, 2023	Study Status, Adverse Events, Outcome Measures

Comparison Format:

Merged
Side-by-Side

Study Identification


Unique Protocol ID:	2019P003518D
Brief Title:	HEALEY ALS Platform Trial - Regimen D Pridopidine
Official Title:	HEALEY ALS Platform Trial - Regimen D Pridopidine
Secondary IDs:

Study Status


Record Verification:	August 2023
Overall Status:	Completed
Study Start:	December 18, 2020
Primary Completion:	July 14, 2022 [Actual]
Study Completion:	July 14, 2022 [Actual]

First Submitted:	October 29, 2020
First Submitted that Met QC Criteria:	October 29, 2020
First Posted:	November 4, 2020 [Actual]

Results First Submitted:	June 30, 2023
Results First Submitted that Met QC Criteria:	August 12, 2023
Results First Posted:	August 23, 2023 [Actual]

Last Update Submitted that Met QC Criteria:	August 12, 2023
Last Update Posted:	August 23, 2023 [Actual]

Sponsor/Collaborators


Sponsor:	Merit E. Cudkowicz, MD
Responsible Party:	Sponsor-Investigator Investigator: Merit E. Cudkowicz, MD Official Title: Chief, Neurology Department Affiliation: Massachusetts General Hospital
Collaborators:	Prilenia Therapeutics

Oversight


U.S. FDA-regulated Drug:	Yes
U.S. FDA-regulated Device:	No
Data Monitoring:	Yes

Study Description

Brief Summary:

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 D will evaluate the safety and efficacy of a single study drug, pridopidine, in participants with ALS.

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

Regimen D will enroll by invitation, as participants may not choose to enroll in Regimen D. 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 D.

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

Conditions


Conditions:	Amyotrophic Lateral Sclerosis
Keywords:	ALS Placebo-Controlled Double-Blind Regimen Specific Appendix Lou Gehrig's Disease Pridopidine Prilenia Therapeutics

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 2/Phase 3
Interventional Study Model:	Parallel Assignment
Number of Arms:	2
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation:	Randomized
Enrollment:	163 [Actual]

Arms and Interventions

Arms	Assigned Interventions
Experimental: Pridopidine Pridopidine is administered orally twice daily for 24 weeks.	Drug: Pridopidine Administration: Oral Dose: 45mg twice daily
Placebo Comparator: Matching Placebo Matching placebo is administered orally twice daily for 24 weeks.	Drug: Matching Placebo Administration: Oral Dose: one capsule twice daily

Outcome Measures

[See Results Section.]


Primary Outcome Measures:
1.	Disease Progression as Assessed by the ALSFRS-R Total Score [ Time Frame: Baseline to 24 Weeks ] 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.
2.	Mortality Event Rate [ Time Frame: Baseline to 24 Weeks ] 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. The rate of mortality was estimated from a Bayesian shared-parametric model that assumed exponentially distributed survival times.
Secondary Outcome Measures:
1.	Change in Bulbar Function in Participants With Bulbar Dysfunction at Baseline [ Time Frame: Baseline to 24 Weeks ] Change in bulbar function over time in participants with bulbar dysfunction at baseline as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function. Participants were classified as having bulbar dysfunction at baseline if their score on the ALSFRS-R bulbar domain (Q1-Q3) score was less than 12.
2.	Bulbar Function in All Randomized Participants [ Time Frame: Baseline to 24 Weeks ] Change in bulbar function over time in all randomized participants as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function.
3.	Respiratory Function [ Time Frame: Baseline to 24 Weeks ] Change in respiratory function over time as measured by Slow Vital Capacity (SVC).
4.	Bulbar Function in Participants With Rapid Pre-baseline Progression [ Time Frame: Baseline to 24 Weeks ] Change in bulbar function over time in participants with rapid pre-baseline progression as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function. Participants were classified with rapid pre-baseline progression if their change in ALSFRS-R total score between Master Protocol Screening and Regimen Baseline was greater than or equal or 0.75 points per month.
5.	Time to Bulbar Decline [ Time Frame: Baseline to 24 Weeks ] Time to first decline of 1-point or greater post baseline in the ALSFRS-R bulbar domain score among all participants. Analysis performed using interval-censored survival analysis. Results presented as median interval (upper & lower bounded) time to event.
6.	Muscle Strength [ Time Frame: Baseline to 24 Weeks ] Change in muscle strength over time as measured isometrically using hand-held dynamometry (HHD).
7.	Number of Participants That Experienced Death or Death Equivalent [ Time Frame: Baseline to 24 Weeks ] 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 24visit 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.

Eligibility


Minimum Age:	18 Years
Maximum Age:
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	No
Criteria:	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). Participants with a confirmed prolonged Fridericia-corrected QT (QTcF) interval (defined as a QTcF interval of >450 ms for men and >470 ms for women). Participants with clinically significant heart disease, clinically significant history of arrhythmia, symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia, or presence of left bundle branch block. Participants with known history of long QT syndrome or a first degree relative with this condition. Participants using prohibited medications within the 4 weeks prior to the Regimen Specific Screening Visit, as detailed in section 5.9. Participants using the following medications at the time of the Regimen Specific Screening Visit: Nuedexta - at a dosage higher than 20 mg dextromethorphan + 10 mg quinidine BID Citalopram - at a dosage higher than 20 mg/day Escitalopram - at a dosage higher than 10 mg/day Participants with a known allergy to any ingredient of the study intervention (pridopidine, silicified microcrystalline cellulose, and magnesium stearate).

Contacts/Locations


Study Officials:	Merit Cudkowicz, MD Principal Investigator Massachusetts General Hospital
Locations:	United States, Massachusetts
	Healey Center for ALS at Mass General Boston, Massachusetts, United States, 02114

IPDSharing


Plan to Share IPD:	No

References


Citations:
Links:
Available IPD/Information:

Document Section


	Study Protocol Document Date: July 15, 2021 Uploaded: 06/28/2023 11:56 File Name: Prot_000.pdf
	Statistical Analysis Plan Document Date: October 6, 2022 Uploaded: 06/28/2023 11:57 File Name: SAP_001.pdf

Participant Flow

Recruitment Details

Pre-assignment Details

Arm/Group Title	Pridopidine	Matching Placebo
Arm/Group Description	Pridopidine is administered orally twice daily for 24 weeks. Pridopidine: Administration: Oral Dose: 45mg twice daily	Matching placebo is administered orally twice daily for 24 weeks. Matching Placebo: Administration: Oral Dose: one capsule twice daily

Period Title: Overall Study
Started	120	42
Completed	96	38
Not Completed	24	4

Baseline Characteristics

Arm/Group Title

Pridopidine

Matching Placebo

Total

Arm/Group Description

Pridopidine is administered orally twice daily for 24 weeks.

Pridopidine: Administration: Oral

Dose: 45mg twice daily

Matching placebo is administered orally twice daily for 24 weeks.

Matching Placebo: Administration: Oral

Dose: one capsule twice daily

Total of all reporting groups

Overall Number of Baseline Participants

120

162

Baseline Analysis Population Description

Age, Continuous

Mean (Standard Deviation)
Unit of measure: years

Number Analyzed

120 Participants

42 Participants

162 Participants

57.9(10.10)

57.1(9.86)

57.7(10.01)

Sex: Female, Male

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

120 Participants

42 Participants

162 Participants

Female

40%

21.43%

35.19%

Male

60%

78.57%

105

64.81%

Ethnicity (NIH/OMB)

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

120 Participants

42 Participants

162 Participants

Hispanic or Latino

9.17%

2.38%

7.41%

Not Hispanic or Latino

107

89.17%

97.62%

148

91.36%

Unknown or Not Reported

1.67%

1.23%

Race (NIH/OMB)

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

120 Participants

42 Participants

162 Participants

American Indian or Alaska Native

Asian

4.17%

2.38%

3.7%

Native Hawaiian or Other Pacific Islander

Black or African American

5.83%

4.76%

5.56%

White

105

87.5%

92.86%

144

88.89%

More than one race

0.83%

0.62%

Unknown or Not Reported

1.67%

1.23%

El Escorial Diagnosis

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

120 Participants

42 Participants

162 Participants

Clinically Definite ALS

41.67%

42.86%

41.98%

Clinically Probable ALS

33.33%

28.57%

32.1%

Clinically Probable ALS - Laboratory Supported

18.33%

11.9%

16.67%

Clinically Possible ALS

6.67%

16.67%

9.26%

ALS Onset Location

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

120 Participants

42 Participants

162 Participants

Axial

0.83%

4.76%

1.85%

Bulbar

19.17%

23.81%

20.37%

Generalized

1.67%

1.23%

Limb

77.5%

71.43%

123

75.93%

Multiple

0.83%

0.62%

Baseline Edaravone Use Flag

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

120 Participants

42 Participants

162 Participants

76.67%

76.19%

124

76.54%

Yes

23.33%

23.81%

23.46%

Baseline Riluzole Use Flag

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

120 Participants

42 Participants

162 Participants

25%

21.43%

24.07%

Yes

75%

78.57%

123

75.93%

Kings Stage^[1]

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

120 Participants

42 Participants

162 Participants

1 Region with Neuromuscular Dysfunction

17.5%

16.67%

17.28%

2 Regions with Neuromuscular Dysfunction

30%

16.67%

26.54%

3 Regions with Neuromuscular Dysfunction

25.83%

42.86%

30.25%

4a/4b Nutritional/Respiratory Failure

26.67%

23.81%

25.93%

[1]

Measure Description: The King's ALS Clinical Staging System is a 4-level ordinal scale with the first three levels indicating the number (1, 2, or 3) of distinct central nervous system regions (bulbar, upper limb, and lower limb) with neuromuscular dysfunction. Level 4a indicates nutritional failure and level 4b indicates respiratory failure. Higher scores indicate a worse disease state.

ALSFRS-R Total Score^[1]

Mean (Standard Deviation)
Unit of measure: points

Number Analyzed

120 Participants

42 Participants

162 Participants

34.3(6.71)

35.0(7.07)

34.5(6.79)

[1]

Measure Description: The ALS Functional Rating Score-Revised (ALSFRS-R) measures 12 aspects of physical function. Each of the 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. Patients with higher scores have more physical function.

Baseline Decline in ALSFRS-R^[1]

Mean (Standard Deviation)
Unit of measure: points per month

Number Analyzed

120 Participants

42 Participants

162 Participants

0.77(0.5)

0.71(0.455)

0.75(0.488)

[1]

Measure Description:

The ALS Functional Rating Score-Revised (ALSFRS-R) measures 12 aspects of physical function. Each of the 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. Patients with higher scores have more physical function.

Baseline is divided by the number of months between onset of weakness due to ALS and the date of Baseline.

A higher number indicates greater decline.

Body Mass Index

Mean (Standard Deviation)
Unit of measure: kg/m^2

Number Analyzed

120 Participants

42 Participants

162 Participants

26.1(4.63)

25.9(4.07)

26.1(4.48)

Delay in ALS Symptom Onset and Diagnosis

Mean (Standard Deviation)
Unit of measure: months

Number Analyzed

120 Participants

42 Participants

162 Participants

10.5(6.34)

10.4(6.50)

10.5(6.36)

SVC^[1]

Mean (Standard Deviation)
Unit of measure: percent predicted

Number Analyzed

120 Participants

42 Participants

162 Participants

78.3(17.35)

77.5(16.72)

78.1(17.13)

[1]	Measure Analysis Population Description: Number analyzed in row differs from overall number due to missing data.

Serum Cereatinine Concentration

Mean (Standard Deviation)
Unit of measure: mg/dL

Number Analyzed

120 Participants

42 Participants

162 Participants

0.7(0.19)

0.8(0.18)

0.7(0.19)

Time Since Symptom Onsent at Baseline (Months since ALS symptom onset)

Mean (Standard Deviation)
Unit of measure: months

Number Analyzed

120 Participants

42 Participants

162 Participants

20.6(8.16)

21.6(10.0)

20.8(8.65)

Weight

Mean (Standard Deviation)
Unit of measure: kg

Number Analyzed

120 Participants

42 Participants

162 Participants

76.6(15.92)

79.3(15.63)

77.3(15.84)

Serum NfL Concentration^[1]

Mean (Standard Deviation)
Unit of measure: ng/L

Number Analyzed

120 Participants

42 Participants

162 Participants

92.7(61.24)

114.6(73.25)

98.2(64.93)

[1]	Measure Analysis Population Description: Number analyzed in row differs from overall number due to missing data.

Outcome Measures

1. Primary Outcome:

Title

Disease Progression as Assessed by the ALSFRS-R Total Score

Description

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.

Time Frame

Baseline to 24 Weeks

Outcome Measure Data

Analysis Population Description

Outcome measure data was analyzed using the Full Analysis Set, which included shared placebo from other regimens, as pre-specified in the Regimen Statistical Analysis Plan. Regimen A (NCT04436497), Regimen B (NCT04436510) and Regimen C (NCT04414345) contributed placebo participants into the shared placebo cohort used for analysis.


Arm/Group Title	Pridopidine	Matching Placebo
Arm/Group Description	Pridopidine is administered orally twice daily for 24 weeks. Pridopidine: Administration: Oral Dose: 45mg twice daily	Matching placebo is administered orally twice daily for 24 weeks. Matching Placebo: Administration: Oral Dose: one capsule twice daily
Overall Number of Participants Analyzed	120	162
Mean (Standard Deviation) Unit of Measure: points per month	-0.99(0.077)	-1.00(0.070)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Pridopidine, Matching Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value
	Comments	Posterior probability that the disease rate ratio (DRR) is less than 1 (i.e. Pridopidine slowed progression) was (0.5475). NOTE: p-value is not provided for Bayesian model.
	Method	Bayesian shared-parameter model
	Comments	A Bayesian shared-parameter model of change in disease severity as measured by ALSFRS-R total score and mortality.


Method of Estimation	Estimation Parameter	Disease Rate Ratio
	Estimated Value	0.99
	Confidence Interval	(2-sided) 95% 0.801 to 1.207
	Parameter Dispersion	Type: Standard Deviation Value: 0.103
	Estimation Comments	DDR <1 imply slowing of disease progression by verdiperstat relative to placebo.Note: reported "Confidence Interval" is actually a Bayesian credible interval.


Other Statistical Analysis		The DRR parameter for active treatment represents the relative change to the rate of decline of ALSFRS-R and the rate of mortality of treated participant relative to a placebo participant. The estimated DRR can also be interpreted as the average rate of decline in function and mortality. The model includes covariates for baseline use of edaravone, baseline use of riluzole, months since onset of symptoms, and pre-baseline slope of ALSFRS-R, and random effects for regimen and participant-specific slopes.

2. Primary Outcome:

Title

Mortality Event Rate

Description

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. The rate of mortality was estimated from a Bayesian shared-parametric model that assumed exponentially distributed survival times.

Time Frame

Baseline to 24 Weeks

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Pridopidine	Matching Placebo
Arm/Group Description	Pridopidine is administered orally twice daily for 24 weeks. Pridopidine: Administration: Oral Dose: 45mg twice daily	Matching placebo is administered orally twice daily for 24 weeks. Matching Placebo: Administration: Oral Dose: one capsule twice daily
Overall Number of Participants Analyzed	120	162
Mean (Standard Deviation) Unit of Measure: events per month	0.012(0.0029)	0.012(0.0029)

3. Secondary Outcome:

Title

Change in Bulbar Function in Participants With Bulbar Dysfunction at Baseline

Description

Change in bulbar function over time in participants with bulbar dysfunction at baseline as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function.

Participants were classified as having bulbar dysfunction at baseline if their score on the ALSFRS-R bulbar domain (Q1-Q3) score was less than 12.

Time Frame

Baseline to 24 Weeks

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Pridopidine	Matching Placebo
Arm/Group Description	Pridopidine is administered orally twice daily for 24 weeks. Pridopidine: Administration: Oral Dose: 45mg twice daily	Matching placebo is administered orally twice daily for 24 weeks. Matching Placebo: Administration: Oral Dose: one capsule twice daily
Overall Number of Participants Analyzed	75	103
Least Squares Mean (Standard Error) Unit of Measure: point change from baseline	-1.78(0.261)	-1.69(0.210)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Pridopidine, Matching Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.78
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Covariates include baseline use of edaravone and riluzole, months since symptom onset, and pre-baseline ALSFRS-R slope.


Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-0.09
	Confidence Interval	(2-sided) 95% -0.75 to 0.57
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.334
	Estimation Comments	Pridopidine 24-week change from baseline relative to placebo 24-week change from baseline.

4. Secondary Outcome:

Title

Bulbar Function in All Randomized Participants

Description

Change in bulbar function over time in all randomized participants as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function.

Time Frame

Baseline to 24 Weeks

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Pridopidine	Matching Placebo
Arm/Group Description	Pridopidine is administered orally twice daily for 24 weeks. Pridopidine: Administration: Oral Dose: 45mg twice daily	Matching placebo is administered orally twice daily for 24 weeks. Matching Placebo: Administration: Oral Dose: one capsule twice daily
Overall Number of Participants Analyzed	120	162
Least Squares Mean (Standard Error) Unit of Measure: point change from baseline	-1.16(0.169)	-1.25(0.141)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Pridopidine, Matching Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.6594
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Covariates include baseline use of edaravone and riluzole, months since symptom onset, and pre-baseline ALSFRS-R slope.


Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.10
	Confidence Interval	(2-sided) 95% -0.33 to 0.52
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.217
	Estimation Comments	Pridopidine 24-week change from baseline relative to placebo 24-week change from baseline.

5. Secondary Outcome:

Title

Respiratory Function

Description

Change in respiratory function over time as measured by Slow Vital Capacity (SVC).

Time Frame

Baseline to 24 Weeks

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Pridopidine	Matching Placebo
Arm/Group Description	Pridopidine is administered orally twice daily for 24 weeks. Pridopidine: Administration: Oral Dose: 45mg twice daily	Matching placebo is administered orally twice daily for 24 weeks. Matching Placebo: Administration: Oral Dose: one capsule twice daily
Overall Number of Participants Analyzed	120	162
Least Squares Mean (Standard Error) Unit of Measure: percent change	-8.81(1.351)	-8.35(1.132)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Pridopidine, Matching Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.7918
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Covariates include baseline use of edaravone and riluzole, months since symptom onset, and pre-baseline ALSFRS-R slope.


Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.46
	Confidence Interval	(2-sided) 95% -3.89 to 2.96
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.745
	Estimation Comments	Pridopidine 24-week change from baseline relative to placebo 24-week change from baseline.

6. Secondary Outcome:

Title

Bulbar Function in Participants With Rapid Pre-baseline Progression

Description

Change in bulbar function over time in participants with rapid pre-baseline progression as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function.

Participants were classified with rapid pre-baseline progression if their change in ALSFRS-R total score between Master Protocol Screening and Regimen Baseline was greater than or equal or 0.75 points per month.

Time Frame

Baseline to 24 Weeks

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Pridopidine	Matching Placebo
Arm/Group Description	Pridopidine is administered orally twice daily for 24 weeks. Pridopidine: Administration: Oral Dose: 45mg twice daily	Matching placebo is administered orally twice daily for 24 weeks. Matching Placebo: Administration: Oral Dose: one capsule twice daily
Overall Number of Participants Analyzed	51	48
Least Squares Mean (Standard Error) Unit of Measure: points change from baseline	-1.54(0.297)	-1.54(0.302)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Pridopidine, Matching Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.9903
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Covariates include baseline use of edaravone and riluzole, months since symptom onset, and pre-baseline ALSFRS-R slope.


Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.01
	Confidence Interval	(2-sided) 95% -0.83 to 0.84
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.426
	Estimation Comments	Pridopidine 24-week change from baseline relative to placebo 24-week change from baseline.

7. Secondary Outcome:

Title

Time to Bulbar Decline

Description

Time to first decline of 1-point or greater post baseline in the ALSFRS-R bulbar domain score among all participants.

Analysis performed using interval-censored survival analysis. Results presented as median interval (upper & lower bounded) time to event.

Time Frame

Baseline to 24 Weeks

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Pridopidine	Matching Placebo
Arm/Group Description	Pridopidine is administered orally twice daily for 24 weeks. Pridopidine: Administration: Oral Dose: 45mg twice daily	Matching placebo is administered orally twice daily for 24 weeks. Matching Placebo: Administration: Oral Dose: one capsule twice daily
Overall Number of Participants Analyzed	120	162
Median (95% Confidence Interval) Unit of Measure: days
Lower Bound of Interval	84(53 to 141)	66(56 to 105)
Upper Bound of Interval	86(83 to 141)	77(68 to 115)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Pridopidine, Matching Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	Analysis performed using interval-censored survival analysis. This type of model accommodates interval censoring between ALSFRS-R assessments


Statistical Test of Hypothesis	P-Value
	Comments	[Not specified]
	Method	Regression, Cox
	Comments	Interval censored cox model adjusted for time since symptom onset, pre-baseline change in ALSFRS-R, baseline use of edaravone, riluzole, and neudexta


Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-sided) 95% 0.69 to 1.27
	Estimation Comments	[Not specified]

8. Secondary Outcome:

Title

Muscle Strength

Description

Change in muscle strength over time as measured isometrically using hand-held dynamometry (HHD).

Time Frame

Baseline to 24 Weeks

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Pridopidine	Matching Placebo
Arm/Group Description	Pridopidine is administered orally twice daily for 24 weeks. Pridopidine: Administration: Oral Dose: 45mg twice daily	Matching placebo is administered orally twice daily for 24 weeks. Matching Placebo: Administration: Oral Dose: one capsule twice daily
Overall Number of Participants Analyzed	120	162
Least Squares Mean (Standard Error) Unit of Measure: percent change	-26.74(2.556)	-24.97(2.123)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Pridopidine, Matching Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.5888
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	Covariates include baseline use of edaravone and riluzole, months since symptom onset, and pre-baseline ALSFRS-R slope.


Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.78
	Confidence Interval	(2-sided) 95% -8.23 to 4.67
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.285
	Estimation Comments	Pridopidine 24-week change from baseline relative to placebo 24-week change from baseline.

9. Secondary Outcome:

Title

Number of Participants That Experienced Death or Death Equivalent

Description

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 24visit 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.

Time Frame

Baseline to 24 Weeks

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Pridopidine	Matching Placebo
Arm/Group Description	Pridopidine is administered orally twice daily for 24 weeks. Pridopidine: Administration: Oral Dose: 45mg twice daily	Matching placebo is administered orally twice daily for 24 weeks. Matching Placebo: Administration: Oral Dose: one capsule twice daily
Overall Number of Participants Analyzed	120	162
Measure Type: Count of Participants Unit of Measure: Participants	5 4.2%	6 3.7%

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Pridopidine, Matching Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.9690
	Comments	[Not specified]
	Method	Log Rank
	Comments	[Not specified]

Adverse Events


Time Frame	Up to 35 weeks after participant signed Master Protocol consent.
Adverse Event Reporting Description	The total at risk number for serious adverse events and other adverse events differs from the overall numbers due to a participant excluded from full analysis set for efficacy analyses and baseline characteristics due to a diagnosis other than ALS in one participant and due to participant included in the full analysis set for efficacy analyses and baseline characteristics due to being randomized but who never initiated study drug and thus was not considered as risk for safety outcomes.

Arm/Group Title	Pridopidine		Matching Placebo
Arm/Group Description	Pridopidine is administered orally twice daily for 24 weeks. Pridopidine: Administration: Oral Dose: 45mg twice daily		Matching placebo is administered orally twice daily for 24 weeks. Matching Placebo: Administration: Oral Dose: one capsule twice daily
All-Cause Mortality
	Pridopidine		Matching Placebo
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	2 / 120 (1.67%)		0 / 42 (0%)
Serious Adverse Events
	Pridopidine		Matching Placebo
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	16 / 121 (13.22%)		3 / 41 (7.32%)
Cardiac disorders
Atrial fibrillation ^{∗ A}	2 / 121 (1.65%)	2	0 / 41 (0%)	0
Gastrointestinal disorders
Pneumoperitoneum ^{∗ A}	1 / 121 (0.83%)	1	0 / 41 (0%)	0
Infections and infestations
COVID-19 pneumonia ^{∗ A}	1 / 121 (0.83%)	1	0 / 41 (0%)	0
Sepsis ^{∗ A}	0 / 121 (0%)	0	1 / 41 (2.44%)	1
Injury, poisoning and procedural complications
Ankle fracture ^{∗ A}	0 / 121 (0%)	0	1 / 41 (2.44%)	1
Hip fracture ^{∗ A}	1 / 121 (0.83%)	1	0 / 41 (0%)	0
Post lumbar puncture syndrome ^{∗ A}	1 / 121 (0.83%)	1	0 / 41 (0%)	0
Traumatic intracranial haemorrhage ^{∗ A}	1 / 121 (0.83%)	1	0 / 41 (0%)	0
Metabolism and nutrition disorders
Failure to thrive ^{∗ A}	1 / 121 (0.83%)	1	0 / 41 (0%)	0
Nervous system disorders
Amyotrophic lateral sclerosis ^{∗ A}	2 / 121 (1.65%)	2	0 / 41 (0%)	0
Cerebellar stroke ^{∗ A}	1 / 121 (0.83%)	1	0 / 41 (0%)	0
Ischaemic stroke ^{∗ A}	1 / 121 (0.83%)	1	0 / 41 (0%)	0
Presyncope ^{∗ A}	1 / 121 (0.83%)	1	0 / 41 (0%)	0
Syncope ^{∗ A}	2 / 121 (1.65%)	2	0 / 41 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism ^{∗ A}	1 / 121 (0.83%)	1	0 / 41 (0%)	0
Respiratory failure ^{∗ A}	3 / 121 (2.48%)	3	1 / 41 (2.44%)	1
∗Indicates events were collected by non-systematic methods. ATerm from vocabulary, MedDRA 23.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pridopidine		Matching Placebo
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	106 / 121 (87.6%)		37 / 41 (90.24%)
Gastrointestinal disorders
Constipation ^{∗ A}	14 / 121 (11.57%)	18	8 / 41 (19.51%)	9
Diarrhoea ^{∗ A}	15 / 121 (12.4%)	22	4 / 41 (9.76%)	5
Dry mouth ^{∗ A}	10 / 121 (8.26%)	10	3 / 41 (7.32%)	3
Dysphagia ^{∗ A}	13 / 121 (10.74%)	13	5 / 41 (12.2%)	6
Gastroesophageal reflux disease ^{∗ A}	4 / 121 (3.31%)	4	4 / 41 (9.76%)	4
Nausea ^{∗ A}	15 / 121 (12.4%)	18	3 / 41 (7.32%)	3
Salivary hypersecretion ^{∗ A}	10 / 121 (8.26%)	10	2 / 41 (4.88%)	2
General disorders
Complication associated with device ^{∗ A}	7 / 121 (5.79%)	8	2 / 41 (4.88%)	2
Fatigue ^{∗ A}	12 / 121 (9.92%)	14	5 / 41 (12.2%)	5
Oedema peripheral ^{∗ A}	9 / 121 (7.44%)	10	3 / 41 (7.32%)	4
Infections and infestations
COVID-19 ^{∗ A}	12 / 121 (9.92%)	12	4 / 41 (9.76%)	4
Injury, poisoning and procedural complications
Contusion ^{∗ A}	8 / 121 (6.61%)	11	3 / 41 (7.32%)	6
Fall ^{∗ A}	34 / 121 (28.1%)	65	12 / 41 (29.27%)	28
Post lumbar puncture syndrome ^{∗ A}	4 / 121 (3.31%)	4	4 / 41 (9.76%)	4
Skin abrasion ^{∗ A}	2 / 121 (1.65%)	2	4 / 41 (9.76%)	6
Musculoskeletal and connective tissue disorders
Arthralgia ^{∗ A}	9 / 121 (7.44%)	13	0 / 41 (0%)	0
Musculoskeletal pain ^{∗ A}	9 / 121 (7.44%)	12	2 / 41 (4.88%)	2
Pain in extremity ^{∗ A}	3 / 121 (2.48%)	3	3 / 41 (7.32%)	3
Nervous system disorders
Cognitive disorder ^{∗ A}	3 / 121 (2.48%)	3	3 / 41 (7.32%)	3
Dizziness ^{∗ A}	9 / 121 (7.44%)	10	4 / 41 (9.76%)	5
Dysarthria ^{∗ A}	10 / 121 (8.26%)	10	4 / 41 (9.76%)	5
Headache ^{∗ A}	6 / 121 (4.96%)	7	1 / 41 (2.44%)	1
Muscle contractions involuntary ^{∗ A}	4 / 121 (3.31%)	4	3 / 41 (7.32%)	4
Muscular weakness ^{∗ A}	29 / 121 (23.97%)	33	13 / 41 (31.71%)	21
Neuromyopathy ^{∗ A}	24 / 121 (19.83%)	37	3 / 41 (7.32%)	3
Psychiatric disorders
Anxiety ^{∗ A}	8 / 121 (6.61%)	8	4 / 41 (9.76%)	4
Depression ^{∗ A}	6 / 121 (4.96%)	6	1 / 41 (2.44%)	1
Insomnia ^{∗ A}	9 / 121 (7.44%)	10	1 / 41 (2.44%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea ^{∗ A}	7 / 121 (5.79%)	7	2 / 41 (4.88%)	2
∗Indicates events were collected by non-systematic methods. ATerm from vocabulary, MedDRA 23.0

Limitations and Caveats


[Not specified]

More Information


Certain Agreements:
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact:
Name/Official Title:	Healey Center for ALS Project Management
Organization:	Healey Center for ALS at Massachusetts General Hospital
Phone:	833-425-8257 (HALT ALS)
Email:	healeyalsplatform@mgh.harvard.edu