FORTITUDE-ALS: A Study to Evaluate Efficacy, Safety and Tolerability of CK-2127107 in Patients With Amyotrophic Lateral Sclerosis (ALS)

• Sponsor: Cytokinetics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03160898
• Collaborator: Astellas Pharma Inc (Industry)
• Enrollment: 458
• Locations: 64
• Arms: 4
• Actual Duration (Months): 19.4
• Patients Per Site: 7.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study was to assess the effect of CK-2127107 (hereafter referred to as reldesemtiv) versus placebo on respiratory function and other measures of skeletal muscle function in patients with ALS.

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Reldesemtiv; Drug: Placebo	Phase 2

Detailed Description

This was a double-blind, randomized, placebo-controlled, dose ranging study of reldesemtiv in patients with ALS. Eligible patients were randomized (1:1:1:1) to receive placebo or one of three doses of reldesemtiv (150, 300, or 450 mg twice daily) for 12 weeks. Randomization was stratified by riluzole concomitant use/non-use and edaravone concomitant use/non-use. Concomitant riluzole and edaravone were allowed as long as the riluzole dose had been stable for at least 30 days prior to screening and edaravone had been taken for 2 cycles prior to screening; these drugs could not be initiated during the study.

A total of 7 study visits were planned: screening, Day 1 (first dosing day), Weeks 2, 4, 8, and 12, and follow-up (4 weeks after the last dose of study drug). Study drug (placebo or reldesemtiv) was to be taken twice daily, approximately 12 hours (± 2 hours) apart and within 2 hours following a meal.

Study Design

• Study Type: Interventional
• Actual Enrollment: 458 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multi-Center, Double-Blind, Randomized, Dose-Ranging, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of CK-2127107 in Patients With Amyotrophic Lateral Sclerosis (ALS)
• Actual Study Start Date: Jul 24, 2017
• Actual Primary Completion Date: Mar 7, 2019
• Actual Study Completion Date: Mar 7, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Reldesemtiv 150 mg twice daily Patients in this arm took 1 reldesemtiv 150 mg oral tablet and 2 matching placebo tablets every 12 hours for 12 weeks.	Drug: Reldesemtiv; Oral tablet; Other Names: CK-2127107
Experimental: Reldesemtiv 300 mg twice daily Patients in this arm took 2 reldesemtiv 150 mg oral tablets and 1 matching placebo tablet every 12 hours for 12 weeks.	Drug: Reldesemtiv; Oral tablet; Other Names: CK-2127107
Experimental: Reldesemtiv 450 mg twice daily Patients in this arm took 3 reldesemtiv 150 mg oral tablets every 12 hours for 12 weeks.	Drug: Reldesemtiv; Oral tablet; Other Names: CK-2127107
Placebo Comparator: Placebo Patients in this arm took 3 placebo oral tablets every 12 hours for 12 weeks.	Drug: Placebo; Oral tablet

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 12 in the Percent Predicted Slow Vital Capacity (SVC) [Baseline to Week 12]

   Slow vital capacity was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, patients were instructed to take as deep an inspiration as possible followed by a maximum exhalation (blowing out all the air in their lungs). Values obtained were converted to percent predicted values using the Global Lung Initiative equation (ie, the test result as a percent of predicted values for patients of similar demographic and baseline characteristics [eg, height, age, sex]).

Secondary Outcome Measures

1. Change From Baseline to Week 12 in the ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score [Baseline to Week 12]

   The ALSFRS-R is used to measure the progression and severity of disability in patients with ALS. The ALSFRS-R consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in the following 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The total score ranges from 0 to 48. Higher scores reflect more normal function and lower scores reflect more impaired function.

2. Slope of Muscle Strength Mega-score From Baseline to Week 12 [Baseline to Week 12]

   A hand-held dynamometer, with a scale of 0 to 300 pounds, was used to measure muscle strength and handgrip strength (bilateral). The muscle groups tested were: elbow flexion, wrist extension, first dorsal interosseous, hip flexion, knee extension, and ankle dorsiflexion; all muscle groups were evaluated bilaterally. For each postbaseline assessment of muscle strength, the percent change from baseline was calculated for each muscle group and handgrip strength, using the following equation: ([postbaseline value - baseline value] / baseline value) × 100. The muscle-strength mega-score was calculated as the average of the changes (ie, percent change from baseline) observed for each of the muscle groups as well as handgrip strength. For this endpoint, negative values indicate a decline in muscle strength.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of familial or sporadic ALS ≤ 24 months prior to screening

• Upright Slow Vital Capacity (SVC) ≥ 60% of predicted for age, height and sex at screening

• Able to swallow tablets

• A caregiver (if one is needed)

• Able to perform reproducible pulmonary function tests

• Pre-study clinical laboratory findings within the normal range or, if outside the normal range, deemed not clinically significant by the Investigator

• Male patients who have not had a vasectomy and confirmed zero sperm count must agree after receiving the first dose of study drug until 10 weeks after the last dose to either use acceptable methods of contraception or abstain from sex

• Female patients must be post-menopausal or sterilized or must not be breastfeeding, have a negative pregnancy test, have no intention to become pregnant during the study and use acceptable methods of contraception or abstain from heterosexual intercourse from Screening until 10 weeks after last dose of study drug

• Patients must be either on riluzole for at least 30 days prior to screening or have not taken riluzole for at least 30 days prior to screening and not planning to start riluzole during the course of the study.

• Patients on edaravone must have completed at least 2 cycles of dosing with edaravone at the time of screening or have not taken edaravone for at least 30 days prior to screening and not planning to start edaravone during the course of the study.

Exclusion Criteria:

• At the time of screening, any use of non-invasive ventilation (NIV), e.g. continuous positive airway pressure [CPAP], noninvasive bi-level positive airway pressure [NPPV] or noninvasive volume ventilation [NVV] for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation

• Neurological impairment due to a condition other than ALS

• Presence at screening of any medically significant cardiac, pulmonary, GI, musculoskeletal, or psychiatric illness that might interfere with the patient's ability to comply with study procedures or that might confound the interpretation of clinical safety or efficacy data

• Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is longer, prior to dosing

• Known to have received CK-2127107 or tirasemtiv in any previous clinical trial

• Has received or is considering receiving during the course of the study any form of stem cell therapy for the treatment of ALS

• Has received or is considering receiving during the course of the study any form of gene therapy for the treatment of ALS

• Has received or is considering obtaining during the course of the study a diaphragmatic pacing system

• History of substance abuse within the past 2 years

• Use of certain medications

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Joseph's Hospital and Medical Center - Barrow Neurological Clinics	Phoenix	Arizona	United States	85013
2	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
3	University of California Irvine	Orange	California	United States	92868
4	Forbes Norris MDA/ALS Research Center	San Francisco	California	United States	94115
5	Stanford Hospital and Clinics	Stanford	California	United States	94305
6	University of Colorado Hospital Anschutz Outpatient Pavilion	Aurora	Colorado	United States	80045
7	Hospital for Special Care	New Britain	Connecticut	United States	06053
8	George Washington University Medical Faculty Associates	Washington	District of Columbia	United States	20037
9	University of Florida	Gainesville	Florida	United States	32610
10	Mayo Clinic	Jacksonville	Florida	United States	32224
11	Carol & Frank Morsani Center for Advanced Healthcare - University of South Florida	Tampa	Florida	United States	33612
12	Emory Clinic	Atlanta	Georgia	United States	30322
13	Duchossois Center for Advanced Medicine	Chicago	Illinois	United States	60637
14	IU Health Neuroscience Center of Excellence	Indianapolis	Indiana	United States	46202
15	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
16	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
17	Johns Hopkins University - Outpatient Center	Baltimore	Maryland	United States	21287
18	University of Massachusetts Memorial Medical Center/University of Massachusetts Medical School	Worcester	Massachusetts	United States	01655
19	Michigan Medicine	Ann Arbor	Michigan	United States	48109
20	Henry Ford Health System	Detroit	Michigan	United States	48202
21	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
22	Mayo Clinic	Rochester	Minnesota	United States	55905
23	Saint Louis University, Department of Neurology	Saint Louis	Missouri	United States	63104
24	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
25	Neurology Associates, P.C.	Lincoln	Nebraska	United States	68506
26	Hospital For Special Surgery	New York	New York	United States	10021
27	Neurological Institute, Columbia University Medical Center	New York	New York	United States	10032
28	SUNY Upstate Medical University	Syracuse	New York	United States	13210
29	Neurosciences Institute, Neurology - Charlotte	Charlotte	North Carolina	United States	28207
30	Duke Neurological Disorders Clinic	Durham	North Carolina	United States	27705
31	Wake Forest School of Medicine	Winston-Salem	North Carolina	United States	27157
32	Cleveland Clinic	Cleveland	Ohio	United States	44195
33	The Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
34	Providence Brain and Spine Institute ALS Center	Portland	Oregon	United States	97213
35	Oregon Health & Science University	Portland	Oregon	United States	97239
36	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
37	Temple University School of Medicine	Philadelphia	Pennsylvania	United States	19140
38	Vanderbilt University Medical Center - Clinical Research Center	Nashville	Tennessee	United States	37232
39	Texas Neurology	Dallas	Texas	United States	75214
40	Houston Methodist Hospital	Houston	Texas	United States	77030
41	UTHSCSA Medical Arts and Research Center	San Antonio	Texas	United States	78229
42	University of Vermont Medical Center	Burlington	Vermont	United States	05405
43	University of Virginia Health System	Charlottesville	Virginia	United States	22908
44	VCU Health - Ambulatory Care Center (ACC)	Richmond	Virginia	United States	23298
45	University of Washington Medical Center	Seattle	Washington	United States	98195
46	West Virginia University, Dept. of Neurology	Morgantown	West Virginia	United States	26506-9180
47	Froedtert Memorial Lutheran Hospital	Milwaukee	Wisconsin	United States	53226
48	Brain and Mind Centre, The University of Sydney	Camperdown	New South Wales	Australia	2050
49	Department of Neurology, Westmead Hospital	Westmead	New South Wales	Australia	2145
50	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
51	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
52	The Perron Institute for Neurological and Translation Science	Nedlands	Western Australia	Australia	6009
53	University of Calgary, Heritage Medical Research Center	Calgary	Alberta	Canada	T2N 4Z6
54	Edmonton Kaye Clinic	Edmonton	Alberta	Canada	T6GT 1Z1
55	McMaster University Medical Centre	Hamilton	Ontario	Canada	L8N 3Z5
56	London Health Sciences Centre University Hospital	London	Ontario	Canada	N6A 5A5
57	Sunnybrook Health Science Centre	Toronto	Ontario	Canada	M4N 3M5
58	Montreal Neurological Institute and Hospital	Montreal	Quebec	Canada	H3A 2B4
59	Centre de recherche du Centre Hospitalier de l'Universite de Montreal	Montréal	Quebec	Canada	H2X 0A9
60	Saskatoon City Hospital	Saskatoon	Saskatchewan	Canada	S7H 0G9
61	CHU de Quebec-Universite Laval, Hopital de l'Enfant Jesus	Quebec		Canada	G1J 1Z4
62	Beaumont Hospital	Dublin		Ireland	Dublin 9
63	University Medical Center Utrecht	Utrecht		Netherlands	3584 CX
64	Hospital San Rafael Servicio de Neurologia	Madrid		Spain	28016

Sponsors and Collaborators

• Cytokinetics
• Astellas Pharma Inc

Investigators

• Study Director: MD Cytokinetics, Cytokinetics

Study Documents (Full-Text)

• Study Protocol - Apr 18, 2018
• Statistical Analysis Plan - Dec 14, 2018

More Information

Publications

None provided.

• Responsible Party: Cytokinetics
• ClinicalTrials.gov Identifier: NCT03160898
• Other Study ID Numbers: CY 5022
• First Posted: May 19, 2017
• Last Update Posted: Sep 11, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Cytokinetics: Amyotrophic Lateral Sclerosis; ALS; CK-2127107; Reldesemtiv
• Additional relevant MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis

Study Results

Participant Flow

Recruitment Details	Patients with familial or sporadic ALS were enrolled at 65 sites in Australia, Canada, Ireland, Netherlands, Spain, and the United States. The first patient was screened on 16 August 2017 and the last patient completed on 07 March 2019.
Pre-assignment Detail	Eligible patients were male or female, ≥18 - ≤80 years of age, with familial or sporadic ALS diagnosed for ≤24 months. At screening, patients were to have upright slow vial capacity (SVC) ≥60% of predicted; must have been able to swallow tablets, perform reproducible pulmonary function tests; have normal lab tests; and have a caregiver (if needed).

Arm/Group Title	Placebo	Reldesemtiv 150 mg Twice Daily	Reldesemtiv 300 mg Twice Daily	Reldesemtiv 450 mg Twice Daily
Arm/Group Description	Patients in this group received placebo twice daily for 12 weeks	Patients in this group received 150 mg reldesemtiv twice daily for 12 weeks	Patients in this group received 300 mg reldesemtiv twice daily for 12 weeks	Patients in this group received 450 mg reldesemtiv twice daily for 12 weeks
Period Title: Overall Study
STARTED	115	113	113	117
COMPLETED	95	100	97	98
NOT COMPLETED	20	13	16	19

Baseline Characteristics

Arm/Group Title	Placebo	Reldesemtiv 150 mg Twice Daily	Reldesemtiv 300 mg Twice Daily	Reldesemtiv 450 mg Twice Daily	Total
Arm/Group Description	Patients in this group received placebo twice daily for 12 weeks	Patients in this group received 150 mg reldesemtiv twice daily for 12 weeks	Patients in this group received 300 mg reldesemtiv twice daily for 12 weeks	Patients in this group received 450 mg reldesemtiv twice daily for 12 weeks	Total of all reporting groups
Overall Participants	115	112	113	117	457
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.6 (10.60)	57.1 (10.91)	57.8 (10.17)	60.1 (11.00)	58.7 (10.72)
Sex: Female, Male (Count of Participants)
Female	47 40.9%	41 36.6%	42 37.2%	50 42.7%	180 39.4%
Male	68 59.1%	71 63.4%	71 62.8%	67 57.3%	277 60.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	4 3.5%	2 1.8%	7 6.2%	1 0.9%	14 3.1%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.9%	0 0%	0 0%	1 0.2%
Black or African American	1 0.9%	3 2.7%	6 5.3%	0 0%	10 2.2%
White	107 93%	103 92%	100 88.5%	113 96.6%	423 92.6%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	3 2.6%	3 2.7%	0 0%	3 2.6%	9 2%
Region of Enrollment (participants) [Number]
Canada	24 20.9%	22 19.6%	27 23.9%	27 23.1%	100 21.9%
Netherlands	4 3.5%	2 1.8%	1 0.9%	4 3.4%	11 2.4%
United States	72 62.6%	73 65.2%	71 62.8%	68 58.1%	284 62.1%
Ireland	2 1.7%	2 1.8%	0 0%	0 0%	4 0.9%
Spain	8 7%	9 8%	10 8.8%	11 9.4%	38 8.3%
Australia	5 4.3%	4 3.6%	4 3.5%	7 6%	20 4.4%
Time since ALS symptom onset (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	22.13 (12.375)	23.87 (27.503)	22.52 (14.635)	22.69 (18.662)	22.80 (19.080)
Site of symptom onset (Count of Participants)
Upper limb	49 42.6%	52 46.4%	56 49.6%	44 37.6%	201 44%
Lower limb	44 38.3%	42 37.5%	40 35.4%	43 36.8%	169 37%
Bulbar	22 19.1%	18 16.1%	17 15%	30 25.6%	87 19%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 12 in the Percent Predicted Slow Vital Capacity (SVC)
Description	Slow vital capacity was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, patients were instructed to take as deep an inspiration as possible followed by a maximum exhalation (blowing out all the air in their lungs). Values obtained were converted to percent predicted values using the Global Lung Initiative equation (ie, the test result as a percent of predicted values for patients of similar demographic and baseline characteristics [eg, height, age, sex]).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The outcome measure was analyzed for the Full Analysis Set, which consisted of all randomized patients who received any amount of study drug and had a baseline and at least 1 postbaseline efficacy assessment during double-blind treatment.

Arm/Group Title	Placebo	Reldesemtiv 150 mg Twice Daily	Reldesemtiv 300 mg Twice Daily	Reldesemtiv 450 mg Twice Daily	Reldesemtiv 300 mg & 450 mg
Arm/Group Description	Patients in this group received placebo twice daily for 12 weeks	Patients in this group received 150 mg reldesemtiv twice daily for 12 weeks	Patients in this group received 300 mg reldesemtiv twice daily for 12 weeks	Patients in this group received 450 mg reldesemtiv twice daily for 12 weeks	For analysis purposes, the results from the reldesemtiv 300 mg group and the 450 mg group were pooled.
Measure Participants	114	112	113	117	230
Least Squares Mean (Standard Error) [percent predicted]	-6.46 (0.964)	-4.97 (0.952)	-4.62 (0.963)	-4.58 (0.927)	-4.60 (0.701)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 150 mg Twice Daily, Reldesemtiv 300 mg Twice Daily, Reldesemtiv 450 mg Twice Daily
	Comments	The statistical null hypothesis was as follows: there was no assumed dose-response relationship in percent predicted SVC change from baseline to Week 12 among all three active doses and placebo, expressed as: H0: -5 x µ placebo - 1 x µ 150 mg twice daily + 3 x µ 300 mg twice daily + 3 x µ 450 mg twice daily = 0 where µ was the mean of the efficacy endpoint for the designated group.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1095
	Comments
	Method	Mixed Models Analysis
	Comments	Analyzed by an MMRM with contrast (-5, -1, 3, 3) to reflect the assumed relationship for the 4 groups: placebo, 150, 300, and 450 mg twice daily.
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; -0.36 to 3.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.003
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 150 mg Twice Daily
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2501
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; -1.05 to 4.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.291
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 300 mg Twice Daily
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1549
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	1.84
	Confidence Interval	(2-Sided) 95%; -0.7 to 4.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.29
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 450 mg Twice Daily
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1417
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	1.88
	Confidence Interval	(2-Sided) 95%; -0.63 to 4.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.274
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 300 mg & 450 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0964
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	1.86
	Confidence Interval	(2-Sided) 95%; -0.33 to 4.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.115
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Week 12 in the ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score
Description	The ALSFRS-R is used to measure the progression and severity of disability in patients with ALS. The ALSFRS-R consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in the following 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The total score ranges from 0 to 48. Higher scores reflect more normal function and lower scores reflect more impaired function.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The outcome measure was analyzed for the Full Analysis Set, which consisted of all randomized patients who received any amount of study drug and had a baseline and at least 1 postbaseline efficacy assessment during double-blind treatment.

Arm/Group Title	Placebo	Reldesemtiv 150 mg Twice Daily	Reldesemtiv 300 mg Twice Daily	Reldesemtiv 450 mg Twice Daily	Reldesemtiv 300 mg & 450 mg
Arm/Group Description	Patients in this group received placebo twice daily for 12 weeks	Patients in this group received 150 mg reldesemtiv twice daily for 12 weeks	Patients in this group received 300 mg reldesemtiv twice daily for 12 weeks	Patients in this group received 450 mg reldesemtiv twice daily for 12 weeks	For analysis purposes, the results from the reldesemtiv 300 mg group and the 450 mg group were pooled.
Measure Participants	114	112	113	117	230
Least Squares Mean (Standard Error) [change in score]	-3.53 (0.313)	-2.40 (0.311)	-2.62 (0.317)	-2.94 (0.307)	-2.78 (0.228)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 150 mg Twice Daily, Reldesemtiv 300 mg Twice Daily, Reldesemtiv 450 mg Twice Daily
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0930
	Comments
	Method	Mixed Models Analysis
	Comments	Analyzed by an MMRM with contrast (-5, -1, 3, 3) to reflect the assumed relationship for the 4 groups: placebo, 150, 300, and 450 mg twice daily.
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.56
	Confidence Interval	(2-Sided) 95%; -0.09 to 1.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.335
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 150 mg Twice Daily
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0087
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.29 to 1.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.427
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 300 mg Twice Daily
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0351
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.06 to 1.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.43
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 450 mg Twice Daily
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1642
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; -0.24 to 1.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.425
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 300 mg & 450 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0435
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.02 to 1.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.371
	Estimation Comments

3. Secondary Outcome

Title	Slope of Muscle Strength Mega-score From Baseline to Week 12
Description	A hand-held dynamometer, with a scale of 0 to 300 pounds, was used to measure muscle strength and handgrip strength (bilateral). The muscle groups tested were: elbow flexion, wrist extension, first dorsal interosseous, hip flexion, knee extension, and ankle dorsiflexion; all muscle groups were evaluated bilaterally. For each postbaseline assessment of muscle strength, the percent change from baseline was calculated for each muscle group and handgrip strength, using the following equation: ([postbaseline value - baseline value] / baseline value) × 100. The muscle-strength mega-score was calculated as the average of the changes (ie, percent change from baseline) observed for each of the muscle groups as well as handgrip strength. For this endpoint, negative values indicate a decline in muscle strength.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The outcome measure was analyzed for the Full Analysis Set, which consisted of all randomized patients who received any amount of study drug and had a baseline and at least 1 postbaseline efficacy assessment during double-blind treatment.

Arm/Group Title	Placebo	Reldesemtiv 150 mg Twice Daily	Reldesemtiv 300 mg Twice Daily	Reldesemtiv 450 mg Twice Daily	Reldesemtiv 300 mg & 450 mg
Arm/Group Description	Patients in this group received placebo twice daily for 12 weeks	Patients in this group received 150 mg reldesemtiv twice daily for 12 weeks	Patients in this group received 300 mg reldesemtiv twice daily for 12 weeks	Patients in this group received 450 mg reldesemtiv twice daily for 12 weeks	For analysis purposes, the results from the reldesemtiv 300 mg group and the 450 mg group were pooled.
Measure Participants	114	112	113	117	230
Least Squares Mean (Standard Error) [change in mega-score per day]	-0.1444 (0.02492)	-0.1198 (0.02463)	-0.1299 (0.02474)	-0.0956 (0.02421)	-0.1127 (0.01731)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 150 mg Twice Daily, Reldesemtiv 300 mg Twice Daily, Reldesemtiv 450 mg Twice Daily
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3134
	Comments
	Method	Mixed Models Analysis
	Comments	Analyzed by an MMRM with contrast (-5, -1, 3, 3) to reflect the assumed relationship for the 4 groups: placebo, 150, 300, and 450 mg twice daily.
Method of Estimation	Estimation Parameter	Slope difference
	Estimated Value	0.0276
	Confidence Interval	(2-Sided) 95%; -0.0261 to 0.0813
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.02734
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 150 mg Twice Daily
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4824
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.0246
	Confidence Interval	(2-Sided) 95%; -0.0442 to 0.0935
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 300 mg Twice Daily
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6787
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.0146
	Confidence Interval	(2-Sided) 95%; -0.0544 to 0.0835
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 450 mg Twice Daily
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1604
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.0488
	Confidence Interval	(2-Sided) 95%; -0.0194 to 0.1171
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reldesemtiv 300 mg & 450 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2966
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.0317
	Confidence Interval	(2-Sided) 95%; -0.0279 to 0.0913
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events (AEs) were collected from administration of the first dose of study drug through 4 weeks after the last dose of study drug.
Adverse Event Reporting Description	An AE was treatment-emergent if it started or worsened (eg, increased in severity) during or after the first dose of study drug. AEs and SAEs were summarized for the Safety Analysis Set, which consisted of all randomized patients who received at least 1 dose or portion of a dose of study drug.
Arm/Group Title	Placebo		Reldesemtiv 150 mg Twice Daily		Reldesemtiv 300 mg Twice Daily		Reldesemtiv 450 mg Twice Daily
Arm/Group Description	Patients in this group received placebo twice daily for 12 weeks		Patients in this group received 150 mg reldesemtiv twice daily for 12 weeks		Patients in this group received 300 mg reldesemtiv twice daily for 12 weeks		Patients in this group received 450 mg reldesemtiv twice daily for 12 weeks
All Cause Mortality
	Placebo		Reldesemtiv 150 mg Twice Daily		Reldesemtiv 300 mg Twice Daily		Reldesemtiv 450 mg Twice Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/115 (1.7%)		0/112 (0%)		0/113 (0%)		1/117 (0.9%)
Serious Adverse Events
	Placebo		Reldesemtiv 150 mg Twice Daily		Reldesemtiv 300 mg Twice Daily		Reldesemtiv 450 mg Twice Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/115 (8.7%)		8/112 (7.1%)		8/113 (7.1%)		8/117 (6.8%)
Cardiac disorders
Cardiac failure	0/115 (0%)	0	0/112 (0%)	0	1/113 (0.9%)	1	0/117 (0%)	0
Palpitations	0/115 (0%)	0	0/112 (0%)	0	1/113 (0.9%)	1	0/117 (0%)	0
Acute myocardial infarction	1/115 (0.9%)	1	0/112 (0%)	0	0/113 (0%)	0	0/117 (0%)	0
Gastrointestinal disorders
Dysphagia	0/115 (0%)	0	2/112 (1.8%)	2	0/113 (0%)	0	0/117 (0%)	0
Oesophagitis	0/115 (0%)	0	1/112 (0.9%)	1	0/113 (0%)	0	0/117 (0%)	0
Rectal prolapse	1/115 (0.9%)	1	0/112 (0%)	0	0/113 (0%)	0	0/117 (0%)	0
General disorders
Pain	0/115 (0%)	0	1/112 (0.9%)	1	0/113 (0%)	0	0/117 (0%)	0
Hepatobiliary disorders
Hepatotoxicity	0/115 (0%)	0	0/112 (0%)	0	1/113 (0.9%)	1	1/117 (0.9%)	1
Infections and infestations
Urinary tract infection	1/115 (0.9%)	1	1/112 (0.9%)	1	1/113 (0.9%)	1	0/117 (0%)	0
Appendicitis	0/115 (0%)	0	1/112 (0.9%)	1	0/113 (0%)	0	0/117 (0%)	0
Device related sepsis	0/115 (0%)	0	0/112 (0%)	0	1/113 (0.9%)	1	0/117 (0%)	0
Parainfluenzae virus infection	0/115 (0%)	0	0/112 (0%)	0	1/113 (0.9%)	1	0/117 (0%)	0
Pneumonia	1/115 (0.9%)	1	0/112 (0%)	0	0/113 (0%)	0	0/117 (0%)	0
Urosepsis	1/115 (0.9%)	1	0/112 (0%)	0	0/113 (0%)	0	0/117 (0%)	0
Injury, poisoning and procedural complications
Head injury	0/115 (0%)	0	0/112 (0%)	0	0/113 (0%)	0	1/117 (0.9%)	1
Joint dislocation	0/115 (0%)	0	1/112 (0.9%)	1	0/113 (0%)	0	0/117 (0%)	0
Traumatic fracture	0/115 (0%)	0	0/112 (0%)	0	1/113 (0.9%)	1	0/117 (0%)	0
Investigations
Alanine aminotransferase increased	0/115 (0%)	0	0/112 (0%)	0	0/113 (0%)	0	2/117 (1.7%)	2
Aspartate aminotransferase increased	0/115 (0%)	0	0/112 (0%)	0	0/113 (0%)	0	1/117 (0.9%)	1
Blood creatine phosphokinase increased	0/115 (0%)	0	0/112 (0%)	0	0/113 (0%)	0	1/117 (0.9%)	1
Glomerular filtration rate decreased	0/115 (0%)	0	0/112 (0%)	0	0/113 (0%)	0	1/117 (0.9%)	1
Weight decreased	1/115 (0.9%)	1	1/112 (0.9%)	1	0/113 (0%)	0	0/117 (0%)	0
Nervous system disorders
Amyotrophic lateral sclerosis	0/115 (0%)	0	0/112 (0%)	0	0/113 (0%)	0	1/117 (0.9%)	1
Dizziness	0/115 (0%)	0	0/112 (0%)	0	1/113 (0.9%)	2	0/117 (0%)	0
Muscle contractions involuntary	0/115 (0%)	0	1/112 (0.9%)	1	0/113 (0%)	0	0/117 (0%)	0
Transient ischaemic attack	0/115 (0%)	0	0/112 (0%)	0	0/113 (0%)	0	1/117 (0.9%)	1
Renal and urinary disorders
Urinary retention	0/115 (0%)	0	0/112 (0%)	0	1/113 (0.9%)	1	0/117 (0%)	0
Reproductive system and breast disorders
Prostatomegaly	0/115 (0%)	0	0/112 (0%)	0	0/113 (0%)	0	1/117 (0.9%)	1
Haemorrhagic ovarian cyst	1/115 (0.9%)	1	0/112 (0%)	0	0/113 (0%)	0	0/117 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/115 (0%)	0	1/112 (0.9%)	1	1/113 (0.9%)	1	1/117 (0.9%)	1
Respiratory distress	0/115 (0%)	0	0/112 (0%)	0	1/113 (0.9%)	1	0/117 (0%)	0
Pneumonia aspiration	2/115 (1.7%)	2	0/112 (0%)	0	0/113 (0%)	0	0/117 (0%)	0
Pulmonary embolism	2/115 (1.7%)	2	0/112 (0%)	0	0/113 (0%)	0	0/117 (0%)	0
Vascular disorders
Jugular vein thrombosis	1/115 (0.9%)	1	0/112 (0%)	0	0/113 (0%)	0	0/117 (0%)	0
Subclavian vein thrombosis	1/115 (0.9%)	1	0/112 (0%)	0	0/113 (0%)	0	0/117 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Reldesemtiv 150 mg Twice Daily		Reldesemtiv 300 mg Twice Daily		Reldesemtiv 450 mg Twice Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	95/115 (82.6%)		99/112 (88.4%)		97/113 (85.8%)		107/117 (91.5%)
Gastrointestinal disorders
Nausea	14/115 (12.2%)	16	10/112 (8.9%)	13	13/113 (11.5%)	14	22/117 (18.8%)	23
Constipation	5/115 (4.3%)	5	7/112 (6.3%)	8	13/113 (11.5%)	15	10/117 (8.5%)	10
Diarrhoea	8/115 (7%)	8	12/112 (10.7%)	15	6/113 (5.3%)	6	4/117 (3.4%)	4
Dry mouth	2/115 (1.7%)	2	2/112 (1.8%)	2	6/113 (5.3%)	6	1/117 (0.9%)	1
General disorders
Fatigue	12/115 (10.4%)	14	14/112 (12.5%)	14	19/113 (16.8%)	20	20/117 (17.1%)	24
Infections and infestations
Viral upper respiratory tract infection	9/115 (7.8%)	9	6/112 (5.4%)	6	10/113 (8.8%)	10	9/117 (7.7%)	9
Urinary tract infection	8/115 (7%)	9	3/112 (2.7%)	5	5/113 (4.4%)	5	5/117 (4.3%)	7
Upper respiratory tract infection	3/115 (2.6%)	4	7/112 (6.3%)	7	1/113 (0.9%)	1	1/117 (0.9%)	1
Injury, poisoning and procedural complications
Contusion	15/115 (13%)	28	8/112 (7.1%)	15	14/113 (12.4%)	15	17/117 (14.5%)	26
Post-traumatic pain	2/115 (1.7%)	2	6/112 (5.4%)	8	8/113 (7.1%)	11	6/117 (5.1%)	6
Skin abrasion	5/115 (4.3%)	7	8/112 (7.1%)	10	3/113 (2.7%)	4	5/117 (4.3%)	7
Investigations
Cystatin C increased	2/115 (1.7%)	2	7/112 (6.3%)	7	9/113 (8%)	9	20/117 (17.1%)	22
Glomerular filtration rate decreased	1/115 (0.9%)	1	6/112 (5.4%)	6	6/113 (5.3%)	6	10/117 (8.5%)	11
Alanine aminotransferase increased	1/115 (0.9%)	1	2/112 (1.8%)	2	5/113 (4.4%)	6	11/117 (9.4%)	14
Aspartate aminotransferase increased	1/115 (0.9%)	1	2/112 (1.8%)	2	3/113 (2.7%)	3	9/117 (7.7%)	11
Metabolism and nutrition disorders
Decreased appetite	4/115 (3.5%)	4	3/112 (2.7%)	3	7/113 (6.2%)	7	7/117 (6%)	8
Dehydration	0/115 (0%)	0	1/112 (0.9%)	1	6/113 (5.3%)	6	6/117 (5.1%)	7
Musculoskeletal and connective tissue disorders
Arthralgia	2/115 (1.7%)	2	8/112 (7.1%)	9	4/113 (3.5%)	5	8/117 (6.8%)	10
Pain in extremity	5/115 (4.3%)	6	1/112 (0.9%)	1	3/113 (2.7%)	3	6/117 (5.1%)	7
Muscle spasms	1/115 (0.9%)	1	6/112 (5.4%)	7	2/113 (1.8%)	2	1/117 (0.9%)	1
Nervous system disorders
Headache	15/115 (13%)	18	16/112 (14.3%)	18	16/113 (14.2%)	19	12/117 (10.3%)	13
Dizziness	11/115 (9.6%)	13	8/112 (7.1%)	12	11/113 (9.7%)	13	7/117 (6%)	7
Skin and subcutaneous tissue disorders
Pruritus	2/115 (1.7%)	4	1/112 (0.9%)	1	2/113 (1.8%)	3	6/117 (5.1%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.