COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success

Figures & data

Figure 1 Change in ALSFRS-R total score for subgroups of participants according to pre-study rate of progression in FORTITUDE-ALS. Analysis includes all participants with an ALSFRS-R total score measured at baseline and at least one timepoint after baseline. ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; FPT: fastest-progressing tertile; LS: least squares; IPT: intermediate-progressing tertile; SPT: slowest-progressing tertile. Reprinted by permission of the publisher (Taylor & Francis. Ltd, http://www.tandfonline.com) from Shefner et al. [9]

Table 1 Change in ALSFRS-R total score in FORTITUDE-ALS, showing (A) the overall study population and (B) the subgroup with symptom onset ≤24 months and baseline ALSFRS-R total score ≤44.

	Placebo		Reldesemtiv (bid)
			150 mg		300 mg		450 mg		All active
	A (n = 100)	B (n = 51)	A (n = 104)	B (n = 62)	A (n = 98)	B (n = 55)	A (n = 103)	B (n = 65)	A (n = 305)	B (n = 182)
LS mean (SE)	−3.53 (0.31)	−4.87 (0.45)	−2.40 (0.31)	−3.05 (0.42)	−2.62 (0.32)	−2.77 (0.43)	−2.94 (0.31)	−3.23 (0.40)	−2.66 (0.19)	−3.03 (0.25)
Diff. of LS mean versus placebo (SE)			1.13 (0.43)	1.82 (0.60)	0.91 (0.43)	2.10 (0.61)	0.59 (0.43)	1.64 (0.58)	0.87 (0.35)	1.84 (0.49)
p Value (reldesemtiv versus placebo)			0.009	0.003	0.035	<0.001	0.16	0.005	0.013	<0.001

LS mean change in ALSFRS-R. (A) Overall FORTITUDE-ALS population includes all participants with an ALSFRS-R total score measured at baseline and at least one timepoint after baseline. (B) The subgroup includes FORTITUDE-ALS participants who had symptom onset ≤24 months before screening and baseline ALSFRS-R total score ≤44.

ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; LS: least-squares; SE: standard error.

Figure 2 COURAGE-ALS study design schematic. Participants completing week 48 may enter a planned open-label extension instead of the 4-week follow-up. ALSAQ-40: Amyotrophic Lateral Sclerosis Assessment Questionnaire; ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; EQ-5D-5L: EuroQol-5-dimension-5-level; EQ-VAS: EuroQol Visual Analogue Scale; FVC: forced vital capacity

Table 2 COURAGE-ALS key inclusion criteria.

Men and women aged 18–80 years at screening

Diagnosis of familial or sporadic ALS

First symptom of ALS ≤24 months prior to screening Qualifying symptoms limited to manifestations of weakness in extremity, bulbar, or respiratory muscles Cramps, fasciculations, or fatigue in isolation were not to be considered as a first symptom of ALS

ALSFRS-R total score ≤44 at screening^a

Upright FVC ≥65.0% of predicted for age, height, sex, and ethnicity at screening

Able to perform reproducible pulmonary function tests^b

Taking standard-of-care treatments for ALS for ≥30 days prior to screening or not taking such treatments for ≥30 days prior to screening^c

Able to swallow whole tablets

Diagnosis of familial or sporadic ALS according to El Escorial criteria (12). FVC according to Global Lung Initiative equation/reference values (13).

^aParticipants with a total score of ≥45 can be re-screened once 60 ± 7 days after the original screening date and are eligible if their ALSFRS-R total score was ≤44 or if their score is ≥2 lower than at initial screening.

^bDefined as being able to perform FVC at screening with variability of the two highest raw values of <10% with a maximum of five trials permitted.

^cParticipants not on stable doses at their original screening can be re-screened once the necessary time interval has passed.

ALS: amyotrophic lateral sclerosis; ALSFRS-R: ALS Functional Rating Scale-Revised; FVC: forced vital capacity.

Table 3 COURAGE-ALS key exclusion criteria.

Other medically significant neurological conditions that could interfere with the assessment of ALS symptoms, signs, or progression

Any medically significant cardiac, pulmonary, gastrointestinal, musculoskeletal, or psychiatric illness that might interfere with the participant’s ability to comply with study procedures or that might confound the interpretation of clinical safety or efficacy data^a

eGFRCysC <45.0 mL/min/1.73 m^2 at screening

Has received or is considering receiving during the course of the trial any form of gene therapy or stem cell therapy for the treatment of ALS, or a diaphragmatic pacing system

Use of a strong CYP3A4 inhibitor within 7 days prior to first dose of study drug or a strong CYP3A4 inducer within 14 days prior to first dose of study drug

Use of a medication that is an OCT1/OCT2 substrate within 7 days prior to first dose of study drug

Has a tracheostomy

^a Participants with poorly controlled systemic hypertension at their original screening can be re-screened once the hypertension is adequately controlled.

CYP: cytochrome P450; eGFR_CysC: estimated glomerular filtration rate calculated using cystatin C; OCT: organic cation transporter.

Table 4 Dates for milestones of DME use in COURAGE-ALS.

	Type of DME
Milestone	Manual wheelchair	Power wheelchair	Noninvasive ventilation	PEG	AAC
Acceptance	Prescribed and agreed to accept
Received	Has obtained but not using
First use	Use for any reason and in any location	Use for any reason and in any location	Any use outside of being instructed on how to use it—can be day or night use	Any use outside of being instructed on how to use it or solely flushing it Can be for the purposes of administering medication, free water, and nutrition	Any use outside of being instructed on how to use for the purposes of communicating with someone
Regular use	Daily use (any duration)	Daily use (any duration)	Daily use (can be day or night use) for ≥4 hours per 24 h	Daily use for replacing or supplementing 1≥ meals per day	Daily use for the purposes of communicating with someone
Dependence	Nonambulatory, wheelchair-dependent	Nonambulatory, wheelchair-dependent	Uses ≥22 hours per 24 hours	Uses for essentially all nutrition, may still take food by mouth for pleasure	Uses for all communication

DME: durable medical equipment; PEG: percutaneous endoscopic gastrostomy; AAC: augmentative and alternative communication.

Table 5 COURAGE-ALS study endpoints.

Objectives	Endpoint(s)
To assess the effect of reldesemtiv versus placebo on:
Primary
Functional outcomes	Change from baseline to week 24 in ALSFRS-R total score^a
Secondary
Combined functional and survival outcomes	Combined assessment of change in ALSFRS-R total score, time to onset of respiratory insufficiency, and survival time up to week 24
Ventilatory function	Change from baseline to week 24 in the percent predicted FVC
Quality of life	Change from baseline to week 24 in the ALSAQ-40 total score
Handgrip strength	Change from baseline to week 24 in handgrip strength (average of both hands)
Exploratory
Progression of ALS	Changes in durable medical equipment items from randomization to week 24 and week 48 Change from baseline to week 24 in the four subdomain scores of the ALSFRS-R Time spent in each MiToS stage and number of participants who transition stages from baseline to week 24 Change from baseline to week 48 in ALSFRS-R total score Change from baseline to week 48 in FVC Combined assessment of change in ALSFRS-R total score, time to onset of respiratory insufficiency, and survival time up to Week 48 Change from baseline to Week 24 in the mega-score of muscle strength measured by hand-held dynamometry in bilateral first dorsal interosseous muscles, abductor pollicus brevis muscles, or abductor digiti minimi muscles Change from baseline to week 24 and week 48 in the EQ-5D-5L Change from baseline to week 24 and week 48 in the EQ-VAS Time to first hospitalization, in the periods to week 24 and week 48
Safety
To assess the safety and tolerability of reldesemtiv compared with placebo	Participant incidence of adverse events and serious adverse events

^a The primary estimand will be the difference in the mean changes from baseline to Week 24 in ALSFRS-R total score between patients randomized to placebo and those randomized to reldesemtiv during the placebo-controlled double-blind treatment in the full analysis set. Analysis with a mixed-model for repeated measures is planned, and specific analyses will be finalized in a statistical analysis plan prior to database lock. The family-wise error rate at overall alpha of 0.05 will be controlled using a closed testing procedure.

ALSAQ-40: Amyotrophic Lateral Sclerosis Assessment Questionnaire; EQ-5D-5L: EuroQol-5D-5L; EQ VAS: EuroQol Visual Analogue Scale; FVC: forced vital capacity; MiToS: Milano-Torino Staging.

Shefner JM, Andrews JA, Genge A, Jackson C, Lechtzin N, Miller TM, et al. A phase 2, double-blind, randomized, dose-ranging trial of reldesemtiv in patients with ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2021;22:287–99.

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Data availability statement

Data reported herein are part of a sponsor-led clinical development program that is ongoing, and thus study protocols and complete datasets for the trial will not be made available with this report.