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CENTAUR

Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis

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Year of Publication: 2020

Authors: Paganoni S, Macklin EA, Hendrix S, ..., Cudkowicz ME

Journal: New England Journal of Medicine

Citation: N Engl J Med 2020;383:919-30

Link: https://doi.org/10.1056/NEJMoa1916945

Clinical Question

Does the combination of sodium phenylbutyrate and taurursodiol slow functional decline in persons with ALS compared to placebo?

Bottom Line

Sodium phenylbutyrate–taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over 24 weeks, though secondary outcomes did not reach statistical significance. Longer and larger trials are needed.

        Major Points
        Phase 2, multicenter, randomized, double-blind, placebo-controlled trial
137 participants with definite ALS randomized 2:1 to active drug vs placebo
Primary outcome showed 0.42 points/month slower decline in ALSFRS-R (P=0.03)
At 24 weeks, 2.32-point absolute difference in ALSFRS-R favoring active treatment
Fine-motor subscore showed most prominent improvement
Secondary outcomes (ATLIS, pNF-H, SVC, survival endpoints) not significantly different
77% of participants were receiving riluzole or edaravone at baseline
Gastrointestinal adverse events were more common with active drug, especially in first 3 weeks
19% discontinued active drug due to adverse events vs 8% placebo

      

Design

Study Type: Phase 2 randomized controlled trial

Randomization: 1

Blinding: Double-blind; participants, investigators, and outcome assessors blinded

Enrollment Period: June 2017 to September 2019

Follow-up Duration: 24 weeks (with 28-week telephone follow-up)

Centers: 25

Countries: United States

Sample Size: 137

Analysis: Modified intention-to-treat; shared-baseline linear mixed-effects model adjusted for age and prebaseline ALSFRS-R slope

Inclusion Criteria

Adults with definite ALS by revised El Escorial criteria
Upper and lower motor neuron signs in at least three body regions
Within 18 months after symptom onset
Slow vital capacity (SVC) >60% of predicted
Either no riluzole use or stable riluzole dose for ≥30 days before screening
Edaravone use permitted after protocol amendment (August 2017)

Exclusion Criteria

Did not meet El Escorial criteria for definite ALS
SVC ≤60% predicted
Symptom onset >18 months prior
Unstable riluzole dosing

Arms

Field	Sodium phenylbutyrate–taurursodiol	Control
Intervention	3g sodium phenylbutyrate + 1g taurursodiol per sachet, dissolved in water; 1 sachet daily for 3 weeks, then 2 sachets daily (morning and evening)	Matching placebo powder in sachets, same administration schedule
Duration	24 weeks	24 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Rate (slope) of decline in ALSFRS-R total score from baseline through week 24	Primary	−1.66 points/month	−1.24 points/month		0.03
ATLIS total score change per month (% predicted)	Secondary	−3.54%/month	−3.03%/month		NS (hierarchy failed)
ATLIS upper-limb score at week 24	Secondary	32.36 ± 2.59	36.63 ± 2.32		Exploratory
Plasma pNF-H change per month (pg/ml)	Secondary	−2.34 pg/ml/month	3.58 pg/ml/month		NS
SVC change per month (% predicted)	Secondary	−4.03%/month	−3.10%/month		NS
Death, tracheostomy, or hospitalization	Secondary	33.1%	19.3%	0.53	NS (95% CI 0.27-1.05)
Death or tracheostomy	Secondary	4.4%	2.8%	0.63	NS (95% CI 0.11-3.92)
Any adverse event	Adverse	96%	97%
Serious adverse events	Adverse	19%	12%
Gastrointestinal disorders	Adverse	60%	67%
Diarrhea leading to discontinuation	Adverse	0%	6%
Respiratory failure leading to discontinuation	Adverse	6%	0%
Respiratory serious adverse events	Adverse	8%	3%
Death	Adverse	4% (2 patients)	6% (5 patients)
Cardiac disorders	Adverse	0%	8%

Subgroup Analysis

Sensitivity analysis correcting for edaravone use showed similar direction but did not reach significance (difference 2.15 points, 95% CI −0.05 to 4.35). Sensitivity analysis correcting for riluzole yielded difference of 2.34 points (95% CI 0.19 to 4.48). Exploratory subdomain analysis showed fine-motor subscale most prominently improved.

Criticisms

Phase 2 trial with relatively small sample size (137 participants)
Short follow-up duration (24 weeks)
Secondary outcomes did not reach statistical significance
Higher discontinuation rate in active group (19% vs 8%) due to adverse events
Imbalance in edaravone use at baseline (50% placebo vs 25% active)
Higher percentage of bulbar-onset ALS in active group (30% vs 21%)
Early randomization error affected first 26 participants
Hierarchical testing failed at first secondary outcome
ALSFRS-R sum score validity as measure of disease severity debated
Limited literature on clinically meaningful ALSFRS-R change

Funding

Amylyx Pharmaceuticals, ALS Finding a Cure Foundation, ALS Association

Based on: CENTAUR (New England Journal of Medicine, 2020)

Authors: Paganoni S, Macklin EA, Hendrix S, ..., Cudkowicz ME

Citation: N Engl J Med 2020;383:919-30

Content summarized and formatted by NeuroTrials.ai.

CENTAUR

(2020)

Objective

To evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol combination in persons with ALS

Study Summary

• Sodium phenylbutyrate–taurursodiol slowed functional decline by 0.42 points/month vs placebo (P=0.03)
• 2.32-point absolute difference in ALSFRS-R at 24 weeks favoring active treatment
• Secondary outcomes (muscle strength, SVC, pNF-H, survival events) did not reach significance

Intervention

Sodium phenylbutyrate 3g + taurursodiol 1g (AMX0035), once daily for 3 weeks then twice daily vs placebo

Inclusion Criteria

Definite ALS by El Escorial criteria, symptom onset within 18 months, SVC >60% predicted, stable riluzole use or no riluzole

Study Design

Arms: Sodium phenylbutyrate–taurursodiol vs Placebo

Patients per Arm: 87 active vs 48 placebo (modified ITT)

Outcome

• Primary: ALSFRS-R decline −1.24 vs −1.66 points/month (difference 0.42; 95% CI 0.03-0.81; P=0.03)
• ATLIS total score: −3.03 vs −3.54%/month (NS)
• Death/tracheostomy/hospitalization HR 0.53 (95% CI 0.27-1.05)

Bottom Line

Major Points

Phase 2, multicenter, randomized, double-blind, placebo-controlled trial
137 participants with definite ALS randomized 2:1 to active drug vs placebo
Primary outcome showed 0.42 points/month slower decline in ALSFRS-R (P=0.03)
At 24 weeks, 2.32-point absolute difference in ALSFRS-R favoring active treatment
Fine-motor subscore showed most prominent improvement
Secondary outcomes (ATLIS, pNF-H, SVC, survival endpoints) not significantly different
77% of participants were receiving riluzole or edaravone at baseline
Gastrointestinal adverse events were more common with active drug, especially in first 3 weeks
19% discontinued active drug due to adverse events vs 8% placebo

Study Design

Study Type: Phase 2 randomized controlled trial
Randomization: Yes
Blinding: Double-blind; participants, investigators, and outcome assessors blinded
Sample Size: 137
Follow-up: 24 weeks (with 28-week telephone follow-up)
Centers: 25
Countries: United States

Primary Outcome

Definition: Rate (slope) of decline in ALSFRS-R total score from baseline through week 24

Control	Intervention	HR/OR	P-value
−1.66 points/month	−1.24 points/month	- (0.03 to 0.81 (for difference))	0.03

Limitations & Criticisms

Phase 2 trial with relatively small sample size (137 participants)
Short follow-up duration (24 weeks)
Secondary outcomes did not reach statistical significance
Higher discontinuation rate in active group (19% vs 8%) due to adverse events
Imbalance in edaravone use at baseline (50% placebo vs 25% active)
Higher percentage of bulbar-onset ALS in active group (30% vs 21%)
Early randomization error affected first 26 participants
Hierarchical testing failed at first secondary outcome
ALSFRS-R sum score validity as measure of disease severity debated
Limited literature on clinically meaningful ALSFRS-R change

Citation

N Engl J Med 2020;383:919-30

View Original Publication →

CENTAUR

Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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