New England Journal of Medicine SEPTEMBER 03, 2020

Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis (CENTAUR)

Paganoni S, Macklin EA, Hendrix S, et al.

Bottom Line

The CENTAUR trial demonstrated that sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline and prolonged survival in patients with amyotrophic lateral sclerosis.

Key Findings

1. The primary endpoint was met, with participants receiving PB-TURSO demonstrating a significantly slower rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score over the 6-month randomized period compared to placebo (p=0.03).

2. Long-term survival analysis indicated a survival benefit for those originally randomized to the PB-TURSO group compared to the placebo group, with a median overall survival of 25.0 months versus 18.5 months (Hazard Ratio, 0.56; 95% CI, 0.34–0.92; p=0.023).

3. Sensitivity analyses accounting for placebo-to-active crossover in the open-label extension suggest that the early initiation of PB-TURSO at baseline resulted in a 6.5-month longer median survival duration.

Study Design

Design

RCT

Double-Blind

Sample

137

Patients

Duration

35 mo

Median

Setting

Multicenter, US

Population Adults (18-80 years) with a diagnosis of definite ALS by revised El Escorial criteria and symptom onset within the previous 18 months.

Intervention Oral fixed-dose coformulation of sodium phenylbutyrate (3 g) and taurursodiol (1 g) administered twice daily.

Comparator Matching placebo administered twice daily.

Outcome Rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score over 24 weeks.

Study Limitations

• The study was a phase 2 trial with a relatively small sample size, which limits the power for definitive survival conclusions.

• The trial had a high rate of crossover, as 71% of placebo-arm participants entered the open-label extension, which complicates the interpretation of long-term survival data.

• The study population was restricted to patients with definite ALS and symptom onset within the previous 18 months, limiting the generalizability of the findings to the broader, more heterogeneous ALS patient population.

• The trial was conducted at a limited number of centers in the United States, potentially impacting external validity.

Clinical Significance

The CENTAUR results provided the pivotal evidence for the clinical potential of PB-TURSO as a disease-modifying therapy for ALS, addressing both functional decline and mortality in a condition with extremely limited therapeutic options.

Historical Context

Prior to CENTAUR, only two medications, riluzole and edaravone, were FDA-approved for ALS. CENTAUR represented a significant milestone in ALS research as it was the first trial for a neuroprotective agent to demonstrate a combined benefit in both functional outcomes and overall survival.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

The CENTAUR trial utilizes a combination therapy of sodium phenylbutyrate and taurursodiol. Explain the specific cellular mechanisms each component targets and how these contribute to the pathophysiology of ALS.

Key Response

ALS involves protein misfolding and oxidative stress. Sodium phenylbutyrate is a chemical chaperone that reduces endoplasmic reticulum (ER) stress by preventing protein aggregation. Taurursodiol (also known as ursodoxicoltaurine) is a bile acid that reduces mitochondrial dysfunction and the threshold for apoptosis. Together, they target the 'multi-hit' hypothesis of neurodegeneration by addressing two distinct pathways of cellular death.

Resident

In the CENTAUR trial, the primary outcome was the rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R). Given a mean difference of 2.32 points over 24 weeks compared to placebo, how should you translate this benefit into a clinical conversation with a newly diagnosed patient?

Key Response

The ALSFRS-R measures 12 functions, including speech, swallowing, and walking. A 2.32-point difference suggests a roughly 25% slowing of functional decline. Residents should explain that while the drug does not stop or reverse the disease, it aims to extend the duration of independence and 'functional' time (e.g., maintaining the ability to eat or walk longer) before progression to more severe stages.

Fellow

The CENTAUR study utilized an enrichment strategy by enrolling only patients with 'definite ALS' (El Escorial criteria) within 18 months of symptom onset. Discuss how this recruitment strategy impacts the external validity of the survival benefit observed in the open-label extension.

Key Response

Enrichment focuses on 'fast progressors' to ensure the study is powered to detect a treatment effect within a short (24-week) period. While this confirms efficacy in a specific subgroup, the findings may not be directly generalizable to 'slow progressors' or patients later in their disease course, who may have different metabolic profiles or already irreversible neuronal loss.

Attending

Following the CENTAUR trial, the FDA granted approval for PB-TURSO, but the subsequent Phase 3 PHOENIX trial failed to meet its primary endpoint. How does this sequence of events influence your teaching on the ethics of 'Expanded Access' and early approval for terminal neurodegenerative conditions?

Key Response

This is a practice-defining dilemma. It teaches the importance of recognizing that Phase 2 results (like CENTAUR) are preliminary. In terminal diseases, there is a tension between 'the right to try' and 'the duty to evidence.' Attending physicians must guide students in understanding that early approval based on small samples (N=137) carries a high risk of false positives (Type I error), which can lead to patients using ineffective, costly medications.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the use of the linear mixed-effects model for the primary analysis of ALSFRS-R in CENTAUR. Why might the 'Joint Rank Test' or 'Combined Assessment of Function and Survival' (CAFS) be a more robust statistical choice for this specific patient population?

Key Response

In ALS trials, death acts as a 'competing risk.' Linear mixed-effects models often treat missing data from death as 'missing at random,' which is logically flawed. The Joint Rank or CAFS approach ranks participants first by time to death and then by functional decline among survivors, providing a more integrated and less biased assessment of treatment effect by preventing the 'survivor effect' from skewing the functional data.

Journal Editor

As a reviewer, if you noted that the CENTAUR trial achieved a p-value of 0.03 for its primary endpoint but failed to show significant differences in secondary endpoints like muscle strength (ATALANTE) or respiratory function (SVC), how would you characterize the 'strength of evidence' for the final manuscript?

Key Response

A single positive p-value just below 0.05 on the primary endpoint, combined with non-significant secondary outcomes, suggests a 'fragile' result. An editor would flag that without consistency across secondary physiological measures (like SVC), the functional benefit might be an artifact of the specific scale used or the small sample size, necessitating a cautious interpretation and a strong call for Phase 3 replication.

Guideline Committee

Based on the CENTAUR data, the initial recommendation for PB-TURSO was often 'conditional.' After the failure of the PHOENIX trial to replicate these results, how should the clinical practice guidelines for ALS management be updated regarding the Level of Evidence for PB-TURSO?

Key Response

Guidelines (e.g., AAN or EFNS) typically require at least two high-quality Class I trials for a 'Level A' recommendation. Since the PHOENIX trial contradicted the CENTAUR trial, the Level of Evidence must be downgraded. Most committees would now move to recommend against the routine use of PB-TURSO or remove it from the 'standard of care' algorithms, emphasizing that functional outcomes in ALS are highly variable and sensitive to study design.

Clinical Landscape

Noteworthy Related Trials

1994

Riluzole Trial

n = 155 · NEJM

Tested

Riluzole 100 mg/day

Population

Patients with definite or probable ALS

Comparator

Placebo

Endpoint

Survival time

Key result: Riluzole extended survival by approximately 3 months compared to placebo.

2010

AVP-923 (Nuedexta) STAR Trial

n = 326 · JAMA Neurol

Tested

Dextromethorphan/quinidine

Population

ALS patients with pseudobulbar affect

Comparator

Placebo

Endpoint

Center for Neurologic Study-Lability Scale (CNS-LS) score

Key result: Treatment significantly reduced the frequency and severity of laughing and crying episodes in patients with pseudobulbar affect.

2017

Edaravone MCI186-19 Trial

n = 137 · Lancet Neurol

Tested

Edaravone 60 mg

Population

Patients with early-stage ALS

Comparator

Placebo

Endpoint

Change in ALS Functional Rating Scale-Revised (ALSFRS-R) score

Key result: Patients receiving edaravone showed a significantly smaller decline in functional status over 24 weeks compared to placebo.

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