Evidence map›Paper›PMID 35508892›Full record

Trial reportMuscle & nerve2022

Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes.

Sabrina Paganoni, Claire Watkins, Matthew Cawson, Suzanne Hendrix, Samuel P Dickson, Newman Knowlton, Jamie Timmons, Machelle Manuel, Merit Cudkowicz

Registry-linked trialOpen access · hybridAbstract readRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Muscle & nerve, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03488524 (Evaluation of the Safety, Tolerability, Efficacy, and Activity of AMX0035, a Fixed Combination of Phenylbutyrate), which is not on this map. Cited by 22 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
22citing papers in PubMed, 1 pooled it
5.8field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT03488524 phase2completednot on this map

Evaluation of the Safety, Tolerability, Efficacy, and Activity of AMX0035, a Fixed Combination of Phenylbutyrate (PB) and Tauroursodeoxycholic Acid (TUDCA), for Treatment of Amyotrophic Lateral Sclerosis: Open-Label Extension

TypeinterventionalSponsorAmylyx Pharmaceuticals Inc.Ran2018 to 2021Enrolled90ConditionsAmyotrophic Lateral Sclerosis, ALSArmsAMX0035
3 · Its place in the literature

Who cites it

22 citing papers in PubMed, 1 synthesis or guideline pooled it, 48 citations in OpenAlex.

  1. Pooled it
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  5. Review
  6. Article
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  14. Therapeutic targeting of ALS pathways: Refocusing an incomplete picture.Annals of clinical and translational neurology · 2023
    Review
  15. Review
  16. Article
  17. Routes of Albumin Overload Toxicity in Renal Tubular Epithelial Cells.International journal of molecular sciences · 2023
    Article
  18. Parkinson's disease therapy: what lies ahead?Journal of neural transmission (Vienna, Austria : 1996) · 2023
    Review
  19. Review
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 5 institutions in 2 countries.

Sabrina PaganoniSean M. Healey and AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.ORCID 0000-0003-0505-1168
Claire WatkinsMaple Health Group, New York, New York, USA.ORCID 0000-0001-6475-2795
Matthew CawsonFormerly with Maple Health Group, New York, New York, USA.
Suzanne HendrixPentara Corporation, Millcreek, Utah, USA.
Samuel P DicksonPentara Corporation, Millcreek, Utah, USA.
Newman KnowltonPentara Corporation, Millcreek, Utah, USA.
Jamie TimmonsAmylyx Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
Machelle ManuelAmylyx Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
Merit CudkowiczSean M. Healey and AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
TetraLogic Pharmaceuticals (United States) · USAmplyx Pharmaceuticals (United States) · USHarvard University · USCheshire West and Chester · GBNorthwell Health · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

INTRODUCTION/

aimsTrials incorporating placebo-to-active treatment crossover are encouraged in fatal conditions like amyotrophic lateral sclerosis (ALS) but may underestimate active treatment survival benefit. Here, we apply methods for modeling survival without crossover, including the rank-preserving structural failure time model (RPSFTM), to data from the CENTAUR trial of sodium phenylbutyrate and taurursodiol (PB and TURSO) in ALS incorporating both randomized placebo-controlled and open-label extension (OLE) phases.

methodsIntent-to-treat (ITT) and RPSFTM survival analyses were performed with final data at a July 2020 cutoff date. Analyses of subgroups based on randomized treatment and OLE phase participation were also performed.

resultsHazard ratios (95% confidence intervals) of death for PB and TURSO versus participants initially on placebo were 0.57 (0.35-0.92) on ITT analysis and 0.39 (0.17-0.88) in the primary on-treatment RPSFTM analysis (p = .023). Median ITT survival duration for PB and TURSO (25.8 mo) was 6.9 mo longer than placebo (18.9 mo) on ITT analysis and 10.6 mo longer than the median RPSFTM-adjusted survival duration for placebo (15.2 mo). Median survival duration was 18.8 mo longer in the PB and TURSO-randomized subgroup who continued into the OLE phase versus the placebo-randomized subgroup who did not continue into the OLE phase (p < .0001), although OLE phase selection bias may have potentially confounded these results. DISCUSSION: Similar to the prespecified ITT analysis, post hoc analyses adjusting for treatment crossover in CENTAUR showed a significant survival benefit for PB and TURSO. Such methods may provide clinical context for observed survival outcomes in future ALS crossover trials.

Indexed as

Amyotrophic Lateral SclerosisCross-Over StudiesDouble-Blind MethodHumansSurvival Analysisamyotrophic lateral sclerosisclinical trialcrossover trial designsodium phenylbutyrate and taurursodiolsurvival

Identifiers

PMID35508892
PMCPMC9540225
OpenAlexW4229000223

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.