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Arimoclomol in IBM

Safety and efficacy of arimoclomol for inclusion body myositis: a multicentre, randomised, double-blind, placebo-controlled trial

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Year of Publication: 2023

Authors: Pedro M Machado, Michael P McDermott, Thomas Blaettler, ..., Mazen M Dimachkie

Journal: Lancet Neurology

Citation: Lancet Neurol 2023;22:900-11

Link: https://doi.org/10.1016/S1474-4422(23)00275-2

Clinical Question

Does arimoclomol, a co-inducer of the cellular heat shock response, improve functional outcomes and slow disease progression in patients with inclusion body myositis compared to placebo?

Bottom Line

Arimoclomol 400 mg TID did not improve the IBMFRS total score or any secondary functional outcomes compared to placebo in patients with IBM over 20 months, despite having an acceptable safety profile. This negative trial adds to the growing list of failed therapies for IBM.

Major Points

  • Primary endpoint not met: IBMFRS change -3.26 (arimoclomol) vs -2.26 (placebo), difference -0.99 (95% CI -2.23 to 0.24, p=0.12)
  • No secondary endpoints showed statistically significant benefit
  • 126/151 (83%) completed trial on treatment; discontinuation higher in arimoclomol group (23% vs 10%)
  • 18% arimoclomol vs 5% placebo discontinued due to adverse events
  • Fewer serious adverse events in arimoclomol (15%) than placebo (23%)
  • Elevated transaminases ≥3x ULN: 7% arimoclomol vs 1% placebo
  • One case of tubulointerstitial nephritis in arimoclomol group
  • One of the largest randomized controlled trials in IBM providing natural history data for future trial design

Design

Study Type: Phase 3, multicentre, randomized, double-blind, placebo-controlled trial

Randomization: 1

Blinding: Double-blind; computer-generated permuted block randomization stratified by center; placebo matched in texture, appearance, solubility, smell, and flavour

Enrollment Period: August 16, 2017 to May 22, 2019

Follow-up Duration: 20 months

Centers: 12

Countries: USA, UK

Sample Size: 150

Analysis: Restricted maximum likelihood mixed model for repeated measurements (MMRM); full analysis set excluding randomisation errors; Satterthwaite approximation for degrees of freedom; sequential hierarchical testing for secondary endpoints

Inclusion Criteria

  • Diagnosis of inclusion body myositis fulfilling ENMC 2011 research diagnostic criteria
  • Onset of weakness at age >45 years
  • Ability to rise from a chair without support from another person or device
  • Ability to walk at least 20 feet (6 m) with or without an assistive device

Exclusion Criteria

  • Taking >7.5 mg/day prednisolone or equivalent
  • Taking intravenous immunoglobulin within previous 3 months
  • Taking other immunosuppressants or immunomodulators within previous 3 months

Arms

FieldControlArimoclomol
InterventionMatching placebo capsules (two capsules three times daily), matched in texture, appearance, solubility, smell, and flavourArimoclomol 400 mg (two 200 mg capsules) orally three times daily, total daily dose 1200 mg/day
Duration20 months20 months

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change from baseline to month 20 in IBMFRS (Inclusion Body Myositis Functional Rating Scale) total score (0-40, higher = less limitation)Primary-2.26 (95% CI -3.11 to -1.41)-3.26 (95% CI -4.15 to -2.36)0.12
Hand grip strength (strongest hand, kg)Secondary-2.60 (95% CI -3.82 to -1.38)-3.71 (95% CI -5.05 to -2.37)Not significant (difference -1.11, 95% CI -2.93 to 0.70)
Modified Timed Up and Go (mTUG, m/s)Secondary-0.11 (95% CI -0.16 to -0.06)-0.12 (95% CI -0.18 to -0.06)Not significant (difference -0.01, 95% CI -0.09 to 0.07)
Manual Muscle Testing (MMT) total scoreSecondary-0.56 (95% CI -0.76 to -0.37)-0.53 (95% CI -0.75 to -0.32)Not significant (difference 0.03, 95% CI -0.26 to 0.32)
6-minute walk test (6MWT, m)Secondary-34.58 (95% CI -50.90 to -18.27)-36.37 (95% CI -54.35 to -18.39)Not significant (difference -1.79, 95% CI -26.09 to 22.51)
SF-36 Physical Component ScoreSecondary-2.88 (95% CI -4.36 to -1.40)-1.39 (95% CI -2.96 to 0.17)Not significant (difference 1.49, 95% CI -0.69 to 3.66)
Knee extensor strength (strongest knee, kg)Secondary-4.13 (95% CI -5.40 to -2.86)-5.62 (95% CI -7.02 to -4.22)Not significant (difference -1.49, 95% CI -3.38 to 0.40)
HAQ-DI total scoreSecondary0.32 (95% CI 0.21 to 0.43)0.36 (95% CI 0.24 to 0.47)Not significant (difference 0.04, 95% CI -0.12 to 0.20)
2-minute walk test (2MWT, m)Secondary-9.72 (95% CI -15.29 to -4.15)-10.53 (95% CI -16.75 to -4.30)Not significant (difference -0.81, 95% CI -9.17 to 7.56)
SF-36 Mental Component ScoreSecondary-0.95 (95% CI -2.81 to 0.92)-3.41 (95% CI -5.38 to -1.43)Not significant (difference -2.46, 95% CI -5.20 to 0.27)
Any adverse eventAdverse70 (90%)72 (99%)
Treatment-related adverse eventsAdverse38 (49%)61 (84%)
Serious adverse eventsAdverse18 (23%); 28 events11 (15%); 18 events
AEs leading to discontinuationAdverse4 (5%)13 (18%)
ALT or AST ≥3x ULNAdverse1 (1%)5 (7%)
Creatinine >1.5x baselineAdverse3 (4%)8 (11%)
NauseaAdverse1 (1%)9 (12%)
ConstipationAdverse9 (12%)14 (19%)
DiarrhoeaAdverse9 (12%)12 (16%)
RashAdverse4 (5%)14 (19%)
HeadacheAdverse4 (5%)7 (10%)
DizzinessAdverse08 (11%)
DeathsAdverse1 (off-treatment, unknown cause)1 (cholangiocarcinoma, unrelated)

Subgroup Analysis

Subgroup analyses by country, baseline IBMFRS score (<27.5 vs ≥27.5), baseline 6MWT distance (<321.3m vs ≥321.3m), and CN1A antibody status (positive vs negative) consistently favored placebo, with some variation in effect magnitude. No subgroup showed benefit from arimoclomol.

Criticisms

  • Single dose used (1200 mg/day); no dose-ranging in this population
  • Rate of IBMFRS decline in placebo group (-2.26 points over 20 months) was lower than expected based on pilot study, reducing power to detect treatment effect
  • Average disease duration ~8 years; earlier intervention might yield different results
  • Higher discontinuation rate in arimoclomol group (23% vs 10%) may have biased results
  • 18% treatment discontinuation due to AEs in arimoclomol group suggests tolerability issues at this dose
  • Heterogeneity of IBM progression rates at individual level complicates trial design
  • COVID-19 pandemic necessitated protocol amendments allowing remote visits
  • Heat shock response may not adequately address the complex pathophysiology of IBM involving both degeneration and inflammation

Funding

US FDA Office of Orphan Products Development (grant R01FD004809) and Orphazyme (sponsor transferred to Zevra Denmark after study completion)

Based on: Arimoclomol in IBM (Lancet Neurology, 2023)

Authors: Pedro M Machado, Michael P McDermott, Thomas Blaettler, ..., Mazen M Dimachkie

Citation: Lancet Neurol 2023;22:900-11

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