Background: Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis., Methods: This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed., Findings: Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 [76%] male and 36 [24%] female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 [77%] and 70 [90%], respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (-3·26, 95% CI -4·15 to -2·36 in the arimoclomol group vs -2·26, -3·11 to -1·41 in the placebo group; mean difference -0·99 [95% CI -2·23 to 0·24]; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group., Interpretation: Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design., Funding: US Food and Drug Administration Office of Orphan Products Development and Orphazyme., Competing Interests: Declaration of interests PMM has received consulting fees and funding support from Orphazyme, paid to his academic institution (University College London) for the oversight and conduct of this study, and has also received honoraria from Abbvie, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche, and UCB. MPM has received research funding from the US National Institutes of Health (NIH), the US Food and Drug Administration, Cure SMA, and PTC Therapeutics; received consulting fees from NeuroDerm and Fulcrum Therapeutics; and served on data and safety monitoring boards for NIH, Eli Lilly and Company, Catabasis Pharmaceuticals, Vaccinex, Neurocrine Biosciences, Voyager Therapeutics, Prilenia Therapeutics Development, ReveraGen BioPharma, and NS Pharma. TB, CS, AR, TDC, KB, ANJ, and KP are previous employees of Orphazyme. MF has received consulting fees from UCB, Argenx, Alexion, and CSL Behring; and research support paid to her institution (Ohio State University) from UCB, Argenx, Alexion, Fulcrum, Avidity, Pharnext, Janssen, and Roche. TEL has served as a consultant for Aavogen, Abata Therapeutics, Abcuro, Acceleron, DrenBio, EMD Serano, Kezar Life Sciences, Ono Pharma, Orphazyme, Regenacy, Sarepta, and Takeda; DSMB was Chair of the data and safety monitoring board for a Pharnext-sponsored clinical trial; and received research support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH (R01 AR076390), the Muscular Dystrophy Association (MDA630399), Horizon Therapeutics, and The Peter and Carmen Lucia Buck Foundation. TM has served as an advisor to Alexion (AstraZeneca), Amicus, AnnJi, Argenx, Arvinas, Ask-Bio, Audentes (now Astellas Gene Therapy), Horizon Therapeutics, Maze Therapeutics, Momenta (now Janssen), Sanofi, Sarepta, Spark Therapeutics, UCB/Ra Pharmaceuticals, and Modis/Zogenix (now UCB); has served on the speaker's bureau for Sanofi-Genzyme, Alexion, and Argenx; has served on the medical advisory board for the Myositis Association, Neuromuscular Disease Foundation, Myasthenia Gravis Foundation of California, and Myasthenia Gravis Foundation of America; has received research funding from the Myositis Association, the Muscular Dystrophy Association, NIH, and from the following commercial sponsors: Alexion, Amicus, AnnJi, Argenx, Audentes/Astellas Gene Therapy, Bristol Myers Squibb, Cartesian Therapeutics, Grifols, ML-Bio, Momenta, Ra Pharmaceuticals, Sanofi, Spark Therapeutics, UCB, and Valerion; and he serves on the data safety monitoring boards for Acceleron, Avexis, Sarepta, and NIH. RJB has received funding from the FDA Office Orphan Products Development grant for his role in this study. MGH receives research funding from the Medical Research Council UK and has previously acted as a consultant for Novartis and Orphazyme. MMD is a consultant for Orphazyme and received funding support, paid to his academic institution (University of Kansas Medical Center, Research Institute), from Orphazyme for the oversight and conduct of this study. He also serves or recently served as a consultant for Abcuro, Amazentis, ArgenX, Astellas, Catalyst, Cello, Covance/Labcorp, CSL-Behring, EcoR1, Janssen, Kezar, MDA, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, Roivant Sciences, Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, Abata/Third Rock, UCB Biopharma and received research grants or contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA Office of Orphan Products Development, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, Muscular Dystrophy Association, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, Ra Pharma/UCB, Viromed/Healixmith, and The Myositis Association. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)