Optimism in inclusion body myositis: a double-blind randomised controlled phase III trial investigating the effect of sirolimus on disease progression in patients with IBM as measured by the IBM Functional Rating Scale

Umesh A Badrising¹, Robert Henderson², Stephen Reddel³, Alastair Corbett⁴, Christina Liang⁵, Katrina Reardon⁶, Roula Ghaoui⁷, Max Bulsara⁸, Stefen Brady⁹, Anna Brusch¹⁰, Doris Chan¹¹, Jerome D Coudert¹², Timothy Fairchild¹³, Gayatri Jain¹⁴, Matthew C Kiernan¹⁵, Dag Leonard¹⁶, Thomas Lloyd¹⁷, Jens Schmidt¹⁸, Mike P McDermott¹⁹, Lauren Sanders²⁰, Christine Lowe²¹, Anneke J van der Kooi²², Chris Weihl²³, Payam Mohassel²⁴, Marion Simpson²⁵, Antonia Carroll²⁶, Ian Cooper²⁷, Kelly Beer²⁷, Krystyne Hiscock²⁸, Susan Walters²⁹, Annik Panicker²⁷, Althea Doverty³⁰, Andrew Heim³¹, Marjolein van Heur-Neuman¹, Olivier Benveniste³², Mazen M Dimachkie^#³³, Merrilee Needham^#³⁴

Affiliations

¹ Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.
² Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane; and Centre for Clinical Research, University of Queensland, Brisbane, Australia.
³ Brain and Mind Centre, University of Sydney, Camperdown, New South Wales, Australia.
⁴ Department of Neurology, Concord Repatriation Hospital, Concord, New South Wales, Australia.
⁵ Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales; Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, New South Wales; and Neuroscience Research Australia, Sydney, New South Wales, Australia.
⁶ Department of Neurology, St Vincent's Hospital Melbourne, Fitzroy, Victoria; and The University of Melbourne, Victoria, Australia.
⁷ Department of Neurology, Central Adelaide Local Health Network/Royal Adelaide Hospital, Adelaide, South Australia; and Adelaide Medical School, University of Adelaide, South Australia, Australia.
⁸ Institute for Health Research, The University of Notre Dame Australia, Fremantle, Western Australia, Australia.
⁹ Oxford Adult Muscle Service, John Radcliffe Hospital, Oxford University Hospital Trust, Oxford, UK.
¹⁰ Department of Clinical Immunology, Sir Charles Gairdner Hospital and PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia; Perron Institute for Neurological and Translational Science, Nedlands, Western Australia; and Centre for Neuromuscular and Neurological Disorders, University of Western Australia Medical School, Perth, Western Australia, Australia.
¹¹ Department of Renal Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
¹² Perron Institute for Neurological and Translational Science, Nedlands, Western Australia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia; and University of Notre Dame Australia, School of Medicine, Fremantle, Western Australia, Australia.
¹³ Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia; School of Allied Health (Exercise Science), Murdoch University, Murdoch, Western Australia; and Centre for Healthy Aging, Murdoch University, Murdoch, Western Australia, Australia.
¹⁴ Department of Neurology, St Vincent's Hospital Melbourne, Fitzroy, Victoria; and Department of Neurology, Austin Hospital, Austin Health, Heidelberg, Victoria, Australia.
¹⁵ Neuroscience Research Australia, University of New South Wales, Sydney, New South Wales; and Neurology Department, South Eastern Sydney Local Health District, Sydney, New South Wales, Australia.
¹⁶ Department of Medical Sciences, University of Uppsala, Sweden.
¹⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology, Baylor College of Medicine, Houston, TX; and Department of Clinical Research, Imricor Medical Systems, Burnsville, MN, USA.
¹⁸ Klinik für Neurologie, Universitätsmedizin Göttingen; Abteilung für Neurologie und Schmerztherapie, Neuromuskuläres Zentrum, Zentrum für Translationale Medizin, Immanuel Klinik Rüdersdorf, Universitätsklinikum der Medizinischen Hochschule Brandenburg, Rüdersdorf bei Berlin; and Fakultät für Gesundheitswissenschaften Brandenburg, Medizinische Hochschule Brandenburg Theodor Fontane, Rüdersdorf bei Berlin, Germany.
¹⁹ Department of Biostatistics and Computational Biology and Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
²⁰ Department of Neurology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia.
²¹ The Myositis Association- Australia Inc, Berry, New South Wales, Australia.
²² Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, the Netherlands.
²³ Neuromuscular Division, Washington University School of Medicine, Saint Louis, USA.
²⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁵ Department of Neurology, Austin Hospital, Austin Health, Heidelberg, Victoria, Australia.
²⁶ Brain and Mind Centre, Faculty of Medicine and Health, Translational Research Collective, University of Sydney and Department of Neurology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
²⁷ Perron Institute for Neurological and Translational Science, Nedlands, Western Australia; and Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia, Australia.
²⁸ Affinity Clinical Research, Nedlands, Western Australia, Australia.
²⁹ Perron Institute for Neurological and Translational Science, Nedlands, Western Australia, Australia.
³⁰ PPerron Institute for Neurological and Translational Science, Nedlands, Western Australia; and Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia, Australia.
³¹ University of Kansas Medical Center, Kansas City, KS, USA. aheim2@kumc.edu.
³² Sorbonne University, AP-HP, Paris; and Department of Internal Medicine and Clinical Immunology, National Reference Centre for Inflammatory Myopathies, Hôpital Pitié-Salpêtrière, Paris, France.
³³ University of Kansas Medical Center, Kansas City, KS, USA.
³⁴ Perron Institute for Neurological and Translational Science, Nedlands, Western Australia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia; University of Notre Dame Australia, School of Medicine, Fremantle, Western Australia, and Fiona Stanley Hospital, Murdoch, Western Australia, Australia.

^# Contributed equally.

PMID: 40018746
DOI: 10.55563/clinexprheumatol/zvffa0

Free article

Optimism in inclusion body myositis: a double-blind randomised controlled phase III trial investigating the effect of sirolimus on disease progression in patients with IBM as measured by the IBM Functional Rating Scale

Umesh A Badrising et al. Clin Exp Rheumatol. 2025 Feb.

Free article

. 2025 Feb;43(2):316-325.

doi: 10.55563/clinexprheumatol/zvffa0. Epub 2025 Feb 26.

Authors

Affiliations

¹ Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.
² Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane; and Centre for Clinical Research, University of Queensland, Brisbane, Australia.
³ Brain and Mind Centre, University of Sydney, Camperdown, New South Wales, Australia.
⁴ Department of Neurology, Concord Repatriation Hospital, Concord, New South Wales, Australia.
⁵ Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales; Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, New South Wales; and Neuroscience Research Australia, Sydney, New South Wales, Australia.
⁶ Department of Neurology, St Vincent's Hospital Melbourne, Fitzroy, Victoria; and The University of Melbourne, Victoria, Australia.
⁷ Department of Neurology, Central Adelaide Local Health Network/Royal Adelaide Hospital, Adelaide, South Australia; and Adelaide Medical School, University of Adelaide, South Australia, Australia.
⁸ Institute for Health Research, The University of Notre Dame Australia, Fremantle, Western Australia, Australia.
⁹ Oxford Adult Muscle Service, John Radcliffe Hospital, Oxford University Hospital Trust, Oxford, UK.
¹⁰ Department of Clinical Immunology, Sir Charles Gairdner Hospital and PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia; Perron Institute for Neurological and Translational Science, Nedlands, Western Australia; and Centre for Neuromuscular and Neurological Disorders, University of Western Australia Medical School, Perth, Western Australia, Australia.
¹¹ Department of Renal Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
¹² Perron Institute for Neurological and Translational Science, Nedlands, Western Australia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia; and University of Notre Dame Australia, School of Medicine, Fremantle, Western Australia, Australia.
¹³ Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia; School of Allied Health (Exercise Science), Murdoch University, Murdoch, Western Australia; and Centre for Healthy Aging, Murdoch University, Murdoch, Western Australia, Australia.
¹⁴ Department of Neurology, St Vincent's Hospital Melbourne, Fitzroy, Victoria; and Department of Neurology, Austin Hospital, Austin Health, Heidelberg, Victoria, Australia.
¹⁵ Neuroscience Research Australia, University of New South Wales, Sydney, New South Wales; and Neurology Department, South Eastern Sydney Local Health District, Sydney, New South Wales, Australia.
¹⁶ Department of Medical Sciences, University of Uppsala, Sweden.
¹⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology, Baylor College of Medicine, Houston, TX; and Department of Clinical Research, Imricor Medical Systems, Burnsville, MN, USA.
¹⁸ Klinik für Neurologie, Universitätsmedizin Göttingen; Abteilung für Neurologie und Schmerztherapie, Neuromuskuläres Zentrum, Zentrum für Translationale Medizin, Immanuel Klinik Rüdersdorf, Universitätsklinikum der Medizinischen Hochschule Brandenburg, Rüdersdorf bei Berlin; and Fakultät für Gesundheitswissenschaften Brandenburg, Medizinische Hochschule Brandenburg Theodor Fontane, Rüdersdorf bei Berlin, Germany.
¹⁹ Department of Biostatistics and Computational Biology and Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
²⁰ Department of Neurology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia.
²¹ The Myositis Association- Australia Inc, Berry, New South Wales, Australia.
²² Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, the Netherlands.
²³ Neuromuscular Division, Washington University School of Medicine, Saint Louis, USA.
²⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁵ Department of Neurology, Austin Hospital, Austin Health, Heidelberg, Victoria, Australia.
²⁶ Brain and Mind Centre, Faculty of Medicine and Health, Translational Research Collective, University of Sydney and Department of Neurology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
²⁷ Perron Institute for Neurological and Translational Science, Nedlands, Western Australia; and Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia, Australia.
²⁸ Affinity Clinical Research, Nedlands, Western Australia, Australia.
²⁹ Perron Institute for Neurological and Translational Science, Nedlands, Western Australia, Australia.
³⁰ PPerron Institute for Neurological and Translational Science, Nedlands, Western Australia; and Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia, Australia.
³¹ University of Kansas Medical Center, Kansas City, KS, USA. aheim2@kumc.edu.
³² Sorbonne University, AP-HP, Paris; and Department of Internal Medicine and Clinical Immunology, National Reference Centre for Inflammatory Myopathies, Hôpital Pitié-Salpêtrière, Paris, France.
³³ University of Kansas Medical Center, Kansas City, KS, USA.
³⁴ Perron Institute for Neurological and Translational Science, Nedlands, Western Australia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia; University of Notre Dame Australia, School of Medicine, Fremantle, Western Australia, and Fiona Stanley Hospital, Murdoch, Western Australia, Australia.

^# Contributed equally.

PMID: 40018746
DOI: 10.55563/clinexprheumatol/zvffa0

Abstract

Objectives: Inclusion body myositis (IBM) is a complex inflammatory muscle disease in adults over 40, with histological features of autoinflammation, cell stress and autophagic abnormalities, and marked clinically by relentless progression with no effective disease-modifying therapy. Sirolimus (rapamycin) may help maintain function by inhibiting T effector cells, preserving T regulatory cells, inducing autophagy, and improving mitochondrial function. This international trial follows a phase II pilot study.

Methods: This phase IIb/III double-blind, randomised, controlled trial (RCT) of sirolimus involves 140 IBM patients randomly assigned with equal allocation to sirolimus (2 mg) or matching placebo. This RCT aims to assess the efficacy of sirolimus compared to placebo in slowing or stabilising IBM progression, as measured by the mean change in patient function using the IBM Functional Rating Scale (IBM-FRS) from Baseline to Week 84. Secondary outcomes will evaluate efficacy and safety to inform future clinical trial design.

Results: Ethical approval has been granted in Australia (St Vincent's Hospital Melbourne HREC-D 311/20) and the USA (University of Kansas Medical Center Human Research Protection Program FWA no. 00003411), with European approval pending. The protocol is version 3.0 (02-Dec-2022).

Trial registration: ANZCTR: ACTRN12620001226998p, ClinicalTrials.gov: NCT04789070, UTN: U1111-1258-1354, and EU CT 2024-514575-17-00.

Conclusions: This phase IIb/III trial builds on prior findings to assess sirolimus's potential in slowing or halting IBM progression, preserving patient function and independence, and advancing IBM therapeutic strategies and trial design.

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Optimism in inclusion body myositis: a double-blind randomised controlled phase III trial investigating the effect of sirolimus on disease progression in patients with IBM as measured by the IBM Functional Rating Scale

Affiliations

Optimism in inclusion body myositis: a double-blind randomised controlled phase III trial investigating the effect of sirolimus on disease progression in patients with IBM as measured by the IBM Functional Rating Scale

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical

Research Materials