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Reduction of new he...
Reduction of new heterotopic ossification (HO) in the open-label, phase 3 MOVE trial of palovarotene for fibrodysplasia ossificans progressiva (FOP)
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- Pignolo, Robert J. (författare)
- Department of Medicine, Mayo Clinic, MN, Rochester, United States
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- Hsiao, Edward C. (författare)
- Division of Endocrinology and Metabolism, the UCSF Metabolic Bone Clinic, the Eli and Edythe Broad Institute for Regeneration Medicine, and the Institute of Human Genetics, Department of Medicine, and the UCSF Program in Craniofacial Biology, University of California-San Francisco, CA, San Francisco, United States
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- Al Mukaddam, Mona (författare)
- Departments of Orthopaedic Surgery & Medicine, The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United States
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- Baujat, Geneviève (författare)
- Département de Génétique, Institut IMAGINE and Hôpital Universitaire Necker-Enfants Malades, Paris, France
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- Berglund, Staffan K. (författare)
- Umeå universitet,Pediatrik
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- Brown, Matthew A. (författare)
- Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; Genomics England Ltd, London, United Kingdom
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- Cheung, Angela M. (författare)
- Department of Medicine and Joint Department of Medical Imaging, University Health Network, University of Toronto, ON, Toronto, Canada
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- De Cunto, Carmen (författare)
- Pediatric Rheumatology Section, Department of Pediatrics, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
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- Delai, Patricia (författare)
- Centro de Pesquisa Clinica, Hospital Israelita Albert Einstein, São Paulo, Brazil
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- Haga, Nobuhiko (författare)
- Department of Rehabilitation Medicine, The University of Tokyo Hospital, Tokyo, Japan
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- Kannu, Peter (författare)
- Hospital for Sick Children, ON, Toronto, Canada
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- Keen, Richard (författare)
- Centre for Metabolic Bone Disease, Royal National Orthopaedic Hospital, Stanmore, United Kingdom
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- Le Quan Sang, Kim-Hanh (författare)
- Département de Génétique, Institut IMAGINE and Hôpital Universitaire Necker-Enfants Malades, Paris, France
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- Mancilla, Edna E. (författare)
- Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United States
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- Marino, Rose (författare)
- Ipsen, MA, Cambridge, United States
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- Strahs, Andrew (författare)
- Ipsen, MA, Cambridge, United States
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- Kaplan, Frederick S. (författare)
- Departments of Orthopaedic Surgery & Medicine, The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United States
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(creator_code:org_t)
- 2023-01-25
- 2023
- Engelska.
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Ingår i: Journal of Bone and Mineral Research. - : John Wiley & Sons. - 0884-0431 .- 1523-4681. ; 38:3, s. 381-394
- Relaterad länk:
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single-arm, open-label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged ≥4 years received palovarotene once daily (chronic: 5 mg; flare-up: 20 mg for 4 weeks, then 10 mg for ≥8 weeks; weight-adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square-root transformation. Twelve-month interim analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18-month interim analyses utilized BcPM with square-root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed-effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen-month interim analyses included 97 MOVE and 101 NHS individuals with post-baseline WBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS. wLME results were similar (54% reduction fitted; nominal p = 0.039). All palovarotene-treated patients reported ≥1 adverse event (AE); 97.0% reported ≥1 retinoid-associated AE; 29.3% reported ≥1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses using WBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene-treated patients. Thus, post hoc analyses showed evidence for efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Nyckelord
- clinical trial
- fibrodysplasia ossificans progressiva
- therapeutics
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- ref (ämneskategori)
- art (ämneskategori)
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Pignolo, Robert ...
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Hsiao, Edward C.
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Al Mukaddam, Mon ...
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Baujat, Genevièv ...
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Berglund, Staffa ...
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Brown, Matthew A ...
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visa fler...
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Cheung, Angela M ...
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De Cunto, Carmen
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Delai, Patricia
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Haga, Nobuhiko
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Kannu, Peter
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Keen, Richard
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Le Quan Sang, Ki ...
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Mancilla, Edna E ...
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Marino, Rose
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Strahs, Andrew
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Kaplan, Frederic ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Endokrinologi oc ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Neurologi
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Journal of Bone ...
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