Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy
Abstract Background Mitochondrial disease is a heterogenous group of rare, complex neurometabolic disorders. Despite their individual rarity, collectively mitochondrial diseases represent the most common cause of inherited metabolic disorders in the UK; they affect 1 in every 4300 individuals, up to...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-09-01
|
| Series: | Trials |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13063-022-06544-x |
| _version_ | 1811265174490841088 |
|---|---|
| author | The AIMM Trial Group: Alaa Abouhajar Lisa Alcock Theophile Bigirumurame Penny Bradley Laura Brown Ian Campbell Sylvia Del Din Julie Faitg Gavin Falkous Gráinne S. Gorman Rachel Lakey Robert McFarland Jane Newman Lynn Rochester Vicky Ryan Hesther Smith Alison Steel Renae J. Stefanetti Huizhong Su Robert W. Taylor Naomi J.P. Thomas Helen Tuppen Amy E. Vincent Charlotte Warren Gillian Watson |
| author_facet | The AIMM Trial Group: Alaa Abouhajar Lisa Alcock Theophile Bigirumurame Penny Bradley Laura Brown Ian Campbell Sylvia Del Din Julie Faitg Gavin Falkous Gráinne S. Gorman Rachel Lakey Robert McFarland Jane Newman Lynn Rochester Vicky Ryan Hesther Smith Alison Steel Renae J. Stefanetti Huizhong Su Robert W. Taylor Naomi J.P. Thomas Helen Tuppen Amy E. Vincent Charlotte Warren Gillian Watson |
| author_sort | The AIMM Trial Group: |
| collection | DOAJ |
| description | Abstract Background Mitochondrial disease is a heterogenous group of rare, complex neurometabolic disorders. Despite their individual rarity, collectively mitochondrial diseases represent the most common cause of inherited metabolic disorders in the UK; they affect 1 in every 4300 individuals, up to 15,000 adults (and a similar number of children) in the UK. Mitochondrial disease manifests multisystem and isolated organ involvement, commonly affecting those tissues with high energy demands, such as skeletal muscle. Myopathy manifesting as fatigue, muscle weakness and exercise intolerance is common and debilitating in patients with mitochondrial disease. Currently, there are no effective licensed treatments and consequently, there is an urgent clinical need to find an effective drug therapy. Aim To investigate the efficacy of 12-week treatment with acipimox on the adenosine triphosphate (ATP) content of skeletal muscle in patients with mitochondrial disease and myopathy. Methods AIMM is a single-centre, double blind, placebo-controlled, adaptive designed trial, evaluating the efficacy of 12 weeks’ administration of acipimox on skeletal muscle ATP content in patients with mitochondrial myopathy. Eligible patients will receive the trial investigational medicinal product (IMP), either acipimox or matched placebo. Participants will also be prescribed low dose aspirin as a non-investigational medical product (nIMP) in order to protect the blinding of the treatment assignment. Eighty to 120 participants will be recruited as required, with an interim analysis for sample size re-estimation and futility assessment being undertaken once the primary outcome for 50 participants has been obtained. Randomisation will be on a 1:1 basis, stratified by Fatigue Impact Scale (FIS) (dichotomised as < 40, ≥ 40). Participants will take part in the trial for up to 20 weeks, from screening visits through to follow-up at 16 weeks post randomisation. The primary outcome of change in ATP content in skeletal muscle and secondary outcomes relating to quality of life, perceived fatigue, disease burden, limb function, balance and walking, skeletal muscle analysis and symptom-limited cardiopulmonary fitness (optional) will be assessed between baseline and 12 weeks. Discussion The AIMM trial will investigate the effect of acipimox on modulating muscle ATP content and whether it can be repurposed as a new treatment for mitochondrial disease with myopathy. Trial registration EudraCT2018-002721-29 . Registered on 24 December 2018, ISRCTN 12895613. Registered on 03 January 2019, https://www.isrctn.com/search?q=aimm |
| first_indexed | 2024-04-12T20:18:54Z |
| format | Article |
| id | doaj.art-0e77b4f741a34930bece1b228e941d9a |
| institution | Directory Open Access Journal |
| issn | 1745-6215 |
| language | English |
| last_indexed | 2024-04-12T20:18:54Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Trials |
| spelling | doaj.art-0e77b4f741a34930bece1b228e941d9a2022-12-22T03:18:03ZengBMCTrials1745-62152022-09-0123111510.1186/s13063-022-06544-xAcipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathyThe AIMM Trial Group:Alaa Abouhajar0Lisa Alcock1Theophile Bigirumurame2Penny Bradley3Laura Brown4Ian Campbell5Sylvia Del Din6Julie Faitg7Gavin Falkous8Gráinne S. Gorman9Rachel Lakey10Robert McFarland11Jane Newman12Lynn Rochester13Vicky Ryan14Hesther Smith15Alison Steel16Renae J. Stefanetti17Huizhong Su18Robert W. Taylor19Naomi J.P. Thomas20Helen Tuppen21Amy E. Vincent22Charlotte Warren23Gillian Watson24Newcastle Clinical Trials Unit, 1-4 Claremont Terrace, Newcastle UniversityBrain and Movement Research Group, Clinical Ageing Research Unit, Translational and Clinical Research Institute, Newcastle UniversityPopulation Health Sciences Institute, Newcastle UniversityPharmacy Directorate, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman HospitalWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityPharmacy Directorate, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman HospitalBrain and Movement Research Group, Clinical Ageing Research Unit, Translational and Clinical Research Institute, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityNewcastle Clinical Trials Unit, 1-4 Claremont Terrace, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityBrain and Movement Research Group, Clinical Ageing Research Unit, Translational and Clinical Research Institute, Newcastle UniversityPopulation Health Sciences Institute, Newcastle UniversityPharmacy Directorate, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman HospitalNewcastle Clinical Trials Unit, 1-4 Claremont Terrace, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityNewcastle Clinical Trials Unit, 1-4 Claremont Terrace, Newcastle UniversityAbstract Background Mitochondrial disease is a heterogenous group of rare, complex neurometabolic disorders. Despite their individual rarity, collectively mitochondrial diseases represent the most common cause of inherited metabolic disorders in the UK; they affect 1 in every 4300 individuals, up to 15,000 adults (and a similar number of children) in the UK. Mitochondrial disease manifests multisystem and isolated organ involvement, commonly affecting those tissues with high energy demands, such as skeletal muscle. Myopathy manifesting as fatigue, muscle weakness and exercise intolerance is common and debilitating in patients with mitochondrial disease. Currently, there are no effective licensed treatments and consequently, there is an urgent clinical need to find an effective drug therapy. Aim To investigate the efficacy of 12-week treatment with acipimox on the adenosine triphosphate (ATP) content of skeletal muscle in patients with mitochondrial disease and myopathy. Methods AIMM is a single-centre, double blind, placebo-controlled, adaptive designed trial, evaluating the efficacy of 12 weeks’ administration of acipimox on skeletal muscle ATP content in patients with mitochondrial myopathy. Eligible patients will receive the trial investigational medicinal product (IMP), either acipimox or matched placebo. Participants will also be prescribed low dose aspirin as a non-investigational medical product (nIMP) in order to protect the blinding of the treatment assignment. Eighty to 120 participants will be recruited as required, with an interim analysis for sample size re-estimation and futility assessment being undertaken once the primary outcome for 50 participants has been obtained. Randomisation will be on a 1:1 basis, stratified by Fatigue Impact Scale (FIS) (dichotomised as < 40, ≥ 40). Participants will take part in the trial for up to 20 weeks, from screening visits through to follow-up at 16 weeks post randomisation. The primary outcome of change in ATP content in skeletal muscle and secondary outcomes relating to quality of life, perceived fatigue, disease burden, limb function, balance and walking, skeletal muscle analysis and symptom-limited cardiopulmonary fitness (optional) will be assessed between baseline and 12 weeks. Discussion The AIMM trial will investigate the effect of acipimox on modulating muscle ATP content and whether it can be repurposed as a new treatment for mitochondrial disease with myopathy. Trial registration EudraCT2018-002721-29 . Registered on 24 December 2018, ISRCTN 12895613. Registered on 03 January 2019, https://www.isrctn.com/search?q=aimmhttps://doi.org/10.1186/s13063-022-06544-xAcipimoxAdenosine triphosphateMitochondrial diseaseMitochondriaMyopathyRandomised controlled trial |
| spellingShingle | The AIMM Trial Group: Alaa Abouhajar Lisa Alcock Theophile Bigirumurame Penny Bradley Laura Brown Ian Campbell Sylvia Del Din Julie Faitg Gavin Falkous Gráinne S. Gorman Rachel Lakey Robert McFarland Jane Newman Lynn Rochester Vicky Ryan Hesther Smith Alison Steel Renae J. Stefanetti Huizhong Su Robert W. Taylor Naomi J.P. Thomas Helen Tuppen Amy E. Vincent Charlotte Warren Gillian Watson Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy Trials Acipimox Adenosine triphosphate Mitochondrial disease Mitochondria Myopathy Randomised controlled trial |
| title | Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy |
| title_full | Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy |
| title_fullStr | Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy |
| title_full_unstemmed | Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy |
| title_short | Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy |
| title_sort | acipimox in mitochondrial myopathy aimm study protocol for a randomised double blinded placebo controlled adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy |
| topic | Acipimox Adenosine triphosphate Mitochondrial disease Mitochondria Myopathy Randomised controlled trial |
| url | https://doi.org/10.1186/s13063-022-06544-x |
| work_keys_str_mv | AT theaimmtrialgroup acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT alaaabouhajar acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT lisaalcock acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT theophilebigirumurame acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT pennybradley acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT laurabrown acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT iancampbell acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT sylviadeldin acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT juliefaitg acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT gavinfalkous acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT grainnesgorman acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT rachellakey acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT robertmcfarland acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT janenewman acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT lynnrochester acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT vickyryan acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT hesthersmith acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT alisonsteel acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT renaejstefanetti acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT huizhongsu acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT robertwtaylor acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT naomijpthomas acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT helentuppen acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT amyevincent acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT charlottewarren acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy AT gillianwatson acipimoxinmitochondrialmyopathyaimmstudyprotocolforarandomiseddoubleblindedplacebocontrolledadaptivedesigntrialoftheefficacyofacipimoxinadultpatientswithmitochondrialmyopathy |