A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A
Abstract Background Charcot–Marie–Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This p...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-10-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-021-02040-8 |
| _version_ | 1797219622694420480 |
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| author | Shahram Attarian Peter Young Thomas H. Brannagan David Adams Philip Van Damme Florian P. Thomas Carlos Casanovas Jafar Kafaie Céline Tard Maggie C. Walter Yann Péréon David Walk Amro Stino Marianne de Visser Camiel Verhamme Anthony Amato Gregory Carter Laurent Magy Jeffrey M. Statland Kevin Felice |
| author_facet | Shahram Attarian Peter Young Thomas H. Brannagan David Adams Philip Van Damme Florian P. Thomas Carlos Casanovas Jafar Kafaie Céline Tard Maggie C. Walter Yann Péréon David Walk Amro Stino Marianne de Visser Camiel Verhamme Anthony Amato Gregory Carter Laurent Magy Jeffrey M. Statland Kevin Felice |
| author_sort | Shahram Attarian |
| collection | DOAJ |
| description | Abstract Background Charcot–Marie–Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. Methods In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. Results High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: − 0.37 points; 97.5% CI [− 0.68 to − 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. Conclusion The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot–Marie–Tooth disease type 1A. |
| first_indexed | 2024-03-10T17:03:17Z |
| format | Article |
| id | doaj.art-cdd77817d00b47deb0f0fb315c44524e |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-04-24T12:36:35Z |
| publishDate | 2021-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-cdd77817d00b47deb0f0fb315c44524e2024-04-07T11:30:34ZengBMCOrphanet Journal of Rare Diseases1750-11722021-10-0116111210.1186/s13023-021-02040-8A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1AShahram Attarian0Peter Young1Thomas H. Brannagan2David Adams3Philip Van Damme4Florian P. Thomas5Carlos Casanovas6Jafar Kafaie7Céline Tard8Maggie C. Walter9Yann Péréon10David Walk11Amro Stino12Marianne de Visser13Camiel Verhamme14Anthony Amato15Gregory Carter16Laurent Magy17Jeffrey M. Statland18Kevin Felice19Reference Center for Neuromuscular Disorders and ALS, CHU La TimoneDepartment of Neurology, Medical Park Bad FeilnbachColumbia University Medical Center, The Neurological InstituteFrench Reference Center for Rare Peripheral Neuropathies, Service de Neurologie Adulte, APHP, CHU BicêtreDepartment of Neurology, University Hospitals Leuven, KUDepartment of Neurology, Hackensack University Medical CenterNeuromuscular Unit, Neurology Department, Bellvitge University HospitalDepartment of Neurology, Saint Louis University School of MedicineU1171, Centre de référence des maladies neuromusculaires Nord Est Ile de France, Hôpital Salengro CHU de LilleDepartment of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University of MunichCentre de Référence Maladies Neuromusculaires AOC, Filnemus, Euro-NMD, CHU NantesClinical Neuroscience Research Unit, University of MinnesotaUniversity of Michigan Health SystemDepartment of Neurology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam NeuroscienceDepartment of Neurology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam NeuroscienceDepartment of Neurology, Brigham and Women’s HospitalSt. Luke’s Rehabilitation Institute, Physical Medicine and RehabilitationCHU DupuytrenUniversity of Kansas Medical CenterDepartment of Neuromuscular Medicine, Hospital for Special CareAbstract Background Charcot–Marie–Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. Methods In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. Results High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: − 0.37 points; 97.5% CI [− 0.68 to − 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. Conclusion The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot–Marie–Tooth disease type 1A.https://doi.org/10.1186/s13023-021-02040-8Charcot–Marie–ToothCMT1ANeuromuscular disorderOverall Neuropathy Limitations ScalePMP22PXT3003 |
| spellingShingle | Shahram Attarian Peter Young Thomas H. Brannagan David Adams Philip Van Damme Florian P. Thomas Carlos Casanovas Jafar Kafaie Céline Tard Maggie C. Walter Yann Péréon David Walk Amro Stino Marianne de Visser Camiel Verhamme Anthony Amato Gregory Carter Laurent Magy Jeffrey M. Statland Kevin Felice A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A Orphanet Journal of Rare Diseases Charcot–Marie–Tooth CMT1A Neuromuscular disorder Overall Neuropathy Limitations Scale PMP22 PXT3003 |
| title | A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A |
| title_full | A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A |
| title_fullStr | A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A |
| title_full_unstemmed | A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A |
| title_short | A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A |
| title_sort | double blind placebo controlled randomized trial of pxt3003 for the treatment of charcot marie tooth type 1a |
| topic | Charcot–Marie–Tooth CMT1A Neuromuscular disorder Overall Neuropathy Limitations Scale PMP22 PXT3003 |
| url | https://doi.org/10.1186/s13023-021-02040-8 |
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