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| ID | Type | Description | Link |
|---|---|---|---|
| 2015-002378-19 | EudraCT Number |
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The purpose of this study is to determine whether PXT3003 is effective and safe in the treatment of Charcot-Marie-Tooth disease - Type 1 A (CMT1A). This double-blind study will assess in parallel groups 2 doses of PXT3003 compared to Placebo in CMT1A patients treated for 15 months.
PXT3003 is a fixed dose combination of (RS)-baclofen, naltrexone hydrochloride and D-sorbitol selected via a Systems Biology approach and developed by Pharnext, with the aim to limit the production of PMP22 and protect/improve axonal function in patients with CMT1A. On September 18th 2017, PXT3003 dose 2 was prematurely discontinued, due to an unexpected investigational medicinal product quality event (failed month 18 stability testing). This resulted in a large proportion of missing data that led us to reconsider the efficacy analysis that was initially planned in the protocol.The independent data safety monitoring committee did not identify any safety concern on September 5th 2017. All patients randomised to dose 2 were requested to undergo the end of study visit, and were offered to enter the extension study (CLN-PXT3003-03).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PXT3003 dose 1 | Active Comparator | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months |
|
| PXT3003 dose 2 | Active Comparator | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months |
|
| placebo | Placebo Comparator | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PXT3003 dose 1 | Drug | Liquid oral solution, 5 ml twice a day, morning and evening with food |
|
| Measure | Description | Time Frame |
|---|---|---|
| Overall Neuropathy Limitation Scale (ONLS) Total Score | The primary efficacy variable used in the main analysis is the mean of the available ONLS values at month 12 and month 15. The ONLS is a disability scale that was derived and improved from the Overall Disability Sum Score (ODSS) to measure limitations in the everyday activities of the upper limbs (rated on 5 points) and the lower limbs (rated on 7 points). The total score is a 12-point scale: 0 (no disability) to 12 (maximum disability). Lower values in the ONLS indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | From Baseline to Month 15 |
| Measure | Description | Time Frame |
|---|---|---|
| Mean of Ten Meter Walking Test (10MWT) | This outcome measure is the mean of the available 10MWT values at month 12 and month 15. The 10MWT is a simple to administer, standardized, reliable and valid evaluation of functional exercise capacity and gait that has been used to evaluate neurologic disorders and CMT patients. Lower Time to Walk 10 Meters values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). |
| Measure | Description | Time Frame |
|---|---|---|
| Mean of the CMTNS-v2 Sensory Symptoms | This outcome measure is the mean of the available CMTNS-v2 Sensory Symptoms values at month 12 and month 15. The CMTNS-v2 is a specific scale designed to assess severity of impairment in CMT disease. It is a 36-point scale based on nine items to quantify impairment (sensory symptoms, pin sensibility, vibration and arm and leg strength), activity limitations (motor symptoms arms and legs) and electrophysiological function (amplitudes of ulnar CMAP and SNAP). The CMTNS-v2 goes from 0 (no impairment) to 36 (maximum impairment) whom each sub-items goes from 0 to 4. The CMTNS-v2 Sensory Symptoms is the first item of the CMTNS-v2. It is a 4-point score: 0 (no impairment) to 4 (maximum impairment). Lower CMTNS-v2 Sensory Symptoms values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Shahram Attarian, MD | CHU La Timone, Marseille, France | Principal Investigator |
| Peter Young, MD | University Hospital Munster, Germany | Principal Investigator |
| Teresa Sevilla, MD | Hospital Universitari i Politécnic La Fe, Valencia, Spain | Principal Investigator |
| Marianne De Visser, MD | Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) | Principal Investigator |
| Philip Van Damme, MD | UZ Leuven, Belgium | Principal Investigator |
| Mark Roberts, MD | Salford Royal NHS Foundation Trust, Manchester, UK | Principal Investigator |
| Florian Thomas, MD | Saint-Louis University, Saint-Louis, USA | Principal Investigator |
| Jack Puymirat, MD | University Hospital of Quebec | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Neurology, Cedars-Sinai Medical Center | Los Angeles | California | 90048 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25519680 | Result | Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, Pereon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre MN, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Gres C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D. An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2014 Dec 18;9:199. doi: 10.1186/s13023-014-0199-0. | |
| 25491744 |
| Label | URL |
|---|---|
| Attarian et al., 2016 | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | PXT3003 Dose 1 | Liquid oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months. PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food). |
| FG001 | PXT3003 Dose 2 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 5, 2017 |
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| PXT3003 dose 2 | Drug | Liquid oral solution, 5 ml twice a day, morning and evening with food |
|
|
| placebo | Drug | Liquid oral solution, 5 ml twice a day, morning and evening with food |
|
| From Baseline to Month 15 |
| Mean of the CMTNS-v2 Sensory Score | This outcome measure is the mean of the available CMTNS-v2 Sensory Score values at month 12 and month 15. The CMTNS-v2 is a specific scale designed to assess severity of impairment in CMT disease. It is a 36-point scale based on nine items to quantify impairment (sensory symptoms, pin sensibility, vibration and arm and leg strength), activity limitations (motor symptoms arms and legs) and electrophysiological function (amplitudes of ulnar CMAP and SNAP). The CMTNS-v2 goes from 0 (no impairment) to 36 (maximum impairment) whom each sub-items goes from 0 to 4. The CMTNS-v2 Sensory score is summed of items 1+4+5 of CMTNS-v2 (Sensory symptoms, Pinprick sensibility and Vibration). It is a 12-point score: 0 (no impairment) to 12 (maximum impairment). Lower CMTNS-v2 Sensory Score values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | From Baseline to Month 15 |
| Mean of the CMTNS-v2 Examination Score (CMTES-v2) | This outcome measure is the mean of the available CMTNS-v2 Examination Score values at month 12 and month 15. The CMTNS-v2 is a specific scale designed to assess severity of impairment in CMT disease. It is a 36-point scale based on nine items to quantify impairment (sensory symptoms, pin sensibility, vibration and arm and leg strength), activity limitations (motor symptoms arms and legs) and electrophysiological function (amplitudes of ulnar CMAP and SNAP). The CMTNS-v2 goes from 0 (no impairment) to 36 (maximum impairment) whom each sub-items goes from 0 to 4. The CMTES-v2 is summed of item 1 to 7 of the CMTNS-v2 (limited to impairment items and excluding electrophysiological items). It is a 28-point score: 0 (no impairment) to 28 (maximum impairment). Lower CMTES-v2 values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | From Baseline to Month 15 |
| Mean of the Results at the Nine-Hole Peg Test (9-HPT) | This outcome measure is the mean of the available 9-HPT values at month 12 and month 15. The Nine-Hole Peg Test (9HPT) is a simple timed test of fine motor coordination of extremitied in the upper limbs. It measures the time needed by the patient to insert 9 pegs in nine holes and to remove them (normal required time 18 seconds). Lower 9HPT values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | From Baseline to Month 15 |
| Number of Subjects With at Least One TEAE | Safety selection was to include all randomized patients that have received at least one dose of study treatment. Safety and tolerability of PXT3003 were compared to placebo on the incidence of treatment-emergent adverse events (TEAEs); they were evaluated by type/nature, severity/intensity, seriousness, and relationship to study drug. | The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months) |
| Incidence of AE Leading to Withdrawal of Study Drug | Safety and tolerability of PXT3003 were compared to placebo on the incidence of TEAEs leading to withdrawal of study drug. | The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months) |
| Incidence of SAEs | Safety and tolerability of PXT3003 were compared to placebo on the incidence of serious adverse events (SAEs). | The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months). |
| From Baseline to Month 15 |
| Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake | Plasma concentration of PXT3003 components were measured at trough (prior to dose) and 90 minutes after drug intake. The mean plasma values of the baseline correspond to half of the administered dose. | At Month 12 and Month 15 |
| Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake | Plasma concentration of PXT3003 components were measured at trough (prior to dose) and 90 minutes after drug intake. The mean plasma values of the baseline correspond to half of the administered dose. | At Month 12 and month 15 |
| Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake | Plasma concentration of PXT3003 components were measured at trough (prior to dose) and peak (90 minutes post dose). The mean plasma values of the baseline correspond to half of the administered dose. | At Month 12 and Month 15 |
| Number of Participants With ONLS Therapy Response 1 | ONLS Therapy Response 1 was defined as the number of participants (responders) with an improvement on final ONLS Total Score of at least one point. A higher response rate indicate a better clinical condition. | From Baseline to Month 15 |
| Number of Participants With ONLS Therapy Response 2 | ONLS Therapy Response 2 was defined as the number of participants with no deterioration (responders) on final ONLS Total Score. A higher response rate indicates a better clinical condition. | From Baseline to Month 15 |
| Hospital for Special Care, New Britain |
| New Britain |
| Connecticut |
| 06053 |
| United States |
| Department of Neurology, McKnight Brain Institute | Gainesville | Florida | 32610 | United States |
| University of Kansas Medical Center | Kansas City | Kansas | 66160 | United States |
| Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
| University of Michigan Health System | Ann Arbor | Michigan | 48109-5322 | United States |
| Department of Neurology, University of Minnesota | Minneapolis | Minnesota | 55455 | United States |
| Department of Neurology and Psichiatry, Saint Louis University | St Louis | Missouri | 63104-1027 | United States |
| Peripheral Neuropathy Center, Neurological Institue Building, Columbia University Medical Center | New York | New York | 10032 | United States |
| Ohio State University | Columbus | Ohio | 43210 | United States |
| Saint Luke's Rehabilitation Institute | Spokane | Washington | 99202-1330 | United States |
| Departement of Neurology, UZ Leuven | Leuven | Belgium |
| University Hospital of Quebec | Québec | Quebec | G1J 1Z4 | Canada |
| Centre de Référence des Maladies Neuromusculaires, Hôpital Swynghedauwl, CHU de Lille | Lille | France |
| Centre de Référence des Neuropathies Périphériques Rares, Hôpital Dupuytren, CHU Limoges | Limoges | France |
| Service de Neurologie et du Sommeil, CHU Lyon Sud | Lyon | France |
| Centre de Référence des Maladies Neuromusculaires, Pôle des Neurosciences Clinique, CHU la Timone | Marseille | France |
| Centre de Référence des Maladies Neuromusculaires; Hôtel Dieu, CHU de Nantes | Nantes | France |
| Service de Neurologie, Hôpital Kremlin Bicêtre | Paris | France |
| Department of Neurology and Institute for Neuropathology, University Hospital RWTH Aachen | Aachen | Germany |
| Department of Clinical Neurophysiology, University Medical Center Göttingen | Göttingen | Germany |
| Department of Neurology, Ludwig-Maximillian University, Munich | Munich | Germany |
| Department for Sleep Medicine and Neuromuscular, University Hospital Münster | Münster | Germany |
| Departement of Neurology, Academic Medical Center | Amsterdam | Netherlands |
| Department of neurology, Hospital Univesitario de Bellvitge | Barcelona | Spain |
| Servicio de Neurologia, Hospital Universitario La Paz | Madrid | Spain |
| Centro de Diagnostico y Tratamiento, Hospital Universitario Virgen del Rocio | Seville | Spain |
| Servicio de Neurologia, Hospital Univesitari i Politécnic La Fe | Valencia | Spain |
| Department of Neurology, Salford Royal NHS Foundation Trust | Salford | Manchester | M6 8HD | United Kingdom |
| Ninewells Hospital and Medical School | Dundee | Scotland | DD1 9SY | United Kingdom |
| Result |
| Chumakov I, Milet A, Cholet N, Primas G, Boucard A, Pereira Y, Graudens E, Mandel J, Laffaire J, Foucquier J, Glibert F, Bertrand V, Nave KA, Sereda MW, Vial E, Guedj M, Hajj R, Nabirotchkin S, Cohen D. Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy. Orphanet J Rare Dis. 2014 Dec 10;9:201. doi: 10.1186/s13023-014-0201-x. |
| 26070802 | Result | Mandel J, Bertrand V, Lehert P, Attarian S, Magy L, Micallef J, Chumakov I, Scart-Gres C, Guedj M, Cohen D. A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment. Orphanet J Rare Dis. 2015 Jun 13;10:74. doi: 10.1186/s13023-015-0293-y. |
| 30650121 | Result | Prukop T, Stenzel J, Wernick S, Kungl T, Mroczek M, Adam J, Ewers D, Nabirotchkin S, Nave KA, Hajj R, Cohen D, Sereda MW. Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A). PLoS One. 2019 Jan 16;14(1):e0209752. doi: 10.1371/journal.pone.0209752. eCollection 2019. |
| Result | Hajj R, Prukop T, Wernick S, Ewers D, Brureau A, Cholet N, Laffaire J, Nave KA, Cohen D, Sereda M. Baclofen, Naltrexone and Sorbitol all contribute to the efficacy of PXT3003 in CMT1A Rats. EMJ Neurol, 2019;7[1]:47-49 |
| 27387831 | Result | Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, Pereon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre MN, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Gres C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D. Erratum to: An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2016 Jul 7;11(1):92. doi: 10.1186/s13023-016-0463-6. No abstract available. |
| Chumakov et al., 2014 | View source |
| Mandel et al., 2015 | View source |
| Prukop et al., 2019 | View source |
| Attarian et al., Erratum, 2016 | View source |
| Hajj et al., 2019 | View source |
Liquid oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months. PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food). |
| FG002 | Placebo | Liquid oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months. PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food). |
| COMPLETED | Completed at 12 months |
|
| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | PXT3003 Dose 1 | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months PXT3003 dose 1: Liquid oral solution, 5 ml twice a day, morning and evening with food |
| BG001 | PXT3003 Dose 2 | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months PXT3003 dose 2: Liquid oral solution, 5 ml twice a day, morning and evening with food |
| BG002 | Placebo | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months placebo: Liquid oral solution, 5 ml twice a day, morning and evening with food |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Overall Neuropathy Limitation Scale (ONLS) Total Score | The primary efficacy variable used in the main analysis is the mean of the available ONLS values at month 12 and month 15. The ONLS is a disability scale that was derived and improved from the Overall Disability Sum Score (ODSS) to measure limitations in the everyday activities of the upper limbs (rated on 5 points) and the lower limbs (rated on 7 points). The total score is a 12-point scale: 0 (no disability) to 12 (maximum disability). Lower values in the ONLS indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | mFAS selection | Posted | Mean | Standard Deviation | Scores on the ONLS | From Baseline to Month 15 |
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| Secondary | Mean of Ten Meter Walking Test (10MWT) | This outcome measure is the mean of the available 10MWT values at month 12 and month 15. The 10MWT is a simple to administer, standardized, reliable and valid evaluation of functional exercise capacity and gait that has been used to evaluate neurologic disorders and CMT patients. Lower Time to Walk 10 Meters values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | mFAS selection | Posted | Mean | Standard Deviation | Seconds (s) | From Baseline to Month 15 |
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| Secondary | Mean of the CMTNS-v2 Sensory Score | This outcome measure is the mean of the available CMTNS-v2 Sensory Score values at month 12 and month 15. The CMTNS-v2 is a specific scale designed to assess severity of impairment in CMT disease. It is a 36-point scale based on nine items to quantify impairment (sensory symptoms, pin sensibility, vibration and arm and leg strength), activity limitations (motor symptoms arms and legs) and electrophysiological function (amplitudes of ulnar CMAP and SNAP). The CMTNS-v2 goes from 0 (no impairment) to 36 (maximum impairment) whom each sub-items goes from 0 to 4. The CMTNS-v2 Sensory score is summed of items 1+4+5 of CMTNS-v2 (Sensory symptoms, Pinprick sensibility and Vibration). It is a 12-point score: 0 (no impairment) to 12 (maximum impairment). Lower CMTNS-v2 Sensory Score values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | mFAS selection | Posted | Mean | Standard Deviation | Scores on the CMTNS-v2 Sensory Score | From Baseline to Month 15 |
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| Secondary | Mean of the CMTNS-v2 Examination Score (CMTES-v2) | This outcome measure is the mean of the available CMTNS-v2 Examination Score values at month 12 and month 15. The CMTNS-v2 is a specific scale designed to assess severity of impairment in CMT disease. It is a 36-point scale based on nine items to quantify impairment (sensory symptoms, pin sensibility, vibration and arm and leg strength), activity limitations (motor symptoms arms and legs) and electrophysiological function (amplitudes of ulnar CMAP and SNAP). The CMTNS-v2 goes from 0 (no impairment) to 36 (maximum impairment) whom each sub-items goes from 0 to 4. The CMTES-v2 is summed of item 1 to 7 of the CMTNS-v2 (limited to impairment items and excluding electrophysiological items). It is a 28-point score: 0 (no impairment) to 28 (maximum impairment). Lower CMTES-v2 values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | mFAS selection | Posted | Mean | Standard Deviation | Scores on the CMTES-v2 | From Baseline to Month 15 |
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| Secondary | Mean of the Results at the Nine-Hole Peg Test (9-HPT) | This outcome measure is the mean of the available 9-HPT values at month 12 and month 15. The Nine-Hole Peg Test (9HPT) is a simple timed test of fine motor coordination of extremitied in the upper limbs. It measures the time needed by the patient to insert 9 pegs in nine holes and to remove them (normal required time 18 seconds). Lower 9HPT values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | mFAS selection | Posted | Mean | Standard Deviation | Seconds (s) | From Baseline to Month 15 |
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| Secondary | Number of Subjects With at Least One TEAE | Safety selection was to include all randomized patients that have received at least one dose of study treatment. Safety and tolerability of PXT3003 were compared to placebo on the incidence of treatment-emergent adverse events (TEAEs); they were evaluated by type/nature, severity/intensity, seriousness, and relationship to study drug. | FAS selection | Posted | Number | participants | The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months) |
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| Secondary | Incidence of AE Leading to Withdrawal of Study Drug | Safety and tolerability of PXT3003 were compared to placebo on the incidence of TEAEs leading to withdrawal of study drug. | FAS selection | Posted | Number | participants | The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months) |
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| Secondary | Incidence of SAEs | Safety and tolerability of PXT3003 were compared to placebo on the incidence of serious adverse events (SAEs). | FAS selection | Posted | Number | participants | The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months). |
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| Other Pre-specified | Mean of the CMTNS-v2 Sensory Symptoms | This outcome measure is the mean of the available CMTNS-v2 Sensory Symptoms values at month 12 and month 15. The CMTNS-v2 is a specific scale designed to assess severity of impairment in CMT disease. It is a 36-point scale based on nine items to quantify impairment (sensory symptoms, pin sensibility, vibration and arm and leg strength), activity limitations (motor symptoms arms and legs) and electrophysiological function (amplitudes of ulnar CMAP and SNAP). The CMTNS-v2 goes from 0 (no impairment) to 36 (maximum impairment) whom each sub-items goes from 0 to 4. The CMTNS-v2 Sensory Symptoms is the first item of the CMTNS-v2. It is a 4-point score: 0 (no impairment) to 4 (maximum impairment). Lower CMTNS-v2 Sensory Symptoms values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | mFAS selection | Posted | Mean | Standard Deviation | Scores on the CMTNS-v2 Sensory Symptoms | From Baseline to Month 15 |
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| Other Pre-specified | Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake | Plasma concentration of PXT3003 components were measured at trough (prior to dose) and 90 minutes after drug intake. The mean plasma values of the baseline correspond to half of the administered dose. | PP selection LLOQ = 30 pg/mL The placebo arm has not been described for this endpoint. | Posted | Mean | Standard Deviation | pg/mL | At Month 12 and Month 15 |
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| Other Pre-specified | Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake | Plasma concentration of PXT3003 components were measured at trough (prior to dose) and 90 minutes after drug intake. The mean plasma values of the baseline correspond to half of the administered dose. | PP selection LLOQ = 30 pg/mL The placebo arm has not been described for this endpoint. | Posted | Mean | Standard Deviation | pg/mL | At Month 12 and month 15 |
|
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| Other Pre-specified | Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake | Plasma concentration of PXT3003 components were measured at trough (prior to dose) and peak (90 minutes post dose). The mean plasma values of the baseline correspond to half of the administered dose. | PP selection LLOQ = 50 pg/mL The placebo arm has not been described for this endpoint. | Posted | Mean | Standard Deviation | pg/mL | At Month 12 and Month 15 |
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| Other Pre-specified | Number of Participants With ONLS Therapy Response 1 | ONLS Therapy Response 1 was defined as the number of participants (responders) with an improvement on final ONLS Total Score of at least one point. A higher response rate indicate a better clinical condition. | Completers selection | Posted | Number | Number of Participants | From Baseline to Month 15 |
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| Other Pre-specified | Number of Participants With ONLS Therapy Response 2 | ONLS Therapy Response 2 was defined as the number of participants with no deterioration (responders) on final ONLS Total Score. A higher response rate indicates a better clinical condition. | Completers selection | Posted | Number | Number of Participants | From Baseline to Month 15 |
|
The AE reporting period therefore started with the subject signing the informed consent form and ended 30 days after the end of study (corresponding to the date of "Date of completion/early discontinuation/last contact" recorded in the termination module up to 15 months)
This definition was extended due to the discontinuation of Dose 2 and study on hold in Germany. The period of AE reporting was extended to 1 month after the end of study, without informed consent signed for study CLN-PXT3003-03 during this period.
Only Treatment-Emergent Adverse Events (TEAE) have been reported for non-serious advers events.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | PXT3003 Dose 1 | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months. PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food). | 0 | 109 | 10 | 109 | 89 | 109 |
| EG001 | PXT3003 Dose 2 | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months. PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food). | 0 | 113 | 3 | 113 | 87 | 113 |
| EG002 | Placebo | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months. PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food). | 0 | 101 | 5 | 101 | 83 | 101 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Arthrolysis | Surgical and medical procedures | MedDRA 21.0 | Systematic Assessment |
| |
| Basal cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 21.0 | Systematic Assessment |
| |
| Thyroid adenoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 21.0 | Systematic Assessment |
| |
| Uterine leiomyoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 21.0 | Systematic Assessment |
| |
| Suicide attempt | Psychiatric disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Endometriosis | Reproductive system and breast disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Clavicle fracture | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Femoral neck fracture | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Hand fracture | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Injury | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Median nerve injury | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Patella fracture | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Rib fracture | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Palpitations | Cardiac disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Congenital foot malformation | Congenital, familial and genetic disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Patent ductus arteriosus | Congenital, familial and genetic disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Sleep apnoea syndrome | Respiratory, thoracic and mediastinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Seizure | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Proctitis | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Cholecystitis | Hepatobiliary disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Hydronephrosis | Renal and urinary disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Ureterolithiasis | Renal and urinary disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Chest wall haematoma | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Appendicitis | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Enteritis infectious | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypotension | Vascular disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Asthenia | General disorders | MedDRA 21.0 | Systematic Assessment | and administation site conditions |
|
| Fatigue | General disorders | MedDRA 21.0 | Systematic Assessment | and administation site conditions |
|
| Influenza like illness | General disorders | MedDRA 21.0 | Systematic Assessment | and administation site conditions |
|
| Peripheral swelling | General disorders | MedDRA 21.0 | Systematic Assessment | and administation site conditions |
|
| Anxiety | Psychiatric disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Depression | Psychiatric disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Sleep disorder | Psychiatric disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Contusion | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Fall | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Laceration | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Ligament sprain | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Limb injury | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Weight increased | Investigations | MedDRA 21.0 | Systematic Assessment |
| |
| Palpitations | Cardiac disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Hypoaesthesia | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Migraine | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Paraesthesia | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Sciatica | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Somnolence | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Tremor | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Tinnitus | Ear and labyrinth disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Vertigo | Ear and labyrinth disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Dry mouth | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Dyspepsia | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Toothache | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Bone callus excessive | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Joint swelling | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Rotator cuff syndrome | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Tendonitis | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Vitamin D deficiency | Metabolism and nutrition disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Bronchitis | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Cystitis | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Pharyngitis | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Respiratory tract infection | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Rhinitis | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Sinusitis | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Tracheitis | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
|
Two events occured during the trial due to crytals in Dose 2 formulation: hold of all subjects enrolled in Germany (Jun-17) and discontinuation of Dose 2 arm by the sponsor worldwide due to discovery of crystals in the ICH stability batch in Sep-17.
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Susanne Dorn | Pharnext | +33 (0)1 41 09 22 30 | contact@pharnext.com |
| Nov 22, 2019 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D002607 | Charcot-Marie-Tooth Disease |
| ID | Term |
|---|---|
| D015417 | Hereditary Sensory and Motor Neuropathy |
| D009421 | Nervous System Malformations |
| D009422 | Nervous System Diseases |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D011115 | Polyneuropathies |
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
Not provided
Not provided
| Between 18 and 65 years |
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| >=65 years |
|
| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
|
| Netherlands |
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| Belgium |
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| United States |
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| United Kingdom |
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| France |
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| Germany |
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| Spain |
|
|
| The main analysis was performed as follows:
| ANCOVA | 0.287 | Mean Difference (Final Values) | -0.13 | Standard Error of the Mean | 0.12 | 2-Sided | 97.5 | -0.39 | 0.14 | Superiority |
| This analysis was performed as follows:
| Longitudinal mixed model | 0.013 | Mean Difference (Final Values) | -0.31 | Standard Error of the Mean | 0.13 | 2-Sided | 97.5 | -0.59 | -0.03 | Superiority |
| This analysis was performed as follows:
| Longitudinal mixed model | 0.05 | Mean Difference (Final Values) | -0.19 | Standard Error of the Mean | 0.1 | 2-Sided | 97.5 | -0.42 | 0.03 | Superiority |
| Dose effect: Dose is defined as a numerical variable proportional to quantity of PXT3003 administered (0 for Placebo, 1 for Dose 1, 2 for Dose 2). The analysis was performed as follows:
| Regression, Linear | 0.013 | Slope | -0.17 | Standard Error of the Mean | 0.07 | 2-Sided | 95 | -0.31 | -0.04 | Superiority |
|
|
|
| OG002 | Placebo | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food). |
|
|
|
| OG002 | Placebo | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months. PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food). |
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| OG002 | Placebo | Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months. PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food). |
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| Units | Counts |
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| Participants |
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| Units | Counts |
|---|---|
| Participants |
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