Evaluation of the Safety and Efficacy of N-desmethylclobazam in Patients With Peripheral Neuropathic Pain

Study Overview
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Brief Summary
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Neuropathic pain (NP) affects up to 8% of the general population and its successful management is an unmet medical need. Half of the patients report inadequate response to therapy and unwanted side effects such as sedation and cognitive impairments, limiting drug use in daily practice and significantly accounting for the high incidence of treatment failure. Dysfunction of synaptic inhibition within the spinal cord is known to be one of the main contributing factors to central sensitization that governs NP. Facilitation of GABAergic inhibition in the dorsal horn through GABAA receptors allosteric modulation would be a rational approach to NP management. New insights on the associations between GABAA receptors α subunits and function have opened new perspectives in preclinical research. Data from genetically modified mice demonstrates the possibility, through selective allosteric modulation of the GABAA receptor, to induce its beneficial antihyperalgesic effects without inducing its cognitive and sedative effects. N-Desmethylclobazam (NDMC), clobazam's main active metabolite, demonstrated in vitro and in vivo a high selectivity profile with a clear preference for GABAA α2-subtypes receptors (antihyperalgesia) over α1 receptors responsible for sedative effects across a wide concentration range. Taking into consideration the high prevalence and burden of neuropathic and chronic pain worldwide and the fact that these patients are nowadays left with sedative and only partially effective drugs, NDMC qualifies as a good molecule to seek confirmation of the clinical utility of selective GABAA allosteric modulators in NP patients.The main objective is to assess the efficacy of repeated doses of NDMC on neuropathic pain compared to placebo.

Official Title
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A Randomized Double-blind Ascending-dose Placebo-controlled Study of N-desmethylclobazam in Patients With Peripheral Neuropathic Pain

Conditions
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Neuropathic Pain

Intervention / Treatment
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* Drug: NDMC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed Consent as documented by signature (Appendix 1: Informed Consent Form); Male or female participants (if female: post-menopausal or surgically sterile, or using a highly effective method of contraception); Between 18 and 85 years of age; Body mass index ≥ 18 and < 40 (kg/m2); Patients diagnosed with small fiber neuropathy OR suffering from peripheral neuropathic pain related to diabetic peripheral neuropathy; post-herpetic neuralgia; HIV-associated neuropathic pain; post-traumatic/postoperative peripheral neuropathy; chemotherapy associated peripheral neuropathy or nerve root/medullar compression with sensory/motor deficit OR presenting with neuropathic pain associated with diagnosed rare hereditary or acquired neurological disease; AND who presented insufficient response to at least one attempt with one of the currently recommended pharmacological treatment for neuropathic pain taken at efficacious dose OR who have interrupted treatment because of tolerance issue OR who have previously declined pharmacological pain management;; Pain duration for at least 3 months; Preceding week pain recall score ≥ 4 on NRS Scale; Score ≥ 4 on DN4 questionnaire; Willing to withdraw from prohibited medications; Poor-metabolizers (PM) for CYP2C19 are only eligible for Sequence 3 Exclusion Criteria: Contraindications to benzodiazepines.(including known hypersensitivity reaction) Women who are pregnant or breast feeding or who intend on becoming pregnant during the course of the study; Woman of childbearing potential, not using and not willing to continue using a highly effective method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases; Abnormal ASAT or ALAT plasma levels (> 3x ULN); Reduced renal function (GFR < 60 mL/min/1.73m2); Changes in existing (or addition of new) concomitant interventional pain management (including local anaesthetic infiltration, local nerve block, central neurostimulation therapy) and other non-pharmacological intervention such as desensitization techniques, acupuncture, transcutaneous electrostimulation, hypnosis; Co-existing nociceptive or inflammatory aetiology to the current pain symptoms; Unable to withdraw from prohibited medications before randomization; Epilepsy; History of drug, alcohol or substance abuse in the past 5 years (with the exception of stable opioid substitution therapy in the past 5 years); Current unstable psychiatric disorder or any such disorder that may impair patient's abilities to follow study procedures; Sleep apnea (unless treated with CPAP with an oxygen desaturation index < 5 per hour), myasthenia gravis, severe respiratory failure; Participation in another study with investigational drug within the 3 month preceding and during the present study (a wash-out of period at least 3 months is necessary prior to screening). Score < 24 on MMS in patients over 65 years of age

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3 Sequences separated by 2 interim analyses evaluating safety and PK linearity. Sequence 1: 8 Patients randomized to placebo or NDMC 40mg/day (ratio 1:3) qd for 6 weeks. Sequence 2 will be initiated following the first interim analysis. Sequence 2: 8 Patients randomized to placebo or NDMC 60mg/day (ratio 1:3) qd for 6 weeks. Sequence 3 will be initiated following the second interim analysis. Otherwise Sequence 2 will be extended to a total of 30 placebo and 32 patients. Sequence 3: 60 Patients randomized to placebo or NDMC 60mg/day (ratio 28:32) bid for 6 weeks. Patients who do not tolerate 120mg/day will be authorized to step down to 60mg/day during the up titration period.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NDMC 40 mg/day<br>Oral administration of two NDMC 20mg capsules per day over 6 weeks | Drug: NDMC<br>* Repeated oral administration of ascending daily doses of NDMC (40mg, 60mg,120mg/day) vs placebo in 3 sequential cohorts<br>* Other names: Placebo;|
| Experimental: NDMC 60 mg/day<br>Oral administration of three NDMC 20mg capsules per day over 6 weeks | Drug: NDMC<br>* Repeated oral administration of ascending daily doses of NDMC (40mg, 60mg,120mg/day) vs placebo in 3 sequential cohorts<br>* Other names: Placebo;|
| Experimental: NDMC 120 mg/day<br>Oral administration of six NDMC 20mg capsules per day over 6 weeks | Drug: NDMC<br>* Repeated oral administration of ascending daily doses of NDMC (40mg, 60mg,120mg/day) vs placebo in 3 sequential cohorts<br>* Other names: Placebo;|
| Placebo Comparator: Placebo<br>Oral administration respectively, according to the experimental arm considered, of two, three or six placebo capsules per day over 6 weeks | Drug: NDMC<br>* Repeated oral administration of ascending daily doses of NDMC (40mg, 60mg,120mg/day) vs placebo in 3 sequential cohorts<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weekly Average of daily Pain intensity score (WAP) | Participant will self-rate once every day his average daily pain. The weekly average of daily pain intensity score will be derived from the 7 (at least 5) recordings preceding Baseline (Week 0) and Final evaluation (Week 6). Numerical Rating Scale = 0 no pain to 10 = worst possible pain. The primary outcome will be the change from Baseline to Final evaluation. | Week 0, Week 6 following first drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolution of Weekly Average of daily Pain intensity score (EWAP) | Assessment of the evolution overtime of the weekly average of daily pain intensity score between Baseline (Week 0) and Final evaluation (Week 6). | Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 following first drug administration | 
| Weekly Average of daily subjective feeling of Sedation (WAS) | Participant will self-rate once every day his daily subjective feeling of sedation. The weekly average of daily subjective feeling of sedation score will be derived from the 7 (at least 5) recordings preceding Baseline (Week 0) and Final Evaluation (Week 6). Numerical Rating Scale = 0 not sleepy to 10 = extremely sleepy. | Week 0, Week 6 following first drug administration | 
| Evolution of Weekly Average of daily subjective feeling of Sedation (EWAS) | Assessments of the evolution overtime of the weekly average of daily subjective feeling of sedation score, each week between Baseline (Week 0) and Final evaluation (Week 6). | Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 following first drug administration | 
| Composite 2-Dimension Score (C2-D) | The Composite 2-Dimension score will assess the benefit/tolerance balance of NDMC for each dose. The score is defined as the aggregated value of the changes between baseline and final evaluation on the weekly average of daily pain intensity score and the weekly average of daily subjective sedation score. Score ranges from -10 to + 16. Score ≤ -2 indicates a favorable balance and score ≥ 2 an unfavorable balance. | Week 0, Week 6 following first drug administration | 
| Evolution of Composite 2-Dimension Score (EC2-D) | Assessments of the evolution overtime of the Composite 2-Dimension score, each week between Baseline (Week 0) and Final evaluation (Week 6). | Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 following first drug administration | 
| Douleur neuropathique 4 questionnaire (DN4) | Participant will complete the DN4 questionnaire which is a screening tool for neuropathic pain consisting of interview questions. This questionnaire gives a score ranging from 0 (better) to 10 (worse); a score ≥4 is an indicator of plausible neuropathic pain. | Week 0, Week 2, Week 6 following first drug administration | 
| Neuropathic Pain Symptom Inventory (NPSI) | Participant will complete the NPSI questionnaire which is an inventory tool for neuropathic pain consisting of interview questions.This questionnaire has 12 scaled scores and gives a score ranging from 0 (better) to 100 (worse) | Week 0, Week 2, Week 6 following first drug administration | 
| Short Form Questionnaire (SF-36) | Participant will complete the health status questionnaire consisting of 36 interview questions. The SF-36 has eight scaled scores; the scores are weighted sums of the questions in each section. Scores range from 0 - 100. Lower scores = more disability, higher scores = less disability. | Week 0, Week 2, Week 6 following first drug administration | 
| Hospital Anxiety and Depression Scale (HADS) | Participant will complete the anxiety and depression questionnaire consisting in two sets of 7 questions on anxiety or depression. HADS gives anxiety and depression scores both ranging from 0 (better) to 21 (worse) | Week 0, Week 2, Week 6 following first drug administration | 
| Patient Global Impression of Change (PGIC) | Participant will complete the PGIC questionnaire, which is a 7-point scale ranging from -3 (very much worse), 0 (no change), to +3 (very much improved) answering the question: Please, indicate how you feel now, compared to how you felt before receiving treatment in this study | Visit 1 to Visit 7 | 
| Clinician Global Impression of Improvement (CGI-I) | Investigator will complete CGI questionnaire which is a 7-point CGI scale: from 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse) to 7 (very much worse) answering the question: Please, indicate how much the patient's condition has improved or worsened relative to a baseline state at the beginning of the intervention | Week 0, Week 2, Week 6 following first drug administration | 
| Medical Outcome Study Sleep Score (MOS-Sleep) | Participant will complete the MOS-sleep questionnaire, which is composed of 12 items. Higher scores reflect more of the attribute implied by the scale names | Week 0, Week 2, Week 6 following first drug administration | 
| Responder Rates (30% / 50%) | Participants will be dichotomized into responders and non-responders categories. These transformations will be based on the reduction of at least 30%, respectively 50%, of the weekly average daily pain intensity score between Baseline (Week 0) and Final evaluation (Week 6). | Week 0, Week 6 following first drug administration | 
| Rescue Medication Rate | Participants will be dichotomized into rescue med and no rescue med categories. This transformation will be based on the use of rescue medications between Baseline (Week 0) and Final evaluation (Week 6). | Week 0, Week 6 following first drug administration | 
| Withdrawal Rate | Participants will be dichotomized into early withdrawal and completion categories. This transformation will be based on the occurrence of premature withdrawal related to lack of efficacy or due treatment emergent adverse effect between Baseline (Week 0) and Final evaluation (Week 6). | throughout the study (up to 6 weeks) |