Clinical trial NCT04480164: Evaluation of the Safety and Efficacy of N-desmethylclobazam in Patients With Peripheral Neuropathic Pain
Official title: A Randomized Double-blind Ascending-dose Placebo-controlled Study of N-desmethylclobazam in Patients With Peripheral Neuropathic Pain
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Neuropathic Pain
Lead sponsor: University Hospital, Geneva
Sponsor class: OTHER
First posted: 2020-07-21
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Weekly Average of daily Pain intensity score (WAP)
timeFrame: Week 0, Week 6 following first drug administration
Secondary outcomes:
measure: Evolution of Weekly Average of daily Pain intensity score (EWAP)
timeFrame: Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 following first drug administration
measure: Weekly Average of daily subjective feeling of Sedation (WAS)
timeFrame: Week 0, Week 6 following first drug administration
measure: Evolution of Weekly Average of daily subjective feeling of Sedation (EWAS)
timeFrame: Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 following first drug administration
measure: Composite 2-Dimension Score (C2-D)
timeFrame: Week 0, Week 6 following first drug administration
measure: Evolution of Composite 2-Dimension Score (EC2-D)
timeFrame: Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 following first drug administration
measure: Douleur neuropathique 4 questionnaire (DN4)
timeFrame: Week 0, Week 2, Week 6 following first drug administration
measure: Neuropathic Pain Symptom Inventory (NPSI)
timeFrame: Week 0, Week 2, Week 6 following first drug administration
measure: Short Form Questionnaire (SF-36)
timeFrame: Week 0, Week 2, Week 6 following first drug administration
measure: Hospital Anxiety and Depression Scale (HADS)
timeFrame: Week 0, Week 2, Week 6 following first drug administration
measure: Patient Global Impression of Change (PGIC)
timeFrame: Visit 1 to Visit 7
measure: Clinician Global Impression of Improvement (CGI-I)
timeFrame: Week 0, Week 2, Week 6 following first drug administration
measure: Medical Outcome Study Sleep Score (MOS-Sleep)
timeFrame: Week 0, Week 2, Week 6 following first drug administration
measure: Responder Rates (30% / 50%)
timeFrame: Week 0, Week 6 following first drug administration
measure: Rescue Medication Rate
timeFrame: Week 0, Week 6 following first drug administration
measure: Withdrawal Rate
timeFrame: throughout the study (up to 6 weeks)
Other outcomes:
measure: Steady state NDMC Cmin concentration
timeFrame: Week 0, Week 2, Week 6 following first drug administration
Locations:
city: Geneva
country: Switzerland
facility: Geneva University Hospitals
state: GE
Study officials:
affiliation: University Hospital, Geneva
name: Marie Besson, MD
role: PRINCIPAL_INVESTIGATOR
References: