Evaluation of the Safety and Efficacy of N-desmethylclobazam in Patients With Peripheral Neuropathic Pain
Evaluation of the Safety and Efficacy of N-desmethylclobazam in Patients With Peripheral Neuropathic Pain
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.
Inclusion Criteria:

 -  Informed Consent as documented by signature

 -  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 between 18 and 30 (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 radicular low back pain with sensory
 deficit 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

 -  Current unstable psychiatric disorder or any such disorder that may impair patient's
 abilities to follow study procedures

 -  Sleep apnea, 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 patient over 65 years of age