A Randomized Double-blind Ascending-dose Placebo-controlled Study of N-desmethylclobazam in Patients With Peripheral Neuropathic Pain
试验速览
- 阶段
- 2 期
- 状态
- 暂停
- 发起方
- 入组人数
- 76
- 试验地点
- 1
- 主要终点
- Weekly Average of daily Pain intensity score (WAP)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
NDMC 40 mg/day
Oral administration of two NDMC 20mg capsules per day over 6 weeks
干预措施: NDMC (Drug)
NDMC 60 mg/day
Oral administration of three NDMC 20mg capsules per day over 6 weeks
干预措施: NDMC (Drug)
NDMC 120 mg/day
Oral administration of six NDMC 20mg capsules per day over 6 weeks
干预措施: NDMC (Drug)
Placebo
Oral administration respectively, according to the experimental arm considered, of two, three or six placebo capsules per day over 6 weeks
干预措施: NDMC (Drug)
结局指标
主要结局
Weekly Average of daily Pain intensity score (WAP)
时间窗: Week 0, Week 6 following first drug administration
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.
次要结局
- Weekly Average of daily subjective feeling of Sedation (WAS)(Week 0, Week 6 following first drug administration)
- Composite 2-Dimension Score (C2-D)(Week 0, Week 6 following first drug administration)
- Neuropathic Pain Symptom Inventory (NPSI)(Week 0, Week 2, Week 6 following first drug administration)
- Douleur neuropathique 4 questionnaire (DN4)(Week 0, Week 2, Week 6 following first drug administration)
- Hospital Anxiety and Depression Scale (HADS)(Week 0, Week 2, Week 6 following first drug administration)
- Responder Rates (30% / 50%)(Week 0, Week 6 following first drug administration)
- Evolution of Weekly Average of daily Pain intensity score (EWAP)(Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 following first drug administration)
- Evolution of Composite 2-Dimension Score (EC2-D)(Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 following first drug administration)
- Short Form Questionnaire (SF-36)(Week 0, Week 2, Week 6 following first drug administration)
- Patient Global Impression of Change (PGIC)(Visit 1 to Visit 7)
- Clinician Global Impression of Improvement (CGI-I)(Week 0, Week 2, Week 6 following first drug administration)
- Medical Outcome Study Sleep Score (MOS-Sleep)(Week 0, Week 2, Week 6 following first drug administration)
- Evolution of Weekly Average of daily subjective feeling of Sedation (EWAS)(Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 following first drug administration)
- Rescue Medication Rate(Week 0, Week 6 following first drug administration)
- Withdrawal Rate(throughout the study (up to 6 weeks))
研究者
Besson Marie
Principal Investigator
University Hospital, Geneva