Efficacy and Safety of Fixed-Dose Combination (FDC) Products Containing Trazodone and Gabapentin in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose Finding Study.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 240
- 试验地点
- 30
- 主要终点
- Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS).
研究概览
简要总结
The primary objective of the study is to collect preliminary information on the effect of three doses of trazodone/gabapentin FDC products on pain intensity in patients with painful diabetic neuropathy after 8-week treatment period.
详细描述
The present phase II study is designed to collect preliminary data on the efficacy and safety of trazodone/gabapentin Fixed-Dose Combination (FDC)products for treatment of patients affected by painful diabetic neuropathy in a randomized controlled clinical trial. Diabetic peripheral neuropathic pain represents an important therapeutic challenge as its pathophysiology is not yet fully understood and pain relief is still unsatisfactory. The pharmacological treatments, with exception to those targeted to the glycemic control, are symptomatic and their use is limited by not universal efficacy, side effects or by the development of tolerance. A wide variety of drugs, used both alone and in combination, has shown to significantly reduce neuropathic pain when compared with placebo in randomized controlled trials, even though pain relief remains inadequate for most of the patients.
In this contest, Angelini S.p.A is developing a fixed-dose combination medicinal product for the treatment of neuropathic pain containing low doses of active ingredients: trazodone, a widely used antidepressant drug, and gabapentin which is indicated for the treatment of neuropathic pain.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The present study will be performed in double blind conditions. During the study neither the Investigator nor the patient will be aware of the treatment assigned.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female patient of any ethnic origin between 18 and 75 years of age (limits included).
- •Neuropathic pain at feet/legs confirmed by Douleur Neuropatique 4 (DN4) score ≥ 4 at Screening Visit.
- •Patient with bilateral distal symmetrical polyneuropathy confirmed by Toronto Clinical Neuropathy Scoring System (TCNSS) score > 5 at Screening visit.
- •Pain persisting or taking pain medication for neuropathic pain for at least 3 months.
- •Diabetic patient (type 1 or 2 diabetes mellitus) with value of glycated haemoglobin ≤ 11% at Screening Visit and stable antidiabetic medication regimen for ≥30 days.
- •Patient who is currently not receiving treatment for diabetic neuropathic pain or patient who is receiving treatment, with drug/s other than gabapentin, and has completed the required washout.
- •Average daily pain score ≥ 4 based on the 11-point Numeric Rating Scale (NRS) at Visit 0, calculated from a minimum of four pain ratings in daily electronic device entries during the baseline period.
- •Women of childbearing potential must have a negative pregnancy test at Screening Visit and have to agree not to start a pregnancy from the signature of the informed consent up to thirty days after the last administration of the investigational product, using an appropriate birth control method, such as combined estrogen and progestogen containing hormonal contraception (e.g. oral, intravaginal, transdermal), progestogen-only hormonal contraception (e.g. oral, injectable, implantable), intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) in combination with male condom, bilateral tubal occlusion, vasectomised partner, sexual abstinence.
- •Legally capable to give their consent to participate in the study (including personal data processing) and available to sign and date the written informed consent.
排除标准
- •Known hypersensitivity to trazodone or gabapentin or any excipients of the test drugs.
- •Any other form of non-diabetic distal symmetric polyneuropathy or any other pain condition that can impair the study endpoint (e.g. painful conditions where the intensity of pain is significantly more severe than the diabetic peripheral neuropathic pain).
- •Concomitant treatment with medications for pain management that could not be discontinued.
- •Concomitant treatment with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, indinavir) or drugs known to prolong QT interval.
- •Use of trazodone or gabapentin in the previous 3 months.
- •Known history of previous non-responder to gabapentin treatment.
- •Use of high dose morphine (e.g. > 120 mg/day) at the Screening Visit.
- •Clinically significant abnormalities on physical examination, vital signs, elettrocardiogram, laboratory tests at Screening Visit that in the opinion of Investigator would compromise patient's participation in the study.
- •Active foot ulcer or previous major limb amputation.
- •Concurrent heart failure ≥ 4 class according to New York Heart Association (NYHA) or myocardial infarction or angioplasty or by-pass graft procedures within the past 6 months.
- •Patient with increased risk of Torsade de Pointes (e.g. family history of long QT syndrome) or QTcF value higher than 450 msec (male) and QTcF value higher than 470 msec (female) at Screening Visit.
- •Transient ischemic attack or cerebral vascular accident within the past 6 months.
- •Glomerular Filtration Rate value < 50 ml/min calculated with Modification of Diet in Renal Disease formula.
- •Significant liver disease, defined as known active hepatitis or elevated liver enzymes over 3-fold the upper normal limit of laboratory normal ranges.
- •Patient with latent or known hereditary problems of galactose intolerance or the Lapp lactase deficiency or glucose-galactose malabsorption.
- •Positive urine drug screen for Central Nervous System active drugs (cocaine, opioids, amphetamines and cannabinoids) at Screening Visit.
- •Positive present history of glaucoma.
- •Hyperthyroidism, even if pharmacologically corrected.
- •Significant mental disorders.
- •Suicide risk score ≥ 2 on question 9 of the Beck Depression Inventory-II (BDI-II) at Screening visit or Visit
- •History of epilepsy or seizure events other than a single childhood febrile seizure.
- •History of alcohol or psychoactive substance abuse or addiction.
- •Use of neurological device (e.g. neurostimulation devices, etc).
- •Women during pregnancy or lactation period.
- •Inability to comply with the protocol requirements, instructions or study-related restrictions (e.g. uncooperative attitude, inability to return for study visits, improbability of completing the clinical study, etc).
- •Subject involved in the conduct of the study (e.g. Investigator or his/her deputy, first grade relatives, pharmacist, assistant or other personnel, etc).
- •Participation to an interventional clinical trial within 3 months prior to Screening Visit.
研究组 & 干预措施
trazodone/gabapentin 2.5/25 mg
One capsule, three times a day, for 8 weeks. The total daily doses administered will be trazodone 7,5 mg and gabapentin 75 mg.
干预措施: trazodone/gabapentin 2.5/25 mg (Drug)
trazodone/gabapentin 5/50 mg
One capsule, three times a day, for 8 weeks.
干预措施: trazodone/gabapentin 5/50 mg (Drug)
trazodone/gabapentin 10/100 mg
One capsule, three times a day, for 8 weeks.
干预措施: trazodone/gabapentin 10/100 (Drug)
placebo
Two capsules, three times a day, for 8 weeks.
干预措施: Placebo oral capsule (Drug)
Gabapentin
according to the following scheduling dosage regimen:
- 100 mg (2 capsules) 3 times a day, from day 0 to day 6 (±1);
- 300 mg (1 capsule) 3 times a day, from day 7 (±1) to day 13 (±1);
- 400 mg (1 capsule) 3 times a day, from day 14 (±1) to day 20 (±1);
- 300 mg (2 capsules) 3 times a day, from day 21 (±1) to day 55 (±2).
干预措施: Gabapentin (Drug)
结局指标
主要结局
Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS).
时间窗: Baseline - Day 56
The NRS is based on a 11-point from 0 for \[no pain\] to 10 \[worst possible pain\].
次要结局
- Change of Insomnia Severity Index (ISI).(Baseline - Days 28, 56)
- Clinical Global Improvement or Change (CGI-C).(Baseline - Days 28, 56)
- Frequency of adverse events(65 days)
- Change of Brief Pain Inventory Short Form (BPI-SF) items 3, 4, 5, 6, 8 and 9 score.(Baseline - Days 28, 56)
- Change of Hospital Anxiety and Depression Scale (HADS).(Baseline - Days 28, 56)
- Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS).(Baseline - Days 7, 14, 21, 28, 42)
- Change of Euroqol-5D-5L (EQ-5D-5L)(Baseline - Days 28, 56)
- Percentage of responder patients(Baseline - Day 56)
- Change of the average daily pain score based on the 11-point NRS between gabapentin and placebo as assay sensitivity.(Baseline - Day 56)
- Change of Neuropathic Pain Symptom Inventory (NPSI) total score.(Baseline - Days 28, 56)
- Change of Beck Depression Inventory - Second Edition (BDI-II)(Baseline - Days 28, 56)