Trazodone/Gabapentin Fixed Dose Combination Products in Painful Diabetic Neuropathy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Painful Diabetic Neuropathy

Intervention / Treatment
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* Drug: trazodone/gabapentin 2.5/25 mg
* Drug: trazodone/gabapentin 5/50 mg
* Drug: trazodone/gabapentin 10/100
* Drug: Gabapentin
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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 0. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo and reference controlled, placebo unbalanced, double-dummy, dose finding, parallel group, multicentre, international, prospective study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: trazodone/gabapentin 2.5/25 mg<br>One capsule, three times a day, for 8 weeks. The total daily doses administered will be trazodone 7,5 mg and gabapentin 75 mg. | Drug: trazodone/gabapentin 2.5/25 mg<br>* The total daily doses administered will be trazodone 7,5 mg and gabapentin 75 mg.<br>|
| Experimental: trazodone/gabapentin 5/50 mg<br>One capsule, three times a day, for 8 weeks. | Drug: trazodone/gabapentin 5/50 mg<br>* The total daily doses administered will be trazodone 15 mg and gabapentin 150 mg.<br>|
| Experimental: trazodone/gabapentin 10/100 mg<br>One capsule, three times a day, for 8 weeks. | Drug: trazodone/gabapentin 10/100<br>* The total daily doses administered will be trazodone 30 mg and gabapentin 300 mg.<br>|
| Placebo Comparator: placebo<br>Two capsules, three times a day, for 8 weeks. | Drug: Placebo oral capsule<br>* Two capsules, three times a day, for 8 weeks.<br>|
| Active Comparator: Gabapentin<br>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). | Drug: Gabapentin<br>* The total daily doses administered will be: 600 mg from day 0 to day 6 (±1) 900 mg from day 7 (±1) to day 13 (±1) 1200 mg from day 14 (±1) to day 20 (±1) 1800 mg from day 21 (±1) to day 56 (±2)<br>* Other names: Neurontin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS). | The NRS is based on a 11-point from 0 for [no pain] to 10 [worst possible pain]. | Baseline - Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS). | The NRS is based on a 11-point from 0 for [no pain] to 10 [worst possible pain]. | Baseline - Days 7, 14, 21, 28, 42 | 
| Percentage of responder patients | Responder patients are defined as ≥30% and ≥50% reduction from baseline of the average daily pain score based on the 11-point NRS. | Baseline - Day 56 | 
| Change of the average daily pain score based on the 11-point NRS between gabapentin and placebo as assay sensitivity. | The NRS is based on a 11-point from 0 for [no pain] to 10 [worst possible pain]. | Baseline - Day 56 | 
| Change of Brief Pain Inventory Short Form (BPI-SF) items 3, 4, 5, 6, 8 and 9 score. | The BPI-SF is a numeric rating scale that assesses the severity of pain, its impact on daily functioning and other aspects of pain (e.g. location of pain, relief from medications). Items use a 0-10 numeric rating scale anchored at zero for no pain and 10 for pain as bad as you can imagine for Severity, and does not interfere to completely interferes for Interference. | Baseline - Days 28, 56 | 
| Change of Neuropathic Pain Symptom Inventory (NPSI) total score. | The NPSI is a self-questionnaire specifically designed to evaluate the different symptoms of neuropathic pain: It includes 10 descriptors plus two temporal items that allow discrimination and quantification of five distinct clinically relevant dimensions of neuropathic pain syndromes. | Baseline - Days 28, 56 | 
| Change of Beck Depression Inventory - Second Edition (BDI-II) | The BDI-II consists of 21 items to assess the intensity of depression in clinical and normal patients. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression and scored from 0 to 3. | Baseline - Days 28, 56 | 
| Change of Hospital Anxiety and Depression Scale (HADS). | The HADS is used to assess the level of anxiety and depression that a patient is experiencing. This is 14-item scale: seven related to the anxiety and seven to depression. Each item is scored from 0 to 3. | Baseline - Days 28, 56 | 
| Change of Insomnia Severity Index (ISI). | The ISI is a 7-item self-reported instrument measuring the patient's perception of his/her insomnia.Total score ranges from 0-28 and the following categorization is applicable: 0-7 = absence of insomnia; 8-14 = subthreshold insomnia; 15-21 = moderate insomnia; 22-28 = severe insomnia. | Baseline - Days 28, 56 | 
| Change of Euroqol-5D-5L (EQ-5D-5L) | The EQ-5D-5L consists of the EQ-5D descriptive system (five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression assessed as no problems, slight problems, moderate problems, severe problems and extreme problems) and the EQ visual analogue scale (where the patient self-rates his/her health on a vertical visual analogue scale from 'The best health you can imagine' to 'The worst health you can imagine'). | Baseline - Days 28, 56 | 
| Clinical Global Improvement or Change (CGI-C). | CGI-C provides a global rating of patient's Improvement and scores range from 0 - not assessed through to 7 - very much worse. | Baseline - Days 28, 56 | 
| Frequency of adverse events | Monitoring of the treatment related adverse events. | 65 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trazodone, Gabapentin, Neuropathic pain, Placebo