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Trazodone/Gabapentin Fixed Dose Combination Products in Painful Diabetic Neuropathy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03749642
Recruitment Status : Recruiting
First Posted : November 21, 2018
Last Update Posted : January 9, 2020
Chiltern International Inc.
Information provided by (Responsible Party):
Aziende Chimiche Riunite Angelini Francesco S.p.A

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Painful Diabetic Neuropathy Drug: trazodone/gabapentin 2.5/25 mg Drug: trazodone/gabapentin 5/50 mg Drug: trazodone/gabapentin 10/100 Drug: Gabapentin Drug: Placebo oral capsule Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, double-blind, placebo and reference controlled, placebo unbalanced, double-dummy, dose finding, parallel group, multicentre, international, prospective study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: 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.
Actual Study Start Date : November 20, 2018
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: 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.
Drug: trazodone/gabapentin 2.5/25 mg
The total daily doses administered will be trazodone 7,5 mg and gabapentin 75 mg.

Experimental: trazodone/gabapentin 5/50 mg
One capsule, three times a day, for 8 weeks.
Drug: trazodone/gabapentin 5/50 mg
The total daily doses administered will be trazodone 15 mg and gabapentin 150 mg.

Experimental: trazodone/gabapentin 10/100 mg
One capsule, three times a day, for 8 weeks.
Drug: trazodone/gabapentin 10/100
The total daily doses administered will be trazodone 30 mg and gabapentin 300 mg.

Placebo Comparator: placebo
Two capsules, three times a day, for 8 weeks.
Drug: Placebo oral capsule
Two capsules, three times a day, for 8 weeks.

Active Comparator: 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).
Drug: Gabapentin

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)
Other Name: Neurontin

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

Secondary Outcome Measures :
  1. Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS). [ Time Frame: Baseline - Days 7, 14, 21, 28, 42 ]
    The NRS is based on a 11-point from 0 for [no pain] to 10 [worst possible pain].

  2. Percentage of responder patients [ Time Frame: Baseline - Day 56 ]
    Responder patients are defined as ≥30% and ≥50% reduction from baseline of the average daily pain score based on the 11-point NRS.

  3. Change of the average daily pain score based on the 11-point NRS between gabapentin and placebo as assay sensitivity. [ Time Frame: Baseline - Day 56 ]
    The NRS is based on a 11-point from 0 for [no pain] to 10 [worst possible pain].

  4. Change of Brief Pain Inventory Short Form (BPI-SF) items 3, 4, 5, 6, 8 and 9 score. [ Time Frame: Baseline - Days 28, 56 ]
    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.

  5. Change of Neuropathic Pain Symptom Inventory (NPSI) total score. [ Time Frame: Baseline - Days 28, 56 ]
    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.

  6. Change of Beck Depression Inventory - Second Edition (BDI-II) [ Time Frame: Baseline - Days 28, 56 ]
    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.

  7. Change of Hospital Anxiety and Depression Scale (HADS). [ Time Frame: Baseline - Days 28, 56 ]
    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.

  8. Change of Insomnia Severity Index (ISI). [ Time Frame: Baseline - Days 28, 56 ]
    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.

  9. Change of Euroqol-5D-5L (EQ-5D-5L) [ Time Frame: Baseline - Days 28, 56 ]
    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').

  10. Clinical Global Improvement or Change (CGI-C). [ Time Frame: Baseline - Days 28, 56 ]
    CGI-C provides a global rating of patient's Improvement and scores range from "0 - not assessed" through to "7 - very much worse".

  11. Frequency of adverse events [ Time Frame: 65 days ]
    Monitoring of the treatment related adverse events.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Male and female patient of any ethnic origin between 18 and 75 years of age (limits included).
  2. Neuropathic pain at feet/legs confirmed by Douleur Neuropatique 4 (DN4) score ≥ 4 at Screening Visit.
  3. Patient with bilateral distal symmetrical polyneuropathy confirmed by Toronto Clinical Neuropathy Scoring System (TCNSS) score > 5 at Screening visit.
  4. Pain persisting or taking pain medication for neuropathic pain for at least 3 months.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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:

  1. Known hypersensitivity to trazodone or gabapentin or any excipients of the test drugs.
  2. 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).
  3. Concomitant treatment with medications for pain management that could not be discontinued.
  4. Concomitant treatment with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, indinavir) or drugs known to prolong QT interval.
  5. Use of trazodone or gabapentin in the previous 3 months.
  6. Known history of previous non-responder to gabapentin treatment.
  7. Use of high dose morphine (e.g. > 120 mg/day) at the Screening Visit.
  8. 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.
  9. Active foot ulcer or previous major limb amputation.
  10. 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.
  11. 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.
  12. Transient ischemic attack or cerebral vascular accident within the past 6 months.
  13. Glomerular Filtration Rate value < 50 ml/min calculated with Modification of Diet in Renal Disease formula.
  14. Significant liver disease, defined as known active hepatitis or elevated liver enzymes over 3-fold the upper normal limit of laboratory normal ranges.
  15. Patient with latent or known hereditary problems of galactose intolerance or the Lapp lactase deficiency or glucose-galactose malabsorption.
  16. Positive urine drug screen for Central Nervous System active drugs (cocaine, opioids, amphetamines and cannabinoids) at Screening Visit.
  17. Positive present history of glaucoma.
  18. Hyperthyroidism, even if pharmacologically corrected.
  19. Significant mental disorders.
  20. Suicide risk score ≥ 2 on question 9 of the Beck Depression Inventory-II (BDI-II) at Screening visit or Visit 0.
  21. History of epilepsy or seizure events other than a single childhood febrile seizure.
  22. History of alcohol or psychoactive substance abuse or addiction.
  23. Use of neurological device (e.g. neurostimulation devices, etc).
  24. Women during pregnancy or lactation period.
  25. 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).
  26. Subject involved in the conduct of the study (e.g. Investigator or his/her deputy, first grade relatives, pharmacist, assistant or other personnel, etc).
  27. Participation to an interventional clinical trial within 3 months prior to Screening Visit.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03749642

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Contact: Paola Lipone +390691045 ext 349
Contact: Alessandra Del Vecchio +390691045 ext 311

Show Show 30 study locations
Sponsors and Collaborators
Aziende Chimiche Riunite Angelini Francesco S.p.A
Chiltern International Inc.
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Principal Investigator: Solomon Tesfaye, MD Sheffield Teaching Hospitals
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Responsible Party: Aziende Chimiche Riunite Angelini Francesco S.p.A Identifier: NCT03749642    
Other Study ID Numbers: 039(1)PO16357
2018-000133-12 ( EudraCT Number )
First Posted: November 21, 2018    Key Record Dates
Last Update Posted: January 9, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Aziende Chimiche Riunite Angelini Francesco S.p.A:
Neuropathic pain
Additional relevant MeSH terms:
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Diabetic Neuropathies
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Neurologic Manifestations
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antimanic Agents
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Serotonin Agents
Antidepressive Agents, Second-Generation