Trazodone/Gabapentin Fixed Dose Combination Products in Painful Diabetic Neuropathy

NCT03749642 | Completed Phase 2

• 2 other identifiers: 039(1)PO163572018-000133-12
• Study Type: interventional
• Target: 240
• Locations: 4 countries
• Sites: 30

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.

Conditions

Painful Diabetic Neuropathy

Keywords

Trazodone; Gabapentin; Neuropathic pain; Placebo

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (11)

• Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS).

  Baseline - Days 7, 14, 21, 28, 42

• 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 Brief Pain Inventory Short Form (BPI-SF) items 3, 4, 5, 6, 8 and 9 score.

  Baseline - Days 28, 56

• Change of Neuropathic Pain Symptom Inventory (NPSI) total score.

  Baseline - Days 28, 56

Study Arms (5)

trazodone/gabapentin 2.5/25 mg

EXPERIMENTAL

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

trazodone/gabapentin 5/50 mg

EXPERIMENTAL

One capsule, three times a day, for 8 weeks.

Drug: trazodone/gabapentin 5/50 mg

trazodone/gabapentin 10/100 mg

EXPERIMENTAL

One capsule, three times a day, for 8 weeks.

Drug: trazodone/gabapentin 10/100

placebo

PLACEBO COMPARATOR

Two capsules, three times a day, for 8 weeks.

Drug: Placebo oral capsule

Gabapentin

ACTIVE COMPARATOR

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

Interventions

trazodone/gabapentin 2.5/25 mg DRUG

The total daily doses administered will be trazodone 7,5 mg and gabapentin 75 mg.

trazodone/gabapentin 2.5/25 mg

trazodone/gabapentin 5/50 mg DRUG

The total daily doses administered will be trazodone 15 mg and gabapentin 150 mg.

trazodone/gabapentin 5/50 mg

trazodone/gabapentin 10/100 DRUG

The total daily doses administered will be trazodone 30 mg and gabapentin 300 mg.

trazodone/gabapentin 10/100 mg

Gabapentin DRUG

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)

Also known as: Neurontin

Gabapentin

Placebo oral capsule DRUG

Two capsules, three times a day, for 8 weeks.

placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Aziende Chimiche Riunite Angelini Francesco S.p.A: lead
• Chiltern International Inc.: collaborator

Study Sites (30)

Neurosanatio s.r.o.

Litomyšl, 570 01, Czechia

Location

Cerebrovaskulární poradna, s.r.o.

Ostrava - Poruba, 70800, Czechia

Location

Nemocnice Pardubického kraje a.s. Pardubická nemocnice Neurologická klinika

Pardubice, 532 03, Czechia

Location

Diabetologická ambulance Milan Kvapil s.r.o.

Praha 4, 149 00, Czechia

Location

Axon Clinical s.r.o

Praha 5, 15000, Czechia

Location

FORBELI s.r.o.

Praha 6, 160 00, Czechia

Location

Clintrial s.r.o.

Praha, 100 00, Czechia

Location

Fondation Hôtel Dieu Groupe SOS Service de Diabétologie

Le Creusot, France

Location

GHR MSA - Hôpital Emile Muller Service de Diabétologie-Endocrinologie-Nutrition

Mulhouse, France

Location

CHU de Nantes - Hôpital Guillaume-et-René-Laënnec Clinique d'Endocrinologie, maladies métaboliques et nutrition CIC Endocrino - Nutrition - UF 7015

Nantes Cedex 144 093, France

Location

Centre de Recherche Clinique G.H.M les Portes du Sud Departement d'Endocrinologie

Vénissieux, France

Location

Centrum Badań Klinicznych PI-House

Gdansk, 80-546, Poland

Location

Silmedic Sp. z o.o.

Katowice, 40-282, Poland

Location

Pro Familia Altera Poradnia Wielospecjalistyczna

Katowice, 40-648, Poland

Location

Medyczne Centrum Diabetologiczno-Endokrynologiczno-Metaboliczne DIAB-ENDO-MET

Kraków, 31-261, Poland

Location

NZOZ Neuromed M. i M. Nastaj Sp. P.

Lublin, 20-064, Poland

Location

Instytut Medycyny Wsi im. Witolda Chodźki Klinika Diabetologii

Lublin, 20-090, Poland

Location

Centrum Medyczne HCP Sp. z o.o.

Poznań, 61-485, Poland

Location

RCMed Oddział Sochaczew

Sochaczew, 96-500, Poland

Location

Nasz Lekarz Przychodnie Medyczne

Toruń, 87-100, Poland

Location

Medycyna Kliniczna

Warszawa, 00-874, Poland

Location

Instytut Diabetologii

Warszawa, 04-736, Poland

Location

WroMedica I. Bielicka, A. Strzałkowska s.c.

Wrocław, 51- 685, Poland

Location

Centrum Badań Klinicznych Ośrodek Badań Wczesnej Fazy

Wrocław, 51-162, Poland

Location

Medical Innovation Development and Research Unit (MIDRU) Heartlands Hospital

Birmingham, United Kingdom

Location

Diabetes Centre Wythenshawe Hospital

Manchester, United Kingdom

Location

Manchester Clinical Research Facility Manchester Royal Infirmary

Manchester, United Kingdom

Location

Diabetes Centre George Eliot Hospital NHS Trust

Nuneaton, United Kingdom

Location

Lancashire Clinical Research Facility The Avondale Unit Royal Preston Hospital

Preston, United Kingdom

Location

Clinical Research Facility Royal Hallamshire Hospital

Sheffield, United Kingdom

Location

Related Publications (1)

• Tesfaye S, Saravanan P, Ehler E, Zinek K, Palka-Kisielowska I, Nastaj M, Serusclat P, Lipone P, Vergallo A, Quarchioni E, Calisti F, Comandini A, Cattaneo A. Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study. Pain Ther. 2024 Aug;13(4):987-1006. doi: 10.1007/s40122-024-00624-3. Epub 2024 Jun 24.

  PMID: 38914876 DERIVED

MeSH Terms

Conditions

Diabetic Neuropathies; Neuralgia

Interventions

Trazodone; Gabapentin

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyridones; Pyridines; Amines; Organic Chemicals; gamma-Aminobutyric Acid; Aminobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Cyclohexanecarboxylic Acids; Acids, Carbocyclic; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Solomon Tesfaye, MD

  Sheffield Teaching Hospitals NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Randomized, double-blind, placebo and reference controlled, placebo unbalanced, double-dummy, dose finding, parallel group, multicentre, international, prospective study

Study Record Dates

• First Submitted: November 20, 2018
• First Posted: November 21, 2018
• Study Start: November 22, 2018
• Primary Completion: June 6, 2020
• Study Completion: June 6, 2020
• Last Updated: May 27, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

FR (4); GB (6); CZ (7); PL (13)