Trazodone/Gabapentin Fixed Dose Combination Products in Painful Diabetic Neuropathy

NCT ID: NCT03749642

Last Updated: 2021-05-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 240 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-22
• Study Completion Date: 2020-06-06

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.

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.

Conditions

Painful Diabetic Neuropathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

trazodone/gabapentin 2.5/25 mg

Intervention Type: DRUG

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

trazodone/gabapentin 5/50 mg

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

Group Type: EXPERIMENTAL

trazodone/gabapentin 5/50 mg

Intervention Type: DRUG

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

trazodone/gabapentin 10/100 mg

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

Group Type: EXPERIMENTAL

trazodone/gabapentin 10/100

Intervention Type: DRUG

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

placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo oral capsule

Intervention Type: DRUG

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

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).

Group Type: ACTIVE_COMPARATOR

Gabapentin

Intervention Type: 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)

Interventions

trazodone/gabapentin 2.5/25 mg

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

Intervention Type: DRUG

trazodone/gabapentin 5/50 mg

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

Intervention Type: DRUG

trazodone/gabapentin 10/100

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

Intervention Type: 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)

Intervention Type: DRUG

Placebo oral capsule

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

Intervention Type: DRUG

Other Intervention Names

Neurontin

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chiltern International Inc.

INDUSTRY

Sponsor Role: collaborator

Aziende Chimiche Riunite Angelini Francesco S.p.A

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Solomon Tesfaye, MD

Role: PRINCIPAL_INVESTIGATOR

Sheffield Teaching Hospitals NHS Foundation Trust

Locations

Neurosanatio s.r.o.

Litomyšl, 570 01, , Czechia

Cerebrovaskulární poradna, s.r.o.

Ostrava - Poruba, 70800, , Czechia

Nemocnice Pardubického kraje a.s. Pardubická nemocnice Neurologická klinika

Pardubice, 532 03, , Czechia

Diabetologická ambulance Milan Kvapil s.r.o.

Praha 4, 149 00, , Czechia

Axon Clinical s.r.o

Praha 5, 15000, , Czechia

FORBELI s.r.o.

Praha 6, 160 00, , Czechia

Clintrial s.r.o.

Praha, 100 00, , Czechia

Fondation Hôtel Dieu Groupe SOS Service de Diabétologie

Le Creusot, , France

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

Mulhouse, , France

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

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

Vénissieux, , France

Centrum Badań Klinicznych PI-House

Gdansk, 80-546, , Poland

Silmedic Sp. z o.o.

Katowice, 40-282, , Poland

Pro Familia Altera Poradnia Wielospecjalistyczna

Katowice, 40-648, , Poland

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

Kraków, 31-261, , Poland

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

Lublin, 20-064, , Poland

Instytut Medycyny Wsi im. Witolda Chodźki Klinika Diabetologii

Lublin, 20-090, , Poland

Centrum Medyczne HCP Sp. z o.o.

Poznań, 61-485, , Poland

RCMed Oddział Sochaczew

Sochaczew, 96-500, , Poland

Nasz Lekarz Przychodnie Medyczne

Toruń, 87-100, , Poland

Medycyna Kliniczna

Warszawa, 00-874, , Poland

Instytut Diabetologii

Warszawa, 04-736, , Poland

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

Wrocław, 51- 685, , Poland

Centrum Badań Klinicznych Ośrodek Badań Wczesnej Fazy

Wrocław, 51-162, , Poland

Medical Innovation Development and Research Unit (MIDRU) Heartlands Hospital

Birmingham, , United Kingdom

Diabetes Centre Wythenshawe Hospital

Manchester, , United Kingdom

Manchester Clinical Research Facility Manchester Royal Infirmary

Manchester, , United Kingdom

Diabetes Centre George Eliot Hospital NHS Trust

Nuneaton, , United Kingdom

Lancashire Clinical Research Facility The Avondale Unit Royal Preston Hospital

Preston, , United Kingdom

Clinical Research Facility Royal Hallamshire Hospital

Sheffield, , United Kingdom

Countries

Czechia; France; Poland; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 38914876 (View on PubMed)

Other Identifiers

2018-000133-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

039(1)PO16357

Identifier Type: -

Identifier Source: org_study_id