Trazodone/Gabapentin Fixed Dose Combination Products in Painful Diabetic Neuropathy

Painful Diabetic Neuropathy Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03749642
• Other study ID #: 039(1)PO16357
• Secondary ID: 2018-000133-12
• Status: Completed
• Phase: Phase 2
• Start date: November 22, 2018
• Est. completion date: June 6, 2020

Study information

• Verified date: May 2021
• Source: Aziende Chimiche Riunite Angelini Francesco S.p.A
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 240
• Est. completion date: June 6, 2020
• Est. primary completion date: June 6, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetic Neuropathies
• Pain
• Painful Diabetic Neuropathy

Intervention

Drug:
• trazodone/gabapentin 2.5/25 mg
The total daily doses administered will be trazodone 7,5 mg and gabapentin 75 mg.
• trazodone/gabapentin 5/50 mg
The total daily doses administered will be trazodone 15 mg and gabapentin 150 mg.
• trazodone/gabapentin 10/100
The total daily doses administered will be trazodone 30 mg and gabapentin 300 mg.
• 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)
• Placebo oral capsule
Two capsules, three times a day, for 8 weeks.

Locations

Country	Name	City	State
Czechia	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
France	Fondation Hôtel Dieu Groupe SOS Service de Diabétologie	Le Creusot, 71200
France	GHR MSA - Hôpital Emile Muller Service de Diabétologie-Endocrinologie-Nutrition	Mulhouse, 68100
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	Venissieux, 69200
Poland	Centrum Badan 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 Chodzki Klinika Diabetologii	Lublin, 20-090
Poland	Centrum Medyczne HCP Sp. z o.o.	Poznan, 61-485
Poland	RCMed Oddzial Sochaczew	Sochaczew, 96-500
Poland	Nasz Lekarz Przychodnie Medyczne	Torun, 87-100
Poland	Medycyna Kliniczna	Warszawa, 00-874
Poland	Instytut Diabetologii	Warszawa, 04-736
Poland	WroMedica I. Bielicka, A. Strzalkowska s.c.	Wroclaw, 51- 685
Poland	Centrum Badan Klinicznych Osrodek Badan Wczesnej Fazy	Wroclaw, 51-162
United Kingdom	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

Sponsors (2)

Lead Sponsor	Collaborator
Aziende Chimiche Riunite Angelini Francesco S.p.A	Chiltern International Inc.

Countries where clinical trial is conducted

Czechia,  France,  Poland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Frequency of adverse events	Monitoring of the treatment related adverse events.	65 days