Clinical trial NCT03749642: Trazodone/Gabapentin Fixed Dose Combination Products in Painful Diabetic Neuropathy
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Painful Diabetic Neuropathy
Keywords: Trazodone
Gabapentin
Neuropathic pain
Placebo
Lead sponsor: Aziende Chimiche Riunite Angelini Francesco S.p.A
Sponsor class: INDUSTRY
Collaborators: name: Chiltern International Inc.
First posted: 2018-11-21
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind, placebo and reference controlled, placebo unbalanced, double-dummy, dose finding, parallel group, multicentre, international, prospective study
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS).
timeFrame: Baseline - Day 56
Secondary outcomes:
measure: Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS).
timeFrame: Baseline - Days 7, 14, 21, 28, 42
measure: Percentage of responder patients
timeFrame: Baseline - Day 56
measure: Change of the average daily pain score based on the 11-point NRS between gabapentin and placebo as assay sensitivity.
timeFrame: Baseline - Day 56
measure: Change of Brief Pain Inventory Short Form (BPI-SF) items 3, 4, 5, 6, 8 and 9 score.
timeFrame: Baseline - Days 28, 56
measure: Change of Neuropathic Pain Symptom Inventory (NPSI) total score.
timeFrame: Baseline - Days 28, 56
measure: Change of Beck Depression Inventory - Second Edition (BDI-II)
timeFrame: Baseline - Days 28, 56
measure: Change of Hospital Anxiety and Depression Scale (HADS).
timeFrame: Baseline - Days 28, 56
measure: Change of Insomnia Severity Index (ISI).
timeFrame: Baseline - Days 28, 56
measure: Change of Euroqol-5D-5L (EQ-5D-5L)
timeFrame: Baseline - Days 28, 56
measure: Clinical Global Improvement or Change (CGI-C).
timeFrame: Baseline - Days 28, 56
measure: Frequency of adverse events
timeFrame: 65 days
Other outcomes:
Locations:
city: Litomyšl, 570 01
country: Czechia
facility: Neurosanatio s.r.o.
city: Ostrava - Poruba, 70800
country: Czechia
facility: Cerebrovaskulární poradna, s.r.o.
city: Pardubice, 532 03
country: Czechia
facility: Nemocnice Pardubického kraje a.s. Pardubická nemocnice Neurologická klinika
city: Praha 4, 149 00
country: Czechia
facility: Diabetologická ambulance Milan Kvapil s.r.o.
city: Praha 5, 15000
country: Czechia
facility: Axon Clinical s.r.o
city: Praha 6, 160 00
country: Czechia
facility: FORBELI s.r.o.
city: Praha, 100 00
country: Czechia
facility: Clintrial s.r.o.
city: Le Creusot, 71200
country: France
facility: Fondation Hôtel Dieu Groupe SOS Service de Diabétologie
city: Mulhouse, 68100
country: France
facility: GHR MSA - Hôpital Emile Muller Service de Diabétologie-Endocrinologie-Nutrition
city: Nantes Cedex 144 093
country: France
facility: CHU de Nantes - Hôpital Guillaume-et-René-Laënnec Clinique d'Endocrinologie, maladies métaboliques et nutrition CIC Endocrino - Nutrition - UF 7015
city: Venissieux, 69200
country: France
facility: Centre de Recherche Clinique G.H.M les Portes du Sud Departement d'Endocrinologie
city: Gdansk, 80-546
country: Poland
facility: Centrum Badań Klinicznych PI-House
city: Katowice, 40-282
country: Poland
facility: Silmedic Sp. z o.o.
city: Katowice, 40-648
country: Poland
facility: Pro Familia Altera Poradnia Wielospecjalistyczna
city: Kraków, 31-261
country: Poland
facility: Medyczne Centrum Diabetologiczno-Endokrynologiczno-Metaboliczne DIAB-ENDO-MET
city: Lublin, 20-064
country: Poland
facility: NZOZ Neuromed M. i M. Nastaj Sp. P.
city: Lublin, 20-090
country: Poland
facility: Instytut Medycyny Wsi im. Witolda Chodźki Klinika Diabetologii
city: Poznań, 61-485
country: Poland
facility: Centrum Medyczne HCP Sp. z o.o.
city: Sochaczew, 96-500
country: Poland
facility: RCMed Oddział Sochaczew
city: Toruń, 87-100
country: Poland
facility: Nasz Lekarz Przychodnie Medyczne
city: Warszawa, 00-874
country: Poland
facility: Medycyna Kliniczna
city: Warszawa, 04-736
country: Poland
facility: Instytut Diabetologii
city: Wrocław, 51- 685
country: Poland
facility: WroMedica I. Bielicka, A. Strzałkowska s.c.
city: Wrocław, 51-162
country: Poland
facility: Centrum Badań Klinicznych Ośrodek Badań Wczesnej Fazy
city: Birmingham
country: United Kingdom
facility: Medical Innovation Development and Research Unit (MIDRU) Heartlands Hospital
city: Manchester
country: United Kingdom
facility: Diabetes Centre Wythenshawe Hospital
city: Manchester
country: United Kingdom
facility: Manchester Clinical Research Facility Manchester Royal Infirmary
city: Nuneaton
country: United Kingdom
facility: Diabetes Centre George Eliot Hospital NHS Trust
city: Preston
country: United Kingdom
facility: Lancashire Clinical Research Facility The Avondale Unit Royal Preston Hospital
city: Sheffield
country: United Kingdom
facility: Clinical Research Facility Royal Hallamshire Hospital
Study officials:
affiliation: Sheffield Teaching Hospitals NHS Foundation Trust
name: Solomon Tesfaye, MD
role: PRINCIPAL_INVESTIGATOR
References: