Trazodone in Painful Diabetic Neuropathy

Phase 2

Completed

• Conditions: Painful Diabetic Neuropathy
• Interventions: Drug: Trazodone 10 mg; Drug: Trazodone 20 mg; Drug: Placebo

• Registration Number: NCT03202979
• Lead Sponsor: Aziende Chimiche Riunite Angelini Francesco S.p.A

Brief Summary

The aim of the study is to collect preliminary information on the effect of low doses of trazodone on pain intensity in patients with painful diabetic neuropathy and to evaluate the neuropathic pain symptoms, anxiety, sleep, quality of life, safety and tolerability.

Detailed Description

This is a randomized, double-blind, placebo controlled, double-dummy, dose finding, parallel group, multicentre, international, prospective, pilot study.

The present study is planned to assess the efficacy and the safety of an 8-week treatment period with low doses of trazodone (30 mg daily or 60 mg total daily, respectively) administered to patients affected by painful diabetic neuropathy.

Gabapentin will be administered together with the investigational drug in open label conditions in order to assure an effective pharmacological treatment to all patients. A slow titration of gabapentin will be applied in this trial in order to control possible side effects when co-administered with trazodone.

Study Timeline

• Study Start: 2017-05-16
• Study First Submitted: 2017-06-23
• Study First Submitted QC: 2017-06-27
• Study First Posted: 2017-06-29
• Primary Completion: 2018-08-09
• Study Completion: 2018-08-09
• Status Verified: 2018-09
• Last Update Submitted: 2018-09-27
• Last Update Posted: 2018-09-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 142

Inclusion Criteria

1. Male and female patient of any ethnic origin between 18 and 75 years of age (limits included).
2. Patient with painful diabetic symmetric polyneuropathy manifesting with distally distributed neuropathic pain.
3. Stable glycaemic control with a value of HbA1c ≤ 10% at Screening Visit.
4. Pain persisting for at least 3 months.
5. Neuropathic pain confirmed by DN4 score ≥ 4 at Screening Visit.
6. BPI-SF 24-hour average pain score (item 5) ≥ 4 at Screening Visit and Baseline Visit.
7. Patient who is currently not receiving treatment for diabetic neuropathic pain or patient who is receiving treatment, with drug/s other than gabapentin, and have completed the required washout.
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 and available to sign and date the written informed consent.

Exclusion Criteria

1. Known hypersensitivity to trazodone or gabapentin or their excipients.
2. Other forms of neuropathic pain or non-neuropathic pain (included but not limited to peripheral arterial disease, radiculopathy, mononeuropathy, proximal motor neuropathy, post-operative pain, etc).
3. Concomitant treatment with other medications for pain management.
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. Clinically significant abnormalities on physical examination, vital signs, ECG, laboratory tests at Screening Visit that in the opinion of Investigator would compromise patient's participation in the study.
7. Active foot ulcer or previous major limb amputation.
8. Myocardial infarction or angioplasty or by-pass graft procedures within the past 6 months.
9. 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.
10. Transient ischemic attack or cerebral vascular accident within the past 6 months.
11. GFR value < 60 ml/min calculated with MDRD formula.
12. Significant liver disease, defined as known active hepatitis or elevated liver enzymes over 3 fold the upper normal limit of laboratory normal ranges.
13. Patient with latent or known hereditary problems of galactose intolerance or the Lapp lactase deficiency or glucose-galactose malabsorption.
14. Positive urine drug screen for CNS active drugs (cocaine, opioids, amphetamines and cannabinoids) a Screening Visit.
15. Positive present history of glaucoma.
16. Hyperthyroidism, even if pharmacologically corrected.
17. Significant mental disorders.
18. History of seizure events other than a single childhood febrile seizure.
19. History of alcohol or psychoactive substance abuse or addiction.
20. Patient suffering from adrenal hypofunction (e.g. Addison's disease).
21. Women during pregnancy or lactation period.
22. 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).
23. Subject involved in the conduct of the study (e.g. Investigator or his/her deputy, first grade relatives, pharmacist, assistant or other personnel, etc).
24. Participation to an interventional clinical trial within 3 months prior to Screening Visit.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 2	Trazodone 10 mg	Trazodone 10 mg
Group 1	Trazodone 20 mg	Trazodone 20 mg
Group 3	Placebo	Placebo

Primary Outcome Measures

Name	Time	Method
Change of item 5 score in Brief Pain Inventory Short Form (BPI-SF) scale	Baseline - Day 56	Change from baseline of item 5 score in BPI-SF numering scale after 56 days.

Secondary Outcome Measures

Name	Time	Method
Change of item 5 score in Brief Pain Inventory Short Form (BPI-SF) scale	Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.	Change from baseline of item 5 score in BPI-SF numering scale after 7, 14, 21, 28, 35, 42, 49, 56 and 63 days.
Change of item 3 score in Brief Pain Inventory Short Form (BPI-SF) scale	Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.	Change from baseline of item 3 score in BPI-SF numering scale after 7, 14, 21, 28, 35, 42, 49, 56 and 63 days.
Change of item 4 score in Brief Pain Inventory Short Form (BPI-SF) scale	Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.	Change from baseline of item 4 score in BPI-SF numering scale after 7, 14, 21, 28, 35, 42, 49, 56 and 63 days.
Change of item 6 score in Brief Pain Inventory Short Form (BPI-SF) scale	Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.	Change from baseline of item 6 score in BPI-SF numering scale after 7, 14, 21, 28, 35, 42, 49, 56 and 63 days.
Change of item 8 score in Brief Pain Inventory Short Form (BPI-SF) scale	Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.	Change from baseline of item 8 score in BPI-SF numering scale after 7, 14, 21, 28, 35, 42, 49, 56 and 63 days.
Change of item 9 score in Brief Pain Inventory Short Form (BPI-SF) scale	Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.	Change from baseline of item 9 score in BPI-SF numering scale after 7, 14, 21, 28, 35, 42, 49, 56 and 63 days.
Change in Neuropathic Pain Symptom Inventory (NPSI) scale	Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.	Change from baseline of total score in NPSI scale after 7, 14, 21, 28, 35, 42, 49, 56 and 63 days.
Change in 36-item Short-Form Health Survey (SF-36)	Baseline - Day 56	Change from baseline of SF-36 after 56 days.
Change in Hamilton Anxiety Rating Scale (HAM-A)	Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.	Change from baseline of total score in HAM-A scale after 7, 14, 21, 28, 35, 42, 49, 56 and 63 days.
Patient Global Impression of Change (PGIC)	Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.	Assessment by patient of the overall efficacy and tolerability by PGIC after 7, 14, 21, 28, 35, 42, 49, 56 and 63 days
Change in Leeds Sleep Evaluation Questionnaire (LSEQ)	Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.	Change from baseline in LSEQ after 7, 14, 21, 28, 35, 42, 49, 56 and 63 days.
Frequency of treatment-related adverse events	9 weeks	Monitoring of the frequency of adverse events, physical examination, vital signs, ECG, laboratory analyses

Trial Locations

Locations (20)

NZOZ Neuromed M. i M. Nastaj Sp. P.; 🇵🇱 Lublin, Poland

RCMed Oddział Sochaczew; 🇵🇱 Sochaczew, Poland

NBR Polska Tomasz Klodawski; 🇵🇱 Warszawa, Poland

Medycyna Kliniczna; 🇵🇱 Warszawa, Poland

Nemocnice Pardubickeho kraje a.s. Pardubicka nemocnice Neurologická klinika; 🇨🇿 Pardubice, Czechia

MP-neuro s.r.o. Poliklinika Modry pavilon; 🇨🇿 Ostrava, Czechia

Litnea s.r.o. Neurologicka ambulance; 🇨🇿 Litomerice, Czechia

Semmelweis Egyetem AOK I. sz. Belgyogyaszati Klinika; 🇭🇺 Budapest, Hungary

NEUROHK s.r.o.; 🇨🇿 Chocen, Czechia

Neurosanatio s.r.o.; 🇨🇿 Litomysl, Czechia

Markhot Ferenc Oktatokorhaz es Rendelointezet Diabetesz Gondozo; 🇭🇺 Eger, Hungary

Pro Familia Altera Sp. z o.o.; 🇵🇱 Katowice, Poland

Vestra Clinics s.r.o.; 🇨🇿 Rychnov nad Knežnou, Czechia

Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont I. Sz. Belgyogyaszati Klinika; 🇭🇺 Szeged, Hungary

Silmedic Sp. z o.o.; 🇵🇱 Katowice, Poland

Bacs-Kiskun Megyei Korhaz II. sz. Belgyogyaszati Osztaly; 🇭🇺 Kecskemet, Hungary

Budai Irgalmasrendi Korhaz Belgyógyászati Centrum; 🇭🇺 Budapest, Hungary

Bekes Megyei Kozponti Korhaz Pandy Kalman Tagkorhaz I. sz. Belgyogyaszati Osztaly; 🇭🇺 Gyula, Hungary

Diabetologicka ambulance Milan Kvapil s.r.o.; 🇨🇿 Praha 4, Czechia

Jeka Sławomir Niepubliczny Zakład Opieki Zdrowotnej "Nasz Lekarz" Praktyka Grupowa Lekarzy Rodzinnych z Przychodnia Specjalistyczna; 🇵🇱 Torun, Poland