Clinical trial NCT03202979: Trazodone in Painful Diabetic Neuropathy
Official title: Efficacy and Safety of Low Doses of Trazodone in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Pilot Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Painful Diabetic Neuropathy
Keywords: Trazodone
Placebo
Gabapentin
Neuropathic pain
Lead sponsor: Aziende Chimiche Riunite Angelini Francesco S.p.A
Sponsor class: INDUSTRY
Collaborators: name: Chiltern International Inc.
First posted: 2017-06-29
Enrollment: 142
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: Double-blind, placebo controlled, double-dummy, dose finding, multicentre, international, prospective, pilot study.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change of item 5 score in Brief Pain Inventory Short Form (BPI-SF) scale
timeFrame: Baseline - Day 56
Secondary outcomes:
measure: Change of item 5 score in Brief Pain Inventory Short Form (BPI-SF) scale
timeFrame: Baseline - Days 7, 14, 21, 28, 35, 42, 49, 63
measure: Change of item 3 score in Brief Pain Inventory Short Form (BPI-SF) scale
timeFrame: Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.
measure: Change of item 4 score in Brief Pain Inventory Short Form (BPI-SF) scale
timeFrame: Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.
measure: Change of item 5 score in Brief Pain Inventory Short Form (BPI-SF) scale
timeFrame: Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.
measure: Change of item 6 score in Brief Pain Inventory Short Form (BPI-SF) scale
timeFrame: Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.
measure: Change of item 8 score in Brief Pain Inventory Short Form (BPI-SF) scale
timeFrame: Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.
measure: Change of item 9 score in Brief Pain Inventory Short Form (BPI-SF) scale
timeFrame: Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.
measure: Change in Neuropathic Pain Symptom Inventory (NPSI) scale
timeFrame: Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.
measure: Change in 36-item Short-Form Health Survey (SF-36)
timeFrame: Baseline - Day 56
measure: Change in Hamilton Anxiety Rating Scale (HAM-A)
timeFrame: Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.
measure: Patient Global Impression of Change (PGIC)
timeFrame: Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.
measure: Change in Leeds Sleep Evaluation Questionnaire (LSEQ)
timeFrame: Baseline - Days 7, 14, 21, 28, 35, 42, 49, 56 and 63.
measure: Frequency of treatment-related adverse events
timeFrame: 9 weeks
Other outcomes:
Locations:
city: Chocen
country: Czechia
facility: NEUROHK s.r.o.
city: Litomerice
country: Czechia
facility: Litnea s.r.o. Neurologicka ambulance
city: Litomysl
country: Czechia
facility: Neurosanatio s.r.o.
city: Ostrava
country: Czechia
facility: MP-neuro s.r.o. Poliklinika Modry pavilon
city: Pardubice
country: Czechia
facility: Nemocnice Pardubickeho kraje a.s. Pardubicka nemocnice Neurologická klinika
city: Praha 4
country: Czechia
facility: Diabetologicka ambulance Milan Kvapil s.r.o.
city: Rychnov nad Knežnou
country: Czechia
facility: Vestra Clinics s.r.o.
city: Budapest
country: Hungary
facility: Budai Irgalmasrendi Korhaz Belgyógyászati Centrum
city: Budapest
country: Hungary
facility: Semmelweis Egyetem AOK I. sz. Belgyogyaszati Klinika
city: Eger
country: Hungary
facility: Markhot Ferenc Oktatokorhaz es Rendelointezet Diabetesz Gondozo
city: Gyula
country: Hungary
facility: Bekes Megyei Kozponti Korhaz Pandy Kalman Tagkorhaz I. sz. Belgyogyaszati Osztaly
city: Kecskemet
country: Hungary
facility: Bacs-Kiskun Megyei Korhaz II. sz. Belgyogyaszati Osztaly
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont I. Sz. Belgyogyaszati Klinika
city: Katowice
country: Poland
facility: Silmedic Sp. z o.o.
city: Katowice
country: Poland
facility: Pro Familia Altera Sp. z o.o.
city: Lublin
country: Poland
facility: NZOZ Neuromed M. i M. Nastaj Sp. P.
city: Sochaczew
country: Poland
facility: RCMed Oddział Sochaczew
city: Torun
country: Poland
facility: Jeka Sławomir Niepubliczny Zakład Opieki Zdrowotnej "Nasz Lekarz" Praktyka Grupowa Lekarzy Rodzinnych z Przychodnia Specjalistyczna
city: Warszawa
country: Poland
facility: NBR Polska Tomasz Klodawski
city: Warszawa
country: Poland
facility: Medycyna Kliniczna
Study officials:
References:
citation: Lipone P, Ehler E, Nastaj M, Palka-Kisielowska I, Cruccu G, Truini A, Di Loreto G, Del Vecchio A, Pochiero I, Comandini A, Calisti F, Cattaneo A. Efficacy and Safety of Low Doses of Trazodone in Patients Affected by Painful Diabetic Neuropathy and Treated with Gabapentin: A Randomized Controlled Pilot Study. CNS Drugs. 2020 Nov;34(11):1177-1189. doi: 10.1007/s40263-020-00760-2.