E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Painful diabetic neuropathy |
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E.1.1.1 | Medical condition in easily understood language |
Painful diabetic neuropathy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012683 |
E.1.2 | Term | Diabetic peripheral neuropathy |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012680 |
E.1.2 | Term | Diabetic neuropathy |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10014698 |
E.1.2 | Term | Endocrine disorders |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To collect preliminary information on the effect of low doses of trazodone on pain intensity in patients with painful diabetic neuropathy after 8-week treatment period.
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E.2.2 | Secondary objectives of the trial |
To evaluate the neuropathic pain symptoms, anxiety, sleep, quality of life, safety and tolerability. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 glycemic 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.
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E.4 | Principal 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. Women during pregnancy or lactation period.
21. 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).
22. Subject involved in the conduct of the study (e.g. Investigator or his/her deputy, first grade relatives, pharmacist, assistant or other personnel, etc).
23. Participation to an interventional clinical trial within 3 months prior to Screening Visit.
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline of the BPI-SF item 5 score at Visit 8 (Day 56 ±2). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline - Visit 8 (Day 56 ±2). |
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E.5.2 | Secondary end point(s) |
• Change from baseline of BPI-SF item 5 score at V1, V2, V3, V4, V5, V6, V7 and V9.
• Change from baseline of BPI-SF items 3, 4, 5, 6, 8 and 9 score at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Change from baseline of NPSI total score at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Change from baseline in quality of life score (SF-36 short form) at V8.
• Change from baseline of HAM-A at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Change from baseline of Leeds Sleep Evaluation Questionnaire at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• PGIC score at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Safety and tolerability evaluation.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Change from baseline of BPI-SF item 5 score at V1, V2, V3, V4, V5, V6, V7 and V9.
• Change from baseline of BPI-SF items 3, 4, 5, 6, 8 and 9 score at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Change from baseline of NPSI total score at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Change from baseline in quality of life score (SF-36 short form) at V8.
• Change from baseline of HAM-A at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Change from baseline of Leeds Sleep Evaluation Questionnaire at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• PGIC score at V1, V2, V3, V4, V5, V6, V7, V8 and V9.
• Safety and tolerability evaluation.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
double-dummy, dose finding, multicentre, international, prospective, pilot study |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial will be the date of the last visit performed by the last ongoing patient. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 18 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 18 |