| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Neuropathic pain associated with diabetic peripheral neuropathy |
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| E.1.1.1 | Medical condition in easily understood language |
| Pain associated with complications of diabetes. |
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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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067547 |
| E.1.2 | Term | Diabetic peripheral neuropathic pain |
| E.1.2 | System Organ Class | 100000004852 |
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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 investigate the effect of repeat oral dosing of CNV2197944 on neuropathic pain in patients with diabetic peripheral neuropathy (DPN). |
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
To investigate the effects of repeat oral dosing of CNV2197944 75 mg tid on overall global function in patients with pain from DPN.
To investigate the safety and tolerability of CNV2197944 in patients with DPN.
To assess the blood concentrations and exposures of CNV2197944.
Exploratory Objectives:
To explore the frequency of genetic mutation in sodium and calcium channels in DPN and the relationship to response to CNV2197944. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female between 18 and 85 years of age inclusive, at the time of signing the informed consent.
2. A female patient is eligible to participate if she is of:
• Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL and estradiol < 40 pg/mL (<140 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in the protocol if they wish to continue their HRT during the study.
• Child-bearing potential and agrees to use one of the contraception methods listed in the protocol for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female patients must agree to use contraception until the follow-up visit.
3. Male patients must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until the follow-up visit.
4. Body weight ≥ 50 kg for men and ≥ 45 kg for women at screening.
5. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
6. Diabetes mellitus (Type I or II) that is documented to be under stable glycaemic control over a period of 3 months as indicated by a HgA1c of ≤9%. Diabetes should be controlled by diet, hypoglycaemics or insulin for 3 months prior to starting study medication, and no significant change in diabetic medication should be planned for the duration of the study.
7. Evidence of symmetrical, bilateral pain in the lower extremities due to DPN, which is defined as pain in the legs or feet with decreased sensation in the feet or decreased/absent ankle jerk deep tendon reflexes.
8. Presence of daily pain due to DPN for at least 6 months, but less than 5 years.
9. Score of ≥ 3 on the physical examination section of the Michigan Neuropathy Screening Instrument at screening.
10. Patient’s baseline average daily pain score for neuropathic pain due to DPN on the PI-NRS, calculated as the average of their daily PI-NRS scores over the first baseline period (study baseline - the 5 days immediately prior to randomisation), is greater than or equal to 4 and not greater than 9 on the PI-NRS, and to have no individual daily score less than 3. Subjects will need to have recorded their daily PI-NRS for a minimum of 4 days during the baseline period. Subjects will not be told that the entry requirement of the average PI-NRS is at least 4, in order not to bias their pain intensity score.
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| E.4 | Principal exclusion criteria |
1. Patients having other severe pain, which may impair the self-assessment of the pain due to DPN.
2. Diabetic related medical conditions that might impair the assessment of pain due to DPN. This would include amputations, major skin ulcers, physical injury to the affected limb, or any planned surgeries during the course of the study.
3. Patients who have received nerve blocks for neuropathic pain within 4 weeks prior to the start of the single-blind placebo run-in (Day 1).
4. Certain medications used to relieve the pain of DPN such as gabapentanoids, tricyclic antidepressants, SNRIs, anticonvulsants/antiepileptics, opioids, topical analgesics, capsaicin products, mexiletine, dextromethorphan, tramadol, cannabinoids, ketamine and oral/injectable corticosteroids are prohibited during the study and must be washed out prior to the start of the run-in period (Day 1).
5. Patients with a documented failure to respond to a maximum tolerated dose regimen of gabapentin or pregabalin. The dose should fall within the approved regulatory labelling for DPN for this exclusion to apply. In case of uncertainty the case should be discussed with the medical monitor.
6. Use of other prohibited medications.
7. History or presence of significant cardiovascular or gastro-intestinal or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs which, in the opinion of the Investigator may interfere with the study procedures or compromise patient safety. In case of uncertainty the case should be discussed with the medical monitor.
8. A positive pre-study HIV, Hepatitis B surface antigen or positive Hepatitis C antibody result.
9. History of regular alcohol consumption during the 6 months prior to screening, defined as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units for male patients and of greater than 14 units weekly or an average daily intake of greater than 2 units for female patients. One unit is equivalent to a half-pint (280 mL) of beer or 1 (25 mL) measure of spirits or 1 glass (125 mL) of wine.
10. A significant medical history of recurrent syncope or symptomatic orthostatic hypotension, blackouts, fainting or vaso-vagal attacks during the twelve months prior to screening, or evidence of low blood pressure at screening or baseline (systolic BP < 90 mmHg or diastolic BP < 50 mmHg, mean of triplicate readings) after repeated measurements.
11. Patients with a history of uncontrolled or poorly controlled hypertension during the twelve months prior to screening, with a systolic BP frequently exceeding 160 mmHg and/or diastolic BP frequently exceeding 100 mmHg, or with evidence of BP greater than 160 mmHg and/or greater than 100 mmHg diastolic, mean of triplicate readings, at screening and baseline after repeated measurement.
12. A history of second or third degree heart block during the twelve months prior to screening, or evidence of second or third degree heart block on ECG’s recorded at screening and baseline.
13. At the screening and baseline visit both QTcB and QTcF must be <450msec on two out of three ECG recordings taken at 5 minute intervals.
14. A history of any significant liver or renal disease during the twelve months prior to screening. In case of uncertainty the case should be discussed with the medical monitor.
15. AST, ALT and/or GGT >2x upper limit of normal. Alkaline phosphatase or bilirubin >1.5x upper limit of normal.
16. Creatinine clearance ≤30 mL/min estimated from serum creatinine, body weight, age and sex using the Cockcroft and Gault equation.
17. A significant medical history of depression or history of suicidality.
18. A depression subscale score of >10 on the Hospital Anxiety and Depression Scale.
19. History or presence of any medical or psychiatric condition, or clinically significant abnormality in vital signs, ECG, laboratory tests, or history of illicit drug use which, in the opinion of the Investigator may interfere with the study procedures or compromise subject safety. In case of uncertainty the case should be discussed with the medical monitor.
20. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates participation.
21. Participation in a clinical trial in which the subject has received an investigational product during the month prior to screening or, in the case of a biological agent with a long half-life, three months.
22. Exposure to more than four new chemical entities (medications for which no marketing authorisation has been obtained) during the 12 months prior to the first dosing day.
23. Previous participation in a study involving CNV2197944.
24. Subject is mentally or legally incapacitated.
25. Unwillingness or inability to follow the procedures outlined in the protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Change in average daily neuropathic pain score between the third week of treatment and baseline based on the 11 point PI-NRS (0=no pain, 10=maximum pain imaginable.)
Subjects should specifically rate the pain intensity for the neuropathic pain associated with DPN and not pain from other causes.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Change from baseline following 3 weeks of active treatment. |
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| E.5.2 | Secondary end point(s) |
Efficacy:
The following endpoints specifically refer to the neuropathic pain from DPN.
• Change in average daily pain score from baseline over time (weeks 1, 2 and 3 of treatment).
• Change in Neuropathic Pain Symptom Inventory total score and sub-scales from baseline to week 3 of treatment.
• ≥ 30% reduction in PI-NRS score after 3 weeks of treatment.
• ≥ 50% reduction in PI-NRS score after 3 weeks of treatment.
• Improved Patient Global Impression of Change (PGIC) after 3 weeks of treatment.
• Improved Clinician Global Impression of Change (CGIC) after 3 weeks of treatment.
Safety:
• Incidence, severity, seriousness and relatedness of adverse events.
• Changes in laboratory safety test results (clinical chemistry, haematology, urinalysis) and the incidence of abnormal laboratory test results.
• Changes in blood pressure and heart rate.
• Changes in ECG parameters.
Pharmacokinetics:
• Pre-dose and post-dose blood CNV2197944 concentrations – AUC(0-24)-ss, Cmin-ss and Cmax-ss.
Exploratory Endpoints:
• Total dose of paracetamol taken during treatment periods as a rescue medication for DPN pain only.
• Presence of genetic mutations in sodium channel (Nav1.1, Nav1.2, Nav1.3, Nav1.6 and Nav1.7) or calcium channel (Cav2.2 and Cav2.1) genes (optional).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 3 weeks of active treatment. |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Patients start in single-blind run-in phase and, if eligible, continue to double-blind phase. |
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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 | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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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| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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