| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic non-malignant neuropathic pain |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pain caused by damage or disease affecting the sensory system |
|
| 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029223 |
| E.1.2 | Term | Neuralgia |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 |
| The primary objective of the trial is to investigate the effect of Ketamine HCl PR tablets administered twice daily as add-on therapy to the individual standard treatment regimen of each patient in comparison to placebo in the relief of chronic non-malignant neuropathic pain as determined by absolute changes in the “current” pain intensity (PI) score on the visual analogue scale (VAS). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to investigate the effect of Ketamine HCl PR tablets administered twice daily as add-on therapy to the individual standard treatment regimen of each patient in comparison to placebo in improvement of symptoms of chronic non-malignant neuropathic pain as determined by relative changes in the “current” PI score on the VAS, as well as by absolute and relative changes in the Neuropathic Pain Symptom Inventory (NPSI), “recalled” average PI during the day and “recalled” average PI during the night.
Moreover, a secondary objective is to assess the safety and tolerability of Ketamine HCl PR tablets administered twice daily as add-on therapy to the individual standard treatment regimen in patients with chronic non-malignant neuropathic pain.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female patients ≥18 years of age at Visit 1 (Screening)
2. Patients with a documented history of chronic non-malignant neuropathic pain at Visit 1
3. Patients with a DN4 Neuropathic Pain Diagnostic Questionnaire score of ≥4 at Visit 1
4. Stable individual regular standard treatment regimen for chronic neuropathic pain, i.e. no change in drug and non-drug treatments for at least two weeks prior to Visit 1 and anticipated to remain stable until the end of the single-blind treatment phase. Use of rescue medication for neuropathic pain (including topical treatments, physical measures etc.) or any other co-medication used on an “as-needed” basis that might affect pain perception or pain intensity as well as opioids as part of the regular standard treatment are not allowed in this trial.
5. Patients with inadequate pain control (mean “current” PI on VAS >50 mm) by their current individual standard treatment regimen on at least three days of the seven-day screening phase (to be checked at Visit 2)
6. Patients willing and able (e.g. mental and physical condition) to participate in all aspects of the trial, including use of medication, completion of subjective evaluations, attending scheduled visits, completing telephone contacts, and compliance with protocol requirements as evidenced by providing signed written informed consent at Visit 1 |
|
| E.4 | Principal exclusion criteria |
1. Hypersensitivity or intolerance to ketamine or any of the excipients
2. Patients treated with any other ketamine preparation within the last month prior to Visit 1
3. Patients receiving opioids , regardless if as part of their individual standard treatment regimen for chronic neuropathic pain or in context with any other indication, within the last two weeks prior to Visit 1
4. Patients with untreated or uncontrolled arterial hypertension (sitting systolic blood pressure at rest ≥160 mmHg and/or sitting diastolic blood pressure at rest ≥90 mmHg)
5. History of cerebrovascular event (stroke, PRIND, TIA) within the previous six months prior to Visit 1
6. Known or suspected cardiac disease, especially coronary artery disease (e.g. unstable angina, congestive heart failure), tachyarrhythmia and history of myocardial infarction
7. Known or suspected hypovolemia or dehydration
8. Known or suspected hyperthyroidism or patients receiving thyroid replacement therapy within the last two weeks prior to Visit 1
9. Concomitant treatment with theophylline or aminophylline within the last two weeks prior to Visit 1
10. Long-term therapy for any chronic disease, if suspected to be unstable during the course of the trial
11. Regular or intermittent intake of St. John’s wort (hypericum perforatum), if not stopped at Visit 1
12. Other non-drug treatments such as physical measures, acupuncture, etc., if not stable since at least two weeks prior to Visit 1 or suspected to be unstable during the course of the trial
13. Known or suspected globe injury or increased intraocular pressure (e.g. glaucoma)
14. Known or suspected cranio-cerebral trauma, intracranial mass lesions, hydrocephalus or elevation of intracranial pressure within the last three months prior to Visit 1 or sequelae of previous events
15. Known or suspected convulsive disorder
16. Known or suspected acute intermittent porphyria
17. History or presence of moderate or severe psychiatric disorder (e.g. moderate or severe depression, schizophrenia or acute psychosis)
18. Known or suspected current pulmonary or upper respiratory infection
19. Known or suspected acute or chronic alcoholism, delirium tremens, or toxic psychosis
20. History of any malignancy in the last five years; except history of in-situ cancer or basal or squamous cell skin cancer. Patients with other malignancies are eligible if they have been continuously disease free for at least five years
21. Known or suspected CNS depression (signs/symptoms: decreased vital signs, impaired thinking and perception, slurred speech, slowed reflexes, fatigue, decreased consciousness)
22. History of drug addiction or drug seeking behaviour, positive test of illicit drugs (other than medication used for individual standard treatment of pain) at Visit 1
23. Surgery within one month, denervation procedures within six months or neural blockade (e.g. injection of a local anaesthetic into or near to a nerve), neuromodulatory measures (e.g. TENS) or radiotherapy two weeks prior to trial Visit 1 and/or anticipated and/or scheduled during the course of the trial
24. Evidence of impaired hepatic function (total bilirubin, AST, ALT, GGT, or AP >3 times the upper limit of normal)
25. Evidence of moderate or severe renal impairment (CRCL <60 ml/min) or patients with renal failure who are on any form of dialysis
26. Any gastro-intestinal pathology or surgery or intractable vomiting likely to significantly influence drug absorption
27. Inability to swallow the trial drugs whole (e.g. due to dysphagia).
28. For women: Pregnancy or breast-feeding. Women of childbearing potential unable or unwilling to undergo pregnancy tests and practice adequate contraceptive measures. Reliable methods for women are hormonal contraceptives, surgical intervention (e.g. tubal ligation), intrauterine device (IUD), double-barrier methods and true sexual abstinence (i.e. when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. For men: Men unable or unwilling to practice adequate contraceptive measures. Reliable methods for men are surgical intervention (e.g. vasectomy), double-barrier methods or true sexual abstinence (i.e. when this is in line with the preferred and usual lifestyle of the patient).
29. Any other condition of the patient that in the opinion of the investigator may compromise evaluation of the trial treatment or may jeopardize patient’s safety, compliance or adherence to protocol requirements
30. Previous enrolment in the single-blind treatment phase of this trial or participation in any other clinical trial within the past 30 days prior to enrolment
31. Persons committed to an institution by virtue of an order issued either by the judicial or other authorities
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary end point is defined as the absolute change from baseline in “current” PI on 0 - 100 mm VAS (mean of all “current” PIs of the last four days of each treatment period) after Ketamine HCl PR Placebo tablets versus Ketamine HCl PR tablets. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary end point is evaluated at the end of the trial. |
|
| E.5.2 | Secondary end point(s) |
• relative change from baseline in “current” PI on 0 – 100 mm VAS (mean of all “current” PIs of the last four days of each treatment period) after Ketamine HCl PR Placebo tablets versus Ketamine HCl PR tablets
• absolute and relative change from baseline in NPSI total intensity score and NPSI sub-scores after Ketamine HCl PR Placebo tablets versus Ketamine HCl PR tablets
• absolute and relative change from baseline in “recalled average PI during the day on 0 – 100 mm VAS (mean of all “recalled” PIs during day-time of the last four days of each treatment period) after Ketamine HCl PR Placebo tablets versus Ketamine HCl PR tablets
• absolute and relative change from baseline in “recalled average PI during night on 0 – 100 mm VAS (mean of all “recalled” PIs during night-time of the last four days of each treatment period) after Ketamine HCl PR Placebo tablets versus Ketamine HCl PR tablets
• adverse events (AEs)
• vital signs, standard laboratory evaluations, electrocardiogram (ECG) and physical examinations
• the rate of discontinuations due to AEs during the active treatment phase (defined as the time from the first ketamine intake in Period 2 until the last ketamine intake in Period 3).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary end points are evaluated at the end of the trial. In addition, an interim review based on safety and tolerability outcomes (mainly occurrence of AEs) will occur after stage 1, in order to determine dosing levels for stage 2 as outlined in the protocol. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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 | 1 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
