| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic neuropathic low back pain. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054095 |
| E.1.2 | Term | Neuropathic pain |
|
| 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 objectives of this study are to evaluate the efficacy, safety and tolerability of two doses of orally administered ralfinamide, compared to placebo, in patients with chronic neuropathic low back pain. |
|
| E.2.2 | Secondary objectives of the trial |
The following secondary efficacy measures will be used:
• “Responder” rates, based on the proportion of patients experiencing a 50% improvement from baseline to
endpoint in mean pain rating on the 11-point Likert scale (daily pain assessment),
• Change from baseline in the subject’s perception of of the impact of pain on sleep (11-point Likert scale),
• Change from baseline in the subject’s perception of the impact of pain on daily activity (11-point Likert scale)
• Total number of days without taking any additional pain medication. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient presents in the physical/neurological examination (see Section 6.2.1) with low back pain with or without radiation into the lower limb that must display a topography compatible with the L1 to S1 territory and/or respective sensory or motoric impairments.
2. Patient must have chronic neuropathic low back pain with a minimum intensity of “40 mm” (moderate) or greater on the Visual Analogue Scale (VAS; 100-mm) at screening, and a score of “40 mm” on each of the 5-7 days of diary recording priot to baseline (see Section 5.5).
3. The onset of pain has occurred at least three months, but not longer than 3 years, prior to the screening visit, as assessed by the investigator in the patient’s medical history.
4. Patient is affected by current neuropathic pain (pain provoked by a lesion of the peripheral nervous system). The diagnosis should be made by a neurologist / anaesthesiologist / orthopaedist / pain specialist and based on history, clinical evaluation and/or laboratory findings (rule out systemic cause, e.g., hypothyroidism, rheumatoid arthritis, nephropathy, diabetes [MNSI score >2]) in accordance with the taxonomy of the diagnostic criteria documented in the International Association for the Study of Pain (IASP) Classification of Chronic Pain. A neurological disease must be directly correlated with pain, including pain due to spinal root compression.
If radiologic data supporting the diagnosis had been obtained previously it should be
documented in the patient’s records. In case results of imaging examinations are not available, the Investigator should consider performing these examinations, if necessary to support the diagnosis during the screening phase, prior to randomizing the patient to treatment.
5. Patient has one of the following causes of neuropathic low back pain: Non-cancer lumbar pain due to compression radiculopathy or post-traumatic/post-surgical lumbar radiculopathy.
6. Patient’s low back pain has a clear neuropathic component, as indicated by a rating on the Pain Detect Questionnaire (PD-Q) of greater than 18.
7. Patients aged 18-85 years, inclusive. Patients greater than 85 years of age may be enrolled if they are in good health and approved by the Medical Monitor.
8. Patient is able to understand and signs an approved Informed Consent form. |
|
| E.4 | Principal exclusion criteria |
The exclusion criteria has been abbreviated (for full details please see the protocol):
1. Females who are pregnant or lactating, or of childbearing potential.
2. Patients with any other cause of peripheral or central neuropathic pain (including
psychogenic and nociceptive pain), pain due to metabolic (including diabetes; MNSI
score > 2), infectious, inflammatory or proliferative diseases, or pain due to any condition that is as severe as the neuropathic pain.
3. Patients with a history of migrating pain and former mononeuropathy or neuralgias in other anatomical territories.
4. Based on medical history or ophthalmological examination, patient has one of the following conditions:
• is albino
• family history of hereditary retinal disease
• progressive and/or severe diminution of visual acuity, i.e. 20/70
• retinitis pigmentosa
• retinal pigmentation due to any cause
• any active retinopathy or ocular inflammation (uveitis),
• moderate or severe diabetic retinopathy, or
• moderate proliferative retinopathy
5. Patients who may qualify for back surgery or any other treatment of the cause of their pain (e.g. disc herniations, mechanical entrapment syndromes) within 52 weeks after baseline, or patients with severe trophic changes, severe swelling, joint deformities or stiff joint with limited passive movement.
6. History or current diagnosis of positive test for Hepatitis B or C (unless vaccinated).
7. Clinically significant, uncontrolled gastrointestinal, renal, hepatic, endocrine, pulmonary or cardiovascular disease, asthma, uncompensated chronic obstructive pulmonary disease (COPD), severe uncontrolled diabetes (HbA1c > 10.0).
8. Second- or third-degree atrioventricular block or sick sinus syndrome, uncontrolled atrial fibrillation, severe or unstable angina, congestive heart failure, myocardial infarction within 3 months of the screening visit, significant ECG abnormalities or QTc > 450 msec, where QTc is based on Bazett’s correction method.
9. Concomitant disease likely to interfere with the study drug.
10. History of psychosis or any current DSM-IV Axis I diagnosis.
11. Neoplastic disorder which is either active or has been in remission for less than one year.
12. History or concomitant diagnosis of seizure disorder, or severe dizziness or fainting on standing due to postural hypotension.
13. History of allergic response, hypersensitivity or contraindications to anticonvulsant drugs or MAO-B inhibitors.
14. Treatment with potentially hepatotoxic, nephrotoxic, or antineoplastic drugs within the past the 6 months, depot neuroleptics in the previous 6 months, or oral neuroleptics in the 30 days prior to randomisation.
15. Patients who participated in prior trials.
16. Treatment with guanethidine or other sympathetic blockers in the 3 months prior to randomisation.
17. Treatment within 4 weeks preceding randomisation with any of the following: drug known to significantly inhibit or induce enzymes (e.g., barbiturates, phenothiazines, etc.), opioids (other than tramadol), tri- or tetra-cyclic antidepressants, SNRIs (e.g., venlafaxine, duloxetine), MAO inhibitors (e.g., selegiline), dextromethorphan, meperidine derivatives, neuro-stimulating devices, such as spinal cord stimulation (SCS), transcutaneous electrical nerve stimulation (TENS) or peripheral nerve stimulation (PNS), acupuncture, homeopathic remedies for pain or any kind of surgical treatment or blockade for the pain. Treatment with SSRIs, NSAIDs (including COX-inhibitors) and minor analgesics (e.g., paracetamol) will be permitted if taken at a stable dose from at least 4 weeks prior to study start (screening), provided that the dose will not be changed during the study.
18. Treatment with antiepileptic drugs (AEDs, e.g. pregabalin, gabapentin, carbamazepine, etc.), benzodiazepines (except if used as hypnotic at a stable dose), tramadol, mexiletine, skeletal muscle relaxants, steroids (except if used for allergies, asthma, etc. and maintained at a stable dose), capsaicin, coumarin anticoagulants, topical analgesics or injection of local anesthetics in the 2 weeks prior to randomisation.
19. Any abnormality noted during the screening period that the investigator deems to be clinically significant, either on medical history, physical examination, ECG, or diagnostic laboratory test, especially ASAT (SGOT), ALAT (SGPT), γGT or bilirubin greater than the upper limit of normal (ULN). Patients with abnormalities at screening (Day -7) whose test results are normal on repeat examination (Day -4) would be eligible for the study.
20. In the judgment of the Investigator, the subject is likely to be noncompliant.
21. The patient is currently institutionalized based on the decision of a judge or other authority.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint analysis will be the change from baseline to Week 12 of the mean weekly pain score using the “ON Treatment” ITT analysis set with BOCF imputation of missing data (only in the case of premature discontinuation). A ‘sequence of comparisons’ approach will be used in analyzing the data for the
primary efficacy measure. The analysis will be done in a two-step process, in which the high dose of ralfinamide (320 mg/day) will be compared to placebo first. If, and only if, a statistically significant difference is noted in this analysis, the comparison between the low dose of ralfinamide (160 mg/day) and placebo will be performed.
The treatments will be compared using analysis of covariance (ANCOVA) using SAS PROC GLM. The mean baseline pain score will be used as a covariate. The model will also include terms for treatment, centre, and treatment-by-centre interaction. If the treatment-by-centre interaction is not significant (p > 0.10) using a type II contrast, then it will be removed from the final model. The type III sum of squares will be used for the final model. |
|
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 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.8.3 |
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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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