E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Painful chronic idiopathic axonal polyneuropathy |
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E.1.1.1 | Medical condition in easily understood language |
Peripheral nerve pain without known cause |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040040 |
E.1.2 | Term | Sensory polyneuropathy axonal |
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 |
The main objective is to evaluate the efficacy and safety of two concentrations of phenytoin cream (10% and 20%) in participants with neuropathic pain due to CIAP. |
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E.2.2 | Secondary objectives of the trial |
The second objective is to determine the predictive value of a double-blind placebo-controlled response test (DOBRET) to identify sustained responders. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age 40 years or older • Patients have been diagnosed with CIAP defined as: presence of symmetrical distal sensory or sensorimotor symptoms such as numbness, pins and needles, tightness, coldness, unsteadiness, muscle cramps, and weakness with onset in the feet, compatible with polyneuropathy; presence of symmetrical distal sensory or sensorimotor signs with evidence of large nerve fiber involvement such as decreased sense of touch, vibration, and propriocepsis, usually in the presence of decreased pin prick/temperature sense, decreased/absent tendon reflexes, or slight muscle weakness on neurologic examination, compatible with polyneuropathy; an insidious onset and slow or no progression of the polyneuropathy over the course of at least 6 months; no identifiable cause for the polyneuropathy after thorough history-taking, clinical examination, and extensive laboratory testing; no suggestion of a hereditary polyneuropathy based on detailed kinship history (i.e., one or more affected family member), neurologic examination, or confirmation by genetic analysis; and nerve conduction studies excluding a demyelinating polyneuropathy and confirming large nerve fiber involvement if the findings on neurologic examination are equivocal considering the patient’s age. • Presence of chronic localized neuropathic pain due to CIAP • Neuropathic pain localized in two anatomically symmetrical areas of feet/lower legs • Duration of neuropathic pain ≥3 months • Duration of ≥1 hour neuropathic pain per day • Neuropathic pain characteristics defined by a DN4 score ≥4 • Mean pain score of ≥4 and <10 on the NRS at study entry (baseline) • Difference of pain intensity between left and right foot and/or lower leg of not more than 1 point on the NRS
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E.4 | Principal exclusion criteria |
• Painful (poly)neuropathy other than CIAP • Presence of neuropathic pain due to any other condition than CIAP • Neuropathic pain (distribution, duration, characteristics, intensity) not fulfilling the inclusion criteria • Pregnancy or planned pregnancy in the study period • Use of oral phenytoin • Open wounds in the neuropathic pain area • Current use of topical analgesics • Presence of other pain syndromes such as the widespread pain syndrome or pain in joints • Presence of serious psychological/psychiatric morbidity • Addiction to intoxicants • Hypersensitivity to the study medication (active substance and excipients) • Insufficient mastery of the Dutch language • Cognitive impairment and insufficiently capable to understand the purpose of the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the change in pain intensity from baseline NRS to the mean NRS in the second week in DOBRET positive participants. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1) Change in pain intensity from baseline NRS to the mean NRS in the second week of each treatment period in DOBRET negative participants and all participants combined. Furthermore, the following will be evaluated in DOBRET positive participants, DOBRET negative participants, and all participants combined: 2) Change from baseline to the end of the second week of each treatment period in quality of life as assessed with the EQ5-5D-5L, subscales of the BPI, pain characteristics as assessed with the NPSI, worst pain characteristics 3) Correlations between the following items: duration of painful CIAP, baseline NRS level, PCS, pain treatment naïve versus pain treatment resistant participants, worst pain characteristic, pain reducing effect on NRS, DOBRET results and PGIC 4) 30% and 50% improvement (MEC30 and MEC50) or more on the NRS compared to placebo within one patient 5) Time of carry-over effects after a treatment period 6) Number of participants who are responders on the PGIC after a treatment period 7) Onset of analgesic effect after application 8) Duration of analgesic effect 9) Daily number of cream applications 10) Percentage of analgesic effect as rated by the patient 11) Local and/or systemic side effects 12) Detection of phenytoin in plasma 13) Predictive value of DOBRET 14) Use of escape pain medication
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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) | 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 | No |
E.8.1.6 | Cross over | Yes |
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 | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
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 | |
E.8.9.1 | In the Member State concerned days | |