Phenytoin Cream for the Treatment of Neuropathic Pain (EPHENE)

Enrichment Randomized Double-blind, Placebo-controlled Cross-over Trial With PHEnytoin Cream in Patients With Painful Chronic Idiopathic Axonal polyNEuropathy

Objectives: The main objective is to evaluate the efficacy and safety of phenytoin cream in patients with neuropathic pain due to chronic idiopathic axonal polyneuropathy (CIAP). The second objective is to determine the predictive value of a double-blind placebo-controlled response test (DOBRET) to identify sustained responders.

Study design: This is a 6-week enrichment randomized double-blind, placebo-controlled cross-over trial evaluating phenytoin cream in 84 participants with painful CIAP, whereafter an open label extension phase is offered with phenytoin 20 percent cream for up to one year.

At baseline a DOBRET with phenytoin 10 percent and placebo cream will be performed in each study participant to stratify participants according to their response to the DOBRET before entering the double-blind cross-over phase. DOBRET positive participants are those who experience at least two points pain reduction on the 11-point numerical rating scale (NRS) on the phenytoin 10 percent cream applied area within 30 minutes and at least one-point difference in pain reduction on the NRS between phenytoin 10 percent and placebo cream applied area, in favour of the former.

Participants will receive three treatments in a double blind fashion and in a randomized order: phenytoin 10 percent, phenytoin 20 percent and placebo cream. The duration of each treatment period is two weeks. Participants will cross-over two times to each of the other treatments. The study does not have wash-out periods between treatments, because the mean duration of analgesic effect after an application is expected to be less than nine hours. A blood sample will be collected at the end of the second week of the first treatment period to test for phenytoin plasma levels.

Study population: The investigators aim to include 84 participants, age 40 years or older, who have been diagnoses with painful CIAP at the University Medical Center Utrecht and fulfil the inclusion criteria and have given written informed consent.

Interventions: Phenytoin cream in concentrations of 10 percent and 20 percent cream compared to placebo cream.

Primary endpoint: Change in pain intensity measured on the NRS between baseline and week 2 for phenytoin 20% cream versus placebo cream.

Study Overview

• Status: Completed
• Conditions: Chronic Idiopathic Axonal Polyneuropathy
• Intervention / Treatment: Drug: phenytoin cream; Other: Placebo cream

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: David J Kopsky, MD; Phone Number: +31628671847; Email: david@topicalinnovations.com
• Study Contact Backup: Name: Janna K Warendorf, MD; Phone Number: +31887551546; Email: ciapstudie@umcutrecht.nl

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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 proprioception, 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 the Douleur Neuropathique 4 questions (DN4) score ≥4
• Mean pain score during daytime 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
• No changes in neuropathic pain medication for at least 1 month
• Absence of any of the exclusion criteria outlined below

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 (will only be asked)
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phenytoin 10 percent cream; Phenytoin 10 percent cream, 2 to 4 times daily application, 2 weeks long	Drug: phenytoin cream; Phenytoin cream to be applied on the neuropathic pain area
Experimental: Phenytoin 20 percent cream; Phenytoin 20 percent cream, 2 to 4 times daily application, 2 weeks long	Drug: phenytoin cream; Phenytoin cream to be applied on the neuropathic pain area
Placebo Comparator: Placebo cream; Placebo cream, 2 to 4 times daily application, 2 weeks long	Other: Placebo cream; Placebo cream to be applied on the neuropathic pain area

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mean pain intensity measured on the 11-point numerical rating scale (NRS) between baseline and week 2 for phenytoin 20% cream versus placebo cream.	0 = no pain, 10 = worst imaginable pain. The bigger the mean change, the better the outcome	Mean baseline vs. mean of second week of each intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mean pain intensity from baseline 11-point numerical rating scale (NRS) to the mean NRS in the second week in double-blind response test in positive and negative participants and all participants combined	0 = no pain, 10 = worst imaginable pain. The bigger the mean change, the better the outcome	Mean baseline vs. mean of second week of each intervention
Change of EuroQol (EQ5-5D-5L) from baseline to the end of the second week of each treatment period	EQ5-5D-5L consists of 5 quality of life questions assessed on a 5 point scale: the lower the score, the better quality of life. Furthermore, a visual analogue scale from 0 to 100 is included. The higher the score, the better quality of life.	Baseline vs. end of second week of each intervention
Change of Neuropathic Pain Symptom Inventory (NPSI) from baseline to the end of the second week of each treatment period	The NPSI consists of 10 neuropathic pain descriptors on the NRS, and 2 items assessing the duration of spontaneous ongoing and paroxysmal pain. The lower the score, the less pain.	Baseline vs. end of second week of each intervention
Change of subscales of the Brief Pain Inventory (sBPI) from baseline to the end of the second week of each treatment period	The sBPI consists of 7 quality of life questions, assessed on the NRS. The lower the score, the better quality of life.	Baseline vs. end of second week of each intervention
Change of the 3 worst pain characteristics from baseline to the end of the second week of each treatment period	The 3 worst pain characteristics are scored on the NRS. The lower the score, the less pain.	Baseline vs. end of second week of each intervention
Change of Patient Global Impression of Change Scale (PGIC) from baseline to the end of the second week of each treatment period	The PGIC is a 7-point satisfaction scale. The lower the score, the better.	Baseline vs. end of second week of each intervention
30 percent and 50 percent improvement or more on the NRS compared to placebo within one patient		Baseline vs. end of second week of each intervention
Time of carry-over effects after a treatment period		First week of each intervention
Onset of analgesic effect after application	The onset of analgesic effect will be noted in minutes.	At the end of second week of each intervention
Duration of analgesic effect	The duration of analgesic effect will be noted in hours.	At the end of second week of each intervention
Daily number of cream applications		At the end of second week of each intervention
Percentage of analgesic effect as rated by the participant	The participant will be asked about the percentage of pain reduction at the end of the second week of each intervention. The higher, the better.	At the end of second week of each intervention.
Local and/or systemic side effects	At each visit and telephone call participants will be asked about possibly occurring side effects.	During the 6 weeks of double-blind phase and 1 year open phase
Detection of phenytoin in plasma	Two hours after last application phenytoin plasma level will be evaluated	At the end of second week of first treatment period
Predictive value of DOBRET	Correlation with DOBRET response and mean pain reduction while using phenytoin 10 percent or 20 percent cream. The stronger the correlation, the more predictive the DOBRET is.	Baseline vs. mean of second week of each intervention
Use of escape pain medication	The daily amount of acetaminophen and/or non-steroid anti-inflammatory drugs	During the 6 weeks of double-blind phase and 1 year open phase

Collaborators and Investigators

• Sponsor: David J. Kopsky
• Collaborators: Princess Beatrix Muscle Foundation; Dr. C.J. Vaillant Fonds
• Investigators: Principal Investigator: Alexander FJE Vrancken, MD, PhD, UMC Utrecht

Publications and helpful links

General Publications

• Kopsky DJ, Vrancken AFJE, Keppel Hesselink JM, van Eijk RPA, Notermans NC. Usefulness of a Double-Blind Placebo-Controlled Response Test to Demonstrate Rapid Onset Analgesia with Phenytoin 10% Cream in Polyneuropathy. J Pain Res. 2020 May 1;13:877-882. doi: 10.2147/JPR.S243434. eCollection 2020.
• Kopsky DJ, Keppel Hesselink JM. Single-Blind Placebo-Controlled Response Test with Phenytoin 10% Cream in Neuropathic Pain Patients. Pharmaceuticals (Basel). 2018 Nov 12;11(4):122. doi: 10.3390/ph11040122.
• Kopsky DJ, Keppel Hesselink JM. Phenytoin Cream for the Treatment for Neuropathic Pain: Case Series. Pharmaceuticals (Basel). 2018 May 28;11(2):53. doi: 10.3390/ph11020053.
• Kopsky DJ, Keppel Hesselink JM, Russell AL, Vrancken AFJE. No Detectable Phenytoin Plasma Levels After Topical Phenytoin Cream Application in Chronic Pain: Inferences for Mechanisms of Action. J Pain Res. 2022 Feb 9;15:377-383. doi: 10.2147/JPR.S345347. eCollection 2022.
• Kopsky DJ, van Eijk RPA, Warendorf JK, Keppel Hesselink JM, Notermans NC, Vrancken AFJE. Enriched enrollment randomized double-blind placebo-controlled cross-over trial with phenytoin cream in painful chronic idiopathic axonal polyneuropathy (EPHENE): a study protocol. Trials. 2022 Oct 22;23(1):888. doi: 10.1186/s13063-022-06806-8.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2020
• Primary Completion (Actual): June 15, 2023
• Study Completion (Actual): June 15, 2023

Study Registration Dates

• First Submitted: November 16, 2020
• First Submitted That Met QC Criteria: November 30, 2020
• First Posted (Actual): December 1, 2020

Study Record Updates

• Last Update Posted (Actual): June 28, 2023
• Last Update Submitted That Met QC Criteria: June 27, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: neuropathic pain; cryptogenic sensory polyneuropathy; CIAP
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Polyneuropathies; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Anticonvulsants; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Phenytoin
• Other Study ID Numbers: UMC-NMZ-EPHENE2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No