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Phenytoin Cream for the Treatment of Neuropathic Pain (EPHENE)

Primary Purpose

Chronic Idiopathic Axonal Polyneuropathy

Status

Completed

Phase

Phase 2

Locations

Netherlands

Study Type

Interventional

Intervention

phenytoin cream

Placebo cream

About this trial

This is an interventional treatment trial for Chronic Idiopathic Axonal Polyneuropathy focused on measuring cryptogenic sensory polyneuropathy, CIAP, neuropathic pain

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University Medical Center Utrecht

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

Phenytoin 10 percent cream

Phenytoin 20 percent cream

Placebo cream

Arm Description

Phenytoin 10 percent cream, 2 to 4 times daily application, 2 weeks long

Phenytoin 20 percent cream, 2 to 4 times daily application, 2 weeks long

Placebo cream, 2 to 4 times daily application, 2 weeks long

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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.

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.

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.

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.

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.

30 percent and 50 percent improvement or more on the NRS compared to placebo within one patient

Time of carry-over effects after a treatment period

Onset of analgesic effect after application

The onset of analgesic effect will be noted in minutes.

Duration of analgesic effect

The duration of analgesic effect will be noted in hours.

Daily number of cream applications

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.

Local and/or systemic side effects

At each visit and telephone call participants will be asked about possibly occurring side effects.

Detection of phenytoin in plasma

Two hours after last application phenytoin plasma level will be evaluated

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.

Use of escape pain medication

The daily amount of acetaminophen and/or non-steroid anti-inflammatory drugs

Full Information

NCT ID

NCT04647877

First Posted

November 16, 2020

Last Updated

June 27, 2023

Sponsor

David J. Kopsky

Collaborators

Princess Beatrix Muscle Foundation, Dr. C.J. Vaillant Fonds

1. Study Identification

Unique Protocol Identification Number

NCT04647877

Brief Title

Phenytoin Cream for the Treatment of Neuropathic Pain

Acronym

EPHENE

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Completed

Study Start Date

September 17, 2020 (Actual)

Primary Completion Date

June 15, 2023 (Actual)

Study Completion Date

June 15, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

David J. Kopsky

Collaborators

Princess Beatrix Muscle Foundation, Dr. C.J. Vaillant Fonds

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Idiopathic Axonal Polyneuropathy

Keywords

cryptogenic sensory polyneuropathy, CIAP, neuropathic pain

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

81 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Phenytoin 10 percent cream

Arm Type

Experimental

Arm Description

Phenytoin 10 percent cream, 2 to 4 times daily application, 2 weeks long

Arm Title

Phenytoin 20 percent cream

Arm Type

Experimental

Arm Description

Phenytoin 20 percent cream, 2 to 4 times daily application, 2 weeks long

Arm Title

Placebo cream

Arm Type

Placebo Comparator

Arm Description

Placebo cream, 2 to 4 times daily application, 2 weeks long

Intervention Type

Drug

Intervention Name(s)

phenytoin cream

Intervention Description

Phenytoin cream to be applied on the neuropathic pain area

Intervention Type

Other

Intervention Name(s)

Placebo cream

Intervention Description

Placebo cream to be applied on the neuropathic pain area

Primary Outcome Measure Information:

Title

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.

Description

0 = no pain, 10 = worst imaginable pain. The bigger the mean change, the better the outcome

Time Frame

Mean baseline vs. mean of second week of each intervention

Secondary Outcome Measure Information:

Title

Description

0 = no pain, 10 = worst imaginable pain. The bigger the mean change, the better the outcome

Time Frame

Mean baseline vs. mean of second week of each intervention

Title

Change of EuroQol (EQ5-5D-5L) from baseline to the end of the second week of each treatment period

Description

Time Frame