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Completed

NCT Number: NCT04647877

Phenytoin Cream for the Treatment of Neuropathic Pain

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.

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Key information

Conditions

Chronic Idiopathic Axonal Polyneuropathy Nervous System Diseases Neuralgia Neurologic Manifestations Neuromuscular Diseases Pain Pathological Conditions, Signs and Symptoms Peripheral Nervous System Diseases Signs and Symptoms

Age range

40 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

University Medical Center Utrecht

Utrecht, 3584 CX, Netherlands

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

phenytoin cream

Drug

Phenytoin cream to be applied on the neuropathic pain area

Placebo Cream

Other

Placebo cream to be applied on the neuropathic pain area

Primary outcomes

  1. 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.

    Time frame: Mean baseline vs. mean of second week of each intervention

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

Secondary outcomes

  1. 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

    Time frame: Mean baseline vs. mean of second week of each intervention

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

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

    Time frame: Baseline vs. end of second week of each intervention

    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.

  3. Change of Neuropathic Pain Symptom Inventory (NPSI) from baseline to the end of the second week of each treatment period

    Time frame: Baseline vs. end of second week of each intervention

    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.

  4. Change of subscales of the Brief Pain Inventory (sBPI) from baseline to the end of the second week of each treatment period

    Time frame: Baseline vs. end of second week of each intervention

    The sBPI consists of 7 quality of life questions, assessed on the NRS. The lower the score, the better quality of life.

  5. Change of the 3 worst pain characteristics from baseline to the end of the second week of each treatment period

    Time frame: Baseline vs. end of second week of each intervention

    The 3 worst pain characteristics are scored on the NRS. The lower the score, the less pain.

  6. Change of Patient Global Impression of Change Scale (PGIC) from baseline to the end of the second week of each treatment period

    Time frame: Baseline vs. end of second week of each intervention

    The PGIC is a 7-point satisfaction scale. The lower the score, the better.

  7. 30 percent and 50 percent improvement or more on the NRS compared to placebo within one patient

    Time frame: Baseline vs. end of second week of each intervention

  8. Time of carry-over effects after a treatment period

    Time frame: First week of each intervention

  9. Onset of analgesic effect after application

    Time frame: At the end of second week of each intervention

    The onset of analgesic effect will be noted in minutes.

  10. Duration of analgesic effect

    Time frame: At the end of second week of each intervention

    The duration of analgesic effect will be noted in hours.

  11. Daily number of cream applications

    Time frame: At the end of second week of each intervention

  12. Percentage of analgesic effect as rated by the participant

    Time frame: At the end of second week of each intervention.

    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.

  13. Local and/or systemic side effects

    Time frame: During the 6 weeks of double-blind phase and 1 year open phase

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

  14. Detection of phenytoin in plasma

    Time frame: At the end of second week of first treatment period

    Two hours after last application phenytoin plasma level will be evaluated

  15. Predictive value of DOBRET

    Time frame: Baseline vs. mean of second week of each intervention

    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.

  16. Use of escape pain medication

    Time frame: During the 6 weeks of double-blind phase and 1 year open phase

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

Sponsors and collaborators

Lead sponsor

David J. Kopsky

Other

Collaborators

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

Registry information

Official study title

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

Acronym: EPHENE

Important dates

Study start
2020
Primary completion
2023
Study completion
2023
First posted
Dec 1, 2020
Registry last updated
Jun 28, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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