The main objective is to evaluate the efficacy and safety of phenytoin cream in patients with neuropathic pain due to CIAP. The second objective is to determine the predictive value of a DOBRET to identify sustained responders.
ID
Source
Brief title
Condition
- Peripheral neuropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the change in pain intensity from baseline NRS to the
mean NRS in the second week.
Secondary outcome
All secondary endpoints are for phenytoin 20% versus 10% versus placebo cream
in DOBRET positive, negative and all participants.
The change between baseline and week 2 of each intervention is assessed for:
1) pain intensity measured on the NRS,
2) 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
Background summary
CIAP is a slowly progressive distal symmetric sensory or sensorimotor axonal
polyneuropathy without a known cause. Approximately one-third of CIAP patients
have neuropathic pain. Until now, no randomized controlled trials have been
conducted in painful CIAP. Peripheral neuropathic pain can be very debilitating
and influences the quality of life considerably. For most patients current
treatments have insufficient pain reducing effects, and/or give rise to
considerable side effects. Therefore, more than half of the patients
discontinue oral neuropathic pain medication within 3 months. New treatment
strategies are needed to improve neuropathic pain management. Phenytoin cream
could fulfill this need.
Study objective
The main objective is to evaluate the efficacy and safety of phenytoin cream in
patients with neuropathic pain due to CIAP. The second objective is to
determine the predictive value of a DOBRET to identify sustained responders.
Study design
Enrichment randomized double-blind, placebo-controlled cross-over trial with
phenytoin cream in patients with painful CIAP (EPHENE study) with the duration
of 6 weeks will be performed. At baseline a DOBRET with phenytoin 10% 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 within 30 minutes at least two points pain reduction on the 11-point
numerical rating scale (NRS) on the phenytoin 10% cream applied area and at
least one-point difference on the NRS between phenytoin 10% and placebo cream
area, in favour of the former.
For the randomized phase of the cross-over trial, 48 DOBRET positive
participants will enter the DOBRET positive group and 24 DOBRET negative
participants the DOBRET negative group. Participants will be assigned to a
random order of the 3 treatments: phenytoin 10%, phenytoin 20% and placebo
cream. The duration of each treatment period is two weeks. Participants will
cross-over two times to each of the other treatments.
After the 6-week study, participants can choose to participate in a 1-year open
label extension study with phenytoine 20% cream.
Intervention
Patients will test one of the following interventions every 2 weeks: phenytoin
20% cream, phenytoin 10% cream and placebo cream, with the instruction to apply
the cream 2 to 4 times a day to the painful areas.
Study burden and risks
Burden of study participation consists of time needed to complete
questionnaires and keep a daily pain diary, three extra hospital visits and one
venipuncture for detection of phenytoin in plasma after the second week (T1).
The risks are minimal, because we do not expect clinically relevant
side-effects from the intervention and there is only once a minimally invasive
procedure (venipuncture). The advantage of study participation is that
participants can experience within a short timeframe if 10% and/or 20%
phenytoin cream has a clinically relevant analgesic effect (personalized
medicine).
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
* CIAP is 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
Exclusion criteria
* Painful (poly)neuropathy other than CIAP
* 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-001340-25-NL |
| CCMO | NL73339.041.20 |