Chronic Idiopathic Axonal Polyneuropathy Clinical Trial
Official title:
A Pilot Study in a Double Blind, Randomized, Placebo-Controlled, Parallel-Group, 16 Week, Trial Design Evaluating the Efficacy and Safety of Levetiracetam 500 mg Tablets in Bid Administration (Daily Dose Ranging From 1000 mg to 3000 mg), in Adults (>18 Years of Ages) Suffering From Chronic Idiopathic Axonal Polyneuropathy
Considering the mechanisms of action which provide efficacy in epilepsy, it is hypothesized that treatment with levetiracetam will reduce the neuronal excitability involved in neuropathic pain associated with CIAP. Thus, there is a potential for levetiracetam to bring therapeutic benefit for the subjects because of its specific mechanism of action, its safety profile and the absence of interaction with other drugs.
Based on literature and expert opinion, and despite the efforts made to better treat the
spectrum of neuropathic pains, there are still unmet needs. The available treatments are not
effective as monotherapy administration in the vast majority of patients and polypharmacy
with several medications is often necessary. Tricyclic antidepressants (TCAs), mainly
amitriptyline, are still a mainstay of treatment for painful peripheral neuropathy, but at
the risk of some dose-limiting adverse events, which may reduce their effectiveness. TCA
treatment effect is inconsistent and limited by side effects. In one clinical trial while
about 50% of patients achieved significant or complete relief of pain 81% experienced side
effects and in 71% the side effects were dose limiting. TCAs can produce sedation, urinary
retention, and orthostatic hypotension that are of particular concern in the elderly and
patients with cardiovascular disease. In the same study desipramine was associated with a
slightly lower rate of side effects it offered only 40% of patients significant or complete
relief of neuropathic pain. Fluoxetine was no more effective than placebo in pain relief.
(Max, 1992). Due to the scarcity of controlled clinical trials and the inconclusive results
of available trials, physicians vary markedly in their suggested regimens for neuropathic
pain management. (Beydoun, 1999).
Antiepileptic drugs are being used more frequently in non-epileptic indications such as
neuropathic pain. One of the mechanisms by which neuropathic pain occurs is related to an
increased excitability of central neurons. Although their precise mechanism of action in
neuropathic pain remains unknown, antiepileptic drugs are believed to exert their
antineuralgic activity by suppressing the neuronal hyperexcitability state that
characterizes neuropathic pain. A small crossover trial of carbamazepine produced clinical
benefit is a significant number of patients but with side effects of somnolence in 50%,
dizziness in 40% and rash in 6% (Rull, 1969). Gabapentin showed benefit over placebo in a
165-subject randomized study of painful diabetic neuropathy pain; side effects were noted to
be mild or moderate in most but 8% withdrew due to side effects (Backonja, 1998). In a
placebo controlled study of lamotrigine in diabetic neuropathy there was s significant
reduction in daily pain scores compared to placebo; side effects were noted in about half of
the treated group but were minor. (Eisenberg, 2001). Results of treatment trials sing
valproate in painful diabetic neuropathy have been variable with both positive (Kochar,
2004) and negative trials (Otto, 2004). Treatment of neuropathic pain in chronic idiopathic
axonal polyneuropathy has received limited study. In a single open label study or CIDP pain
tiagabine produced about 30% reduction in pain severity but almost half of the patients
discontinued the trial (Novak, 2001).
Levetiracetam has been tested in two animal models of neuropathic pain (Ardidd, 2001). In
the streptozocin diabetic rat model, reactivity to a pressure on the paw was assessed and
revealed that the ED50 for levetiracetam was comparable to the one observed in the epilepsy
models. Further, hyperalgesia was dose-dependently decreased by levetiracetam. On the other
hand, in the mononeuropathic sciatic nerve ligature model, hyperalgesia was not
significantly diminished. Carbamazepine is effective in the sciatic nerve ligature model.
Animal models of neuropathic pain are considered suggestive of activity in humans but they
are not directly predictive.
Based on the data from the animal studies in neuropathic pain models, levetiracetam has been
tested in a limited basis in two human types of neurological pain, painful diabetic
peripheral neuropathy and sural nerve stimulation in healthy volunteers. The diabetic
neuropathy study was a 12-week, multicenter, randomized, placebo-controlled, parallel group
study to evaluate the efficacy and safety of flexible dosing with LEV at 500 to 1500 mg bid.
A total of 105 subjects were included in the ITT population, 52 subjects in placebo and 53
subjects in the LEV group. At baseline, the treatment groups were comparable with respect to
demographic and other baseline characteristics. There were no statistically significant or
clinically meaningful treatment differences observed throughout the evaluation period
relative to baseline (personal communication).
In the randomized, double-blind, crossover, electrical sural nerve stimulation study, pain
was assessed in healthy volunteers before and 2, 4, 6, 8 and 24 hours after 1500 mg
levetiracetam or placebo was orally administered. Levetiracetam significantly increased the
threshold for pain detection when single electrical sural nerve stimulation was used, but
had no effect on temporal pain summation after repetitive sural nerve stimulation (CDC). It
has, however, been demonstrated that results from one type of neuropathic pain cannot
necessarily be extrapolated to other types, as the negative results of the 1998 study of
amitriptyline in HIV-related painful neuropathy demonstrates (Beydoun, 1999).
A small, investigator-initiated open label trial using levetiracetam in postherpetic
neuralgia (PHN) was recently completed. The study, published in Neurology, reported 6/10
patients had improvement in PHN symptomatology after a 12-week treatment with levetiracetam.
All 10 patients exposed had received multiple prior treatments for PHN (Rowbotham, 2003).
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT04647877 -
Phenytoin Cream for the Treatment of Neuropathic Pain
|
Phase 2/Phase 3 |