Donepezil for Oxaliplatin-induced Neuropathy Peripheral Neuropathy: Proof of Concept Study
Status:
Not yet recruiting
Trial end date:
2024-08-01
Target enrollment:
Participant gender:
Summary
The use of oxaliplatin in the treatment of colorectal or pancreas cancer induces (>75% of
patients) severe sensorimotor neuropathy decreasing the quality of life of cancer survivors.
Today, no treatment remains univocal for these peripheral neuropathies. But preclinical works
have demonstrated that donepezil (acetylcholinesterase inhibitor use for Alzheimer's disease)
was able to prevent and treat neuropathic symptoms in oxaliplatin-treated rats.
Present study aims to assess the therapeutic efficacy of donepezil on oxaliplatin-induced
peripheral neuropathy (OIPN) in cancer survivors. Bibliographic data suggests an
antineuropathic effect of donepezil in human and animal models. In clinic, a study have shown
in healthy volunteers that donepezil (associated with gabapentin) reduced the pain threshold
(better than gabapentin alone) caused by stimulation of the sural nerve, without severe
adverse effect. Similarly, two studies in patients with neuropathic pain demonstrated that
donepezil increases analgesic effect of gabapentin. Finally, a case report demonstrated an
analgesic effect of donepezil in painful Alzheimer's disease patients. In animals, several
studies demonstrated that donepezil induces analgesic and neuroprotective effects. Recently,
a preclinical study demonstrated that donepezil induced antineuropathic effect in diabetic
mice with neuropathic pain. Research unit INSERM U1107 (partner of the DONEPEZOX study)
demonstrated the antineuropathic effects of donepezil in several animal models of
chemotherapy-induced peripheral neuropathies, and very recently, a study have confirmed these
results with oxaliplatin and cisplatin. These clinical and preclinical data have thus
highlighted the potential beneficial effect of donepezil on neuropathic symptoms, without any
significant adverse effects. Therefore the hypothesis is that the use of donepezil could
reduce the symptoms of OIPN, limit the decrease in quality of life and the appearance of
comorbidities (anxiety/depression) in cancer survivors.
For this purpose, the investigators propose here a proof of concept, multicentre, phase II,
randomised, double-blind, placebo-controlled clinical study. The primary objective will be
the curative efficacy of donepezil on the severity of OIPN in patients who have completed
oxaliplatin-based chemotherapy for the treatment of colorectal or pancreas cancer and have
peripheral neuropathy of grade ≥2. This will be assessed using the EORTC QLQ-CIPN20 sensory
scale. Our methodological choice to use the QLQ-CIPN20 as the primary endpoint will allow us
to more accurately (and in a standardized manner) characterize neuropathic symptoms and
assess the therapeutic effect of donepezil on these symptoms. In addition, as secondary
objectives, we will study the effect of donepezil on neuropathic pain, the intensity of
neuropathic symptoms, health-related quality of life, and the tolerance of donepezil.
The 80 patients required will be randomized (1:1) to receive either placebo or donepezil (5
mg daily for 4 weeks and then 10 mg daily for 12 weeks as a single dose and according to
tolerance and efficacy). Patients will be followed for 1 month after the end of treatment to
assess the OIPN. As a proof of concept study, responder rate will be assessed only for
Donepezil arm (primary objective) and compared between each treatment arm (secondary
objective) after a minimum of 12 weeks of treatment. A responder will be defined as a patient
with a decrease of neuropathic grade according to CIPN20 sensory score compraed to baseline.