Donepezil for Oxaliplatin-induced Neuropathy Peripheral Neuropathy: Proof of Concept Study (DONEPEZOX)

  • STATUS
    Recruiting
  • End date
    Aug 1, 2024
  • participants needed
    80
  • sponsor
    University Hospital, Clermont-Ferrand
Updated on 8 July 2022

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.

Details
Condition Digestive Oncology, Supportive Care
Treatment Placebo, donepezil
Clinical Study IdentifierNCT05254639
SponsorUniversity Hospital, Clermont-Ferrand
Last Modified on8 July 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Patient who received chemotherapy with oxaliplatin for all stage of colorectal or pancreas cancer
QLQ-CIPN20 sensory score ≥30
Diagnosis of chemotherapy-induced peripheral neuropathy treated or not by stable antineuropathic/analgesic treatment (opioids, pregabalin, gabapentin, duloxetine and other antidepressants or anticonvulsants) for at least 1 month
Chemotherapy completed for at least 6 months
Patients affiliated to the French national health insurance
Written informed consent
French language comprehension

Exclusion Criteria

Cancer relapse or secondary cancer
Lack of effective contraception in patients (female) of childbearing age, pregnant or breastfeeding women, women of childbearing age who have not taken a pregnancy test
Patient with a chronic progressive disease with associated chronic pain (excluding oxaliplatin-induced peripheral neuropathy)
Diabetic patient (excluding non-insulin- or insulin-treated diabetes less than 5 years old) or presence of proven diabetic neuropathy
Other types of neuropathies
ALT / AST elevated more than 3 times the normal values
Severe cardiovascular disease (as determined by clinician), bradycardia (< 55 bpm), cardiac conduction disorders such as sinus disease or other supraventricular conduction abnormalities such as sino-auricular or atrioventricular block (assessed by electrocardiogram)
History of peptic ulcer disease or active peptic ulcer disease
Asthma or chronic obstructive pulmonary disease
Known allergy to donepezil or piperidine derivatives
Known galactose intolerance, known Lapp lactase deficiency or known glucose or galactose malabsorption syndrome (rare hereditary diseases)
Drug interactions: CYP3A4 inhibitors (ketoconazole, itraconazole and erythromycin); CYP2D6 inhibitors (fluoxetine, quinidine) and enzymatic inducers (rifampicin, phenytoin, carbamazepine)
Known dependence on alcohol and/or drugs
Known psychotic disorders, patient under antipsychotics
Impossible to undergo the medical follow-up of the trial for geographical, social or psychological reasons
Person under guardianship, curatorship, safeguard of justice or person deprived of liberty
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