Clinical trial NCT05254639: Donepezil for Oxaliplatin-induced Neuropathy Peripheral Neuropathy: Proof of Concept Study
Official title: Evaluation of the Efficacy of Donepezil in the Treatment of Oxaliplatin-induced Peripheral Neuropathy: Proof of Concept Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Digestive Oncology
Supportive Care
Keywords: Pharmacology
Chronic Pain
Oxaliplatin
Chemotherapy-induced peripheral neuropathy
Donepezil
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
Collaborators: name: Federation Francophone de Cancerologie Digestive
First posted: 2022-02-24
Enrollment: 77
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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,
* Planned surgery during the trial,
* 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.

Primary outcomes:
measure: Quality of Life Questionnaire-Chemotherapy Induced Peripheral Neuropathy 20 (QLQ-CIPN20)
timeFrame: through study completion, an average of 4 months.
Secondary outcomes:
measure: 11-point pain Numeric Rating Scale (NRS)
timeFrame: through study completion, an average of 4 months
measure: Douleur Neuropathique-4 (DN4) interview
timeFrame: At inclusion
measure: Neuropathic Pain Symptoms Inventory (NPSI)
timeFrame: through study completion, an average of 4 months.
measure: Quality of Life Questionnaire-Cancer 30 (QLQ-C30)
timeFrame: through study completion, an average of 4 months.
measure: Hospital Anxiety and Depression scale (HADS)
timeFrame: through study completion, an average of 4 months.
measure: Patients' Global Impression of Change (PGIC)
timeFrame: 4 months
Other outcomes:
Locations:
city: Antony
country: France
facility: Hôpital privé d'Antony
city: Argenteuil
country: France
facility: CH d'Argenteuil
city: Besançon
country: France
facility: CHU de Besançon
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord Aquitaine
city: Cherbourg
country: France
facility: Centre Hospitalier du Cotentin
city: Cherbourg
country: France
facility: Centre Hospitalier Public du Cotentin
city: Cholet
country: France
facility: CH de Cholet
city: Clermont-Ferrand
country: France
facility: CHU clermont-ferrand
city: Compiègne
country: France
facility: Centre Hospitalier Compiègne-Noyon
city: Coudekerque-Branche
country: France
facility: Clinique de Flandre
city: Dijon
country: France
facility: CHU de Dijon Bourgogne
city: Dijon
country: France
facility: Institut de Cancérologie de Bourgogne - GRReCC
city: La Roche-sur-Yon
country: France
facility: CHD de Vendée
city: Le Puy-en-Velay
country: France
facility: CH Le puy
city: Levallois-Perret
country: France
facility: Hôpital Franco-Britanique
city: Limoges
country: France
facility: chu de Limoges
city: Lyon
country: France
facility: CH Saint Joseph Saint Luc
city: Lyon
country: France
facility: Clinique de la sauvegarde
city: Lyon
country: France
facility: Hôpital privé Jean Mermoz
city: Marseille
country: France
facility: Hopital Saint Joseph de Marseille
city: Marseille
country: France
facility: Hôpital Européen de Marseille
city: Montélimar
country: France
facility: Groupe Hospitalier des Portes de Provence
city: Paris
country: France
facility: Hôpital Saint-Louis - AP-HP
city: Plérin
country: France
facility: Hôpital Privé des Cotes d'Armor
city: Poitiers
country: France
facility: CHU de Poitiers
city: Quint-Fonsegrives
country: France
facility: Clinique La Croix du Sud
city: Reims
country: France
facility: CHU de Reims
city: Reims
country: France
facility: Institut Godinot
city: Saint-Étienne
country: France
facility: CHU de Saint-Etienne
city: Sarcelles
country: France
facility: Institut de Cancérologie Paris Nord
city: Strasbourg
country: France
facility: Groupe Hospitalier Saint Vincent - Clinique Saint Anne
city: Talence
country: France
facility: CHU de Bordeaux
city: Toulon
country: France
facility: Hôpital d'Instruction des Armées Sainte-Anne
city: Valence
country: France
facility: CH de Valence
Study officials:
affiliation: University Hospital, Clermont-Ferrand
name: Denis PEZET
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kerckhove N, Tougeron D, Lepage C, Pezet D, Le Malicot K, Pelkowski M, Pereira B, Balayssac D. Efficacy of donepezil for the treatment of oxaliplatin-induced peripheral neuropathy: DONEPEZOX, a protocol of a proof of concept, randomised, triple-blinded and multicentre trial. BMC Cancer. 2022 Jul 7;22(1):742. doi: 10.1186/s12885-022-09806-8.