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

NCT ID: NCT05254639

Last Updated: 2024-04-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 77 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-02
• Study Completion Date: 2024-01-24

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.

Conditions

Digestive Oncology; Supportive Care

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Donepezil

5 mg/day for 4 weeks then 10 mg/day for 12 weeks

Group Type: EXPERIMENTAL

DONEPEZIL

Intervention Type: DRUG

5 mg daily for 4 weeks + 10 mg daily for 12 weeks according to tolerance or efficacy

Placebo

5 mg/day for 4 weeks then 10 mg/day for 12 weeks

Group Type: PLACEBO_COMPARATOR

PLACEBO

Intervention Type: DRUG

5 mg daily for 4 weeks + 10 mg daily for 12 weeks according to tolerance or efficacy

Interventions

DONEPEZIL

5 mg daily for 4 weeks + 10 mg daily for 12 weeks according to tolerance or efficacy

Intervention Type: DRUG

PLACEBO

5 mg daily for 4 weeks + 10 mg daily for 12 weeks according to tolerance or efficacy

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Federation Francophone de Cancerologie Digestive

OTHER

Sponsor Role: collaborator

University Hospital, Clermont-Ferrand

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Denis PEZET

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Clermont-Ferrand

Locations

Hôpital privé d'Antony

Antony, , France

CH d'Argenteuil

Argenteuil, , France

CHU de Besançon

Besançon, , France

Polyclinique Bordeaux Nord Aquitaine

Bordeaux, , France

Centre Hospitalier du Cotentin

Cherbourg, , France

Centre Hospitalier Public du Cotentin

Cherbourg, , France

CH de Cholet

Cholet, , France

CHU clermont-ferrand

Clermont-Ferrand, , France

Centre Hospitalier Compiègne-Noyon

Compiègne, , France

Clinique de Flandre

Coudekerque-Branche, , France

CHU de Dijon Bourgogne

Dijon, , France

Institut de Cancérologie de Bourgogne - GRReCC

Dijon, , France

CHD de Vendée

La Roche-sur-Yon, , France

CH Le puy

Le Puy-en-Velay, , France

Hôpital Franco-Britanique

Levallois-Perret, , France

chu de Limoges

Limoges, , France

CH Saint Joseph Saint Luc

Lyon, , France

Clinique de la sauvegarde

Lyon, , France

Hôpital privé Jean Mermoz

Lyon, , France

Hopital Saint Joseph de Marseille

Marseille, , France

Hôpital Européen de Marseille

Marseille, , France

Groupe Hospitalier des Portes de Provence

Montélimar, , France

Hôpital Saint-Louis - AP-HP

Paris, , France

Hôpital Privé des Cotes d'Armor

Plérin, , France

CHU de Poitiers

Poitiers, , France

Clinique La Croix du Sud

Quint-Fonsegrives, , France

CHU de Reims

Reims, , France

Institut Godinot

Reims, , France

CHU de Saint-Etienne

Saint-Etienne, , France

Institut de Cancérologie Paris Nord

Sarcelles, , France

Groupe Hospitalier Saint Vincent - Clinique Saint Anne

Strasbourg, , France

CHU de Bordeaux

Talence, , France

Hôpital d'Instruction des Armées Sainte-Anne

Toulon, , France

CH de Valence

Valence, , France

Countries

France

References

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.

Reference Type: DERIVED

PMID: 35799138 (View on PubMed)

Other Identifiers

2021-005326-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PHRC K 2020 PEZET

Identifier Type: -

Identifier Source: org_study_id