Donepezil for Oxaliplatin-induced Neuropathy Peripheral Neuropathy: Proof of Concept Study
DONEPEZOX
Evaluation of the Efficacy of Donepezil in the Treatment of Oxaliplatin-induced Peripheral Neuropathy: Proof of Concept Study
2 other identifiers
interventional
77
1 country
34
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_2
Started Jun 2022
34 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
February 4, 2022
CompletedFirst Posted
Study publicly available on registry
February 24, 2022
CompletedStudy Start
First participant enrolled
June 2, 2022
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 24, 2024
CompletedStudy Completion
Last participant's last visit for all outcomes
January 24, 2024
CompletedApril 5, 2024
April 1, 2024
1.6 years
February 4, 2022
April 4, 2024
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Quality of Life Questionnaire-Chemotherapy Induced Peripheral Neuropathy 20 (QLQ-CIPN20)
A self-reported questionnaire, consisting of 20 questions which assess the symptoms and functional limitations of CIPN from the patients' perspective. The questionnaire is divided in 3 subscales: sensory, motor, and autonomic and gives a comprehensive picture of the nature, frequency, and severity of CIPN. For each subscale and for the entire questionnaire, a score from 0 to 100 is generated. The higher the score, the more severe the neuropathic symptoms.
through study completion, an average of 4 months.
Secondary Outcomes (6)
11-point pain Numeric Rating Scale (NRS)
through study completion, an average of 4 months
Douleur Neuropathique-4 (DN4) interview
At inclusion
Neuropathic Pain Symptoms Inventory (NPSI)
through study completion, an average of 4 months.
Quality of Life Questionnaire-Cancer 30 (QLQ-C30)
through study completion, an average of 4 months.
Hospital Anxiety and Depression scale (HADS)
through study completion, an average of 4 months.
- +1 more secondary outcomes
Study Arms (2)
Donepezil
EXPERIMENTAL5 mg/day for 4 weeks then 10 mg/day for 12 weeks
Placebo
PLACEBO COMPARATOR5 mg/day for 4 weeks then 10 mg/day for 12 weeks
Interventions
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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,
- +2 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (34)
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
Related Publications (1)
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.
PMID: 35799138DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Denis PEZET
University Hospital, Clermont-Ferrand
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
February 4, 2022
First Posted
February 24, 2022
Study Start
June 2, 2022
Primary Completion
January 24, 2024
Study Completion
January 24, 2024
Last Updated
April 5, 2024
Record last verified: 2024-04