Symptoms and General Pathology

All Conditions

Nervous System Diseases

Rare Diseases

Chronic Pain

Peripheral Nervous System Diseases

Pain

Neuromuscular Diseases

Chronic Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Nootropic Agents

Oxaliplatin

Donepezil

Cholinesterase Inhibitors

Enzyme Inhibitors

Cholinergic Agents

Neurotransmitter Agents

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

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

DONEPEZIL

PLACEBO

Denis PEZET

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.

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

Evaluation of the Efficacy of Donepezil in the Treatment of Oxaliplatin-induced Peripheral Neuropathy: Proof of Concept Study

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.

The NRS is an 11-point scale for patient self-reporting of pain. It is for adults and children 10 years old or older. The score of 0 = No pain and 10 = worst possible pain.

The interview portion of the DN4 questionnaire is a clinician-administered screening tool for neuropathic pain.

The questionnaire includes 7 items, grouped into two questions. Each item, is answered as either YES or NO.

A final cumulative patient's score is obtained by allocating 1 point for each YES and 0 point for each NO. If the patient's score ≥3/7, the test is positive.

This evaluation will be carried out only if the 11-point pain NRS ≥4/10.

This self-reported questionnaire assesses different neuropathic pain symptoms. The French NPSI includes 12 items that discriminates and quantifies five distinct dimensions of neuropathic pain.

This evaluation will be carried out only if the 11-point pain NRS ≥4/10.

This EORTC self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials. The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease.

This self-reported questionnaire permits to detect anxiety and depressive disorders. There are 14 items rated from 0 to 3. Seven questions relate to anxiety (total A) and 7 to the depressive dimension (total D), thus obtaining two scores (maximum score of each score = 21). To detect anxiety and depressive symptoms, the following interpretation is proposed for each of the scores (A and D):

* ≤7: absence of symptomatology
* 8 to 10: suspicious symptomatology
* ≥11: certain symptomatology

PGIC is aimed at assessing the general effectiveness of the treatment. This scale consists of 7 level descriptors answering the question "How are you?" distributed in three ways: (i) improved (very/medium/slightly), (ii) unchanged and (iii) aggravated (slight/medium/very).

Federation Francophone de Cancerologie Digestive

University Hospital, Clermont-Ferrand

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Olaparib

Anti-Bacterial Agents

Antibiotics, Antitubercular

Poly(ADP-ribose) Polymerase Inhibitors

AZD2281

liposomal doxorubicin

Jane Robertson, BSc, MBCHB, MD

The study will be an open label, multicenter, dose finding study. Depending on the tolerated dose up to 7 dose levels will be explored in this study, approximately 33 patients (21-54 depending on number of cohorts) may be enrolled into this study. Three patients will be initially dosed in each cohort. The primary objective of this study is to determine the recommended dose (RD) of twice daily oral doses of AZD2281 either as intermittent therapy for 7 days out of a 28-day schedule or given continuously, administered in combination with liposomal doxorubicin to patients with advanced solid tumors.

AZD2281 in Combination With Liposomal Doxorubicin in Advanced Solid Tumours

A Phase I, Open Label, Multicenter Study to Assess the Safety, Tolerability and Pharmacology of AZD2281 in Combination With Liposomal Doxorubicin (Caelyx®) in Patients With Advanced Solid Tumors

AstraZeneca

Neoplasms

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Micronutrients

Vitamins

Tocopherols

Vitamin E

Tocotrienols

alpha-Tocopherol

Tocovid

Antioxidants

Protective Agents

Trace Elements

Tocopherol

Tocotrienol

Pre-operative patients will be receiving TRF at different doses assigned to them in a cohort of 3 patients at each level.

TRF consists of alpha, gamma and delta tocotrienols in addition to small amount of alpha-tocopherol

Tocotrienol-rich Fraction (TRF)

Nur Aishah Taib, MBBS

Phase Ib: Maximum Tolerated Dose, Safety and Pharmacologic Study of TRF in Women with Breast Cancer is aimed to determine the highest, safest and tolerable dose of Tocotrienol-rich Fraction (maximal tolerated dose: MTD) that can be used in women with breast cancer.

3+3 step up design method will be used in this study.

Single arm intervention study 3+3 step up design

Maximum Tolerated Dose, Safety and Pharmacologic Study of TRF in Women With Breast Cancer

Malaysian Tocotrienol Rich Fraction: Immunomodulatory Effect in Women With Breast Cancer

Number of participants with treatment-related adverse events as assessed by CTCAE version 5.0

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Donepezil for Oxaliplatin-induced Neuropathy Peripheral Neuropathy: Proof of Concept Study	NCT05254639	Digestive Oncol... Supportive Care	DONEPEZIL PLACEBO	18 Years -	University Hospital, Clermont-Ferrand
Donepezil for Oxaliplatin-induced Neuropathy Peripheral Neuropathy: Proof of Concept Study	NCT05254639	Digestive Oncol... Supportive Care	DONEPEZIL PLACEBO	18 Years -	University Hospital, Clermont-Ferrand
AZD2281 in Combination With Liposomal Doxorubicin in Advanced Solid Tumours	NCT00819221	Solid Tumors	AZD2281 liposomal doxor...	18 Years - 130 Years	AstraZeneca
Maximum Tolerated Dose, Safety and Pharmacologic Study of TRF in Women With Breast Cancer	NCT03855423	Breast Cancer F...	Tocotrienol-ric...	18 Years -	University of Malaya

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