Effectiveness Assessment of Riluzole in the Prevention of Oxaliplatin-induced Peripheral Neuropathy.

Study Overview
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Brief Summary
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It is a phase II trial, randomized, parallel, double blind, multicenter, comparing riluzole versus placebo. The trial population is composed of patients ≥18 years old that have developed stage II/III colorectal cancer and are eligible for Simplified FOLFOX4 (6-12 cycles) adjuvant chemotherapy. The primary objective is to assess the preventive efficacy of riluzole on the severity of oxaliplatin-induced peripheral neuropathy during the Simplified FOLFOX4 adjuvant chemotherapy of stage II/III colorectal cancers.

Official Title
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Effectiveness Assessment of Riluzole in the Prevention of Oxaliplatin-induced Peripheral Neuropathy: A Phase II Randomized Study by UNICANCER With the Cooperation of AFSOS

Conditions
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Oxaliplatin-induced Peripheral Neuropathy

Intervention / Treatment
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* Drug: Riluzole
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged ≥ 18 years old, Eligible patient starting adjuvant oxaliplatin-based chemotherapy (6-12 cycles, Simplified FOLFOX4) for stage II/III colorectal cancer, Histological or cytological confirmation of colorectal cancer, Performance status (ECOG) ≤2, Normal hematological function (ANC ≥1.5 x 10⁹/L; platelets count ≥100 x 10⁹/L; hemoglobin ≥9.0 g/dL), Normal hepatic function: total bilirubin ≤1.5 x upper limit of normal (ULN) (unless documented Gilbert's syndrome); aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤3 x ULN, and gamma-glutamyltransferase (GGT) ≤3 x ULN, Normal renal function: serum creatinine ≤1.5 x ULN, Normal cardiac function: ECG, Patients affiliated to the French national health insurance, Patient must have signed a written informed consent form prior to any study specific procedures, French language comprehension, Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Exclusion Criteria: Metastatic cancer, Diagnosis of neuropathy, EORTC QLQ-CIPN20 sensory score >6, Previous neurotoxic chemotherapy treatment, Patients with chronic obstructive pulmonary disease, ALAT/ASAT elevated more than 3 times the normal value, Patients with known allergy or severe hypersensitivity to riluzole or any of the study drug excipients, Dependence on alcohol or drugs, Psychotic disorders, Women pregnant or breastfeeding, Patients undergoing a measure of legal protection (trusteeship, guardianship ...).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Riluzole arm: The patient will be taken one tablet (riluzole 50 mg, film-coated tablet) twice a day, in the morning and in the evening during the meal (12h interval). The medication is taken during the 14 days of each chemotherapy cycle, beginning 7 days before the start of chemotherapy and ending 2 weeks after the start of last cycle of chemotherapy (25 weeks). The treatment ends with the cessation of chemotherapy (visit V3 or anticipated stop).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Riluzole<br>The patient will be taken one tablet twice a day, in the morning and in the evening during the meal (12h interval). The medication is taken during the 14 days of each chemotherapy cycle, beginning 7 days before the start of chemotherapy and ending 2 weeks after the start of last cycle of chemotherapy (25 weeks). The treatment ends with the cessation of chemotherapy (visit V3 or anticipated stop). | Drug: Riluzole<br>* Riluzole during chemotherapy (oxaliplatin)<br>|
| Placebo Comparator: Placebo<br>Posology, administration and duration of treatment will be equivalent to riluzole group. | Drug: Placebo Oral Tablet<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life questionnaire-chemotherapy-induced peripheral neuropathy (QLQ-CIPN20) | QLQ-CIPN20 Questionnaire (EORTC): Self-reported questionnaire consisting of 20 questions that assess the symptoms and functional limitations of chemotherapy-induced peripheral neuropathy. The questionnaire is divided in 3 subscales: sensory, motor, and autonomic and gives a comprehensive picture of the nature, frequency, and severity of chemotherapy-induced peripheral neuropathy (CIPN). Using a 4-point Likert scale (1 = not at all, 2 = a little, 3 = quite a bit, and 4 = very much), patients indicate the degree to which they have experienced sensory, motor, and autonomic symptoms. | 3 months afer initiation of oxaliplatin based chemotherapy (1 cycle = 14 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QLQ-CIPN20 | Self-reported questionnaire consisting of 20 questions that assess the symptoms and functional limitations of chemotherapy-induced peripheral neuropathy. The questionnaire is divided in 3 subscales: sensory, motor, and autonomic and gives a comprehensive picture of the nature, frequency, and severity of CIPN. Using a 4-point Likert scale (1 = not at all, 2 = a little, 3 = quite a bit, and 4 = very much), patients indicate the degree to which they have experienced sensory, motor, and autonomic symptoms. | At inclusion (V0), 3 months (V2), up to 7 months (V3), up to 9 months (V4), up to 12 months (V5), up to 15 months (V6), and up to 18 months (V7) after initiation of oxaliplatin based chemotherapy. | 
| National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 | The NCI-CTCAE v5.0 is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale will assess the severity of sensory neuropathic disorders, this derivative into 5 grades determined by the investigator. | throughout study completion, assessed up to 43 months | 
| Brief Pain Inventory (BPI) questionnaire | This self-report questionnaire includes: A body schema The maximum pain, lowest pain, usual pain within the last 15 days (Numerical Numeric rating scales (NRS) 0 to 10 Description of current analgesic treatment, An assessment of relief by a percentage scale (0-100%), Assessment of the impact of pain on: mood, relationships with others, walking, sleep, work, happiness the joy - of living, recreation, activities in general (digital scales, rating from 0 [normal] to 10 [no activity]). | At inclusion (V0), 3 months (V2), up to 7 months (V3), up to 9 months (V4), up to 12 months (V5), up to 15 months (V6), and up to 18 months (V7) after initiation of oxaliplatin based chemotherapy. | 
| Douleur Neuropathique 4 (DN4) questionnaire (interview portion) | 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 is ≥3/7, the test is positive. | This evaluation will be carried out only if the item 5 of BPI general pain felt in the last 7 days is ≥4/10. | 
| Neuropathic Pain Symptom Inventory (NPSI) questionnaire | 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. Each of these items are quantified on a (0-10) numerical scale. | This evaluation will be carried out only if the item 5 of BPI general pain felt in the last 7 days is ≥4/10. | 
| QLQ-C30 questionnaire (EORTC) | This 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. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. | At inclusion (V0), 3 months (V2), up to 7 months (V3), up to 9 months (V4), up to 12 months (V5), up to 15 months (V6), and up to 18 months (V7) after initiation of oxaliplatin based chemotherapy. | 
| Disease progression | Disease Free Survival, defined as the interval between the date of randomization and the date of cancer relapse (local, regional, metastases, second cancer) or death from any cause, whichever occurs first. | From date of randomisation until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 43 months. | 
| Time to HRQoL score deterioration | The interval between randomization and deterioration ≥5 points in the HRQoL score as compared to baseline score or death (all causes). | At inclusion (V0), 3 months (V2), up to 7 months (V3), up to 9 months (V4), up to 12 months (V5), up to 15 months (V6), and up to 18 months (V7) after initiation of oxaliplatin based chemotherapy. | 
| Quantification of chemotherapy dose reductions | The number of chemotherapy dose reduction caused by severe neuropathy and/or poor tolerance of treatment will be recorded. | 3 months (V2) and up to 7 months (V3) after initiation of oxaliplatin based chemotherapy. | 
| Quantification of cumulative dose | The cumulative dose (mg/m²) of chemotherapy delivered to patients will be recorded. | 3 months (V2) and up to 7 months (V3) after initiation of oxaliplatin based chemotherapy. | 
| Evaluation of study exit rates | The study exit rate caused by severe neuropathy and/or poor tolerance of treatment will be recorded. | 3 months (V2) and up to 7 months (V3) after initiation of oxaliplatin based chemotherapy. | 
| Assessment of glutamate serum level | Correlation with colorectal cancer tumors/nodes/metastases (TNM) score (and eventually neuropathic symptoms), glutamate plasmatic | Glutamate serum level will be dose at inclusion (V0), 3 months (V2), up to 7 months (V3), and up to 18 months (V7) after initiation of oxaliplatin based chemotherapy. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Riluzole, oxaliplatin, colorectal cancer, neuropathy