RILUZOX-01: Effectiveness Assessment of Riluzole in the Prevention of Oxaliplatin-induced Peripheral Neuropathy.

Sponsor

UNICANCER (Other)

Overall Status

Recruiting

CT.gov ID

NCT03722680

Collaborator

(none)

210

Enrollment

Locations

Arms

Anticipated Duration (Months)

13.1

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Oxaliplatin-induced Peripheral Neuropathy	Drug: Riluzole Drug: Placebo Oral Tablet	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

210 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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).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 (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Placebo arm: The patient will be taken on tablet (placebo :50 mg, film-coated tablet) Posology, administration and duration of treatment will be equivalent to riluzole group.

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Oct 28, 2020

Anticipated Primary Completion Date :

Jan 1, 2023

Anticipated Study Completion Date :

Apr 28, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Riluzole 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 Riluzole during chemotherapy (oxaliplatin)
Placebo Comparator: Placebo Posology, administration and duration of treatment will be equivalent to riluzole group.	Drug: Placebo Oral Tablet placebo

Arm

Intervention/Treatment

Experimental: Riluzole

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

Riluzole during chemotherapy (oxaliplatin)

Placebo Comparator: Placebo

Posology, administration and duration of treatment will be equivalent to riluzole group.

Drug: Placebo Oral Tablet

placebo

Outcome Measures

Primary Outcome Measures

Quality of life questionnaire-chemotherapy-induced peripheral neuropathy (QLQ-CIPN20) [3 months afer initiation of oxaliplatin based chemotherapy (1 cycle = 14 days)]
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.

Secondary Outcome Measures

QLQ-CIPN20 [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.]
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.
National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 [throughout study completion, assessed up to 43 months]
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.
Brief Pain Inventory (BPI) questionnaire [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.]
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]).
Douleur Neuropathique 4 (DN4) questionnaire (interview portion) [This evaluation will be carried out only if the item 5 of BPI "general pain felt in the last 7 days" is ≥4/10.]
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.
Neuropathic Pain Symptom Inventory (NPSI) questionnaire [This evaluation will be carried out only if the item 5 of BPI "general pain felt in the last 7 days" is ≥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. Each of these items are quantified on a (0-10) numerical scale.
QLQ-C30 questionnaire (EORTC) [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.]
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.
Disease progression [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.]
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.
Time to HRQoL score deterioration [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.]
The interval between randomization and deterioration ≥5 points in the HRQoL score as compared to baseline score or death (all causes).
Quantification of chemotherapy dose reductions [3 months (V2) and up to 7 months (V3) after initiation of oxaliplatin based chemotherapy.]
The number of chemotherapy dose reduction caused by severe neuropathy and/or poor tolerance of treatment will be recorded.
Quantification of cumulative dose [3 months (V2) and up to 7 months (V3) after initiation of oxaliplatin based chemotherapy.]
The cumulative dose (mg/m²) of chemotherapy delivered to patients will be recorded.
Evaluation of study exit rates [3 months (V2) and up to 7 months (V3) after initiation of oxaliplatin based chemotherapy.]
The study exit rate caused by severe neuropathy and/or poor tolerance of treatment will be recorded.
Assessment of glutamate serum level [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.]
Correlation with colorectal cancer tumors/nodes/metastases (TNM) score (and eventually neuropathic symptoms), glutamate plasmatic

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 ...).

Contacts and Locations

Locations

	Site	City	Country
1	ICO - Site Paul Papin	Angers	France
2	CH Beauvais	Beauvais	France
3	Centre François Baclesse	Caen	France
4	Hia Percy	Clamart	France
5	CHU de Clermont -Ferrand	Clermont-Ferrand	France
6	Clinique St Côme	Compiègne	France
7	GHPSO	Creil	France
8	Centre Georges François Leclerc	Dijon	France
9	CHU de Dijon	Dijon	France
10	CH Annecy-Genevois	Pringy	France
11	CHU de Reims	Reims	France
12	Institut Jean Godinot	Reims	France
13	ICO - Site René Gauducheau	Saint-Herblain	France
14	Hia Begin	Saint-Mandé	France
15	CHU de Saint-Etienne	Saint-Priest	France
16	Hôpital Foch	Suresnes	France