A Phase 2 Trial of Rebamipide Liquid to Determine the Effective Dose for Prevention of Chemoradiotherapy-induced Oral Mucositis in Patients With Head and Neck Cancer

A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Phase 2 Trial of Rebamipide Liquid to Determine the Effective Dose for Prevention of Chemoradiotherapy-induced Oral Mucositis in Patients With Head and Neck Cancer

To investigate the efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer following administration of rebamipide and to determine the optimal dose of rebamipide.

Study Overview

• Status: Completed
• Conditions: Head and Neck Cancer
• Intervention / Treatment: Drug: Placebo; Drug: 2% Rebamipide liquid; Drug: 4% Rebamipide liquid

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Chubu Region, Japan
  • Chugoku Region, Japan
  • Kanto Region, Japan
  • Kinki Region, Japan
  • Tohoku Region, Japan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Head and neck cancer patients scheduled for definitive or postoperative chemoradiotherapy.

• Patients with a histopathological diagnosis of head and neck cancer and primary tumor in one of the following regions.

  1. Definitive therapy: nasopharynx, oropharynx, hypopharynx, or larynx
  2. Postoperative therapy: oral cavity, oropharynx, hypopharynx, or larynx
• Patients with no history of chemotherapy, radiotherapy, or chemoradiotherapy for head and neck cancer
• Patients with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
• Patients who are able to hold fluid in the mouth
• Patients who are able to swallow the investigational medicinal product (IMP)
• Patients expected to survive for at least 3 months
• Patients who have given written informed consent in person
• Patients who can stay at or visit the hospital for scheduled examinations and observations
• Patients who are able to take contraceptive measures to avoid pregnancy of the patient or their partner from the time of informed consent until 4 weeks after completion of IMP administration

Exclusion Criteria:

• Patients with primary malignant tumors other than head and neck cancer.
• Patients with symptomatic viral, bacterial, or fungal infection
• Patients with serious renal impairment
• Patients with distant metastasis
• Patients with severe complications (uncontrolled cardiac disease, diabetes, hypertension, etc)

• Patients with any of the following laboratory test results:

  1. Neutrophil count: <1500 L
  2. Platelet count: <75000 L
  3. Hemoglobin: <10.0 g/L
  4. Aspartate aminotransferase (AST): >3 times the upper limit of the reference value at the trial site
  5. Alanine aminotransferase (ALT): >3 times the upper limit of the reference value at the trial site
  6. Serum bilirubin: >1.5 times the upper limit of the reference value at the trial site
  7. Serum albumin: <3.0 g/dL
  8. Serum creatinine: >1.5 the upper limit of the reference value at the trial site
  9. Creatinine clearance : <30 mL/min
• Patients complicated with autoimmune disease
• Patients requiring continuous systemic administration of glucocorticoid
• Female patients who are pregnant or lactating, who may possibly be pregnant, or who wish to become pregnant
• Patients who have participated in any other clinical trial within 4 weeks prior to initiation of chemoradiotherapy
• Patients who have a history of drug allergy to rebamipide, cisplatin, or other platinum compounds
• Patients who are otherwise judged by the investigator or sub-investigator to be inappropriate for inclusion in the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 6 times daily	Drug: Placebo
Experimental: 2% Rebamipide liquid; 6 times daily	Drug: 2% Rebamipide liquid
Experimental: 4% Rebamipide liquid; 6 times daily	Drug: 4% Rebamipide liquid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Grade ≥3 Oral Mucositis Determined by Clinical Examination and Assessed by Central Review According to the Common Terminology Criteria of Adverse Events (CTCAE) Version 3.0.	Investigators who had undergone specific training assessed the severity of oral mucositis twice every week. To evaluate the severity of oral mucositis objectively, the clinical findings of the oral mucosa as well as functional disorders and symptomatic aspects were recorded in the Oral Mucositis Assessment Sheet by each investigator. Photographic documentation of the oral mucosa was also submitted by each investigator, 3 days before or 57 days after initiation of chemoradiotherapy, or at the time of withdrawal. The Oral Mucositis Assessment Sheets and photographic documentation were then reviewed by the Oral Mucositis Evaluation Committee to grade the severity of oral mucositis according to the CTCAE 3.0.z	77 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Who Did Not Developed Grade ≥3 Mucositis	Day 1 was defined as the start of chemotherapy.	Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 77

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Co., Ltd.

Publications and helpful links

General Publications

• Ueno T, Zenda S, Konishi T, Yurikusa T, Shibasaki Y, Nagamoto H, Fujii M. The post hoc analysis comparing the severity grades of chemoradiotherapy-induced oral mucositis scored between the central and local assessors in a multicenter, randomized controlled trial of rebamipide for head and neck cancer. Int J Clin Oncol. 2019 Mar;24(3):241-247. doi: 10.1007/s10147-018-1355-7. Epub 2018 Nov 13.
• Yokota T, Ogawa T, Takahashi S, Okami K, Fujii T, Tanaka K, Iwae S, Ota I, Ueda T, Monden N, Matsuura K, Kojima H, Ueda S, Sasaki K, Fujimoto Y, Hasegawa Y, Beppu T, Nishimori H, Hirano S, Naka Y, Matsushima Y, Fujii M, Tahara M. Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study. BMC Cancer. 2017 May 5;17(1):314. doi: 10.1186/s12885-017-3295-4.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: March 11, 2014
• First Submitted That Met QC Criteria: March 11, 2014
• First Posted (Estimate): March 12, 2014

Study Record Updates

• Last Update Posted (Actual): October 18, 2021
• Last Update Submitted That Met QC Criteria: September 22, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Diseases; Gastroenteritis; Stomatognathic Diseases; Mouth Diseases; Head and Neck Neoplasms; Mucositis; Stomatitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Protective Agents; Anti-Ulcer Agents; Antioxidants; Rebamipide
• Other Study ID Numbers: 037-12-001; JapicCTI-142467 (Other Identifier: Japic)