Head and Neck Cancer
Conditions
Brief summary
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.
Interventions
DRUGPlacebo
DRUG2% Rebamipide liquid
DRUG4% Rebamipide liquid
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 77 days | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 77 | Day 1 was defined as the start of chemotherapy. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 2% Rebamipide Liquid 6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.) | 31 |
| 4% Rebamipide Liquid 6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.) | 32 |
| Placebo 6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.) | 31 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 1 |
| Overall Study | Physician Decision | 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 11 | 5 | 7 |
Baseline characteristics
| Characteristic | 2% Rebamipide Liquid | 4% Rebamipide Liquid | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 13 Participants | 12 Participants | 39 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 19 Participants | 19 Participants | 55 Participants |
| Race/Ethnicity, Customized Asian | 31 Participants | 32 Participants | 31 Participants | 94 Participants |
| Region of Enrollment Japan | 31 Participants | 32 Participants | 31 Participants | 94 Participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Male | 26 Participants | 26 Participants | 25 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 32 | 0 / 31 |
| other Total, other adverse events | 31 / 31 | 32 / 32 | 31 / 31 |
| serious Total, serious adverse events | 5 / 31 | 5 / 32 | 4 / 31 |
Outcome results
Primary
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
Time frame: 77 days
Population: Full analysis set comprised patients who received the study drug or placebo at least once and whose efficacy data were collected immediately after beginning the treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2% Rebamipide Liquid | 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. | 29.0 percentage of participants |
| 4% Rebamipide Liquid | 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. | 25.0 percentage of participants |
| Placebo | 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. | 38.7 percentage of participants |
Secondary
Number of Subjects Who Did Not Developed Grade ≥3 Mucositis
Day 1 was defined as the start of chemotherapy.
Time frame: Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 77
Population: Full analysis set comprised patients who received the study drug or placebo at least once and whose efficacy data were collected immediately after beginning the treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 1 | 31 participants |
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 8 | 29 participants |
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 15 | 27 participants |
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 22 | 25 participants |
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 29 | 23 participants |
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 36 | 20 participants |
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 43 | 18 participants |
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 50 | 17 participants |
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 57 | 12 participants |
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 64 | 11 participants |
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 71 | 8 participants |
| 2% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 77 | 6 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 77 | 11 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 1 | 31 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 43 | 18 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 57 | 16 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 8 | 31 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 36 | 20 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 71 | 13 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 15 | 30 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 50 | 18 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 29 | 25 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 22 | 29 participants |
| 4% Rebamipide Liquid | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 64 | 15 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 22 | 23 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 29 | 23 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 64 | 11 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 36 | 19 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 43 | 16 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 50 | 15 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 71 | 8 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 1 | 31 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 8 | 30 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 57 | 13 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 15 | 29 participants |
| Placebo | Number of Subjects Who Did Not Developed Grade ≥3 Mucositis | Day 77 | 8 participants |