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

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ClinicalTrials.gov Identifier: NCT02085460

Recruitment Status : Completed

First Posted : March 12, 2014

Results First Posted : April 6, 2021

Last Update Posted : October 18, 2021

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Sponsor:

Information provided by (Responsible Party):

Otsuka Pharmaceutical Co., Ltd.

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Head and Neck Cancer
Interventions	Drug: Placebo Drug: 2% Rebamipide liquid Drug: 4% Rebamipide liquid
Enrollment	94

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	2% Rebamipide Liquid	4% Rebamipide Liquid	Placebo
Arm/Group Description	6 times daily (The treatment starte...	6 times daily (The treatment starte...	6 times daily (The treatment starte...
Arm/Group Description	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)
Period Title: Overall Study
Started	31	32	31
Completed	17	24	21
Not Completed	14	8	10
Reason Not Completed
Adverse Event	2	2	1
Physician Decision	1	1	2
Withdrawal by Subject	11	5	7

Baseline Characteristics

Arm/Group Title		2% Rebamipide Liquid	4% Rebamipide Liquid	Placebo	Total
Arm/Group Description		6 times daily (The treatment starte...	6 times daily (The treatment starte...	6 times daily (The treatment starte...	Total of all reporting groups
Arm/Group Description		6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)	Total of all reporting groups
Overall Number of Baseline Participants		31	32	31	94
Baseline Analysis Population Description		...
Baseline Analysis Population Description		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.
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	31 participants	32 participants	31 participants	94 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	17 54.8%	19 59.4%	19 61.3%	55 58.5%
	>=65 years	14 45.2%	13 40.6%	12 38.7%	39 41.5%
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	31 participants	32 participants	31 participants	94 participants
	Female	5 16.1%	6 18.8%	6 19.4%	17 18.1%
	Male	26 83.9%	26 81.3%	25 80.6%	77 81.9%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants
Asian	Number Analyzed	31 participants	32 participants	31 participants	94 participants
Asian		31 100.0%	32 100.0%	31 100.0%	94 100.0%
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants
Japan	Number Analyzed	31 participants	32 participants	31 participants	94 participants
Japan		31 100.0%	32 100.0%	31 100.0%	94 100.0%

Outcome Measures

1.Primary Outcome


Title	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.
Description	Investigators who had undergone specific training assessed the severit...
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	2% Rebamipide Liquid	4% Rebamipide Liquid	Placebo
Arm/Group Description:	6 times daily (The treatment starte...	6 times daily (The treatment starte...	6 times daily (The treatment starte...
Arm/Group Description:	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)
Overall Number of Participants Analyzed	31	32	31
Measure Type: Number Unit of Measure: percentage of participants
	29.0	25.0	38.7

2.Secondary Outcome


Title	Number of Subjects Who Did Not Developed Grade ≥3 Mucositis
Description	Day 1 was defined as the start of chemotherapy.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	2% Rebamipide Liquid	4% Rebamipide Liquid	Placebo
Arm/Group Description:	6 times daily (The treatment starte...	6 times daily (The treatment starte...	6 times daily (The treatment starte...
Arm/Group Description:	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)
Overall Number of Participants Analyzed	31	32	31
Measure Type: Number Unit of Measure: participants
Day 1	31	31	31
Day 8	29	31	30
Day 15	27	30	29
Day 22	25	29	23
Day 29	23	25	23
Day 36	20	20	19
Day 43	18	18	16
Day 50	17	18	15
Day 57	12	16	13
Day 64	11	15	11
Day 71	8	13	8
Day 77	6	11	8

Adverse Events

Time Frame	Treatment-emergent adverse events were collected from start of the study drug administration up to Day 85
Adverse Event Reporting Description	Safety set comprised those who received the study drug or placebo at least once and whose safety data were collected at least once after beginning the treatment.

Arm/Group Title	2% Rebamipide Liquid	4% Rebamipide Liquid	Placebo
Arm/Group Description	6 times daily (The treatment starte...	6 times daily (The treatment starte...	6 times daily (The treatment starte...
Arm/Group Description	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)	6 times daily (The treatment started 3 days prior to the initiation of chemoradiotherapy and continued for another 77 days.)
All-Cause Mortality
	2% Rebamipide Liquid	4% Rebamipide Liquid	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/31 (0.00%)	0/32 (0.00%)	0/31 (0.00%)
Serious Adverse Events Serious Adverse Events
	2% Rebamipide Liquid	4% Rebamipide Liquid	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	5/31 (16.13%)	5/32 (15.63%)	4/31 (12.90%)
Cardiac disorders
Sinus node dysfunction ^* 1	1/31 (3.23%)	0/32 (0.00%)	0/31 (0.00%)
Gastrointestinal disorders
Dysphagia ^* 1	1/31 (3.23%)	0/32 (0.00%)	0/31 (0.00%)
Nausea ^* 1	0/31 (0.00%)	0/32 (0.00%)	1/31 (3.23%)
Hepatobiliary disorders
Hepatic function abnormal ^* 1	0/31 (0.00%)	0/32 (0.00%)	1/31 (3.23%)
Investigations
Alanine aminotransferase increased ^* 1	1/31 (3.23%)	0/32 (0.00%)	0/31 (0.00%)
Blood creatinine increased ^* 1	0/31 (0.00%)	1/32 (3.13%)	0/31 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pharyngeal cancer metastatic ^* 1	0/31 (0.00%)	1/32 (3.13%)	0/31 (0.00%)
Nervous system disorders
Subarachnoid haemorrhage ^* 1	0/31 (0.00%)	0/32 (0.00%)	1/31 (3.23%)
Renal and urinary disorders
Acute kidney injury ^* 1	0/31 (0.00%)	1/32 (3.13%)	1/31 (3.23%)
Renal impairment ^* 1	1/31 (3.23%)	0/32 (0.00%)	0/31 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration ^* 1	1/31 (3.23%)	3/32 (9.38%)	0/31 (0.00%)
1 Term from vocabulary, MedDRA Ver. 18.0 * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	2% Rebamipide Liquid	4% Rebamipide Liquid	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	31/31 (100.00%)	32/32 (100.00%)	31/31 (100.00%)
Blood and lymphatic system disorders
Anaemia ^* 1	7/31 (22.58%)	9/32 (28.13%)	10/31 (32.26%)
Leukopenia ^* 1	1/31 (3.23%)	2/32 (6.25%)	2/31 (6.45%)
Neutropenia ^* 1	1/31 (3.23%)	1/32 (3.13%)	3/31 (9.68%)
Febrile neutropenia ^* 1	0/31 (0.00%)	2/32 (6.25%)	1/31 (3.23%)
Ear and labyrinth disorders
Tinnitus ^* 1	3/31 (9.68%)	1/32 (3.13%)	1/31 (3.23%)
Hearing impaired ^* 1	2/31 (6.45%)	0/32 (0.00%)	1/31 (3.23%)
Gastrointestinal disorders
Stomatitis ^* 1	27/31 (87.10%)	30/32 (93.75%)	30/31 (96.77%)
Nausea ^* 1	25/31 (80.65%)	24/32 (75.00%)	25/31 (80.65%)
Constipation ^* 1	21/31 (67.74%)	25/32 (78.13%)	24/31 (77.42%)
Dry mouth ^* 1	20/31 (64.52%)	24/32 (75.00%)	19/31 (61.29%)
Vomiting ^* 1	9/31 (29.03%)	13/32 (40.63%)	12/31 (38.71%)
Diarrhoea ^* 1	8/31 (25.81%)	4/32 (12.50%)	10/31 (32.26%)
Dysphagia ^* 1	4/31 (12.90%)	5/32 (15.63%)	6/31 (19.35%)
Cheilitis ^* 1	3/31 (9.68%)	2/32 (6.25%)	2/31 (6.45%)
Dyspepsia ^* 1	3/31 (9.68%)	0/32 (0.00%)	1/31 (3.23%)
Oral pain ^* 1	1/31 (3.23%)	1/32 (3.13%)	2/31 (6.45%)
Abdominal discomfort ^* 1	2/31 (6.45%)	1/32 (3.13%)	0/31 (0.00%)
Toothache ^* 1	2/31 (6.45%)	0/32 (0.00%)	1/31 (3.23%)
Odynophagia ^* 1	2/31 (6.45%)	0/32 (0.00%)	0/31 (0.00%)
General disorders
Malaise ^* 1	14/31 (45.16%)	12/32 (37.50%)	14/31 (45.16%)
Fatigue ^* 1	0/31 (0.00%)	6/32 (18.75%)	4/31 (12.90%)
Oedema peripheral ^* 1	2/31 (6.45%)	5/32 (15.63%)	3/31 (9.68%)
Pyrexia ^* 1	1/31 (3.23%)	4/32 (12.50%)	2/31 (6.45%)
Face oedema ^* 1	2/31 (6.45%)	2/32 (6.25%)	0/31 (0.00%)
Infusion site extravasation ^* 1	0/31 (0.00%)	3/32 (9.38%)	1/31 (3.23%)
Thirst ^* 1	0/31 (0.00%)	0/32 (0.00%)	2/31 (6.45%)
Vessel puncture site inflammation ^* 1	2/31 (6.45%)	0/32 (0.00%)	0/31 (0.00%)
Hypersensitivity ^* 1	1/31 (3.23%)	2/32 (6.25%)	0/31 (0.00%)
Hepatobiliary disorders
Hepatic function abnormal ^* 1	2/31 (6.45%)	1/32 (3.13%)	1/31 (3.23%)
Infections and infestations
Oral candidiasis ^* 1	6/31 (19.35%)	12/32 (37.50%)	7/31 (22.58%)
Pharyngitis ^* 1	4/31 (12.90%)	3/32 (9.38%)	4/31 (12.90%)
Device related infection ^* 1	0/31 (0.00%)	1/32 (3.13%)	2/31 (6.45%)
Influenza ^* 1	1/31 (3.23%)	0/32 (0.00%)	2/31 (6.45%)
Rhinitis ^* 1	2/31 (6.45%)	0/32 (0.00%)	1/31 (3.23%)
Lung infection ^* 1	2/31 (6.45%)	0/32 (0.00%)	0/31 (0.00%)
Otitis externa ^* 1	0/31 (0.00%)	2/32 (6.25%)	0/31 (0.00%)
Staphylococcal infection ^* 1	0/31 (0.00%)	2/32 (6.25%)	0/31 (0.00%)
Injury, poisoning and procedural complications
Radiation skin injury ^* 1	22/31 (70.97%)	26/32 (81.25%)	20/31 (64.52%)
Wound complication ^* 1	1/31 (3.23%)	2/32 (6.25%)	1/31 (3.23%)
Investigations
Weight decreased ^* 1	15/31 (48.39%)	12/32 (37.50%)	18/31 (58.06%)
White blood cell count decreased ^* 1	12/31 (38.71%)	12/32 (37.50%)	12/31 (38.71%)
Neutrophil count decreased ^* 1	9/31 (29.03%)	8/32 (25.00%)	9/31 (29.03%)
Lymphocyte count decreased ^* 1	9/31 (29.03%)	9/32 (28.13%)	6/31 (19.35%)
Blood creatinine increased ^* 1	5/31 (16.13%)	4/32 (12.50%)	3/31 (9.68%)
Platelet count decreased ^* 1	3/31 (9.68%)	4/32 (12.50%)	1/31 (3.23%)
Alanine aminotransferase increased ^* 1	2/31 (6.45%)	2/32 (6.25%)	0/31 (0.00%)
Weight increased ^* 1	2/31 (6.45%)	1/32 (3.13%)	2/31 (6.45%)
Aspartate aminotransferase increased ^* 1	2/31 (6.45%)	2/32 (6.25%)	0/31 (0.00%)
C-reactive protein increased ^* 1	1/31 (3.23%)	2/32 (6.25%)	1/31 (3.23%)
Gamma-glutamyltransferase increased ^* 1	2/31 (6.45%)	1/32 (3.13%)	0/31 (0.00%)
Metabolism and nutrition disorders
Decreased appetite ^* 1	21/31 (67.74%)	22/32 (68.75%)	23/31 (74.19%)
Hyponatraemia ^* 1	4/31 (12.90%)	4/32 (12.50%)	7/31 (22.58%)
Hyperkalaemia ^* 1	4/31 (12.90%)	5/32 (15.63%)	5/31 (16.13%)
Hypokalaemia ^* 1	4/31 (12.90%)	2/32 (6.25%)	5/31 (16.13%)
Dehydration ^* 1	4/31 (12.90%)	3/32 (9.38%)	3/31 (9.68%)
Hypoalbuminaemia ^* 1	4/31 (12.90%)	4/32 (12.50%)	2/31 (6.45%)
Hypomagnesaemia ^* 1	2/31 (6.45%)	4/32 (12.50%)	2/31 (6.45%)
Hyperglycaemia ^* 1	1/31 (3.23%)	2/32 (6.25%)	1/31 (3.23%)
Hypertriglyceridaemia ^* 1	1/31 (3.23%)	3/32 (9.38%)	0/31 (0.00%)
Hyperuricaemia ^* 1	1/31 (3.23%)	0/32 (0.00%)	2/31 (6.45%)
Diabetes mellitus ^* 1	2/31 (6.45%)	0/32 (0.00%)	0/31 (0.00%)
Nervous system disorders
Dysgeusia ^* 1	22/31 (70.97%)	26/32 (81.25%)	25/31 (80.65%)
Headache ^* 1	1/31 (3.23%)	1/32 (3.13%)	4/31 (12.90%)
Somnolence ^* 1	1/31 (3.23%)	2/32 (6.25%)	0/31 (0.00%)
Psychiatric disorders
Insomnia ^* 1	6/31 (19.35%)	6/32 (18.75%)	4/31 (12.90%)
Renal and urinary disorders
Renal impairment ^* 1	5/31 (16.13%)	5/32 (15.63%)	3/31 (9.68%)
Acute kidney injury ^* 1	0/31 (0.00%)	2/32 (6.25%)	1/31 (3.23%)
Respiratory, thoracic and mediastinal disorders
Hiccups ^* 1	11/31 (35.48%)	15/32 (46.88%)	10/31 (32.26%)
Pharyngeal inflammation ^* 1	8/31 (25.81%)	9/32 (28.13%)	10/31 (32.26%)
Oropharyngeal pain ^* 1	3/31 (9.68%)	9/32 (28.13%)	9/31 (29.03%)
Dysphonia ^* 1	2/31 (6.45%)	5/32 (15.63%)	2/31 (6.45%)
Laryngeal pain ^* 1	3/31 (9.68%)	2/32 (6.25%)	3/31 (9.68%)
Epistaxis ^* 1	1/31 (3.23%)	2/32 (6.25%)	1/31 (3.23%)
Cough ^* 1	1/31 (3.23%)	2/32 (6.25%)	0/31 (0.00%)
Nasal congestion ^* 1	0/31 (0.00%)	0/32 (0.00%)	2/31 (6.45%)
Skin and subcutaneous tissue disorders
Alopecia ^* 1	4/31 (12.90%)	7/32 (21.88%)	7/31 (22.58%)
Dermatitis ^* 1	1/31 (3.23%)	2/32 (6.25%)	2/31 (6.45%)
Rash ^* 1	4/31 (12.90%)	0/32 (0.00%)	1/31 (3.23%)
Vascular disorders
Hypertension ^* 1	2/31 (6.45%)	0/32 (0.00%)	2/31 (6.45%)
1 Term from vocabulary, MedDRA Ver. 18.0 * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Director of Clinical Trials
Organization:	Otsuka Pharmaceutical Co., LTD.
Phone:	+81-3-6361-7366
EMail:	CL_OPCJ_RDA_Team@otsuka.jp

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Layout table for additonal information

Responsible Party:	Otsuka Pharmaceutical Co., Ltd.
ClinicalTrials.gov Identifier:	NCT02085460
Other Study ID Numbers:	037-12-001 JapicCTI-142467 ( Other Identifier: Japic )
First Submitted:	March 11, 2014
First Posted:	March 12, 2014
Results First Submitted:	March 11, 2021
Results First Posted:	April 6, 2021
Last Update Posted:	October 18, 2021

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