Dexamethasone to Prevent Oral Chronic Graft-versus-Host Disease

Study Overview
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Brief Summary
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This study will determine if a dexamethasone mouth rinse can reduce the risk of developing oral chronic graft-versus-host disease (cGVHD) in patients who have undergone a bone marrow (stem cell) transplant procedure. cGVHD is a common complication of stem cell transplantation, resulting from the donor cells attacking the transplant recipient's tissues. In oral cGVHD, the tissues in the mouth are damaged, causing painful mouth sores. Dexamethasone is a corticosteroid that is commonly used to treat inflammation. It is the only corticosteroid available that can be used as a mouth rinse. Patients 12 years of age or older who have received a stem cell transplant may be eligible to participate if they are enrolled within 70 to 90 days of their transplant. Candidates are screened with a medical history and oral exam. Participants are randomly assigned to receive either the dexamethasone rinse or a placebo (a solution that looks and tastes like the dexamethasone rinse but has no active medication). They undergo the following procedures: Treatment with the study solution. Patients rinse their mouth with the dexamethasone solution or placebo three times a day for 3 months. Clinic visits before starting treatment and at 1, 2 and 3 months after starting the study drug for the following procedures: Oral exam (before starting treatment and at each visit). Photographs of the mouth (before starting treatment and at 3 months). Biopsy from inside the cheek (before starting treatment). The inside of the cheek is numbed and a small piece of tissue is removed for examination by a pathologist. Saliva sample collection (before starting treatment). Blood draw (before starting treatment and at each visit). Quality-of-life questionnaires (before starting treatment and at 3 months). Questionnaire to assess level of dry mouth and mouth pain (before starting treatment and at each visit). Review of medications (at each visit). ACTH stimulation test to evaluate adrenal gland function (at 3 months). Patients are given an injection of a drug called ACTH or cosyntropin which is a version of a hormone normally produced by the pituitary gland. Blood samples are drawn before the injection and at 30 and 60 minutes after the injection to measure levels of the hormone cortisol. After treatment ends, participants are contacted by telephone every month for 6 months to report any symptoms of cGVHD, and they return to the clinic at 6 months for a final evaluation.

Detailed Description
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Prevention of oral chronic graft versus host disease (GVHD) by topical agents is an attractive strategy because it would potentially avoid the adverse effects associated with systemic immunosuppression. Topically administered dexamethasone solution is a commonly used agent for the prophylaxis of oral inflammatory conditions including GVHD. However, the efficacy and systemic effects of topically administered dexamethasone solution are unknown. We therefore propose this trial designed to evaluate the efficacy and safety of topical dexamethasone solution for prevention of oral chronic GVHD in stem cell transplant recipients. This pilot phase II study will follow a randomized, double-blind, placebo controlled, parallel group design. Consenting subjects who have undergone hematopoietic stem cell transplantation at the NIH Clinical Center and the surrounding transplant clinics will be randomized 50/50 to receive dexamethasone 0.01% solution or placebo as an oral rinse for 3 months starting 90-100 days post-transplant. Subjects will be evaluated monthly after the start of intervention. Diagnostic and research evaluations will include a complete oral examination, oral mucosal biopsy prior to the beginning of the intervention (day -7) and at the time of development of oral chronic GVHD or at the completion of intervention in the absence of clinical GVHD. We will measure serum dexamethasone levels and perform short cosyntropin (ACTH stimulation) test at the end of the 3 months of intervention or onset of clinically significant GVHD. The primary objective of the study is to evaluate the safety and efficacy of topical dexamethasone 0.01% solution used as an oral rinse for prevention of oral chronic GVHD. Our primary endpoint will be the proportion of subjects that develop clinically significant (severity score 3 or higher) oral chronic GVHD after three months. Secondary objectives will include the impact of oral chronic GVHD on the quality of life, characterization of the changes in tissue and salivary biomarkers associated with development of oral graft versus host disease, and measures of the effects of topical dexamethasone on hypothalamo-pituitary-adrenal axis. Secondary outcomes will include oral cavity specific quality of life as measured by Oral Health Impact Profile (OHIP)-14 questionnaire, oral discomfort levels, improvement in general quality of life scores, and severity of oral chronic GVHD as measured by the site-specific GVHD scoring system.

Official Title
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Pilot Study of Topical Dexamethasone 0.01% Solution for Prevention of Oral Chronic Graft Versus Host Disease

Conditions
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Graft vs Host Disease

Intervention / Treatment
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* Drug: Topical Dexamethasone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: History of allogeneic hematopoietic stem cell transplantation within 60-90 days of enrollment. Age 12 or older. Ability to rinse and expectorate study medication rather than swallow it. Ability and willingness to come to Clinical Center for follow-up appointments and at the time of development of symptoms/signs suggestive of oral GVHD. EXCLUSION CRITERIA: Clinically significant oral chronic GVHD at the time of the screening. Active viral or fungal infection involving oral cavity not resolving by day 90. Platelet count less than 20,000/ml at the time of the screening appointment. Life expectancy less than 4 months at the time of enrollment. Documented hypersensitivity to dexamethasone. Pregnancy or lactation. Inability to understand the investigational nature of the study. Inability to provide informed consent.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 110 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexamethasone oral rinse in stem cell transplant participants<br>Dexamethasone 0.01% (0.5mg/5 mL) oral rinse solution in post allogeneic hematopoietic stem cell transplant participants. Rinse oral cavity three times daily for two minutes with ten milliliters then expectorate. Complete for three months duration. | Drug: Topical Dexamethasone<br>* dexamethasone 0.01%<br>|
| Placebo Comparator: Placebo oral rinse in stem cell transplant participants<br>Placebo oral rinse in post allogeneic hematopoietic stem cell transplant participants. Rinse oral cavity three times daily for two minutes with ten milliliters then expectorate. Complete for three months duration. | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants That Developed Severity Score 3 or Higher Oral Chronic Graft Versus Host Disease (GVHD). | Participants that developed clinically significant (severity score 3 or higher) oral chronic graft versus host disease (GVHD) within 90 days of initiating treatment. Oral chronic GVHD is defined by Lichen Planus (Oral GVHD) Severity Scale (Thongprasom et al., 2003). Score 5: White striae with erosive area > 1 cm^2 Score 4: White striae with erosive area < 1 cm^2 Score 3: White striae with erythematous area > 1 cm^2 Score 2: White striae with erythematous area < 1 cm^2 Score 1: Mild white striae only Score 0: No lesions, normal mucosa | Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Chronic Oral Graft Versus Host Disease (GVHD) Based on Severity Scores | Participants that developed oral chronic graft versus host disease (GVHD) within 90 days of initiating treatment. Oral chronic GVHD is defined by Lichen Planus (Oral GVHD) Severity Scale (Thongprasom et al., 2003). Score 5: White striae with erosive area > 1 cm^2 Score 4: White striae with erosive area < 1 cm^2 Score 3: White striae with erythematous area > 1 cm^2 Score 2: White striae with erythematous area < 1 cm^2 Score 1: Mild white striae only Score 0: No lesions, normal mucosa | Day 90 | 
| Participants With Systemic Absorption of Topical Dexamethasone | Participants with systemic absorption of topical dexamethasone based on plasma dexamethasone level < 30 ng/dL. | 3 months | 
| Participants With Suppressed Adrenal Cortical Function Due to Topical Dexamethasone | Number of participants who are not on systemic steroids with suppressed adrenal cortical function after completing study intervention phase (3 month) based on serum morning cortisol levels. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oral Chronic GVHD, Topical Dexamethasone, Tissue Markers, Salivary Proteomics, Quality of Life, Oral Chronic Graft Versus Host Disease, Oral Pain, Mouth Pain