Clobetasol for Oral Graft-Versus-Host Disease

Study Overview
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Brief Summary
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Background: - Oral graft-versus-host disease (GVHD) is a possible complication of bone marrow transplants. It is the result of the donor cells trying to attack the recipients body. Symptoms include dry mouth, sensitivity and pain when tasting certain spices and flavors, and painful swallowing. Steroids are a possible effective treatment for GHVD, but they can cause side effects when given as pills or injections. Steroids given in a cream or rinse form, applied directly to the site of the symptoms, can have fewer side effects. However, their effectiveness as a rinse has not been tested in the mouth. Researchers want to see if a steroid called clobetasol can be used as a mouth rinse to treat oral GHVD. Objectives: - To see if a clobetasol rinse is a safe and effective treatment for oral graft-versus-host disease. Eligibility: - Individuals at least 12 years of age who have oral GHVD and are not allergic to clobetasol. Design: Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. They will also have an oral exam, a mouth tissue biopsy, and other tests before starting the study drug. Participants will be separated into two groups. One group will receive clobetasol; the other will have a placebo liquid. Participants will rinse their mouths with the study liquid three times a day after meals for 2 weeks. After 2 weeks, participants will have another study visit with blood tests and other exams. After the study visit, all participants will start to use the clobetasol rinse. Those who originally had clobetasol will use the rinse for another 2 weeks. Those who originally had a placebo will use the rinse for 4 weeks. Participants will have a follow-up exam after the end of treatment....

Detailed Description
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BACKGROUND: Chronic Graft versus Host Disease (cGVHD) is a major late complication of allogeneic hematopoietic stem cell transplantation. The oral cavity is the second most commonly affected area in cGVHD and is a major cause of morbidity. Clobetasol is a high-potency topical corticosteroid widely used for a variety of inflammatory disorders of the skin and oral mucosa. Treatment of oral cGVHD by topical agents is an attractive strategy to potentially avoid adverse effects associated with systemic immunosuppression. OBJECTIVES: - To investigate efficacy of topical clobetasol 0.05% oral rinse for oral chronic graft versus-host disease (cGVHD) ELIGIBILITY: - Patients age 12-99 years with clinically significant oral cGVHD. DESIGN: This is a randomized, double blind, placebo-controlled, pilot study of clobetasol 0.05% topical oral rinse with an open label extension period. Patients will rinse oral cavity with 10cc of clobetasol 0.05% or placebo oral rinse for 2 minutes 3 times a day. Treatment duration will be for 2 weeks in the randomized phase and 2-4 weeks in the open label phase. Up to 40 patients will be enrolled on this pilot trial until 34 evaluable patients are assessed.

Official Title
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A Randomized Double-Blind Pilot Study of Topical Clobetasol 0.05% Oral Rinse for Oral Chronic Graft-Versus-Host-Disease

Conditions
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Oral Chronic Graft vs Host Disease

Intervention / Treatment
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* Drug: Clobetasol Oral Rinse
* Drug: Placebo oral rinse


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Age: 12 years 99 years. Diagnosis: clinically significant oral chronic graft versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplant (HSCT) with severity score of at least 2 on erythema subset and/or at least 1 on ulceration subset and a composite score greater than or equal to 20 of the Oral Mucositis Rating Scale (OMRS) scale confirmed by the principal investigator (PI), clinical study chair (CSC), or lead associate investigator (LAI). Hematologic Function: Patients must have a platelet count greater than or equal to 20,000/microL at the time of the initial evaluation. Informed Consent: All patients or their legal representative (for patients <18 years old) must sign an institutional review board (IRB) approved informed consent document (cGVHD natural history protocol 04-C-0281 or any National Cancer Institute (NCI) protocol allowing for screening procedures) prior to performing studies to determine patient eligibility. After confirmation of patient eligibility all patients or their legal representative must sign the protocol specific informed consent. For pediatric patients age appropriate assent will be obtained in accordance with National Institutes of Health (NIH) guidelines. Patients must be able to rinse and expectorate study medication rather than swallow it. Female patients must be willing to practice birth control (including abstinence) during and for two months after treatment, if of childbearing potential. Patients must have the ability and willingness to come to Clinical Center for bi-weekly follow-up appointments. No change in systemic immunosuppressive therapy (type or intensity level) within 2 weeks prior to enrollment. A 7-day washout period is required if patients are currently using another oral topical treatment for mouth lesions. Patients currently using clobetasol oral topical treatment are not eligible for this study. EXCLUSION CRITERIA: Documented hypersensitivity to clobetasol. Use of clobetasol ointment intra-orally at any time during the last 6-month period. Pregnant or breast-feeding females due to possible toxicity to the fetus or infant. Inability to understand the investigational nature of the study to provide informed consent. Patients who, for medical or other reasons, are unable to comply with the study procedures.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 99 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clobetasol<br>Patients will rinse oral cavity with 10cc of clobetasol 0.05% for 2 minutes 3 times a day. | Drug: Clobetasol Oral Rinse<br>* Cycle= up to 4 weeks Patients will rinse oral cavity with 10cc of clobetasol 0.05% oral rinse for 2 minutes 3 times a day.<br>|
| Placebo Comparator: Placebo<br>Patients will rinse oral cavity with 10cc of placebo oral rinse for 2 minutes 3 times a day. | Drug: Placebo oral rinse<br>* Patients will rinse oral cavity with 10cc of placebo oral rinse for 2 minutes 3 times a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Response as Assessed by the 273-point Oral Mucositis Rating Scale (OMRS) Who Received Topical Clobetasol 0.05% Oral Rinse for Oral Chronic Graft-versus-host-disease (cGVHD) During a Four-week Treatment Period | Mucosal changes were assessed by the Oral Mucositis Rating Scale. The primary endpoint was evaluated using the OMRS. Oral tissue changes are rated on a scale of 0-3 compared with normal oral tissue (0-normal/no change, 1-mild change, 2-moderate change, and 3-severe change). Total score is the sum of all OMRS items with a possible range of 0. Total score is the sum of all OMRS items with a possible range of 0-273. Lower score=more normal oral mucosa. There is no standard definition of response in this field. Definitions we used in this pilot study to grade the response to study intervention are: Progress of 25% of initial score (rounded to the closest number) on the OMRS scale. Completion (PD) is defined as an increase of 25% of initial score (rounded to the closest number). Partial Response (PR) is defined as a decrease Response (CR) is defined as a PR plus a score of 0 on the erythema and ulceration components. Stable Disease (SD) does not meet criteria for progression or response. | At 4 weeks on active treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Participants' Raw Score of Oral cGVHD Related Pain on a 0-10 Rating Scale | Oral cavity pain was assessed by an oral cavity specific quality of life questionnaire. Pain was rated based on a 0-10 rating scale on which subjects selected a single integer. 0 = no pain and 10 = worst pain. A negative value indicates an increase in oral pain. A positive value indicates an improvement in patient-perceived oral pain. | Baseline to Day 14 and baseline to Day 28 | 
| Percent Change in Participants' Raw Score of Oral cGVHD Related Sensitivity on a 0-10 Rating Scale | Oral cavity sensitivity was assessed by an oral cavity specific quality of life questionnaire. Sensitivity was rated based on a 0-10 rating scale on which subjects selected a single integer. 0 = no sensitivity and 10 = worst sensitivity. A negative value indicates an increase in oral sensitivity. A positive value indicates an improvement in patient-perceived oral sensitivity. | Baseline and 4 weeks on active treatment | 
| Percent Change in Participants' Raw Score of Oral cGVHD Related Dryness on a 0-10 Rating Scale | Oral cavity dryness was assessed by an oral cavity specific quality of life questionnaire. Dryness was rated based on a 0-10 rating scale on which subjects selected a single integer. 0 = no dryness and 10 = worst dryness. A negative value indicates an increase in patient-perceived oral dryness. A positive value indicates an improvement in patient-perceived oral dryness. | Baseline and 4 weeks on active treatment | 
| Maximum Plasma Concentration (Cmax) of Clobetasol During Pharmacokinetic Testing | Steady-state pharmacokinetics of systemic clobetasol were assessed following a single 2 min oral rinse of 0.05% clobetasol on day 14 (1 patient collected on day 12). A noncompartmental pharmacokinetic assessment was performed using WinNonlin v5 (Pharsight Corp, Mountain View, CA) from three sampling times (pre-rinse, 15-45 min post-rinse, and 90-120 min post-rinse). Plasma concentrations of clobetasol were measured using a newly designed and validated LC-MS/MS assay, with a lower limit of quantification of 0.05 ng/mL. The maximum plasma concentrations (CMAX) were recorded as observed values and the area under the plasma-concentration time curve using all three sampling time points (AUCALL) was calculated using the Linear Trapezoidal rule. | pre-rinse, 15-45 min post-rinse, and 90-120 min post-rinse | 
| Plasma Concentrations of Clobetasol Mouth Rinse in cGVHD Patients at Baseline (Day 0) and Day 28 | Peripheral blood was drawn at baseline and day 28 of clobetasol rinse use, and clobetasol levels were measured in the blood sample. Plasma concentrations of clobetasol were measured using a validated LC-MS/MS assay with a lower limit of quantification of 0.05 ng/mL. Any values below detectable limit or with no peak were adjusted to 0. | Baseline Day 0 and Day 28 | 
| Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately 62 months and 12 days. | 
| Time to Maximum Plasma Concentration (Cmax) of Clobetasol | Steady-state pharmacokinetics of systemic clobetasol were assessed following a single 2 min oral rinse of 0.05% clobetasol on day 14 (1 patient collected on day 12). A noncompartmental pharmacokinetic assessment was performed using WinNonlin v5 (Pharsight Corp, Mountain View, CA) from three sampling times (pre-rinse, 15-45 min post-rinse, and 90-120 min post-rinse). Plasma concentrations of clobetasol were measured using a newly designed and validated LC-MS/MS assay, with a lower limit of quantification of 0.05 ng/mL. The maximum plasma concentrations (CMAX) were recorded as observed values and the area under the plasma-concentration time curve using all three sampling time points (AUCALL) was calculated using the Linear Trapezoidal rule. | pre-rinse, 15-45 min post-rinse, and 90-120 min post-rinse | 
| Area Under the Plasma Concentration vs Time Curve for All Time Points | Steady-state pharmacokinetics of systemic clobetasol were assessed following a single 2 min oral rinse of 0.05% clobetasol on day 14 (1 patient collected on day 12). A noncompartmental pharmacokinetic assessment was performed using WinNonlin v5 (Pharsight Corp, Mountain View, CA) from three sampling times (pre-rinse, 15-45 min post-rinse, and 90-120 min post-rinse). Plasma concentrations of clobetasol were measured using a newly designed and validated LC-MS/MS assay, with a lower limit of quantification of 0.05 ng/mL. The maximum plasma concentrations (CMAX) were recorded as observed values and the area under the plasma-concentration time curve using all three sampling time points (AUCALL) was calculated using the Linear Trapezoidal rule. | pre-rinse, 15-45 min post-rinse, and 90-120 min post-rinse | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cGVHD, Oral cGVHD, Topical, Oral Rinse, Clobetasol, Oral Graft-Versus-Host Disease, GVHD