Effectiveness of Topical Thalidomide to Treat Chronic Graft-Versus-Host-Disease Related Stomatitis - Full Text View

Sponsored by:	National Institute of Nursing Research (NINR)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00075023

Purpose

This study will be conducted in two parts. The first part is a pilot study testing the effects of a thalidomide ointment in patients who have developed oral chronic graft-versus-host-disease (GVHD)-related ulcerative stomatitis following allogeneic bone marrow transplantation (ABMT). Stomatitis is an inflammation of the lining of the throat and mouth that may lead to ulcers and pain in the mouth and throat. GVHD - a condition in which the donor cells see patient's cells as foreign and mount an immune response to them - may be related to increased levels of a substance called TNF-alpha following ABMT.

Thalidomide's anti-inflammatory effects may lower TNF-alpha levels and decrease chronic GVHD-related stomatitis and oral pain in these patients.

If this first part of the study is successful, then the second part of the study will be conducted. The second part of this study will test the effects of a thalidomide mouthwash in treating stomatitis in patients who have developed oral chronic graft-versus-host-disease (GVHD)-related stomatitis following allogeneic bone marrow transplantation (ABMT). Applying thalidomide directly to the GVHD-related mouth ulcer in ointment form or to the entire oral cavity by mouthwash form rather than taking it as a pill may reduce the amount of drug that enters the blood stream and cause fewer side effects.

Patients between 18 and 80 years of age who have received an ABMT and developed oral chronic GVHD-related stomatitis as confirmed by surgical biopsy may be eligible for this study. The only eligible female participants for the pilot study will be women who are unable to have children. In the pilot study, participants will be randomly assigned to receive thalidomide ointment or placebo (an ointment with no thalidomide) to use four times a day. In the mouthwash study, participants will be randomly assigned to receive thalidomide mouthwash or placebo (a mouth rinse with no thalidomide) to use four times a day. Participants will also undergo the following procedures before beginning medication, then once a week for 4 weeks, and then approximately 8 weeks after the first visit.

Interview about current medications and use of alcohol and cigarettes.
Self-report of mouth and throat pain ratings.
Dental examination.
Quality of life questionnaire (The questionnaire is repeated only at week 8 of the study.).
Mouth photography to measure and record the response to treatment.
Saliva sampling to look for chemicals, including TNF-alpha.
Ulcer exudate collected by filter paper to obtain fluid for measuring TNF-alpha levels.
Gentle swabbing of ulcers to culture for virus, fungus, and bacteria that may be present.
Small punch biopsy of the area near the ulcer or affected area to check for TNF-alpha (The punch biopsy is repeated only at week 4 of the study.)
Blood sampling to monitor thalidomide and TNF-alpha levels.
A urine pregnancy test for women who are able to have children. (The pregnancy test is repeated at weeks 2, 4, and 8.)

Condition	Intervention	Phase
Graft vs Host Disease Stomatitis Bone Marrow Transplantation	Drug: Thalidomide Drug: Thalidomide Gel	Phase II

Study Type:	Interventional
Study Design:	Treatment
Official Title:	Evaluation of Efficacy and Mechanisms of Topical Thalidomide for Chronic Graft-Versus-Host-Disease Related Stomatitis

Resource links provided by NLM:

MedlinePlus related topics: Bone Marrow Transplantation

Drug Information available for: Thalidomide

U.S. FDA Resources

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

Progress in oral ulcer healing. [ Designated as safety issue: Yes ]

Estimated Enrollment:	132
Study Start Date:	December 2003
Estimated Study Completion Date:	January 2006
Estimated Primary Completion Date:	January 2006 (Final data collection date for primary outcome measure)

Intervention Details:

N/A

Detailed Description:

Oncology patients undergoing allogeneic bone marrow/peripheral blood stem cell transplant (HSCT) frequently experience an allo-immune condition termed graft-versus-host-disease (GVHD). The pathogenesis of GVHD derives from an immune attack mediated by donor T-cells recognizing antigens expressed on normal tissues of the patient. This condition occurs in ABMT rather than autologous BMT because of disparities in minor histocompability antigens between donor and recipient, inherited independently of HLA genes. GVHD may be conceptualized as a cytokine storm stemming from an outpouring of endogenous cytokines resulting in many tissue effects. Oral chronic GVHD (cGVHD), which is classically diagnosed as a late complication of ABMT occurring more than 100 days post transplant, presents with tissue atrophy and erythema, lichenoid changes (hyperkeratotic striae, patches, plaques, and papules) and pseudomembranous ulcerations typically occurring on the buccal and labial mucosa and the lateral tongue, mucoceles due to inflammation of minor salivary glands, and xerostomia. The ulcerative phase often leads to a cascade of negative sequelae including oropharyngeal pain, critical treatment alterations or cessation, diminished capacity for food intake, and decreased quality of life. We hypothesize that the mechanisms of tissue injury occurring at the mucosal level leading to cGVHD-related stomatitis are similar to other types of stomatitis, such as chemotherapy-related and aphthous stomatitis, and are therefore amenable to treatment with anti-inflammatory strategies.

Optimal treatment strategies for cGVHD-related ulcerative stomatitis and related oropharyngeal pain have not been established. Therefore, there is a critical need to examine the pathogenesis of and to evaluate interventions for cGVHD-related ulcerative stomatitis and related acute oropharyngeal pain in the randomized controlled clinical trial setting to both advance the science of cancer treatment-related oral complications and to improve patient care. Therefore, the purpose of this study is to elucidate the role of inflammation in GVHD-related ulcerative stomatitis by testing the efficacy of topical thalidomide on the resolution of cGVHD-related stomatitis and related oropharyngeal pain. The actions of thalidomide, which include inhibition of the release of tumor necrosis factor-alpha (TNF-alpha) and resultant alteration of the inflammatory cascade, may provide insight into the role of local mucosal inflammation in cGVHD-related stomatitis.

Eligibility

Ages Eligible for Study:	18 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

INCLUSION CRITERIA:

Participating in HSCT or cGVHD protocols and willing to participate in this study concurrently;

Diagnosed with oral cGVHD stomatitis confirmed by surgical biopsy results;

Oral ulceration present

Able to understand and sign protocol informed consent;

Ages 18 to 80 years of age.

EXCLUSION CRITERIA:

Pregnant or lactating females;

For the proof of concept study, females who are not surgically sterilized by means of hysterectomy or tubal ligation;

For the main study, females of childbearing potential who do not agree to the use of two forms of highly effective contraception for at least four weeks prior, during, and for four weeks following the last dose of study drug;

Sexually active males who do not agree to the use of a latex condom while receiving study drug and for four weeks following the last dose of study drug;

Unwilling to follow precautions for use of thalidomide;

Unable to demonstrate appropriate use of study medication;

Concurrent use of non-protocol-related medications confounding assessment of the inflammatory response (antihistamines, non-steroidal anti-inflammatory drugs);

Allergic reaction to thalidomide;

Pre-existing oral infection, which might maximize the possibility of an infection or sepsis contributing to a drug-related adverse event;

Unwilling or unable to forego concurrent treatment for mucosal lesions and/or related oral pain (including topical steroids, viscous lidocaine, topical anti-fungals);

Requiring addition of new systemic therapy including thalidomide, steroids, or radiation therapy;

Use of sedatives (including CNS depressants);

Absolute neutrophil count (ANC) less than 750/mm(3)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00075023

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892
United States, Washington
Fred Hutchinson Cancer Research Center	Recruiting
Seattle, Washington, United States, 28104

Sponsors and Collaborators

National Institute of Nursing Research (NINR)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

Publications:

Albandar JM, Brunelle JA, Kingman A. Destructive periodontal disease in adults 30 years of age and older in the United States, 1988-1994. J Periodontol. 1999 Jan;70(1):13-29. Erratum in: J Periodontol 1999 Mar;70(3):351.

Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood. 1992 Dec 15;80(12):2964-8. Review.

Aucott DM, Ashley FP. Assessment of the WHO partial recording approach in identification of individuals highly susceptible to periodontitis. Community Dent Oral Epidemiol. 1986 Jun;14(3):152-5.

Responsible Party:	National Institutes of Health ( Jane M. Fall-Dickson, Ph.D./National Institutes of Nursing Research )
Study ID Numbers:	040069, 04-NR-0069
Study First Received:	December 30, 2003
Last Updated:	June 9, 2009
ClinicalTrials.gov Identifier:	NCT00075023 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Stomatitis
Oropharyngeal Pain
TNF-Alpha
Allogeneic BMT
Inflammation

Study placed in the following topic categories:

Mouth Diseases
Stomatitis
Thalidomide
Immunologic Factors
Pain
Immunosuppressive Agents
Angiogenesis Inhibitors

Homologous Wasting Disease
Inflammation
Graft Versus Host Disease
Anti-Bacterial Agents
Graft vs Host Disease
Stomatognathic Diseases

Additional relevant MeSH terms:

Mouth Diseases
Anti-Infective Agents
Stomatitis
Immune System Diseases
Thalidomide
Immunologic Factors
Antineoplastic Agents
Growth Substances
Physiological Effects of Drugs
Angiogenesis Inhibitors

Immunosuppressive Agents
Pharmacologic Actions
Anti-Bacterial Agents
Therapeutic Uses
Graft vs Host Disease
Growth Inhibitors
Angiogenesis Modulating Agents
Stomatognathic Diseases
Leprostatic Agents

ClinicalTrials.gov processed this record on July 02, 2009