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

Primary Purpose

Graft-versus-Host Disease, Stomatitis

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Thalidomide Gel
Placebo Gel
Sponsored by
National Institute of Nursing Research (NINR)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft-versus-Host Disease focused on measuring Stomatitis, Oropharyngeal pain, TNF-alpha, Allogeneic hematopoietic stem cell transplant, Inflammation, Thalidomide, Oral chronic graft-versus-host disease

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • National Institutes of Health Clinical Center, 9000 Rockville Pike
  • Fred Hutchinson Cancer Research Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Thalidomide gel

Placebo

Arm Description

Thalidomide gel 20 mg applied topically 4 times daily for 4 weeks to a maximum of 3 target oral ulcers

Placebo gel with no Thalidomide applied topically 4 times daily for 4 weeks to a maximum of 3 target oral ulcers

Outcomes

Primary Outcome Measures

Mean Percentage Change in Total Surface Area of Oral Ulceration.
Mean percentage change in total surface area of oral ulceration

Secondary Outcome Measures

Full Information

First Posted
December 30, 2003
Last Updated
October 29, 2015
Sponsor
National Institute of Nursing Research (NINR)
Collaborators
Fred Hutchinson Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT00075023
Brief Title
Effectiveness of Topical Thalidomide to Treat Chronic Graft-Versus-Host-Disease Related Stomatitis
Official Title
Evaluation of Efficacy and Mechanisms of Topical Thalidomide for Chronic Graft-Versus-Host-Disease Related Stomatitis
Study Type
Interventional

2. Study Status

Record Verification Date
October 2015
Overall Recruitment Status
Terminated
Why Stopped
unable to enroll adequate subjects
Study Start Date
December 2003 (undefined)
Primary Completion Date
April 2010 (Actual)
Study Completion Date
April 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Nursing Research (NINR)
Collaborators
Fred Hutchinson Cancer Center

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study was designed to be conducted in 2 parts. The first part is a pilot study to test the effects of topical thalidomide gel 20mg applied to up to 3 oral ulcers in patients who have developed oral chronic graft-versus-host-disease (cGVHD)-related ulcerative stomatitis following allogeneic bone marrow/peripheral blood stem cell transplant (HSCT). Chronic GVHD may be related to increased levels of a cytokine called TNF-alpha (TNFa) following HSCT. Thalidomide's anti-inflammatory effects may lower TNFa levels, lead to healing of these oral ulcers, and decrease oral pain. If the pilot study is successful, the second part of the study will be done. This will test the effects of a 0.1% (20mg) thalidomide mouthwash in treating oral cGVHD-related stomatitis in patients following allogeneic HSCT. Applying thalidomide directly to the GVHD-related mouth ulcer in gel form or to the entire oral cavity in mouthwash form rather than taking it in pill form may reduce the amount of drug that enters the blood stream and cause less side effects. In the pilot study, participants will be randomly assigned to receive thalidomide gel 20mg or placebo (identical gel with no thalidomide) to use 4 times a day for 4 weeks. In the mouthwash study, participants will be randomly assigned to receive 0.1% 20mg thalidomide mouthwash or placebo (identical mouth rinse with no thalidomide) to use 4 times a day for 4 weeks. Participants will undergo the following procedures before beginning experimental treatment, 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 Oral examination for stomatitis rating, and oral ulcer(s) measurement Quality of life questionnaire (repeated only at week 8 of the study) Mouth photography to measure and record the oral ulcer response to treatment Saliva sampling to look for proinflammatory cytokines (small proteins), including TNFa Oral ulcer exudate collected by filter paper to obtain fluid for measuring TNFa levels Gentle swabbing of oral 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 presence of TNFa (repeated only at week 4 of the study) Blood sampling to monitor TNFa levels A urine pregnancy test for women who are able to have children (repeated at weeks 2, 4, and 8)
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 HSCT rather than autologous BMT because of disparities in minor histocompatibility antigens between donor and recipient, inherited independently of HLA genes (Lazarus, Vogelsang, and Rowe, 1997). GVHD may be conceptualized as a cytokine storm stemming from an outpouring of endogenous cytokines resulting in many tissue effects (Lazrarus et al, 1997). Oral chronic GVHD (cGVHD) 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 (Lloid, 1995). 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. 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. 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 cancer chemotherapy-related stomatitis and aphthous stomatitis, and are therefore amenable to treatment with anti-inflammatory strategies. Therefore, the purpose of this study is to elucidate the role of inflammation in GVHD-related ulcerative stomatitis by testing the efficacy of a topical thalidomide gel 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 (TNFa) and resultant alteration of the inflammatory cascade, may provide insight into the role of local mucosal inflammation in cGVHD-related stomatitis. This study will be conducted in two parts. The first part is a pilot study testing the effects of a thalidomide gel 20mg in patients who have developed oral cGVHD-related ulcerative stomatitis following allogeneic bone marrow/peripheral blood stem cell transplant (HSCT). 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 (TNFa) following HSCT. Thalidomide's anti-inflammatory effects may lower TNFa levels and decrease cGVHD-related stomatitis and oral pain in these patients. If this pilot 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 0.1% (20mg) thalidomide mouthwash in treating oral cGVHD-related stomatitis in patients following allogeneic HSCT. Applying thalidomide directly to the GVHD-related mouth ulcer in gel form or to the entire oral cavity in mouthwash form rather than taking the thalidomide in pill form 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 a HSCT and developed oral cGVHD-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 gel 20mg or placebo (a gel with no thalidomide) to use four times a day for 4 weeks. In the mouthwash study, participants will be randomly assigned to receive 0.1% 20mg thalidomide mouthwash or placebo (a mouth rinse with no thalidomide) to use four times a day for 4 weeks. Participants will have the following data collected and undergo the following procedures before beginning experimental treatment, 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. Oral examination for stomatitis rating Quality of life questionnaire (The questionnaire is repeated only at week 8 of the study.). Mouth photography to measure and record the oral ulcer response to treatment. Saliva sampling to look for proinflammatory cytokines (small proteins), including TNFa. Oral ulcer exudate collected by filter paper to obtain fluid for measuring TNFa levels. Gentle swabbing of oral 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 presence of TNFa. (The punch biopsy is repeated only at week 4 of the study.) Blood sampling to monitor TNFa levels. A urine pregnancy test for women who are able to have children. (The pregnancy test is repeated at weeks 2, 4, and 8.)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft-versus-Host Disease, Stomatitis
Keywords
Stomatitis, Oropharyngeal pain, TNF-alpha, Allogeneic hematopoietic stem cell transplant, Inflammation, Thalidomide, Oral chronic graft-versus-host disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Thalidomide gel
Arm Type
Experimental
Arm Description
Thalidomide gel 20 mg applied topically 4 times daily for 4 weeks to a maximum of 3 target oral ulcers
Arm Title
Placebo
Arm Type
Experimental
Arm Description
Placebo gel with no Thalidomide applied topically 4 times daily for 4 weeks to a maximum of 3 target oral ulcers
Intervention Type
Drug
Intervention Name(s)
Thalidomide Gel
Intervention Type
Drug
Intervention Name(s)
Placebo Gel
Primary Outcome Measure Information:
Title
Mean Percentage Change in Total Surface Area of Oral Ulceration.
Description
Mean percentage change in total surface area of oral ulceration
Time Frame
baseline to 4 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jane Fall-Dickson, RN, PhD
Organizational Affiliation
NIH/NINR
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
28104
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
10052767
Citation
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. doi: 10.1902/jop.1999.70.1.13. Erratum In: J Periodontol 1999 Mar;70(3):351.
Results Reference
background
PubMed Identifier
1467511
Citation
Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood. 1992 Dec 15;80(12):2964-8.
Results Reference
background
PubMed Identifier
3459612
Citation
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. doi: 10.1111/j.1600-0528.1986.tb01521.x.
Results Reference
background
PubMed Identifier
23000649
Citation
St John L, Gordon SM, Childs R, Marquesen M, Pavletic SZ, Wu TX, Cozzarelli T, Schroeder E, Saria MG, Fall-Dickson JM. Topical thalidomide gel in oral chronic GVHD and role of in situ cytokine expression in monitoring biological activity. Bone Marrow Transplant. 2013 Apr;48(4):610-1. doi: 10.1038/bmt.2012.178. Epub 2012 Sep 24. No abstract available.
Results Reference
derived
Links:
URL
http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2004-NR-0069.html
Description
NIH Clinical Center Detailed Web Page

Learn more about this trial

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

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