Clinical trial NCT01557517
Conditions: Oral Chronic Graft vs Host Disease
Keywords: cGVHD Oral cGVHD Topical Oral Rinse Clobetasol Oral Graft-Versus-Host Disease GVHD
Sponsor: National Cancer Institute (NCI)
Start date: 2012-03-28; Completion date: 2017-08-24
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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:
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.

Arms: arm 1: Patients will rinse oral cavity with 10cc of clobetasol 0.05% for 2 minutes 3 times a day. arm 2: Patients will rinse oral cavity with 10cc of placebo oral rinse for 2 minutes 3 times a day.
Interventions: intervention 1: Clobetasol Oral Rinse intervention 2: Placebo oral rinse
Intervention descriptions: intervention 1: 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. intervention 2: Patients will rinse oral cavity with 10cc of placebo oral rinse for 2 minutes 3 times a day.

Protocol documents:
Prot_SAP_001.pdf: 
Abbreviated Title: Clobetasol oral rinse for oral cGVHD
Version Date: January 24, 2017
Abbreviated Title: Clobetasol rinse for oral cGVHD
NCI Protocol #: 12C0068
Version Date: 3/25/2025
NCT Number:  NCT01557517
Title: A Randomized Double-Blind Pilot Study of Topical Clobetasol 0.05% Oral rinse for Oral 
Chronic Graft-Versus-Host Disease
  NCI Principal Investigator:
Najla El Jurdi, MD 
Immune Deficiency Cellular Therapy Program (IDCTP)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
National Institutes of Health (NIH)
10 Center Drive, CRC 8D44C
9000 Rockville Pike
Bethesda, MD 20892
Phone: 240-858-3287
E-mail: najla.eljurdi@nih.gov
Drug Name:
Clobetasol
IND Number:
77313
Sponsor:
Center for Cancer Research
Manufacturer:
Spectrum Chemicals


Abbreviated Title: Clobetasol rinse for oral cGVHD
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PRÉCIS 
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.
Objective:
•
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.


Abbreviated Title: Clobetasol rinse for oral cGVHD
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TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................3
STATEMENT OF COMPLIANCE ................................................................................................6
1
INTRODUCTION ...................................................................................................................6
1.1
Study Objectives ...............................................................................................................6
1.2
Background and Rationale................................................................................................7
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .........................................................9
2.1
Eligibility Criteria .............................................................................................................9
2.2
Screening Evaluation ......................................................................................................10
2.3
Registration Procedures ..................................................................................................10
2.4
Randomization (or Stratification) Procedures: ...............................................................11
3
STUDY IMPLEMENTATION .............................................................................................11
3.1
Study Design...................................................................................................................11
3.2
Drug Administration .......................................................................................................16
3.3
Treatment modifications .................................................................................................16
3.4
Dose Modifications.........................................................................................................20
3.5
Questionnaires.................................................................................................................20
3.6
Study Calendar................................................................................................................22
3.7
Duration of Follow- Up...................................................................................................22
3.8
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................23
4
SUPPORTIVE CARE ...........................................................................................................24
4.1
Concurrent Therapy ........................................................................................................24
5
BIOSPECIMEN COLLECTION...........................................................................................24
5.1
Correlative Studies for Research/Pharmacokinetic Studies............................................24
5.2
Sample Storage, Tracking and Disposition.....................................................................25
6
DATA COLLECTION AND EVALUATION .....................................................................27
6.1
Data Collection ...............................................................................................................27
6.2
Oral GVHD Severity Scales ...........................................................................................27
6.3
Response Criteria ............................................................................................................28
6.4
Toxicity Criteria..............................................................................................................28
7
NIH Reporting Requirements /  Data and Safety Monitoring Plan.......................................28


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7.1
Definitions.......................................................................................................................28
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................28
7.3
NCI Clinical Director Reporting.....................................................................................28
7.4
NIH Required Data and Safety Monitoring Plan............................................................29
8
SPONSOR PROTOCOL/SAFETY REPORTING................................................................29
8.1
Definitions.......................................................................................................................29
8.2
Assessment of Safety Events ..........................................................................................30
8.3
Reporting of Serious Adverse Events .............................................................................31
8.4
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................31
8.5
Sponsor Protocol Deviation Reporting ...........................................................................31
9
CLINICAL MONITORING..................................................................................................32
10
STATISTICAL CONSIDERATIONS ...............................................................................32
10.1
Subject Accrual ...........................................................................................................32
10.2
Statistical Considerations ............................................................................................32
11
HUMAN SUBJECTS PROTECTIONS.............................................................................35
11.1
Rationale For Subject Selection ..................................................................................35
11.2
Participation of Children .............................................................................................35
11.3
Participation of NIH Subjects Unable to Give Consent..............................................35
11.4
Evaluation of Benefits and Risks/Discomforts ...........................................................35
11.5
Risks/Benefits Analysis...............................................................................................36
11.6
Consent and Assent Process and Documentation........................................................37
12
REGULATORY AND OPERATIONAL CONSIDERATIONS.......................................39
12.1
Study Discontinuation and Closure.............................................................................39
12.2
Quality Assurance and Quality Control ......................................................................40
12.3
Conflict of Interest Policy ...........................................................................................40
12.4
Confidentiality and Privacy.........................................................................................40
13
PHARMACEUTICAL INFORMATION ..........................................................................41
13.1
Clobetasol Oral Rinse..................................................................................................41
13.2
Study Placebo Oral Rinse............................................................................................42
14
REFERENCES ...................................................................................................................43
15
APPENDICES ....................................................................................................................46
15.1
Appendix A: Oral Mucositis Rating Scale (OMRS)...................................................46
15.2
Appendix B: Oral cGVHD Clinical Scoring Instrument.............................................47


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15.3
Appendix C: Numeric Rating Scales (0-10) for Oral Pain, Sensitivity, and Dryness.48
15.4
Appendix D: Global Scale...........................................................................................49
15.5
Appendix E: Painometer (POM) Assessment Sheet ...................................................50
15.6
Appendix F: Oral Health Impact Profile (OHIP-14) 38 ...............................................52
15.7
Appendix G: Schedule of Evaluations and Events......................................................53
15.8
Appendix H: Data Collection Elements Required By Protocol ..................................56
15.9
Appendix I: Topical Clobetasol 0.05% Oral Rinse for Oral Chronic Graft-Versus-
Host Disease Patient Diary ........................................................................................................58
15.10
Appendix J: Spanish language translations of the patient-reported outcome forms ...60
15.11
Appendix K: Oral Health Impact Profile (OHIP-14) ..................................................64


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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective 
To investigate efficacy of topical clobetasol 0.05% oral rinse for oral chronic graft-versus-host-
disease (cGVHD) during a four-week treatment period as assessed by Oral Mucositis Rating 
Scale (OMRS).
1.1.2
Secondary Objectives
1.1.2.1
To assess the effect of topical clobetasol on oral cGVHD related pain, sensitivity, and 
dryness.
1.1.2.2
To evaluate the basic pharmacodynamics and pharmacokinetics of clobetasol mouth 
rinse in cGVHD patients.
1.1.2.3
To obtain a pilot assessment of patient perceived oral health in cGHVD and its response 
to treatment with topical clobetasol.
1.1.2.4
To evaluate the validity of the NIH Oral cGVHD Clinical Scoring instrument.
1.1.2.5
To evaluate the immunological profile present at baseline and after clobetasol treatment 
in oral tissue to identify potential biomarkers for disease response or resistance to 
clobetasol.
1.1.2.6
To evaluate blood and saliva to identify potential biomarkers for oral cGVHD disease 
activity and response to topical clobetasol.


Abbreviated Title: Clobetasol rinse for oral cGVHD
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1.2
BACKGROUND AND RATIONALE
1.2.1
Chronic Graft-Versus-Host-Disease
Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been used increasingly for 
malignant and non-malignant disorders 1. Graft-versus-host disease (GVHD) is a major 
complication and a leading cause of morbidity and mortality in recipients of alloHSCT. GVHD 
results from immunologic attack by the donor’s immune cells on the recipient’s tissues and 
organs. Incidence and severity of GVHD vary depending on degree of mismatch of major 
histocompatibility antigens of the donor and host, age of donor and recipient, source of stem 
cells, and type of preparative regimen2.  Development of non-myeloablative conditioning 
regimens has led to a decrease in early post-transplant mortality and an increase in chronic 
GVHD (cGVHD). Almost 70% of patients who survive more than 100 days after alloHSCT will 
develop cGVHD, with the majority manifesting in the first year.2-5 The undersupply of related 
donors led to expanded use of unrelated and partially matched unrelated donors. Use of non-
myeloablative conditioning regimens is related to more frequent use of both older donors and 
recipients6. Taken together, these factors have increased the incidence of cGVHD.
Chronic GVHD has many similar features of autoimmune diseases, such as lupus, lichen planus, 
and scleroderma, and can have a varied clinical presentation. Mononuclear cellular infiltrates are 
found in many areas of the graft recipient, including the liver, skin, oral mucosa, and salivary 
glands7. Recent NIH consensus conferences proposed new criteria for staging of cGVHD that 
consider extent of the disease, number of involved organs, and severity of functional 
impairment2,8,9. Some of these criteria have been validated, and others require validation in 
future trials2,4,8,10-12. Chronic GVHD can persist for months to years and requires long-term 
multidisciplinary management.
1.2.2
Oral involvement in cGVHD
Oral cGVHD is a common, major cause of morbidity and decrease in health-related quality of 
life (HRQOL) in long-term alloHSCT survivors10,13-15. In a recent randomized trial of peripheral 
blood stem cell (PBSC) vs. bone marrow stem cells (BMSC) transplants, oral mucosal changes 
were the most common manifestation of cGVHD in BMSC recipients and the second most 
common (after skin) in PBSC transplants. Overall incidence in cGVHD was around 85%3. Oral 
manifestations of cGVHD include lichen planus-like changes, mucosal atrophy and ulcerations, 
taste disturbances, and salivary gland hypofunction. Oral pain and food sensitivity are common, 
and not limited to patients with ulcerations10,16,17.  Oral discomfort was shown to be associated 
with decrease in food intake and weight loss in this group of patients10,18.  Recently, the 
contribution of oral cGVHD to inferior health-related QOL was reported 10,19. There have been 
several reports of increased incidence of oral squamous cell carcinoma (SCCA) after allo-HSCT, 
with history of oral cGVHD identified as an independent risk factor20,21.
1.2.3
cGVHD Therapy
1.2.3.1
Systemic and topical corticosteroids
The treatment for cGVHD consists of various systemic immunosuppressive agents, most 
commonly systemic corticosteroids, cyclosporine, tacrolimus, mycophenolate, sirolimus and 
phototherapy9. Long-term immunosuppressive treatment for GVHD has a variety of serious 
complications including life-threatening infections, aseptic bone necrosis, hypertension, and 
secondary diabetes.6,22


Abbreviated Title: Clobetasol rinse for oral cGVHD
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Corticosteroids are the most commonly used systemic treatment of both acute and chronic 
GVHD. Immunosuppressive and anti-inflammatory effects of corticosteroids are mediated 
through multiple mechanisms including immune cell apoptosis and interference with dendritic 
cell maturation. The critical role of dendritic cells in the development of GVHD has been 
outlined in several studies. One study demonstrated the potential of GVHD prevention via 
depletion of host antigen presenting cells in a murine model.23. In another animal study, local 
depletion of Langerhans cells in skin prevented GVHD. Corticosteroids have been shown to 
prevent development of dermal dendritic cells in vitro.24. Additionally, topical corticosteroids 
induced apoptosis in the murine epidermal Langerhans cells and CD8+T cells25.
Topical corticosteroids such as dexamethasone 0.01% oral rinse and clobetasol 0.05% ointment 
are used widely for treatment of oral cGVHD, although their efficacy has not been formally 
evaluated in this condition4.  Ointments and creams have a disadvantage of uneven and 
cumbersome application, furthermore, it is difficult to estimate the systemic versus local effect. 
Unlike solutions used as rinses, ointments can be easily swallowed and absorbed through the 
gastrointestinal tract. At the NIH Clinical Center, both dexamethasone oral rinse and clobetasol 
ointment have been used with variable success. In general, complicated application procedures 
reduce compliance and make evaluation of response difficult. Oral rinses have a particular 
advantage when a significant oral cavity area is affected as the contact with the entire surface is 
ensured with potential decrease in systemic absorption.
1.2.3.2
Clobetasol
Clobetasol is a readily available corticosteroid used topically in a wide variety of inflammatory 
conditions. Clobetasol 0.05% ointment is FDA approved for the treatment of inflammatory skin 
diseases and clobetasol spray is approved for psoriasis. Clobetasol ointment is widely used 
topically by oral medicine practitioners for the treatment of oral ulcerative conditions including 
oral lichen planus, a condition clinically and pathologically similar to oral cGVHD and has been 
shown to be safe and effective26-28. When used 2 times a day for 4-8 weeks, the response rates 
exceeded 90%.28,29 There are few side effects associated with oral topical corticosteroid use with 
the most common being oral candidiasis. To reduce incidence of oral candidiasis infection, 
patients will be asked to swish and spit once per day with nystatin (100,000u/ml) rinse, which is 
a standard preventative measure in high-risk patients.  Although there have been reports of 
adrenal suppression associated with high potency topical steroids, these were generally rare and 
occurred primarily in young children and in patients with large surface areas of involvement 
(skin). In one study, no changes in morning cortisol levels were observed when clobetasol was 
applied topically in the oral cavity for 2 months for oral lichen planus.23 However, other reports 
have indicated signs and symptoms of adrenal suppression in patients with severe erosion of the 
oral mucosa, as in erosive oral lichen planus, and long term use (years) of topical clobetasol30,31. 
The effect of clobetasol and other steroids applied topically in the oral cavity on the ability of 
adrenal glands to respond to stress levels of ACTH has not been formally evaluated in cGVHD 
or in normal patients.
1.2.4
Trial Plan
Treatment of oral GVHD by topical agents is an appealing strategy because it would potentially 
avoid the adverse effects associated with systemic immunosuppression and reduce systemic 
exposure to glucocorticoids. Most importantly, using immunosuppressive agents locally would 
concentrate the treatment effects for potential maximum benefit. Conversely, use of systemic 


Abbreviated Title: Clobetasol rinse for oral cGVHD
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agents for the same purpose would interfere not only with the undesirable GVH response, but 
also with immune responses directed against the malignancy (the graft vs. tumor effect), which is 
the principal mechanism through which reduced intensity transplants achieve sustained disease 
remission.
Therefore, we propose this pilot randomized double blind placebo controlled trial of topical 
clobetasol 0.05% oral rinse for oral cGVHD. Consenting subjects with clinically significant oral 
cGVHD will be randomized to receive clobetasol or placebo oral rinse for 2 weeks. All subjects 
will be evaluated biweekly. Clinically significant oral cGVHD is defined as a score of 20 or 
greater on the Oral Mucositis Rating Scale (OMRS) based on the patient cohort (over 250) seen 
in the NIH natural history of cGVHD protocol. At the first 2 week appointment, patients will be 
unblinded and subjects randomized to placebo will be assigned to additional 2-4 week open label 
treatment period with topical clobetasol rinse. All patients will therefore complete 4 weeks of 
treatment with the study drug (2 additional weeks for patients originally assigned to clobetasol 
arm and 4 weeks for patients assigned to placebo arm). All patients will be reevaluated 1 month 
following the open label period to evaluate the response and collect follow-up data.
Patients with progressive disease while on the clobetasol treatment as determined at any 
scheduled evaluation visit will be considered non-responders for the primary endpoint evaluation 
and will be taken off-study. Within 90 days of the end of the open label treatment period, all 
patients with evidence of benefit (response or stable disease) will be given an option to continue 
treatment with clobetasol 0.05% with or without additional treatment as deemed clinically 
necessary, up to one month. The proportion of responders in the active and placebo arm will be 
used as the primary outcome variable. As no standard definition of oral cGVHD response exists, 
for purposes of this pilot study, response will be defined as decrease of 25% or more on the 
OMRS (Appendix A). Difference in OMRS scores between the groups at the end of the 2 week 
blinded period and the change in OMRS score between beginning and the end of the 4 week 
treatment period with clobetasol oral rinse will serve as a secondary outcome variables. The 
study schedule of events is outlined in Appendix E.
The placebo design is justified by the following: a) there is no proven standard topical therapy 
for oral cGVHD, b) patients will be unblinded after 2 weeks of treatment (defined in Section 
3.2.4) and those on placebo will be allowed to cross over to the alternate treatment arm. This will 
allow all participants to receive the study drug for 4 weeks.
In addition to potential direct benefit to the cGVHD patients, this study is likely to provide 
valuable insights into the cellular and molecular alterations associated with the development of 
cGVHD and treatment with topical corticosteroids. This will lead to better understanding of the 
pathogenesis of cGVHD needed as the foundation for development of new therapeutic 
interventions.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Age: 12 years – 99 years.
2.1.1.2
Diagnosis: clinically significant oral cGVHD after allogeneic HSCT with severity score 
of at least 2 on erythema subset and/or at least 1 on ulceration subset and a composite 


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score >20 of the Oral Mucositis Rating Scale (OMRS) scale (Appendix A) confirmed 
by the principal investigator (PI), clinical study chair (CSC), or lead associate 
investigator (LAI).
2.1.1.3
Hematologic Function: Patients must have a platelet count ≥20,000/µL at the time of the 
initial evaluation.
2.1.1.4
Informed Consent: All patients or their legal representative (for patients  <18 years old) 
must sign an IRB approved informed consent document (cGVHD natural history 
protocol 04-C-0281 or any 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 NIH guidelines.
2.1.1.5
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.
2.1.1.6
Patients must have the ability and willingness to come to Clinical Center for bi-weekly 
follow-up appointments.
2.1.1.7
No change in systemic immunosuppressive therapy (type or intensity level) within 2 
weeks prior to enrollment.
2.1.1.8
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. 
2.1.2
Exclusion Criteria
2.1.2.1
Documented hypersensitivity to clobetasol.
2.1.2.2
Use of clobetasol ointment intra-orally at any time during the last 6 weeks period.
2.1.2.3
Pregnant or breast-feeding females due to possible toxicity to the fetus or infant.
2.1.2.4
Inability to understand the investigational nature of the study to provide informed 
consent.
2.1.2.5
Patients who, for medical or other reasons, are unable to comply with the study 
procedures.
2.2
SCREENING EVALUATION
Evaluation outlined in Section 3.3.1 and Appendix A.
2.3
REGISTRATION PROCEDURES
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and must be 
completed and sent via encrypted email to:  NCI Central Registration Office (HOIS) 
<ncicentralregistration-l@mail.nih.gov>.  After confirmation of eligibility at Central 
Registration Office, CRO staff will call pharmacy to advise them of the acceptance of the patient 
on the protocol prior to the release of any investigational agents.  Verification of Registration 


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will be forwarded electronically via e-mail to the research team. Voicemail is available during 
non-working hours. 
2.4
RANDOMIZATION (OR STRATIFICATION) PROCEDURES:
Dr. Steinberg will create the randomization lists using variable block sizes.  Patients will be 
randomized with a single stratification factor to try to ensure a balanced distribution among those 
getting placebo or not initially: being identified as having a high intensity of immunosuppression 
(2 or more agents/modalities ± prednisone≥0.5 mg/kg/day) vs. no or a lesser intensity of 
systemic immunosuppression according to the Intensity of Immunosuppression Scale10.  
Once patients have been evaluated and meet all eligibility requirements, patients will be 
registered with the NCI Central Registration Office and be randomized to either clobetasol or 
placebo.  Change of systemic immunosuppressive regimen occurring after enrollment will not be 
allowed, and if this is necessary during the 2-week blinded phase of the study to control 
progressive systemic cGVHD, the patient will come off the study.  Other medication changes 
will be documented at the interim or final (end of treatment) appointment and taken into 
consideration in the final analysis. However, given the small, pilot nature of the study, it is 
unlikely that the effect of all potential confounders can be meaningfully taken into account.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a randomized, double blind, placebo-controlled, pilot study of clobetasol 0.05% topical 
oral rinse with an open label cross-over or extension period. Consenting subjects with clinically 
significant oral chronic GVHD will be randomized to clobetasol 0.05% or placebo oral rinse. 
The placebo will be flavored with quinine, to approximate the “bitter” taste of clobetasol.  
Subjects will be evaluated at bi-weekly intervals while on the study intervention. OMRS score 
will serve as the primary outcome measure. At the first 2 week interim appointment patients will 
be unblinded and started on the clobetasol oral rinse open label. In the absence of progressive 
oral disease on the scheduled interim evaluations during the 4-week clobetasol treatment period, 
all patients will complete a total of 4 weeks of treatment with clobetasol. Therefore, patients who 
were originally assigned to clobetasol arm will receive additional 2 weeks of treatment, and 
patients assigned to placebo arm will undergo an additional 4 weeks of treatment with clobetasol 
after unblinding. Patients with progressive disease after 2 weeks of therapy with clobetasol will 
be considered non-responders, taken off-treatment and treated as appropriate in consultation with 
primary clinician. Within 90 days of the end of the 1 month of treatment, all patients with 
evidence of benefit (response or stable disease) will be given an option to continue treatment 
with clobetasol 0.05% with or without additional treatment as deemed clinically necessary for 1 
month after the conclusion of the initial treatment period. Additional follow-up appointment will 
be scheduled for all patients 1 month after completion of treatment. The change in OMRS scores 
from baseline to 4 weeks of mouth rinse usage will be the primary outcome variable.  For the 
placebo group, the OMRS score at the end of the blinded phase/beginning of clobetasol rinse use 
(day 14) will serve as the baseline for the primary outcome.  Difference in OMRS score between 
the groups (placebo and clobetasol) at the end of the 14-day blinded phase will serve as a 
secondary outcome measure. The study schedule of events is outlined in Appendix G.


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Date: ____/____/____    Timepoint: __________  LIP print name:  Jacqueline 
Mays   LIP Signature:_______________________
#
Because of problems with your teeth, 
denture or mouth have you…
Never (0)
Hardly 
ever (1)
Occasionally 
(2)
Often 
(3)
Very 
Often 
(4)
1
Had trouble pronouncing words
 
 
 
 
 
2
Felt sense of taste has worsened
 
 
 
 
 
3
Had painful aching in the mouth
 
 
 
 
 
4
Found it uncomfortable to eat any foods
 
 
 
 
 
5
Have been self-conscious
 
 
 
 
 
6
Felt tense
 
 
 
 
 
7
Had an unsatisfactory diet
 
 
 
 
 
8
Had to interrupt meals
 
 
 
 
 
9
Found it difficult to relax
 
 
 
 
 
10
Have been a bit embarrassed
 
 
 
 
 
11
Have been irritable with other people
 
 
 
 
 
12
Had difficulty doing usual jobs
 
 
 
 
 
13
Felt life in general was less satisfying
 
 
 
 
 
14
Have been totally unable to function
 
 
 
 
 
Total ________________________________


Abbreviated Title: Clobetasol oral rinse for oral cGVHD
Version Date: January 24, 2017
Appendix G
Date: ____/____/____    Timepoint: __________  LIP print name:  Jacqueline 
Mays   LIP Signature:_______________________
#
Because of problems with your teeth, 
denture or mouth have you…
Never (0)
Hardly 
ever (1)
Occasionally 
(2)
Often 
(3)
Very 
Often 
(4)
1
Had trouble pronouncing words
 
 
 
 
 
2
Felt sense of taste has worsened
 
 
 
 
 
3
Had painful aching in the mouth
 
 
 
 
 
4
Found it uncomfortable to eat any foods
 
 
 
 
 
5
Have been self-conscious
 
 
 
 
 
6
Felt tense
 
 
 
 
 
7
Had an unsatisfactory diet
 
 
 
 
 
8
Had to interrupt meals
 
 
 
 
 
9
Found it difficult to relax
 
 
 
 
 
10
Have been a bit embarrassed
 
 
 
 
 
11
Have been irritable with other people
 
 
 
 
 
12
Had difficulty doing usual jobs
 
 
 
 
 
13
Felt life in general was less satisfying
 
 
 
 
 
14
Have been totally unable to function
 
 
 
 
 
Total ________________________________


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ate: ____/____/____    Timepoint: __________  LIP print name:  Jacqueline 
ays   LIP Signature:_______________________
ecause of problems with your teeth, denture or mouth have you…
Never 
(0)
Hardly 
ever (1)
Occasionally 
(2)
Often 
(3)
ad trouble pronouncing words
 
 
 
 
 
elt sense of taste has worsened
 
 
 
 
 
ad painful aching in the mouth
 
 
 
 
 
ound it uncomfortable to eat any foods
 
 
 
 
 
ave been self-conscious
 
 
 
 
 
elt tense
 
 
 
 
 
ad an unsatisfactory diet
 
 
 
 
 
ad to interrupt meals
 
 
 
 
 
ound it difficult to relax
 
 
 
 
 
ave been a bit embarrassed
 
 
 
 
 
ave been irritable with other people
 
 
 
 
 
ad difficulty doing usual jobs
 
 
 
 
 
elt life in general was less satisfying
 
 
 
 
 
ave been totally unable to function
 
 
 
 
 
otal 
_______________________________


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Appendix GFor pediatric patients (< 18 years of age at enrollment), ACTH stimulation test and oral biopsy will be done as clinically 
indicated, and are not required by the protocol.  These procedures may still be done for clinical diagnostic and monitoring purposes.  
3.1.1
Study Schema


Abbreviated Title: Clobetasol oral rinse for oral cGVHD
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3.2
DRUG ADMINISTRATION
3.2.1
Clobetasol Administration
Clobetasol 0.05% oral rinse and placebo rinse which will be identical in appearance and taste 
will be labeled and dispensed by the NIH Clinical Center Pharmacy. Subjects will be instructed 
to rinse oral cavity 3 times daily with the 10 cc of the study medication for 2 minutes and spit out 
and not to eat, drink, or brush teeth for 30 minutes after the study drug administration. 
Additionally, the use of oral topical analgesic (viscous lidocaine) will not be allowed for 30 
minutes before and after study drug administration.
3.2.2
Duration of Drug Therapy
Patients will be treated with study medication for up to 4 weeks initially.  If patients enter the 
continuation treatment period, they can be treated for up to an additional 4 weeks. Patients may 
be allowed to enter the continuation treatment period up to 90 days after the last day of 
treatment.
3.2.3
Progressive disease 
Patients with progressive oral cGVHD after 2 weeks of treatment with the clobetasol oral rinse 
will be taken off study. See also Section 6.3.1. 
3.2.4
Treatment after 2 week blinded phase
Patients who switch to the clobetasol arm due to initial placebo assignment will be treated with 
clobetasol 0.05% oral rinse for 4 weeks. Patients originally assigned to clobetasol arm will be 
treated for another 2 weeks. 
3.3
TREATMENT MODIFICATIONS
All dose modifications must be discussed with the PI, or LAI. Given favorable toxicity profile of 
clobetasol, no treatment modifications are expected. Grade 2 – 3 CTCAE v.4 events attributable 
to underlying disease and occurring prior to administration of clobetasol will not be reported as 
an adverse event. These physical findings must be documented at baseline. Expected pre-existing 
manifestations of cGVHD or systemic steroid therapy may include the following examples: 
fatigue, colitis, cushingoid appearance, anorexia, dyspepsia, xerostomia, parotid swelling, 
nausea, taste alteration, arthritis, fibrosis, myositis, osteonecrosis, osteopenia, dry eye, watery 
eye, pain, dyspnea, vaginal dryness, skin atrophy, alopecia, hyperpigmentation, skin dryness, 
hypopigmentation, nail changes, photosensitivity, pruritus, rash, and ulcers12. In the event of 
grade 2-3 adverse event attributable to study agent that cannot be easily alleviated without 
compromising the integrity of the study (such as severe local or systemic hypersensitivity) the 
subject will be taken off study and treated appropriately as detailed in Protocol Evaluations 
3.3.1
Pre-Treatment Evaluation 
Pre-treatment tests should be performed within 1 month prior to enrollment on the trial unless 
otherwise stated. Evaluation may be performed as part of enrollment onto NIH Protocol #04-C-
0281 entitled: “Prospective Assessment of Clinical and Biological Factors Determining 
Outcomes in Patients with Chronic Graft-Versus-Host Disease.” All attempts will be made to 
enroll patients on this study; however evaluation may be done as part of any ongoing NCI 
protocol.  A 7-day washout period is required if patients are currently using another oral topical 
treatment for mouth lesions. 


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1. Optional History and Physical Examination  
2. NIH global scoring and data collection, including prior and concurrent therapy, 
(Appendix H)
3. Chronic GVHD NIH organ staging
4. Assessment of oral GVHD using OMRS and oral cGVHD Clinical Scoring Instrument 
(Appendix A and Appendix B)
5. Numeric rating scales for (0 to 10) for oral pain, oral sensitivity, and oral dryness 


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Appendix C) 
6. Oral Global Scale (Appendix D) 
7. Painometer (POM) Assessment (Appendix E)
8. Oral Health Impact Profile- OHIP-14 (Appendix F)
9. Hematology: Complete blood counts, with differential and platelet count.  Within 72 
hours prior to initial evaluation.
10. Chemistries: Electrolytes (including sodium, potassium, chloride, CO2, calcium, 
phosphorus and magnesium), creatinine, BUN, glucose, SGOT, alkaline phosphatase, 
SGPT, bilirubin, PT/INR and PTT, serum cortisol level and TBNK panel. Within 72 
hours prior to initial evaluation.
11. FSH, LH, TSH, T4, CMV by PCR, and HSV by PCR.
12. Urine or Serum Pregnancy test: For all females of childbearing potential.  This test is to 
be performed within 7 days prior to enrollment on the trial.
13. Urine glucose - Within 72 hours prior to initial evaluation.
14. Biopsy of buccal mucosa (4 mm punch) on patient’s right side OR of buccal area with 
GVHD involvement for histopathological examination.
15. Research blood sample collection (18cc)
16. Five minute saliva sample, with and without paraffin stimulation
17. Short ACTH stimulation test, within 1 week prior to initial evaluation.
18. Clinical oral photo series
19. Adrenocorticotropic Hormone blood level within 1 week prior to initial evaluation.
20. Hemoglobin A1C level
3.3.2
Interim Evaluation
Patients should be evaluated at the NIH 14 days after the start of intervention until Day 28 of 
active rinse use for the following:
1. Optional History and Physical Examination
2. Assessment of oral GVHD using OMRS and oral cGVHD Clinical Scoring 
Instrument (Appendix A and Appendix B)
3. Numeric rating scales for (0 to 10) for oral pain, oral sensitivity, and oral dryness 
(Appendix C) 
4. Oral Global Scale (Appendix D) 
5. Painometer (POM) Assessment (Appendix E)
6. Oral Health Impact Profile- OHIP-14 (Appendix F)
7. Hematology: Complete blood counts, with differential and platelet count


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8. Chemistries: Electrolytes (including sodium, potassium, chloride, CO2, calcium, 
phosphorus and magnesium), creatinine, BUN, glucose, SGOT, alkaline phosphatase, 
SGPT, bilirubin, PT/INR and PTT, cortisol level and TBNK panel.
9. Research blood sample collection (18cc)
10. Urine glucose
11. Five minute saliva sample, with and without paraffin stimulation
12. Clinical oral photo series
13. Optional pharmacokinetic study
14. Hemoglobin A1C level
3.3.3
End of  Treatment Evaluation 
The following tests and procedures should be performed at the end of scheduled open label 
treatment period (28 d.) or, if possible, at the time a patient comes off treatment regardless of the 
reason: 
1. Optional History and Physical Examination
2. Assessment of oral GVHD using OMRS and oral cGVHD Clinical Scoring 
Instrument(Appendix A and Appendix B)
3. Numeric rating scales for (0 to 10) for oral pain, oral sensitivity, and oral dryness 
(Appendix C) 
4. Oral Global Scale (Appendix D) 
5. Painometer (POM) Assessment (Appendix E)
6. Oral Health Impact Profile- OHIP-14 (Appendix F)
7. Hematology: Complete blood counts, with differential and platelet count
8. Chemistries: Electrolytes (including sodium, potassium, chloride, CO2, calcium, 
phosphorus and magnesium), creatinine, BUN, glucose, SGOT, alkaline phosphatase, 
SGPT, bilirubin, PT/INR and PTT, HSV by PCR, cortisol level and TBNK panel.
9. Urine glucose
10. Research blood sample collection (18 cc)
11. Biopsy of buccal mucosa (4 mm punch) near baseline biopsy site
12. Five minute saliva sample, with and without paraffin stimulation
13. Clinical oral photo series
14. Short ACTH stimulation test
15. Adrenocorticotropic Hormone blood level
16. Hemoglobin A1C level
The goal of the day 28 biopsy is to assess microscopic and molecular changes associated with 
response (or lack thereof) to topical clobetasol for the purpose of potential cGVHD marker 
development. The primary response variable in this study is clinical grading of cGVHD. 


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3.3.4
Follow-up Evaluation 
The following tests and procedures should be performed at the end of the scheduled follow-up 
period (28 days post end of open label treatment period):
1. Optional History and Physical Examination
2. Chronic GVHD NIH organ staging
3. Assessment of oral GVHD using OMRS and oral cGVHD Clinical Scoring Instrument 
(Appendix A and Appendix B)
4. Numeric rating scales for (0 to 10) for oral pain, oral sensitivity, and oral dryness 
(Appendix C) 
5. Oral Global Scale (Appendix D) 
6. Painometer (POM) Assessment (Appendix E)
7. Oral Health Impact Profile- OHIP-14 (Appendix F)
8. Hematology: Complete blood counts, with differential and platelet count
9. Chemistries: Electrolytes (including sodium, potassium, chloride, CO2, calcium, 
phosphorus and magnesium), creatinine, BUN, glucose, SGOT, alkaline phosphatase, 
SGPT, bilirubin, PT/INR and PTT, cortisol level and TBNK panel.
10. Research blood sample collection (18cc)
11. Five minute saliva sample, with and without paraffin stimulation
12. Clinical oral photo series
13. Hemoglobin A1C level
14. Short ACTH stimulation test (Per PI discretion at day 56 or day 70 depending on subject 
randomization group) if there is concern for endocrine side-effects)
3.4
DOSE MODIFICATIONS 
No dose modifications are expected during this study. 
3.5
QUESTIONNAIRES 
3.5.1
Oral Mucositis Rating Scale
Description. The OMRS was constructed through the careful selection of clinical descriptors of 
oral mucosal changes related to GVHD and also related to BMT16. The OMRS was developed 
“…as a research tool for the comprehensive measurement of a broad range of oral tissue changes 
associated with cancer therapy” and “to develop an index for assessing acute oral mucositis after 
BMT36”. Preliminary development of this scale was performed in studies of chemotherapy 
toxicities and cGVHD and use of the tool allowed “expedient, efficient, detailed, and 
reproducible classification of oral changes36”.  The OMRS was used by Schubert, Sullivan, 
Morton et al. (1984) with 60 patients, who were 180 to 500 days after ABMT, to determine if 
late oral abnormalities were associated with the presence of cGVHD. Oral manifestations found 
to be most strongly associated with cGVHD included atrophy and erythema or lichenoid lesions 
of the buccal and labial mucosa and oral pain16.


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The tool divides the oral cavity into seven distinct anatomic areas: lips; labial and buccal 
mucosa; tongue; floor of mouth; palate; and attached gingiva. Each site is further divided into 
upper and lower (lips and labial mucosa), right and left (buccal mucosa), dorsal, ventral, and 
lateral (tongue), and hard and soft (palate). Descriptive categories include atrophy, 
pseudomembrane, erythema, hyperkeratosis, lichenoid, ulceration, and edema. Erythema, 
atrophy, hyperkeratosis, lichenoid, and edema are rated on scales of 0 to 3 (0 = normal/no 
change, 1 = mild, 2 = moderate, and 3 = severe change). Ulceration and pseudomembrane are 
rated on scores based on estimated surface area involved (0 = none, 1 =  0 but ≤ 1cm2, 2 =  
1cm2 but ≤ 2cm2, and 3 =  2cm2). The item pool consists of 91 items for 13 areas of the mouth 
that are assessed for several types of changes. The score is obtained by summing the scores of all 
items on the OMRS to yield a total possible score ranging from 0 to 273.
3.5.2
Painometer 
Description. Pain will be self-assessed by subjects using a paper version of the Painometer , 
contains a visual analogue scale (VAS) to rate overall intensity of pain and a list of 14 sensory 
and 11 affective pain descriptors ranked by intensity values from 1 to 5 (POM-WDS)37. The 
POM is capable of capturing the multidimensionality of the pain experience. Patients are asked 
to look at the list of sensory and affective words (POM-WDS) and select sensory and affective 
words that describe their pain. The weighted scores assigned to the selected words are added 
together to obtain a pain intensity score for the sensory as well as for the affective components. 
The weights assigned to the words are derived from research involving people with various 
ethnic and educational backgrounds37.  A vertical 10cm VAS (POM-VAS) is located on the 
POM with a centimeter scale allowing for overall pain intensity quantification. The POM-VAS is 
anchored with the words “no pain” located at the bottom of the scale and the words “worst 
possible pain” located at the top representing the extreme limits of pain. The patient is requested 
to circle a number indicating the amount of pain being experienced at the present time. The pain 
intensity score for the POM-VAS has a range of 1 to 10.
The affective and sensory pain scores are obtained by adding all of the respective intensity 
values. The range of possible sensory scores is from 0 to 48 and the range of possible affective 
scores is from 0 to 37. The sensory and affective scores may be added together to obtain the total 
pain intensity score for the POM-WDS, which may range from 0 to 85. 
In a psychometric study that employed correlational and comparative designs, the test-retest 
reliability and the concurrent and construct validity of the POM-VAS and the POM-WDS were 
assessed in 279 patients with acute or chronic pain37. The following time intervals were used for 
data collection using the POM: labor pain- admitted to labor and delivery, cervical dilation at 2 
to 4 cm x 2 with a 10-minute interval, cervical dilation at 5 to 7 cm and again at 8 to 10 cm, 
immediately prior to epidural block, and another 30 minutes after epidural block; post-operative 
pain-4 hours after the patients were admitted to the recovery room after surgery, each time the 
patient complained of pain, and routinely every 4 hours, prior to and after pain medication was 
given; chronic pain in RA patients on two occasions with a 2-hour interval between each pain 
measurement. Relatively high correlations were found between initial and repeat intensity ratings 
for the POM-VAS (r = .88, p < .001). Test-retest reliability of the POM-WDS ranged from .68 (p 
< .001) to .73 (p < .001) in RA patients, from .80 (p < .001) to 0.84 (p < .001) in labor patients, 
and from .70 (p < .001) to .74 (p < .001) in postoperative patients. Concurrent validity of the 
POM-WDS was supported by correlations between the POM-WDS and the McGill Pain 
Questionnaire (r = .069, p < .001) and POM-VAS (r  = .85, p< .001). Construct validity evidence 


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was gathered for the POM by showing that pain scores decreased significantly for POM-WDS (t 
= 5.53, p < .001), and POM-VAS (t = 6.18, p < .001) after the patients had received pain 
medication. A correlation between the traditional paper-and-pencil VAS and the POM-VAS was 
reported to be 0.98 (p < .001).
A modified Gaston-Johansson Painometer Assessment Sheet will be used to record the following 
data regarding stomatitis-related acute oropharyngeal pain experienced at rest and with 
swallowing: intensity; sensory and affective descriptive words from the POM-WDS; duration 
(continuous or periodic). 
3.5.3
Visual analogue scales for subject reported oral pain, oral sensitivity, and oral 
dryness
Subject reported oral pain, oral sensitivity, and oral dryness will be captured through use of a 0 
to 10 visual analogue scale (VAS) anchored with the words “no pain” to “worst pain” (Appendix 
C). We will use this VAS to evaluate these symptoms over treatment.
3.5.4
Global Rating Scale (perception of changes in oral condition)
At the interim and final visits, we will assess patients’ perceptions of the changes in the oral 
condition on a 5 item scale (worsened greatly, worsened somewhat, stayed the same, improved 
somewhat, improved greatly). The data will be correlated with the results from the numerical 
scoring systems to assess internal validity (Appendix D).
3.5.5
Oral Health Impact Profile–14
Oral Health Impact Profile–14 (OHIP-14, Appendix F) is a 14 item questionnaire developed to 
assess the state of oral health as perceived by a patient 38,39. Increased use of patient centered 
outcome measures has been advocated in the recent years. Patient centered outcome measures 
complement objective measures to provide a more complete picture of the impact of disease and 
treatment. OHIP-14 has been used in oral disease studies including oral lichen planus (a 
dermatological condition with manifestation similar to chronic oral GVHD). It has been shown 
to have high validity and reliability, and to be sensitive to treatment effects.
3.6
STUDY CALENDAR 
See also Appendix G. 
3.6.1
Compliance
Subject adherence to the trial interventions will be estimated by measuring the volume of the 
remaining study medication at follow up appointments, study medication use diaries (Appendix 
I) and compliance with clinic visits. Correct use of the study medication will be demonstrated at 
the beginning of the study. Reinforcement such as periodic phone calls by the study nurses will 
be used to maximize compliance.
3.7
DURATION OF FOLLOW- UP
Patients will be followed for 6 months total after discontinuing clobetasol oral rinse treatment 
every 3 months by telephone or in-person interview to assess duration of treatment response, 
recurrence of oral GVHD, survival and resolution of any side-effects.  Patients removed from 
treatment for unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event.  Once there is resolution of adverse events, patients will be removed from study.  
Patients who become unavailable within 6 months of completing treatment will not be followed 


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beyond the terminating event.  Only adverse events at least possibly related to study treatment 
will be collected during the follow-up period.
3.8
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.
3.8.1
Criteria for removal from protocol therapy
•
Progressive oral cGVHD after 2 weeks of treatment with clobetasol:  Patients will be 
unblinded at the time of GVHD progression and taken off treatment.
•
Unacceptable toxicity: we do not expect significant adverse events associated with the 
study medication or procedures. In the event of unexpected toxicity attributable to the 
study drug (grade 2 or greater) patients will be taken off treatment.
•
Change in the systemic immunosuppressive therapy while in the 2 week blinded phase 
•
Patient requests to stop therapy
•
Investigator discretion
3.8.2
Off-Study Criteria
•
Progressive oral cGVHD after 2 weeks of treatment with clobetasol:  Patients will be 
unblinded at the time of GVHD progression and taken off study as defined in Section 
6.3.1.
•
Unacceptable toxicity: we do not expect significant adverse events associated with the 
study medication or procedures. In the event of unexpected toxicity attributable to the 
study drug (grade 2 or greater) patients will be taken off study.
•
Patients unable to comply with study requirements will come off study.  This includes 
>75% non-compliance with study oral rinse usage.
•
Patients will come off study upon completion of follow-up Period (6 months after 
discontinuing clobetasol oral rinse treatment).
•
Death
•
Patient lost to follow up
•
Patient withdrawal from follow-up period
•
Change in the systemic immunosuppressive therapy while in the 2 week blinded phase 
•
PI decision to end this study 
3.8.3
Off-Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
must be completed and sent via encrypted email to:  NCI Central Registration Office (HOIS) 
ncicentralregistration-l@mail.nih.gov. 


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4
SUPPORTIVE CARE
Supportive care will be provided as specified in the primary transplant protocol and may include 
standard infection prophylaxis, anti-emetics, CMV surveillance at follow-up, topical care 
including topical analgesics, physical therapy, nutritional, and psychosocial support per NIH 
Blood & Marrow Consortium Supportive Care Guidelines 
(http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml).  Anti-emetic therapy should not 
include dexamethasone or other corticosteroids.
4.1
CONCURRENT THERAPY
Topical corticosteroid treatment is associated with few potential complications. The most 
common is overgrowth of oral candidiasis. Many but not all patients with chronic GVHD are 
already taking antifungal prophylaxis such as oral fluconazole.  Thus, to reduce incidence of oral 
candidiasis infection, patients will be asked to swish and spit once per day with nystatin 
(100,000u/ml) rinse, which is a standard preventative measure in high-risk patients. In case oral 
candidiasis develops, standard therapy according to NIH Consortium guidelines 
(http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml) with topical or systemic antifungals 
will be administered. 
The use of additional topical or systemic immunosuppression is prohibited during the study 
period and should be avoided if possible during the cross-over/extension period. Other topical 
agents (oral or skin), are prohibited with the exception of topical viscous lidocaine supplied by 
the NIH pharmacy. However, the change in the systemic immunosuppressive medications will 
not be allowed while on the blinded phase of the study and will be avoided, if possible, on the 
open label phase. If the absolute necessity develops to change or increase the systemic 
immunosuppressive therapy while in the blinded phase (e.g. for progressive GVHD in the organ 
sites other than oral cavity), patients will be taken off-study. Topical analgesic solution, available 
in NIH pharmacy (viscous lidocaine) will be permitted for control of oral discomfort. Other 
topical analgesics or mouthwashes will not be allowed. All interventions and medications 
dictated by the subject’s primary transplant protocol and clinical necessity, including systemic 
analgesics, will be permitted. Subjects will keep daily records reflecting topical and systemic 
analgesic use (Appendix I). Factors that can potentially confound the results (such as change in 
systemic steroids and other immunosuppressants) will be taken into consideration in the final 
statistical analysis.
5
BIOSPECIMEN COLLECTION
5.1
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES
5.1.1
Biologic Studies
Adult patients will have no more than 10.5 ml/kg or 550 ml peripheral blood, whichever is 
smaller, drawn in 8-week study period for research studies.  Children under 18 years of age will 
have no more than 9.5 ml/kg drawn in 8-week study period for research studies.  These 
guidelines are according to The Clinical Center Policy and Communications Bulletin M95-9.  
5.1.2
Additional Analyses
Note:  All samples will be sent for storage until analysis as detailed in Section 5.2 under 
appropriate storage conditions. 


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The oral tissue sections will be examined by a pathologist to assess oral cGVHD status.  Half of 
the biopsy will be formalin-fixed and sent to pathology for H&E staining.  One quarter will be 
flash frozen for analysis of gene expression, and one quarter will be frozen in OCT media, and 
both quarters will be stored until analysis. Immunohistochemical and PCR analysis will focus on 
characterization of cellular infiltrate, inflammatory cytokines, chemokines and protein mediators 
present at baseline and after clobetasol treatment.   
Whole saliva samples will be examined for evidence of disease-related biomarkers associated 
with cGVHD and clobetasol treatment.  Saliva will be collected in two 5-minute periods, one 
unstimulated and one stimulated with inert chewing (paraffin wax)32.  The volume collected will 
be compared and used to indicate gland function32.  
Blood samples will be used to measure cortisol levels and in a subset of samples, to determine 
blood levels of clobetasol during treatment with the mouth rinse formulation. Heparinized 
plasma and cells will be stored for potential analysis of inflammatory markers and cellularity 
associated with cGVHD and clobetasol treatment.  
One plasma sample (6 ml) will for LC-MS-MS analysis for clobetasol content.  
5.1.3
Pharmacokinetic Studies
To determine if and how much clobetasol is absorbed through the oral mucosa in these cGVHD 
patients, blood levels of clobetasol (6 ml sample) will be monitored at baseline, 2- and 4-weeks 
of clobetasol rinse use.  A random subset of half of the subjects (expected n=17) will be initially 
assessed for clobetasol plasma concentration. The determination of clobetasol concentrations in 
plasma samples, as well as the pharmacokinetic data analysis, will be performed by the Clinical 
Pharmacology Program. Samples will be analyzed using a validated LC-MS/MS method 
developed at the end of the trial.  If this data indicates a positive correlation between plasma 
clobetasol level and the other study measures of adrenosuppression (ACTH stimulation test, 
morning cortisol levels), or if we see either unexpected clinical or surrogate responses, or wide 
variability in levels, the analysis will be extended to all study patients.  
In a subset of consenting patients (up to n=10), the pharmacokinetics of clobetasol 0.05% mouth 
rinse will be assessed in a single session. After one two-minute oral rinse use, a venous blood 
sample will be collected in a 6 ml sodium heparin (green top) tube (BD Sodium Heparin 367878 
or 367879) at x0, x15-45 and x90-120 minutes. The plasma clobetasol levels from these samples 
will be used to analyze the basic pharmacokinetics of clobetasol 0.5% oral suspension. 
Participation in this part of the study is optional, and a separate section has been included on the 
consent form to allow patients to elect participation or not.  The first 10 patients who consent for 
the pharmacokinetics study will be selected for sampling.  
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. 
5.2.1
 Sample Procedures
The saliva, blood and tissue samples, collected for the purpose of research under IRB approved 
protocols of the Experimental Transplantation and Immunology Branch (ETIB)/Immune 


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Deficiency Cellular Therapy Program (IDCTP) will be stored and may be archived by the 
Biospecimen Processing Core (BPC), with the exception of blood samples for clobetasol 
analysis, which will be stored separately by the Clinical Pharmacology Program (CPP) until 
analysis. These will be barcoded, with data entered and stored in the Labmatrix utilized by the 
BPC. This is a secure program, with access to Labmatrix limited to defined Figg lab personnel, 
who are issued individual user accounts. Installation of Labmatrix is limited to computers 
specified by Dr. Figg. These computers all have a password restricted login screen. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.).
Barcoded samples are stored in locked freezers at -20 or -80°C (sera and plasma) or under liquid 
nitrogen (cells), or as otherwise applicable according to stability requirements. These freezers are 
located onsite in the BPC and offsite at NCI Frederick Central Repository Services in Frederick, 
MD. Visitors to the laboratory are required to be accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval.
5.2.2
Protocol Completion/Sample Destruction
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material. 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed or returned to the participant, if so requested. The PI will record any 
loss or unanticipated destruction of samples as a deviation. Reporting will be per the 
requirements of Section 7.2.
5.2.3
Sample Processing 
The determination of clobetasol concentrations in plasma samples, as well as the 
pharmacokinetic data analysis, will be performed by the Biospecimen Processing Core (BPC). A 
venous blood sample will be collected in an 8ml SST tube to be processed for serum. Record the 
date and exact time of draw on the tube. 
Please email Clinical Pharmacology Blood Processing Core (BPC) at 
NCIBloodcore@mail.nih.gov at least 24 hours before the scheduled research blood draw time 
and before patient treatment start times (the Friday before is preferred).
For sample pickup, page 102-11964. 


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For immediate help, call the main line for the BPC at (240) 760-6180. If no answer, call the main 
clinical pharmacology lab phone number at (240) 760-6190.
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
The samples will be processed, barcoded, and stored in Dr. Figg’s lab until requested by the 
investigator.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
6.1.1
Data Collection
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
Grade I AEs will only be recorded if they are deemed possibly, probably or definitely related to 
the study intervention.  
6.1.2
Eligibility Checklist
To be completed at study entry and forwarded to protocol research nurse. 
6.1.3
Protocol Deviations 
Any protocol deviations should be directly reported to the PI or LAI.
6.2
ORAL GVHD SEVERITY SCALES
The primary endpoint will be evaluated using expanded oral GVHD severity scale (Appendix 
A)33,34. There is no standard definition of response in this field. The definitions we will use in 
this pilot study to grade the level of response to study intervention will be as follows:
•
Progression (PD): defined as increase of 25% of initial score (rounded to the closest 
number) on the OMRS scale (Appendix A).
•
Partial Response (PR): defined as decrease of 25% of initial score (rounded to the 
closest number) on the OMRS scale (Appendix A).
•
Complete Response (CR): defined as score of 0 on the erythema and ulceration 
components of the OMRS scale (Appendix A).
•
Stable Disease (SD): does not meet criteria for progression or response.
For the purpose of OMRS instrument evaluation validation, we will also use a simplified scale 
developed for assessment of cGVHD response in the oral cavity (Appendix B)35. Scoring will be 
performed by investigators trained in assessment of oral cavity lesions. As part of the evaluation 


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of the scales, the results will be correlated with scores from symptom-oriented instruments and 
global scale.
6.3
RESPONSE CRITERIA
6.3.1
Response Criteria
The primary endpoint will be evaluated by using the OMRS (Appendix A). Secondary endpoints 
will be assessed using scales for oral discomfort and xerostomia, patient-reported global scale, 
and oral cavity specific quality of life questionnaire (OHIP-14).
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
7
NIH REPORTING REQUIREMENTS /  DATA AND SAFETY MONITORING 
PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem or present new information that 
might affect the willingness of participants to enroll or remain on the study will need to be 
reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease. 


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To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
Serious adverse events potentially attributable to the study medication or procedures will be 
reported to IRB. If trends are noted and/or risks warrant it, accrual will be interrupted and/or the 
protocol and/or consent document will be amended accordingly.
7.4.1
Principal Investigator/Research Team 
The clinical research team consisting of the PI, LAI, research nurse and data manager will meet 
on a weekly basis when patients are being actively treated on the trial to discuss each patient, 
data acquisition, approve CRFs for data entry and address any other logistical issues pertinent to 
the integrity of the protocol implementation and data management.
All data will be collected in a timely manner and reviewed by the Principal Investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
Section 7.2.1 will be submitted within the appropriate timelines. 
The Principal Investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The Principal Investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2)).
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death,
•
A life-threatening adverse event (see Section 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.


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o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
•
A congenital anomaly/birth defect
•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version [X].
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms: related or not 
related. 
•
Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site Principal Investigator or sub-investigator. AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship. AEs will be followed through resolution.
SAEs will be:
•
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 


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the site Principal Investigator or sub-investigator.
•
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.
•
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site Principal Investigator or sub-investigator.
For timeframe of recording adverse events, please refer to Section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in Section 8.4. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in Section 8.4.
All SAE reporting must include the elements described in Section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and 
instructions can be found at: https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-
Communications/SitePages/Forms-and-Instructions.aspx?csf=1&web=1&e=uWBXtI
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.
8.4
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32. 
8.5
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 


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deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations.
9
CLINICAL MONITORING 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through 
independent verification of study data with source documentation focusing on:
•
Informed consent process
•
Eligibility confirmation
•
Drug administration and accountability
•
Adverse events monitoring
•
Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
10 STATISTICAL CONSIDERATIONS
10.1 SUBJECT ACCRUAL
Subjects of both sexes, from all racial and ethnic groups are eligible for this trial if they meet the 
criteria outlined in Section 2.1. To date, there is no information that suggests differences in drug 
metabolism or disease response among racial or ethnic groups or between the two sexes, 
indicating that results of the trial will be applicable to all groups. Efforts will be made to extend 
the accrual to a representative population, but achievement of a fully representative subject 
population is unlikely in a pilot study with limited accrual.
10.2 STATISTICAL CONSIDERATIONS
The primary objective of this randomized pilot study is to determine if the use of clobetasol may 
result in improvement or stabilization in outcomes in patients with oral chronic GVHD.  An 
important secondary objective is to preliminarily validate and explore the utility of the response 
measurement instruments.
Patients with oral cGVHD meeting the eligibility criteria will be separately randomized to either 
1 month of clobetasol 0.05% oral rinse or placebo; there will not be separate accrual goals for 
each age group or type of underlying disease. The patients will be followed every 2 weeks for 1 
month for their primary endpoint, and once 1 month after completion of study agents.


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The primary endpoint will be the change in OMRS score (Appendix A) after 1 month of 
clobetasol 0.05% oral rinse compared to baseline. We will consider a 25% or larger decrease in 
the score to be clinically significant and a ‘response’ for the purpose of this study.  As this is a 
pilot study, the association between this level of change and other scales will also be assessed to 
determine if this is a meaningful measure to use in future trials or if modification is warranted. 
Thus, this study will be a pilot for the determination of a meaningful response as well for 
determining if the agent tested may be beneficial.
After the first 2 weeks of clobetasol treatment, patients can be removed from study if oral disease 
progression is documented. Patients who are taken off study for oral disease progression will be 
counted as non-responders at the time of the final analysis.  Patients taken off study for non-
compliance, specifically >75% non-use of the oral rinse, will not be included in the data analysis
The patients enrolled on this study may be a very heterogeneous group with respect to prior 
treatments, extent of disease, etc. Patients taken off study for reasons unrelated to the primary 
outcome will be classified as non-responders and analyzed accordingly. The results will be 
interpreted in the context of a pilot study with potential limitations noted.
This study will aim to enroll a total of 34 evaluable patients randomized in a 1:1 fashion (17 per 
arm) to receive clobetasol rinse or placebo.  The initial phase of the study will involve two weeks 
of either clobetasol rinse or placebo. At the end of the initial 2 weeks, patients receiving placebo 
will receive 28 days of clobetasol while those receiving clobetasol initially will receive an 
additional 14 days of clobetasol. Thus, each group will receive 28 days of clobetasol following 
either a 14 day placebo or immediately after randomization.
Patients will be randomized with a single stratification factor to try to ensure a balanced 
distribution among those getting placebo or not initially: being identified as having a high 
intensity of immunosuppression (2 or more agents/modalities ± prednisone≥0.5 mg/kg/day) vs. 
no or a lesser intensity of systemic immunosuppression according to the Intensity of 
Immunosuppression Scale 10.  This scale was developed using expert opinion, and has been 
preliminarily demonstrated to have predictive validity as measure of the intensity of systemic 
immunosuppression10,40.  A low intensity regimen is defined as treatment with prednisone alone 
at a dose of less than 0.5 mg per kilogram per day.  Moderately intense regimens include single 
agent prednisone at a dose greater than or equal to 0.5 mg per kilogram per day, and/or any other 
single agent or modality.  Regimens comprised of two or more agents or modalities (+/- 
prednisone greater than or equal to 0.5 mg per kilogram per day), are categorized as highly 
intensive systemic immunosuppression. When scoring the intensity of systemic 
immunosuppression, the use of topical agents is not captured. 
The primary endpoint is the fraction of subjects who experience a 25% improvement in their 
OMRS compared to their own baseline. The fraction will be estimated with a two-tailed 95% 
confidence interval as the primary outcome. This will be done using all 34 patients together 
provided that the changes from baseline to day 28 for the two groups are sufficiently similar. A 
formal test will be performed assess their comparability. This will be determined conservatively, 
by obtaining the actual difference in the individual OMRS for each patient at baseline (day 0 for 
initial clobetasol and day 14 for those initially given placebo) vs. the value after day 28 of 
clobetasol and comparing those differences between the two randomized groups using a two-
tailed Wilcoxon rank sum test. If the p-value for that comparison is >0.30, then the two groups 
will be considered sufficiently similar to allow pooling of the results and to report a combined 


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fraction of patients who have a ‘response’ to 28 days of clobetasol. In this case 34 patients will 
be sufficient to allow the proportion of patients with a response of 75% or more to have a two-
sided 95% confidence interval of +/- 15% or less, which will be considered sufficiently precise. 
Fractions of responses <75% would have slightly wider confidence interval widths.
An important secondary endpoint is to compare the changes from day 0 in the OMRS until day 
14 between those who only receive placebo by that point vs. those who received clobetasol. This 
evaluation will be done both with respect to the fraction with a response by 2 weeks, as well as 
comparing the actual changes in OMRS from day 0 to day 14.
By enrolling 17 patients per arm, a 0.10 alpha level one-tailed Fisher’s exact test will have 80% 
power to detect a difference between a potential 75% of patients having a 25% or greater 
decrease in severity score on the clobetasol arm and about half that amount, 35%, on the placebo 
arm. A one-tailed test is sufficient for this secondary objective in this study since we will not 
expect clobetasol to be associated with a lower fraction of patients with benefit compared to 
placebo and because this is intended to be a pilot study to determine if a potential trend of 
magnitudes anticipated, but not necessarily a statistically significant gain, may be detected. 
Should very promising results be obtained, then a subsequent trial could be conducted to build 
upon and further confirm the benefit noted. 
A comparison of the actual levels of changes in the oral severity score between the arms will also 
be done using a Wilcoxon rank sum test as a secondary analysis. With 17 patients per arm, there 
is approximately 80% power to detect a difference between the arms in the changes from 
baseline to day 14 equal to one standard deviation of the change (effect size=1.0), using a two-
tailed Wilcoxon rank sum test with a 0.05 significance level. 
All patients will be placed on clobetasol for one month, whether following a two-week period 
with placebo or beginning at the time of randomization. In addition, comparisons between actual 
oral severity scores at the beginning of this period and one month later will be made using a 
paired t-test, or using a Wilcoxon signed rank test if the differences are not normally distributed 
(p<0.05 by Shapiro-Wilks test). These results will be evaluated separately according to the 
randomized treatment arm as well as overall if the changes in score according to the randomized 
assignments are similar (p>0.30 for Wilcoxon rank sum test comparing changes in scores 
between the two arms over the one month clobetasol period). Although this would also be 
considered a secondary evaluation, there would be 82% power to identify a 0.75 standard 
deviation change to be significant with a two-tailed 0.05 alpha level paired t-test if all 17 patients 
are available within each arm for this comparison.
Patients will undergo oral mucosa biopsies at the beginning of the study, and many are expected 
to have biopsies at the end of 28 days of treatment. Although required, these biopsies may not be 
obtained on all patients, and the number of patients with paired data will determine the 
differences in immunologic parameters from the biopsies that can be detected. For example, if 
there were 20 patients with paired biopsy data and 5 immunologic parameters of interest, each 
one would have 93% power to detect a change with an effect size of 1.0, with a very 
conservative two-tailed 0.01 significance level, to account for multiple comparisons. Fewer than 
20 patients with paired biopsies would reduce the power accordingly, but since this is a 
secondary objective, the results of these tests will be presented in the context of an exploratory 
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At a rate of 1 patient per 2 weeks accrual, approximately 16 to 20 months will be required to 
meet the accrual goal of 34 evaluable patients. To allow for a small number of inevaluable 
patients, the accrual ceiling will be set at 40 patients.
11 HUMAN SUBJECTS PROTECTIONS 
11.1 RATIONALE FOR SUBJECT SELECTION
No subjects will be excluded from participation based on sex, race or ethnicity. The study will be 
open to all subjects who satisfy the inclusion criteria and provide an informed consent to the 
protocol. From previous transplant protocol recruitment patterns at NIH we expect that over 80% 
of patients in this study will be adults over 18.
Recruitment: Subjects will be primarily recruited from NIH Clinical Center hematopoietic stem 
cell transplant clinics but could be referred from the outside institutions.
11.2 PARTICIPATION OF CHILDREN
This study will be limited to subjects aged 12 or older. Given the preliminary nature of the study 
and requirement for precise compliance with the instructions to minimize swallowing and 
systemic absorption of clobetasol, children < 15 who are less likely to comply will be excluded. 
In addition, due to the risk of swallowing, oral rinses such as topical fluorides are not 
recommended for young children.
11.3 PARTICIPATION OF NIH SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 11.5), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed.
11.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
11.4.1 Related to Clobetasol
The side-effects of topical steroids are usually limited to Candida (yeast) infection. This is 
relatively uncommon in our patient population (<5%), easily treatable and does not require 
discontinuation of the treatment. Low levels of topical steroids are absorbed through the oral 
mucosa, but the exact rate is not known.  While adrenal suppression is very rare with topically 
applied corticosteroids, it is physiologically possible. Cases of adrenal suppression following 
topically-applied steroid creams have been reported with long-term use on extensive body 
surface primarily in young children. In other reports, it was difficult to determine if there was 
adrenal suppression. Symptoms of adrenal suppression are non-specific and include fatigue, 


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nausea and abdominal discomfort. Since these symptoms are extremely common in the general 
hospital population, routine monitoring in the context of this study is not indicated. In this study, 
blood pressure and serum cortisol will be monitored at every visit, and adrenal function will be 
assessed at baseline and at the end of the study. Given the short duration of this study, we do not 
expect significant side effects. We will use blood pressure, urine glucose, blood cortisol, and a 
baseline and repeat ACTH stimulation test at day 28 of clobetasol oral rinse use to monitor 
systemic steroid exposure.  In the highly unlikely event of significant adrenal suppression as 
assessed by repeat ACTH stimulation test, Clinical Center Endocrinology Service will be 
consulted and subject will be placed on the standard oral hydrocortisone taper.  
Topical steroid treatment may allow for local reactivation of viral infections, including but not 
limited to HSV.  Patients will be monitored for oral HSV by PCR at the baseline and Day 28 
visits.
11.4.2 Related to Blood Collection
Minor complications including bleeding, pain, and hematoma formation at the site of blood 
draws or infections may rarely occur.
11.4.3 Related to Tissue Biopsy
Oral mucosal punch biopsy is a minor surgical procedure that may be associated with temporary 
bleeding, hematoma at the site, local infection and postoperative discomfort. These risks are 
small (generally <5%) and transient.
11.4.4 Related to Pregnancy
Many post-transplant patients are not expected to become pregnant since ovarian failure is 
common in women after transplant. Women who are able to become pregnant will be expected to 
use an effective method of birth control. Although clobetasol will be applied topically in the 
mouth in this study, there is no way of knowing how much medication will be absorbed into the 
bloodstream. Strong corticosteroids have caused birth defects in animals.
11.5 RISKS/BENEFITS ANALYSIS
11.5.1 For Adult Subjects
Post-transplant patients require monitoring for post procedure complications.  Although this 
monitoring represents a minor increase over minimal risk monitoring is medically indicated. The 
risks of participating in this trial are limited to side-effects of clobetasol and the risks of standard 
diagnostic procedures (oral mucosal biopsy, plasma collection). Subjects may receive direct 
health benefits from participation in this protocol due to additional clinical monitoring such as 
thorough oral examination for oral GVHD. In addition, subjects on the active medication arm 
may receive direct benefit from treatment of oral GVHD. 
This companion protocol to the primary transplant protocol requires the collection of an 
additional blood sample for research purposes only. Samples will be collected during sample 
collection procedures that are part of their routine standard therapy.
Therefore this study meets the DHHS Regulations 45 CFR § 46. criteria for “more than minimal 
risk to subjects with prospect of direct benefit to individual subjects”.


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11.5.2 For Pediatric Subjects
This study meets the DHHS Regulations as follows:
“The risk represents a minor increase over minimal risk”. The risks of participating in this trial 
are limited to side-effects of clobetasol and the risks of standard diagnostic procedures (oral 
mucosal biopsy, plasma collection). Post-transplant patients require monitoring for post 
procedure complications.  Although this represents a minor increase over minimal risk, said 
monitoring is medically indicated.  This companion protocol to the primary transplant protocol 
requires the collection of additional blood samples for research purposes only.  Oral biopsy is 
optional for the pediatric patients and will be performed only for clinical indications to rule out 
alternative diagnoses at enrollment and part of the tissue will be saved for research purposes. 
“The intervention or procedure presents experiences to subjects that are reasonably 
commensurate with those inherent in their actual or expected medical, dental, psychological, 
social, or educational situations.”  Post-transplant patients who enroll in this protocol are 
familiar with blood collection and hospital procedures due to their frequent need for 
monitoring for their primary disease and for post-transplant complications. The monitoring 
that will be done is in line with the monitoring that would be done post-transplant.
“The intervention or procedure is likely to yield generalizable knowledge about the subjects’ 
disorder or condition which is of vital importance for the understanding or amelioration of 
the subjects’ disorder or condition.”  The generalizable knowledge would include the 
collection of information about the features of their post-transplant complication and the 
possible discovery of an effective treatment of oral GVHD for pediatric patients in the future. 
Subjects may receive direct health benefits from participation in this protocol due to 
additional clinical monitoring such as thorough oral examination for oral GVHD. In addition, 
subjects on the active medication arm may receive direct benefit from prevention of oral 
GVHD.
“Adequate provisions are made for soliciting assent of the children and permission of the 
parent or guardian, as set forth in § 46.408.”  Only adult patients or pediatric patients via 
their guardians who satisfy the previously described inclusion/exclusion criteria and 
understand and have given informed consent and assent may enroll in the protocol.  Some of 
the participants in this protocol will be children (less than 18 years of age).  In these cases, 
full and informed consent must be obtained from the parent or the legal guardian and an 
assent obtained from the child.  If the child does not wish to participate in the study, then 
enrollment of the child into the study is prohibited.  Importantly, any subject who enrolls in 
the protocol has the option of withdrawing from the protocol at any time.
Therefore, the protocol meets 45 CFR § 46.406 criteria for “a minor increase over minimal risk 
to subjects with prospect of direct benefit to individual subjects”.
11.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION
The investigational nature and research objectives of this trial, the procedure and its attendant 
risks and discomforts will be carefully explained to the patient or the patient’s parents or 
guardian if he/she is a child, and a signed informed consent document will be obtained prior to 
entry onto the study.  The potential subject will be educated regarding the nature of the 
condition, proposed intervention, and outcome measures. Study subjects will be informed that 
participation is entirely voluntary and that withdrawal from the study can be made at any time 


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without penalty of benefits to which they may be entitled. Informed consent will be obtained by 
Dr. Jacqueline Mays, Dr. Steven Pavletic or an associate investigator of this protocol.
Where deemed appropriate by the clinician and the child’s parent(s) or guardian, the child will 
also be included in all discussions about the trial and age-appropriate language will be used to 
describe the procedures and tests involved in this study, along with the risks, discomforts and 
benefits of participation.  Written assent will not be obtained from children as the study holds out 
the prospect of direct benefit that is important to the health and well-being of the child and is 
available only in the context of the research. Verbal assent will be obtained as appropriate for 
children ages 12-17 and the parent or guardian will sign the designated line on the informed 
consent attesting to the fact that the child has given assent.  The consent/assent process will be 
documented in the child’s medical record, including the assessment of the child’s ability to 
provide assent (verbal versus written) as applicable. All children will be contacted after they 
have reached the age of 18 to determine whether they wish to continue on the trial and informed 
consent will be obtained from them at that time.
At any time during participation in the protocol that new information becomes available relating 
to risks, adverse events, or toxicities, this information will be provided orally or in writing to all 
enrolled or prospective patient participants.  Documentation will be provided to the IRB and if 
necessary the informed consent amended to reflect relevant information.
The investigators are requesting a waiver from the IRB to allow only one parent to sign the 
informed consent to enter a child on the protocol. Because many patients must travel to the NIH 
from long distances at substantial expense, requiring both parents to be present for the consent 
process could be a financial hardship for many families. When guardianship status of the child is 
uncertain, a social worker will be asked to investigate and, if necessary, seek documentation of 
custody status.
In situations where there is joint custody of a child, both parents must sign consent. If only one 
parent can be present at NIH, the other parent’s consent can be obtained by telephone via the 
procedure described in Section 11.6.1.  
11.6.1 Telephone re-consent procedure
Re-consent on this study may be obtained via telephone according to the following procedure: 
the informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent.  The original informed consent document will be sent back to the 
consenting investigator who will sign and date the consent form with the date the consent was 
obtained via telephone.  A fully executed copy will be returned via mail for the subject’s records.  
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record.
11.6.2 Informed consent of Spanish speaking subjects
We anticipate the enrollment of Spanish speaking research participants into our study. The IRB 
approved full consent document will be translated into that language in accordance with the 
Clinical MAS Policy M77-2. 


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11.6.3 Short form consent process for other non-English speaking patients
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OSHRP SOP 12, and 45 CFR 46.117 (b) (2).  The summary that will be used is 
the English version of the extant IRB approved consent document.  Signed copies of both the 
English version of the consent and the translated short form will be given to the subject or their 
legally authorized representative and the signed original will be filed in the medical record.
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible). 
We request prospective IRB approval of the use of the short form process and will notify the IRB 
at the time of continuing review of the frequency of the use of the Short Form.
12 REGULATORY AND OPERATIONAL CONSIDERATIONS 
12.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension. Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping 
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).


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12.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted, and data are generated, and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council for 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices [GMP]). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
12.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership in conjunction with the National Cancer Institute has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest.
12.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.


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Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the NCI CCR. This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by the clinical site(s) and by NCI CCR research staff will be secured 
and password protected. At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
13 PHARMACEUTICAL INFORMATION  
13.1 CLOBETASOL ORAL RINSE
Other: Clobetatasol propionate, Temovate
Classification: Corticosteroid
Action: Anti-inflammatory and Immunosuppressive. Clobetasol is a high-potency corticosteroid 
with mainly glucocorticoid activity; 
Supply / Availability: Commercially available in powder form (Spectrum Chemicals). The 
commercial supply will be prepared as a 0.05% oral rinse and labeled as study drug specific to 
this protocol by the Pharmaceutical Development Section of the NIH CC Pharmacy.
Product description: Clobetasol oral rinse 0.05% (500mcg/mL) is a clear, colorless solution 
Active Ingredient: clobetasol propionate
Preparation: The commercially available clobetasol powder will be dissolved in the diluent, 
hydroxypropylated cyclodextrin in water, then methylparaben, propylparaben and ascorbic acid 
will be added.  Oral rinse will be repackaged in an 8 ounce amber bottle and relabeled as study 
drug for the purposes of this study and to allow blinding of the patient, clinical staff, and 
investigators.
Storage: Store at room temperature (20o to 25oC (68o to 77oF) (see USP controlled room 
temperature.
Administration: Rinse oral cavity for 2 minutes and spit out. Use 3 times daily: after breakfast, 
lunch and before bedtime. DO NOT SWALLOW. Do not eat or drink for 30 minutes after use. 
Dose: 10 mL (5mg)
Toxicities: see Section 6.4.


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13.2 STUDY PLACEBO ORAL RINSE
Supply: The placebo oral rinse will be prepared by the Pharmaceutical Development Section of 
the NIH Clinical Center Pharmacy and labeled as study supply for purposes of this study and to 
allow blinding of patients, clinical staff, and investigators.
Product Description: 
The 
placebo 
oral 
rinse 
contains 
the 
following 
ingredients: 
hydroxypropylated cyclodextrin, methylparaben, propylparaben, ascorbic acid, quinine, and 
water for injection. 
Storage: Store at room temperature (20o to 25oC (68o to 77oF) (see USP controlled room 
temperature.
Administration: Rinse oral cavity for 2 minutes and spit out. Use 3 times daily: after breakfast, 
lunch and before bedtime. DO NOT SWALLOW. Do not eat or drink for 30 minutes after use. 
Dose: 10 mL


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Flowers ME, Parker PM, Johnston LJ, et al. Comparison of chronic graft-versus-host 
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Imanguli MM, Pavletic SZ, Guadagnini JP, Brahim JS, Atkinson JC. Chronic graft versus 
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Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood 
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Imanguli MM, Swaim WD, League SC, Gress RE, Pavletic SZ, Hakim FT. Increased T-
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Greinix HT, Loddenkemper C, Pavletic SZ, et al. Diagnosis and staging of chronic graft-
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Wolff D, Gerbitz A, Ayuk F, et al. Consensus conference on clinical practice in chronic 
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Mitchell SA, Leidy NK, Mooney KH, et al. Determinants of functional performance in 
long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-
versus-host disease (cGVHD). Bone Marrow Transplant. 2009;45:762-769.
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Martires KJ, Baird K, Steinberg SM, et al. Sclerotic-type chronic GVHD of the skin: 
clinical risk factors, laboratory markers, and burden of disease. Blood. 2011;118:4250-4257.
12.
Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. 
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Schubert MM, Correa ME. Oral graft-versus-host disease. Dent Clin North Am. 
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14.
Sullivan KM, Shulman HM, Storb R, et al. Chronic graft-versus-host disease in 52 
patients: adverse natural course and successful treatment with combination immunosuppression. 
Blood. 1981;57:267-276.


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15.
Jacobsohn DA, Margolis J, Doherty J, Anders V, Vogelsang GB. Weight loss and 
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Schubert MM, Sullivan KM, Morton TH, et al. Oral manifestations of chronic graft-v-
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18.
Lenssen P, Sherry ME, Cheney CL, et al. Prevalence of nutrition-related problems among 
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Fall-Dickson JM, Mitchell SA, Marden S, et al. Oral symptom intensity, health-related 
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20.
Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone marrow transplantation. J 
Clin Oncol. 2001;19:464-471.
21.
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22.
Bacigalupo A, Palandri F. Management of acute graft versus host disease (GvHD). 
Hematol J. 2004;5:189-196.
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Gonzalez-Moles MA, Morales P, Rodriguez-Archilla A, Isabel IR, Gonzalez-Moles S. 
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Conrotto D, Carbone M, Carrozzo M, et al. Ciclosporin vs. clobetasol in the topical 
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29.
Carbone M, Conrotto D, Carrozzo M, Broccoletti R, Gandolfo S, Scully C. Topical 
corticosteroids in association with miconazole and chlorhexidine in the long-term management 
of atrophic-erosive oral lichen planus: a placebo-controlled and comparative study between 
clobetasol and fluocinonide. Oral Dis. 1999;5:44-49.


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Pramick M, Whitmore SE. Cushing's syndrome caused by mucosal corticosteroid 
therapy. Int J Dermatol. 2009;48:100-101.
31.
Gonzalez-Moles MA, Scully C. HPA-suppressive effects of aqueous clobetasol 
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33.
Piboonniyom SO, Treister N, Pitiphat W, Woo SB. Scoring system for monitoring oral 
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treatment of oral lichen planus with topical fluocinolone acetonide: a 2-year follow-up. J Oral 
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Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in chronic graft-
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Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group 
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Schubert MM, Williams BE, Lloid ME, Donaldson G, Chapko MK. Clinical assessment 
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Hegarty AM, McGrath C, Hodgson TA, Porter SR. Patient-centred outcome measures in 
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Grkovic L, Baird K, Steinberg SM, et al. Clinical laboratory markers of inflammation as 
determinants of chronic graft-versus-host disease activity and NIH global severity. Leukemia.


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15 APPENDICES
15.1 APPENDIX A: ORAL MUCOSITIS RATING SCALE (OMRS)


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15.2 APPENDIX B: ORAL CGVHD CLINICAL SCORING INSTRUMENT


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15.3 APPENDIX C: NUMERIC RATING SCALES (0-10) FOR ORAL PAIN, SENSITIVITY, AND 
DRYNESS 
ORAL PAIN
On a 0 to 10 scale, how PAINFUL is your mouth now? Please circle the number.
0
1
2
3
4
5
6
7
8
9
10
No pain
Worst pain 
ORAL SENSITIVITY
On a 0 to 10 scale, how SENSITIVE is your mouth now? Please circle the number.
0
1
2
3
4
5
6
7
8
9
10
No sensitivity
            Worst 
sensitivity
ORAL DRYNESS
On a 0 to 10 scale, how DRY is your mouth NOW? Please circle the number.
0
1
2
3
4
5
6
7
8
9
10
No dryness
Worst dryness


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15.4 APPENDIX D: GLOBAL SCALE
Compared to TWO WEEKS ago, what is the overall condition of your mouth? Please circle.
Much worse
A little worse
Same
A little better
Much better


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15.5 APPENDIX E: PAINOMETER (POM) ASSESSMENT SHEET
______________________________________________________________________________________
Baseline                 Date: _____/______/_____       Time: _________   Subject Study Number:  _______
______________________________________________________________________________________
I
INSTRUCTIONS: Ask the participant to choose words from the Sensory pain intensity list and the 
Affective pain intensity list below to describe present oral pain- Circle the chosen letter/word and 
number/word from the lists.
SENSORY
        AFFECTIVE
A
Cramping
1.
Nagging
B.
Dull
2.
Agonizing
C.
Splitting
3.
Annoying
D.
Burning
4.
Troublesome
E.
Sore
5.
Killing
F.
Shooting
6.
Tiring
G.
Radiating
7.
Unbearable
H.
Hurting
8.
Sickening
I.
Crushing
9.
Terrifying
J.
Aching
10. Miserable
K.
Stabbing
11. Torturing
L.
Sharp
M. Tearing
N.
Pressing
II.
INSTRUCTIONS: Ask the participant to choose the word which describes the duration of oral pain 
and check the response:
Continuous
Periodic (Comes and goes) 
III.
INSTRUCTIONS: Ask the participant to choose words from the Sensory pain intensity list and the 
Affective pain intensity list below to describe present oral pain with swallowing 
Circle the letters/numbers and words chosen from the lists. 
 SENSORY
       AFFECTIVE
A.
Cramping
1.
Nagging
B.
Dull
2.
Agonizing
C.
Splitting
3.
Annoying
D.
Burning
4.
Troublesome
E.
Sore
5.
Killing
F.
Shooting
6.
Tiring
G.
Radiating
7.
Unbearable
H.
Hurting
8.
Sickening
I.
Crushing
9.
Terrifying
J.
Aching
10. Miserable
K.
  Stabbing
11. Torturing
L.
Sharp
M. Tearing
N.
Pressing
IV.
 INSTRUCTIONS: Ask the participant to choose the word which describes the duration of oral pain 
with swallowing and (') the response 
Continuous
Periodic (Comes and goes) 


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51
Scoring of Painometer (POM) Assessment Sheet
Weighted scores for the Painometer sensory word descriptors are:
A. Cramping = 4
B. Dull = 1
C. Splitting = 5
D. Burning = 4
E. Sore = 1
F. Shooting = 5
G. Radiating = 3
H. Hurting = 2
I.
Crushing = 4
J.
Aching = 3
K. Stabbing = 5
L. Sharp = 5
M. Tearing = 5
N. Pressing = 2
Weighted scores for the Painometer affective word descriptors are:
1. Nagging = 1
2. Agonizing = 4
3. Annoying = 1
4. Troublesome = 2
5. Killing = 5
6. Tiring = 3
7. Unbearable = 5
8. Sickening = 4
9. Terrifying = 5
10. Miserable = 3
11. Torturing = 5
Total score is calculated by simple summation of individual weighted scores. 


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
52
15.6 APPENDIX F: ORAL HEALTH IMPACT PROFILE (OHIP-14) 38
Date: ____/____/____    Timepoint: __________  LIP print name:  Jacqueline 
Mays   LIP Signature:_______________________
#
Because of problems with your teeth, 
denture or mouth have you…
Never (0)
Hardly 
ever (1)
Occasionally 
(2)
Often 
(3)
Very 
Often 
(4)
1
Had trouble pronouncing words
 
 
 
 
 
2
Felt sense of taste has worsened
 
 
 
 
 
3
Had painful aching in the mouth
 
 
 
 
 
4
Found it uncomfortable to eat any foods
 
 
 
 
 
5
Have been self-conscious
 
 
 
 
 
6
Felt tense
 
 
 
 
 
7
Had an unsatisfactory diet
 
 
 
 
 
8
Had to interrupt meals
 
 
 
 
 
9
Found it difficult to relax
 
 
 
 
 
10
Have been a bit embarrassed
 
 
 
 
 
11
Have been irritable with other people
 
 
 
 
 
12
Had difficulty doing usual jobs
 
 
 
 
 
13
Felt life in general was less satisfying
 
 
 
 
 
14
Have been totally unable to function
 
 
 
 
 
Total ________________________________


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
53
15.7 APPENDIX G: SCHEDULE OF EVALUATIONS AND EVENTS
Patients Randomized to Clobetasol Oral Rinse Schedule:
Patient Evaluations and Events
Screening and 
Baseline     
(Day -7 to 0 )*
Day 0 *
Interim 
Evaluation 
(Day 14) *g
End of 
Intervention 
(Day 28) *
Follow-up 
(Day 56) *
(or end of 
treatment visit)
Follow up
(3 months and 
6 months post 
treatment)#
History and Physical Examt
Xt
Xt
Xt
Xt
Xt
NIH Advanced Directives Form
cGVHD NIH Organ Staging
X
X
Clinical Photographs
X
X
X
X
Urine pregnancy test
X
Informed Consent
X
Randomization
X
CBC,  Acute care, mineral and 
liver panel & LDH, TBNK
X
X
X
X
Serum Cortisol Level
X
X
X
X
Research Saliva and Plasma 
Collection
X
X
X
X
OMRS
X
X
X
X
Oral cGVHD Clinical Scoring
X
X
X
X


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
54
Patient Evaluations and Events
Screening and 
Baseline     
(Day -7 to 0 )*
Day 0 *
Interim 
Evaluation 
(Day 14) *g
End of 
Intervention 
(Day 28) *
Follow-up 
(Day 56) *
(or end of 
treatment visit)
Follow up
(3 months and 
6 months post 
treatment)#
Oral HSV by PCR
X
X
Oral Pain, Sensitivity, Dryness 
Scales
X
X
X
X
Global Scale
X
X
X
POM
X
X
X
X
OHIP-14 (Oral QOL)
X
X
X
X
Biopsy/Tissue Collection
X
Xt
ACTH Stimulation Test
X
X
Xp
Adrenocorticotropic Hormone blood 
level
X
X
X
Hemoglobin A1C level
X
X
X
X
X
Compliance Evaluation
X
X
Monitoring for Adverse Events
X
X
X
X
Start of intervention
X
Completion of the intervention
X
* ± 2 days
t Optional


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
55
p Per PI discretion (at day 56 or day 70 visit depending on subject randomization group) if there is concern for endocrine side-effects)
# This follow up can be done in person or via telephone call as per Section 3.7g Patients initially randomized to 2 weeks of placebo 
will have two Day 14 Interim Evaluation visits, one at unblinding and one after 14 days of clobetasol therapy.
h As indicated in Section 11.5, all subjects ≥ age 18 will be offered the opportunity to complete an NIH advanced directives form.  
This should be done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained.  
The completion of the form is strongly recommended, but is not required.


Abbreviated Title: Clobetasol oral rinse for oral cGVHD
Version Date: January 24, 2017
15.8 APPENDIX H: DATA COLLECTION ELEMENTS REQUIRED BY PROTOCOL
All of the following elements will be recorded in the research database.
Patient Enrollment 
Recipient
•
Date of birth, age, sex, race, ethnicity
•
Height
•
Weight
•
Karnofsky Performance Status
•
Date of original diagnosis of the underlying disease (month/year)
•
Diagnosis for which transplant was performed
•
Date and type of transplant
•
Conditioning regimen
•
Acute GVHD yes/no
•
Chronic GVHD date of diagnosis
•
Chronic GVHD classification (late, overlap, classic)
•
Prior systemic therapy for cGVHD
•
Prior oral therapy for cGVHD
•
Date of Informed Consent signature, consent version and date of registration
•
Optional Baseline History/Physical
•
Baseline Symptoms 
•
Intensity of current immunosuppression: None, Mild (single agent prednisone <0.5 
mg/kg/day), Moderate (prednisone >0.5 mg/kg/day and or any single 
agent/modality), High (2 or more agents/modalities +prednisone >0.5 mg/kg/day)
•
Clinician’s impression of activity: Inactive, off systemic therapy or topical 
immunosuppression; Inactive, on systemic therapy or topical immunosuppression; 
Active, irrespective of the level of current therapy; Highly Active, irrespective of the 
level of current therapy
•
Findings of consultations done at screening
Donor
•
Age at transplant
•
Relationship, sex
•
Degree and type of HLA match (allele or serologic)
•
CMV status
Study Drug administration and response for each course of therapy given
•
Dates study rinse given
•
Actual dose given
•
Response assessment (OMRS score) for each visit


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
57
Laboratory and Diagnostic Test Data
•
All Clinical laboratory and diagnostic test results done at screening except diagnostic 
tests which are not specified in the protocol, and if the results are not needed to document 
the start or end of an adverse event that requires reporting.
•
All tests done to document resolution of adverse events
•
Serologies-CMV and HSV
•
Volume of stimulated and unstimulated saliva at each visit.  
Adverse Events
•
All unexpected serious adverse events that are possibly, probably, or definitely related to 
the research 
•
All deaths, except deaths due to progressive disease 
•
All Protocol Deviations
•
All Unanticipated Problems
Concomitant Measures
•
Baseline immunosuppressive medications 
•
Other therapy for recorded adverse events
Off study
•
Date and reason for off study
•
Date and cause of death
•
Autopsy findings


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
58
15.9 APPENDIX I: TOPICAL CLOBETASOL 0.05% ORAL RINSE FOR ORAL CHRONIC GRAFT-VERSUS-HOST DISEASE PATIENT 
DIARY
INSTRUCTIONS:  Rinse with the study medication THREE times a day for 2 minutes and spit out.  Do not eat, drink or brush your teeth for at 
least 30 minutes after study medication use.
Rinse with the nystatin suspension ONE time a day for at least 30 seconds after your evening meal.  Do not eat, drink or brush your teeth for at 
least 10 minutes after nystatin use.
You can use painkiller rinse (viscous lidocaine) as needed to relieve oral discomfort. Do not use the painkiller rinse at least 30 minutes before and 
after using the study rinse or nystatin. Do not use any other mouthwashes, rinses or oral hygiene products except toothpaste. 
Record the level of oral pain and oral dryness for the day at its WORST using a number from 0 (no pain/dryness) to 10 (the worst possible 
pain/dryness).


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
59
Patient Signature:_______________________  Date:_________


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
60
15.10 APPENDIX J: SPANISH LANGUAGE TRANSLATIONS OF THE PATIENT-REPORTED OUTCOME 
FORMS
Painometer (POM) Assessment Sheet
Date: ____/____/____    Time: _______   Timepoint: _______  LIP:  Jacqueline Mays   LIP 
Signature:__________________
______________________________________________________________________________
________
I
INSTRUCCIONES: Pídale al participante que elija palabras de la lista de 
intensidad del dolor Sensorial tanto como de la lista de intensidad de dolor Afectivo a 
continuación, para describir el dolor oral en estos momentos.  Haga un círculo alrededor de 
la letra y palabra y del número y palabra de las listas a continuación. 
SENSORIAL
        AFECTIVO
A Calambre
1. Irritante
B. Leve
2. Agobiante
C. Enloquecedor
3. Fastidioso
D. Ardor
4. Molestoso
E. Adolorido
5. Mortal
F. Punzante
6. Fatigoso
G. Que irradia
7. Insoportable
H. Que duele
8. Deprimente
I.
Triturante
9. Espantoso
J.
Resentido
10. Miserable
K. Como puñaladas
11. Torturante
O. Agudo
P. Desgarrante
Q. Insistente
II.
INSTRUCCIONES: Pídale al participante que elija la palabra que describe la 
duración del dolor oral y marque la respuesta:
Continuo
Periódico (Se viene y se va) 
III.
INSTRUCCIONES: Pídale al participante que elija palabras del listado de 
intensidad del dolor Sensorial y del dolor Afectivo a continuación, para describir el dolor 
oral al deglutir.  Marque con un círculo las letras/números y los números/palabras de estas 
listas.  
SENSORIAL
        AFECTIVO
A Calambre
1. Irritante
B. Leve
2. Agobiante
C. Enloquecedor
3. Fastidioso
D. Ardor
4. Molestoso
E. Adolorido
5. Mortal
F. Punzante
6. Fatigoso
G. Que irradia
7. Insoportable


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
61
H. Que duele
8. Deprimente
I.
Triturante
9. Espantoso
J.
Resentido
10. Miserable
K. Como puñaladas
11. Torturante
L. Agudo
M. Desgarrante
N. Insistente
IV.
 INSTRUCCIONES: Pídale al participante que elija la palabra que describa la 
duración del dolor oral al deglutir y la respuesta.  
Continuo
Periódico (Se viene y se va) 


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
62
Global Scale-0 to 10 Scales
Numeric Rating Scales (0-10) for Oral Pain, Sensitivity, and Dryness 
DOLOR ORAL
En una escala del 0 al 10, ¿qué tanto DOLOR siente en su boca en este momento?  Por 
favor marque el número adecuado con un círculo.
0
1
2
3
4
5
6
7
8
9
10
No siento dolor
El peor que he sentido
SENSIBILIDAD ORAL
En una escala del 0 al 10, ¿qué tan SENSIBLE siente su boca en este momento? Por favor 
marque el número adecuado con un círculo. 
0
1
2
3
4
5
6
7
8
9
10
No sufro de sensibilidad
La peor sensibilidad que he 
sentido
            
RESEQUEDAD ORAL
En una escala del 0 al 10, ¿qué tan SECA siente su boca EN ESTE MOMENTO? Por favor 
marque el número adecuado con un círculo. 
0
1
2
3
4
5
6
7
8
9
10
No siento resequedad
La peor resequedad que he 
sentido


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
63
Escala Global 
Si compara la condición actual de su boca, con la condición en la que estaba HACE DOS 
SEMANAS, ¿en que condición general esta su boca? Por favor, marque con un círculo. 
Mucho peor
Un poco peor
Igual
Un poco mejor
Mucho mejor
LIP Print Name:  Jacqueline Mays      LIP Signature:_____________________________
Date of Evaluation:__________
Timepoint:___________ 


Abbreviated Title: Clobetasol rinse for oral cGVHD
Version Date: 3/25/2025
64
15.11 APPENDIX K: ORAL HEALTH IMPACT PROFILE (OHIP-14)
Date: ____/____/____    Timepoint: __________  LIP print name:  Jacqueline Mays   LIP 
Signature:_______________________
#
Ha tenido los siguientes problemas, 
debido a dificultades con su boca, sus 
dientes o dientes postizos:
Nunca (0)
Casi 
nunca 
(1)
Ocasional- 
mente (2)
Frecuente-
mente (3)
Muy 
frecuen-
te (4)
1
¿Ha tenido dificultad al pronunciar 
palabras?
 
 
 
 
 
2
¿Se ha empeorado el sentido del gusto ha 
empeorado?
 
 
 
 
 
3
¿Ha estado adolorida su boca?
 
 
 
 
 
4
¿Se siente incómodo al comer?
 
 
 
 
 
5
¿Se siente muy consciente de sí mismo?
 
 
 
 
 
6
¿Se siente tenso/a?
 
 
 
 
 
7
¿Ha sido insatisfactoria su dieta?
 
 
 
 
 
8
¿Ha tenido que interrumpir tiempos de 
comida?
 
 
 
 
 
9
¿Se da cuenta que le es muy difícil 
relajarse?
 
 
 
 
 
10
¿Se siente un poco avergonzado/a?
 
 
 
 
 
11
¿Se ha sentido muy irritable hacia otras 
personas?
 
 
 
 
 
12
¿Ha tenido dificultad haciendo cosas que 
usualmente ha hecho sin dificultad?
 
 
 
 
 
13
¿Se siente menos satisfecho/a con su vida 
en términos generales?
 
 
 
 
 
14
No ha podido funcionar del todo.
 
 
 
 
 
Total ________________________________


 
Protocol 12C0068  
English version translation of Appendix J  
Painometer (POM) Assessment Sheet 
______________________________________________________________________________________ 
Baseline 
                 Date: _____/______/_____       Time: _________   Subject Study Number:  _______ 
______________________________________________________________________________________ 
I 
INSTRUCTIONS: Ask the participant to choose words from the Sensory pain intensity list and the 
Affective pain intensity list below to describe present oral pain- Circle the chosen letter/word and 
number/word from the lists. 
 
 
SENSORY 
        AFFECTIVE 
 
A 
Cramping 
1. Nagging 
 
B. Dull 
2. Agonizing 
 
C. Splitting 
3. Annoying 
 
D. Burning 
4. Troublesome 
 
E. Sore 
5. Killing 
 
F. Shooting 
6. Tiring 
 
G. Radiating 
7. Unbearable 
 
H. Hurting 
8. Sickening 
 
I. 
Crushing 
9. Terrifying 
 
J. 
Aching 
10. Miserable 
 
K. Stabbing 
11. Torturing 
L. Sharp 
M. Tearing 
N. Pressing 
 
II. 
INSTRUCTIONS: Ask the participant to choose the word which describes the duration of oral pain 
and check the response: 
 
Continuous 
 
 
 
Periodic (Comes and goes)  
 
 
III. 
INSTRUCTIONS: Ask the participant to choose words from the Sensory pain intensity list and the 
Affective pain intensity list below to describe present oral pain with swallowing  
Circle the letters/numbers and words chosen from the lists.  
 
 
 SENSORY 
       AFFECTIVE 
 
A. Cramping 
1. Nagging 
 
B. Dull 
2. Agonizing 
 
C. Splitting 
3. Annoying 
 
D. Burning 
4. Troublesome 
 
E. Sore 
5. Killing 
 
F. Shooting 
6. Tiring 
 
G. Radiating 
7. Unbearable 
 
H. Hurting 
8. Sickening 
 
I. 
Crushing 
9. Terrifying 
 
J. 
Aching 
10. Miserable 
K.   Stabbing 
11. Torturing 
L. Sharp 


M. Tearing 
N. Pressing 
 
IV. 
 INSTRUCTIONS: Ask the participant to choose the word which describes the duration of oral pain 
with swallowing and (') the response  
 
Continuous 
 
 
Periodic (Comes and goes)  
 
 
 
 
 
Scoring of Painometer (POM) Assessment Sheet 
Weighted scores for the Painometer sensory word descriptors are: 
A. Cramping = 4 
B. Dull = 1 
C. Splitting = 5 
D. Burning = 4 
E. Sore = 1 
F. Shooting = 5 
G. Radiating = 3 
H. Hurting = 2 
I. Crushing = 4 
J. Aching = 3 
K. Stabbing = 5 
L. Sharp = 5 
M. Tearing = 5 
N. Pressing = 2 
Weighted scores for the Painometer affective word descriptors are: 
1. Nagging = 1 
2. Agonizing = 4 
3. Annoying = 1 
4. Troublesome = 2 
5. Killing = 5 
6. Tiring = 3 
7. Unbearable = 5 
8. Sickening = 4 
9. Terrifying = 5 
10. Miserable = 3 
11. Torturing = 5 
Total score is calculated by simple summation of individual weighted scores.  


Numeric Rating Scales (0-10) for Oral Pain, Sensitivity, and Dryness  
 
ORAL PAIN 
 
On a 0 to 10 scale, how PAINFUL is your mouth now? Please circle the number. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No pain 
 
 
 
 
 
 
 
 
 
Worst pain  
 
 
 
ORAL SENSITIVITY 
 
On a 0 to 10 scale, how SENSITIVE is your mouth now? Please circle the number. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No sensitivity  
 
 
 
 
 
 
 
            Worst 
sensitivity 
 
 
ORAL DRYNESS 
 
On a 0 to 10 scale, how DRY is your mouth NOW? Please circle the number. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No dryness 
 
 
 
 
 
 
 
 
 
Worst dryness 


 
Global Scale 
 
Compared to TWO WEEKS ago, what is the overall condition of your mouth? Please circle. 
 
Much worse  
A little worse  
Same  
A little better  
Much better 


Oral Health Impact Profile (OHIP-14) 38 
 
Date: ____/____/____    Timepoint: __________  LIP print name:  Jacqueline 
Mays   LIP Signature:_______________________ 
 
 
 
 
 
 
 
 
 
 
 
# 
Because of problems with your teeth, 
denture or mouth have you… 
Never (0) 
Hardly 
ever (1) 
Occasionally 
(2) 
Often 
(3) 
Very 
Often 
(4) 
1 Had trouble pronouncing words 
  
  
  
  
  
2 Felt sense of taste has worsened 
  
  
  
  
  
3 Had painful aching in the mouth 
  
  
  
  
  
4 
Found it uncomfortable to eat any 
foods 
  
  
  
  
  
5 Have been self-conscious 
  
  
  
  
  
6 Felt tense 
  
  
  
  
  
7 Had an unsatisfactory diet 
  
  
  
  
  
8 Had to interrupt meals 
  
  
  
  
  
9 Found it difficult to relax 
  
  
  
  
  
10 Have been a bit embarrassed 
  
  
  
  
  
11 Have been irritable with other people 
  
  
  
  
  
12 Had difficulty doing usual jobs 
  
  
  
  
  
13 Felt life in general was less satisfying 
  
  
  
  
  
14 Have been totally unable to function 
  
  
  
  
  
 
 
 
 
 
 
 
 
Total ________________________________ 
 
 
 
 
 

ICF_002.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
12-C-0068 
PRINCIPAL INVESTIGATOR: 
Steven Pavletic, MD 
STUDY TITLE:  
A Randomized Double-Blind Pilot Study of Topical Clobetasol 0.05% Oral Rinse for 
Oral Chronic Graft Versus-Host Disease 
Continuing Review Approved by the IRB on 08/22/16 
Amendment Approved by the IRB on 02/14/17 (H) 
Date posted to web: 03/01/17   
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
If you are signing for a minor child, “you” refers to “your child” throughout the consent 
document. 
Description of Research Study 
You are being invited to participate in a research study testing whether a drug called clobetasol is 
effective in oral chronic graft versus host disease (oral cGVHD) - a common complication of 
stem cell transplantation that occurs in up to 60% of transplant patients.  GVHD occurs when, 
after a transplant, the donor’s cells attack and damage the recipient’s tissues.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:12-C-0068 
CONTINUATION: page 2 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Clobetasol is a corticosteroid, a class of drugs that are commonly used to treat inflammation. 
Corticosteroids are known to affect the cells of immune system and may help to “turn down” the 
activity of the donor cells. Corticosteroids taken by mouth or injected have been proven to be 
effective for the treatment of cGVHD however they are associated with many side effects such 
as high blood pressure and diabetes. Topically applied (used on the surface, like creams or 
rinses) corticosteroids have relatively few side–effects but their role in the treatment of oral 
GVHD has not been well studied. Therefore, this study will investigate whether clobetasol rinse 
can decrease the severity of oral cGVHD in patients after their transplant and its effects on the 
cells of the lining of the mouth. 
You can participate in this study if you:  
• have signs of oral GVHD, 
• are not allergic to clobetasol, 
• are 12 years of age and older, 
• did not have any changes in systemic (taken by mouth or injected, i.e. pills or shots) 
immunosuppressive therapy in the two preceding weeks  
• are able to rinse with the study medication by mouth,  
• are able to come back to NIH for follow-up appointments, and 
• are not pregnant and are using a birth control method that meets the requirements of this 
study  
What Are the Treatments and What is the Course of the Study? 
Investigational Treatment 
If you decide to participate, you will be first randomly (like the flip of a coin) assigned to receive 
either (1) clobetasol rinse or (2) placebo (an oral rinse that looks and tastes like the clobetasol 
rinse but has not active medication). You and the research team will not have a choice of which 
medication you receive in the first 2 weeks of the study. Likewise, neither you nor the 
investigators will know which medications you are taking until completion of the first 2 weeks of 
the study. However, in case of emergency, the information regarding which drug you are using 
will be available from the NIH pharmacy.  
After the first 2 weeks, you will start using clobetasol rinse for another 2 or 4 weeks depending 
on whether you were originally assigned to placebo or clobetasol. That way every patient on the 
study will receive clobetasol for a total of 4 weeks.    
You will rinse your mouth out with the study oral rinse 3 times a day after meals every day.   
You will take 10 ml of the oral rinse using the measuring cup, put it in your mouth and swish it 
around for 2 minutes and spit out the oral rinse into the sink.  DO NOT SWALLOW THE 
RINSE! The oral rinse that we are using is not intended for internal use and we want to limit the 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:12-C-0068 
CONTINUATION: page 3 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
action of the drug to the mouth and decrease the effects of the steroid on the rest of the body.  
Please do not eat or drink for 30 minutes after use.  
Should you swallow the rinse, please contact Dr. Pavletic.  
Additional Treatment Period 
After you have completed four weeks of clobetasol treatment, it may be possible for you to be 
treated with the clobetasol for up to an additional four weeks.  You would need to restart the 
clobetasol within 90 days of your last dose of clobetasol in order for this to occur, and a follow-
up exam at NIH must be done for you to qualify for re-treatment.   
Non-Investigational Treatments 
You will be given a painkiller rinse (viscous lidocaine, numbing rinse) that you can use to relieve 
the discomfort in the mouth. You can apply it to the affected areas in the mouth up to 3 times a 
day before eating but at least 30 minutes apart from the study rinse.    
A potential anticipated side-effect of local corticosteroid treatment is yeast infection in the 
mouth.  To prevent this, you will be asked to rinse once per day with an anti-fungal medication, 
nystatin suspension.    
You will continue to take all medications that are prescribed as part of your post transplant care.  
However, no changes in the immunosuppressive medications will be allowed for the first two 
weeks of the study. The immunosuppressive medications include but are not limited to 
cyclosporine, tacrolimus (Prograf), mycophenolate (MMF, Cellcept) and prednisone. Changes in 
immunosuppressive medications will be allowed after the first 2 weeks of the study if necessary 
to control GVHD in sites other than the mouth. We will ask you about the use systemic steroids, 
immunosuppressants and pain medication use at the time of each evaluation. 
Study Evaluations  
Evaluations done to assess study eligibility 
To ensure your safety, you will undergo a series of brief assessments to determine if you are a 
good candidate for protocol participation. These tests and procedures will be done under a 
separate screening protocol and will be fully described in that consent document. 
History, oral exam, physical: We will perform a brief oral examination and explain the protocol 
procedures.  We may also perform a physical exam and take your medical history. 
Medication review:  Some medications might reduce the effectiveness or increase the side effects 
of clobetasol and clobetasol may increase the side effects of or lessen the effectiveness of some 
medications. Therefore, we will need to review over-the counter-medications, health food 
supplements, and prescription medication that you are taking before you take part in this study.  
Pregnancy testing: Women of childbearing age will have a pregnancy test, which must be 
negative before they take part in the study. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:12-C-0068 
CONTINUATION: page 4 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Evaluations and procedures done after consent but before starting study medication  
Oral Exam:  We will do a complete soft tissue exam of your mouth. 
Oral photographs: We will take photographs of your mouth and the surrounding area. 
Biopsy of Your Mouth:  At the first visit, we will take one small piece of tissue (about 4mm 
across) from the inside of your cheek.  We will numb the inside of your cheek and use a punch 
(size of a pencil eraser tip) to remove the tissue. This is a minor procedure with few side effects 
usually limited to some post-operative discomfort for about a day. Half of the tissue will be 
saved for research, and the other will be sent to the lab to be reviewed by a pathologist. Part of 
this tissue will be used for pathological examination to confirm your condition. Another part will 
be used in our lab to study factors that are associated with the development of GVHD in the 
mouth. This biopsy is required as part of this research study. After the initial biopsy, if you 
decide not to have further biopsies, you will still receive study drugs and have other tests as part 
of this study. You will be asked to sign a separate consent form for each biopsy procedure. 
Children will only have oral biopsy done if it is needed for medical reasons.   
Saliva Tests: Saliva will be collected by spitting in the tube for 5 minutes. This will be done two 
times at each appointment: once while chewing a small piece of paraffin wax and once without 
wax. This is a simple procedure that does not have any risks or discomforts. We will use saliva 
samples to measure your salivary gland function and to study in our laboratory factors that may 
be associated with the development of GVHD including the types of protein in the mouth. 
Blood sample collection:  We will draw blood from your arm by a trained person. We will ask 
you sit or lie down when we take your blood. We will tie a large rubber band around the upper 
arm, and then we will cleanse the area on your arm with an alcohol swab, where we intend to 
take the blood. At the site we cleansed, we will place a tiny needle under the skin into a vein in 
your arm and we will fill-up 5 of tubes or less the size of your pinky with your blood. Once we 
are done getting the blood, we will remove the tiny need and cover the site with a band aid. 
 Questionnaires:    You will be asked to fill out questionnaires which will measure your quality 
of life, your mouth pain and mouth dryness. 
ACTH Stimulation Test: This test is used to evaluate the how well your adrenal glands work. 
Adrenal glands are normally responsible for production of steroids in the body. Sometimes, if 
steroids are taken for a long time, the adrenal glands react by decreasing their own production. 
This is called “adrenal suppression” and may result in decreased blood pressure and decreased 
ability to fight infection and cope with stress of trauma or surgery. Although, this generally 
happens when corticosteroids are given orally it is possible that in some cases corticosteroid 
from a rinse is taken by the body through oral lining. It is unknown how much effect this could 
have on the adrenal glands; therefore, we would like to evaluate your adrenal gland function by 
performing ACTH stimulation test. 
This test is performed in the morning at 8 o’clock. You will have to be in a bed and we will give 
you an intravenous injection of a drug called “ACTH” or “cosynthropin” which is version of a 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:12-C-0068 
CONTINUATION: page 5 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
hormone normally produced by your pituitary gland. We will draw blood before and at 30 and 60 
minutes after the injection to measure your cortisol levels. Children will only have an ACTH 
stimulation test done if it is needed for medical reasons. 
Evaluations and procedures done during study drug administration (Day 0 to 4-6 weeks) 
We ask that you return to the Clinical Center 2 weeks after starting study drug at which time 
baseline assessments will be repeated.  
Oral exam: at each visit 
Oral photographs: at each visit 
Oral biopsy:  at the 4-6 weeks visit (at the end of the treatment phase of the study). We will 
obtain an additional small (4 mm) punch biopsy sample for research purposes only.  The biopsy 
will be taken from inside of your cheek from an area of the cheek near the healed spot from the 
first biopsy.   This will be used to compare to the sample obtained before treatment was started. 
The biopsy to be performed is exclusively for research purposes and will not benefit you.  It may 
help other people in the future. 
Saliva samples: at each visit 
Review of medications: at each visit 
Study drug compliance: at each visit we ask that you return the medication diary and any unused 
medication so we can measure how much study drug you have taken.  
Blood collection: at each visit  
Questionnaires:  You will be asked to assess your level of dry mouth and oral pain at each visit 
and complete one quality of life assessment at the 1-month visit only. 
ACTH Stimulation Test: at the end of the investigational treatment or if you are taken off-study. 
This may be repeated at your final study visit, 8 weeks after starting active clobetasol rinse, if 
your doctors are concerned about adrenal suppression. 
Follow-Up Evaluations 
We will contact you every 3 months after you stop using clobetasol oral rinse for 6 months to 
assess duration of treatment response, recurrence of oral GVHD, and resolution of any side-
effects you may have experienced.  You will be contacted by a study team member by telephone 
or in person if you are already at the NIH for other treatment at a follow-up time point.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:12-C-0068 
CONTINUATION: page 6 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
Related to Clobetasol: 
Corticosteroids can be taken either internally as a pill or injections or topically as a cream or 
ointment.  In this study the corticosteroid is used topically which hopefully will avoid many of 
the unwanted side-effects that are associated with the drug which include:  
Likely 
• Yeast infection (thrush).  Short-term topical corticosteroid treatment is associated with 
few potential complications.  The most common is yeast overgrowth. This is easily 
treated and does not require discontinuation of the study. To prevent this, you will be 
asked to rinse once per day with an anti-fungal medication, nystatin suspension.  
However, should oral yeast infection occur, you will be given a full course of medication 
that works in yeast infections. This will not prevent you from continuing in the study.  
Less Likely 
• Adrenal suppression:  Problems associated with the adrenal gland are very rare (<1%) 
with topically applied steroids. Cases of adrenal suppression from topically-applied 
steroid creams have been reported in young children and adults. In some cases, the cream 
was applied too frequently, and the thinner skin of children was felt to enhance systemic 
absorption. In other reports, it was difficult to determine if there was true adrenal 
suppression.  In this study adrenal function will be assessed at the beginning and the end 
of the study. Given the relatively short duration of this study, we do not expect side 
effects. 
• Viral Reactivation: Local immunosuppression in the mouth from topical corticosteroid 
use may allow certain viruses present in your body, including herpes simplex virus, to 
reactivate in the mouth or elsewhere in your body.  Symptoms of oral viral reactivation 
include oral ulcers and oral pain, similar to symptoms of oral cGVHD.  You will be 
monitored for viral activity during the study.  If reactivation is detected, you will be 
treated systemically with anti-viral medication. 
Rare but Serious 
• allergic reaction 
• thinning of the lining of the mouth 
• dilation of the small blood vessels in the mouth (spider veins).  
• Very rare side effects possible with an individual with extensive internal absorption 
include acne-like skin rash, cataracts, bruising, water retention, heartburn or stomach 
upset, swelling of the parotid (large salivary glands) stomach ulcer, glaucoma, increased 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:12-C-0068 
CONTINUATION: page 7 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
body hair, high blood pressure, decreased blood potassium, hypopigmentation or other 
changes in skin pigmentation, and unusual loss of hair.  These are side effects usually 
seen with systemic steroids, and are not expected with the topical steroid treatment used 
in this study. 
Unknown side effects: You might also develop a side effect that hasn’t yet been reported. Please 
tell us about any changes in your health that develop during and after your participation in this 
study. Treatment will be interrupted, delayed, or stopped if you develop any serious side effect. 
All complications from this treatment will receive full and prompt medical attention from NIH 
Clinical Center staff.  You will be told of any newly reported risks that may affect your decision 
to continue in the study. 
 
Because evaluation the safety of the oral rinse is one of the endpoints of this study you will be 
asked to evaluate your symptoms and any side-effects at follow-up visits. You will be asked to 
keep a medication diary to record when you take the study medication and any additional 
medications or side effects you experience while on this study. The study nurse or investigator 
will meet with you every month to review your progress and the medication diary.  
Related to Oral Biopsy:  
Oral biopsy is a minor surgical procedure that is performed under local anesthesia.  
Likely 
• Expect a minor degree of soreness.  This generally goes away in a couple of days.  
Rare but Serious 
• Bruising and infection at the biopsy site. These are generally rare (<5%). 
Related to blood testing: Collection of blood will be done primarily in association with post-
transplant sampling.   
Likely 
• Some discomfort: You will feel a little needle pinch at the site the needle is inserted.  
• Pain and bruising in the area where the blood was drawn. 
• Lightheadedness, or on a rare occasion fainting 
Related to Saliva collection:  There is no associated risk or discomfort. 
Related to ACTH Stimulation Test: Side effects of a single ACTH injection are rare, but may 
include changes in heart rate, increased blood pressure, dizziness, and pain at the injection site. 
Risks regarding pregnant or nursing women: It is not known whether clobetasol can harm 
pregnant women or nursing babies. Pregnant women or women who are breast-feeding may not 
take part in this study.   Women who are participating in this study must be using effective 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:12-C-0068 
CONTINUATION: page 8 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
methods of birth control during their enrollment in this study. Effective methods include 
abstinence, surgical sterilization, barrier methods (such as diaphragm, condom, cervical cap, and 
sponge), birth control pills, and Depo-Provera. 
Potential Benefits of Participation  
The aim of this study is to see if this experimental clobetasol mouth rinse will be beneficial in 
treatment of oral GVHD. We do not know if you will receive personal, medical benefit from 
taking part in this study. These potential benefits could include healing of oral ulcers or lessening 
of your symptoms, such as pain, that are caused by the oral GVHD.  There may be indirect 
benefits associated with thorough oral examinations performed in the study.  Because there is not 
much information about clobetasol’s effect in this form on oral cGVHD we do not know if you 
will benefit from taking part in this study, although the knowledge gained from this study may 
help others in the future who have chronic GVHD. 
Alternative Approaches or Treatments 
We do not know whether the treatment used in the study will have any effect (good or bad) on 
your disease.  If your disease worsens after two weeks of treatment with clobetasol you will be 
taken off study and offered alternative treatment.   
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• Getting treatment or care for your oral cGVHD without being in a study.  Alternative 
treatment for oral GVHD includes other topical or systemic steroids and systemic 
immunosuppressive drugs. 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain and 
other problems caused by oral cGVHD.  It does not treat oral cGVHD directly. 
Please talk to your doctor about these and other options. 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if we determine that your oral condition worsened at the 2 week of receiving clobetasol 
rinse  
• if a change in systemic immunosuppression is necessary to control GVHD outside the 
mouth in the first 2 weeks of the study 
• if you have side effects from the treatment that your doctor thinks are too severe 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:12-C-0068 
CONTINUATION: page 9 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
• if study if you are unable to follow the study procedures and evaluations. 
• if new information shows that another treatment would be better for you 
• if the study doctor decides to end the study 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Spectrum Chemicals or 
designated representatives. If you withdraw your consent and leave the trial, any samples of 
yours that have been obtained for the study and stored at the NCI can be destroyed upon request. 
However, any samples and data generated from the samples that have already been distributed to 
other researchers or placed in the research databases cannot be recalled and destroyed. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• You will receive study treatment at no charge to you. This may include medicines, 
laboratory testing, x-rays or scans done at the Clinical Center, National Institutes of 
Health (NIH), or arranged for you by the research team to be done outside the Clinical 
Center, NIH if the study related treatment is not available at the NIH.  
• There are limited funds available to cover the cost of some tests and procedures 
performed outside the Clinical Center, NIH.  You may have to pay for these costs if they 
are not covered by your insurance company. 
• Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH. 
• Once you have completed taking part in the study, medical care will no longer be 
provided by the Clinical Center, NIH. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.   This process is detailed in a Protocol Review Guide. You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:12-C-0068 
CONTINUATION: page 10 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
Optional Blood Tests  
We would like measure the rate at which the study drug reaches the bloodstream after one two-
minute rinse in a subset of patients.  This would involve a single appointment at which you 
would rinse with the study drug for 2 minutes, and then a small blood sample would be taken at 0 
minutes, 15-45 minutes, and 90-120 minutes after rinsing.  This would be done at the same visit 
as one of your scheduled study visits.  We do not expect that much of the study drug will reach 
the bloodstream, however it will provide valuable information to know how quickly this occurs.  
This information will help us screen patients in this study for side effects, and will improve the 
design of future treatments.    
You will be given the chance to decide if you want to participate at the time of the procedure. No 
matter what you decide to do, it will not affect your care or study participation. 
Use of Specimens and Data for Future Research 
 To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that it may be used for future research on any topic and shared broadly for 
research purposes. Your specimens and data will be used for research purposes only and will not 
benefit you.  It is also possible that the stored specimens and data may never be used.  Results of 
research done on your specimens and data will not be available to you or your doctor.  It might 
help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:12-C-0068 
CONTINUATION: page 11 of 12 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions. If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Steven Pavletic, M.D., Building 10, Room 3-3330 Telephone:  240-760-6174. You 
may also call the Clinical Center Patient Representative at (301) 496-2626. If you have any 
questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone:  240-760-6070. 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
 
 
 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:12-C-0068 
CONTINUATION: page 12 of 12 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and 
have been given the opportunity to discuss it and to 
ask questions.  I hereby consent to take part in this 
study. 
I have read the explanation about this study and 
have been given the opportunity to discuss it and to 
ask questions.  I hereby give permission for my 
child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/ 
Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the 
study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM AUGUST 22, 2016 THROUGH AUGUST 21, 2017. 
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name