Conditions: Oral Lichen Planus Mucous Membrane Pemphigoid Pemphigus Vulgaris Chronic Graft-versus-host-disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 29
Healthy volunteers: yes

Brief summary:
Topical steroid therapy is considered the first line of treatment for Oral Inflammatory Ulcerative Diseases with current treatment regimens requiring multiple application or rinses daily. Using Mucolox™ as a vehicle to deliver topical dexamethasone to the oral mucosa has the potential to effectively prolong contact time between the medication. The primary objective of this study is to determine the clinical efficacy and tolerability of compound dexamethasone at 0.5 mg/5 mL in Mucolox™ for the treatment of Oral Inflammatory Ulcerative Diseases as measured by a reduction in oral symptoms between patients treated with compounded dexamethasone 0.5mg/5ml solution in Mucolox™ (group A) and patients treated with topical commercial dexamethasone 0.5mg/5ml solution only (group B). and mucosa, leading to improved clinical outcomes due to the need for less frequent application.

Detailed description:

Arms:
arm 1: Dexamethasone solution (0.5mg/5ml) in Mucolox™ three times a day (TID) swish and spit for 4 weeks arm 2: Dexamethasone solution (0.5mg/5ml) TID swish and spit for 4 weeks

Interventions: intervention 1: dexamethasone 0.5mg/5ml solution intervention 2: dexamethasone 0.5mg/5ml solution in Mucolox™
Intervention descriptions: intervention 1: Patient with oral ulcerative conditions will be asked to rinse with dexamethasone 0.5mg/5ml solution three times a day for 4 weeks and expectorate intervention 2: Patient with oral ulcerative conditions will be asked to rinse with dexamethasone 0.5mg/5ml solution in Mucolox™ three times a day for 4 weeks and expectorate

Protocol document:
Prot_SAP_001.pdf: 
Protocol Number NCT04540133
Confidential
DEXAMETHASONE SOLUTION AND DEXAMETHASONE IN MUCOLOX FOR THE
TREATMENT OF ORAL INFLAMMATORY ULCERATIVE DISEASES
PROTOCOL: NCT04540133
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TABLE OF CONTENTS
1           BACKGROUND        9
1.1 Overview of Clinical Studies 10
1.1.1        Management of Oral Inflammatory Ulcerative Diseases        10
1.1.2        Dexamethasone solution for Oral Inflammatory Ulcerative Diseases
11
1.1.3        Mucolox      11
2           STUDY RATIONALE           12
2.1 Risk / Benefit Assessment       12
2.1.1        Drug side effects and toxicities           12
2.1.2        Potential benefits for participating individuals           13
3           STUDY OBJECTIVES           13
3.1 Primary Objective       13
3.2 Secondary Objectives 13
4           STUDY DESIGN       13
4.1 Study Overview          13
5           Criteria for evaluation14
5.1 Primary Efficacy Endpoint     14
5.2 Secondary Efficacy Endpoints            14
5.3 Safety Evaluations      14
6           SUBJECT SELECTION         14
6.1 Study Population         14
6.2 Inclusion Criteria        14
6.3 Exclusion Criteria       15
7           Concurrent Medications          15
8           STUDY TREATMENTS        15
8.1 Method of Assigning Subjects to Treatment Groups 15
8.2 Blinding           15
8.3 Formulation of Test and Control Products      16
8.3.1        Mucolox      16
8.4 Dexamethasone solution         18
8.5 Study Drug Accountability     19
8.6 Measures of Treatment Compliance 19
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9           STUDY PROCEDURES AND GUIDELINES          19
9.1 Clinical Assessments 20
9.1.1        Concomitant Medications       20
9.1.2        Demographics 20
9.1.3        Medical History          20
9.2 Study procedures         20
9.2.1        Clinician Reported Outcomes21
9.2.2        Oral Health Impact Profile      21
9.2.3        Patient Reported Outcomes 21
9.2.4        Treatment Regimen     22
9.3 Study Agents Administration 22
9.3.1        Adverse Events           23
9.3.2        Pregnancy Test            23
10         ADVERSE Experience REPORTING AND DOCUMENTATION 23
10.1 Adverse Events           23
10.2 Serious Adverse Experiences (SAE) 24
10.2.1      Serious Adverse Experience Reporting          25
10.3 Medical Monitoring 25
11         DISCONTINUATION And Replacement of subjects            25
11.1 Early Discontinuation of Study Drug 25
12.3 Withdrawal of Subjects from the Study          26
12.4 Replacement of Subjects         26
12         PRotocol Violations 26
13         STATISTICAL METHODS AND CONSIDERATIONS      27
13.1 Study design/Endpoints          27
13.1.1      Analysis of Primary Endpoints           27
13.1.2      Analysis of Secondary Endpoints       27
13.2 Sample Size, Accrual Rate and Study Duration         28
13.3 Interim Analysis          28
14         DATA COLLECTION, RETENTION AND MONITORING          28
14.1 Data Collection Instruments 28
14.2 Data Management Procedures            28
14.3 Data Quality Control and Reporting 29
14.4 Archival of Data          29
14.5 Availability and Retention of Investigational Records           29
14.6 Monitoring      29
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14.7 Subject Confidentiality           29
15         ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 29
15.1 Protocol Amendments30
15.2 Institutional Review Boards and Independent Ethics Committees     30
15.3 Informed Consent Form          30
15.4 Publications     31
15.5 Investigator Responsibilities 31
16         APPENDICES            35
Appendix 1:      Patient instructions            35
Appendix 2:
Appendix 3:
Appendix 4:
Treatment diary     35
Visit #1 CRF          35
Visit #2 CRF          35
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LIST OF ABBREVIATIONS
AE
CFR
CRF
DMC
DSMB
FDA
GCP
cGVHD
HIPAA
ICF
ICH
IEC
IRB
OLP
PI
SAE
Version #:
adverse event
Code of Federal Regulations
case report form
Data Monitoring Committee
Data Safety Monitoring Board
Food and Drug Administration
Good Clinical Practice
chronic graft versus host disease
Health Insurance Portability and Accountability Act of 1996
informed consent form
International Conference on Harmonisation
Independent Ethics Committee
Institutional Review Board
Oral lichen planus
Principal Investigator
serious adverse experience
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PROTOCOL SYNOPSIS
TITLE
SPONSOR
FUNDING
ORGANIZATION
NUMBER OF SITES
RATIONALE
STUDY DESIGN
PRIMARY OBJECTIVE
SECONDARY
OBJECTIVES
NUMBER OF
SUBJECTS
SUBJECT SELECTION
DEXAMETHASONE SOLUTION AND DEXAMETHASONE IN
MUCOLOX FOR THE TREATMENT OF ORAL INFLAMMATORY
ULCERATIVE DISEASES
Professional Compounding Centers of America
1
Topical steroid therapy is considered the first line of treatment for Oral
Inflammatory Ulcerative Diseases with current treatment regimens requiring
multiple application or rinses daily. Although topical steroid therapy can be
successful for most patients, the treatment schedule can be challenging to
maintain. There is therefore considerable interest in developing new and
more effective therapies that require less frequent applications. The
possibility of having a treatment agent that is safe, easy to use, and cost
effective, with potentially greater efficacy than the current standard of care
available topical steroid solutions would be ideal. Using Mucolox as a
vehicle to deliver topical dexamethasone to the oral mucosa has the potential
to effectively prolong contact time between the medication and mucosa,
leading to improved clinical outcomes due to the need for less frequent
application. This technology would help to more efficiently achieve high
drug concentrations locally. By possibly shortening the frequency and time
of topical therapy and improving patient compliance, this may translate to
greater therapeutic benefit.
This is a randomized, phase 2 study.
The primary objective of this study is to determine the clinical efficacy and
tolerability of compound dexamethasone at 0.5 mg/5 mL in Mucolox for
the treatment of Oral Inflammatory Ulcerative Diseases as measured by a
reduction in oral symptoms between patients treated with compounded
dexamethasone 0.5mg/5ml solution in Mucolox (group A) and patients
treated with topical commercial dexamethasone 0.5mg/5ml solution only
(group B).
The secondary objectives are:
x To determine the clinical improvement in clinician-reported
outcome measures achieved by treatment with topical compounded
dexamethasone at 0.5 mg/5 mL in Mucolox compared to
commercial dexamethasone 0.5mg/5ml solution alone.
x To assess the tolerability of Oral Inflammatory Ulcerative Diseases
as measured with the 14-item Oral Health Impact Profile (OHIP-
14).
30
Inclusion Criteria:
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CRITERIA
Age 18 years and older.
Patients with symptomatic biopsy proven Oral Inflammatory Ulcerative
Diseases (worst VAS sensitivity score  7 over the last week).
Ability to understand and the willingness to sign a written informed consent
document.
Exclusion Criteria:
Patients already on topical or systemic steroids.
Inability to comply with study instructions.
Uncontrolled intercurrent illness or psychiatric illness/social situations that
would limit compliance with study requirements.
VAS sensitivity score < 7.
Pregnant women. A urine pregnancy test will be performed for women of
child bearing potential.
Allergy to fluconazole
Patients on medications that have a strong interaction with fluconazole
Patients with advanced liver disease
TEST PRODUCT, DOSE,
AND ROUTE OF
ADMINISTRATION
CONTROL PRODUCT,
DOSE AND ROUTE OF
ADMINISTRATION
DURATION OF SUBJECT
PARTICIPATION AND
DURATION OF STUDY
Dexamethasone 0.5 mg/5mL in Mucolox compounded oral solution swish
and spit TID for 4 weeks
Dexamethasone 0.5 mg/5mL (NDC 00054-3177-63; Roxane Laboratories,
Columbus, OH 43216-6532) oral solution swish and spit TID for 4 weeks
Subjects will be on study for up to 28 days
Screening: day 0
Treatment: 28 days
Follow-up: Day 28 + 5 days
The total duration of the study is expected to be 4 weeks.
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CONCOMMITANT
MEDICATIONS
EFFICACY
EVALUATIONS
PRIMARY ENDPOINT
SECONDARY
ENDPOINTS
Allowed: all
Prohibited: none
x
Change from pre to post treatment in each subject¶s subjective
sensitivity score (0-10) evaluated at baseline and 4 weeks post treatment
for each arm. We will also compare changes of the daily subject¶s
subjective sensitivity score (0-10) over time for each arm.
x
The secondary endpoints include the evaluation of objective data using
the REU scoring system and the oral health related quality of life using
the OHIP-14.
OTHER EVALUATIONS
SAFETY
EVALUATIONS
PLANNED INTERIM
ANALYSES
STATISTICS
Primary Analysis Plan
Rationale for Number of
Subjects
None
The safety of participants and the overall study will be monitored
continuously throughout the study period. At the 4 week visit, evaluating
doctors will review the participants¶ diaries for self-reported adverse events.
When approximately 50% of patients have completed the study, an interim
analysis for safety will be conducted by an independent data monitoring
committee. Serious adverse events will be monitored by the committee on an
ongoing basis throughout the study.
Pre-to-post treatment improvement will be assessed using McNemar¶s test
within each arm. The REU scores will be summarized descriptively for each
arm at pre-treatment, post-treatment, and pre-to-post treatment change. The
pre-to-post treatment change will be compared between the arms using
either student¶s t-test or Mann±Whitney test, depending on the distribution
of the data.
The sample size was calculated to ensure at least 80% power and two-sided
alpha of 0.05 in detecting a t difference of 2.0 points oral pain on an 11 point
scale (VAS 0-10) between Arm A and B.
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1
BACKGROUND
Oral Inflammatory Ulcerative Diseases are relatively common conditions seen in oral medicine
practices. These include oral lichen planus (OLP), pemphigus vulgaris, mucous membrane
pemphigoid (MMP) and oral chronic graft versus host disease (cGVHD).
Oral lichen planus
Oral lichen planus (OLP) is a benign, chronic condition that occurs in 1 to 2% of adults1. Middle-
aged women are twice as likely to be affected as men. OLP may be associated with a variety of
systemic and local conditions and medication use such as thiazide diuretics, angiotensin
converting enzyme (ACE) inhibitors, beta blockers, gold salts, sulfasalazine, sulfonylureas and
penicillamine. Biologic agents such as tumor necrosis factor (TNF) alpha inhibitors may also
cause lichen planus-like eruptions2. Amalgam and composite restorations may cause localized
contact lichenoid hypersensitivity reactions possibly to mercury and formaldehyde.
OLP can affect any mucosal surface, and most commonly affects the buccal mucosa and tongue
bilaterally. OLP can present with three distinct forms: reticular/keratotic, erosive/erythematous,
and ulcerative forms. The reticular/keratotic form, characterized by Wickham striae, is the most
common form and is often asymptomatic. Occasionally patients will report discomfort and
describe the buccal mucosa as ³rough,´ ³thick,´ or ³tight´. The erosive/erythematous form
typically presents as desquamative gingivitis. Patients may complain of discomfort while eating
acidic, spicy or crunchy food. The ulcerative form is the most severe and presents as shallow
ulcerations that have a yellow fibrin membrane on the surface. Often, there is a combination of the
three forms at different sites, or at different times. Most patients exhibit a characteristic bilateral
and symmetric distribution of lesions, typically involving the buccal mucosa, dorsum and ventral
surfaces of the tongue and/or gingiva.
The diagnosis of oral lichen planus is based primarily on clinical characteristics, although biopsy
may be indicated when the presentation is not typical (e.g. unilateral presentation, or lack of
reticulation features)3,4. Histopathological examination demonstrates a lymphocytic band of
variable thickness at the interface and degeneration or loss of the basal cell layer.
Mucous membrane pemphigoid
Mucous membrane pemphigoid is an autoimmune vesiculobullous disease associated with
increased frequency of HLA-DQB1*0301 and characterized by autoreactive antibodies, usually
IgG and sometimes IgA that target antigens in the epithelium-attachment complex resulting in
subepithelial blistering and mucosal fragility 5. MMP may involve the larynx, nose, eyes, and
genital mucosa. One of the major complications is conjunctival scarring that can lead to blindness
(hence the older term ³cicatricial pemphigoid´). Scarring may also involve the larynx and
esophagus, but fortunately is uncommon in the oral mucosa.
The oral mucosal lesions almost always affect the gingiva leading to bright red or ³desquamative
gingivitis´. This is caused by epithelium peeling off the gingiva leaving only exposed connective
tissue which is the basis for a positive Nikolsky sign. Ulcers may develop on the gingiva and
elsewhere in the mouth such as the palatal, buccal and tongue mucosa. Biopsy of a perilesional
area for histopathological examination and direct immunofluorescence (DIF) studies is essential
for a definitive diagnosis; DIF shows deposition of IgG, C3 and sometimes IgA at the basement
membrane zone.
Management includes topical treatment with corticosteroids or tacrolimus. Systemic agents such
as prednisone, dapsone, azathioprine, tetracycline, nicotinamide and cyclophosphamide may be
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required for management of refractory oral MMP. When the skin is involved, the diagnosis is
bullous pemphigoid.
Pemphigus vulgaris
Pemphigus vulgaris (PV) is an uncommon autoimmune vesiculo-bullous disorder that affects
mainly older adults and was fatal in the pre-steroid era. PV has a predilection for Ashkenazi Jews
(who exhibit a high frequency of HLA-B38 or HLA-B35), Arabs and others individuals from the
Mediterranean region. Different HLA subtypes are implicated in PV in Caucasians and Asians.
Autoantibodies, mostly IgG are directed towards the inter-epithelial cementing substance, leading
to intra-epithelial blistering 6. Oral ulcers, present in 95% of patients, are often the first sign of PV
with skin lesions developing later. Oral lesions are characterized by painful, irregular,
erythematous depressed erosions with whitish tissue tags at the edges; yellow ulcerations may also
be present. The most common affected oral sites are the hard and soft palatal mucosa (likely
because of physiologic trauma from swallowing), gingiva (also presenting as ³desquamative
gingivitis´), buccal mucosa and tongue. Diagnosis is established through a perilesional tissue
biopsy for histopathologic evaluation and DIF which shows intercellular deposition of IgG.
Topical corticosteroid therapy or topical tacrolimus are the mainstays of therapy. More severe or
refractory cases require systemic agents such as prednisone, mycophenolate mofetil, azathioprine
and cyclosporine. For severe cases and if the skin is involved, specialist referral is indicated and
treatment is generally with prednisone, rituximab (a monoclonal antibody), IVIg, or extracorporeal
photopheresis.
Chronic graft-versus-host disease
Chronic graft-versus-host disease remains a significant complication of allogeneic hematopoietic
cell (bone marrow) transplantation and continues to be the leading cause of non-relapse mortality.
The oral cavity is affected in around 80% of cases. 7 The spectrum of oral manifestations in
cGVHD includes reticular white lichen planus-like changes with erythema and minimal ulceration
that affects both the keratinized and non-keratinized mucosa. Patients typically complain of
sensitivity to spicy, acidic food or strongly flavored products. Topical therapy is similar to that for
OLP. Based on the NIH ancillary therapy and supportive care guidelines, initial therapy for most
patients is with dexamethasone solution 0.5mg/5mL; patients are instructed to swish/gargle for 4-6
minutes then spit, 4-6 times per day and to avoid eating or drinking for 10-15 minutes using the
medication. Other topical steroids with higher potency may also be prescribed (e.g., clobetasol).
1.1
Overview of Clinical Studies
1.1.1
Management of Oral Inflammatory Ulcerative Diseases
Available therapies for Oral Inflammatory Ulcerative Diseases are aimed at managing symptoms
through the reduction of inflammation. The mainstay of therapy remains use of topical
corticosteroids which can be delivered in various vehicles including gels and solutions1,8,9. A
response to treatment with midpotency corticosteroids (e.g., triamcinolone acetonide 0.1%), potent
fluorinated corticosteroids (e.g., fluocinolone acetonide 0.1% and fluocinonide 0.05%), and super-
potent halogenated corticosteroids (e.g., clobetasol propionate 0.05%), has been reported in 30±
100% of treated individuals10-15.
One of the challenges in applying topical corticosteroids is the lack of adherence to the oral
mucosa for an adequate duration for the medication to be locally absorbed. Numerous obstacles
are encountered when a topical steroid is prescribed to treat Oral Inflammatory Ulcerative
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Diseases, including the presence of saliva, changes in taste, poor tissue penetration, enzymatic
degradation, and the need for frequent dosing, all of which may negatively affect patient
compliance16. One approach to develop more efficacious and safer therapies could be
inflammation-targeting drug delivery to achieve high drug concentrations locally at the site of
inflammation with minimal exposure of healthy or distant tissues.
Use of topical steroids for Oral Inflammatory Ulcerative Diseases may lead to the development of
secondary candidiasis in 11-47% of patients, which requires antifungal therapy13,17,18. Fluconazole
200 mg once weekly has been showed to be an effective prophylaxis measure to prevent oral
candidiasis infection19-21. Although there are some reports of systemic absorption and adrenal
suppression from super-potent topical steroids in the treatment of chronic dermatologic disorders,
adrenal suppression is uncommon even in long-term oral application of topical corticosteroids
such as fluocinonide and clobetasol22-24. Systemic absorption from topical steroids has been
reported and it is thought that absorption of small amounts through the oral mucosa can take place,
but clinical experience and laboratory studies have shown this not to be of clinical significance in
almost all cases25. Gonzalez-Moles et al. reported two cases of moon facies (2/30) and two cases
of hirsutism (2/30) secondary to long-term use (> 4 weeks) of clobetasol 0.05% solution for the
treatment of oral erosive lesions. All cases resolved upon discontinuation of the medication and/or
reduction in frequency of administration. Other side effects reported include nausea, mucosal
atrophy, xerostomia, halitosis and delayed healing25,26.
1.1.2
Dexamethasone solution for Oral Inflammatory Ulcerative Diseases
The efficacy of dexamethasone solution has been well described in several clinical trials. Rhodus
et al. conducted a prospective controlled clinical trial to test the efficacy of dexamethasone
solution in 13 patients with oral erosive-ulcerative lichen planus27. Patients were instructed to rinse
with 5 ml of dexamethasone 0.1% solution for 3 min and then to expectorate. Subjective
symptomatology (pain and/or discomfort) was recorded on a 100 mm visual analogue scale (VAS)
at first visit and at 6 week follow up. Patients experienced significant subjective improvement in
symptoms following the dexamethasone treatment (VAS score pre-treatment: 6.7 ± 1.4; VAS
score post-treatment: 2.3 ± 0.6).
Hambly et al. conducted a single-blinded, cross-over pilot trial in nine patients to compare the
efficacy of compounded dexamethasone solution for OLP28. Patients were instructed to rinse with
2 ml of dexamethasone 0.5 mg/2 mL compounded as a solution or one 0.5 mg tablet crushed and
mixed with 20 ml water three times per day for 3 weeks. All patients were instructed to rinse and
hold the medication in their mouths for at least 2±3 minutes and then expectorate. Participants
were evaluated at weeks 0, 3, 4, and 7. Symptoms were recorded with a 100-mm VAS; other
assessments included the Treatment Satisfaction Questionnaire for Medication-9, comparisons of
clinical photographs, and self-assessment via patient daily diary (Appendix 2) entries to record
compliance with each dose. Results showed the compounded dexamethasone solution to be more
effective compared to 0.5 mg dexamethasone tablet crushed and mixed with 20 ml water in terms
of compliance, patient-perceived faster onset of action, and improved symptom relief.
1.1.3
Mucolox
Mucolox is a mucoadhesive polymer gel that can be used in pharmaceutical compounding for
the management of diseases and conditions of the oral mucosa including oral mucositis, and
mouth ulcers29,30. The safety and toxicological profile of Mucolox was evaluated in vitro and
compared to Triton X- 100 (positive control) and distilled water (negative control), using a 3-
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dimensional model of the human oral mucosa. Results showed that Mucolox can bind to tissues
six times longer than Triton X-100 (before 50% cell viability) therefore offering increased
retention of medication at the site of action. Additionally, at 4.5 hours, the difference in percent
cell viability between Mucolox and distilled water was not significant, making it a safe water-
soluble mucosal delivery system.
A recent study from our group showed that commercial dexamethasone 0.5mg/5mL solution
compounded with Mucolox was found to be a safe option for the management of oral lichen
planus when rinsed three times a day for 5-minute swish and expectorate31. Subjects receiving
dexamethasone 0.5mg/5mL solution in Mucolox had a better clinical response compared to
dexamethasone 0.5mg/5mL commercial solution alone (6-point reduction vs. 4.3; p<0.001) of
reticulation/keratosis, erythema, and ulceration (REU) scores. Both arms had a subjective
improvement of the oral symptoms after 4 weeks of treatment.
2
STUDY RATIONALE
There is a significant unmet need for optimized topical therapies for Oral Inflammatory Ulcerative
Diseases. Topical steroid therapy is considered the first line of treatment for Oral Inflammatory
Ulcerative Diseases with current treatment regimens requiring multiple application or rinses
daily27,32,33. Although topical steroid therapy can be successful for most patients, the treatment
schedule can be challenging to maintain. There is therefore considerable interest in developing
new and more effective therapies that require less frequent applications. The possibility of having
a treatment agent that is safe, easy to use, and cost effective, with potentially greater efficacy than
the current standard of care available topical steroid solutions would be ideal. Using Mucolox as
a vehicle to deliver topical dexamethasone to the oral mucosa has the potential to effectively
prolong contact time between the medication and mucosa, leading to improved clinical outcomes
due to the need for less frequent application. This technology would help to more efficiently
achieve high drug concentrations locally. By possibly shortening the frequency and time of topical
therapy and improving patient compliance, this may translate to greater therapeutic benefit. Our
initial work in a small number of oral lichen planus patients has demonstrated the efficacy of
dexamethasone 0.5mg/5mL solution in Mucolox in significantly improving signs and symptoms
of OLP compared to dexamethasone 0.5mg/5mL solution only31. As such, dexamethasone
0.5mg/5mL solution in Mucolox has the potential to be used also for other Oral Inflammatory
Ulcerative Diseases.
2.1
Risk / Benefit Assessment
2.1.1
Drug side effects and toxicities
Potential side effects with dexamethasone 0.5mg/5mL solution used as an oral topical rinse
include an increased risk of developing oropharyngeal candidiasis and systemic absorption. All
patients will be prescribed antifungal prophylaxis while on study with fluconazole 200 mg once a
week. All participants will be informed that they may withdraw from the study at any time. As a
topically applied agent, dexamethasone therapy can be discontinued at any time without any
complications. Any noted clinical response will be expected to be reversed in such situations.
Prolonged application of potent topical corticosteroids (e.g., > 50 g of clobetasol propionate or >
500 g of hydrocortisone per week) may lead to short-term hypothalamic-pituitary-adrenal axis
alteration. In our study, in case of any systemic absorption, the maximum dose would be 10.5
mg/week (5 mL x 0.1 mg/mL = 0.5 mg/rinse, 3 times/day = 1.5 mg, 7 days/week = 10.5 g). We do
not expect there to be significant systemic absorption, and therefore do not expect systemic side
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effects of dexamethasone solution when used as a swish and spit. Mucolox is a vehicle for drug
delivery used in compounding medications with ingredients expected to be harmless. No major
side effects from dexamethasone 0.5mg/5mL solution and dexamethasone 0.5mg/5mL solution in
Mucolox use were reported in our first preliminary study31.
2.1.2
Potential benefits for participating individuals
All subjects will be assigned an active treatment. Thus, it is anticipated that the majority of
participants may benefit from participation in this study. Additionally, most participants may
benefit from the satisfaction in knowing that their involvement has a potential impact on the
clinical care of future patients suffering from their condition.
3
STUDY OBJECTIVES
3.1
Primary Objective
The objective of this single center, 4-week, open label randomized, phase II study is to determine
the clinical efficacy and tolerability of compound dexamethasone at 0.5 mg/5mL in Mucolox
for the treatment of Oral Inflammatory Ulcerative Diseases as measured by a reduction in oral
symptoms between patients treated with compounded dexamethasone 0.5mg/5ml solution in
Mucolox (group A) and patients treated with commercial topical dexamethasone 0.5mg/5ml
solution only (group B).
Completion of this study will establish important data on the efficacy of topical steroid therapy
when combined with a carrier and delivery system such as Mucolox.
3.2
Secondary Objectives
The secondary objectives are:
x To determine the clinical improvement in clinician-reported outcome measures achieved
by treatment with topical compounded dexamethasone at 0.5 mg/5 mL in Mucolox
compared to commercial dexamethasone 0.5mg/5ml solution alone.
x To assess the tolerability of Oral Inflammatory Ulcerative Diseases as measured with the
14-item Oral Health Impact Profile (OHIP-14).
4
STUDY DESIGN
4.1
Study Overview
This is a single center, 4-week, open label randomized, phase II study. Randomization will be
conducted by the UCSF Investigational Drugs Services (IDS) Pharmacy. The study period will be
four weeks, which based on previous studies should be an adequate period to assess significant
clinical improvement. Subjects will be evaluated clinically at baseline before starting treatment
and at the end of the four-week period, for a total of two visits. Subjects will be randomized to
either compounded dexamethasone in Mucolox or commercial dexamethasone solution only.
Subjects will return for evaluation after four weeks at which time the primary end-points will be
assessed. Screening data will be reviewed to determine subject eligibility. Subjects who meet all
inclusion criteria and none of the exclusion criteria will be entered into the study.
The following treatment regimens will be used:
Experimental treatment: Dexamethasone solution (0.5mg/5ml) in Mucolox
Comparator: Commercial Dexamethasone solution (0.5mg/5ml)
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Total duration of subject participation will be four weeks. Total duration of the study is expected
to be 4-5 weeks.
5
CRITERIA FOR EVALUATION
5.1
Primary Efficacy Endpoint
The primary endpoint will be a change from pre to post treatment in each subject¶s subjective
sensitivity score (0-10) evaluated at baseline and 4 weeks post treatment for each arm. We will
also compare changes of the daily subject¶s subjective sensitivity score (0-10) over time for each
arm.
5.2
Secondary Efficacy Endpoints
The secondary objectives include the evaluation of objective data using the REU scoring system
and the oral health related quality of life using the OHIP-14. For the analysis of secondary
endpoints see the statistical section.
5.3
Safety Evaluations
The safety of participants and the overall study will be monitored continuously throughout the
study period. At the 4 week visit, evaluating physicians will review the participants¶ diaries for
self-reported adverse events. Subjects will be instructed to contact their treating physician by
phone or email to report any unexpected side effects or side effects lasting more than 7 days,
should they occur. Any necessary medical intervention will be handled by the treating physician.
Data accuracy and protocol compliance will be monitored and assured by the Principal
Investigator and toxicities will be reported promptly to the IRB
6
SUBJECT SELECTION
6.1
Study Population
The Sol Silverman Oral Medicine Clinic is a major referral center for oral medicine patients
including patients with Oral Inflammatory Ulcerative Diseases. Clinical diagnosis of Oral
Inflammatory Ulcerative Diseases will be made by the patient¶s oral medicine specialist. Patients
with a confirmed clinical diagnosis of Oral Inflammatory Ulcerative Diseases and with oral
symptoms (defined as the worst VAS sensitivity score 7 over the last week) will be eligible for
participation in this study. Potentially eligible subjects will be screened by one of the
investigators by asking patients to rate their worst oral pain score (0-10) over the previous week.
Those answering with at least a score of ³7´ (1/10) and that meet all other eligibility requirements
(see below) will be eligible for enrollment. All patients (and/or parents/guardians) will sign
informed consent for participation. All patients will be offered the opportunity to take home the
consent form, and call back if they wish to participate.
6.2
Inclusion Criteria
1.
Male or female  18 years of age at Visit 1.
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2.
Patients with symptomatic (worst VAS sensitivity score  7 over the last week) Oral
Inflammatory Ulcerative Diseases
3.
Written informed consent (and assent when applicable) obtained from subject or subject¶s
legal representative and ability for subject to comply with the requirements of the study.
6.3
Exclusion Criteria
1. Patients already on topical or systemic steroids.
2. Inability to comply with study instructions.
3. Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit
compliance with study requirements.
4. VAS sensitivity score < 7.
5. Pregnant women. A urine pregnancy test will be performed for women of child bearing
potential.
6. Allergy to fluconazole
7. Allergy to dexamethasone or other steroids
8. Patients on medications that have a strong interaction with fluconazole
9. Patients with advanced liver disease
10. Presence of a condition or abnormality that in the opinion of the Investigator would
compromise the safety of the patient or the quality of the data.
7
CONCURRENT MEDICATIONS
There will be no restrictions on concomitant medications or supportive care measures.
All subjects will be treated with fluconazole 200 mg tablets once-a-week dosing for prophylaxis as
topical steroid therapy may increase the risk of candidiasis. This is typically very effective at
preventing candidiasis in susceptible patients, and since there are no interim clinical visits, this
will minimize the risk of secondary infection, which if not detected early, could confound the
results at the week 4 evaluation. A single weekly dose of fluconazole is not sufficient to have an
impact on therapeutic levels of other medications. Fluconazole is a pregnancy category D drug. A
such, pregnant women will be excluded from this study.
Any subjects that are already taking a systemic antifungal medication at the time of study
enrollment will continue their prescribed medication and will not need to take the additional
weekly fluconazole dose.
8
STUDY TREATMENTS
8.1
Method of Assigning Subjects to Treatment Groups
Randomization will be predetermined by a computer-generated list and coordinated by the UCSF
Investigational Drugs Services Pharmacy. Patients will be assigned to one of two groups: 1) Arm
A: compounded dexamethasone 0.5mg/5ml solution in Mucolox or 2) commercial
dexamethasone 0.5mg/5ml solution only (ARM B).
8.2
Blinding
This is an open label trial with no blinding.
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8.3
Formulation of Test and Control Products
8.3.1
Mucolox
Description
Mucolox (PCCA, Houston, TX 77099) is a mucoadhesive polymer designed to improve
mucoadhesion and prolong retention of medications at application sites within the oral mucosa.
The composition of Mucolox is outlined in the table below.
Ingredient Name
INCI Name/Technical Classification
FDA Reference
Potassium Sorbate NF Potassium Sorbate
Sodium Benzoate NF Sodium Benzoate
Subpart D ± Chemical
Preservatives
Subpart D ± Chemical
Preservatives
21 CFR
582.3640
21 CFR
582.3733
Glycerin USP
(Natural)
Edetate Disodium
USP Dihydrate
Pullulan
Glycerin
Disodium EDTA
Pullulan
Subpart B ± General Purpose
Food Additive
FDA has no questions regarding
intended use.
FDA has no questions regarding
intended use in certain foods.
21 CFR
582.1320
GRN000363
GRN000099
Tamarindus Indica
Seed Polysaccharide
Tamarindus Indica Seed FDA has no questions regarding
Polysaccharide
intended use.
GRN000503
Isomalt
Simethicone USP
Sodium Hyaluronate
Poloxamer 407
Isomalt
Simethicone
Sodium Hyaluronate
Poloxamer 407
Self-Determined GRAS (1996)
Used in Various Routes, Dosage
Forms and Maximum Potencies
Used in Various Routes, Dosage
Forms and Maximum Potencies
Used in Various Routes, Dosage
Forms and Maximum Potencies
GRN6G0321
UNII: Multiple
(Mixture)
UNII:
YSE9PPT4TH
UNII:
TUF2IVW3M2
Zea Mays (Corn)
Starch
Used in Various Routes, Dosage
Forms and Maximum Potencies
UNII:
O8232NY3SJ
Carbomer
Water
Carbomer
Water
Used in Various Routes, Dosage
Forms and Maximum Potencies
(Type: Proprietary)
N/A
UNII: Type
Proprietary
UNII:
059QF0KO0R
Compatibility
N/A
Handling
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There are no special handling requirements.
Availability
Compounded dexamethasone solution in Mucolox will be dosed at a concentration of 0.5
mg/5mL and dispensed through the UCSF Investigational Drugs Services Pharmacy. The
prescription for the patients in ARM B (dexamethasone) will also be dispensed through the UCSF
Investigational Drugs Services Pharmacy.
Preparation
Study subjects will be given a kit with the following, including detailed written instructions (see
Appendix 1):
ARM A
x
A four week supply of compounded dexamethasone solution in Mucolox will be dispensed,
with extra for error and spillage, which will be rounded to 480 mL bottle at a concentration of
0.5 mg/5mL.
x
Small dosing cups
Administration
Subjects will be instructed to rinse with 5 ml of compounded dexamethasone solution in
Mucolox (0.5 mg/5ml; ARM A) for 5 minutes. After 5 minutes, subjects will be instructed to
expectorate and to not eat or drink for 15 minutes after. The rinses will be completed three times
per day, equally spaced during awake hours. If a study rinse is missed, subjects will be asked to
attempt to make up for the missed rinse later the same day, to maintain four rinses per day. If
necessary, for example, two consecutive 5-minute rinses can be completed at night before bed.
This does not pose any known safety risk.
Ordering
Study rinses will be ordered through the UCSF Investigational Drugs Services Pharmacy.
Availability
Dexamethasone 0.5mg/5mL solution in Mucolox will be compounded and dispensed through the
UCSF Investigational Drugs Services Pharmacy.
Destruction and Return
Patients should not continue to use any unused study supply once they have completed the study.
It should be returned to the investigator and will be sent to pharmacy for destruction.
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8.4
Dexamethasone solution
Description
Dexamethasone (NDC 00054-3177-63; Roxane Laboratories, Columbus, OH 43216-6532)
is a synthetic adrenocortical steroid commercially available as a 0.5mg/5mL solution. It is stable
in air and practically insoluble in water.
x
The molecular weight is 392.47.
x
The molecular formula is C22H29FO5
x
The structural formula is:
Each 5 mL of oral solution contains 0.5 mg of dexamethasone and citric acid, disodium edetate,
flavoring, glycerin, methylparaben, propylene glycol, propylparaben, sorbitol and water.
Storage and Stability
Dexamethasone solution is stable at room temperature for 30 days after opening per package
insert.
Compatibility
N/A
Handling
There are no special handling requirements.
Availability
Dexamethasone 0.5mg/5mL solution will be dispensed through the UCSF Investigational Drugs
Services Pharmacy.
Preparation
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Study subjects will be given a kit with the following, including detailed written instructions (see
Appendix 1):
ARM B
x
A four-week supply of dexamethasone solution will be dispensed, with extra for error and
spillage, which will be rounded to 480 mL bottle at a concentration of 0.5 mg/5mL.
x
Small dosing cups
Administration
Subjects will be instructed to rinse with 5 ml of the prescribed dexamethasone 0.5mg/5ml solution
(ARM B) for 5 minutes. After 5 minutes, subjects will be instructed to expectorate and to not eat
or drink for 15 minutes after. The rinses will be completed three times per day, equally spaced
during awake hours. If a study rinse is missed, subjects will be asked to attempt to make up for
the missed rinse later the same day, to maintain four rinses per day. If necessary, for example, two
consecutive 5 minute rinses can be completed at night before bed. This does not pose any known
safety risk.
Ordering
Dexamethasone solution will be ordered through the UCSF Investigational Drugs Services
Pharmacy.
Destruction and Return
Patients should not continue to use any unused study supply once they have completed the study.
It should be returned to the investigator for destruction.
8.5
Study Drug Accountability
An accurate and current accounting of the dispensing and return of study drug for each subject will
be maintained on an ongoing basis by a member of the study site staff. The number of study drug
dispensed and returned by the subject will be recorded on the Investigational Drug Accountability
Record. The study monitor will verify these documents throughout the course of the study.
8.6
Measures of Treatment Compliance
Subjects will be asked to keep a patient diary (Appendix 2) noting the day and date they take their
study drug and any adverse events. They will be asked to bring their patient diary to each study
visit along with all used and unused study drug containers.
9
STUDY PROCEDURES AND GUIDELINES
Prior to conducting any study-related activities, written informed consent and the Health Insurance
Portability and Accountability Act (HIPAA) authorization must be signed and dated by the subject
or subject¶s legal representative. If appropriate, assent must also be obtained prior to conducting
any study-related activities.
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9.1
Clinical Assessments
9.1.1
Concomitant Medications
All concomitant medication and concurrent therapies will be documented at Baseline/Screening
and at Study Visits 1, and at early termination when applicable. Dose, route, unit frequency of
administration, and indication for administration and dates of medication will be captured.
9.1.2
Demographics
Demographic information (date of birth, gender, race) will be recorded at Screening.
9.1.3
Medical History
Relevant medical history, including history of current disease, other pertinent respiratory history,
and information regarding underlying diseases will be recorded at Screening.
9.2
Study procedures
Potentially eligible subjects will be screened by one of the investigators by asking patients to rate
their worst oral pain or pain score (0-10) over the previous week on a VAS. Those answering with
at least a score of ³7´ (1/10) and that meet all other eligibility requirements (see Section 6) will be
eligible for enrollment. All patients will sign informed consent for study participation. Each study
visit is anticipated to take approximately 45 minutes. A urine pregnancy test will be performed for
women of child bearing potential.
There is no financial compensation for participating in this study. Treatment will be administered
on an outpatient basis. Study medication will be prescribed by authorized study staff physicians
and filled by the Investigational Pharmacy at no expense for the patient. No investigational or
commercial agents or therapies other than those described below may be administered with the
intent to treat the participant¶s Oral Inflammatory Ulcerative Diseases.
Subjects will be evaluated clinically at baseline before starting treatment and at the end of the
four-week period, for a total of two visits. Comprehensive subjective and objective data will be
collected (Appendix 3 & 4) and intraoral photographs will be obtained. Oral mucosal disease will
be evaluated using both patient reported (questions/visual analog scales) and clinician assessed
measures.
Subjects will be prescribed compounded dexamethasone 0.5mg/5ml solution in Mucolox (ARM
A) or commercial dexamethasone 0.5mg/5ml solution only (ARM B). All subjects will also
receive a prescription for fluconazole 200 mg tablets once-a-week as prophylactic antifungal
therapy. Any subjects that are already taking an antifungal oral medication at the time of the study
enrollment will continue their prescribed medication and will not need to take the additional
weekly fluconazole dose. Subjects will return for evaluation after four weeks at which time the
study endpoints will be assessed.
If there is worsening of Oral Inflammatory Ulcerative Diseases that requires initiation of new
immunomodulatory medications (systemic or topical), patients will remain on treatment, but will
be regarded as unevaluable for the primary endpoint.
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Clinical examination
OHIP-14
Patient Reported Outcomes
Day 1
(baseline)
x
x
x
Day 28 + 5 days
(end of study)
x
x
x
9.2.1
Clinician Reported Outcomes
Mucosal disease will be measured using the REU scoring system for monitoring Oral
Inflammatory Ulcerative Diseases34. Assessment requires only a light source and a dental mirror.
This is a validated semiquantitative instrument for monitoring reticular/hyperkeratotic,
erosive/erythematous, and ulcerative OLP lesions. The oral cavity is divided into ten sites: right
buccal mucosa, left buccal mucosa, tongue dorsum, tongue ventrum, maxillary gingiva,
mandibular gingiva, floor of mouth, hard palatal mucosa, soft palate and tonsil, and labial mucosa
(upper and lower together). The severity of each type of lesion is scored according to the presence
or absence of reticulations/hyperkeratosis (0 = absent; 1 = present), and the size of the
erosions/erythema or ulcers (in cm2) (0 = no involvement; 1-3 in increasing area of involvement).
Because each type of lesion causes different degrees of discomfort and pain, each type of lesion is
weighted accordingly: reticular lesions are weighted 1 because this presentation tends to be
asymptomatic; erosive/erythematous lesions are weighted 1.5 since they tend to cause some
degree of discomfort; ulcerative lesions are weighted 2.0 since they tend to be the most painful.
The scores for each anatomic site are then totaled.
Intraoral photographs will be obtained at each visit.
9.2.2
Oral Health Impact Profile
Patients will complete the 14-item Oral Health Impact Profile (OHIP-14) instrument at baseline
and at the end of treatment35. This is a validated instrument that assesses various aspects of oral
health and function that has been shown to perform well in patients with oral mucosal diseases,
including Oral Inflammatory Ulcerative Diseases36.
9.2.3
Patient Reported Outcomes
Subjective assessments of subjects¶ oral symptoms will be obtained by using instruments from the
NIH consensus documents for oral cGVHD, a condition that is very similar to other Oral
Inflammatory Ulcerative Diseases (see Appendix 3 &4). These include report of mouth sensitivity
at rest and sensitivity with stimulation (e.g. eating) on an eleven point scale. For the primary
endpoint the worst sensitivity in the past week will be used. The clinician seeing the subject will
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complete these forms at each study visit. Patients will also report daily sensitivity on an eleven
point scale (see Appendix 2). Tolerability and compliance will also be evaluated, and a patient
reported global assessment of overall improvement will be evaluated at the four-week visit.
9.2.4
Treatment Regimen
A four week supply of compounded dexamethasone 0.5mg/5ml solution in Mucolox (Arm A)
and dexamethasone 0.5mg/5ml solution (Arm B) will be dispensed. The treatment instructions
will be to rinse and spit (NOT swallow) with one teaspoon (5 mL) of solution, three times a day
for 5 minutes at a time, and not to eat or drink for 15 minutes afterwards. Subjects will maintain a
diary (Appendix 2) and record each dose, the length of time rinsing, and any adverse effects (e.g.
transient burning).
Regimen Description
Arm A
Arm B
(standard
of care)
Agent
Dexamethasone
in Mucolox
Dexamethasone
solution
Premedications;
Precautions*
None
None
Dose
5mL x
0.1mg/mL
= 0.5
mg/rinse, 3
times/day
=1.5 mg
5mL x
0.1mg/mL
= 0.5
mg/rinse, 3
times/day
=1.5 mg
Route
Oral Rinse, 5
mins. each time
(do not
swallow)
Oral Rinse, 5
mins. each time
(do not
swallow)
Schedule
7
days/week
7
days/week
Cycle
Length
28 days
(4
weeks)
One
Cycle
Only*
28 days
(4
weeks)
One
Cycle
Only*
*All subjects will be treated with fluconazole 200 mg once-a-week dosing for prophylaxis (see
section 5.5)
9.3
Study Agents Administration
The Investigator or co-investigators will prescribe the study drug in the clinic and instruct the
patient on study drug use. Both dexamethasone compounded 0.5mg/5ml solution in Mucolox
and commercial dexamethasone solution will be dosed topically at a concentration of 0.5 mg/5mL.
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A four week supply will be dispensed. The treatment instructions will be to rinse and spit (NOT
swallow) with one teaspoon (5 mL) of the solution, three times a day for 5 minutes at a time, and
not to eat or drink for 15 minutes afterwards. Subjects will maintain a diary (Appendix 2) and
record each dose, the length of time rinsing, and any adverse effects.
9.3.1
Adverse Events
Information regarding occurrence of adverse events will be captured throughout the study.
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation to study
drug will be recorded on the case report form (CRF). The PI or covering clinician will determine
whether an adverse event was expected and/or related to study procedures. Study subjects will be
asked to report any adverse events or concerns to study staff as they arise.
9.3.2
Pregnancy Test
A urine pregnancy test will be obtained from female subjects who are of childbearing age prior to
their participation in the study.
10 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION
10.1 Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient
administered a pharmaceutical product and that does not necessarily have a causal relationship
with the treatment. An AE is therefore any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom or disease temporally associated with the administration
of an investigational product, whether or not related to that investigational product. An
unexpected AE is one of a type not identified in nature, severity, or frequency in the current
Investigator¶s Brochure or of greater severity or frequency than expected based on the information
in the Investigator¶s Brochure.
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each
subject visit and record the information in the site¶s source documents. Adverse events will be
recorded in the patient CRF. Adverse events will be described by duration (start and stop dates
and times), severity, outcome, treatment and relation to study drug, or if unrelated, the cause.
AE Severity
The National Cancer Institute¶s Common Terminology Criteria for Adverse Events (CTCAE)
Version 3.0 should be used to assess and grade AE severity, including laboratory abnormalities
judged to be clinically significant. The modified criteria can be found in the study manual. If the
experience is not covered in the modified criteria, the guidelines shown in Table 1 below should
be used to grade severity. It should be pointed out that the term ³severe´ is a measure of intensity
and that a severe AE is not necessarily serious.
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Table 1. AE Severity Grading
Severity (Toxicity Grade)
Mild (1)
Moderate (2)
Severe (3)
Life-threatening (4)
Confidential
Description
Transient or mild discomfort; no limitation in activity; no medical
intervention or therapy required. The subject may be aware of the sign
or symptom but tolerates it reasonably well.
Mild to moderate limitation in activity, no or minimal medical
intervention/therapy required.
Marked limitation in activity, medical intervention/therapy required,
hospitalizations possible.
The subject is at risk of death due to the adverse experience as it
occurred. This does not refer to an experience that hypothetically
might have caused death if it were more severe.
AE Relationship to Study Drug
The relationship of an AE to the study drug should be assessed using the following the guidelines
in Table 2.
Table 2. AE Relationship to Study Drug
Relationship
to Drug
Definitely
Probably
Possibly
Unrelated
Comment
Previously known toxicity of agent; or an event that follows a reasonable temporal
sequence from administration of the drug; that follows a known or expected response
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of
the drug; and that is not explained by any other reasonable hypothesis.
An event that follows a reasonable temporal sequence from administration of the
drug; that follows a known or expected response pattern to the suspected drug; that is
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be
explained by the known characteristics of the subject¶s clinical state or by other
interventions.
An event that follows a reasonable temporal sequence from administration of the
drug; that follows a known or expected response pattern to that suspected drug; but
that could readily have been produced by a number of other factors.
An event that can be determined with certainty to have no relationship to the study
drug.
10.2 Serious Adverse Experiences (SAE)
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes:
1. death
2. a life-threatening adverse experience
3. inpatient hospitalization or prolongation of existing hospitalization
4. a persistent or significant disability/incapacity
5. a congenital anomaly/birth defect
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Other important medical events may also be considered an SAE when, based on appropriate
medical judgment, they jeopardize the subject or require intervention to prevent one of the
outcomes listed.
10.2.1 Serious Adverse Experience Reporting
Study sites will document all SAEs that occur (whether or not related to study drug) per UCSF
CHR Guidelines. The collection period for all SAEs will begin after informed consent is obtained
and end after procedures for the final study visit have been completed.
In accordance with the standard operating procedures and policies of the local Institutional Review
Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs to the
IRB/IEC.
10.3 Medical Monitoring
Dr. Alessandro Villa should be contacted directly at these numbers to report medical concerns or
questions regarding safety.
Phone: 415-476-2431 (office); 415-476-2045 (clinic)
11 DISCONTINUATION AND REPLACEMENT OF SUBJECTS
11.1 Early Discontinuation of Study Drug
A subject may be discontinued from study treatment at any time if the subject, the investigator, or
the Sponsor feels that it is not in the subject¶s best interest to continue. The following is a list of
possible reasons for study treatment discontinuation:
-
Subject withdrawal of consent (or assent)
-
Subject is not compliant with study procedures
-
Adverse event that in the opinion of the investigator would be in the best interest of the subject
to discontinue study treatment
-
Protocol violation requiring discontinuation of study treatment
-
Lost to follow-up
-
Sponsor request for early termination of study
-
Positive pregnancy test (females)
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed and
treated by the Investigator until the abnormal parameter or symptom has resolved or stabilized.
All subjects who discontinue study treatment should come in for an early discontinuation visit as
soon as possible and then should be encouraged to complete all remaining scheduled visits and
procedures.
All subjects are free to withdraw from participation at any time, for any reason, specified or
unspecified, and without prejudice.
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Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.
The reason for the subject¶s withdrawal from the study will be specified in the subject¶s source
documents (see below for early termination procedures).
12.3
Withdrawal of Subjects from the Study
A subject may be withdrawn from the study at any time if the subject, the investigator, or the
Sponsor feels that it is not in the subject¶s best interest to continue.
All subjects are free to withdraw from participation at any time, for any reason, specified or
unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.
The reason for the subject¶s withdrawal from the study will be specified in the subject¶s source
documents. As noted above, subjects who discontinue study treatment early (i.e., they withdraw
prior to Visit 2) should have an early discontinuation visit. Subjects who withdraw after Visit 1
but prior to Visit 2 should be encouraged to come in for a final visit (and the procedures to be
followed would include those for their next scheduled visit).
12.4
Replacement of Subjects
Subjects who withdraw from the study treatment will be replaced.
12 PROTOCOL VIOLATIONS
A protocol violation occurs when the subject, investigator, or Sponsor fails to adhere to significant
protocol requirements affecting the inclusion, exclusion, subject safety and primary endpoint
criteria. Protocol violations for this study include, but are not limited to, the following:
-
Failure to meet inclusion/exclusion criteria
-
Use of a prohibited concomitant medication
-
Non-compliance with study drug regimen
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol
violation. The Sponsor will determine if a protocol violation will result in withdrawal of a subject.
When a protocol violation occurs, it will be discussed with the investigator and a Protocol
Violation Form detailing the violation will be generated. This form will be signed by a Sponsor
representative and the Investigator. A copy of the form will be filed in the site¶s regulatory binder
and in the Sponsor¶s files.
Compliance will be monitored closely. Non-compliant patients who use the treatment fewer than 2
times a day for more than 2 weeks (as determined by review of the treatment diary at the week 4
visit) will be considered unevaluable for the primary endpoint and replaced with new patients.
These patients, however, will be included in the toxicity report. During the four-week period when
patients are receiving study treatment, additions of new immunomodulatory medications (systemic
or topical in the mouth) are allowed, but these patients will be regarded as unevaluable for the
primary endpoint and will be replaced.
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13 STATISTICAL METHODS AND CONSIDERATIONS
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be
written describing all analyses that will be performed. The SAP will contain any modifications to
the analysis plan described below.
13.1 Study design/Endpoints
The primary objective of this open label randomized phase II study is to evaluate the efficacy and
tolerability of topical compounded dexamethasone solution in a Mucolox for the treatment of
Oral Inflammatory Ulcerative Diseases. The primary endpoint will be a change from pre to post
treatment in each subject¶s subjective sensitivity score (0-10) evaluated at baseline and 4 weeks
post treatment for each arm. We will also compare changes of the daily subject¶s subjective
sensitivity score (0-10) over time for each arm.
The secondary objectives include the evaluation of objective data using the REU scoring system
and the oral health related quality of life using the OHIP-14.
13.1.1 Analysis of Primary Endpoints
VAS scores will be summarized descriptively for each arm at pre-treatment, post-treatment, and
pre-to-post treatment change. The pre-to-post treatment change will be compared between the
arms using either Student¶s t-test or Mann±Whitney test, depending on the distribution of the data.
13.1.2 Analysis of Secondary Endpoints
Oral health related quality of life will be assessed before and after topical therapy using the 14-item
Oral Health Impacts Profile (OHIP-14; see Appendix 5) instrument that measures subject's
perceptions of the impact of oral conditions on their well-being. The OHIP-14 scores will be
summarized descriptively for each arm at pre-treatment, post-treatment, and pre-to-post treatment
change. The pre-to-post treatment change for each item and for all items combined will be
assessed within each arm using either paired t test or Wilcoxon-signed-rank test depending on its
distribution. In addition, each question will be dichotomized and classified as µresponse¶ if the
answer is µnot at all¶, or µslightly¶ to a question such as ³how isolated do you feel as a result of this
oral condition´, and pre-to-post treatment improvement will be assessed using McNemar¶s test
within each arm.
In order to evaluate the clinical improvement in clinician-reported outcome measures for Oral
Inflammatory Ulcerative Diseases, REU scores within the compound dexamethasone solution in
Mucolox group (Arm A) will be compared to that in the dexamethasone solution only group
(Arm B). The REU scores will be summarized descriptively for each arm at pre-treatment, post-
treatment, and pre-to-post treatment change. The pre-to-post treatment change will be compared
between the arms using either student¶s t-test or Mann±Whitney test, depending on the distribution
of the data.
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13.2 Sample Size, Accrual Rate and Study Duration
The sample size was calculated based on the data by Rhodus et al., as to ensure at least 80% power
and two-sided alpha of 0.05 in detecting a t difference of 2.0 points oral pain on an 11 point scale
(VAS 0-10) between Arm A and B27. The mean expected change for Arm A will be 6.5 points
reduction with a standard deviation of 1.4 points. The mean expected change for Arm B will be
4.5 points reduction with a standard deviation of 1.4 points.
A total of 15 patients per arm will be enrolled (total of 30 subjects). The proposed sample size
includes a loss of follow up of 5%. Approximately 60 patients per year are diagnosed with Oral
Inflammatory Ulcerative Diseases at the Sol Silverman Oral Medicine Clinic at UCSF. We
anticipate the accrual rate will be approximately 2 patients per month, thus the accrual goal will be
achieved in approximately 15 months.
13.3 Interim Analysis
Involvement in this study as a participating investigator implies acceptance of potential audits or
inspections, including source data verification, by representatives designated by or the Overall
Principal Investigator. The purpose of these audits or inspections is to examine study-related
activities and documents to determine whether these activities were conducted, and data were
recorded, analyzed, and accurately reported in accordance with the protocol, institutional policy,
Good Clinical Practice (GCP), and any applicable regulatory requirements.
14 DATA COLLECTION, RETENTION AND MONITORING
14.1 Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents designed to
record all observations and other pertinent data for each subject treated with the study drug.
Study personnel at the study site will enter data from source documents corresponding to a
subject¶s visit into the protocol-specific paper CRF when the information corresponding to that
visit is available. Subjects will not be identified by name in the study database or on any study
documents to be collected by the Sponsor (or designee), but will be identified by a site number,
subject number and initials.
The Investigator is responsible for all information collected on subjects enrolled in this study. All
data collected during the course of this study must be reviewed and verified for completeness and
accuracy by the Investigator. A copy of the CRF will remain at the Investigator¶s site at the
completion of the study.
14.2 Data Management Procedures
The data will be entered into a validated database. The Data Management group will be
responsible for data processing, in accordance with procedural documentation. Database lock will
occur once quality assurance procedures have been completed.
All procedures for the handling and analysis of data will be conducted using good computing
practices meeting FDA guidelines for the handling and analysis of data for clinical trials.
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14.3 Data Quality Control and Reporting
After data have been entered into the study database, a system of computerized data validation
checks will be implemented and applied to the database on a regular basis. Query reports (Data
Clarification Requests) pertaining to data omissions and discrepancies will be forwarded to the
Investigators and study monitors for resolution. The study database will be updated in accordance
with the resolved queries. All changes to the study database will be documented.
14.4 Archival of Data
The database is safeguarded against unauthorized access by established security procedures;
appropriate backup copies of the database and related software files will be maintained.
Databases are backed up by the database administrator in conjunction with any updates or changes
to the database.
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for
analysis is locked and cleaned per established procedures.
14.5 Availability and Retention of Investigational Records
The Investigator must make study data accessible to the monitor, other authorized representatives
of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon
request. A file for each subject must be maintained that includes the signed Informed Consent,
HIPAA Authorization and Assent Form and copies of all source documentation related to that
subject. The Investigator must ensure the reliability and availability of source documents from
which the information on the CRF was derived.
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File
Notebook, etc.) must be kept secured for a period of two years following marketing of the
investigational product or for two years after centers have been notified that the IND has been
discontinued. There may be other circumstances for which the Sponsor is required to maintain
study records and, therefore, the Sponsor should be contacted prior to removing study records for
any reason.
14.6 Monitoring
Monitoring visits will be conducted by representatives of the Sponsor according to the U.S. CFR
Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). By signing this protocol, the
Investigator grants permission to the Sponsor (or designee), and appropriate regulatory authorities
to conduct on-site monitoring and/or auditing of all appropriate study documentation.
14.7 Subject Confidentiality
In order to maintain subject confidentiality, only a site number, subject number and subject initials
will identify all study subjects on CRFs and other documentation submitted to the Sponsor.
Additional subject confidentiality issues (if applicable) are covered in the Clinical Study
Agreement.
15 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of Human
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical
Investigators (21 CFR 312).
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records
will be identified by a coded number and initials only. All study records will be kept in a locked
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file cabinet and code sheets linking a patient¶s name to a patient identification number will be
stored separately in another locked file cabinet. Clinical information will not be released without
written permission of the subject, except as necessary for monitoring by the FDA. The
Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC).
15.1 Protocol Amendments
Any amendment to the protocol will be written by the PI. Protocol amendments cannot be
implemented without prior written IRB/IEC approval except as necessary to eliminate immediate
safety hazards to patients. A protocol amendment intended to eliminate an apparent immediate
hazard to patients may be implemented immediately, provided the IRBs are notified within five
working days.
15.2 Institutional Review Boards and Independent Ethics Committees
The protocol and consent form will be reviewed and approved by the IRB/IEC of each
participating center prior to study initiation. Serious adverse experiences regardless of causality
will be reported to the IRB/IEC in accordance with the standard operating procedures and policies
of the IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress of the
study. The Investigator will obtain assurance of IRB/IEC compliance with regulations.
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, protocol
amendments, Investigator¶s Brochure, consent forms, information concerning patient recruitment,
payment or compensation procedures, or other pertinent information) will be submitted to the
IRB/IEC. The IRB/IECs written unconditional approval of the study protocol and the informed
consent form will be in the possession of the Investigator before the study is initiated. The
IRB/IECs unconditional approval statement will be transmitted by the Investigator to the Sponsor
or designee prior to the shipment of study supplies to the site. This approval must refer to the
study by exact protocol title and number and should identify the documents reviewed and the date
of review.
Protocol and/or informed consent modifications or changes may not be initiated without prior
written IRB/IEC approval except when necessary to eliminate immediate hazards to the patients or
when the change(s) involves only logistical or administrative aspects of the study. Such
modifications will be submitted to the IRB/IEC and written verification that the modification was
submitted and subsequently approved should be obtained.
The IRB/IEC must be informed of revisions to other documents originally submitted for review;
serious and/or unexpected adverse experiences occurring during the study in accordance with the
standard operating procedures and policies of the IRB; new information that may affect adversely
the safety of the patients of the conduct of the study; an annual update and/or request for re-
approval; and when the study has been completed.
15.3 Informed Consent Form
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27,
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if
applicable), and local regulations.
The Investigator will prepare the informed consent form, assent and HIPAA authorization and
provide the documents to the Sponsor or designee for approval prior to submission to the
IRB/IEC. The consent form generated by the Investigator must be acceptable to the Sponsor and
be approved by the IRB/IEC. The written consent document will embody the elements of
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informed consent as described in the International Conference on Harmonisation and will also
comply with local regulations. The Investigator will send an IRB/IEC-approved copy of the
Informed Consent Form to the Sponsor (or designee) for the study file.
A properly executed, written, informed consent will be obtained from each subject prior to
entering the subject into the trial. Information should be given in both oral and written form and
subjects (or their legal representatives) must be given ample opportunity to inquire about details of
the study. If appropriate and required by the local IRB/IEC, assent from the subject will also be
obtained. If a subject is unable to sign the informed consent form (ICF) and the HIPAA
authorization, a legal representative may sign for the subject. A copy of the signed consent form
(and assent) will be given to the subject or legal representative of the subject and the original will
be maintained with the subject¶s records.
15.4 Publications
The preparation and submittal for publication of manuscripts containing the study results shall be
in accordance with a process determined by mutual written agreement among the study Sponsor
and participating institutions. The publication or presentation of any study results shall comply
with all applicable privacy laws, including, but not limited to, the Health Insurance Portability and
Accountability Act of 1996.
15.5 Investigator Responsibilities
By signing the Agreement of Investigator form, the Investigator agrees to:
1.
Conduct the study in accordance with the protocol and only make changes after notifying the
Sponsor (or designee), except when to protect the safety, rights or welfare of subjects.
2.
Personally conduct or supervise the study (or investigation).
3.
Ensure that the requirements relating to obtaining informed consent and IRB review and
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.
4.
Report to the Sponsor or designee any AEs that occur in the course of the study, in
accordance with §21 CFR 312.64.
5.
Ensure that all associates, colleagues and employees assisting in the conduct of the study are
informed about their obligations in meeting the above commitments.
6.
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make
those records available for inspection with the Sponsor (or designee).
7.
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be
responsible for initial and continuing review and approval of the clinical study.
8.
Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity
and all unanticipated problems involving risks to subjects or others (to include amendments
and IND safety reports).
9.
Seek IRB approval before any changes are made in the research study, except when necessary
to eliminate hazards to the patients/subjects.
10. Comply with all other requirements regarding the obligations of clinical investigators and all
other pertinent requirements listed in § 21 CFR part 312.
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References:
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diagnostic and therapeutic considerations. Oral surgery, oral medicine, oral pathology, oral
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Baccaglini L, Thongprasom K, Carrozzo M, Bigby M. Urban legends series: lichen planus.
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Ismail SB, Kumar SK, Zain RB. Oral lichen planus and lichenoid reactions: etiopathogenesis,
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Buajeeb W, Pobrurksa C, Kraivaphan P. Efficacy of fluocinolone acetonide gel in the treatment
of oral lichen planus. Oral surgery, oral medicine, oral pathology, oral radiology, and
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Thongprasom K, Luengvisut P, Wongwatanakij A, Boonjatturus C. Clinical evaluation in
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Hegarty AM, Hodgson TA, Lewsey JD, Porter SR. Fluticasone propionate spray and
betamethasone sodium phosphate mouthrinse: a randomized crossover study for the treatment
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of symptomatic oral lichen planus. Journal of the American Academy of Dermatology.
2002;47(2):271-279.
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Sankar V, Hearnden V, Hull K, et al. Local drug delivery for oral mucosal diseases: challenges
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Malhotra AK, Khaitan BK, Sethuraman G, Sharma VK. Betamethasone oral mini-pulse therapy
compared with topical triamcinolone acetonide (0.1%) paste in oral lichen planus: A
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Gonzalez-Garcia A, Diniz-Freitas M, Gandara-Vila P, Blanco-Carrion A, Garcia-Garcia A,
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Leen CL, Dunbar EM, Ellis ME, Mandal BK. Once-weekly fluconazole to prevent recurrence
of oropharyngeal candidiasis in patients with AIDS and AIDS-related complex: a double-blind
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Vuichard D, Weisser M, Orasch C, et al. Weekly use of fluconazole as prophylaxis in
haematological patients at risk for invasive candidiasis. BMC Infect Dis. 2014;14:573.
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Marriott DJ, Jones PD, Hoy JF, Speed BR, Harkness JL. Fluconazole once a week as secondary
prophylaxis against oropharyngeal candidiasis in HIV-infected patients. A double-blind
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Gilbertson EO, Spellman MC, Piacquadio DJ, Mulford MI. Super potent topical corticosteroid
use associated with adrenal suppression: clinical considerations. Journal of the American
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Pramick M, Whitmore SE. Cushing's syndrome caused by mucosal corticosteroid therapy.
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Plemons JM, Rees TD, Zachariah NY. Absorption of a topical steroid and evaluation of adrenal
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Savage NW, McCullough MJ. Topical corticosteroids in dental practice. Aust Dent J. 2005;50(4
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Thongprasom K, Dhanuthai K. Steriods in the treatment of lichen planus: a review. J Oral Sci.
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Rhodus NL, Cheng B, Bowles W, Myers S, Miller L, Ondrey F. Proinflammatory cytokine
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Oral diseases. 2006;12(2):112-116.
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Hambly JL, Haywood A, Hattingh L, Nair RG. Comparison between self-formulation and
compounded-formulation dexamethasone mouth rinse for oral lichen planus: a pilot,
randomized, cross-over trial. J Investig Clin Dent. 2016.
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Technical Report: Assessment of the Mucoadhesive Properties of MucoLox Using a 3D
Model of the Human Oral Mucosa. Retrieved from: http://wwwpccarxcom/about-pcca/pcca-
studies/studies/item/267-technical-report-assessment-of-the-mucoadhesive-properties-of-
mucolox-using-a-3d-model-of-the-human-oral-mucosa. 2015.
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30.
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http://wwwpccarxcom/pcca-products/pcca-exclusives/bases/mucolox. 2015.
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Villa A, Sankar V, Bassani G, Johnson LB, Sroussi H. Dexamethasone solution and
dexamethasone in Mucolox for the treatment of oral lichen planus: a preliminary study. Oral
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O'Neill ID, Scully C. Biologics in oral medicine: ulcerative disorders. Oral diseases.
2013;19(1):37-45.
34.
Piboonniyom SO, Treister N, Pitiphat W, Woo SB. Scoring system for monitoring oral
lichenoid lesions: a preliminary study. Oral surgery, oral medicine, oral pathology, oral
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Dent Oral Epidemiol. 1997;25(4):284-290.
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Hegarty AM, McGrath C, Hodgson TA, Porter SR. Patient-centred outcome measures in oral
medicine: are they valid and reliable? Int J Oral Maxillofac Surg. 2002;31(6):670-674.
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16 APPENDICES
Appendix 1:
Appendix 2:
Appendix 3:
Appendix 4:
Appendix 5:
Patient instructions
Treatment diary
Visit #1 CRF
Visit #2 CRF
OHIP-14
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Appendix 1
INSTRUCTIONS FOR PREPARING & USING YOUR
TOPICAL SOLUTION
WHAT YOU WILL RECEIVE
x
One 480 mL bottle of concentrated solution (5 mg/5 mL)
x
4 tablets of fluconazole 200 mg
USING YOUR SOLUTION
You will be rinsing with your solution 3 times per day.
1. Gently shake the bottle of solution.
2. Pour 5 mL of solution into the dosing cups provided.
3. Swish the solution in your mouth for 5 minutes, then spit ± DO NOT SWALLOW!
4. Do not eat or drink for 15 minutes after rinsing.
Please take one table of fluconazole once a week
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Appendix 2. Treatment Diary
Week
Day/Date
1
1
Rinse #1 (check/fill)
5 min
Other*
Rinse #2 (check/fill)
5 min
Other*
Rinse #3 (check/fill)
5 min
Other*
From a scale
Comments
0-10, how
would you
rate your
mouth
sensitivity
today?
2
3
4
5
6
7
2
8
9
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11
12
13
14
3
15
16
17
18
19
20
21
4
22
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23
24
25
26
27
28
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Appendix 3
DEXAMETHASONE RINSE IN MUCOLOX FOR THE TREATMENT OF ORAL
INFLAMMATORY ULCERATIVE DISEASES
VISIT #1
Subject Name
Medical Record Number
Date of Visit
SUBJECTIVE DATA (Over last two weeks unless specified)
MUCOSAL PATHOLOGY
1. Does your mouth hurt now?
Y/N
2. Does it hurt to swallow food or drink?
Y/N
3. How would you rate your worst mouth sensitivity over the last week?
No sensitivity
Worst sensitivity
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4. Do you avoid any foods because they make your mouth hurt?
0
=
Not at all
1
=
Slightly
2
=
Moderately
3
=
Quite a bit
4
=
Extremely
If ³yes´, what types of foods?
a. Spicy foods
b. Acidic foods
c. Salty foods
d. Hard/crunchy/crusty foods
e. Other:
5. Do you feel that your oral intake (what you eat) is limited by your oral condition?
Y/N
Not limited at all
Severely limited
Score: _____
If ³Yes´, how limited do you feel it is?
a. Partial limitation
b. Severe limitation
6. Have you been bothered by ulcers in the mouth?
0
=
Not at all
1
=
Slightly
2
=
Moderately
3
=
Quite a bit
4
=
Extremely
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OBJECTIVE DATA (REU score)
(R: 0 = not present, 1 = present; E & U: 0 = not present, 1 = <1cm2, 2 = 1 - 3cm2, 3 = >3cm2)
Total Score:
Total Weighted Score:
PHOTOGRAPHS TAKEN (circle): YES
NO
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Appendix 4
DEXAMETHASONE RINSE AND MUCOLOX FOR THE TREATMENT OF ORAL
INFLAMMATORY ULCERATIVE DISEASES
VISIT #2
Subject Name
Medical Record Number
Date of Visit
SUBJECTIVE DATA (Over last one week unless specified)
MUCOSAL PATHOLOGY
1. Does your mouth hurt now?
Y/N
2. Does it hurt to swallow food or drink?
Y/N
3. How would you rate your worst mouth sensitivity over the last week?
No sensitivity
Worst sensitivity
4. Do you avoid any foods because they make your mouth hurt?
0
=
Not at all
1
=
Slightly
2
=
Moderately
3
=
Quite a bit
4
=
Extremely
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If ³yes´, what types of foods?
a.
Spicy foods
b.
Acidic foods
c.
Salty foods
d.
Hard/crunchy/crusty foods
e.
Other:
5. Do you feel that your oral intake (what you eat) is limited by your oral condition?
Y/N
Not limited at all
Severely limited
Score: _____
If ³Yes´, how limited do you feel it is?
a.           Partial limitation                                b.           Severe limitation                                6. Have you been bothered by ulcers in the mouth?
0
=
Not at all
1
=
Slightly
2
=
Moderately
3
=
Quite a bit
4
=
Extremely
7. Rate your level of comfort while rinsing with the topical therapy:
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Not uncomfortable at all
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Very uncomfortable
Score: _____
8. Rate the taste of the topical treatment:
Very good taste
Very bad taste
Score: _____
9. Rate how your mouth feels since starting topical therapy:
Mouth feels much better
Mouth feels much worse
Score: _____
10. Overall, since beginning topical therapy, my mouth is: (Check one)
Very much better
Moderately better
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A little better
About the same
A little worse
Moderately worse
Very much worse
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OBJECTIVE DATA
(R: 0 = not present, 1 = present; E & U: 0 = not present, 1 = <1cm2, 2 = 1 - 3cm2, 3 = >3cm2)
Total Score:
Total Weighted Score:
PHOTOGRAPHS TAKEN (circle): YES
NO
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Appendix 5. OHIP-14
Never
(0)
Hardly
Ever (1)
Occasionally
(2)
Fairly
Often (3)
Very
Often (4)
FUNCTIONAL
Have you had trouble pronouncing any words because of problems with your teeth, mouth, or
dentures?
Have you felt that your sense of taste has worsened because of problems with your teeth,
mouth, or dentures?
PHYSICAL PAIN
Have you had painful aching in your mouth?
Have you found it uncomfortable to eat any foods because of problems with your teeth,
mouth, or dentures?
Psychological Discomfort
Have you been self-conscious because of problems with your teeth, mouth, or dentures?
Have you felt tense because of problems with your teeth, mouth, or dentures?
PHYSICAL DISABILITY
Has your diet been unsatisfactory because of problems with your teeth, mouth, or dentures?
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Protocol Template © CFFT TDN Effective: 12 SEP 2007


Protocol Number
Confidential
Have you had to interrupt meals because of problems with your teeth, mouth, or dentures?
PSYCHOLOGICAL DISABILITY
Have you found it difficult to relax because of problems with your teeth, mouth, or dentures?
Have you been a bit embarrassed because of problems with your teeth, mouth, or dentures?
SOCIAL DISABILITY
Have you been a bit irritable with others because of problems with your teeth, mouth, or
dentures?
Have you had difficulty doing your usual jobs because of problems with your teeth, mouth, or
dentures?
HANDICAP
Have you felt that life in general was less satisfying because of problems with your teeth,
mouth, or dentures?
Have you been totally unable to function because of problems with your teeth, mouth, or
dentures?
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Protocol Template © CFFT TDN Effective: 12 SEP 2007