Fibroblast Growth Factor Regeneration of Tympanic Membrane Perforations

Study Overview
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Brief Summary
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This study is a double blinded, placebo-controlled phase II study evaluating the efficacy of FGF-2 for the treatment of chronic non-healing tympanic membrane perforations (TMP). The documentation of TM closure will be the main efficacy outcome measure. Pretreatment photographs will document the area of the TM perforation and allow measurement of surface areas of the TMP for comparison of pre- and post-treatment. The study will be divided into two phases, the Randomized Treatment phase (part A), and the Unblinded Crossover phase (part B). In part A of the study, subjects will be randomized 1:1 (using simple randomization) to receive FGF-2 or placebo treatment up to 3 treatments. Subjects that fail three study treatments will move on to part B of the study. Subjects who received placebo in part A and failed three placebo treatments will crossover to receive unblinded FGF-2 for up to 3 treatments. Subjects who received FGF-2 in part A and failed three experimental treatments will not have additional FGF-2 treatment, and will move on to study follow up.

Official Title
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Fibroblast Growth Factor Regeneration of Tympanic Membrane Perforations

Conditions
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Tympanic Membrane Perforation

Intervention / Treatment
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* Drug: FGF-2
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years and older Dry tympanic membrane perforation of at least 6 months duration Any person of child-bearing potential, must have a negative beta-HCG test and must agree to use an adequate form of birth control throughout the clinical trial. Exclusion Criteria: Active otitis media or chronic otorrhea from the middle ear Subjects receiving radiation therapy, corticosteroids, immunosuppressive agents, or chemotherapy Subjects who, at study entry, are taking systemic antibiotics Subjects who are immunosuppressed Subjects experiencing bacterial or viral infection or who may otherwise be febrile or may be with inflammation. Life expectancy of less than 1 year Active alcohol or drug abuse within 6 months prior to study entry Significant medical condition that could prevent full participation in the procedures required for the study Known or suspected allergies to any components used in the study, i.e. porcine collagen Subjects who have cholesteatoma mass, or endothelium invasion in the tympanic cavity Subjects whose total perforation cannot be seen by an endoscope Subjects with inadequately controlled diabetes mellitus (NGSP: HbA1c 6.9% or higher) Subjects with a history of malignant ear canal tumors within 3 years of screening for eligibility Subjects who have undergone prior myringoplasty or tympanoplasty Subjects whose TMP is a result of thermal burn, or radiation therapy. Subjects who have abnormalities in the auditory ossicles or their linkages Subjects having moderate to severe dementia such as Alzheimer's disease or senile dementia Subjects whose hearing ability does not improve to bone-conduction hearing on a hearing acuity test using the tentative closure of perforation with a wet cotton ball. Subject having residual TM with abnormal form or abnormal shape anatomically Subjects having any granulation or soft tissue density due to inflammation, or infection in mastoid antrum determined by CT scanning (Temporal bone CT scanning)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* FGF-2 will be replaced with sterile water to saturate a pledget of gelatin sponge. The method will be otherwise identical to the FGF-2 intervention.<br>|
| Experimental: Human Fibroblast Growth Factor-2 (FGF-2)<br> | Drug: FGF-2<br>* The FGF-2 method of use comprises a pledget of gelatin sponge, with human fibroblast growth factor-2 (FGF-2) added to the pledget just before topical application to the tympanic membrane, and the use of fibrin glue used for applications in ear surgery. The concentration of the FGF-2 solution will be 100μg of FGF-2 per 1 mL with an estimated dose of about 20 μg in 0.2ml. Fibrin glue will be applied to secure gelatin sponge after placement according to the size of the membrane perforation. Application of the study treatment will occur at Visit 1 and may be repeated at each follow up visit as needed for a maximum of three treatments in the Randomized Treatment Phase (Visit 1, Visit 2, and Visit 3).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TMP Closure Ratio | Determined by otoscopic exam and photographic documentation | up to Day 134 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Closure of TMP |  | up to Day 134 | 
| Pure-tone and speech discrimination scores | Measured by audiograms (total range of score: 125, 250, 500, 1000, 2000, 4000, 8000 Hz). S | Pre-treatment (Day 1) | 
| Pure-tone and speech discrimination scores | Measured by audiograms (total range of score: 125, 250, 500, 1000, 2000, 4000, 8000 Hz). S | Post-treatment 1 (Day 22) | 
| Pure-tone and speech discrimination scores | Measured by audiograms (total range of score: 125, 250, 500, 1000, 2000, 4000, 8000 Hz). S | Post-treatment 1 (Day 43) | 
| Pure-tone and speech discrimination scores | Measured by audiograms (total range of score: 125, 250, 500, 1000, 2000, 4000, 8000 Hz). S | Post-treatment 1 (Day 64) | 
| Pure-tone and speech discrimination scores | Measured by audiograms (total range of score: 125, 250, 500, 1000, 2000, 4000, 8000 Hz). S | Post-treatment 1 (Day 85) | 
| Pure-tone and speech discrimination scores | Measured by audiograms (total range of score: 125, 250, 500, 1000, 2000, 4000, 8000 Hz). S | Post-treatment 1 (Day 106) | 
| Pure-tone and speech discrimination scores | Measured by audiograms (total range of score: 125, 250, 500, 1000, 2000, 4000, 8000 Hz). S | Post-treatment 1 (Day 127) | 
| Pure-tone and speech discrimination scores | Measured by audiograms (total range of score: 125, 250, 500, 1000, 2000, 4000, 8000 Hz). S | Post-treatment 1 (Day 134) | 
| Air-Bone Gap (ABG) | Defined as the difference between air-conduction and bone-conduction audiometric thresholds | up to Day 134 | 
| Mobility of the Tympanic Membrane | As measured by tympanometry | Day 134 | 
| Salvage Rate of FGF-2 in Patients who Fail Placebo |  | Day 64 |