Tympanic Membrane Perforation
Conditions
Keywords
tympanic membrane perforation, ear drum, hole
Brief summary
A Phase II randomized trial will be initiated to evaluate closure of the perforated tympanic membrane as the primary measureable outcome. The goal is to determine the safety and efficacy of Fibroblast Growth Factor-2 (FGF-2) in the closure of chronic tympanic membrane perforations (TMP). If FGF-2 is topically applied for the treatment of chronic TMP in humans, it is hypothesized it will be safe, tolerable and effective for use as treatment for tympanic membrane perforation. A total of 60 subjects will be recruited.
Detailed description
A Phase II randomized trial will be initiated to evaluate efficacy as the primary measureable outcome. Eligible and consented patients will be randomized in a 3:1 ratio to the optimal biologic dose (OBD) of FGF-2 or placebo (sterile water). Application of the study treatment may occur at the initial Screening Visit (pending all eligibility requirements can be confirmed) or at Visit 1 and may be repeated at each follow up visit as needed for a maximum of three treatments per treatment arm. These follow up visits will occur three weeks (+/- 7 days) from the last treatment application. During these visits, the subject's tympanic membrane will be examined, photographed, and additional otologic tests will be performed. If the perforation is found to be closed during these visits, then the subject will report in 2 months (+/-7 days) for a final study visit. If the subject's TMP has not closed after the third and final application of their assigned treatment group, then the subject will be crossed over to the other treatment group. Again, the subject may be given up to three additional treatments in this new group. The follow up visits will follow the same schedule, occurring three weeks (+/- 7 days) from the last treatment. The same otologic procedures will be performed as in the previous visits. All subjects will report for a final study visit 2 months (+/- 7 days) after their last follow up visit when the perforation is determined to be closed or when the subject has completed the maximum number of study visits without perforation closure. The study will be completed for reporting purposes after all subjects have completed the 2 month (+/- 7 days) follow up final visit.
Interventions
DRUGFGF-2
The FGF-2 method of use comprises a pledget of gelatin foam with human fibroblast growth factor-2 (FGF-2) added to the pledget just before topical application to the tympanic membrane, and the use of Tisseel, a fibrin glue used for applications in ear surgery.
OTHERPlacebo
Placebo comparator using a sterile saline solution.
Sponsors
United States Department of Defense
D. Bradley Welling, MD, PhD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Dry tympanic membrane perforation of greater than 3 months duration 2. If female, post-menopausal or sterile, or if she is of child-bearing potential, must have a negative beta-human chorionic gonadotropin (HCG) test and must be using an adequate form of birth control such as birth control pills, birth control implants, intrauterine devices (IUDs), diaphragms or condoms.
Exclusion criteria
The presence of any of the following excludes a subject from study enrollment: * 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 * 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 (See body of protocol for full list of exclusions) * Known or suspected allergies to any components used in the study * Subjects who have cholesteatoma mass 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Tympanic Membrane Closure Following Treatment | ~60 days | The efficacy of the treatment is determined by the number of patients whose tympanic membrane perforations closed after study treatments. Subjects from both treatment arms received up to three treatments before determining non-closure of the tympanic membrane. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measurement of Changes in Pure-tone Averages | Baseline, 60 days | measured by pre- and post-treatment audiograms. |
| Measurement of Changes in Speech Discrimination Scores | Baseline, 60 days | Speech discrimination score is determined by having the patient listen to words through headphones and having the patient repeat the words back to the audiologist. A score of 100 percent (100%) is the best outcome, and 0 percent (0%) is the worst. Pre- and post- treatment tests are compared and analyzed. |
| Number of Treatments Required for Closure of the Tympanic Membrane Perforation | 60 days | Out of the patients who healed, some healed with 1 treatment, some with 2 treatments, and some with 3 treatments. |
| Number of Patients With Normal Mobility of the Eardrum as Assessed by Tympanometry | 60 days | Tympanometry is an examination used to test the condition of the middle ear and the mobility of the eardrum. Any type of perforation, regardless of size, would cause the result of the tympanometry to be abnormal. We use this test to determine if the eardrum closed completely. |
Countries
United States
Participant flow
Pre-assignment details
Patients who met exclusion criteria were considered screen-fail and were not assigned to a randomization group.
Participants by arm
| Arm | Count |
|---|---|
| FGF-2 FGF-2 given a minimum of 1 and maximum of 3 times within, approximately, 60 days.
FGF-2: The FGF-2 method of use comprises a pledget of gelatin foam with human fibroblast growth factor-2 (FGF-2) added to the pledget just before topical application to the tympanic membrane, and the use of Tisseel, a fibrin glue used for applications in ear surgery. | 42 |
| Placebo Equal concentration of saline is given a minimum of 1 and maximum of 3 times within, approximately, 60 days.
Placebo: Placebo comparator using a sterile saline solution. | 15 |
| Total | 57 |
Baseline characteristics
| Characteristic | Placebo | Total | FGF-2 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 15 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 42 Participants | 32 Participants |
| Age, Continuous | 55.8 years STANDARD_DEVIATION 15 | 52.7 years STANDARD_DEVIATION 14.2 | 51.7 years STANDARD_DEVIATION 13.9 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 15 participants | 57 participants | 42 participants |
| Sex: Female, Male Female | 8 Participants | 31 Participants | 23 Participants |
| Sex: Female, Male Male | 7 Participants | 26 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 15 |
| other Total, other adverse events | 13 / 42 | 5 / 15 |
| serious Total, serious adverse events | 0 / 42 | 0 / 15 |
Outcome results
Primary
Number of Patients With Tympanic Membrane Closure Following Treatment
The efficacy of the treatment is determined by the number of patients whose tympanic membrane perforations closed after study treatments. Subjects from both treatment arms received up to three treatments before determining non-closure of the tympanic membrane.
Time frame: ~60 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FGF-2 | Number of Patients With Tympanic Membrane Closure Following Treatment | 23 Participants |
| Placebo | Number of Patients With Tympanic Membrane Closure Following Treatment | 10 Participants |
Secondary
Measurement of Changes in Pure-tone Averages
measured by pre- and post-treatment audiograms.
Time frame: Baseline, 60 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FGF-2 | Measurement of Changes in Pure-tone Averages | 7.9 dB | Standard Deviation 8.8 |
| Placebo | Measurement of Changes in Pure-tone Averages | 5.9 dB | Standard Deviation 9.1 |
Secondary
Measurement of Changes in Speech Discrimination Scores
Speech discrimination score is determined by having the patient listen to words through headphones and having the patient repeat the words back to the audiologist. A score of 100 percent (100%) is the best outcome, and 0 percent (0%) is the worst. Pre- and post- treatment tests are compared and analyzed.
Time frame: Baseline, 60 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FGF-2 | Measurement of Changes in Speech Discrimination Scores | 3.2 percent | Standard Deviation 8.1 |
| Placebo | Measurement of Changes in Speech Discrimination Scores | 1.7 percent | Standard Deviation 4.7 |
Secondary
Number of Patients With Normal Mobility of the Eardrum as Assessed by Tympanometry
Tympanometry is an examination used to test the condition of the middle ear and the mobility of the eardrum. Any type of perforation, regardless of size, would cause the result of the tympanometry to be abnormal. We use this test to determine if the eardrum closed completely.
Time frame: 60 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FGF-2 | Number of Patients With Normal Mobility of the Eardrum as Assessed by Tympanometry | 23 Participants |
| Placebo | Number of Patients With Normal Mobility of the Eardrum as Assessed by Tympanometry | 10 Participants |
Secondary
Number of Treatments Required for Closure of the Tympanic Membrane Perforation
Out of the patients who healed, some healed with 1 treatment, some with 2 treatments, and some with 3 treatments.
Time frame: 60 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FGF-2 | Number of Treatments Required for Closure of the Tympanic Membrane Perforation | 1.4 treatments | Standard Deviation 0.6 |
| Placebo | Number of Treatments Required for Closure of the Tympanic Membrane Perforation | 1.7 treatments | Standard Deviation 0.6 |