A Study to Assess ASP0598 Otic Solution Following Topical Application in the Ear in Subjects With Chronic Tympanic Membrane Perforation (CTMP)

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the safety and tolerability of ASP0598 Otic Solution. This study will also evaluate the efficacy of ASP0598 otic solution.

Detailed Description
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This study will consist of a dose escalation (single ascending dose - SAD and multiple ascending dose- MAD) and dose expansion (single dose expansion and/or multiple dose expansion). Dose escalation will consist of up to 4 cohorts for single ascending dose (SAD) and up to 2 cohorts for multiple ascending dose (MAD) with different dose levels. For SAD, after randomization on Day 1, participants will receive ASP0598 Otic Solution or placebo administration into the affected ear. Participants will return to the site on days 2, 3, 8, 15, 29, and 57 [end of study (EOS)]. Day 3 evaluations will only be performed for cohorts 1, 2 and 3. For MAD, after randomization on Day 1, participants will receive ASP0598 Otic Solution or placebo administration into the affected ear and will receive additional treatments into the same ear on Days 15 and 29. Participants will return to the investigative site on Days 8, 15, 22, 29, 36, 57, and 85 (EOS). Dose expansion will be based on the safety and efficacy results from an interim analysis. An interim analysis will be conducted after completion of SAD and again after completion of MAD. If dose expansion is opened, 2 or 3 treatment groups will be selected. If 3 groups are selected, participants will be randomized in a 1:1:1 ratio of high dose ASP0598 Otic Solution, low dose ASP0598 Otic Solution, and Placebo. If 2 groups are selected, participants will be randomized in a 1:1 ratio of high dose ASP0598 Otic Solution and Placebo. For single dose expansion, after randomization on Day 1, participants will receive ASP0598 otic solution or placebo administration into the affected ear. Participants will return to the investigative site on days 15, 29, 57, and 85 (EOS). For multiple dose expansion, after randomization on Day 1, participants will receive ASP0598 Otic Solution or placebo administration into the affected ear. Participants will receive additional treatment in the same ear on Days 15 and 29. In cases where complete closure is confirmed on either Day 15 or Day 29, no additional treatment is required at those visit(s). Participants will return to the investigative site on Days 15, 29, 43, 57, 85 and 113 (EOS).

Official Title
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A Phase 1/2, Randomized, Placebo-controlled Study to Assess the Safety, Tolerability, Efficacy, and Pharmacokinetics of ASP0598 Otic Solution Following Topical Application Into the Ear in Subjects With Chronic Tympanic Membrane Perforation (CTMP)

Conditions
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Chronic Tympanic Membrane Perforation

Intervention / Treatment
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* Drug: ASP0598
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has chronic tympanic membrane perforation (CTMP) documented as persisting longer than 3 months. A female subject is eligible to participate if she is not pregnant and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR WOCBP who agrees to follow the contraceptive guidance starting at screening and for at least 28 days after investigational product (IP) application. Female subject must agree not to breastfeed starting at drug application on Day 1 and for at least 28 days after IP application. Female subject must not donate ova starting on Day 1 and for at least 28 days after investigational product (IP) application. A male subject with female partner(s) of child-bearing potential must agree to use contraception starting on Day 1 and for at least 28 days after IP application. A male subject must not donate sperm starting on Day 1 and for at least 28 days after IP application. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom from Day 1 and for at least 28 days after IP application. Subject must be willing and able to comply with the study requirements including refraining from using prohibited concomitant medications. Subject agrees not to participate in another interventional study during the study period. Exclusion Criteria: Subject has one of following conditions that may affect the ipsilateral side of the ear with chronic tympanic membrane perforation (CTMP): Perforation involving 3 or more quadrants. Pin hole perforation (only for the expansion cohort). Presence of tympanosclerosis adjacent to the perforation. Perforation involves malleus erosion. Absent malleus. Marginal perforation (i.e., involving the annulus or exposing the handle of malleus). Tympanic membrane perforation (TMP) caused by electric/slag/blast/burn injury. Post radiated TMP. History of tympanic membrane repair by any type of live tissue. Active otorrhea or active treatment for otorrhea within the last 3 months prior to Screening. Bellucci otorrhea grade 3 or above. Active external ear canal inflammation (otitis externa, dermatitis) or within the last 3 months prior to Screening. Active diagnosis of Eustachian Tube dysfunction or diagnosis within 6 months prior to Screening. Craniofacial abnormalities, History of head and neck surgery within the last 3 months prior to Screening, history of radiation to head and neck. Recent (within 2 weeks) diagnosis of upper respiratory tract infection. Presence or history of cholesteatoma. Presence of pars-flaccida or pars tensa retraction or adhesion. Presence or history of tumors of the middle or external ear. Contraindications to tympanic membrane closure. An audiometric finding indicates a characteristic of Carhart's notch which is an increase in bone conduction threshold with a peak at 2,000 hertz (Hz). Only hearing ear or better hearing ear and the contralateral ear ≥ 40 dB (decibels) by average four-frequency (500, 1000, 2000 and 4000 Hz). Whole circumference of the tympanic membrane perforation is not visible by endoscope. Presence/history of eosinophilic otitis media in either ear. Subject has a presence of adhesive otitis media in the contralateral ear. Subject has a presence of any wound healing systemic condition. Subject has Obstructive Sleep Apnea where the subject is required to use Continuous Positive Airway Pressure (CPAP) during the study period. Subject is exposed in their daily life to high volume of water into the ear canal (e.g., swimmer or surfer). Subject has health conditions that would prevent him/her from fulfilling the study requirements on the basis of medical history and laboratory test (Serum Chemistries, complete blood count [CBC] with Differential, Urinalysis) results at the screening visit. Subject is receiving any other investigational agents during study participation. Subject has any form of substance abuse, or psychiatric illness/social situations that would limit compliance with study requirements, or a condition that could invalidate communication. Subject has a known or suspected hypersensitivity to ASP0598, or any components of the formulation used. Subject has had previous exposure with ASP0598. Subject is unlikely to comply with the visits scheduled in the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP0598 SAD<br>A single topical application of ASP0598 onto the tympanic membrane through the external auditory canal via syringe at up to 4 dose levels. | Drug: ASP0598<br>* Topical Solution<br>|
| Experimental: ASP0598 MAD<br>Multiple topical applications of ASP0598 onto the tympanic membrane through the external auditory canal via syringe at up to 2 dose levels with additional treatment days. | Drug: ASP0598<br>* Topical Solution<br>|
| Experimental: ASP0598 Single Dose Expansion<br>A single topical application of ASP0598 onto the tympanic membrane through the external auditory canal via syringe at up to 2 dose levels. | Drug: ASP0598<br>* Topical Solution<br>|
| Experimental: ASP0598 Multiple Dose Expansion<br>Multiple topical application of ASP0598 onto the tympanic membrane through the external auditory canal via syringe at up to 2 dose levels with additional treatment days. | Drug: ASP0598<br>* Topical Solution<br>|
| Placebo Comparator: Pooled Placebo in SAD<br>For each dose level ASP0598 matching placebo onto the tympanic membrane through the external auditory canal via syringe. | Drug: Matching Placebo<br>* Placebo Topical Solution<br>|
| Placebo Comparator: Pooled Placebo in MAD<br>For each dose level ASP0598 matching placebo onto the tympanic membrane through the external auditory canal via syringe. | Drug: Matching Placebo<br>* Placebo Topical Solution<br>|
| Placebo Comparator: Placebo in Single Dose Expansion<br>ASP0598 matching placebo onto the tympanic membrane through the external auditory canal via syringe. | Drug: Matching Placebo<br>* Placebo Topical Solution<br>|
| Placebo Comparator: Placebo in Multiple Dose Expansion<br>ASP0598 matching placebo onto the tympanic membrane through the external auditory canal via syringe. | Drug: Matching Placebo<br>* Placebo Topical Solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Treatment Emergent Adverse Events (TEAEs) in SAD | An adverse event (AE) is any untoward medical occurrence in a subject administered an IP, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of investigational product (IP) whether or not considered related to the IP. A TEAE is defined as an AE observed after starting administration of the study drug through end of study visit. A drug-related TEAE is defined as any TEAE with a causal relationship assessed as yes by the investigator. | Up to Day 57 | 
| Number of participants with TEAEs of special interest in SAD | AEs of special interest include cholesteatoma or ear neoplasm, ototoxic symptoms (tinnitus, sensorineural hearing loss, dizziness) and otitis media or otitis externa. | Up to Day 57 | 
| Change from baseline in bone conduction hearing at 1 kHz by pure tone audiometry (PTA) in SAD | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. Pure tone air conduction and bone conduction tests determine whether or not there is any hearing loss; what type of hearing loss it is (conductive, sensorineural or mixed hearing loss); the frequencies that are affected (configuration); magnitude of hearing loss (intensity) and whether hearing loss is unilateral or bilateral. The result is plotted on an audiogram, which is a graph displaying intensity as a function of frequency. | Baseline and Day 57 | 
| Change from baseline in bone conduction hearing at 2 kHz by pure tone audiometry (PTA) in SAD | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. | Baseline and Day 57 | 
| Change from baseline in bone conduction hearing at 4 kHz by pure tone audiometry (PTA) in SAD | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. | Baseline and Day 57 | 
| Change from baseline in Tinnitus Visual Analog Scale (TVAS) in SAD | TVAS is a scale for tinnitus loudness. Participants will be asked to rate their tinnitus on a scale of 0 to 10, where 0 means not at all strong or loud and 10 means extremely strong or loud tinnitus. A lower score means an improvement in tinnitus loudness. | Baseline and Day 57 | 
| Number of participants with Treatment Emergent Adverse Events (TEAEs) in single dose expansion | An AE is any untoward medical occurrence in a subject administered an IP, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of investigational product (IP) whether or not considered related to the IP. A TEAE is defined as an AE observed after starting administration of the study drug through end of study visit. A drug-related TEAE is defined as any TEAE with a causal relationship assessed as yes by the investigator. | Up to Day 85 | 
| Number of incidences of AEs of special interest in single dose expansion | AEs of special interest include cholesteatoma or ear neoplasm, ototoxic symptoms (tinnitus, sensorineural hearing loss, dizziness) and otitis media or otitis externa. | Up to Day 85 | 
| Change from baseline in bone conduction hearing at 1 kHz by pure tone audiometry (PTA) in single dose expansion | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. Pure tone air conduction and bone conduction tests determine whether or not there is any hearing loss; what type of hearing loss it is (conductive, sensorineural or mixed hearing loss); the frequencies that are affected (configuration); magnitude of hearing loss (intensity) and whether hearing loss is unilateral or bilateral. The result is plotted on an audiogram, which is a graph displaying intensity as a function of frequency. | Baseline and Day 85 | 
| Change from baseline in bone conduction hearing at 2 kHz by pure tone audiometry (PTA) in single dose expansion | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. | Baseline and Day 85 | 
| Change from baseline in bone conduction hearing at 4 kHz by pure tone audiometry (PTA) in single dose expansion | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. | Baseline and Day 85 | 
| Change from baseline in Tinnitus Visual Analog Scale (TVAS) in single dose expansion | TVAS is a scale for tinnitus loudness. Participants will be asked to rate their tinnitus on a scale of 0 to 10, where 0 means not at all strong or loud and 10 means extremely strong or loud tinnitus. A lower score means an improvement in tinnitus loudness. | Baseline and Day 85 | 
| Number of participants with Treatment Emergent Adverse Events (TEAEs) in MAD | AE is any untoward medical occurrence in a subject administered an IP, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of investigational product (IP) whether or not considered related to the IP. A TEAE is defined as an AE observed after starting administration of the study drug through end of study visit. A drug-related TEAE is defined as any TEAE with a causal relationship assessed as yes by the investigator. | Up to Day 85 | 
| Number of participants with TEAEs of special interest in MAD | AEs of special interest include cholesteatoma or ear neoplasm, ototoxic symptoms (tinnitus, sensorineural hearing loss, dizziness) and otitis media or otitis externa. | Up to Day 85 | 
| Change from baseline in bone conduction hearing at 1 kHz by pure tone audiometry (PTA) in MAD | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. Pure tone air conduction and bone conduction tests determine whether or not there is any hearing loss; what type of hearing loss it is (conductive, sensorineural or mixed hearing loss); the frequencies that are affected (configuration); magnitude of hearing loss (intensity) and whether hearing loss is unilateral or bilateral. The result is plotted on an audiogram, which is a graph displaying intensity as a function of frequency. | Baseline and Day 85 | 
| Change from baseline in bone conduction hearing at 2 kHz by pure tone audiometry (PTA) in MAD | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. | Baseline and Day 85 | 
| Change from baseline in bone conduction hearing at 4 kHz by pure tone audiometry (PTA) in MAD | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. | Baseline and Day 85 | 
| Change from baseline in Tinnitus Visual Analog Scale (TVAS) in MAD | TVAS is a scale for tinnitus loudness. Participants will be asked to rate their tinnitus on a scale of 0 to 10, where 0 means not at all strong or loud and 10 means extremely strong or loud tinnitus. A lower score means an improvement in tinnitus loudness. | Baseline and Day 85 | 
| Number of participants with Treatment Emergent Adverse Events (TEAEs) in multiple dose expansion | An AE is any untoward medical occurrence in a subject administered an IP, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of investigational product (IP) whether or not considered related to the IP. A TEAE is defined as an AE observed after starting administration of the study drug through end of study visit. A drug-related TEAE is defined as any TEAE with a causal relationship assessed as yes by the investigator. | Up to Day 113 | 
| Number of incidences of AEs of special interest in multiple dose expansion | AEs of special interest include cholesteatoma or ear neoplasm, ototoxic symptoms (tinnitus, sensorineural hearing loss, dizziness) and otitis media or otitis externa. | Up to Day 113 | 
| Change from baseline in bone conduction hearing at 1 kHz by pure tone audiometry (PTA) in multiple dose expansion | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. Pure tone air conduction and bone conduction tests determine whether or not there is any hearing loss; what type of hearing loss it is (conductive, sensorineural or mixed hearing loss); the frequencies that are affected (configuration); magnitude of hearing loss (intensity) and whether hearing loss is unilateral or bilateral. The result is plotted on an audiogram, which is a graph displaying intensity as a function of frequency. | Baseline and Day 113 | 
| Change from baseline in bone conduction hearing at 2 kHz by pure tone audiometry (PTA) in multiple dose expansion | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. | Baseline and Day 113 | 
| Change from baseline in bone conduction hearing at 4 kHz by pure tone audiometry (PTA) in multiple dose expansion | PTA is a behavioral test and generally the 1st quantitative hearing test done to assess the nature and degree of hearing loss in adults and in children. This measure involves the peripheral and central auditory systems. | Baseline and Day 113 | 
| Change from baseline in Tinnitus Visual Analog Scale (TVAS) in multiple dose expansion | TVAS is a scale for tinnitus loudness. Participants will be asked to rate their tinnitus on a scale of 0 to 10, where 0 means not at all strong or loud and 10 means extremely strong or loud tinnitus. A lower score means an improvement in tinnitus loudness. | Baseline and Day 113 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with complete closure of Tympanic Membrane Perforation (TMP) in SAD | Tympanic membrane perforation is a perforation of tympanic membrane in the ear. TMP closure is defined as microscopic TMP closure without presence of pin hole. All images from each visit will be sent to a central imaging vendor for measurement and interpretation. | Up to Day 57 | 
| Change from baseline in the ratio of TMP size per total area of tympanic membrane in SAD | Ratio of TMP size per total area of tympanic membrane will be calculated. | Baseline and Day 57 | 
| Change from baseline in TMP size in SAD | TMP size calculation will be performed by central imaging vendor. | Baseline and Day 57 | 
| Proportion of participants with complete closure of TMP in single dose expansion | Tympanic membrane perforation is a perforation of tympanic membrane in the ear. TMP closure is defined as microscopic TMP closure without presence of pin hole. All images from each visit will be sent to a central imaging vendor for measurement and interpretation. | Up to Day 85 | 
| Change from baseline in the ratio of TMP size per total area of tympanic membrane in single dose expansion | Ratio of TMP size per total area of tympanic membrane will be calculated. | Baseline and Day 85 | 
| Change from baseline in TMP size in single dose expansion | TMP size calculation will be performed by central imaging vendor. | Baseline and Day 85 | 
| Proportion of participants with complete closure of TMP in MAD | Tympanic membrane perforation is a perforation of tympanic membrane in the ear. TMP closure is defined as microscopic TMP closure without presence of pin hole. All images from each visit will be sent to a central imaging vendor for measurement and interpretation. | Up to Day 85 | 
| Change from baseline in TMP size in MAD | TMP size calculation will be performed by central imaging vendor. | Baseline and Day 85 | 
| Change from baseline in the ratio of TMP size per total area of tympanic membrane in MAD | Ratio of TMP size per total area of tympanic membrane will be calculated. | Baseline and Day 85 | 
| Proportion of participants with complete closure of TMP in multiple dose expansion | Tympanic membrane perforation is a perforation of tympanic membrane in the ear. TMP closure is defined as microscopic TMP closure without presence of pin hole. All images from each visit will be sent to a central imaging vendor for measurement and interpretation. | Up to Day 113 | 
| Change from baseline in the ratio of TMP size per total area of tympanic membrane in multiple dose expansion | Ratio of TMP size per total area of tympanic membrane will be calculated. | Baseline and Day 113 | 
| Change from baseline in TMP size in multiple dose expansion | TMP size calculation will be performed by central imaging vendor. | Baseline and Day 113 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASP0598