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

• ClinicalTrials.gov Identifier: NCT04305184
• Recruitment Status: Recruiting
• First Posted: March 12, 2020
• Last Update Posted: November 19, 2020
• Sponsor: Astellas Pharma Global Development, Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Chronic Tympanic Membrane Perforation	Drug: ASP0598; Drug: Matching Placebo	Phase 1; Phase 2

Detailed Description:

This study will consist of a dose escalation (single ascending dose - SAD and multiple ascending dose- MAD) and a dose expansion (single dose expansion and multiple dose expansion) phase. 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)]. 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). The dose expansion phase will be based on the safety and efficacy results from an interim analysis. The interim analysis will be conducted after completion of after completion of SAD and 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 Day 15 or Day 29, the participant will not receive the next scheduled dose(s). Participants will return to the investigative site on Days 15, 29, 43, 57, 85 and 113 (EOS).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 114 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: September 10, 2020
• Estimated Primary Completion Date: December 2022
• Estimated Study Completion Date: December 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: ASP0598 SAD; 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; Topical Solution
Experimental: ASP0598 MAD; 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; Topical Solution
Experimental: ASP0598 Single Dose Expansion; 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; Topical Solution
Experimental: ASP0598 Multiple Dose Expansion; 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; Topical Solution
Placebo Comparator: Pooled Placebo in SAD; For each dose level ASP0598 matching placebo onto the tympanic membrane through the external auditory canal via syringe.	Drug: Matching Placebo; Placebo Topical Solution
Placebo Comparator: Pooled Placebo in MAD; For each dose level ASP0598 matching placebo onto the tympanic membrane through the external auditory canal via syringe.	Drug: Matching Placebo; Placebo Topical Solution
Placebo Comparator: Placebo in Single Dose Expansion; ASP0598 matching placebo onto the tympanic membrane through the external auditory canal via syringe.	Drug: Matching Placebo; Placebo Topical Solution
Placebo Comparator: Placebo in Multiple Dose Expansion; ASP0598 matching placebo onto the tympanic membrane through the external auditory canal via syringe.	Drug: Matching Placebo; Placebo Topical Solution

Outcome Measures

Primary Outcome Measures :

1. Number of participants with Treatment Emergent Adverse Events (TEAEs) in SAD [ Time Frame: Up to Day 57 ]
   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.
2. Number of participants with TEAEs of special interest in SAD [ Time Frame: Up to Day 57 ]
   AEs of special interest include cholesteatoma or ear neoplasm, ototoxic symptoms (tinnitus, sensorineural hearing loss, dizziness) and otitis media or otitis externa.
3. Change from baseline in bone conduction hearing at 1 kHz by pure tone audiometry (PTA) in SAD [ Time Frame: Baseline and Day 57 ]
   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.
4. Change from baseline in bone conduction hearing at 2 kHz by pure tone audiometry (PTA) in SAD [ Time Frame: Baseline and Day 57 ]
   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.
5. Change from baseline in bone conduction hearing at 4 kHz by pure tone audiometry (PTA) in SAD [ Time Frame: Baseline and Day 57 ]
   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.
6. Change from baseline in Tinnitus Visual Analog Scale (TVAS) in SAD [ Time Frame: Baseline and Day 57 ]
   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.
7. Number of participants with Treatment Emergent Adverse Events (TEAEs) in single dose expansion [ Time Frame: Up to Day 85 ]
   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.
8. Number of incidences of AEs of special interest in single dose expansion [ Time Frame: Up to Day 85 ]
   AEs of special interest include cholesteatoma or ear neoplasm, ototoxic symptoms (tinnitus, sensorineural hearing loss, dizziness) and otitis media or otitis externa.
9. Change from baseline in bone conduction hearing at 1 kHz by pure tone audiometry (PTA) in single dose expansion [ Time Frame: Baseline and Day 85 ]
   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.
10. Change from baseline in bone conduction hearing at 2 kHz by pure tone audiometry (PTA) in single dose expansion [ Time Frame: Baseline and Day 85 ]
    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.
11. Change from baseline in bone conduction hearing at 4 kHz by pure tone audiometry (PTA) in single dose expansion [ Time Frame: Baseline and Day 85 ]
    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.
12. Change from baseline in Tinnitus Visual Analog Scale (TVAS) in single dose expansion [ Time Frame: Baseline and Day 85 ]
    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.
13. Number of participants with Treatment Emergent Adverse Events (TEAEs) in MAD [ Time Frame: Up to Day 85 ]
    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.
14. Number of participants with TEAEs of special interest in MAD [ Time Frame: Up to Day 85 ]
    AEs of special interest include cholesteatoma or ear neoplasm, ototoxic symptoms (tinnitus, sensorineural hearing loss, dizziness) and otitis media or otitis externa.
15. Change from baseline in bone conduction hearing at 1 kHz by pure tone audiometry (PTA) in MAD [ Time Frame: Baseline and Day 85 ]
    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.
16. Change from baseline in bone conduction hearing at 2 kHz by pure tone audiometry (PTA) in MAD [ Time Frame: Baseline and Day 85 ]
    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.
17. Change from baseline in bone conduction hearing at 4 kHz by pure tone audiometry (PTA) in MAD [ Time Frame: Baseline and Day 85 ]
    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.
18. Change from baseline in Tinnitus Visual Analog Scale (TVAS) in MAD [ Time Frame: Baseline and Day 85 ]
    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.
19. Number of participants with Treatment Emergent Adverse Events (TEAEs) in multiple dose expansion [ Time Frame: Up to Day 113 ]
    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.
20. Number of incidences of AEs of special interest in multiple dose expansion [ Time Frame: Up to Day 113 ]
    AEs of special interest include cholesteatoma or ear neoplasm, ototoxic symptoms (tinnitus, sensorineural hearing loss, dizziness) and otitis media or otitis externa.
21. Change from baseline in bone conduction hearing at 1 kHz by pure tone audiometry (PTA) in multiple dose expansion [ Time Frame: Baseline and Day 113 ]
    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.
22. Change from baseline in bone conduction hearing at 2 kHz by pure tone audiometry (PTA) in multiple dose expansion [ Time Frame: Baseline and Day 113 ]
    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.
23. Change from baseline in bone conduction hearing at 4 kHz by pure tone audiometry (PTA) in multiple dose expansion [ Time Frame: Baseline and Day 113 ]
    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.
24. Change from baseline in Tinnitus Visual Analog Scale (TVAS) in multiple dose expansion [ Time Frame: Baseline and Day 113 ]
    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.

Secondary Outcome Measures :

1. Proportion of participants with complete closure of Tympanic Membrane Perforation (TMP) in SAD [ Time Frame: Up to Day 57 ]
   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.
2. Change from baseline in the ratio of TMP size per total area of tympanic membrane in SAD [ Time Frame: Baseline and Day 57 ]
   Ratio of TMP size per total area of tympanic membrane will be calculated.
3. Change from baseline in TMP size in SAD [ Time Frame: Baseline and Day 57 ]
   TMP size calculation will be performed by central imaging vendor.
4. Proportion of participants with complete closure of TMP in single dose expansion [ Time Frame: Up to Day 85 ]
   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.
5. Change from baseline in the ratio of TMP size per total area of tympanic membrane in single dose expansion [ Time Frame: Baseline and Day 85 ]
   Ratio of TMP size per total area of tympanic membrane will be calculated.
6. Change from baseline in TMP size in single dose expansion [ Time Frame: Baseline and Day 85 ]
   TMP size calculation will be performed by central imaging vendor.
7. Proportion of participants with complete closure of TMP in MAD [ Time Frame: Up to Day 85 ]
   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.
8. Change from baseline in TMP size in MAD [ Time Frame: Baseline and Day 85 ]
   TMP size calculation will be performed by central imaging vendor.
9. Change from baseline in the ratio of TMP size per total area of tympanic membrane in MAD [ Time Frame: Baseline and Day 85 ]
   Ratio of TMP size per total area of tympanic membrane will be calculated.
10. Proportion of participants with complete closure of TMP in multiple dose expansion [ Time Frame: Up to Day 113 ]
    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.
11. Change from baseline in the ratio of TMP size per total area of tympanic membrane in multiple dose expansion [ Time Frame: Baseline and Day 113 ]
    Ratio of TMP size per total area of tympanic membrane will be calculated.
12. Change from baseline in TMP size in multiple dose expansion [ Time Frame: Baseline and Day 113 ]
    TMP size calculation will be performed by central imaging vendor.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 on Day 1.
• 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 prohibited concomitant medication restrictions.
• Subject agrees not to participate in another interventional study while receiving IP.

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.
  • History of 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 Hz.
  • Only hearing or better hearing ear.
  • 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.

Contacts and Locations

Contacts

Contact: Astellas Pharma Global Development, Inc.; 800-888-7704; Astellas.registration@astellas.com

Locations

United States, Colorado

Colorado ENT & Allergy; Recruiting

Colorado Springs, Colorado, United States, 80909

United States, Indiana

Advanced ENT; Recruiting

New Albany, Indiana, United States, 47150

United States, Kentucky

Advanced ENT; Recruiting

Louisville, Kentucky, United States, 40220

United States, Nebraska

Omaha ENT; Recruiting

Omaha, Nebraska, United States, 68118

Sponsors and Collaborators

Astellas Pharma Global Development, Inc.

Investigators

• Study Director: Medical Director; Astellas Pharma Global Development, Inc.

More Information

• Responsible Party: Astellas Pharma Global Development, Inc.
• ClinicalTrials.gov Identifier: NCT04305184
• Other Study ID Numbers: 0598-CL-0101
• First Posted: March 12, 2020
• Last Update Posted: November 19, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):

ASP0598

Additional relevant MeSH terms:

Tympanic Membrane Perforation; Ear Diseases; Otorhinolaryngologic Diseases; Wounds and Injuries