Clinical trial NCT04305184: A Study to Assess ASP0598 Otic Solution Following Topical Application in the Ear in Subjects With Chronic Tympanic Membrane Perforation (CTMP)
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Chronic Tympanic Membrane Perforation
Keywords: ASP0598
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2020-03-12
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study was to evaluate the safety and tolerability of ASP0598 Otic Solution. This study also evaluated the efficacy of ASP0598 otic solution.

Detailed description: This study consisted 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 consisted 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 received ASP0598 Otic Solution or placebo administration into the affected ear. Participants returned to the site on days 2, 3, 8, 15, 29, and 57 \[end of study (EOS)\]. Day 3 evaluations were only performed for cohorts 1, 2 and 3. For MAD, after randomization on Day 1, participants received ASP0598 Otic Solution or placebo administration into the affected ear and received additional treatments into the same ear on Days 15 and 29. Participants returned to the investigative site on Days 8, 15, 22, 29, 36, 57, and 85 (EOS). Dose expansion was based on the safety and efficacy results from an interim analysis. An interim analysis was conducted after completion of SAD and again after completion of MAD. The single and multiple dose expansion parts of the study were not opened following review of safety and efficacy results of SAD and MAD parts of the study by the DMC per the Interim Analysis Plan.

Eligibility 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.
* 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.

Primary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) in SAD
timeFrame: From first dose up to day 57
measure: Number of Participants With AE of Special Interest as Cholesteatoma or Ear Neoplasm in SAD
timeFrame: From first dose up to day 57
measure: Number of Participants With AE of Special Interest as Ototoxic Symptoms (Tinnitus, Sensorineural Hearing Loss, Dizziness) in SAD
timeFrame: From first dose up to day 57
measure: Number of Participants With AE of Special Interest as Otitis Media or Otitis Externa in SAD
timeFrame: From first dose up to day 57
measure: Change From Baseline in Bone Conduction Hearing at 1, 2, 4 kHz by Pure Tone Audiometry at Week 8/EOS in SAD
timeFrame: Baseline and week 8
measure: Change From Baseline in TVAS at Week 8/EOS in SAD
timeFrame: Baseline and week 8
measure: Number of Participants With TEAEs in MAD
timeFrame: From first dose up to day 85
measure: Number of Participants With AE Special Interest as Cholesteatoma or Ear Neoplasm in MAD
timeFrame: From first dose up to day 85
measure: Number of Participants With AE of Special Interest as Ototoxic Symptoms (Tinnitus, Sensorineural Hearing Loss, Dizziness) in MAD
timeFrame: From first dose up to day 85
measure: Number of Participants With AE of Special Interest as Otitis Media or Otitis Externa in MAD
timeFrame: From first dose up to day 85
measure: Change From Baseline in Bone Conduction Hearing at 1, 2, 4 kHz by Pure Tone Audiometry at Week 12/EOS in MAD
timeFrame: Baseline and week 12
measure: Change From Baseline in TVAS at Week 12/EOS in MAD
timeFrame: Baseline and week 12
Secondary outcomes:
measure: Number of Participants With Complete Closure of Tympanic Membrane Perforation (TMP) at Week 8 for SAD
timeFrame: Week 8
measure: Number of Participants With Complete Closure of TMP at Week 12 for Dose Expansion
timeFrame: Week 12
measure: Change From Baseline in the Ratio of TMP Size Per Total Area of Tympanic Membrane at Week 8 for SAD
timeFrame: Baseline and week 8
measure: Change From Baseline in the Ratio of TMP Size Per Total Area of Tympanic Membrane at Week 12 for Dose Expansion
timeFrame: Baseline and week 12
measure: Change From Baseline in TMP Size at Week 8 for SAD
timeFrame: Baseline and week 8
measure: Change From Baseline in TMP Size at Week 12 for Dose Expansion
timeFrame: Baseline and week 12
measure: Number of Participants With Complete Closure of TMP at Week 12 for MAD
timeFrame: Week 12
measure: Number of Participants With Complete Closure of TMP at Week 16 for Dose Expansion
timeFrame: Week 16
measure: Change From Baseline in the Ratio of TMP Size Per Total Area of Tympanic Membrane at Week 12 for MAD
timeFrame: Baseline and week 12
measure: Change From Baseline in the Ratio of TMP Size Per Total Area of Tympanic Membrane at Week 16 for Dose Expansion
timeFrame: Baseline and week 16
measure: Change From Baseline in TMP Size at Week 12 for MAD
timeFrame: Baseline and week 12
measure: Change From Baseline in TMP Size at Week 16 for Dose Expansion
timeFrame: Baseline and week 16
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford Hospital
state: California
city: Torrance
country: United States
facility: Breathe Clear Institute
state: California
city: Boca Raton
country: United States
facility: ENT and Allergy Associates of Florida
state: Florida
city: New Albany
country: United States
facility: Advanced ENT
state: Indiana
city: Louisville
country: United States
facility: Advanced ENT
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Matthews
country: United States
facility: Charlotte ENT Associates
state: North Carolina
city: Winston-Salem
country: United States
facility: Piedmont ENT
state: North Carolina
city: Orangeburg
country: United States
facility: Carolina ENT Clinic
state: South Carolina
city: Richmond
country: United States
facility: Richmond ENT
state: Virginia
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: