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

Astellas

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Chronic Tympanic Membrane Perforation

Treatments: Drug: ASP0598; Other: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT04305184

0598-CL-0101

Details and patient eligibility

About

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.

Full 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.

Enrollment: 36 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: Double Blind

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36 participants in 8 patient groups, including a placebo group

Single Ascending Dose (SAD): 0.03 mcg

Experimental group

Description:

Participants received single dose of 0.03 microgram (mcg) ASP0598 Otic Solution into the affected ear on day 1 and returned to the investigative site for assessments on days 2, 3, 8, 15, 29, and 57 \[End of Study (EOS)\].

Treatment:

Drug: ASP0598

SAD: 0.15 mcg

Experimental group

Description:

Participants received single dose of 0.15 mcg ASP0598 Otic Solution into the affected ear on Day 1 and returned to the investigative site for assessments on days 2, 3, 8, 15, 29, and 57 (EOS).

Treatment:

Drug: ASP0598

SAD: 0.75 mcg

Experimental group

Description:

Participants received single dose of 0.75 mcg ASP0598 Otic Solution into the affected ear on day 1 and returned to the investigative site for assessments on days 2, 3, 8, 15, 29, and 57 (EOS).

Treatment:

Drug: ASP0598

SAD: 2.25 mcg

Experimental group

Description:

Participants received single dose of 2.25 mcg ASP0598 Otic Solution into the affected ear on day 1 and returned to the investigative site for assessments on days 2, 3, 8, 15, 29, and 57 (EOS).

Treatment:

Drug: ASP0598

SAD: Placebo

Placebo Comparator group

Description:

Participants received single dose of placebo matched to ASP0598 Otic Solution into the affected ear on day 1 and returned to the investigative site for assessments on days 2, 3, 8, 15, 29, and 57 (EOS).

Treatment:

Other: Placebo

Multiple Ascending Dose (MAD): 0.75 mcg

Experimental group

Description:

Participants received multiple doses of 0.75 mcg ASP0598 Otic Solution into the affected ear on days 1, 15 and 29 and returned to the investigative site for assessments on days 8, 15, 22, 29, 36, 57, and 85 (EOS).

Treatment:

Drug: ASP0598

MAD: 2.25 mcg

Experimental group

Description:

Participants received multiple doses of 2.25 mcg ASP0598 Otic Solution into the affected ear on days 1, 15 and 29 and returned to the investigative site for assessments on days 8, 15, 22, 29, 36, 57, and 85 (EOS).

Treatment:

Drug: ASP0598

MAD: Placebo

Placebo Comparator group

Description:

Participants received multiple doses of placebo matched to ASP0598 Otic Solution into the affected ear on days 1, 15 and 29 and returned to the investigative site for assessments on days 8, 15, 22, 29, 36, 57, and 85 (EOS).

Treatment:

Other: Placebo