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)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 36
- 试验地点
- 9
- 主要终点
- Change From Baseline in TVAS at Week 8/EOS in SAD
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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 ASP
- •Subject is unlikely to comply with the visits scheduled in the protocol.
研究组 & 干预措施
Single Ascending Dose (SAD): 0.03 mcg
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)].
干预措施: ASP0598 (Drug)
SAD: 0.15 mcg
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).
干预措施: ASP0598 (Drug)
SAD: 0.75 mcg
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).
干预措施: ASP0598 (Drug)
SAD: 2.25 mcg
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).
干预措施: ASP0598 (Drug)
SAD: Placebo
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).
干预措施: Placebo (Other)
Multiple Ascending Dose (MAD): 0.75 mcg
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).
干预措施: ASP0598 (Drug)
MAD: 2.25 mcg
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).
干预措施: ASP0598 (Drug)
MAD: Placebo
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).
干预措施: Placebo (Other)
结局指标
主要结局
Change From Baseline in TVAS at Week 8/EOS in SAD
时间窗: Baseline and week 8
TVAS was used by participants to rate their tinnitus at baseline and week 8. The scale was a numeric scale and ranged from 0 (not at all strong or loud) to 10 (extremely strong or loud). A lower value indicates less level of discomfort. For the change from baseline, a negative value indicates improvement (less level of discomfort).
Number of Participants With TEAEs in MAD
时间窗: From first dose up to day 85
An AE is any untoward medical occurrence in a participant 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 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.
Number of Participants With AE Special Interest as Cholesteatoma or Ear Neoplasm in MAD
时间窗: From first dose up to day 85
An AE is any untoward medical occurrence in a participant 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 IP whether or not considered related to the IP. Number of participants with cholesteatoma or ear neoplasm is reported.
Number of Participants With AE of Special Interest as Ototoxic Symptoms (Tinnitus, Sensorineural Hearing Loss, Dizziness) in MAD
时间窗: From first dose up to day 85
An AE is any untoward medical occurrence in a participant 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 IP whether or not considered related to the IP. Number of participants with any Ototoxic symptoms (tinnitus, sensorineural hearing loss, dizziness) is reported
Number of Participants With Treatment Emergent Adverse Events (TEAEs) in SAD
时间窗: From first dose up to day 57
An adverse event (AE) is any untoward medical occurrence in a participant administered an investigational product (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 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.
Change From Baseline in Bone Conduction Hearing at 1, 2, 4 kHz by Pure Tone Audiometry at Week 8/EOS in SAD
时间窗: Baseline and week 8
PTA was a behavioral and quantitative hearing test to assess hearing. Pure tone air conduction and bone conduction tests were used to determine whether there was any unilateral or bilateral hearing loss, what type of hearing loss was present, which frequencies were impacted, and the magnitude of the hearing loss.
Number of Participants With AE of Special Interest as Cholesteatoma or Ear Neoplasm in SAD
时间窗: From first dose up to day 57
An AE is any untoward medical occurrence in a participant 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 IP whether or not considered related to the IP. Number of participants with cholesteatoma or ear neoplasm is reported.
Number of Participants With AE of Special Interest as Ototoxic Symptoms (Tinnitus, Sensorineural Hearing Loss, Dizziness) in SAD
时间窗: From first dose up to day 57
An AE is any untoward medical occurrence in a participant 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 IP whether or not considered related to the IP. Number of participants with any ototoxic symptoms (tinnitus, sensorineural hearing loss, dizziness) is reported.
Number of Participants With AE of Special Interest as Otitis Media or Otitis Externa in SAD
时间窗: From first dose up to day 57
An AE is any untoward medical occurrence in a participant 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 IP whether or not considered related to the IP. Number of participants with otitis media or otitis externa is reported.
Number of Participants With AE of Special Interest as Otitis Media or Otitis Externa in MAD
时间窗: From first dose up to day 85
An AE is any untoward medical occurrence in a participant 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 IP whether or not considered related to the IP. Number of participants with otitis media or otitis externa is reported.
Change From Baseline in Bone Conduction Hearing at 1, 2, 4 kHz by Pure Tone Audiometry at Week 12/EOS in MAD
时间窗: Baseline and week 12
PTA was a behavioral and quantitative hearing test to assess hearing. Pure tone air conduction and bone conduction tests were used to determine whether there was any unilateral or bilateral hearing loss, what type of hearing loss was present, which frequencies were impacted, and the magnitude of the hearing loss.
Change From Baseline in TVAS at Week 12/EOS in MAD
时间窗: Baseline and week 12
TVAS was used by participants to rate their tinnitus at baseline and week 12. The scale was a numeric scale and ranged from 0 (not at all strong or loud) to 10 (extremely strong or loud). A lower value indicates less level of discomfort. For the change from baseline, a negative value indicates improvement (less level of discomfort).
次要结局
- Number of Participants With Complete Closure of TMP at Week 12 for MAD(Week 12)
- Number of Participants With Complete Closure of Tympanic Membrane Perforation (TMP) at Week 8 for SAD(Week 8)
- Change From Baseline in the Ratio of TMP Size Per Total Area of Tympanic Membrane at Week 8 for SAD(Baseline and week 8)
- Change From Baseline in the Ratio of TMP Size Per Total Area of Tympanic Membrane at Week 12 for Dose Expansion(Baseline and week 12)
- Change From Baseline in TMP Size at Week 8 for SAD(Baseline and week 8)
- Change From Baseline in TMP Size at Week 12 for Dose Expansion(Baseline and week 12)
- Number of Participants With Complete Closure of TMP at Week 12 for Dose Expansion(Week 12)
- Change From Baseline in the Ratio of TMP Size Per Total Area of Tympanic Membrane at Week 12 for MAD(Baseline and week 12)
- Change From Baseline in the Ratio of TMP Size Per Total Area of Tympanic Membrane at Week 16 for Dose Expansion(Baseline and week 16)
- Change From Baseline in TMP Size at Week 12 for MAD(Baseline and week 12)
- Number of Participants With Complete Closure of TMP at Week 16 for Dose Expansion(Week 16)
- Change From Baseline in TMP Size at Week 16 for Dose Expansion(Baseline and week 16)