Trial Outcomes & Findings for A Study to Assess ASP0598 Otic Solution Following Topical Application in the Ear in Subjects With Chronic Tympanic Membrane Perforation (CTMP) (NCT NCT04305184)

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

36 participants

Primary outcome timeframe

From first dose up to day 57

Results posted on

2024-11-25

Participant Flow

Participants with Chronic Tympanic Membrane Perforation (CTMP) documented as persisting longer than 3 months were enrolled in this study.

Single Ascending Dose (SAD) Multiple Ascending Dose (MAD)

Participant milestones

Participant milestones
Measure	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 \[End of Study (EOS)\].	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).	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).	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).	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).	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).	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).	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).
SAD: Days 1 to 57 STARTED	4	4	4	4	4	0	0	0
SAD: Days 1 to 57 COMPLETED	4	4	4	4	4	0	0	0
SAD: Days 1 to 57 NOT COMPLETED	0	0	0	0	0	0	0	0
MAD: Day 1 to 85 STARTED	0	0	0	0	0	6	6	4
MAD: Day 1 to 85 COMPLETED	0	0	0	0	0	6	6	4
MAD: Day 1 to 85 NOT COMPLETED	0	0	0	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	SAD: 0.03 mcg n=4 Participants Participants received single dose of 0.03 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).	SAD: ASP0598 0.15 mcg n=4 Participants 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).	SAD: ASP0598 0.75 mcg n=4 Participants 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).	SAD: ASP0598 2.25 mcg n=4 Participants 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).	SAD: Placebo n=4 Participants 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).	MAD: 0.75 mcg n=6 Participants 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).	MAD: ASP0598 2.25 mcg n=6 Participants 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).	MAD: Placebo n=4 Participants 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).	Total n=36 Participants Total of all reporting groups
Age, Continuous	32.5 Years STANDARD_DEVIATION 7.0 • n=5 Participants	48.3 Years STANDARD_DEVIATION 20.4 • n=7 Participants	50.8 Years STANDARD_DEVIATION 7.1 • n=5 Participants	49.5 Years STANDARD_DEVIATION 16.0 • n=4 Participants	51.5 Years STANDARD_DEVIATION 8.1 • n=21 Participants	36.5 Years STANDARD_DEVIATION 18.6 • n=10 Participants	44.3 Years STANDARD_DEVIATION 20.1 • n=115 Participants	47.5 Years STANDARD_DEVIATION 14.0 • n=6 Participants	45.11 Years STANDARD_DEVIATION 13.9 • n=6 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	2 Participants n=4 Participants	2 Participants n=21 Participants	2 Participants n=10 Participants	2 Participants n=115 Participants	1 Participants n=6 Participants	18 Participants n=6 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants	2 Participants n=21 Participants	4 Participants n=10 Participants	4 Participants n=115 Participants	3 Participants n=6 Participants	18 Participants n=6 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	2 Participants n=6 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants n=5 Participants	4 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants	3 Participants n=21 Participants	6 Participants n=10 Participants	6 Participants n=115 Participants	4 Participants n=6 Participants	34 Participants n=6 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	0 Participants n=6 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	0 Participants n=6 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	1 Participants n=115 Participants	1 Participants n=6 Participants	3 Participants n=6 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	0 Participants n=6 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	1 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	4 Participants n=6 Participants
Race (NIH/OMB) White	4 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	3 Participants n=21 Participants	5 Participants n=10 Participants	5 Participants n=115 Participants	3 Participants n=6 Participants	29 Participants n=6 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	0 Participants n=6 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	0 Participants n=6 Participants
Bone Conduction Hearing at 1, 2,4 kilohertz (kHz) by Pure Tone Audiometry (PTA) 1 kHz	6.3 decibles STANDARD_DEVIATION 7.5 • n=5 Participants	6.3 decibles STANDARD_DEVIATION 6.3 • n=7 Participants	22.5 decibles STANDARD_DEVIATION 20.2 • n=5 Participants	11.3 decibles STANDARD_DEVIATION 11.1 • n=4 Participants	12.5 decibles STANDARD_DEVIATION 9.6 • n=21 Participants	1.7 decibles STANDARD_DEVIATION 4.1 • n=10 Participants	14.2 decibles STANDARD_DEVIATION 15.3 • n=115 Participants	3.8 decibles STANDARD_DEVIATION 4.8 • n=6 Participants	9.8 decibles STANDARD_DEVIATION 9.9 • n=6 Participants
Bone Conduction Hearing at 1, 2,4 kilohertz (kHz) by Pure Tone Audiometry (PTA) 2 kHz	11.3 decibles STANDARD_DEVIATION 10.3 • n=5 Participants	11.3 decibles STANDARD_DEVIATION 7.5 • n=7 Participants	25.0 decibles STANDARD_DEVIATION 14.7 • n=5 Participants	22.5 decibles STANDARD_DEVIATION 13.2 • n=4 Participants	30.0 decibles STANDARD_DEVIATION 21.2 • n=21 Participants	10.0 decibles STANDARD_DEVIATION 13.4 • n=10 Participants	20.8 decibles STANDARD_DEVIATION 14.6 • n=115 Participants	10.0 decibles STANDARD_DEVIATION 5.8 • n=6 Participants	17.6 decibles STANDARD_DEVIATION 12.5 • n=6 Participants
Bone Conduction Hearing at 1, 2,4 kilohertz (kHz) by Pure Tone Audiometry (PTA) 4 kHz	6.3 decibles STANDARD_DEVIATION 6.3 • n=5 Participants	15.0 decibles STANDARD_DEVIATION 4.1 • n=7 Participants	30.0 decibles STANDARD_DEVIATION 24.2 • n=5 Participants	28.8 decibles STANDARD_DEVIATION 11.1 • n=4 Participants	27.5 decibles STANDARD_DEVIATION 25.3 • n=21 Participants	9.2 decibles STANDARD_DEVIATION 17.7 • n=10 Participants	21.7 decibles STANDARD_DEVIATION 15.4 • n=115 Participants	17.5 decibles STANDARD_DEVIATION 9.6 • n=6 Participants	19.5 decibles STANDARD_DEVIATION 14.2 • n=6 Participants
Tinnitus Visual Analog Scale (TVAS)	1.0 Score on a scale STANDARD_DEVIATION 2.0 • n=5 Participants	1.5 Score on a scale STANDARD_DEVIATION 3.0 • n=7 Participants	3.0 Score on a scale STANDARD_DEVIATION 3.6 • n=5 Participants	3.0 Score on a scale STANDARD_DEVIATION 3.8 • n=4 Participants	2.5 Score on a scale STANDARD_DEVIATION 2.9 • n=21 Participants	0.7 Score on a scale STANDARD_DEVIATION 1.6 • n=10 Participants	3.3 Score on a scale STANDARD_DEVIATION 2.1 • n=115 Participants	2.5 Score on a scale STANDARD_DEVIATION 2.1 • n=6 Participants	2.2 Score on a scale STANDARD_DEVIATION 2.6 • n=6 Participants
Ratio of TMP size per total area of tympanic membrane	10.3 Percentage of total area of TM STANDARD_DEVIATION 5.1 • n=5 Participants	11.6 Percentage of total area of TM STANDARD_DEVIATION 8.1 • n=7 Participants	4.7 Percentage of total area of TM STANDARD_DEVIATION 3.8 • n=5 Participants	15.8 Percentage of total area of TM STANDARD_DEVIATION 11.7 • n=4 Participants	7.3 Percentage of total area of TM STANDARD_DEVIATION 3.8 • n=21 Participants	18.8 Percentage of total area of TM STANDARD_DEVIATION 13.4 • n=10 Participants	17.1 Percentage of total area of TM STANDARD_DEVIATION 9.6 • n=115 Participants	8.7 Percentage of total area of TM STANDARD_DEVIATION 6.7 • n=6 Participants	11.8 Percentage of total area of TM STANDARD_DEVIATION 7.8 • n=6 Participants

PRIMARY outcome

Timeframe: From first dose up to day 57

Population: SAF population

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.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=4 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=4 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	SAD: 2.25 mcg n=4 Participants 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).	SAD: Placebo n=4 Participants 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).
Number of Participants With Treatment Emergent Adverse Events (TEAEs) in SAD	4 Participants	1 Participants	3 Participants	3 Participants	2 Participants

PRIMARY outcome

Timeframe: From first dose up to day 57

Population: SAF population

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.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=4 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=4 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	SAD: 2.25 mcg n=4 Participants 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).	SAD: Placebo n=4 Participants 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).
Number of Participants With AE of Special Interest as Cholesteatoma or Ear Neoplasm in SAD	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From first dose up to day 57

Population: SAF population

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.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=4 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=4 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	SAD: 2.25 mcg n=4 Participants 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).	SAD: Placebo n=4 Participants 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).
Number of Participants With AE of Special Interest as Ototoxic Symptoms (Tinnitus, Sensorineural Hearing Loss, Dizziness) in SAD	2 Participants	0 Participants	1 Participants	1 Participants	0 Participants

PRIMARY outcome

Timeframe: From first dose up to day 57

Population: SAF population

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.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=4 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=4 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	SAD: 2.25 mcg n=4 Participants 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).	SAD: Placebo n=4 Participants 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).
Number of Participants With AE of Special Interest as Otitis Media or Otitis Externa in SAD	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline and week 8

Population: SAF population

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.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=4 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=4 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	SAD: 2.25 mcg n=4 Participants 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).	SAD: Placebo n=4 Participants 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).
Change From Baseline in Bone Conduction Hearing at 1, 2, 4 kHz by Pure Tone Audiometry at Week 8/EOS in SAD 2 kHz	1.3 decibles Standard Deviation 2.5	-1.3 decibles Standard Deviation 2.5	2.5 decibles Standard Deviation 8.7	-3.8 decibles Standard Deviation 8.5	-1.3 decibles Standard Deviation 4.8
Change From Baseline in Bone Conduction Hearing at 1, 2, 4 kHz by Pure Tone Audiometry at Week 8/EOS in SAD 1 kHz	-1.3 decibles Standard Deviation 2.5	0.0 decibles Standard Deviation 4.1	0.0 decibles Standard Deviation 4.1	-2.5 decibles Standard Deviation 6.5	1.3 decibles Standard Deviation 6.3
Change From Baseline in Bone Conduction Hearing at 1, 2, 4 kHz by Pure Tone Audiometry at Week 8/EOS in SAD 4 kHz	0.0 decibles Standard Deviation 4.1	-1.3 decibles Standard Deviation 4.8	1.3 decibles Standard Deviation 7.5	-1.3 decibles Standard Deviation 4.8	0.0 decibles Standard Deviation 7.1

PRIMARY outcome

Timeframe: Baseline and week 8

Population: SAF population

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).

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=4 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=4 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	SAD: 2.25 mcg n=4 Participants 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).	SAD: Placebo n=4 Participants 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).
Change From Baseline in TVAS at Week 8/EOS in SAD	-0.3 Score on a scale Standard Deviation 0.5	0.0 Score on a scale Standard Deviation 0.0	-1.0 Score on a scale Standard Deviation 2.0	0.3 Score on a scale Standard Deviation 2.9	-1.5 Score on a scale Standard Deviation 2.4

PRIMARY outcome

Timeframe: From first dose up to day 85

Population: SAF population

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.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=6 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=6 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	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).	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).
Number of Participants With TEAEs in MAD	6 Participants	5 Participants	4 Participants	—	—

PRIMARY outcome

Timeframe: From first dose up to day 85

Population: SAF population

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.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=6 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=6 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	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).	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).
Number of Participants With AE Special Interest as Cholesteatoma or Ear Neoplasm in MAD	0 Participants	0 Participants	0 Participants	—	—

PRIMARY outcome

Timeframe: From first dose up to day 85

Population: SAF population

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

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=6 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=6 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	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).	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).
Number of Participants With AE of Special Interest as Ototoxic Symptoms (Tinnitus, Sensorineural Hearing Loss, Dizziness) in MAD	2 Participants	1 Participants	0 Participants	—	—

PRIMARY outcome

Timeframe: From first dose up to day 85

Population: SAF population

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.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=6 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=6 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	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).	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).
Number of Participants With AE of Special Interest as Otitis Media or Otitis Externa in MAD	1 Participants	0 Participants	0 Participants	—	—

PRIMARY outcome

Timeframe: Baseline and week 12

Population: SAF population with available data was analyzed.

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.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=5 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=6 Participants 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).	SAD: 0.75 mcg n=3 Participants 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).	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).	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).
Change From Baseline in Bone Conduction Hearing at 1, 2, 4 kHz by Pure Tone Audiometry at Week 12/EOS in MAD 1 kHz	1.0 decibles Standard Deviation 2.2	-3.3 decibles Standard Deviation 6.1	-1.7 decibles Standard Deviation 2.9	—	—
Change From Baseline in Bone Conduction Hearing at 1, 2, 4 kHz by Pure Tone Audiometry at Week 12/EOS in MAD 2 kHz	1.0 decibles Standard Deviation 2.2	-2.5 decibles Standard Deviation 5.2	0.0 decibles Standard Deviation 5.0	—	—
Change From Baseline in Bone Conduction Hearing at 1, 2, 4 kHz by Pure Tone Audiometry at Week 12/EOS in MAD 4 kHz	2.0 decibles Standard Deviation 7.6	-1.7 decibles Standard Deviation 6.8	-6.7 decibles Standard Deviation 2.9	—	—

PRIMARY outcome

Timeframe: Baseline and week 12

Population: SAF population with available data was analyzed.

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).

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=5 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=6 Participants 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).	SAD: 0.75 mcg n=3 Participants 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).	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).	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).
Change From Baseline in TVAS at Week 12/EOS in MAD	-0.6 Score on a scale Standard Deviation 1.3	-0.7 Score on a scale Standard Deviation 2.0	0.0 Score on a scale Standard Deviation 2.0	—	—

SECONDARY outcome

Timeframe: Week 8

Population: The Full Analysis Set (FAS) consisted of all randomized participants who received a dose of study drug and had baseline value and at least 1 post baseline complete closure assessment during study period.

Tympanic membrane perforation is a hole in the thin membrane that separates the ear canal from the middle ear. TMP closure is defined as microscopic TMP closure without presence of pin hole.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=4 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=4 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	SAD: 2.25 mcg n=4 Participants 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).	SAD: Placebo n=4 Participants 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).
Number of Participants With Complete Closure of Tympanic Membrane Perforation (TMP) at Week 8 for SAD	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Week 12

Population: The single and multiple dose expansion parts of the study were not opened following review of safety and efficacy results of the SAD part of the study by the DMC, therefore the data was not collected.

Tympanic membrane perforation is a hole in the thin membrane that separates the ear canal from the middle ear. TMP closure is defined as microscopic TMP closure without presence of pin hole.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and week 8

Population: FAS population with available data was analyzed.

Ratio of TMP size per total area of tympanic membrane calculation was performed by central imaging vendor and measured in percentage.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=4 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=4 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	SAD: 2.25 mcg n=4 Participants 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).	SAD: Placebo n=3 Participants 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).
Change From Baseline in the Ratio of TMP Size Per Total Area of Tympanic Membrane at Week 8 for SAD	-0.4 Percentage of total area of TM Standard Deviation 0.6	4.2 Percentage of total area of TM Standard Deviation 6.3	-1.8 Percentage of total area of TM Standard Deviation 2.3	1.0 Percentage of total area of TM Standard Deviation 0.5	0.3 Percentage of total area of TM Standard Deviation 3.0

SECONDARY outcome

Timeframe: Baseline and week 12

Population: The single and multiple dose expansion parts of the study were not opened following review of safety and efficacy results of the SAD part of the study by the DMC, therefore the data was not collected.

Ratio of TMP size per total area of tympanic membrane calculation was performed by central imaging vendor and was measured by percentage.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and week 8

Population: FAS population

TMP size calculation was be performed by central imaging vendor.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=4 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=4 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	SAD: 2.25 mcg n=4 Participants 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).	SAD: Placebo n=4 Participants 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).
Change From Baseline in TMP Size at Week 8 for SAD	13451.0 mm^2 Standard Deviation 9700.9	14271.5 mm^2 Standard Deviation 11800.6	9572.0 mm^2 Standard Deviation 9462.7	12784.3 mm^2 Standard Deviation 5277.9	27389.0 mm^2 Standard Deviation 37917.3

SECONDARY outcome

Timeframe: Baseline and week 12

Population: The single and multiple dose expansion parts of the study were not opened following review of safety and efficacy results of the SAD part of the study by the DMC, therefore the data was not collected.

TMP size calculation was be performed by central imaging vendor.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 12

Population: FAS population

Tympanic membrane perforation is a hole in the thin membrane that separates the ear canal from the middle ear. TMP closure is defined as microscopic TMP closure without presence of pin hole.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=6 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=6 Participants 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).	SAD: 0.75 mcg n=4 Participants 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).	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).	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).
Number of Participants With Complete Closure of TMP at Week 12 for MAD	0 Participants	0 Participants	1 Participants	—	—

SECONDARY outcome

Timeframe: Week 16

Population: The single and multiple dose expansion parts of the study were not opened following review of safety and efficacy results of the MAD part of the study by the DMC, therefore the data was not collected.

Tympanic membrane perforation is a hole in the thin membrane that separates the ear canal from the middle ear. TMP closure is defined as microscopic TMP closure without presence of pin hole.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and week 12

Population: FAS population

Ratio of TMP size per total area of tympanic membrane calculation was performed by central imaging vendor and measured in percentage.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=5 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=6 Participants 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).	SAD: 0.75 mcg n=3 Participants 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).	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).	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).
Change From Baseline in the Ratio of TMP Size Per Total Area of Tympanic Membrane at Week 12 for MAD	-0.2 Percentage of total area of TM Standard Deviation 2.4	2.5 Percentage of total area of TM Standard Deviation 2.3	0.3 Percentage of total area of TM Standard Deviation 2.3	—	—

SECONDARY outcome

Timeframe: Baseline and week 16

Population: The single and multiple dose expansion parts of the study were not opened following review of safety and efficacy results of the MAD part of the study by the DMC, therefore the data was not collected.

Ratio of TMP size per total area of tympanic membrane calculation was performed by central imaging vendor and measured in percentage.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and week 12

Population: FAS population with available data was analyzed.

TMP size calculation was be performed by central imaging vendor.

Outcome measures

Outcome measures
Measure	SAD: 0.03 mcg n=5 Participants Participants received single dose of 0.03 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).	SAD: 0.15 mcg n=6 Participants 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).	SAD: 0.75 mcg n=3 Participants 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).	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).	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).
Change From Baseline in TMP Size at Week 12 for MAD	1904.2 mm^2 Standard Deviation 18056.6	545.8 mm^2 Standard Deviation 9706.9	-1237.3 mm^2 Standard Deviation 672.5	—	—

SECONDARY outcome

Timeframe: Baseline and week 16

Population: The single and multiple dose expansion parts of the study were not opened following review of safety and efficacy results of the MAD part of the study by the DMC, therefore the data was not collected.

TMP size calculation was be performed by central imaging vendor.