XXX10.

1177/0003489419830116Annals of Otology, Rhinology & LaryngologyAnsley et al

research-article2019

Article
Annals of Otology, Rhinology & Laryngology

OTO-201 for the Treatment of Acute

2019, Vol. 128(6) 524­–533
© The Author(s) 2019

Otitis Externa: Results from a Phase 3 Article reuse guidelines:

Randomized Clinical Study sagepub.com/journals-permissions

DOI: 10.1177/0003489419830116
https://doi.org/10.1177/0003489419830116
journals.sagepub.com/home/aor

John Ansley, MD1 , Eric A. Mair, MD2, Hamid Namini, PhD3,

Chung H. Lu, PharmD3, and Carl LeBel, PhD3

Abstract
Objectives: OTO-201 is a ciprofloxacin otic suspension previously approved by the US Food and Drug Administration
to treat children with bilateral otitis media with effusion requiring tympanostomy tube placement. In this phase 3, double-
blind, randomized, prospective, sham-controlled, multicenter study, a single dose of OTO-201 was administered to the
external auditory canal in subjects with unilateral or bilateral acute otitis externa.
Methods: Two hundred sixty-two subjects, 3 to 83 years of age, were randomized, and 260 subjects were included
in the intent-to-treat analysis population: OTO-201 (0.2 mL, 12 mg, n = 130) or sham (air injection, n = 130). The
primary efficacy measure was clinical cure (CC) on day 8, judged by blinded assessor for erythema, edema, otorrhea, and
tenderness. Subjects were monitored over 28 days for efficacy and safety.
Results: OTO-201 demonstrated a significant increase in CC compared with sham at day 8 (69.2% vs 46.1%, P < .001).
Higher CC was also noted on day 4 (P = .028), day 15 (P < .001), and day 29 (P < .001). A similar effect was observed
in the pathogen-positive population. Single OTO-201 administration in the office setting was well tolerated by subjects.
Conclusions: In this study in subjects with acute otitis externa, a single administration of 12 mg OTO-201 to the external
auditory canal demonstrated a significantly higher proportion of subjects with CC and bacterial eradication compared with
sham starting on day 4 and on all other observation days through day 29, with no safety or tolerability concerns identified.
OTO-201 is the first agent in a randomized phase 3 study to demonstrate the efficacy and safety of a single-dose, health
care professional–administered topical antibiotic for the treatment of acute otitis externa.

Keywords
acute otitis externa, clinical cure, OTO-201, ciprofloxacin, thermosensitive, thermoreversible, otorrhea, single-dose antibiotic

Introduction Symptoms include otalgia, itching, and aural fullness. Signs

Acute otitis externa (AOE), also known as “swimmer’s
ear,” is a common condition in pediatric and adult
populations characterized by diffuse inflammation of the
external auditory canal (EAC). On the basis of 2007 data
from the Centers for Disease Control and Prevention,
approximately 1 in 123 persons in the United States visited
ambulatory care centers and emergency departments
because of AOE, equating to 2.4 million patients. Incidence
of AOE is shown to peak during the summer months,
regionally in the South, and in children between 5 and 14
years of age.1 Per the clinical practice guidelines published
by the American Academy of Otolaryngology–Head and
Neck Surgery Foundation (AAO-HNSF), diagnosis of AOE
requires a rapid onset (generally within 48 hours) in the past
3 weeks of signs and symptoms of EAC inflammation.2,3
include tenderness of the tragus and pinna, diffuse ear canal
edema, conductive hearing loss, erythema, and otorrhea.
Overall, 90% of AOE cases are unilateral; in North America
nearly all of the time (98%), AOE is caused by bacterial
infection.3 Pseudomonas aeruginosa and Staphylococcus
aureus are the most common pathogens responsible for
AOE, with Staphylococcus species being less prevalent in
children than in adults.4
1
Carolina Ear, Nose and Throat Clinic, Orangeburg, SC, USA
2
Charlotte Eye, Ear, Nose, and Throat Associates, Charlotte, NC, USA
3
Otonomy, Inc., San Diego, CA, USA
Corresponding Author:
John Ansley, MD, Carolina Ear, Nose and Throat Clinic, 832 Cook Road,
Orangeburg, SC 29118, USA
Email: jfansley@yahoo.com
Ansley et al 525
Major components of managing AOE include clean-
ing the EAC, addressing pain control, and treating the
infection with a topical antibiotic. Removal of cerumen,
desquamated skin, and purulent discharge from the EAC
improves healing and enhances the penetration of topical
therapies to the site of infection. Current standard of
care, consistent with AAO-HNSF guidelines, recom-
mends the use of topical antibiotics, as opposed to sys-
temic antibiotics, for the treatment of diffuse,
uncomplicated AOE.3 A variety of topical preparations
are approved by the US Food and Drug Administration
(FDA) for treating AOE. These agents incorporate, either
as monotherapy or combination therapy, an antibiotic
(such as aminoglycoside, polymyxin B, quinolones, or
combination agents), a corticosteroid, or a low-pH anti-
septic. Per the guidelines, no meaningful differences in
clinical outcomes have been noted on the basis of class
of drug, use of a quinolone versus nonquinolone prepara-
tion, or for monotherapy versus combination drugs with
or without a steroid.3
A limitation associated with all currently FDA-
approved topical agents for treating AOE is the require-
ment of multiple applications (up to 4 times/day) over
multiple days (usually over 7 days) by the patient or care-
giver.5-7 The practice guideline recognizes multiple chal-
lenges associated with the administration of topical drug
delivery to an infected external ear canal, citing poor
patient adherence to therapy, difficulties with application
(ie, “missing” the ear canal), presence of debris in the
canal, and edema that leads to closing of the EAC.3
Furthermore, the guidelines state that difficulties with
self-administration of topical agents arise because it must
be done by “feel.” Indeed, data from a blinded study in 39
adult patients with AOE prescribed otic drops showed
that only 40% of patients who self-medicated did so
appropriately during the first 3 days, with a tendency
often to undermedicate.8
OTO-201 was designed to be a single-dose, health care
professional (HCP)–administered formulation of cipro-
floxacin suspended in a thermosensitive and thermorev-
ersible poloxamer (P407).9 When OTO-201 is exposed to
the temperature within the ear, it quickly transitions from
a liquid to a gel. P407 serves as a novel drug “carrier,”
allowing suspended microparticles of ciprofloxacin to be
deposited and solubilized over time. OTO-201 was previ-
ously approved by the FDA to treat children with bilateral
otitis media with effusion requiring tympanostomy tube
placement.9 A prior phase 2 clinical study in AOE demon-
strated the feasibility of delivering 0.2 mL of OTO-201 in
children and adult subjects, with >90% of HCPs reporting
that it was “very easy” to administer the treatment in an
outpatient, ambulatory care setting when using readily
available catheters.10 In this phase 3 clinical study we
evaluated the efficacy, safety, and tolerability of a single
administration of OTO-201 to the EAC in subjects pre-
senting with AOE.
Methods
Study Design
This was a double-blind, randomized, prospective, sham-
controlled, multicenter phase 3 clinical study of OTO-201
(6% ciprofloxacin otic suspension; OTIPRIO; Otonomy,
Inc., San Diego, California, USA) administered as a single
dose in the outpatient, office-based setting to children and
adults with AOE. Institutional review board (IRB; Schulman
Associates IRB [IRB00000971], Cincinnati, Ohio, USA;
AltaMed Health Services Corporation [FWA00002187];
Emory IRB [IRB00000569]; Vanderbilt University IRB
[IRB00000475]; Medical University of South Carolina IRB
[IRB00000027]; and Saint Louis University IRB
[FWA00005304]) approval and written informed consent
were obtained prior to study-related procedure initiation.
The study was conducted in accordance with the regula-
tions and guidelines of the FDA, the Declaration of Helsinki,
and the International Conference on Harmonization Good
Clinical Practice guidelines.
Key inclusion criteria required that subjects be male or
female, be 6 months of age or older, have a clinical diagno-
sis of unilateral or bilateral AOE, and have a combined
numeric severity score of ≥4 in at least 1 affected ear at the
screening visit for tenderness, erythema, and edema (ie,
each measure was scored 0 = none [complete absence of
any signs or symptoms], 1 = mild [slight], 2 = moderate
[definitely present], or 3 = severe [marked, intense]). In
subjects with bilateral AOE, only 1 ear must have met this
criterion, and both ears were assessed, cultured, and treated
with OTO-201 or sham. Key exclusion criteria were the fol-
lowing: history of allergy to ciprofloxacin, known tympanic
membrane perforation in either ear, severe otitis externa
(OE) that either included auricular cellulitis or chondritis or
prevented administration of OTO-201, chronic OE, defined
as either having 1 or more previous episodes of OE within
the past 3 months or more than 3 previous episodes of OE
within the past year, eczematoid OE, or fungal OE. Subjects
with baseline cultures growing group A Streptococcus were
excluded from efficacy analysis and treated with standard
of care, including systemic therapy as needed. A complete
list of the inclusion and exclusion criteria is provided in the
Supplemental Section.
Randomization and Study Intervention
OTO-201 (12 mg delivered in 0.2 mL) was evaluated rela-
tive to sham (air injection) using 1:1 randomization. A per-
muted block randomization algorithm schedule was used,
and the randomization process was deployed using a
526 Annals of Otology, Rhinology & Laryngology 128(6)
Web-based interactive response system. Eligible subjects
were randomized to treatment assignment on day 1 to
OTO-201 or sham. Administration of OTO-201 or sham
was conducted by an unblinded investigator. Treatment
syringes were prepared by an unblinded qualified medical
professional or the unblinded investigator. Each syringe
was prepared according to detailed instructions in a man-
ner that prevented the visualization of syringe contents by
all other study staff members through the use of a syringe
overlabel. Any interaction with subjects with regard to the
collection, review, or discussion of study assessments was
done by the study coordinator, blinded investigator, or
someone other than the qualified medical professional
who prepared the syringe and the unblinded investigator
who administered OTO-201 or sham. HCPs who adminis-
tered study drug were not blinded, because of the visual
difference during administration, and were instructed not
to discuss any potential visual differences observed in
study material with subjects or study staff members. Prior
to administration, the ear canal was to be cleaned of all
fluid and debris (ie, dry mop or suctioning). OTO-201 was
administered via blunt catheter slowly into the EAC
(injected into the canal with the syringe tip advanced
medially approximately 5 mm beyond the cartilaginous
junction), and the catheter was slowly withdrawn while
injecting. During the study, antibiotics other than OTO-
201 were discouraged; however, if deemed necessary for
the welfare of the subject, topical antibiotics (eg, lotions,
creams, ointments) could have been administered.
Concomitant use of otic antibiotics and/or otic drops of
any kind was prohibited.
Study Outcomes
Otoscopic examinations were used to assess the signs
(edema, erythema) and symptoms (tenderness) of OE by a
blinded investigator in both ears at every study visit
using the scoring scale used during study entry: 0 = none
(complete absence of any signs or symptoms), 1 = mild
(slight), 2 = moderate (definitely present), 3 = severe
(marked, intense). In addition, the presence and character-
ization of otorrhea were documented for all study visits.
Otorrhea was defined as trace (tympanic membrane is moist
in appearance, with no fluid and/or no accumulation of
otorrhea present in the EAC), moderate (accumulation of
otorrhea that has not obscured the visualization of the
EAC), or copious (accumulation of otorrhea that has
obscured the visualization of the EAC).
A swab of the EAC from each affected ear was taken
for microbiologic culture and susceptibility prior to study
drug or sham administration (day 1) and at subsequent vis-
its if edema, erythema, tenderness, or otorrhea was
observed by the blinded assessor. If culture positive,
microorganisms were identified by using a Bruker
(Billerica, Massachusetts, USA) matrix-assisted laser
desorption ionization time-of-flight Biotyper (only on iso-
lates identified as S aureus, Moraxella catarrhalis,
Streptococcus pneumoniae, Haemophilus influenzae, P
aeruginosa, or Pseudomonas otitidis) performed at a cen-
tral laboratory.
Subjects or their caregivers reported assessment of
otalgia in the affected ear in a daily diary using the
­
Wong-Baker FACES Pain Rating Scale ranging from 0 to
10 (0 = no hurt, 10 = hurts worst) on days 1 through 15.
For subjects whose ear pain ended during days 1 through
15, the date when the ear pain ended was recorded. The
daily diary was completed only for subjects mature enough
to provide appropriate responses to their levels of otalgia,
typically 3 years or older. Any subject who did not show
improvement by the day 8 follow-up visit or whose daily
diary indicated no improvement in otalgia was provided the
standard of care for AOE at the discretion of the investiga-
tor. Safety assessments included adverse events (AEs), vital
sign measurements, otoscopic examinations, and concomi-
tant medications.
The primary endpoint was the proportion of subjects
with clinical cure (CC) on day 8. CC was defined as com-
plete resolution of signs and symptoms (ie, tenderness, ery-
thema, otorrhea, and edema, as determined by the blinded
investigator) with no concomitant antibiotics (systemic or
topical given in the study ear) given for any reason at or
prior to the study visit with complete resolution of signs
and symptoms. Complete resolution of signs and symp-
toms was achieved when scores for tenderness, erythema,
otorrhea, and edema were equal to zero at the assessment
day. Other efficacy endpoints evaluated were CC on days
4, 15, and 29 as determined by blinded investigator; micro-
biologic eradication on days 4, 8, 15, and 29; the propor-
tion of subjects with cessation of otorrhea; and time to
cessation of otalgia.
Statistical Analysis
The intent-to-treat (ITT) analysis set included all subjects
who were randomized and did not have cultures positive for
group A Streptococcus cultured on day 1. The microbio-
logic ITT (mic-ITT; ie, the pathogen-positive population)
included all ITT subjects with positive baseline cultures for
either P aeruginosa or S aureus. The primary efficacy end-
point was compared between the treatment groups at a .05
level of significance using the ITT analysis set. The propor-
tion and corresponding Clopper-Pearson 95% confidence
intervals for subjects demonstrating CC were presented by
treatment group and study visit (through days 4, 8, 15, and
29). Differences in proportions and corresponding exact
95% confidence intervals were also presented. Treatment
comparisons with regard to proportions were performed
using the Fisher exact test. Once the primary objective was
Ansley et al 527
Figure 1.  Consolidated Standards of Reporting Trials diagram indicating flow of study subjects.
met in the ITT analysis set, the secondary endpoints were
compared between the treatment groups in the ITT analysis
set. To control the family-wise type I error for the evalua-
tion of the secondary endpoints, a gatekeeping strategy
(sequential closed testing procedure) was implemented.
The following sequence specified the steps: CC day 15
using ITT analysis set, CC day 8 using mic-ITT analysis set,
CC day 15 using mic-ITT analysis set, CC day 4 using mic-
ITT analysis set, CC day 4 using ITT analysis set, and time
to cessation of otalgia using ITT analysis set.
Results
Subjects and Baseline Characteristics
Two hundred sixty-two subjects were randomized between
June and November 2016 at 37 clinical sites in the United
States (Figure 1). Two randomized subjects (both in the
sham group) tested positive for group A Streptococcus and
completed the study. Per the protocol, both subjects were
excluded from the efficacy analysis but included in the
safety population (Figure 1). Clinical sites included both
ear, nose, and throat (ENT) providers (16 sites) and non-
ENT providers (21 sites, including pediatrician offices, pri-
mary care physician offices, urgent care centers, and
outpatient centers). Table 1 summarizes subjects’ baseline
demographics and disease characteristics. Otorrhea was
present at baseline in the study ear of 59.2% of subjects in
the ITT population. The predominant type of otorrhea in the
study ear at baseline in those subjects who presented with
otorrhea was purulent (37.3% of subjects). The mean com-
bined signs and symptoms score of study ear was similar
between the treatment groups (sham, 6.2; OTO-201, 6.3;
Table 1). Rates of edema, erythema, and tenderness in the
study ear at baseline were 98.5%, 97.7%, and 99.2%,
respectively. Baseline scores were similar for subjects at
ENT sites (mean score, 6.3; n = 81) and non-ENT sites
(mean score, 6.2; n = 179). A total of 109 subjects (41.9%
of the ITT population) had positive cultures in the study ear
at baseline; the most common organisms cultured from the
528 Annals of Otology, Rhinology & Laryngology 128(6)

Table 1.  Baseline Demographics and Disease Characteristics (Intent-to-Treat Population).a

Sham OTO-201 Total

Variable (n = 130) (n = 130) (n = 260)

Age, y 34.8 ± 20.6 36.7 ± 19.3 35.8 (19.9)
Male/female 55 (42.3)/75 (57.7) 55 (42.3)/75 (57.7) 110 (42.3)/150 (57.7)
Race  
 White 109 (83.8) 111 (85.4) 220 (84.6)
  Black or African American 15 (11.5) 14 (10.8) 29 (11.2)
 Other 6 (4.6) 5 (3.8) 11 (4.2)
Number of subjects with affected ears  
 1 121 (91.7) 115 (88.5) 236 (90.1)
 Both 11 (8.3) 15 (11.5) 26 (9.9)
Number of subjects with treated ears  
 1 122 (92.4) 117 (90.0) 239 (91.2)
 Both 10 (7.6) 10 (7.7) 20 (7.6)
Baseline group A Streptococcus culture  
 Positive 2 (1.5) 0 (0.0) 2 (0.8)
 Negative 130 (98.5) 130 (100.0) 260 (99.2)
Baseline microbiology culture result of study ear  
  S pneumonia 1 (0.8) 0 (0.0) 1 (0.4)
  H influenza 0 (0.0) 0 (0.0) 0 (0.0)
  M catarrhalis 0 (0.0) 0 (0.0) 0 (0.0)
  P aeruginosa 38 (29.2) 39 (30.0) 77 (29.6)
  S aureus 24 (18.5) 20 (15.4) 44 (16.9)
  P otitidis 0 (0.0) 1 (0.8) 1 (0.4)
Baseline microbiology target pathogen culture statusb  

 Positive 56 (43.1) 53 (40.8) 109 (41.9)

 Negative 74 (56.9) 77 (59.2) 151 (58.1)
Baseline signs and symptoms of study ear  
  Otorrhea type of study ear  
  None 54 (41.5) 52 (40.0) 106 (40.8)
  Serous 17 (13.1) 12 (9.2) 29 (11.2)
  Purulent 44 (33.8) 53 (40.8) 97 (37.3)
  Sanguineous 1 (0.8) 1 (0.8) 2 (0.8)
  Mucoid 14 (10.8) 12 (9.2) 26 (10.0)
 Edema  
   None (complete absence) 1 (0.8) 3 (2.3) 4 (1.5)
  Mild 45 (34.6) 32 (24.6) 77 (29.6)
  Moderate 75 (57.7) 86 (66.2) 161 (61.9)
  Severe 9 (6.9) 9 (6.9) 18 (6.9)
 Erythema  
   None (complete absence) 3 (2.3) 3 (2.3) 6 (2.3)
  Mild 23 (17.7) 20 (15.4) 43 (16.5)
  Moderate 82 (63.1) 92 (70.8) 174 (66.9)
  Severe 22 (16.9) 15 (11.5) 37 (14.2)
 Tenderness  
   None (complete absence) 2 (1.5) 0 (0.0) 2 (0.8)
  Mild 24 (18.5) 19 (14.6) 43 (16.5)
  Moderate 81 (62.3) 93 (71.5) 174 (66.9)
  Severe 23 (17.7) 18 (13.8) 41 (15.8)
(continued)
Ansley et al 529

Table 1. (continued)

Sham OTO-201 Total

Variable (n = 130) (n = 130) (n = 260)

  Combined score (ITT population)  
  Mean 6.2 6.3 6.2
  SD 1.27 1.24 1.25
  Median 6.0 6.0 6.0
  Range 4-10 4-10 4-10

Abbreviation: ITT, intent-to-treat.

a
Data are expressed as mean ± SD or as no. (%).
b
Subjects were classified as positive for microbiology culture if the study ear had a positive result for any of the following organisms: S pneumoniae, H
influenzae, M catarrhalis, P aeruginosa, S aureus, or P otitidis. Subjects were classified as negative for microbiology culture if the study ear had no positive
results for all the organisms.

Figure 2.  Clinical cure rates on days 4 to 29.

Abbreviations: CI, confidence interval; ITT, intent-to-treat; n/nn, cumulative proportion of subjects with clinical cure through the visit analyzed.

study ear were P aeruginosa (29.6% of subjects) and S
aureus (16.9% of subjects).
Efficacy
The primary endpoint (proportion of subjects with CC on
day 8) demonstrated a significant increase in the OTO-201
group compared with sham (90 of 130 [69.2%] vs 60 of
130 [46.1%]; difference in proportion, 23.1%; 95% confi-
dence interval, 10.7%-34.6%; P < .001) (Figure 2). For the
secondary endpoints, statistical significance was achieved
for CC through day 15 using the ITT analysis set (differ-
ence in proportion, 23.8%; P < .001), CC on day 8 using
the mic-ITT analysis set (difference in proportion, 25.7%;
P = .012) (Figure 3), and CC on day 15 using the mic-ITT
analysis set (difference in proportion, 35.2%; P < .001).
Statistical significance was not achieved for CC on day 4
using the mic-ITT analysis set (difference in proportion,
9.5%; P = .291). CC on day 4 using the ITT analysis set
(difference in proportion, 13.8%; P = .028) followed CC
on day 4 using the mic-ITT in the gatekeeping sequential
testing procedure criteria, and therefore the P value should
be considered nominal. For the primary endpoint (CC on
day 8), OTO-201 results were similar between ENT (66%
CC) and non-ENT sites (71% CC). During the study, the
number of OTO-201 subjects who received antibiotic
530 Annals of Otology, Rhinology & Laryngology 128(6)

Figure 3.  Clinical cure rates in the microbiologic culture–positive group on days 4 to 29.
Abbreviations: CI, confidence interval; Mic-ITT, microbiologic intent-to-treat; n/nn, proportion of subjects with clinical cure at the visit analyzed.

Table 2.  Proportion of Subjects With Cessation of Otorrhea (Intent-to-Treat Population).a

Sham 12 mg OTO-201

  (n = 130) (n = 130)
Day 4  
  n/nn (%) (95% CI) 40/95 (42.1) (32.04-52.67) 51/87 (58.6) (47.55-69.08)
  Difference in proportion (exact 95% CI) 16.5 (1.90-30.62)
  P value .037
Day 8  
  n/nn (%) (95% CI) 45/95 (47.4) (37.03-57.88) 63/87 (72.4) (61.79-81.46)
  Difference in proportion (exact 95% CI) 25.0 (10.61-38.72)
  P value <.001
Day 15  
  n/nn (%) (95% CI) 41/95 (43.2) (33.03-53.72) 63/87 (72.4) (61.79-81.46)
  Difference in proportion (exact 95% CI) 29.3 (14.92-42.66)
  P value <.001
Day 29  
  n/nn (%) (95% CI) 34/95 (35.8) (26.21-46.28) 64/87 (73.6) (63.02-82.45)
  Difference in proportion (exact 95% CI) 37.8 (23.77-50.67)
  P value <.001

Abbreviation: CI, confidence interval.

a
Cessation of otorrhea was defined as the resolution of otorrhea and no concomitant systemic or topical (given in the study ear) antibiotic was taken
for any reason at or prior to the study visit with resolution of otorrhea.

standard of care through day 8 was 12 (9%), and the num- group than the sham group (58.6% vs 42.1%; Table 2).
ber of sham subjects was 42 (32%). The proportion of subjects with cessation of otorrhea was
For the time through day 4, the proportion of subjects greater in the OTO-201 group than the sham group on
with cessation of otorrhea was greater in the OTO-201 days 8, 15, and 29 (differences in proportion, 25.0%
Ansley et al 531

Table 3.  Microbiologic Eradication Results by Culture at Baseline and Following Treatment (Microbiologic Intent-to-Treat
Population)a

Endpoint Sham 12 mg OTO-201

Visit (n = 56) (n = 52)

Proportion of microbiologic eradication, day 8  
  n/nn (%) (95% CI) 21/56 (37.5) (24.92-51.45) 40/52 (76.9) (63.16-87.47)
  Difference in proportion (exact 95% CI) 39.4 (21.25-55.89)
  P value <.001

Abbreviation: CI, confidence interval.

a
The microbiologic intent-to-treat set included all intent-to-treat subjects with positive baseline cultures for either P aeruginosa or S aureus.

Table 4.  Most Frequently Reported TEAEs (≥2% in Any Treatment Group) (Safety Population).a

Sham 12 mg OTO-201 Total

System Organ Class and Preferred Term (n = 132) (n = 127) (n = 259)

Number of subjects with at least 1 TEAE reported 30 (22.7) 24 (18.9) 54 (20.8)
Infections and infestations  
  Otitis externa 9 (6.8) 3 (2.4) 12 (4.6)
Ear and labyrinth disorders  
  Ear pain 3 (2.3) 3 (2.4) 6 (2.3)
  Ear pruritus 2 (1.5) 3 (2.4) 5 (1.9)
Skin and subcutaneous tissue disorders  
 Erythema 3 (2.3) 0 (0.0) 3 (1.2)
Nervous system disorders  
 Headache 1 (0.8) 3 (2.4) 4 (1.5)
a
If a subject experienced more than 1 episode of an adverse event, the subject was counted once for that preferred term. If a subject had more than
1 adverse event in a system organ class, the subject was counted only once in that system organ class. Incidences are displayed in descending order of
frequency of system organ class and by preferred term within system organ class, on the basis of overall frequency. System organ class and preferred
term are based on Version 19.0 of the MedDRA coding dictionary.
Abbreviation: TEAE, treatment-emergent adverse event.

through day 8, 29.3% on day 15, and 37.8% on day 29).
Median time to cessation of otalgia through day 15 was
8.0 and 11.0 days for the OTO-201 group and sham group,
respectively (P = .008).
The proportion of subjects with microbiologic eradica-
tion on day 8 was greater in the OTO-201 group than in the
sham group (76.9% vs 37.5%; difference in proportion,
39.4%; 95% confidence interval, 21.3%-55.9%; P < .001)
(Table 3).
Safety
The safety analysis population comprised all subjects who
received study drug (n = 259). A total of 54 subjects (20.8%)
reported 82 treatment-emergent AEs during the study (Table
4). The proportion of subjects reporting treatment-emergent
AEs was similar in the OTO-201 group and the sham group
(18.9% vs 22.7%, respectively). No deaths, serious AEs, or
treatment-emergent AEs leading to subject discontinuation
were reported. Treatment-emergent AEs reported in 2 or
more patients in the OTO-201 group and greater than the
sham group were headache (2.4% and 0.8%), ear pruritus
(2.4% and 1.5%), ear pain (2.4% and 2.3%), ear discomfort
(1.6% and 0%), nasal congestion (1.6% and 0%), and otitis
media (1.6% and 0.8%). Otoscopic examination observa-
tions (cerumen, middle ear, and tympanic membrane) were
similar between the OTO-201 and sham groups throughout
the study.
Discussion
AOE is diagnosed clinically on the basis of signs and symp-
toms of EAC inflammation. In the present study, more than
97% of subjects presented at baseline with the classic signs
and symptoms of edema, erythema, and tenderness. Given
the bacterial origin for AOE and high local antibiotic
concentrations achieved with topical antibiotic therapies,
the AAO-HNSF practice guidelines for AOE recommend
the use of topical antibiotic therapy while strongly recom-
mending against prescribing systemic antibiotics as initial
532 Annals of Otology, Rhinology & Laryngology 128(6)
therapy for diffuse, uncomplicated AOE. This phase 3 study
evaluated the efficacy of a single topical administration of
OTO-201 for the treatment of AOE. The proportion of sub-
jects meeting the primary endpoint (proportion of subjects
achieving CC on day 8) was greater and statistically signifi-
cant in the OTO-201 group compared with the sham group
(69% vs 46%, a 50% relative increase). Using a statistical
gatekeeping strategy to control family-wise type I error, sta-
tistical significance was achieved for multiple secondary
endpoints including CC on day 15 using the ITT analysis
set and CC on day 8 and 15 using the Mic-ITT analysis set.
All other statistical comparisons were considered explor-
atory but consistently showed treatment group differences
favoring OTO-201 over sham. Cessation of otorrhea
showed treatment group differences in favor of OTO-201
over sham for all visits. OTO-201 treatment also resulted in
greater microbiologic eradication than sham (Mic-ITT
population) through days 4, 8, 15, and 29 and a shorter
median time to cessation of otalgia through day 15.
These findings demonstrate that a single administra-
tion of 0.2 mL (12 mg) OTO-201 provided greater resolu-
tion of the signs and symptoms of AOE compared with
sham control. The CC rate with a single dose in this trial
on day 8 (69.2%) is consistent with the reported rates of
65% to 80% seen by day 10 with existing antibiotic topi-
cal therapies given over multiple days.11 Although a
weakness of this trial is the lack of an active antibiotic
comparator as a third arm, such a trial would be problem-
atic, because subject and investigator blinding cannot be
maintained and treatment bias is likely. Moreover, topical
treatments containing ciprofloxacin are already known to
be effective in the treatment of AOE (while conclusive
data from robust clinical trials are still needed to deter-
mine whether the addition of steroids to topical quinolone
antibiotics provides earlier relief of AOE symptoms).12,13
In addition, this study excluded subjects with atypical,
severe, and chronic OE, and therefore the safety and effi-
cacy of OTO-201 are unknown in treating severe and
chronic OE. Similar to other topical therapies for AOE,
OTO-201 should not be administered alone without sys-
temic antibiotics for subjects who present with severe
AOE.
The results seen with OTO-201 are notable because
they are the first to demonstrate CC and bacterial eradica-
tion in AOE resulting from a single-dose topical ciproflox-
acin suspension administered by HCPs in an office setting.
OTO-201 ensures compliance by eliminating the need for
the subject to self-administer the antibiotic after the visit,
numerous times a day over 7 days, as currently required
with existing FDA-approved topical antibiotic therapies.
Data from England et al8 showed poor patient compliance
when self-administering multidose antibiotic ear drops,
with a tendency often to undermedicate and only 43% of
patients appropriately self-medicating topical therapies
over 7 days. Current AAO-HNSF practice guidelines for
AOE further validate that treatments that involve less fre-
quent dosing schedules and a shorter duration lead to
higher patient treatment acceptability.3 In the study, both
physicians and other HCPs (registered nurses, nurse prac-
titioners, licensed vocational nurses, physician assistants,
and audiologists) administered OTO-201. The HCPs were
able to administer the full 12-mg (2-mL) dose of OTO-201
with either suction needles or Angiocath catheters, which
are commonly found in the outpatient setting.
Future researchers may want to explore through regis-
tries the impact OTO-201 may have on increasing the per-
centage of patients with AOE who are prescribed topical
antibiotic preparations (as opposed to systemic antibiot-
ics), as this is now part of the Centers for Medicare and
Medicaid Services–mandated Physician Quality Reporting
System quality measure for AOE. Additionally, given the
number of treatment options available for patients with
AOE, a greater understanding of priorities that ultimately
affect patient and physician treatment preferences would
be valuable.
Conclusions
This double-blind, randomized, prospective, controlled,
multicenter study phase 3 clinical study demonstrated
that a single administration of 12 mg OTO-201 resulted
in a significantly higher proportion of subjects with CC
and bacterial eradication compared with sham in children
and adults with AOE at all prespecified time points.
OTO-201 treatment was well tolerated by patients.
Administration of OTO-201 eliminated concerns with
patient compliance and was accomplished by ENTs and
non-ENT HCPs in the primary care outpatient setting.
Findings from this trial support the use of OTO-201 as a
single-dose treatment option administered by HCPs for
patients with AOE.
Authors’ Note
This research was the subject of an oral presentation by John
Ansley, MD, at the annual meeting of the American Academy of
Otolaryngology–Head and Neck Surgery, September 11, 2017,
Chicago, Illinois.
Acknowledgments
We thank the subjects for their participation in this study, the clini-
cal study site staff members, and the Rho members of the study
team. We express our sincere gratitude to the following principal
investigators who participated in the study: Aftab Ahmad, MD,
Research Trials Worldwide, Humble, Texas; Rajasekaran
Annamalai, MD, East Montgomery County Clinic, Splendora,
Texas; John Ansley, MD, Carolina Ear, Nose and Throat Clinic,
Orangeburg, South Carolina; Eddie Armas, MD, Well Pharma
Ansley et al 533
Medical Research Corporation, South Miami, Florida; Michael
Armstrong, MD, Richmond Ear, Nose & Throat, Richmond,
Virginia; Paul Beckett, MD, Elite Clinical Trials, Blackfoot,
Idaho; Matthew Brown, MD, Iowa Head & Neck PC, Des Moines,
Iowa; Tami Bruce, MD, Central Arizona Medical Associates PC/
Radiant Research, Mesa, Arizona; James Cain, MD, Family
Medicine Clinic, Lampasas, Texas; Alejandro Cordero, MD,
Miami Dade Medical Research Institute LLC, Miami, Florida;
Hector Cordero, MD, Pharma Research International, Naples,
Florida; Steven Davis, MD, Breathe Clear Institute, Torrance,
California; Patrick Dennis, MD, DelRicht Research, New Orleans,
Louisiana; Franklin Douglas, MD, Conroe and Spring, Texas;
Ann Edmunds, MD, Omaha Ear, Nose & Throat, Omaha,
Nebraska; Dale Robert Ehmer, MD, Ear, Nose & Throat Associates
of Texas, McKinney, Texas; Robert Florea, MD, Buckeye Health
& Research, Columbus, Ohio; Augusto Focil, MD, Diverse
Research Solutions, Oxnard, California; Darin Gregory, MD,
Pioneer Clinical Research LLC, Bellevue, Nebraska; Jonathan
Hubbard, MD, Chrysalis Clinical Research, St. George, Utah;
Matthew Hummel, MD, Fountain Hills Family Practice PC/
Radient Research, Fountain Hills, Arizona; Janice Johnston, MD,
Arrowhead Health Centers, Glendale, Arizona; Najmuddin
Karimjee, MD, Tidwell Medical Center, Houston, Texas; Brian
Keith MacGillivray, MD, DCT-Stone Oak LLC/Discovery
Clinical Trials, San Antonio, Texas; Audrey Lee Jones, MD,
DCT-McAllen Primary Care Research LLC/Discovery Clinical
Trials, McAllen, Texas; Eric A. Mair, MD, Charlotte Eye, Ear,
Nose, and Throat Associates, Charlotte, North Carolina; John
McClay, MD, Frisco ENT for Children, Frisco, Texas; Lorely
Mendez, MD, San Marcus Research Clinic, Miami, Florida; Misal
Khan, MD, Panama City, Florida; Jonathan Moss, MD, Charlotte
Eye, Ear, Nose & Throat Associates, Matthews, North Carolina;
Robert Scott, MD, White Oak Family Physicians PA/Asheboro
Research Associates, Asheboro, North Carolina; Anthony
Mikulec, MD, St. Louis University, St. Louis, Missouri; John
Howard Taylor, MD, Biosolutions Clinical Research Center, La
Mesa, California; Cynthia Wellman, MD, Ear, Nose &
Throat Associates, Fort Wayne, Indiana; Jeffrey Rosenbloom,
MD, Alamo ENT, San Antonio, Texas; and Donald Welsh, MD,
Advanced ENT & Allergy, Louisville, Kentucky.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of inter-
est with respect to the research, authorship, and/or publication of
this article: Dr Ansley’s institution received clinical study fund-
ing from Otonomy, Inc. Dr. Mair’s institution received clinical
study funding from Otonomy, Inc. Dr. Namini is a former
employee and shareholder of Otonomy, Inc. Dr. Lu is a former
employee and shareholder of Otonomy, Inc. Dr. LeBel is a
former employee and shareholder of Otonomy, Inc.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
study was financially supported by Otonomy, Inc.
Supplemental Material
Supplemental material for this article is available online.
ORCID iD
John Ansley https://orcid.org/0000-0003-2493-1566
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