Intranasal Surfactant for Acute Otitis

Media: A Randomized Trial

Gysella B. Muniz, MD,a,b Timothy R. Shope, MD, MPH,a,b Sonika Bhatnagar, MD,a,b Nader Shaikh, MD, MPH,a,b
Mary Ann Haralam, MSN, CRNP,a,b Hui Liu, MS,a Judith M. Martin, MD,a,b Janice M. Pogoda, PhD,c
Alejandro Hoberman, MDa,b

BACKGROUND:Acute otitis media (AOM) is the most frequent reason for children to be prescribed abstract
antimicrobial treatment. Surfactants are naturally occurring substances that may restore the
eustachian tube’s function and potentially enhance resolution of AOM.
METHODS: This was a phase 2a, single-center, double-blind, randomized, placebo-controlled,
parallel group clinical trial to assess safety, tolerability, and efficacy of 20 mg per day
intranasal OP0201 as an adjunct therapy to oral antimicrobial agents for treating AOM in
young children. We randomly assigned 103 children aged 6 to 24 months with AOM to receive
either OP0201 or placebo twice daily for 10 days. All children received amoxicillin-clavulanate
90/6.4 mg/kg per day in 2 divided doses for 10 days. Participants were managed for up to 1
month. Postrandomization visits occurred between days 4 and 6 (visit 2), days 12 and 14
(visit 3), and days 26 and 30 (visit 4). Primary efficacy endpoints were resolution of a bulging
tympanic membrane at visit 2 and resolution of middle-ear effusion at visit 3.
No clinically meaningful differences between treatment groups were apparent for
RESULTS:
primary or secondary endpoints. There were no safety concerns identified.
CONCLUSIONS:In young children with AOM, intranasally administered surfactant (OP0201) did
not improve clinical outcomes. Further research may be warranted among children with
persistent middle-ear effusion.

Full article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2021-051703 WHAT’S KNOWN ON THIS SUBJECT: Animal studies
a
School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; bUPMC Children’s Hospital of Pittsburgh, suggested a potential benefit of intranasally administered
Pittsburgh, Pennsylvania; and cCipher Biostatistics & Reporting, Reno, Nevada surfactant for acute otitis media and otitis media with
effusion.
Drs Muniz and Hoberman conceptualized the study concept and design, participated in the
acquisition of data, drafted the initial manuscript, and approved the final manuscript as submitted; WHAT THIS STUDY ADDS: We found that in young children
Drs Shope, Bhatnagar, Shaikh, Martin and Mrs Haralam participated in the study design, acquisition with acute otitis media, intranasally administered
and interpretation of data, drafted the initial manuscript, and approved the final manuscript as surfactant (OP0201) did not improve clinical outcomes;
submitted; Mses Liu and Pagoda participated in the analysis of data, drafted the initial manuscript, further research may be warranted among children with
and approved the final manuscript as submitted; and all authors approved the final manuscript as persistent middle-ear effusion.
submitted and agree to be accountable for all aspects of the work.
This trial has been registered at www.clinicaltrials.gov (identifier NCT03818815). To cite: Muniz GB, Shope TR, Bhatnagar S, et al. Intranasal
Deidentified individual participant data will not be made available. Surfactant for Acute Otitis Media: A Randomized Trial.
Pediatrics. 2021;148(6):e2021051703
DOI: https://doi.org/10.1542/peds.2021-051703

PEDIATRICS Volume 148, number 6, December 2021:e2021051703 ARTICLE

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 Next to the common cold, acute
otitis media (AOM) is the most
frequently diagnosed illness in
children in the United States and the
leading indication for antimicrobial
treatment in children.1 Establishing
an accurate diagnosis of AOM is
important, particularly in children <2
years of age for whom a 10-day
course of antimicrobial therapy has
been shown to be beneficial.2,3 In
contrast, antimicrobial therapy is not
recommended to treat otitis media
with effusion. Inadequate
antimicrobial prescription in these
cases not only causes significant
financial burden but also undermines
antimicrobial stewardship efforts.
Surfactants are ubiquitous
endogenous compounds present in
human nasal passages, the
eustachian tube (ET), and lung
tissues. The quantity of surfactants
in the ET of children with AOM is
significantly reduced when
compared with otologically healthy
children.4 AOM is triggered by a
viral upper respiratory infection.5,6
Viral pathogens stimulate
nasopharyngeal mucus production,
creating inflammation and
eventually obstruction of the ET,
which, in infants and young
children, tend to be short, floppy,
and horizontal and function poorly,
challenging the flow of middle-ear
fluid.7,8 OP0201, developed by
Novus Therapeutics, Inc, is
composed of 2 active ingredients,
dipalmitoylphosphatidylcholine and
cholesteryl palmitate, and can be
delivered in the anterior nares
toward the opening of the ET.
Together, these 2 active ingredients
reduce interfacial surface tension
within the ET, which reduces the
passive pressure required to open
the ET, restoring its physiologic
functions. Following phase 1 studies
in adults, we evaluated the safety
and feasibility of a 10-day course of
OP0201, in addition to antimicrobial
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therapy, in children 6 to 24 months
of age with AOM.
METHODS
Eligibility and Enrollment
We conducted this trial from
February 2019 to February 2020 at
the University of Pittsburgh Medical
Center Children’s Hospital of
Pittsburgh Primary Care Center and
Express Care and at affiliated
pediatric practices in Pittsburgh,
Pennsylvania, representing urban
and suburban demographics. The
protocol was approved by the
institutional review board, and
written informed consent was
obtained from a parent of each
enrolled child. The authors attest
that the study was performed in
accordance with the protocol,
including its statistical analysis plan.
The study was sponsored by Novus
Therapeutics, Inc, and registered in
ClinicalTrials.gov (NCT03818815).
Novus Therapeutics provided study
product and statistical support for
data analysis.
Eligible children 6 to 24 months of
age were required to have AOM on
the basis of onset of symptoms
within the preceding 48 hours (ie, a
score of 5 or more on the 5-item
semiquantitative Acute Otitis
Media–Severity of Symptoms [AOM-
SOS] scale version 5.0)9,10 and an
intact tympanic membrane with
mild bulging with otalgia or marked
tympanic membrane erythema, or
moderate to severe bulging. The
AOM-SOS scale consists of 5 discrete
items: tugging of ears, crying,
difficulty sleeping, irritability, and
fever. Parents are asked to rate
these symptoms, as compared with
the child’s usual state, as “none,”
‘almost none,” “a little,” “some,” “a
lot,” or “an extreme amount” with
corresponding scores of 0, 1, 2, 3, 4,
and 5. Thus, total scores range from
0 to 25, with higher scores
indicating greater severity of
symptoms. Parents of eligible
children also were required to have
a smartphone or Internet access to
receive electronic surveys. We
excluded children who had a
tympanic membrane perforation or
tympanostomy tubes; were allergic
to amoxicillin or cephalosporins;
had received an antimicrobial agent
within the previous 72 hours; had
used intranasal treatments other
than saline within the previous 7
days; had a history of
immunodeficiency disorders,
craniofacial abnormalities that may
interfere with ET function, disorders
with decreased mucociliary
clearance or higher viscosity of the
mucous, or clinically relevant
blockage of 1 or both nasal
passages; or those whose parents
were employed by the sponsor or
investigator.
Randomization
This was a phase 2a, single center,
double-blind, randomized, placebo-
controlled, parallel group study to
assess the safety, tolerability, and
efficacy of 20 mg per day intranasal
OP0201 as adjunct therapy to oral
antimicrobial treatment of children
aged 6 to 24 months (inclusive)
with AOM (Fig 1). Children who met
eligibility criteria were randomly
assigned in a 1:1 ratio within strata
(age 6 to 11 months or 12 to 24
months, and whether they were
exposed to $3 children for $10
hours per week) to receive a total of
20 intranasal doses of OP0201
(10 mg administered twice daily for
10 days) or placebo, as adjunct
treatment to oral antimicrobial
agents (amoxicillin-clavulanate 90/
6.4 mg/kg in 2 divided doses for 10
days). The study treatment included
a pressurized canister with a
securely attached metering valve,
where OP0201 or placebo was
contained, an actuator device into
which the canister is seated, and an
angled tip on the device that
delivered the product into the
 FIGURE 1
Consort diagram.
nostrils. Placebo contained the
propellant without any active
ingredients (HFA 134a). We trained
parents to administer study treatment
and gave the first dose under
supervision by study personnel.
Follow-up
Participants were managed for 30
days, including 4 clinic visits: visit 1
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(day 1), screening and enrollment
and initiation of the study treatment
and oral antimicrobial agents; visit 2
(day 4 [12]); visit 3 (day 12 [12]);
and visit 4 (day 28 [±2]). Parents
and caregivers of children enrolled
completed an electronic daily diary
on all days when study treatment
was administered (10 days) to
record twice-daily administration of
the oral antimicrobial and study
treatment and to complete the AOM-
SOS scale. At visit 3, parents and
caregivers completed a
questionnaire on their experience
with using the delivery device. We
scheduled interim evaluations if a
parent or caregiver notified
investigators that their child
experienced no improvement,
3
 significantly worsened, or had
recurrence of signs and symptoms
of AOM, or developed symptoms
that may have been related to study
treatment.
Examination, Assessment and
Treatment
All 7 study clinicians successfully
completed an otoscopic validation
program before the start of the
study.11,12 At each study visit,
assessments included a physical
examination (including visual
examination of the nasopharynx and
oropharynx) and measurement of
vital signs, pneumatic otoscopy, and
endoscopic examination with
capture of an image of the tympanic
membrane and tympanometry when
possible. Adverse events and
concomitant medication use were
recorded. At visit 2 (day 4 [12]), we
specifically assessed for bulging of
the tympanic membrane. At the end-
of-treatment visit 3 (day 12 [12]),
we assessed (1) treatment failure as
evidenced by the presence of
moderate to severe bulging of the
tympanic membrane or mild bulging
of the tympanic membrane with
recent (<48 hours) onset of ear
pain (otalgia) or intense erythema
or the tympanic membrane, (2) rate
of persistence of middle-ear
effusion, and (3) AOM-SOS scores
during the 10 days of treatment.
Children categorized as exhibiting
treatment failure were prescribed
an additional treatment course of
amoxicillin-clavulanate for 10 days
or ceftriaxone administered
intramuscularly at a dose of 75 mg/
kg and repeated 48 hours later.
Endpoints
All endpoints were prespecified.
There were 2 primary efficacy
endpoints: (1) no bulging of the
tympanic membrane (with or
without symptoms) at visit 2 on day
4 [12], and (2) no middle-ear
effusion at visit 3 on day 12 [12].
Secondary efficacy endpoints
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included (1) absence of bulging of
the tympanic membrane at visits on
days 12 [12] and 28 [±2]; (2)
absence of middle-ear effusion at
visits on days 4 [12] and 28 [±2];
(3) type A (normal) tympanogram at
visits on days 4 [12], 12 [12], and
28 [±2]; (4) complete or near
complete resolution of symptoms
(AOM cure), defined as an AOM-SOS
score #2, assessed at visits 2, 3, and
4; (5) $50% reduction from
baseline in the AOM-SOS score
assessed at visits on days 4 [12], 12
[12] ,and 28 [±2]; (6) change from
baseline in AOM-SOS score over the
10-day treatment period by parent
or caregiver diary data; (7) clinical
treatment failure at visit 3 (day 12
[12]); and (8) recurrence of AOM.
We also assessed the parent’s
experience with using the device.
We assessed safety by incidence,
seriousness, severity, and
relationship to study treatment
(OP0201 or placebo) of emergent
adverse events; and by shifts from
baseline in vital signs (normal,
abnormal), physical examination
(normal, abnormal), and
examination of the nasopharynx and
oropharynx (normal, abnormal) for
local effects.
Statistical Considerations
We estimated that randomizing 140
children (1:1) in this phase 2a study
would provide 93% power to detect
a treatment effect of at least 0.25
difference in proportions in at least
1 of the 2 primary endpoints (no
bulging of the tympanic membrane
at day 4 [12], and no middle-ear
effusion at day 12 [12]), on the
basis of a 2-sided Pearson x2 test of
a 2-sided hypothesis for each
endpoint and controlling for type 1
error rate of 0.05 using the step-up
Hochberg procedure.13 We assumed
that 40% of placebo-treated
participants would not have a
bulging tympanic membrane at day
4 and that 30% of placebo-treated
participants would not have middle-
ear effusion at day 12 [12]. We also
assumed a 10% drop out rate with
multiple imputation of missing values.
The primary efficacy analysis was
prespecified to be done using the
modified intent-to-treat (mITT)
population, defined as participants
who were assigned randomly;
excluding the first 3 participants
dosed as there was a known device
malfunction for these participants;
and with summaries and analyses
based on randomized treatment
assignment regardless of treatment
received. We based the post hoc
efficacy analyses presented in this
report on the subset of children who
completed the assessments in the
mITT population, whereby for each
endpoint, we included only
participants with complete data, and
used slightly more inclusive analysis
windows than those that were
prespecified. We summarized safety
parameters using the safety
population, defined as children who
received at least one intranasal
spray of study treatment. For safety,
we based summaries on treatment
received, regardless of randomized
treatment assignments.
We summarized categorical
variables (including binary
outcomes) as frequencies and
percentages and analyzed them
using logistic regression to control
for covariates, including the
randomization stratification
variables. Continuous variables were
summarized by numbers of
observations, means, measures of
variances, percentiles, and ranges
and were analyzed by using general
linear models to control for
covariates.
RESULTS
Study Population
We randomly assigned a total of
103 children of the 140 originally
 planned because of sponsor’s therefore included 100 children Efficacy Endpoints
budgetary constraints. For the (46 children in the placebo group
initial 3 children, a device and 54 children in the OP0201 Table 2 summarizes findings
malfunction precluded delivery of group). Sociodemographic and concerning the study’s primary and
an appropriate dose of study clinical characteristics of the 103 secondary endpoints. No statistically
medication; the mITT population children who were randomly significant treatment group
excluded these 3 children and assigned are shown in Table 1. differences were observed for the

TABLE 1 Selected Demographic and Clinical Characteristics of the Children, According to Treatment Group
Characteristica Placebo (n5 47) OP0201 (n5 56) All Children (n5 103)
Site of enrollment, no. of children (%)
Children’s Hospital of Pittsburgh Primary Care Center 27 (57.4) 33 (58.9) 60 (58.3)
Children’s Hospital of Pittsburgh Express Care 14 (29.8) 15 (26.8) 29 (28.2)
Pediatric PittNet 6 (12.8) 8 (14.3) 14 (13.6)
Age at enrollment, no. of children (%)
6–11 mo 21 (44.7) 20 (35.7) 41 (39.8)
12–24 mo 26 (55.3) 36 (64.3) 62 (60.2)
Sex, no. of children (%)
Female 25 (53.2) 23 (41.1) 48 (46.6)
Male 22 (46.8) 33 (58.9) 55 (53.4)
Race,b no. of children (%)
White 16 (34.0) 16 (28.6) 32 (31.1)
Black, African American 25 (53.2) 36 (64.3) 61 (59.2)
Other 6 (12.8) 4 (7.1) 10 (9.7)
Ethnicity,b no. of children (%)
Not Hispanic or Latino 43 (91.5) 53 (94.6) 96 (93.2)
Hispanic or Latino 4 (8.5) 3 (5.4) 7 (6.8)
Maternal level of education, no. of children (%)
Less than high school 2 (4.3) 1 (1.8) 3 (2.9)
High school graduate or equivalent 14 (29.8) 24 (42.9) 38 (36.9)
Technical degree, associate degree, some college 11 (23.4) 21 (37.5) 32 (31.1)
College graduate 15 (31.9) 6 (10.7) 21 (20.4)
Postgraduate 5 (10.6) 4 (7.1) 9 (8.7)
Type of health insurance, no. of children (%)
Private 14 (29.8) 16 (28.6) 30 (29.1)
Public 33 (70.2) 40 (71.4) 73 (70.9)
Exposure to other children,c no. of children (%)
No 22 (46.8) 24 (42.9) 46 (44.7)
Yes 25 (53.2) 32 (57.1) 57 (55.3)
History of AOM, no. of children (%)
Refractoryd 7 (14.9) 7 (12.5) 14 (13.6)
Recurrente 12 (25.5) 7 (12.5) 19 (18.4)
Disease laterality, no. of children (%)
Unilateral 23 (48.9) 31 (55.4) 54 (52.4)
Bilateral 24 (51.1) 25 (44.6) 49 (47.6)
AOM-SOS score at entry
Mean score (SD) 13.6±5.3 15.9±5.1 14.8±5.3
Distribution, no. (%)
5–9 13 (27.7) 8 (14.3) 21 (20.4)
10–14 13 (27.7) 14 (25.0) 27 (26.2)
15–19 16 (34.0) 22 (39.3) 38 (36.9)
20–25 5 (10.6) 12 (21.4) 17 (16.5)
Tympanogram,f no. of children (%)
Normal 2 (4.3) 1 (1.8) 3 (2.9)
Abnormal 19 (40.4) 23 (41.1) 42 (40.8)
Not obtained 26 (55.3) 32 (57.1) 58 (56.3)
a
Percentages may not total 100 because of rounding.
b
Race and ethnicity were reported by the parent.
c
Exposure to other children was defined as exposure to at least 3 children for at least 10 h per week.
d
Experienced an episode of AOM within 30 d.
e
Experienced 3 episodes in 6 mo or 4 episodes in 12 mo.
f
Normal tympanogram 5 type A tympanogram in both ears, abnormal tympanogram 5 type B or C tympanogram in either ear.

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 TABLE 2 Primary and Secondary Outcomes, According to Treatment Assignment categorized as treatment failure at
Placebo OP0201 the visit on day 12 [12] or the
Outcome Measure (n 5 46)a (n 5 54)a Pb proportion of children experiencing
No bulging tympanic membrane, No. children (%) recurrences. There were no
Visit 2 (day 4 [12]): primary outcome 18/39 (46.2) 26/47 (55.3) .48 meaningful differences by treatment
Visit 3 (day 12 [12]) 30/40 (75.0) 36/46 (78.3) .75 group in parents’ experience with
Visit 4 (day 28 [±2]) 29/37 (78.4) 33/37 (89.2) .23 using the device (data not shown).
No middle-ear effusion, No. children (%)
Visit 2 (day 4 [12]) 3/39 (7.7) 7/47 (14.9) .23 Safety Endpoints
Visit 3 (day 12 [12]): primary outcome 18/40 (45.0) 25/47 (53.2) .48
Visit 4 (day 28 [±2]) 18/37 (48.6) 22/37 (59.5) .39 Details concerning selected adverse
Treatment failure (day 12 [12])c events assessed as related to study
No. children (%) 3/40 (7.5) 3/47 (6.4) .84 treatment are summarized in Table 3;
AOM relapsed
No. children (%) 1/36 (2.8) 1/43 (2.3) —
no relevant differences were noted.
AOM recurrencee
No. children (%) 7/37 (18.9) 4/43 (9.3) .21 DISCUSSION
AOM-SOS scale v5.0
10-d adjusted mean (SE)f 5.13 (0.5) 4.97 (0.5) .83 We examined the safety and efficacy
Resolution of symptoms (score #2), No. children (%) of intranasally administered
Visit 2 (day 4 [12]) 26/42 (61.9) 20/50 (40.0) .10 OP0201, in addition to antimicrobial
Visit 3 (day 12 [12]) 36/40 (90.0) 38/47 (80.9) .46 therapy, in improving outcomes
Visit 4 (day 28 [±2]) 24/39 (61.5) 27/43 (62.8) .71
50% symptom reduction from baseline, No. children (%)
(bulging of the tympanic membrane,
Visit 2 (day 4 [12]) 39/42 (92.9) 38/50 (76.0) .04 middle-ear effusion, and resolution
Visit 3 (day 12 [12]) 39/40 (97.5) 43/47 (91.5) .35 of symptoms) in children aged 6 to
Visit 4 (day 28 [±2]) 33/39 (84.6) 37/43 (86.0) .70 24 months with AOM. For the trials’
Normal tympanogram,g No. children (%) primary and secondary outcomes,
Day 4 [12] 4/29 (13.8) 1/31 (3.2) .19
Day 12 [12] 9/28 (32.1) 7/29 (24.1) .49 we found no clinically meaningful
Day 28 [±2] 8/24 (33.3) 10/27 (37.0) .77 differences between treatment
—, not applicable. groups. Of interest, albeit not
a
Total No. for individual visits reflect attendance to the specific visit and may be lower than the total intention-to- reaching significance, the proportion
treat population (N 5 100). Post hoc analysis window was used and included only participants with nonmissing
data.
of children with middle-ear effusion
b
P value from logistic regression for binary end points and general linear modeling for the 10-d mean AOM-SOS was lower among children receiving
scale. All analyses included randomization stratifies (age, group, day care) as covariates. The analyses for the AOM- OP0201 at all study visits. Overall,
SOS scale also included the baseline severity score as a covariate.
c
Treatment failure defined as the presence of moderate to severe bulging of the tympanic membrane (TM) or mild
administration of OP0201 was safe;
bulging of the TM with recent (less than 48 h) onset of ear pain (otalgia) or intense erythema of the TM. we found no evidence of more
d
Clinical success at the day 12 [12] visit and return for an interim/sick visit before day 17 with AOM at that visit. adverse events in OP0201 recipients
Clinical success is defined as no moderate to severe bulging of the TM and no mild bulging of the TM with recent
(<48 h) onset of ear pain (otalgia) or intense erythema of the TM. compared with controls.
e
Clinical success at the day 12 [12] visit and return for an interim/sick visit day 17 through day 28 [12] with AOM
at that visit.
f
Our trial had certain strengths: the
The AOM-SOS scale consists of 5 questions rated on a 6-point scale, with lower scores associated with better symp-
tom status: 0 5 no, 1 5 almost none, 2 5 a little, 3 5 some, 4 5 a lot, 5 5 an extreme amount. A total score for
randomized, double-blind, placebo-
each day is calculated as the sum of the 5 individual scores (range 5 0–25), and a mean total score over the 10-d controlled design, a diverse
treatment period is calculated for each subject. Mean score was not calculated if <10 d of scores were available. participants’ population in the age
g
Normal tympanogram: type A tympanogram in both ears. Abnormal tympanogram: type B or C tympanogram in
either ear.
group most prone to having AOM
recurrences, our use of stringent
AOM diagnostic criteria, otoscopic
primary endpoints (absence of defined as an AOM-SOS score #2, or diagnoses by validated otoscopists, a
bulging at day 4 [12], no middle-ear among those who achieved $50% standardized antimicrobial protocol
effusion at day 12 [12]) or for reduction from baseline at the visits for treating episodes, validated
having a normal (type A) on days 4 [12], 12 [12], and 28 scales for rating severity of
tympanogram at each of these visits. [±2], or in change from baseline in symptoms, and modest attrition.
With regards to symptomatic or AOM-SOS score over the 10-day Limitations of our trial include its
functional improvement, no treatment period according to small sample size and dose selection
treatment effects were apparent in parent and caregiver diary data. based on the maximum dose and
the proportion of children who Finally, no clinically meaningful drug concentration delivered in the
exhibited complete or near complete treatment effects were noted metered-dose inhaler and number of
resolution of symptoms (AOM cure), regarding the proportion of children sprays a parent would be willing to

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 TABLE 3 Incidence and Number of TEAEs Related to Study Treatment
System Organ Class/Preferred Term Placebo (n 5 48), n (%), N OP0201 (n 5 55), n (%), N All Children (n 5 103), n (%), N
a
Any related TEAE 11 (22.9), 14 17 (30.9), 19 28 (27.2), 33
Respiratory, thoracic and mediastinal disorders 11 (22.9), 14 17 (30.9), 19 28 (27.2), 33
Cough 0 (0.0), 0 1 (1.8), 1 1 (1.0), 1
Epistaxis 3 (6.3), 3 2 (3.6), 2 5 (4.9), 5
Nasal congestion 0 (0.0), 0 1 (1.8), 1 1 (1.0), 1
Nasal crusting 0 (0.0), 0 1 (1.8), 1 1 (1.0), 1
Nasal discharge discoloration 0 (0.0), 0 3 (5.5), 3 3 (2.9), 3
Rhinorrhea 5 (10.4), 5 6 (10.9), 6 11 (10.7), 11
Sneezing 5 (10.4), 5 5 (9.1), 5 10 (9.7), 10
Snoring 1 (2.1), 1 0 (0.0), 0 1 (1.0), 1
Values are shown as No. participants with at least 1 event in the given row (%), No. events in the given row. TEAE, treatment-emergent adverse event.
a
TEAEs began or worsened in severity after first dose of study treatment and no later than 2 calendar days after last dose of study treatment.

administer. Furthermore, of the
originally estimated 140 children,
103 were enrolled in the study. As a
phase 2a study, our goal was to
demonstrate evidence of some
clinical efficacy while monitoring for
adverse events. If there is an
undetected true benefit of surfactant
treatment in children with AOM, the
expected treatment effect is likely to
be smaller than 25%. All children
received adequate 10-day treatment
with amoxicillin/clavulanate,
potentially reducing the additional
benefit an adjunct treatment such as
surfactant might provide. On the
basis of our previous reports on
treatment of AOM in young
children2,3 we provided 10 days of
antimicrobial therapy to all children.
It is possible that among children
not treated with antimicrobial
agents, surfactant would have
resulted in significant benefit
compared with placebo. Although it
did not appear that parents had
problems with ease of
administration of study medication,
it was challenging for them to meet
the narrow per-protocol visit
windows, which were the
prespecified analysis windows;
accordingly, the visit days were
chosen to maximize the treatment
effect.
This is the first study of surfactant
administered intranasally in young
children with AOM. A novel therapy
that potentially improves symptoms
of AOM while reducing antimicrobial
use or duration of therapy would be
desirable. The biological basis for
surfactant in the treatment of AOM
derives from its ability to lower
surface tension, which may open the
ET usually obstructed during an
AOM episode. Animal studies with
surfactant have revealed significant
improvements in ET opening
pressures and persistence of middle-
ear effusion.14–16 In chinchillas with
laboratory-induced AOM, surfactant
revealed improvements in
tympanometry at day 12, incidence
of labyrinthitis, microbiologic cure
rates, and middle-ear effusion on
clinical examination.17 Three phase
1 adult studies of surfactant have
been conducted18–20; no pediatric
studies have been reported. We
were unable to reproduce the
encouraging results seen in animal
studies.
Conclusions
In young children with AOM,
intranasally administered surfactant
(OP0201) at the dose evaluated did
not result in improved clinical
outcomes. Further research,
including dose ranging studies, may
be warranted among children with
persistent middle-ear effusion.
ACKNOWLEDGMENTS
We are grateful to the many UPMC
Children’s Hospital of Pittsburgh
house officers, General Academic
Pediatrics faculty and nurses who
referred children to the study, and
to Kris Daw and Marcia Pope who
helped manage children in the
study. We are particularly indebted
to the children and their families for
their generosity and cooperation in
participating in this trial to further
clinical research in children.
ABBREVIATIONS
AOM: acute otitis media
AOM-SOS: Acute Otitis
Media–Severity of
Symptoms
ET: eustachian tube
mITT: modified intent-to-treat

*
Address correspondence to Gysella Muniz MD, UPMC Children's Hospital of Pittsburgh, Primary Care Center, 3414 Fifth Avenue, CHOB, 3rd Floor. Pittsburgh, PA
15213. E-mail: gysella.munizpujalt@chp.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2021 by the American Academy of Pediatrics

PEDIATRICS Volume 148, number 6, December 2021 7

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 FINANCIAL DISCLOSURE: Novus Therapeutics, Inc provided the study product used in the study and statistical support for data analysis.
FUNDING: Sponsored and funded by Novus Therapeutics, Inc.
POTENTIAL CONFLICT OF INTEREST: Drs Bhatnagar, Hoberman, Martin, and Shope have received grants from PhotoniCare Inc. and Merck Sharp & Dohme
Corp. The other authors have no potential conflict of interest to report.
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