Research

JAMA Pediatrics | Original Investigation

Effectiveness of Intranasal Mometasone Furoate vs Saline

for Sleep-Disordered Breathing in Children
A Randomized Clinical Trial
Alice Baker, MBBS; Anneke Grobler, PhD; Karen Davies, MBBCh; Amanda Griffiths, MBBS; Harriet Hiscock, MD;
Haytham Kubba, MD; Rachel L. Peters, PhD; Sarath Ranganathan, PhD; Joanne Rimmer, MA;
Elizabeth Rose, MBBS; Katherine Rowe, MBBS; Catherine M. Simpson, PhD;
Andrew Davidson, MD; Gillian Nixon, MD; Kirsten P. Perrett, PhD

Supplemental content
IMPORTANCE Obstructive sleep-disordered breathing (SDB) in children is characterized by
snoring and difficulty breathing during sleep. SDB affects at least 12% of otherwise healthy
children and is associated with significant morbidity. Evidence from small clinical trials
suggests that intranasal corticosteroids improve SDB as measured by polysomnography;
however, the effect on symptoms and quality of life is unclear.

OBJECTIVE To determine whether intranasal mometasone furoate is more effective than

intranasal saline for improving symptoms and quality of life in children with SDB.

DESIGN, SETTING, AND PARTICIPANTS The MIST trial was a multicenter, randomized,
double-blind, placebo-controlled trial, recruiting participants from June 8, 2018, to
February 13, 2020. Children aged 3 to 12 years who were referred to a specialist for
significant SDB symptoms were included; exclusions were previous adenotonsillectomy,
body mass index greater than the 97th percentile, and severe SDB. Randomization was
stratified by site, and data were analyzed on an intention-to-treat basis from October 28,
2020, to September 25, 2022.

INTERVENTIONS Participants were randomly assigned to receive mometasone furoate, 50 μg,

or sodium chloride (saline), 0.9%, 1 spray per nostril daily, dispensed in identical bottles.

MAIN OUTCOMES AND MEASURES The primary outcome was resolution of significant SDB
symptoms (ie, reduction to a level no longer requiring referral to a specialist as per the
American Academy of Pediatrics guidelines) at 6 weeks, measured by parental report of
symptoms using the SDB Score.

RESULTS A total of 276 participants (mean [SD] age, 6.1 [2.3] years; 146 male individuals
[53%]) were recruited, 138 in each treatment arm. Resolution of significant SDB symptoms
occurred in 56 of 127 participants (44%) in the mometasone group and 50 of 123 participants
(41%) in the saline group (risk difference, 4%; 95% CI, −8% to 16%; P = .51) with 26
participants lost to follow-up and missing values managed by multiple imputation. The main
adverse effects were epistaxis, affecting 12 of 124 participants (9.7%) in the mometasone
group and 18 of 120 participants (15%) in the saline group, and nasal itch/irritation, affecting
12 of 124 participants (9.7%) in the mometasone group and 22 of 120 participants (18%)
in the saline group.

CONCLUSIONS AND RELEVANCE Results of this randomized clinical trial suggest that there
was no difference in treatment effect between intranasal mometasone and saline for the
management of SDB symptoms. The results suggest that almost one-half of children with
SDB could be initially managed in the primary care setting and may not require referral
to specialist services, as is currently recommended.

TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry: Author Affiliations: Author
ANZCTRN12618000448246 affiliations are listed at the end of this
article.
Corresponding Author: Kirsten P.
Perrett, PhD, Population Allergy
Group, Murdoch Children’s Research
Institute, Royal Children’s Hospital,
50 Flemington Rd, Parkville,
JAMA Pediatr. 2023;177(3):240-247. doi:10.1001/jamapediatrics.2022.5258 VIC 3052, Australia (kirsten.perrett@
Published online January 17, 2023. mcri.edu.au).

240 (Reprinted) jamapediatrics.com

© 2023 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Johns Hopkins University User on 08/03/2023

 Effectiveness of Intranasal Mometasone Furoate vs Saline for Sleep-Disordered Breathing in Children
O
bstructive sleep-disordered breathing (SDB) affects at
least 12% of otherwise healthy children.1,2 The um-
brella term SDB describes a continuum from primary
snoring (without sleep disturbance or gas exchange abnor-
malities) through to severe obstructive sleep apnea (OSA)
with frequent repetitive apnea and resultant hypoxia. 1-5
Untreated, SDB of any severity is associated with significant
morbidity; in particular, detrimental effects on cognitive func-
tion, behavior, and cardiovascular health.6,7 Current recom-
mendations for the management of SDB from the American
Academy of Pediatrics are to refer all children with habitual
snoring and other difficulties during sleep (eg, difficulty breath-
ing, restlessness, and/or frequent awakenings) for manage-
ment of their SDB, including polysomnography (PSG) to de-
termine severity or, if not possible, specialist assessment. Those
with moderate-severe OSA (≥5 obstructive respiratory events
per hour on PSG) are recommended to undergo prompt ad-
enotonsillectomy (T&A).4
In many countries, PSG availability is limited and not used
for the majority of children undergoing T&A8,9; the decision to
proceed with surgery is made on history and examination alone
in 90% of children.10 T&A results in improved sleep, quality of
life, behavior, and cardiovascular outcomes in the majority
of children with SDB symptoms.11,12 However, if tested using PSG,
approximately one-half of the children referred for T&A have pri-
mary snoring without OSA,12 and evidence is lacking for the ben-
efit of T&A in this group. Additionally, T&A is painful, costly, and
carries a risk of mortality and postoperative morbidity (hemor-
rhage and respiratory compromise).13 Given the high numbers
of children with SDB and the uncertainty of benefit from T&A for
those who do not have OSA, alternatives to surgery are needed.
Small randomized clinical trials (largest n = 62) have dem-
onstrated improvement in PSG parameters for children with OSA
when treated with an intranasal corticosteroid.14-16 Two of these
compared the corticosteroid with a placebo spray, and 1 study
used saline.16 Treatment periods were 6 weeks to 4 months, and
significant improvements in PSG parameters were found in all
studies over placebo or saline. However, as each of these trials
defined their population as children with OSA, diagnosed by PSG,
these results may not be applicable to the many children who
have undifferentiated SDB without further characterization with
PSG. The primary outcomes were also based on improvements
in PSG measures only, and it is not certain if these changes equate
to an improvement in symptom burden or affect the need for sur-
gery in this group.17 Therefore, our MIST study aimed to deter-
mine the safety and efficacy of intranasal corticosteroid for the
treatment of symptoms of SBD in children at 6 weeks—reflecting
a pragmatic outcome that could be incorporated into clinical care.
Secondary outcomes included parent- and surgeon-assessed
need for surgery, quality of life, behavioral and functional state
of the child, and parental satisfaction with treatment.
Methods
Design
The MIST trial was a multicenter, randomized, double-blind,
placebo-controlled trial carried out at 2 tertiary hospitals in
jamapediatrics.com
© 2023 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Johns Hopkins University User on 08/03/2023
Original Investigation Research
Key Points
Question Is 6 weeks of intranasal mometasone furoate more
effective than intranasal saline for the treatment of symptoms
of obstructive sleep-disordered breathing (SDB) in children?
Findings In this double-blind, randomized clinical trial of 276
children with SDB, there was no difference in treatment effect
between 6 weeks of intranasal corticosteroid and intranasal
saline. Both nasal sprays resulted in resolution of symptoms
in approximately 40% of participants.
Meaning Results suggest that in primary care, first-line treatment
of SDB in children could include 6 weeks of intranasal saline, or
corticosteroid, which may resolve symptoms in almost one-half
of children.
Melbourne, Australia. Approval was obtained from the hu-
man research ethics committee at the Royal Children’s Hos-
pital Melbourne. The trial protocol and statistical analysis plan
are outlined in Supplement 1 and Supplement 2, respectively.
Reporting followed the Consolidated Standards of Reporting
Trials (CONSORT) reporting guidelines.18
Participants
Eligible participants were aged 3 to 12 years, had been re-
ferred to a specialist for SDB management, and had ongoing
significant symptoms of SDB in the preceding 2 weeks based
on parent response to 3 questions, modified from Brouillette
et al.19 The first 2 questions (Does your child snore [S]? Does
your child have difficulty [D] during sleep? eg, difficulty breath-
ing, restlessness, gasping or snorting, or waking multiple times
in 1 night) were scored on a 4-point Likert scale (never = 0,
sometimes [1-2 nights/week] = 1, often [3-5 nights/week] = 2,
or always [6-7 nights/week] = 3) and the last question (have
you seen your child stop breathing while asleep?, ie, an apnea
[A] episode) was scored either yes = 1 or no = 0. A summary
score was obtained using the original equation from Brouil-
lette et al: SDB score = 1.42D + 1.41A + 0.71S − 3.83.19 This
inclusion criterion was aimed at selecting those children
who are defined in the American Academy of Pediatrics guide-
line as requiring specialist referral for management of their SDB
and excluding those without habitual snoring and other
difficulties during sleep. A score less than −1 demonstrates
absence of significant SDB symptoms; a score greater than
or equal to −1 was required for trial inclusion. To control for
intercurrent illness, the questions were introduced with the
phrase “Over the past 2 weeks, or if your child has been
unwell with a cold, when they were well, do they snore…”
Maternal and paternal ethnicity were collected from the
parent or guardian attending the first appointment, as self-
selected from the following list: Aboriginal or Torres Strait
Islander, African, Asian, White, or other. Birthplace of the par-
ticipant was also selected as Australia or overseas. Ethnicity
was included as this has been shown previously to have an
association with severity of obstructive SDB.12 This was not
a requirement of the funding bodies.
Children were excluded if they had previously under-
gone T&A; had a body mass index (BMI) greater than the 97th
(Reprinted) JAMA Pediatrics March 2023 Volume 177, Number 3 241
 Research Original Investigation Effectiveness of Intranasal Mometasone Furoate vs Saline for Sleep-Disordered Breathing in Children
Figure. Consolidated Standards of Reporting Trials (CONSORT) Diagram
2142 Patient referrals/online registration forms
assessed for eligibility for phone screening
469 Declined screening
461 Ineligible
390 Not able to be contacted
822 Screened over the phone
303 Ineligible
225 Declined
294 Consented to trial
18 Ineligible
276 Enrolled and randomized
138 Assigned mometasone furoate 138 Assigned saline
11 Lost to follow-up 15 Lost to follow-up
127 Completed primary outcome 123 Completed primary outcome
and included in ITT analysis and included in ITT analysis
percentile (calculated as weight in kilograms divided by height
in meters squared)20; craniofacial, neuromuscular, or ge-
netic comorbidities affecting sleep; hemorrhagic diathesis
or recurrent or severe epistaxis in the past 2 weeks; intranasal
or systemic corticosteroid treatment, or oral montelukast
within the last 6 weeks; active nasal infection or injury; ac-
tive tonsillitis; or stertor while awake suggesting severe SBD
needing urgent surgery.
Recruitment
Children were recruited from respiratory, sleep, or ear, nose,
and throat clinic waiting lists at The Royal Children’s Hospital
and Monash Children’s Hospital, both tertiary hospitals in
Melbourne, Australia, and from the community following spe-
cialist referral obtained after a parent or guardian registered
their interest following print, television, or social media trial
advertising. Screening was done by telephone following ver-
bal consent from a parent or guardian. Written informed con-
sent was obtained from the parent or guardian at the first study
visit by a study investigator or research nurse, with assent
sought from older children.
Randomization and Masking
Eligible patients were randomly assigned in a 1:1 ratio to re-
ceive either intranasal mometasone furoate or normal saline.
The randomization schedule was generated by an indepen-
dent statistician, using permuted random block randomiza-
tion with block sizes of 2 and 4, and stratified by site. The sched-
ule was given directly to the trial pharmacists, who dispensed
the allocated treatment. The 2 treatments were dispensed in
identical opaque bottles with the same spray mechanism.
242 JAMA Pediatrics March 2023 Volume 177, Number 3 (Reprinted)
© 2023 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Johns Hopkins University User on 08/03/2023
782 Not eligible
210 Previous
adenotonsillectomy
207 Medical comorbidity
118 SDB score too low
87 BMI >97th percentile
66 Interpreter required
60 Intranasal steroid
used in the last 6 wk
19 Other
9 Montelukast or
systemic steroids in
the last 6 wk
4 Recurrent epistaxis
in the last 2 wk
1 Active tonsillitis
1 Stertor
BMI indicates body mass index;
ITT, intention to treat;
SDB, sleep-disordered breathing.
Procedures
Caregivers were asked to give their child 1 spray per nostril daily
of the blinded study spray bottle, either intranasal mometa-
sone furoate, 50 μg per spray, or sodium chloride, 0.9%
(normal saline). Spray bottles were manufactured by Apotex
Pty Ltd and used the same preservative (benzalkonium chlo-
ride, 0.02%). Families watched a video on nasal spray tech-
nique at the first study visit, and the first dose was observed
by a study doctor or nurse. Demographics, medical history, and
height and weight were collected at the first visit, and physi-
cal examination of the upper airway was performed by study
doctor or nurse. Parent-completed questionnaires were col-
lected at baseline and between day 42 and 49 postrandomiza-
tion. Families who could not attend their second visit (some
due to COVID-19 restrictions) provided parent-reported mea-
sures over the telephone or online.
Outcomes
The primary outcome was the proportion of participants in each
treatment group who had resolution of significant SDB symp-
toms, based on an SDB score less than −1, as reported by par-
ents at the second study visit at 6 weeks. Secondary out-
comes were symptoms of SDB at visit 2 based on the Pediatric
Sleep Questionnaire–SDB subscale (PSQ-SBD),21 the OSA-11,
and its subset OSA-522; quality of life (PedsQL)23; functional
and behavioral performance of the child (Strengths and Diffi-
culties Questionnaire)24; as well as the parent’s perception
of their child’s need for surgery for SDB and willingness to
proceed to surgery if it were recommended. The parent-
perceived benefit from study treatment was measured using
the Glasgow Child Benefit Inventory.25
jamapediatrics.com
 Effectiveness of Intranasal Mometasone Furoate vs Saline for Sleep-Disordered Breathing in Children Original Investigation Research

Surgical assessment of each participant at baseline and visit

Table 1. Baseline Characteristics by Treatment Group
2 consisted of randomly allocating 2 of 4 ear, nose, and throat
surgeons involved in the trial to each participant. Then, sur- Allocation, No. (%)
geons independently reviewed the medical history, SDB score, Characteristic Mometasone Saline
No. 138 138
PSQ-SBD, and physical examination findings (performed by
Site
study doctor or nurse) and made a recommendation on sur-
Monash Children’s Hospital 43 (31.2) 43 (31.2)
gery for SDB (yes, no, not enough information/not able to make
Royal Children’s Hospital 95 (68.8) 95 (68.8)
a decision). The surgeons (K.D., H.K., J.R., E.R.) were blinded
Sex
to treatment group and whether the information was from Male 67 (48.6) 79 (57.2)
baseline or visit 2. If there was discrepancy between the 2 sur- Female 71 (51.4) 59 (42.8)
geons’ recommendations, the case was reviewed by a third Age at enrollment, mean (SD), y 6.2 (2.2) 6.2 (2.4)
randomly assigned surgeon to give a final deciding vote. BMI percentile,a mean (SD) 0.6 (0.3) 0.6 (0.3)
Families were asked to record all doses given in a study Age at onset of SDB, mean (SD), y 2.3 (1.9) 2.3 (1.9)
diary and spray bottles were weighed prior to dispensing and Previous intranasal steroid treatment 28 (20.3) 22 (15.9)
on return at the end of the intervention period. Adverse History of asthma 25 (18.1) 26 (18.8)
events (AEs) were recorded by parents in the diary, with Symptoms of AR in last 12 mo 85 (61.6) 95 (68.8)
instructions to record all symptoms of health problems dur- Diagnosed with allergic rhinitis 23 (16.7) 23 (16.7)
ing the intervention period. AEs of interest (defined as those Atopy (eczema, asthma, food allergy, 102 (73.9) 109 (79.0)
or symptoms of AR)
likely to be caused by the nasal spray) were solicited over the
Prematurity (<37 wks’ gestational age) 14 (10.1) 17 (12.3)
first week and included nasal itch or irritation (yes, no) and At least 1 smoker present in household 28 (20.3) 30 (21.7)
nasal bleeding (quantified as specks of blood in the mucus, Maternal ethnicity
estimated blood volume less than 1 teaspoon or 1 teaspoon Aboriginal or Torres Strait Islander 0 2 (1.4)
or more). African 10 (7.2) 3 (2.2)
Asian 25 (18.1) 29 (21.0)
Statistical Analysis Middle Eastern 6 (4.3) 4 (2.9)
Based on the results from the previous randomized trial, and White 89 (64.5) 93 (67.4)
from clinical experience of the investigator group, it was es- Otherb 8 (5.8) 7 (5.1)
timated that 50% of the mometasone group and 30% of the Paternal ethnicity
saline group would respond to treatment. Using a 2-group χ2 Aboriginal or Torres Strait Islander 0 2 (1.4)
test with α of .05 would have 90% power to detect the differ- African 12 (8.7) 6 (4.3)

ence between treatment groups (odds ratio [OR] of 2.33) with Asian 26 (18.8) 25 (18.1)
Middle Eastern 6 (4.3) 4 (2.9)
a sample size of 124 in each treatment arm. Allowing for a loss
White 84 (60.9) 92 (66.7)
to follow-up of 10% increased the sample size in each arm.
Otherb 10 (7.2) 9 (6.5)
The difference in proportion (with 95% CI) of partici-
Examination findings
pants in each group meeting the primary outcome (resolu-
Tonsillar hypertrophy (at least 1 tonsil 94 (68.1) 77 (55.8)
tion of symptoms) was calculated using a generalized linear grade 3 or 4)
model using the binomial family and identity link, with site Friedman palate position III or IV 43 (31.2) 42 (30.4)
as a covariate. The treatment arms were also compared using Septal deviation 14 (10.3) 28 (20.4)
a Mantel Haenszel χ2 test stratified by site. Binary secondary Large turbinate on either side 71 (51.4) 69 (50.0)
outcomes were also compared between groups with this model. Parent questionnaire
Continuous secondary outcomes were analyzed by compar- SDB score, mean (SD) 1.9 (1.3) 1.9 (1.2)

ing the mean difference between treatment arms (with 95% Parent believes the child needs surgery 82 (59.4) 83 (60.6)
Parent willing to proceed with surgery 123 (89.1) 125 (90.6)
CI) using a linear regression adjusted for site and baseline value
Surgery recommended by 86 (62.3) 93 (67.4)
of the measured scale. surgeon consensus
Primary and secondary outcomes were assessed in the in- OSA 11 score, mean (SD) 10.9 (5.3) 10.2 (4.5)
tention-to-treat (ITT) population, which included all partici- OSA 5 score, mean (SD) 6.2 (3.3) 5.5 (2.7)
pants randomly assigned to treatment groups. Missing data OSA 5 ≥ 5 89 (64.5) 84 (60.9)
were managed using multiple imputation. Compliance and AEs PSQ-SDB score, mean (SD) 0.5 (0.2) 0.5 (0.2)
were analyzed for all participants with data available. PSQ-SDB ≥ 0.33 113 (83.1) 124 (89.9)
Analysis for any association between the primary out- Total score, mean (SD)
come and specific a priori defined clinical factors at baseline PedsQL 74.3 (16.4) 74.9 (15.3)

(age >6 years; presence of overweight or obesity; presence of SDQ 11.8 (7.4) 12.3 (6.3)

symptoms of allergic rhinitis in the preceding 12 months;
severity of SDB symptoms based on previously validated
symptom score cutoffs) was performed using multivariable
logistic regression. All analyses were performed from October
28, 2020, to September 25, 2022, using Stata, version 16.0
(StataCorp).
Abbreviations: AR, allergic rhinitis; BMI, body mass index; OSA, obstructive
sleep apnea; PedsQL, Pediatric Quality of Life; PSQ-SBD, Pediatric Sleep
Questionnaire–SDB subscale; SDB, sleep-disordered breathing; SDQ, Strengths
and Difficulties Questionnaire.
a
Calculated as weight in kilograms divided by height in meters squared.
b
Other includes Filipino, Pacific Islander, and South American.

jamapediatrics.com (Reprinted) JAMA Pediatrics March 2023 Volume 177, Number 3 243

© 2023 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Johns Hopkins University User on 08/03/2023

 Research Original Investigation Effectiveness of Intranasal Mometasone Furoate vs Saline for Sleep-Disordered Breathing in Children

Table 2. Primary and Secondary Outcomes at Baseline and After the 6-Week Intervention, by Treatment Group: Using Multiple Imputationa

Baseline, % 6 wk, % (95% CI) Adjusted linear

Mometasone Saline Mometasone Saline Risk difference, % regression, mean
Outcome (n = 138) (n = 138) (n = 138) (n = 138) (95% CI)b difference (95% CI)c P valueb
Primary outcome
SDB score <−1 0 0 44 (36 to 53) 41 (32 to 49) 4 (−8.0 to 16) NA .51
Secondary
outcomes
Surgeons 62.3 67.4 32 (24 to 40) 38 (29 to 47) −6 (−18 to 6.1) NA NA
recommend
surgery
Parent opinion 59.4 60.6 50 (41 to 58) 55 (46 to 64) −5 (−17 to 7.5) NA NA
needs surgery
PSQ-SDB, 0.51 (0.48 0.53 (0.51 to 0.38 (0.34 to 0.40 (0.36 NA 0.00 (−0.05 to NA
mean (95% CI) to 0.54) 0.56) 0.42) to 0.44) 0.05)
OSA5, mean 6.2 (5.7 to 6.8) 5.5 (5.0 to 5.9) 3.6 (3.2 to 4.1) 3.8 (3.3 to 4.3) NA −0.5 (−1.1 to 0.1) NA
(95% CI)
PedsQL total 74 (72 to 77) 75 (72 to 77) 81 (78 to 84) 79 (76 to 82) NA 2.1 (−1.0 to 5.1) NA
score, mean
(95% CI)
SDQ total score, 11 (11 to 13) 12 (11 to 13) 11 (9.5 to 12) 11 (10 to 12) NA −0.2 (−1.1 to 0.8) NA
mean (95% CI)
GCBI, mean NA NA 7.8 (4.9 to 11) 8.6 (5.3 to 12) NA −0.8 (−5.2 to 3.5) NA
(95% CI)
Parent NA NA 2.2 (2.0 to 2.5) 2.3 (2.0 to 2.5) NA 0.08 (−0.43 to 0.27) NA
satisfaction
(1-5), mean
(95% CI)
Abbreviations: GCBI, Glasgow Child Benefit Inventory; NA, not applicable; variables, separately for each treatment arm. A total of 50 completed data
OSA, obstructive sleep apnea; PedsQL, Pediatric Quality of Life; sets were imputed using chained imputation including all randomly assigned
PSQ-SBD, Pediatric Sleep Questionnaire–SDB subscale; SDB, sleep-disordered participants.
breathing; b
Risk difference between treatment arms at 6 weeks using generalized linear
SDQ, Strengths and Difficulties Questionnaire. model using the binomial family and identity link, adjusted for site.
a
Multiple imputation was performed with the assumption that the missing data c
Mean difference between treatment arms at 6 weeks using linear regression
was missing at random. Multiple imputation models included all variables adjusted for site and baseline value of the measured scale.
included in the analysis models as well as baseline variables as auxiliary

tively (risk difference, −6%; 95% CI, −18% to 6.1%). Parent

Results
Between June 8, 2018, to February 13, 2020, 2142 referrals and
registrations of interest in the trial were reviewed for eligibil-
ity to undergo telephone screening. A total of 822 children were
screened over the telephone, and 295 attended the first visit,
of whom 276 (mean [SD] age, 6.1 [2.3] years; 146 male indi-
viduals [53%]; 130 female individuals [47%]) were randomly
assigned to receive either intranasal mometasone furoate
(n = 138) or saline (n = 138) (Figure). One participant found
to be randomized in error (BMI, 98.5th percentile) was still
included in the ITT population. Median (IQR) duration for
follow-up was 43 (42-48) days. Baseline characteristics are
described in Table 1.
At 6 weeks, there were 26 participants lost to follow-up
(9.4%; characteristics in eTable 1 in Supplement 3). Using mul-
tiple imputation, 56 of 127 participants (44%; 95% CI, 36%-
53%) in the mometasone group and 50 of 123 participants (41%;
95% CI, 32%-49%) in the saline group had resolution of SDB
symptoms (risk difference, 4%; 95% CI, −8.0% to 16%; P = .51),
with no significant difference between the 2 groups. The per-
centage, CIs, and risk difference were calculated using mul-
tiple imputation (Table 2). Surgeon consensus was in favor of
surgery at visit 2 in 32% (95% CI, 24%-40%) and 38% (95% CI,
29%-47%) in the mometasone and saline groups, respec-
assessment of need for surgery at 6 weeks was in favor of sur-
gery in 50% (95% CI, 41%-58%) and 55% (95% CI, 46%-53%)
in the mometasone and saline groups, respectively (risk dif-
ference, −5%; 95% CI, −17% to 7.5%). There was no signifi-
cant difference between groups at 6 weeks in symptom scores,
quality of life, behavioral function of the child, parent satis-
faction with treatment, or the perceived benefit from treat-
ment between the 2 groups (Table 2). There were no signifi-
cant differences to these results when using available case
analysis, shown in eTable 2 in Supplement 3).
There was no association between the primary outcome
and baseline factors of age 6 years or older (OR, 1.04; 95% CI,
0.37-2.88; P = .94), overweight or obesity (OR, 1.31; 95% CI, 0.42-
4.08; P = .65), symptoms of allergic rhinitis in the preceding
12 months (OR, 1.56; 95% CI, 0.55-4.47; P = .41), baseline se-
verity of symptoms as measured by previously validated cut-
off scores for PSQ-SBD greater than 0.3326 (OR, 1.43; 95% CI,
0.34-6.07; P = .63), and OSA5 of 5 or greater22 (OR, 0.86; 95%
CI, 0.30-2.41; P = .77). In addition, using these severity scores
as alternative measures for resolution of significant symptoms
at 6 weeks did not demonstrate a difference between treat-
ment groups.
AEs were generally mild and were seen in similar num-
bers between treatment groups (Table 3 and Table 4). AEs of
interest were those considered associated with the nasal spray.

244 JAMA Pediatrics March 2023 Volume 177, Number 3 (Reprinted) jamapediatrics.com

© 2023 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Johns Hopkins University User on 08/03/2023

 Effectiveness of Intranasal Mometasone Furoate vs Saline for Sleep-Disordered Breathing in Children Original Investigation Research

Table 3. Adverse Events by Treatment Group Table 4. Adverse Events (AEs) of Interest

No.a No. (%)

Mometasone Saline Mometasone Saline
Adverse events (N = 491) (n = 218) (n = 273) Participants (n = 138) (n = 138)
Nasal bleeding including specks 39 46 At least 1 AE
Epistaxis (>specks of blood in mucus) 29 34 Yes 93 (67) 97 (70)
Specks of blood in the mucus 10 12 No 31 (22) 23 (17)
Nasal itch/irritation 16 34
Missing AE data 12 (10) 18 (13)
Runny nose 17 18
Adverse event data present (n = 244)
Blocked nose 5 10
No. 124 120
Sneezing 1 7
Nasal itch/irritation 12 (9.7) 22 (18)
Cough 11 8
Epistaxis (≥specks of blood) 12 (9.7) 18 (15)
Sore throat 5 3
Largest volume of bleeding for participant
Hoarse voice 1 1
Spray refusal 1 3 Specks of blood only 3 (2.4) 5 (4.2)

Asthma 4 7 <Teaspoon for all bleeds 7 (5.6) 11 (9.2)

Eczema 3 1 ≥Teaspoon for at least 1 bleed 5 (4.0) 7 (5.8)
Hay fever 1 3 AE data and epistaxis history data present
(n = 108)
Ear pain/ infection 2 9
No. 53 55
Tonsillitis 7 5
Epistaxis in those with
LRTI 4 0
URTI b
49 42 No history of nose bleeds 0/30 1/24 (4)

Rash (including hives and itchy skin) 2 3
Abdominal complaint (pain, nausea, 7 27
vomiting, diarrhea, gastroenteritis)
Fever or viral illness 4 8
Other (eg, leg pain, falls) 21 25
Abbreviations: LRTI, lower respiratory tract infection; URTI, upper respiratory
tract infection.
a
Percentages not provided because there could be multiple adverse events
per child per group.
b
Assigned to any episodes with 2 concurrent URTI symptoms (cough, runny
nose, sore throat), or any fever with a single URTI symptom.
Nasal itch or irritation was seen in 12 of 124 participants
(9.7%) with AE data in the mometasone group and 22 of
120 participants (18%) in the saline group. Epistaxis (any
bleeding > specks of blood in the mucus) was seen in 12 of 124
participants (9.7%) in the mometasone group and 18 of 120
participants (15%) in the saline group. In both groups it was
more common to see epistaxis in children who had a recent
history of epistaxis (within the 3 months preceding the inter-
vention period): 8 of 23 participants (35%) of a subset of 108
participants with data on epistaxis history and AE compared
with those with a nonrecent history of epistaxis (2 of 30 [7%])
or those with no history of epistaxis (1 of 54 [2%]).
Compliance reported by diary (n = 233) was 88% (95% CI,
84%-91%) in the mometasone group and 87% (95% CI, 84%-
91%) in the saline group. By weight of returned bottles (n = 217),
compliance was 93% (95% CI, 88%-98%) and 96% (95% CI,
90%-103%) in the mometasone and saline groups, respec-
tively, among those with compliance data.
Discussion
The MIST randomized clinical trial found no difference in treat-
ment effect between intranasal mometasone and saline for the
History of bleeding prior to preceding 0/12 2/18 (11)
3 mo
History of bleeding within the last 3 mo 2/10 (20) 6/13 (46)
management of SDB symptoms. However, we found substan-
tial rates of SDB symptom improvement and substantial re-
duction in surgeon recommendation for surgery after 6 weeks
of each treatment. There was also no difference between
the 2 groups in other validated measures of SDB symptoms,
the quality of life, or daytime function of the child. These re-
sults did not support our hypothesis that 6 weeks of daily in-
tranasal mometasone would be more effective than saline in
reducing symptoms of SDB. This hypothesis was modeled on
3 small placebo-controlled randomized trials (1 with saline as
the placebo) that demonstrated improvement in the severity
of OSA with intranasal corticosteroids,14-16 as determined by
PSG measures (apnea-hypopnea index). However, the results
of our trial are more consistent with the recent Cochrane meta-
analysis that included 2 of the trials14,15 and concluded in pool-
ing of the results that there is insufficient evidence for the
efficacy of intranasal corticosteroids over placebo for the treat-
ment of OSA in children.27 Another more recent trial17 exam-
ining SDB symptoms in snoring children treated with intrana-
sal corticosteroid or placebo showed a significant improvement
with corticosteroid over placebo, however, this study had a risk
of bias due to nonmatched groups at baseline for the primary
outcome. In the current trial, the resolution of symptoms by
6 weeks in 40% to 44% of children regardless of treatment arm
suggests either a treatment effect of saline, equivalent to the
treatment effect of mometasone, inadequate treatment length
to detect a difference, or that the findings represent the natu-
ral history of the condition. Although the Childhood Adeno-
tonsillectomy Trial (CHAT) has demonstrated a pattern of
similar rates of resolution of OSA with watchful waiting over
7 months,12 suggesting some natural resolution in this condi-
tion, the short duration of our trial makes spontaneous reso-

jamapediatrics.com (Reprinted) JAMA Pediatrics March 2023 Volume 177, Number 3 245

© 2023 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Johns Hopkins University User on 08/03/2023

 Research Original Investigation Effectiveness of Intranasal Mometasone Furoate vs Saline for Sleep-Disordered Breathing in Children

lution less likely. The potential treatment effect of saline could
be due to a cleansing of the nasal passages, similar to the ob-
served effects of saline in treating allergic rhinitis in children.28
This supports the idea that a significant subset of children
could be managed and followed up in the primary care set-
ting, thus reducing the number of children requiring special-
ist review.
AEs were reported more frequently in our study than pre-
vious studies. This is likely to be because families were instructed
to record all health-related symptoms of any severity during the
intervention period, and nasal itch or irritation and epistaxis were
solicited daily over the first 7 days. In addition, we included bleed-
ing of any volume greater than specks of blood in the mucus as
epistaxis, whereas it is unclear what the definition of epistaxis
was in previous trials. Our study demonstrated an increased risk
of epistaxis with either spray if there had been a recent history
of bleeding in the preceding 3 months. This suggests that the epi-
staxis is likely to be associated with trauma from the nozzle or
spray against an already friable nasal mucosa rather than a cor-
ticosteroid effect. It is not clear why there was slightly more ob-
served nasal itch or irritation in the saline group compared with
the mometasone group, as preservatives were identical in each
medication. It is possible that the mometasone treated preexist-
ing inflammation in the nose as 88% of itch or irritation episodes
were seen in the first 7 days of treatment with mometasone,
compared with 55% of episodes with saline, suggesting that
itch resolved faster for those using corticosteroid treatment.
Strengths and Limitations
A key strength of this study was its pragmatic approach, using
clinical information to diagnose and manage SDB instead of
PSG measures. This allows for direct translation of these re-
sults to a broader group of children presenting to primary care
with this condition and refers to outcomes perhaps more per-
tinent to the patient and family.
This study also had some limitations. These include the
potential treatment effect of our control arm; however, the in-
ability to have a truly blinded watchful waiting arm means that
this may be the least biased method to measure effectiveness
of an intranasal corticosteroid. Another limitation is that the
surgeon decision-making was based on documented history
and examination findings rather than their own direct clini-
cal assessment; however, this allowed for a consensus ap-
proach between 2 to 3 surgeons and allowed them to be blinded
to visit (baseline or second) while still assessing the same pa-
tient at both time points. There is now an opportunity to fur-
ther assess the effect of intranasal saline on SDB symptoms in
children and to examine the effects of each of corticosteroid
and saline on the sequelae of SDB. Follow-up of the MIST trial
patient cohort is on-going in an effort to understand any ef-
fect of 6 weeks of intranasal sprays on the rates of T&A over
the following 2 years.
Conclusions
In conclusion, the randomized clinical MIST trial found no
difference between intranasal mometasone and saline in the
treatment of SDB symptoms, and we found substantial rates
of symptom resolution in both groups. Whether the findings
are a result of and equivalence in treatment effect between
mometasone and saline or if they reflect natural resolution of
the condition will be explored in the MIST+ study. However,
it appears possible that a large proportion of children with
SDB may be able to be treated successfully by their primary
care physician, using 6 weeks of intranasal saline as a first-
line treatment. Management with less invasive, cheaper, and
readily available treatment would increase the quality of life
of children with SDB. Further, it would reduce burden on
specialist services and therefore allow more timely access for
those children who need it most, ie those who do not
respond to initial primary care medical management. This, in
turn, could reduce waiting times and improve care for all
children with SDB.

ARTICLE INFORMATION
Accepted for Publication: October 24, 2022.
Published Online: January 17, 2023.
doi:10.1001/jamapediatrics.2022.5258
Author Affiliations: Department of Paediatrics,
University of Melbourne, Melbourne, Australia
(Baker, Grobler, Griffiths, Hiscock, Peters,
Ranganathan, Simpson, Davidson, Perrett);
Murdoch Children's Research Institute, Melbourne,
Australia (Baker, Grobler, Griffiths, Hiscock, Peters,
Ranganathan, Rose, Simpson, Davidson, Perrett);
Department of General Medicine, Royal Children’s
Hospital, Melbourne, Australia (Baker, Rowe);
Department of Otolaryngology, Royal Children’s
Hospital, Melbourne, Australia (Davies, Rose);
Department of Respiratory and Sleep Medicine,
Royal Children’s Hospital, Melbourne, Australia
(Griffiths, Ranganathan); Health Services Research
Unit, Royal Children’s Hospital, Melbourne,
Australia (Hiscock); Centre for Community Child
Health, Royal Children’s Hospital, Melbourne,
Australia (Hiscock, Simpson); Department of
Otolaryngology, Royal Hospital for Children,
Glasgow, Scotland (Kubba); Department of
Otolaryngology–Head and Neck Surgery, Monash
Health, Melbourne, Australia (Rimmer);
Department of Surgery, Monash University,
Melbourne, Australia (Rimmer); Department of
Otolaryngology, University of Melbourne,
Melbourne, Australia (Rose); Melbourne Children’s
Trial Centre, Melbourne Children’s, Melbourne,
Australia (Davidson, Perrett); Melbourne Children's
Sleep Centre, Monash Children’s Hospital, Monash
Health, Melbourne, Australia (Nixon); Department
of Paediatrics, Monash University, Melbourne,
Australia (Nixon); Department of Allergy and
Immunology, Royal Children’s Hospital, Melbourne,
Australia (Perrett).
Author Contributions: Drs Perrett and Grobler had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis. Drs Nixon and Perrett
are considered co–senior authors.
Concept and design: Baker, Grobler, Griffiths,
Hiscock, Kubba, Ranganathan, Rimmer, Rowe,
Simpson, Davidson, Nixon, Perrett.
Acquisition, analysis, or interpretation of data:
Baker, Grobler, Davies, Hiscock, Kubba, Peters,
Ranganathan, Rimmer, Rose, Simpson, Davidson,
Nixon, Perrett.
Drafting of the manuscript: Baker, Grobler, Griffiths,
Ranganathan, Perrett.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Baker, Grobler, Kubba.
Obtained funding: Baker, Nixon, Perrett.
Administrative, technical, or material support:
Baker, Davies, Kubba, Rimmer, Nixon, Perrett.
Supervision: Grobler, Davies, Griffiths, Kubba,
Peters, Ranganathan, Rose, Simpson, Davidson,
Nixon, Perrett.
Conflict of Interest Disclosures: Dr Peters
reported receiving funding from National Health
and Medical Research Council of Australia outside
the submitted work. Dr Nixon reported receiving
funding from ResMed Foundation outside the
submitted work. Dr Perrett reported receiving
grants from National Health and Medical Research
Council of Australia, Immune Tolerance Network,
the Royal Children’s Hospital Foundation, Murdoch

246 JAMA Pediatrics March 2023 Volume 177, Number 3 (Reprinted) jamapediatrics.com

© 2023 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Johns Hopkins University User on 08/03/2023

 Effectiveness of Intranasal Mometasone Furoate vs Saline for Sleep-Disordered Breathing in Children
Children’s Research Institute, DBV Technologies,
Novartis, Siolta, and Aravax outside the submitted
work. No other disclosures were reported.
Funding/Support: The trial was funded by research
grants from The Passe and Williams Foundation,
Murdoch Children’s Research Institute, the Royal
Children’s Hospital Foundation, and the Monash
Health Foundation awarded to Drs Perrett, Nixon,
and Baker.
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review,
or approval of the manuscript; and decision to
submit the manuscript for publication.
Data Sharing Statement: See Supplement 4.
REFERENCES
1. Walter LM, Horne RSC, Nixon GM. Treatment of
obstructive sleep apnea in children. Clin Pract.
2013;10(4):519-533. doi:10.2217/cpr.13.37
2. Schechter MS; Section on Pediatric
Pulmonology, Subcommittee on Obstructive Sleep
Apnea Syndrome. Technical report: diagnosis and
management of childhood obstructive sleep apnea
syndrome. Pediatrics. 2002;109(4):e69.
doi:10.1542/peds.109.4.e69
3. Bixler EO, Vgontzas AN, Lin HM, et al.
Sleep-disordered breathing in children in a general
population sample: prevalence and risk factors. Sleep.
2009;32(6):731-736. doi:10.1093/sleep/32.6.731
4. Marcus CL, Brooks LJ, Draper KA, et al;
American Academy of Pediatrics. Diagnosis and
management of childhood obstructive sleep apnea
syndrome. Pediatrics. 2012;130(3):576-584.
doi:10.1542/peds.2012-1671
5. Marcus CL, Brooks LJ, Draper KA, et al;
American Academy of Pediatrics. Diagnosis and
management of childhood obstructive sleep apnea
syndrome. Pediatrics. 2012;130(3):e714-e755.
doi:10.1542/peds.2012-1672
6. Bourke RS, Anderson V, Yang JS, et al.
Neurobehavioral function is impaired in children
with all severities of sleep disordered breathing.
Sleep Med. 2011;12(3):222-229. doi:10.1016/j.sleep.
2010.08.011
7. Kohyama J, Ohinata JS, Hasegawa T. Blood
pressure in sleep disordered breathing. Arch Dis Child.
2003;88(2):139-142. doi:10.1136/adc.88.2.139
jamapediatrics.com
© 2023 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Johns Hopkins University User on 08/03/2023
8. Australian Institute of Health and Welfare.
Australian Atlas of Healthcare Variation. Australian
Commission on Safety and Quality in Health Care;
2015.
9. Safe Delivery of Paediatric ENT Surgery in the
UK: a National Strategy. Accessed June 2, 2020.
https://www.entuk.org/news_and_events/news/77/
safe_delivery_of_paediatric_ent_surgery_in_the_uk_
a_national_strategy
10. Roland PS, Rosenfeld RM, Brooks LJ, et al;
American Academy of Otolaryngology–Head
and Neck Surgery Foundation. Clinical practice
guideline: polysomnography for sleep-disordered
breathing prior to tonsillectomy in children.
Otolaryngol Head Neck Surg. 2011;145(1)(suppl):S1-
S15. doi:10.1177/0194599811409837
11. Vlahandonis A, Yiallourou SR, Sands SA, et al.
Long-term changes in blood pressure control
in elementary school-aged children with
sleep-disordered breathing. Sleep Med. 2014;15(1):
83-90. doi:10.1016/j.sleep.2013.09.011
12. Marcus CL, Moore RH, Rosen CL, et al;
Childhood Adenotonsillectomy Trial (CHAT).
A randomized trial of adenotonsillectomy for
childhood sleep apnea. N Engl J Med. 2013;368(25):
2366-2376. doi:10.1056/NEJMoa1215881
13. Coté CJ, Posner KL, Domino KB. Death or
neurologic injury after tonsillectomy in children
with a focus on obstructive sleep apnea: Houston,
we have a problem! Anesth Analg. 2014;118(6):
1276-1283. doi:10.1213/ANE.0b013e318294fc47
14. Brouillette RT, Manoukian JJ, Ducharme FM,
et al. Efficacy of fluticasone nasal spray for pediatric
obstructive sleep apnea. J Pediatr. 2001;138(6):
838-844. doi:10.1067/mpd.2001.114474
15. Chan CC, Au CT, Lam HS, Lee DL, Wing YK, Li
AM. Intranasal corticosteroids for mild childhood
obstructive sleep apnea: a randomized,
placebo-controlled study. Sleep Med. 2015;16(3):
358-363. doi:10.1016/j.sleep.2014.10.015
16. Kheirandish-Gozal L, Gozal D. Intranasal
budesonide treatment for children with mild
obstructive sleep apnea syndrome. Pediatrics.
2008;122(1):e149-e155. doi:10.1542/peds.2007-3398
17. Gudnadottir G, Ellegård E, Hellgren J.
Intranasal budesonide and quality of life in pediatric
sleep-disordered breathing: a randomized
controlled trial. Otolaryngol Head Neck Surg. 2018;
158(4):752-759. doi:10.1177/0194599817742597
(Reprinted) JAMA Pediatrics March 2023 Volume 177, Number 3
Original Investigation Research
18. Schulz KF, Altman DG, Moher D; CONSORT
Group. CONSORT 2010 statement: updated
guidelines for reporting parallel group randomized
trials. Ann Intern Med. 2010;152(11):726-732.
doi:10.7326/0003-4819-152-11-201006010-00232
19. Brouilette R, Hanson D, David R, et al.
A diagnostic approach to suspected obstructive
sleep apnea in children. J Pediatr. 1984;105(1):10-14.
doi:10.1016/S0022-3476(84)80348-0
20. Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000
CDC growth charts for the US: methods and
development. Vital Health Stat 11. 2002;(246):1-190.
21. Rosen CL, Wang R, Taylor HG, et al. Utility of
symptoms to predict treatment outcomes in
obstructive sleep apnea syndrome. Pediatrics.
2015;135(3):e662-e671. doi:10.1542/peds.2014-3099
22. Soh HJ, Rowe K, Davey MJ, Horne RSC,
Nixon GM. The OSA-5: Development and validation
of a brief questionnaire screening tool for
obstructive sleep apnea in children. Int J Pediatr
Otorhinolaryngol. 2018;113:62-66. doi:10.1016/j.ijporl.
2018.07.029
23. Varni JW, Seid M, Rode CA. The PedsQL:
measurement model for the pediatric quality of life
inventory. Med Care. 1999;37(2):126-139.
doi:10.1097/00005650-199902000-00003
24. Goodman R. The strengths and difficulties
questionnaire: a research note. J Child Psychol
Psychiatry. 1997;38(5):581-586. doi:10.1111/j.1469-
7610.1997.tb01545.x
25. Kubba H, Rowe K, Pinczower G, et al.
Our experience of a paediatrician-led clinic for the
medical management of children with obstructive
sleep-disordered breathing. Clin Otolaryngol. 2020;
45(2):190-196. doi:10.1111/coa.13479
26. Chervin RD, Hedger K, Dillon JE, Pituch KJ.
Pediatric sleep questionnaire (PSQ): validity and
reliability of scales for sleep-disordered breathing,
snoring, sleepiness, and behavioral problems. Sleep
Med. 2000;1(1):21-32. doi:10.1016/S1389-9457(99)
00009-X
27. Kuhle S, Urschitz MS. Anti-inflammatory
medications for the treatment of pediatric
obstructive sleep apnea. Paediatr Respir Rev. 2020;
34:35-36. doi:10.1016/j.prrv.2020.02.008
28. Scadding GK. Optimal management of allergic
rhinitis. Arch Dis Child. 2015;100(6):576-582.
doi:10.1136/archdischild-2014-306300
247