This randomized clinical trial investigates the effectiveness of intranasal mometasone furoate compared with intranasal saline for the treatment of obstructive sleep-disordered breathing in children.
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.
Abstract
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: ANZCTRN12618000448246
Introduction
Obstructive sleep-disordered breathing (SDB) affects at least 12% of otherwise healthy children.1,2 The umbrella term SDB describes a continuum from primary snoring (without sleep disturbance or gas exchange abnormalities) through to severe obstructive sleep apnea (OSA) with frequent repetitive apnea and resultant hypoxia.1,2,3,4,5 Untreated, SDB of any severity is associated with significant morbidity; in particular, detrimental effects on cognitive function, behavior, and cardiovascular health.6,7 Current recommendations 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 breathing, restlessness, and/or frequent awakenings) for management of their SDB, including polysomnography (PSG) to determine 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 adenotonsillectomy (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 primary snoring without OSA,12 and evidence is lacking for the benefit of T&A in this group. Additionally, T&A is painful, costly, and carries a risk of mortality and postoperative morbidity (hemorrhage 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 demonstrated improvement in PSG parameters for children with OSA when treated with an intranasal corticosteroid.14,15,16 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 surgery in this group.17 Therefore, our MIST study aimed to determine 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 Melbourne, Australia. Approval was obtained from the human research ethics committee at the Royal Children’s Hospital 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 referred 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 breathing, 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 Brouillette 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 guideline 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 participant 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 undergone T&A; had a body mass index (BMI) greater than the 97th percentile (calculated as weight in kilograms divided by height in meters squared)20; craniofacial, neuromuscular, or genetic 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; active 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 specialist referral obtained after a parent or guardian registered their interest following print, television, or social media trial advertising. Screening was done by telephone following verbal consent from a parent or guardian. Written informed consent 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 receive either intranasal mometasone furoate or normal saline. The randomization schedule was generated by an independent statistician, using permuted random block randomization with block sizes of 2 and 4, and stratified by site. The schedule 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.
Procedures
Caregivers were asked to give their child 1 spray per nostril daily of the blinded study spray bottle, either intranasal mometasone 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 chloride, 0.02%). Families watched a video on nasal spray technique 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 physical examination of the upper airway was performed by study doctor or nurse. Parent-completed questionnaires were collected at baseline and between day 42 and 49 postrandomization. Families who could not attend their second visit (some due to COVID-19 restrictions) provided parent-reported measures over the telephone or online.
Outcomes
The primary outcome was the proportion of participants in each treatment group who had resolution of significant SDB symptoms, based on an SDB score less than −1, as reported by parents at the second study visit at 6 weeks. Secondary outcomes 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 Difficulties 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
Surgical assessment of each participant at baseline and visit 2 consisted of randomly allocating 2 of 4 ear, nose, and throat surgeons involved in the trial to each participant. Then, surgeons independently reviewed the medical history, SDB score, PSQ-SBD, and physical examination findings (performed by study doctor or nurse) and made a recommendation on surgery for SDB (yes, no, not enough information/not able to make a decision). The surgeons (K.D., H.K., J.R., E.R.) were blinded to treatment group and whether the information was from baseline or visit 2. If there was discrepancy between the 2 surgeons’ recommendations, the case was reviewed by a third randomly assigned surgeon to give a final deciding vote.
Families were asked to record all doses given in a study diary and spray bottles were weighed prior to dispensing and on return at the end of the intervention period. Adverse events (AEs) were recorded by parents in the diary, with instructions to record all symptoms of health problems during the intervention period. AEs of interest (defined as those likely to be caused by the nasal spray) were solicited over the first week and included nasal itch or irritation (yes, no) and nasal bleeding (quantified as specks of blood in the mucus, estimated blood volume less than 1 teaspoon or 1 teaspoon or more).
Statistical Analysis
Based on the results from the previous randomized trial, and from clinical experience of the investigator group, it was estimated that 50% of the mometasone group and 30% of the saline group would respond to treatment. Using a 2-group χ2 test with α of .05 would have 90% power to detect the difference between treatment groups (odds ratio [OR] of 2.33) with a sample size of 124 in each treatment arm. Allowing for a loss to follow-up of 10% increased the sample size in each arm.
The difference in proportion (with 95% CI) of participants in each group meeting the primary outcome (resolution of symptoms) was calculated using a generalized linear model using the binomial family and identity link, with site as a covariate. The treatment arms were also compared using a Mantel Haenszel χ2 test stratified by site. Binary secondary outcomes were also compared between groups with this model. Continuous secondary outcomes were analyzed by comparing the mean difference between treatment arms (with 95% CI) using a linear regression adjusted for site and baseline value of the measured scale.
Primary and secondary outcomes were assessed in the intention-to-treat (ITT) population, which included all participants randomly assigned to treatment groups. Missing data were managed using multiple imputation. Compliance and AEs were analyzed for all participants with data available.
Analysis for any association between the primary outcome and specific a priori defined clinical factors at baseline (age >6 years; presence of overweight or obesity; presence of 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).
Results
Between June 8, 2018, to February 13, 2020, 2142 referrals and registrations of interest in the trial were reviewed for eligibility 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 individuals [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.
Figure. Consolidated Standards of Reporting Trials (CONSORT) Diagram.
BMI indicates body mass index; ITT, intention to treat; SDB, sleep-disordered breathing.
Table 1. Baseline Characteristics by Treatment Group.
| Characteristic | Allocation, No. (%) | |
|---|---|---|
| Mometasone | Saline | |
| No. | 138 | 138 |
| Site | ||
| Monash Children’s Hospital | 43 (31.2) | 43 (31.2) |
| Royal Children’s Hospital | 95 (68.8) | 95 (68.8) |
| Sex | ||
| Male | 67 (48.6) | 79 (57.2) |
| Female | 71 (51.4) | 59 (42.8) |
| Age at enrollment, mean (SD), y | 6.2 (2.2) | 6.2 (2.4) |
| BMI percentile,a mean (SD) | 0.6 (0.3) | 0.6 (0.3) |
| Age at onset of SDB, mean (SD), y | 2.3 (1.9) | 2.3 (1.9) |
| Previous intranasal steroid treatment | 28 (20.3) | 22 (15.9) |
| History of asthma | 25 (18.1) | 26 (18.8) |
| Symptoms of AR in last 12 mo | 85 (61.6) | 95 (68.8) |
| Diagnosed with allergic rhinitis | 23 (16.7) | 23 (16.7) |
| Atopy (eczema, asthma, food allergy, or symptoms of AR) | 102 (73.9) | 109 (79.0) |
| Prematurity (<37 wks’ gestational age) | 14 (10.1) | 17 (12.3) |
| At least 1 smoker present in household | 28 (20.3) | 30 (21.7) |
| Maternal ethnicity | ||
| Aboriginal or Torres Strait Islander | 0 | 2 (1.4) |
| African | 10 (7.2) | 3 (2.2) |
| Asian | 25 (18.1) | 29 (21.0) |
| Middle Eastern | 6 (4.3) | 4 (2.9) |
| White | 89 (64.5) | 93 (67.4) |
| Otherb | 8 (5.8) | 7 (5.1) |
| Paternal ethnicity | ||
| Aboriginal or Torres Strait Islander | 0 | 2 (1.4) |
| African | 12 (8.7) | 6 (4.3) |
| Asian | 26 (18.8) | 25 (18.1) |
| Middle Eastern | 6 (4.3) | 4 (2.9) |
| White | 84 (60.9) | 92 (66.7) |
| Otherb | 10 (7.2) | 9 (6.5) |
| Examination findings | ||
| Tonsillar hypertrophy (at least 1 tonsil grade 3 or 4) | 94 (68.1) | 77 (55.8) |
| Friedman palate position III or IV | 43 (31.2) | 42 (30.4) |
| Septal deviation | 14 (10.3) | 28 (20.4) |
| Large turbinate on either side | 71 (51.4) | 69 (50.0) |
| Parent questionnaire | ||
| SDB score, mean (SD) | 1.9 (1.3) | 1.9 (1.2) |
| Parent believes the child needs surgery | 82 (59.4) | 83 (60.6) |
| Parent willing to proceed with surgery | 123 (89.1) | 125 (90.6) |
| Surgery recommended by surgeon consensus | 86 (62.3) | 93 (67.4) |
| OSA 11 score, mean (SD) | 10.9 (5.3) | 10.2 (4.5) |
| OSA 5 score, mean (SD) | 6.2 (3.3) | 5.5 (2.7) |
| OSA 5 ≥ 5 | 89 (64.5) | 84 (60.9) |
| PSQ-SDB score, mean (SD) | 0.5 (0.2) | 0.5 (0.2) |
| PSQ-SDB ≥ 0.33 | 113 (83.1) | 124 (89.9) |
| Total score, mean (SD) | ||
| PedsQL | 74.3 (16.4) | 74.9 (15.3) |
| SDQ | 11.8 (7.4) | 12.3 (6.3) |
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.
Calculated as weight in kilograms divided by height in meters squared.
Other includes Filipino, Pacific Islander, and South American.
At 6 weeks, there were 26 participants lost to follow-up (9.4%; characteristics in eTable 1 in Supplement 3). Using multiple 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 percentage, CIs, and risk difference were calculated using multiple 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, respectively (risk difference, −6%; 95% CI, −18% to 6.1%). Parent assessment of need for surgery at 6 weeks was in favor of surgery in 50% (95% CI, 41%-58%) and 55% (95% CI, 46%-53%) in the mometasone and saline groups, respectively (risk difference, −5%; 95% CI, −17% to 7.5%). There was no significant difference between groups at 6 weeks in symptom scores, quality of life, behavioral function of the child, parent satisfaction with treatment, or the perceived benefit from treatment between the 2 groups (Table 2). There were no significant differences to these results when using available case analysis, shown in eTable 2 in Supplement 3).
Table 2. Primary and Secondary Outcomes at Baseline and After the 6-Week Intervention, by Treatment Group: Using Multiple Imputationa.
| Outcome | Baseline, % | 6 wk, % (95% CI) | Risk difference, % (95% CI)b | Adjusted linear regression, mean difference (95% CI)c | P valueb | ||
|---|---|---|---|---|---|---|---|
| Mometasone (n = 138) | Saline (n = 138) | Mometasone (n = 138) | Saline (n = 138) | ||||
| 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 recommend surgery | 62.3 | 67.4 | 32 (24 to 40) | 38 (29 to 47) | −6 (−18 to 6.1) | NA | NA |
| Parent opinion needs surgery | 59.4 | 60.6 | 50 (41 to 58) | 55 (46 to 64) | −5 (−17 to 7.5) | NA | NA |
| PSQ-SDB, mean (95% CI) | 0.51 (0.48 to 0.54) | 0.53 (0.51 to 0.56) | 0.38 (0.34 to 0.42) | 0.40 (0.36 to 0.44) | NA | 0.00 (−0.05 to 0.05) | NA |
| OSA5, mean (95% CI) | 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 |
| PedsQL total score, mean (95% CI) | 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 |
| SDQ total score, mean (95% CI) | 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 |
| GCBI, mean (95% CI) | NA | NA | 7.8 (4.9 to 11) | 8.6 (5.3 to 12) | NA | −0.8 (−5.2 to 3.5) | NA |
| Parent satisfaction (1-5), mean (95% CI) | 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 |
Abbreviations: GCBI, Glasgow Child Benefit Inventory; NA, not applicable; 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.
Multiple imputation was performed with the assumption that the missing data was missing at random. Multiple imputation models included all variables included in the analysis models as well as baseline variables as auxiliary variables, separately for each treatment arm. A total of 50 completed data sets were imputed using chained imputation including all randomly assigned participants.
Risk difference between treatment arms at 6 weeks using generalized linear model using the binomial family and identity link, adjusted for site.
Mean difference between treatment arms at 6 weeks using linear regression adjusted for site and baseline value of the measured scale.
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 severity of symptoms as measured by previously validated cutoff 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 treatment groups.
AEs were generally mild and were seen in similar numbers between treatment groups (Table 3 and Table 4). AEs of interest were those considered associated with the nasal spray. 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 intervention 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%]).
Table 3. Adverse Events by Treatment Group.
| Adverse events (N = 491) | No.a | |
|---|---|---|
| Mometasone (n = 218) |
Saline (n = 273) |
|
| Nasal bleeding including specks | 39 | 46 |
| Epistaxis (>specks of blood in mucus) | 29 | 34 |
| Specks of blood in the mucus | 10 | 12 |
| Nasal itch/irritation | 16 | 34 |
| Runny nose | 17 | 18 |
| Blocked nose | 5 | 10 |
| Sneezing | 1 | 7 |
| Cough | 11 | 8 |
| Sore throat | 5 | 3 |
| Hoarse voice | 1 | 1 |
| Spray refusal | 1 | 3 |
| Asthma | 4 | 7 |
| Eczema | 3 | 1 |
| Hay fever | 1 | 3 |
| Ear pain/ infection | 2 | 9 |
| Tonsillitis | 7 | 5 |
| LRTI | 4 | 0 |
| URTIb | 49 | 42 |
| Rash (including hives and itchy skin) | 2 | 3 |
| Abdominal complaint (pain, nausea, vomiting, diarrhea, gastroenteritis) | 7 | 27 |
| Fever or viral illness | 4 | 8 |
| Other (eg, leg pain, falls) | 21 | 25 |
Abbreviations: LRTI, lower respiratory tract infection; URTI, upper respiratory tract infection.
Percentages not provided because there could be multiple adverse events per child per group.
Assigned to any episodes with 2 concurrent URTI symptoms (cough, runny nose, sore throat), or any fever with a single URTI symptom.
Table 4. Adverse Events (AEs) of Interest.
| Participants | No. (%) | |
|---|---|---|
| Mometasone (n = 138) |
Saline (n = 138) |
|
| At least 1 AE | ||
| Yes | 93 (67) | 97 (70) |
| No | 31 (22) | 23 (17) |
| Missing AE data | 12 (10) | 18 (13) |
| Adverse event data present (n = 244) | ||
| No. | 124 | 120 |
| Nasal itch/irritation | 12 (9.7) | 22 (18) |
| Epistaxis (≥specks of blood) | 12 (9.7) | 18 (15) |
| Largest volume of bleeding for participant | ||
| Specks of blood only | 3 (2.4) | 5 (4.2) |
| <Teaspoon for all bleeds | 7 (5.6) | 11 (9.2) |
| ≥Teaspoon for at least 1 bleed | 5 (4.0) | 7 (5.8) |
| AE data and epistaxis history data present (n = 108) | ||
| No. | 53 | 55 |
| Epistaxis in those with | ||
| No history of nose bleeds | 0/30 | 1/24 (4) |
| History of bleeding prior to preceding 3 mo | 0/12 | 2/18 (11) |
| History of bleeding within the last 3 mo | 2/10 (20) | 6/13 (46) |
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, respectively, among those with compliance data.
Discussion
The MIST randomized clinical trial found no difference in treatment effect between intranasal mometasone and saline for the management of SDB symptoms. However, we found substantial rates of SDB symptom improvement and substantial reduction 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 results did not support our hypothesis that 6 weeks of daily intranasal 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,14,15,16 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 pooling of the results that there is insufficient evidence for the efficacy of intranasal corticosteroids over placebo for the treatment of OSA in children.27 Another more recent trial17 examining SDB symptoms in snoring children treated with intranasal 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 natural history of the condition. Although the Childhood Andenotonsillectomy 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 condition, the short duration of our trial makes spontaneous resolution less likely. The potential treatment effect of saline could be due to a cleansing of the nasal passages, similar to the observed 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 setting, thus reducing the number of children requiring specialist review.
AEs were reported more frequently in our study than previous 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 bleeding 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 epistaxis is likely to be associated with trauma from the nozzle or spray against an already friable nasal mucosa rather than a corticosteroid effect. It is not clear why there was slightly more observed 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 preexisting 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 results to a broader group of children presenting to primary care with this condition and refers to outcomes perhaps more pertinent to the patient and family.
This study also had some limitations. These include the potential treatment effect of our control arm; however, the inability 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 clinical assessment; however, this allowed for a consensus approach between 2 to 3 surgeons and allowed them to be blinded to visit (baseline or second) while still assessing the same patient at both time points. There is now an opportunity to further 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 effect 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.
Trial Protocol
Statistical Analysis Plan
eTable 1. Baseline Characteristics by Loss to Follow-up
eTable 2. Primary and Secondary Outcomes at Baseline and After the 6-Week Intervention, by Treatment Group, Using All Available Data
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
Statistical Analysis Plan
eTable 1. Baseline Characteristics by Loss to Follow-up
eTable 2. Primary and Secondary Outcomes at Baseline and After the 6-Week Intervention, by Treatment Group, Using All Available Data
Data Sharing Statement