Intranasal Steroid as Medical Therapy For Sleep-Disordered Breathing in Children (MIST+)

Efficacy of Intranasal Steroid for Children With Sleep-Disordered Breathing Non-Responsive to Initial Treatment With Intranasal Saline: A Randomized Trial

MIST+ is studying a nasal spray to see if it will reduce the need for surgery for snoring. Children aged 3-12 are invited to take part. Snoring affects up to 10% of children and can cause sleeping problems and concentration or behavioural issues in the daytime. Currently the most common treatment for snoring is surgery to remove the tonsils and/or adenoids, however many children wait a long time to see a specialist. This research is trying to find if nasal sprays can help children with snoring, and whether this can reduce the need for surgery.

Study Overview

• Status: Recruiting
• Conditions: Snoring; Tonsillar Hypertrophy; Sleep Disorder; Breathing-Related; Obstructive Sleep Apnea of Child; Sleep Disorders in Children; Adenoidal Disorder
• Intervention / Treatment: Drug: Mometasone Furoate 50mcg Nasal Spray; Drug: Sodium Chloride 0.9 % Nasal Spray

Detailed Description

MIST+ is a multi centre, double-blind, placebo controlled trial. Children 3-12 years of age, who do not respond to a run-in phase of 6 weeks of normal saline intranasal spray to treat sleep disordered breathing, will be randomised 1:1 to a treatment phase of either intranasal corticosteroid (investigational product) or normal saline (placebo). Participants will receive treatment for 6 weeks and receive follow up at at 12 weeks, 6, and 12 months.

• Study Type: Interventional
• Enrollment (Estimated): 154
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Kirsten Perrett; Phone Number: 61399366278; Email: kirsten.perrett@rch.org.au
• Study Contact Backup: Name: Deborah Anderson; Phone Number: 61383416432; Email: deborah.anderson@mcri.edu.au

Study Locations

• Australia
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Recruiting
      • Monash Children's Hospital
      • Contact: Gillian Nixon; Phone Number: 0385723592; Email: gillian.nixon@monashhealth.org
      • Principal Investigator: Gillian Nixon
    • Parkville, Victoria, Australia, 3052
      • Recruiting
      • Royal Children's Hospital / Murdoch Children's Research Institute
      • Contact: Kirsten Perrett; Phone Number: 0399366278; Email: kirsten.perrett@rch.org.au
      • Contact: Deborah Anderson; Phone Number: 0383416432; Email: deborah.anderson@mcri.edu.au
      • Principal Investigator: Kirsten Perrett

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 12 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Each participant must meet all of the following criteria to be enrolled in this trial:

• Is between the ages of 3 and 12 years inclusive at the time of randomisation
• Has symptoms of Sleep Disordered Breathing (SDB) as determined by a Brouillette score ≥ -1 on telehealth/phone screening
• Has a legally acceptable representative capable of understanding the informed consent document and providing consent on the participant's behalf.

Exclusion Criteria:

Participants meeting any of the following criteria will be excluded from the study:

• Has a BMI over the 97th centile for age and gender
• Has a history of tonsillectomy and/or adenoidectomy
• Has a prior diagnosis of craniofacial, neuromuscular, syndromic or defined genetic disorders
• Has a history of haemorrhagic diathesis or recurrent (daily) or severe epistaxis
• Has a history of nasal surgery or trauma which has not fully healed
• Has active tonsillitis or nasal infection (must be resolved prior to randomisation)
• Is assessed to have stertor (snoring) while awake at rest
• Has a known hypersensitivity to the study drug or its formulation
• Has used oral, intravenous, or intranasal steroids in the past 6 weeks. (Inhaled steroids for asthma will be allowed concomitantly during the study)
• Daily use of antihistamine or decongestant nasal sprays
• Is known to require systemic steroids prior to the completion of the study treatment phase
• Has had treatment with any other investigational drug within 6 months prior to randomisation
• Is unable to provide consent without the aid of an interpreter.
• In the opinion of the Investigator may be unable to follow the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Intranasal Saline	Drug: Sodium Chloride 0.9 % Nasal Spray; Intranasal saline spray (Sodium Chloride 0.9%) one spray each nostril daily for 6 weeks; Other Names: Intranasal Saline Spray
Experimental: Intranasal Steroids	Drug: Mometasone Furoate 50mcg Nasal Spray; Intranasal steroid (Mometasone Furoate 50mcg) one spray each nostril daily for 6 weeks; Other Names: Sensease Nasal Allergy Relief Nasal Spray

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of participants with resolution of significant Sleep Disordered Breathing (SDB) symptoms as defined by the parent completed Brouillette questionnaire </=-1 at 6 weeks	The Brouillette questionnaire is a validated symptom questionnaire that investigates the presence of respiratory sleep disorders and the frequency of apnoea and pathological snoring. Each item is scored from 0 to 3 (0 = absence of symptoms, 1 = occasional symptoms, 2 = frequent symptoms, and 3 = constant symptoms), and the overall score is directly proportional to disease severity. The proportion of participants in each treatment arm with resolution of symptoms at 6 weeks will be calculated with 95% confidence intervals (CIs). The treatment arms will be compared using a Mantel Haenszel chi-squared test.	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of participants with resolution of significant Sleep Disordered Breathing (SDB) symptoms as defined by the parent completed Brouillette questionnaire < -1 at 12 weeks	The Brouillette questionnaire is a validated symptom questionnaire that investigates the presence of respiratory sleep disorders and the frequency of apnoea and pathological snoring. Each item is scored from 0 to 3 (0 = absence of symptoms, 1 = occasional symptoms, 2 = frequent symptoms, and 3 = constant symptoms), and the overall score is directly proportional to disease severity. The proportion of participants in each treatment arm with resolution of symptoms at 12 weeks will be calculated with 95% confidence intervals (CIs). The treatment arms will be compared using a Mantel Haenszel chi-squared test.	12 weeks
An improvement of score in parent completed Pediatric Sleep Questionnaire-sleep disordered breathing subscale (PSQ-SDB subscale) at week 6 when compared with baseline measured at the start of the intervention period (week 0)	The Pediatric Sleep Questionnaire - sleep disordered breathing subscale is a validated questionnaire which contains 22 symptom items that ask about snoring frequency, loud snoring, observed apneas, difficulty breathing during sleep, daytime sleepiness, inattentive or hyperactive behaviour, and other paediatric Obstructive Sleep Apnoea (OSA) features. Responses are "yes" = 1, "no" = 0, and "don't know"=missing. The mean scores and 95% confidence intervals (CIs) in the two treatment arms will be calculated and the treatment arms will be compared using a linear regression adjusted for centre.	6 weeks
An improvement of score in parent completed Obstructive Sleep Apnoea-18 (OSA-18) questionnaire at week 6 when compared with baseline measured at the start of intervention period (week 0).	The Obstructive Sleep Apnoea-18 (OSA-18) questionnaire is a validated questionnaire and consists of 18 questions concerning sleep disturbances, physical symptoms, emotional distress, daytime function, and caregiver concerns. The mean scores and 95% confidence intervals (CIs) in the two treatment arms will be calculated and the treatment arms will be compared using a linear regression adjusted for centre.	6 weeks
An improvement of score in parent completed Pediatric Quality of Life Inventory (PedsQL) at week 6 when compared with baseline measured at the start of the intervention period (week 0).	The Pediatric Quality of Life Inventory (PedsQL) is a validated, standardised, generic assessment instrument that provides a modular approach to measure health related quality of life in healthy children and adolescents and those with acute and chronic disorders. This questionnaire consists of 23 items evaluating physical, emotional, social and scholastic functioning, and it integrates both generic core scales and disease-specific modules. The mean scores and 95% confidence intervals (CIs) in the two treatment arms will be calculated and the treatment arms will be compared using a linear regression adjusted for centre.	6 weeks
An improvement of score in parent completed Strengths and Difficulties Questionnaire (SDQ) at week 6 when compared with baseline measured at the start of the intervention period (week 0).	The Strengths and Difficulties Questionnaire (SDQ) is a validated brief behavioural screening questionnaire about 3-16 year olds. The mean scores and 95% confidence intervals (CIs) in the two treatment arms will be calculated and the treatment arms will be compared using a linear regression adjusted for centre.	6 weeks
An improvement of score in parent completed Glasgow Children's Benefit Inventory (GCBI) at week 6 when compared with baseline measured at the start of the intervention period (week 0).	The Glasgow Children's Benefit Inventory (GCBI) consists of 24 questions on the consequences of a specified intervention on various aspects of the day-to-day child life, without reference to any specific symptoms, and it can be apply to children of any age. The mean scores and 95% confidence intervals (CIs) in the two treatment arms will be calculated and the treatment arms will be compared using a linear regression adjusted for centre.	6 weeks
Proportion of parent responders who think their child needs surgery to remove their tonsils or adenoids (T&A) at 6 weeks	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study. "Do you think your child needs surgery to remove their tonsils or adenoids (T&A)?"	6 weeks
Proportion of parent responders who think their child needs surgery to remove their tonsils or adenoids (T&A) at 12 weeks	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study. "Do you think your child needs surgery to remove their tonsils or adenoids (T&A)?"	12 weeks
Proportion of parent responders who think their child needs surgery to remove their tonsils or adenoids (T&A) at 6 months	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study. "Do you think your child needs surgery to remove their tonsils or adenoids (T&A)?"	6 months
Proportion of parent responders who would be happy to proceed with tonsils and adenoids surgery (T&A) if recommended to them at 6 weeks	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study. "If T&A surgery were recommended to you now, would you be happy to proceed?"	6 weeks
Proportion of parent responders who would be happy to proceed with tonsils and adenoids (T&A) surgery if recommended to them at 12 weeks	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study: "If T&A surgery were recommended to you now, would you be happy to proceed?"	12 weeks
Proportion of parent responders who would be happy to proceed with tonsils and adenoids (T&A) surgery if recommended to them at 6 months	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study: "If T&A surgery were recommended to you now, would you be happy to proceed?"	6 months
Proportion of parent responders who would be happy to proceed with tonsils and adenoids (T&A) surgery if recommended to them at 12 months	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study: "If T&A surgery were recommended to you now, would you be happy to proceed?"	12 months
Proportion of parents who think their child still needs a review by a hospital specialist at 6 weeks	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study: "Do you think your child's symptoms need review by a hospital specialist?"	6 weeks
Proportion of parents who think their child still needs a review by a hospital specialist at 12 weeks	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study: "Do you think your child's symptoms need review by a hospital specialist?"	12 weeks
Proportion of parents who think their child still needs a review by a hospital specialist at 6 months	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study: "Do you think your child's symptoms need review by a hospital specialist?"	6 months
Proportion of parents who think their child still needs a review by a hospital specialist at 12 months	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study: "Do you think your child's symptoms need review by a hospital specialist?"	12 months
Proportion of parents who would be happy to have their child taken off the hospital clinic waiting list at 6 weeks	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study: "Would you be happy to have your child taken off the hospital clinic waiting list?"	6 weeks
Proportion of parents who would be happy to have their child taken off the hospital clinic waiting list at 12 weeks	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study: "Would you be happy to have your child taken off the hospital clinic waiting list?"	12 weeks
Proportion of parents who would be happy to have their child taken off the hospital clinic waiting list at 6 months	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study: "Would you be happy to have your child taken off the hospital clinic waiting list?"	6 months
Proportion of parents who would be happy to have their child taken off the hospital clinic waiting list at 12 months	This will be measured by asking parents the following question on a parent assessment questionnaire developed for the study: "Would you be happy to have your child taken off the hospital clinic waiting list?"	12 months
Parent satisfaction with run-in phase and treatment phase therapy as an alternative to tonsillectomy and/or adenoidectomy at 6 weeks (Likert Scale)	A study specific questionnaire using a 5 point Likert Scale will be used to evaluate parent satisfaction of ease of administration of drug, effectiveness of treatment, side effects. A higher score will indicate higher satisfaction. The mean scores and 95% confidence intervals in the two arms will be calculated and the treatment arms will compared using a linear regression adjusted for center.	6 weeks
Parent satisfaction with run-in phase and treatment phase therapy as an alternative to tonsillectomy and/or adenoidectomy at 12 weeks (Likert Scale)	A study specific questionnaire using a 5 point Likert Scale will be used to evaluate parent satisfaction of ease of administration of drug, effectiveness of treatment, side effects. A higher score will indicate higher satisfaction. The mean scores and 95% confidence intervals in the two arms will be calculated and the treatment arms will compared using a linear regression adjusted for center.	12 weeks
Progression to Tonsillectomy and/or Adenoidectomy for Sleep Disordered Breathing (SDB) defined by Ear Nose Throat (ENT) surgery at 6 months	Parents will be contacted by email with a short survey to record whether their child is either on a waitlist for ENT surgery or has undergone ENT surgery. The proportion of participants in each treatment arm who have progressed to Tonsillectomy and/or Adenoidectomy for SDB will be calculated with 95% confidence intervals. The treatment arms will be compared using a Mantel Haenszel chi-squared test.	6 months
Progression to Tonsillectomy and/or Adenoidectomy for Sleep Disordered Breathing defined by ENT surgery at 12 months	Parents will be contacted by email with a short survey to record whether their child is either on a waitlist for ENT surgery or has undergone ENT surgery. The proportion of participants in each treatment arm who have progressed to Tonsillectomy and/or Adenoidectomy for SDB will be calculated with 95% confidence intervals. The treatment arms will be compared using a Mantel Haenszel chi-squared test.	12 months
Progression to Tonsillectomy and/or Adenoidectomy for Sleep Disordered Breathing (SDB) based on symptoms of SDB reported in parent-completed Brouillette questionnaire at 6 months	The Brouillette questionnaire is a validated symptom questionnaire that investigates the presence of respiratory sleep disorders and the frequency of apnoea and pathological snoring. Each item is scored from 0 to 3 (0 = absence of symptoms, 1 = occasional symptoms, 2 = frequent symptoms, and 3 = constant symptoms), and the overall score is directly proportional to disease severity. The proportion of participants in each treatment arm with resolution of symptoms at 6 months will be calculated with 95% confidence intervals (CIs). The treatment arms will be compared using a Mantel Haenszel chi-squared test.	6 months
Progression to Tonsillectomy and/or Adenoidectomy for Sleep Disordered Breathing (SDB) based on symptoms of SDB reported in parent-completed Brouillette questionnaire at 12 months.	The Brouillette questionnaire is a validated symptom questionnaire that investigates the presence of respiratory sleep disorders and the frequency of apnoea and pathological snoring. Each item is scored from 0 to 3 (0 = absence of symptoms, 1 = occasional symptoms, 2 = frequent symptoms, and 3 = constant symptoms), and the overall score is directly proportional to disease severity. The proportion of participants in each treatment arm with resolution of symptoms at 12 months will be calculated with 95% confidence intervals (CIs). The treatment arms will be compared using a Mantel Haenszel chi-squared test.	12 months
Progression to Tonsillectomy and/or Adenoidectomy for Sleep Disordered Breathing (SDB) based on symptoms of SDB reported in parent-completed Pediatric Quality of Life Inventory (PedsQL) at 6 months	The Pediatric Quality of Life Inventory (PedsQL) is a validated, standardised, generic assessment instrument that provides a modular approach to measure health related quality of life in healthy children and adolescents and those with acute and chronic disorders. This questionnaire consists of 23 items evaluating physical, emotional, social and scholastic functioning, and it integrates both generic core scales and disease-specific modules. The proportion of participants in each treatment arm with resolution of symptoms at 6 months will be calculated with 95% confidence intervals (CIs). The treatment arms will be compared using a Mantel Haenszel chi-squared test.	6 months
Progression to Tonsillectomy and/or Adenoidectomy for Sleep Disordered Breathing (SDB) based on symptoms of SDB reported in parent-completed Pediatric Quality of Life Inventory (PedsQL) at 12 months	The Pediatric Quality of Life Inventory (PedsQL) is a validated, standardised, generic assessment instrument that provides a modular approach to measure health related quality of life in healthy children and adolescents and those with acute and chronic disorders. This questionnaire consists of 23 items evaluating physical, emotional, social and scholastic functioning, and it integrates both generic core scales and disease-specific modules. The proportion of participants in each treatment arm with resolution of symptoms at 12 months will be calculated with 95% confidence intervals (CIs). The treatment arms will be compared using a Mantel Haenszel chi-squared test.	12 months
Progression to Tonsillectomy and/or Adenoidectomy for Sleep Disordered Breathing (SDB) based on treatment for Sleep Disordered Breathing (SDB) at 6 months	Parents will be emailed a survey with the following questions about any treatment their child may have had for SDB; Specialty of Dr seen and number of appointments; Medical Treatment used, and duration of treatment The study team will describe additional treatment received by the treatment arm and investigate and describe any imbalance by the treatment arm.	6 months
Progression to Tonsillectomy and/or Adenoidectomy for Sleep Disordered Breathing (SDB) based on treatment for Sleep Disordered Breathing (SDB) at 12 months.	Parents will be asked the following questions about any treatment their child may have had for SDB; Specialty of Dr seen and number of appointments; Medical Treatment used, and duration he study team will describe additional treatment received by the treatment arm and investigate and describe any imbalance by the treatment arm. of treatment	12 months
Number of adverse events (AEs) throughout the treatment phase	Participants will also be asked questions about hospitalisation, accidents, new or changed medications. In addition AE's will be documented from physical examination findings, clinically significant lab results or other documents (including diaries where solicited AE's are prompted and correspondence from their primary care physician) that are relevant to participant safety. Adverse events and adverse reactions (non-serious or serious will be captured) The number of AEs will be summarised and listed in each of the treatment arms.	6 weeks
Number of adverse events (AEs) within the first week of the treatment	Participants will also be asked questions about hospitalisation, accidents, new or changed medications. In addition AE's will be documented from physical examination findings, clinically significant lab results or other documents (including diaries where solicited AE's are prompted and correspondence from their primary care physician) that are relevant to participant safety. Adverse events and adverse reactions (non-serious or serious will be captured) The number of AEs will be summarised and listed in each of the treatment arms.	1 week
Compliance of medical therapy measured by weight of sent and returned bottles of medication	Bottles will be weighed before they are given to participants and weighed when they are returned. The amount used will be calculated and used to determine if the participant was compliant with dosing. The amount of one spray of medication will be measured to allow for compliance to be calculated. Compliance with treatment will be calculated as the proportion of prescribed doses over 6 weeks that was consumed based on the weight of the bottles. The mean compliance will be summarised for the run-in period and both treatment arms. The proportion of participants with 80% and more compliance will be given for each treatment arm. The amount of one spray of medication will be measured to allow for compliance to be calculated.	-6 weeks and 6 weeks (start of run-in phase to end of treatment phase)
Clinical factors at baseline that are associated with response to interventions, based on statistical analysis	Logistical regression models will be fitted to determine whether clinical factors at baseline or severity of SDB symptoms at baseline were associated with response to the intervention. Treatment arm, the symptom or factor of interest, and the interaction between the treatment arm and the symptom or factor will be included in this model. Symptoms or factors of interest include demographic factors, severity of SDB at baseline, history of atopy and history of tonsillitis.	6 weeks

Collaborators and Investigators

• Sponsor: Murdoch Childrens Research Institute
• Collaborators: Royal Children's Hospital; Monash Health
• Investigators: Principal Investigator: Kirsten Perrett, Murdoch Children's Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: May 16, 2022
• First Submitted That Met QC Criteria: May 16, 2022
• First Posted (Actual): May 19, 2022

Study Record Updates

• Last Update Posted (Actual): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Neurologic Manifestations; Pathological Conditions, Anatomical; Signs and Symptoms, Respiratory; Respiratory Sounds; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Sleep Wake Disorders; Respiratory Aspiration; Parasomnias; Snoring; Hypertrophy; Anti-Inflammatory Agents; Dermatologic Agents; Anti-Allergic Agents; Mometasone Furoate
• Other Study ID Numbers: RCH HREC 81746

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The de-identified data set that will be collected for this analysis of the MIST+ trial will be available six months after publication of the primary outcome. The study protocol may be obtained from the Murdoch Children's Research Institute. Prior to releasing any data, the following are required: a data access agreement must be signed between relevant parties; the MIST+ trial investigators must see and approve the analysis plan describing how the data will be analysed; there must be an agreement around appropriate acknowledgment; and any additional costs involved must be covered.

Should the study investigators be unavailable, this role is delegated to the Murdoch Children's Research Institute. Data will only be shared with a recognised research institute, which has approved the proposed analysis plan.

• IPD Sharing Time Frame: Six months after the publication of the primary outcome
• IPD Sharing Access Criteria: Prior to releasing any data, the following are required: a data access agreement must be signed between relevant parties; the MIST+ trial investigators must see and approve the analysis plan describing how the data will be analysed; there must be an agreement around appropriate acknowledgment; and any additional costs involved must be covered.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No