Clinical trial NCT04473066: Long-term Follow-up of Children With OSA Treated With AT
Official title: Long-term Follow-up of Children With Obstructive Sleep Apnoea Treated With Adenotonsillectomy: Cardiovascular Perspectives
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Obstructive Sleep Apnea
Keywords: obstructive sleep apnea, adenotonsillectomy, cardiovascular
Lead sponsor: Chinese University of Hong Kong
Sponsor class: OTHER
First posted: 2020-07-16
Enrollment: 180
Sex: ALL
Minimum age (years): 10
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Potential subjects for this follow-up study have been identified from two local hospitals, Prince of Wales Hospital and Kwong Wah Hospital. Since 2012, a total of 193 candidates for AT have been identified, of whom 130 underwent AT, whilst the remaining 63 (33%) preferred more conservative treatment. Non-snoring controls have been identified in several of our previous studies that involved normal controls, including OSA family study and primary snoring follow-up study, and an ongoing study which validates a prediction model for childhood OSA. At the time of writing, a total of 258 non-snoring controls have been identified from various studies since 2012.

Brief summary: Objectives: To assess the cardiovascular outcomes of children with obstructive sleep apnoea (OSA) at a mean of 5 years after they had undergone adenotonsillectomy (AT), compared to OSA children who did not undergo AT, and normal controls without OSA.

Hypothesis to be tested: (1) children with OSA underwent AT would have lower cardiovascular risks, namely lower ambulatory blood pressure (ABP), better cardiac function, lower carotid intima-media thickness (CIMT) and lower carotid arterial thickness when compared to those with OSA but did not undergo AT, and that (2) children with OSA, despite treatment with AT, would have higher cardiovascular risks than non-OSA controls. Design: A two-centre prospective case-control follow-up study Subjects: Potential subjects for this follow-up study have been identified from two local hospitals, Prince of Wales and Kwong Wah Hospitals. AT-treated group (n=90) - Children had moderate-to-severe OSA (obstructive apnoea hypopnoea index (OAHI) \>=3 events/h) and underwent AT when they were aged 5-12 years. Refused AT group (n=45) - Children had moderate-to-severe OSA but refused AT. Non-OSA control group (n=45) - Non-snoring controls with OAHI \<1 event/h . Main outcome measures: 24-hour ABP, cardiac function measured by echocardiography, CIMT and carotid arterial stiffness.

Data analysis: Apart from group comparisons, multiple linear regression and logistic regression analysis will also be used to examine whether cardiovascular outcomes are associated with AT, pre- and post-AT OAHI while adjusted for confounders.

Expected results: AT improves cardiovascular outcomes of children with OSA. However they still had higher cardiovascular risks than normal controls even after AT.

Detailed description: Aims and Hypotheses to be Tested:

The primary aim of this study is to assess cardiovascular outcomes of children with OSA at a mean of 5 years after they had undergone AT, compared to OSA children without surgical treatment and children without OSA. The secondary aim is to explore factors associated with cardiovascular outcomes in subjects with OSA after AT.

We hypothesise that (1) children with OSA underwent AT would have lower cardiovascular risks, namely lower ABP, better cardiac function, lower carotid intima-media thickness (CIMT) and lower carotid arterial stiffness when compared to those with OSA but did not undergo AT, and that (2) children with OSA, despite treatment with AT, would have higher cardiovascular risks than non-OSA controls.

Study design: A two-centre prospective case-control follow-up study.

Sample size estimation:

We have conducted a pilot study to compare 12 children with residual OSA after AT (defined as post-AT OAHI \>=3/h) and 12 age-, sex- and BMI-matched non-snoring controls. The results showed that children with residual OSA had a higher nighttime systolic BP (NSBP) than non-snoring controls (98.9 c.f. 95.6 mm Hg, mean difference = 3.35 mmHg, common SD = 6.54 mmHg, effect size = 0.51). We have a total of 130 subjects with moderate-to-severe OSA who had undergone AT. As the main aim of this study is to assess the treatment effects of AT, we will try to recruit as many AT-treated subjects as possible. Assuming a response rate of 70%, 90 subjects will be recruited. If 45 normal controls were also recruited (case/control ratio = 2:1), the study would provide a power of 87% to detect the difference with a 5% type I error rate. The minimum number of subjects required to detect the difference with an 80% power and a 5% type I error rate are 72 cases and 36 controls if the case/control ratio is 2:1. A sample size of 90 AT-treated subjects will also provide an 80% power to detect the potential effects of pre-AT OAHI and follow-up OAHI on cardiovascular outcomes with medium effect size (assuming a partial R-squared of 0.1), while adjusted for age, sex and BMI in multiple linear regression model within the AT group.

Besides, we have also conducted a separate pilot study comparing a group of 18 children with moderate-to-severe OSA treated with AT and a group of 18 age-, sex- and BMI-matched children with similar OSA severity without AT. The results showed that the nighttime systolic BP in the AT group was reduced by a mean of 2.3 mmHg at a 9-month follow-up visit, whereas the non-AT group had an increase in nighttime systolic BP by a mean of 2.3 mmHg (mean difference = 4.52 mmHg, common SD = 7.34 mmHg, effect size = 0.62). We have a total of 63 candidates for AT who had refused to undergo AT. Assuming a response rate of 70%, 45 subjects will be recruited. A total of 90 cases (AT-treated) and 45 controls (refused AT) provides a power of 95% to detect the expected difference with a type I error rate of 5%. The minimum number of subjects required to detect the difference with an 80% power and a 5% type I error rate are 50 cases and 25 controls if the case/control ratio is 2:1. All sample size and power calculations were done using G\*Power (Version 3.1.9.2).

Our target is to recruit a total of 180 subjects, comprising of 90 OSA subjects treated with AT, 45 non-snoring controls and 45 OSA subjects without AT for this follow-up study. We are confident to recruit the target number of subjects as we have been following up the OSA patients regularly in out-patient clinic and we also have a sufficient amount of normal control subjects for matching and recruitment.

Methods:

All participants will have to visit our unit once to undergo anthropometric measurement, overnight polysomnography (PSG), 24-hour ABPM, echocardiographic and arterial assessments. They will be arranged to come to our sleep laboratory at around 9 am in the morning. Twenty-four hour ABPM will be started after resting for 10 minutes upon arrival. Echocardiographic and arterial assessments will be subsequently arranged. They will stay until the next morning after completion of overnight sleep study and 24-h ABPM. For those who are reluctant to complete the whole study protocol, especially for control subjects who may not be willing to stay overnight for the sleep study, their symptoms will be documented by a self- or parent-report questionnaire (appendix 2), and they will have to come to our unit to undergo all the cardiovascular assessments and take the ABP monitor back home and return to us the next day when the 24-h monitoring is completed. Those failed to complete all the outcome assessments will be excluded.

Data processing and analysis:

The AT-treated group will be compared to the refused AT group and the non-snoring controls to assess the between-group differences in various cardiovascular outcomes. Student's t tests, Mann-Whitney U tests and chi-square tests will be used for the comparisons of normally distributed, non-normally distributed and categorical data, respectively. Linear and logistic regression analysis will be used to test whether OSA severity at baseline and follow-up and AT are associated with continuous (e.g. CIMT) and binary (e.g. hypertension) cardiovascular outcomes, respectively, while adjusting for age, gender and body size. Subgroup analysis will also be performed within the AT-treated group to explore factors associated with cardiovascular outcomes after AT. Particularly, the association of pre-AT and follow-up OAHI with various cardiovascular outcomes will be tested. Significance level will be set as 5%. All the analyses will be performed using the statistical software packages SPSS (SPSS Inc., Chicago, Illinois, USA).

Eligibility criteria: General inclusion criteria:

* Participants and their parents must understand Chinese;
* Aged 5-12 years at diagnosis.

Inclusion criteria for AT group:

* Previously diagnosed with moderate-to-severe OSA (OAHI ≥3/h);
* Tonsillar hypertrophy (tonsil grade ≥2);
* Underwent AT.

Inclusion criteria for Refused AT group:

* Previously diagnosed with moderate-to-severe OSA (OAHI ≥3/h);
* Tonsillar hypertrophy (tonsil grade ≥2);
* Refused AT.

Inclusion criteria for Normal Control group:

* Previously confirmed to have no OSA (OAHI \<1/h);
* Reported to have no habitual snoring (less than 3 nights per week).

Exclusion Criteria:

* Additional upper airway surgery other than the one done at baseline visit;
* Known medical conditions that affects the cardiovascular system;
* Any use of medications that alters cardiovascular system.

Primary outcomes:
measure: 24-hour ambulatory blood pressure measurements
timeFrame: At a mean of 5 years after intervention
measure: Cardiac function
timeFrame: At a mean of 5 years after intervention
measure: Carotid intima-media thickness
timeFrame: At a mean of 5 years after intervention
measure: Arterial stiffness
timeFrame: At a mean of 5 years after intervention
Secondary outcomes:
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Department of Paediatrics, Kwong Wah Hospital
state: Kowloon
city: Sha Tin
country: Hong Kong
facility: Department of Paediatrics, The Chinese University of Hong Kong
Study officials:
affiliation: junau@cuhk.edu.hk
name: Chun Ting Au, PhD
role: PRINCIPAL_INVESTIGATOR
References: