The craniofacial abnormalities found in infants and children with cleft palate (CP) lead to increased risk of obstructive sleep apnoea (OSA). In children and adults sleep position is known to influence the patency of the airway during sleep. Altering sleep position in infants with CP may offer a 'low-cost, high impact' intervention to limit the negative impacts of OSA on child development.

Children with CP are at increased risk of impairment in learning, memory and cognition, with OSA representing an additional risk to cognitive development. Infants with CP are at risk of poor weight gain and 'failure to thrive', which can be further exacerbated by co-existing OSA.

The design and conduct of the proposed randomised controlled trial will benefit from lessons learned from both the feasibility and other previous studies. Investigators demonstrated that existing advice given about sleep position varied significantly with some centres recommending back-lying and others side-lying. Sample size calculations were based on this multi-source data. Parents in the feasibility study knew that sleep position advice for infants with CP changes regularly. They understood why not adhering to 'national guidance' (DoH 2009, Back to Sleep) could be necessary as their infants are "different to normal infants".

How will this study benefit infants with cleft palate and their parents? The proposed study will eliminate the current uncertainty and variability in advice provided to parents of infants with CP, whilst potentially limiting the negative impact of OSA on development. This work has been prioritised and received unanimous support from Cleft Lip and Palate Association (CLAPA), Craniofacial Society Great Britain and Ireland (CFSGBI) and Clinical Nurse Specialists. Aim.To determine the clinical effectiveness in infants with CP of side-lying as compared to back-lying sleep positioning in reducing oxygen desaturation resulting from OSA.

The primary aim of this project is to determine the clinical effectiveness in infants with cleft palate (CP) of side-lying as compared to back-lying sleep positioning in reducing oxygen desaturation resulting from obstructive sleep apnoea (OSA). This will be achieved:

• comparing oxygen saturation during sleep in the side- and back-lying positions at 1 month of age.
• comparing sleep quality between the side-lying and back-lying groups using a parental questionnaire.
• co-developing national recommendations with parents regarding sleep position for infants with CP.

A randomised controlled trial (RCT) of side-lying compared with back-lying sleep positioning in reducing oxygen desaturation resulting from OSA in infants with CP. The design and conduct of the study will benefit from lessons learned from the feasibility and other previous studies. All parents in the feasibility study indicated strong interest to participate in further studies evaluating the effects of sleep position. Infants meeting the eligibility criteria will be randomised to side-lying or back-lying in a ratio 1:1 using a minimisation routine incorporating a random element to reduce predictability. Minimisation factors will be clinical site and syndrome suspected or indicated (yes / no). Allocations will be delivered via a password-protected web-based system. The allocated position will only be used on the day(s) when the infant is monitored for the study purposes. Thereafter, parents will be free to revert back to the standard sleep position as advised by their cleft centre, should it be different than that used for the monitoring period. All centres represented at the preparatory meeting with the United Kingdom (UK) Lead Clinical Nurse Specialist group, confirmed that the side-lying position was recommended in some infants at their centre, irrespective of whether it was the standard advice used. As such, all centres had experience of the side-lying position. It was decided not to change the specific advice that centres give to parents regarding how to position the infant in a side-lying position, but any standard written or verbal information would be collected by the study documents.

An internal pilot will investigate participants' opinions about their participation in the study. Using bespoke questionnaires participants' experience will be assessed and it will be decided how it could be improved. After 6 months questionnaire results will be analysed and if necessary study amendments will be put in place to reflect participants' opinions.

Data from the feasibility study and published studies have reported estimates of the standard deviation (SD) of the primary outcome ODI-4 in the side-lying infants at four weeks to range from 8 to 11 units, with a higher SD observed in the back-lying group. The observed difference in mean ODI-4 between the side-lying and back-lying infant cohorts was 15 units (a standardised effect size of 0.91). Investigators considered a smaller but more realistic difference in means of five units to be a clinically important difference (SD 10), a standardised effect size of 0.5. The sample size calculation comparing two means with unequal variances for the primary outcome was, therefore, based on a standardised effect size of 0.5. To account for potential unequal variances in each group a variance ratio of 2 was used in the calculations. To detect a difference of 0.5 standard deviation score (SDS) with 80% power and alpha equal to 0.05 would require 96 infants to be monitored in each arm of the trial (a total of 192 participants). Informed by the multicentre feasibility and oximetry studies the sample size will be inflated to 244 participants in the RCT, to allow for potential attrition of 21%.

This will follow a pre-specified and approved statistical analysis plan. The primary analysis of the RCT data will use intention-to-treat. Baseline data will be analysed to assess the comparability of the demographic and clinical characteristics of the participants. Data from the trial arms will be compared using generalised linear models and adjusted for minimisation covariates where appropriate. Estimates of treatment effect size will be reported as differences in means for continuous outcomes, and risk ratios for dichotomous outcomes and reported along with 95% confidence intervals. Subgroup analyses will explore the effects of sleep position on infants with and without suspected associated syndromes through subgroup treatment interactions, at a stricter alpha level 0.01.

Inclusion Criteria:

• Infants diagnosed with an isolated CP under the care of a collaborating centre
• Infants who are 3 to 5 weeks of age when monitored
• Parents willing to give consent and able to complete study procedures

Exclusion Criteria:

• Infants with associated cleft lip
• Infants born prematurely (before 37 week gestation or up to and including 36 weeks and 6 days)
• Infants with cardiorespiratory disease
• Infants requiring an intervention to assist with breathing (nasopharyngeal airway)
• Infants requiring an intervention to assist with feeding (nasogastric tube)