Prevention of Morbidity in Sickle Cell Disease Phase II (Improvement of Pain and Quality of Life in Children with Sickle Cell Disease with Auto-adjusting Continuous Positive Airways Pressure: Phase II) (POMS 2b pediatric cohort)

Abstract

Background: In addition to pain, sickle cell anaemia (HbSS) complications include neurocognitive difficulties in attention and processing speed associated with low daytime and night-time oxygen saturation. These effects can be compounded by obstructive sleep apnoea (OSA). Continuous Positive Airways Pressure (CPAP) is an accepted treatment for OSA in the general population. However, supplementary oxygen therapy in SCA may lead to bone marrow suppression. The aim of this single-blind, randomised, controlled phase II trial is to compare Auto-adjusting CPAP (APAP) with standard care to standard care alone in subjects with HbSS to determine whether the intervention is safe and improves attention and processing speed and brain structure.

Methods: Eligibility criteria included ability to provide informed consent, age >8 and <16 years, diagnosis of HbSS and mean overnight saturation of <90% for <30% of the night. Key exclusion criteria were overnight respiratory support, respiratory or decompensated cardiac failure, chronic transfusion or contra-indications to APAP therapy or MRI.

Minimisation factors were age group (8-11, 12-15), silent infarction on MRI, minimum overnight oxygen saturation > or < 90%, and hydroxyurea (HU) use.

APAP adherence was defined as using APAP for an average of 4 hours a night for >50% of the time and was recorded using software documenting hours of use each night. Participant support in terms of appropriate facemask and facilitating adherence were provided by an unblinded sleep physiologist.

Full blood counts were obtained at baseline, 2 weeks, 3 months and 6 months.

Data were analysed by intention-to-treat. The primary outcome is change in the cancellation subtest from the Wechsler scales, and secondary outcomes include general cognitive functioning, assessed at baseline and after 6 months of treatment by assessors blind to treatment assignment. Analysis of Covariance (ANCOVA) models, adjusted for minimisation factors, were used to calculate least-square mean changes from baseline to 6 months.

Results: 30 children with HbSS were randomised to standard care + APAP (n=15) or standard care alone (n=15) for 6 months. One child in the standard care arm withdrew after 6 weeks, and 8 children in the APAP arm were not adherent to treatment. There was no difference in hemoglobin change between the arms, but hydroxyurea use was associated with an increase in haemoglobin (p=0.01). Increase in cancellation score was numerically greater in the APAP arm (mean 1.46, SE 0.59 vs 1.01, SE 0.61) but this was not significant (mean difference 0.44, 95% CI: -1.42; 2.31; p=0.626). Increase in cancellation score was greater (mean 2.63; 95%CI: 0.95, 4.30) in those whose adherence was in the highest quartile (> 2.4 hours/night) compared with the other 3 quartiles (mean 0.71, 95%CI: -0.32, 1.75; mean difference 1.91, 95%CI: -0.06, 3.88; p=0.057). In subjects assigned to APAP, cancellation scores were significantly higher with hydroxyurea use (p=0.01). There were 7 subjects with serious adverse events in the placebo group, compared to 3 in the APAP group, all related to SCD pain. There was no evidence of decline in haemoglobin in either group.

Discussion: APAP for 6 months is safe, and feasible in children with SCA but although >50% were not adherent by the pre-defined definition, those who were compliant appeared to have more benefit in terms of attention/processing speed. If delivery of the intervention can be improved, avoidance of oxygen desaturation with overnight respiratory support may play a role in improving cognition in SCD.

Trial registration: ISRCTN 46012373 10^th July 2015

Protocol Version: 6.0 Date: 24th December 2015

Sponsor: University Hospital Southampton Sponsor's protocol code: RHMCHIOT53

Keywords Sickle Cell Anaemia; haemoglobin oxygen saturation; Auto-adjusting Continuous Positive Airways Pressure; Cancellation; Attention; Processing speed