Prevention of Morbidity in Sickle Cell Disease (POMS2a)-overnight auto-adjusting continuous positive airway pressure compared with nocturnal oxygen therapy: a randomised crossover pilot study examining patient preference and safety in adults and children.

DESIGN: This randomised crossover trial compared nocturnal auto-adjusting continuous positive airway pressure (APAP) and nocturnal oxygen therapy (NOT) in adults and children with sickle cell anaemia, with patient acceptability as the primary outcome. Secondary outcomes included pulmonary physiology (adults), safety, and daily pain during interventions and washout documented using tablet technology. METHODS: Inclusion criteria were age > 8 years and the ability to use an iPad to collect daily pain data. Trial participation was 4 weeks; week 1 involved baseline data collection and week 3 was a washout between interventions, which were administered for 7 days each during weeks 2 and 4 in a randomised order. Qualitative interviews were transcribed verbatim and analysed for content using a funnelling technique, starting generally and then gaining more detailed information on the experience of both interventions. Safety data included routine haematology and median pain days between each period. Missing pain day values were replaced using multiple imputation. RESULTS: Ten adults (three female, median age 30.2 years, range 18-51.5 years) and eleven children (five female, median age 12 years, range 8.7-16.9 years) enrolled. Nine adults and seven children completed interviews. Qualitative data revealed that the APAP machine was smaller, easier to handle, and less noisy. Of 16 participants, 10 preferred APAP (62.5%, 95% confidence interval (CI) 38.6-81.5%). Haemoglobin decreased from baseline on APAP and NOT (mean difference -3.2 g/L (95% CI -6.0 to -0.2 g/L) and -2.5 g/L (95% CI -4.6 to 0.3 g/L), respectively), but there was no significant difference between interventions (NOT versus APAP, 1.1 (-1.2 to 3.6)). Pulmonary function changed little. Compared with baseline, there were significant decreases in the median number of pain days (1.58 for APAP and 1.71 for NOT) but no significant difference comparing washout with baseline. After adjustment for carry-over and period effects, there was a non-significant median difference of 0.143 (95% CI -0.116 to 0.401) days additional pain with APAP compared with NOT. CONCLUSION: In view of the point estimate of patient preference for APAP, and no difference in haematology or pulmonary function or evidence that pain was worse during or in washout after APAP, it was decided to proceed with a Phase II trial of 6 months APAP versus standard care with further safety monitoring for bone marrow suppression and pain. TRIAL REGISTRATION: ISRCTN46078697 . Registered on 18 July 2014

Prevention of Morbidity in sickle cell disease - qualitative outcomes, pain and quality of life in a randomised cross-over pilot trial of overnight supplementary oxygen and auto-adjusting continuous positive airways pressure (POMS2a):Study protocol for a randomised controlled trial

BACKGROUND: Sickle cell anaemia (SCA) is an inherited disorder of haemoglobin. Patients experience long-term health care problems, affecting quality of life (QOL) including frequent acute pain, which is difficult to document in trials except as hospital admissions. Pilot data suggests that overnight respiratory support, either supplementary oxygen or auto-adjusting continuous positive airways pressure (APAP), is safe and may have clinical benefit. This pilot trial aims to determine which intervention is more acceptable to participants and whether there are other advantages of one over the other, e.g. in respiratory function or haematological parameters, before conducting the Phase 2 trial of overnight respiratory support funded by the National Institutes of Health Research.METHODS/DESIGN: This is a pilot cross-over interventional trial with the order of interventions decided by simple randomization. Ten adults (age over 18 years) and 10 children (aged between 8 and 18 years) with homozygous sickle cell disease (haemoglobin SS, HbSS), recruited regardless of symptoms of sleep-disordered breathing, will undergo overnight pulse oximetry and will have two interventions, overnight oxygen and APAP, for a week each in randomised order with a washout week between interventions. Participants will complete online diaries via an iPad throughout the 29 days of the study and will complete QOL questionnaires and have measurement of haematology, biochemistry, spirometry and lung volumes (adults only) at 3 time points, at baseline and after each intervention, as well as in-depth semi-structured qualitative interviews after each intervention, carried out by an experienced psychologist. Both qualitative and statistical methods will be used to analyze the data. The primary outcome is qualitative data looking at participant experience from the transcribed interviews after each intervention. The participant's view on feasibility, acceptability and preference will specifically be explored. The QOL, laboratory and lung function data will be compared with baseline for each arm.DISCUSSION: Patient and public involvement is an integral part of this trial and the key outcome is the qualitative result, which is dependent on obtaining good quality data to advise on participant feasibility, acceptability and preference. This is being addressed by using a standard interview. The development of a pain endpoint is another important outcome and collecting daily measurements is likely to be challenging. Research results will be used to inform design of the Phase 2 trial.TRIAL REGISTRATION: ISRCTN46078697 18 July 2014

Prevention of Morbidity in Sickle Cell Disease Phase II (Improvement of Cognition in children with Sickle Cell Disease with Auto-adjusting Continuous Positive Airways Pressure: Phase II) (POMS 2b paediatric cohort)

Background: Complications in sickle cell anemia (SCA, HbSS) 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 apnea (OSA).However, there is concern that oxygen supplementation in SCA may lead to bone marrow suppression. Continuous Positive Airways Pressure (CPAP) is an accepted treatment for OSA in the general population and prevents dips in oxygen saturation.. 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 Cancellation, a measure of selective attention and processing speed. 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/stratification factors were age group (8-11, 12-15 years), silent infarction on MRI, minimum overnight oxygen saturation >90% 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 (18 boys; median age 12.5; range 7.9-16 years) with SCA were randomised to standard care + APAP (n=15) or standard care alone (n=15) for 6 months. One child in the standard care alone arm withdrew after 6 weeks, and 8 children in the APAP arm were not adherent to treatment. 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 was no evidence of decline in haemoglobin in either group; hydroxyurea use was associated with an increase in haemoglobin (p=0.01). There were 7 subjects with serious adverse events in the standard care alone arm, compared to 3 in the APAP + standard care arm, all related to hospital admission for pain. Discussion: APAP for 6 months is feasible and safe in children with SCA. Alhough >50% were not adherent by the pre-defined definition, those who were compliant appeared to have more benefit in terms of improvement in attention/processing speed. There appears to be an interaction with HU use, consistent with the importance of oxygen supply and carriage for brain function. If delivery of the intervention can be improved, avoidance of oxygen desaturation with overnight respiratory support alongside HU use may play a role in improving cognition in SCD. Disclosures: No relevant conflicts of interest to declare

Prevention of morbidity in sickle cell disease phase II (Improvement of cognition in children with Sickle Cell Disease with auto-adjusting Continuous Positive Airways Pressure: Phase II) (POMS 2b paediatric cohort)

Background: Complications in sickle cell anemia (SCA, HbSS) 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 apnea (OSA).However, there is concern that oxygen supplementation in SCA may lead to bone marrow suppression. Continuous Positive Airways Pressure (CPAP) is an accepted treatment for OSA in the general population and prevents dips in oxygen saturation.. 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 Cancellation, a measure of selective attention and processing speed. 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/stratification factors were age group (8-11, 12-15 years), silent infarction on MRI, minimum overnight oxygen saturation >90% 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 (18 boys; median age 12.5; range 7.9-16 years) with SCA were randomised to standard care + APAP (n=15) or standard care alone (n=15) for 6 months. One child in the standard care alone arm withdrew after 6 weeks, and 8 children in the APAP arm were not adherent to treatment. 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 was no evidence of decline in haemoglobin in either group; hydroxyurea use was associated with an increase in haemoglobin (p=0.01). There were 7 subjects with serious adverse events in the standard care alone arm, compared to 3 in the APAP + standard care arm, all related to hospital admission for pain. Discussion: APAP for 6 months is feasible and safe in children with SCA. Alhough >50% were not adherent by the pre-defined definition, those who were compliant appeared to have more benefit in terms of improvement in attention/processing speed. There appears to be an interaction with HU use, consistent with the importance of oxygen supply and carriage for brain function. If delivery of the intervention can be improved, avoidance of oxygen desaturation with overnight respiratory support alongside HU use may play a role in improving cognition in SCD. Disclosures: No relevant conflicts of interest to declare

Whose voice?: an exploration of the current policy interest in pupil involvement in school decision-making

Personal cover image 1: Study logo. (DOC 21 kb

Overnight auto-adjusting continuous airway pressure + standard care compared with standard care alone in the prevention of morbidity in sickle cell disease phase II (POMS2b): study protocol for a randomised controlled trial

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 compounded by obstructive sleep apnoea (OSA). In the general population OSA is treated with continuous positive airways pressure (CPAP). 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 individuals with HbSS to determine whether the intervention improves attention and processing speed, brain structure, pain and quality of life. Methods/Design Eligibility criteria include: ability to provide informed consent; age > 8 years; diagnosis of HbSS; and mean overnight saturation of  23 years); silent infarction on MRI; minimum overnight oxygen saturation > 90% or < 90%; and hydroxyurea use. For APAP individuals, the intervention is administered at home. Adherence and effectiveness are recorded using software documenting hours of use each night and overnight oximetry. Participant support in terms of appropriate facemask and facilitating adherence are provided by an unblinded sleep physiologist. The primary outcome is change in the cancellation subtest from the Wechsler scales. Secondary outcomes include general cognitive functioning, quantitative brain MRI, blood and urine chemistry, quality of life and daily pain via a smartphone App (GoMedSolutions, Inc) and, where possible MRI heart, echocardiography, and 6-min walk. These outcomes will be assessed at baseline and after six months of treatment by assessors blind to treatment assignment. Discussion Altering oxygen saturation in HbSS may lead to bone marrow suppression. This risk will be reduced by monitoring full blood counts at baseline, two weeks, three months and six months, providing treatment as appropriate and reporting as safety events. Trial registration ISRCTN46012373 . Registered on 10 July 2015. Protocol Version: 6.0 Date: 24th December 2015 Sponsor: University Hospital Southampton. Sponsor’s protocol code: RHMCHIOT5

Overnight auto-adjusting continuous airway pressure + standard care compared with standard care alone in the prevention of morbidity in sickle cell disease phase II (POMS2b): study protocol for a randomised controlled trial

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 compounded by obstructive sleep apnoea (OSA). In the general population OSA is treated with continuous positive airways pressure (CPAP). 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 individuals with HbSS to determine whether the intervention improves attention and processing speed, brain structure, pain and quality of life.Methods/desigh: eligibility criteria include: ability to provide informed consent; age &gt; 8 years; diagnosis of HbSS; and mean overnight saturation of &lt; 90% for &lt; 30% of the night (i.e. not meeting current criteria for overnight oxygen therapy). Key exclusion criteria are: overnight respiratory support; respiratory or decompensated cardiac failure; chronic transfusion; or contraindications to APAP therapy or magnetic resonance imaging (MRI). Sixty individuals with HbSS (30 children and 30 adults) will be randomised to standard care + APAP or standard care alone for six months. Minimisation factors are: age group (8-11, 12-15, 16-22 and &gt; 23 years); silent infarction on MRI; minimum overnight oxygen saturation &gt; 90% or &lt; 90%; and hydroxyurea use. For APAP individuals, the intervention is administered at home. Adherence and effectiveness are recorded using software documenting hours of use each night and overnight oximetry. Participant support in terms of appropriate facemask and facilitating adherence are provided by an unblinded sleep physiologist. The primary outcome is change in the cancellation subtest from the Wechsler scales. Secondary outcomes include general cognitive functioning, quantitative brain MRI, blood and urine chemistry, quality of life and daily pain via a smartphone App (GoMedSolutions, Inc) and, where possible MRI heart, echocardiography, and 6-min walk. These outcomes will be assessed at baseline and after six months of treatment by assessors blind to treatment assignment.Discussion: altering oxygen saturation in HbSS may lead to bone marrow suppression. This risk will be reduced by monitoring full blood counts at baseline, two weeks, three months and six months, providing treatment as appropriate and reporting as safety events.Trial registration: ISRCTN46012373 . Registered on 10 July 2015. Protocol Version: 6.0 Date: 24th December 2015 Sponsor: University Hospital Southampton. Sponsor's protocol code: RHMCHIOT53.</p

Overnight auto-adjusting continuous airway pressure + standard care compared with standard care alone in the prevention of morbidity in sickle cell disease phase II (POMS2b): study protocol for a randomised controlled trial

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 compounded by obstructive sleep apnoea (OSA). In the general population OSA is treated with continuous positive airways pressure (CPAP). 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 individuals with HbSS to determine whether the intervention improves attention and processing speed, brain structure, pain and quality of life. METHODS/DESIGN: Eligibility criteria include: ability to provide informed consent; age > 8 years; diagnosis of HbSS; and mean overnight saturation of  23 years); silent infarction on MRI; minimum overnight oxygen saturation > 90% or < 90%; and hydroxyurea use. For APAP individuals, the intervention is administered at home. Adherence and effectiveness are recorded using software documenting hours of use each night and overnight oximetry. Participant support in terms of appropriate facemask and facilitating adherence are provided by an unblinded sleep physiologist. The primary outcome is change in the cancellation subtest from the Wechsler scales. Secondary outcomes include general cognitive functioning, quantitative brain MRI, blood and urine chemistry, quality of life and daily pain via a smartphone App (GoMedSolutions, Inc) and, where possible MRI heart, echocardiography, and 6-min walk. These outcomes will be assessed at baseline and after six months of treatment by assessors blind to treatment assignment. DISCUSSION: Altering oxygen saturation in HbSS may lead to bone marrow suppression. This risk will be reduced by monitoring full blood counts at baseline, two weeks, three months and six months, providing treatment as appropriate and reporting as safety events