BackgroundIn 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/DesignEligibility criteria include: ability to provide informed consent; age > 8 years; diagnosis of HbSS; and mean overnight saturation of < 90% for < 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 > 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.DiscussionAltering 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 registrationISRCTN46012373. Registered on 10 July 2015.Protocol Version: 6.0 Date: 24th December 2015Sponsor: University Hospital Southampton. Sponsor’s protocol code: RHMCHIOT53

BackgroundSickle 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/DesignThis 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.DiscussionPatient 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 2014Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0883-y) contains supplementary material, which is available to authorized users.

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

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Despite the high prevalence of obstructive sleep apnea (OSA) and overnight hypoxia in sickle cell disease (SCD) patients, there are few data on treatment safety and efficacy, with controversy about the optimal management of these complications. Auto-adjusting positive airways pressure (APAP) has been shown to improve attention span and reduce pain episodes in children with sickle cell anemia (SCA) in a pilot randomized trial and there is observational evidence that nocturnal oxygen therapy (NOT) used for a period of at least six months in patients with SCD and severe nocturnal hypoxia is safe and easy to use. The Prevention of Morbidity in Sickle Cell Disease (POMS 2a) study is a National Institute for Health Research (NIHR) funded pilot feasibility trial to compare APAP with NOT in adults and children with SCD to establish the most acceptable treatment strategy and to determine short term safety of both interventions. We also assessed the feasibility of using an iPad app to collect daily pain scores. Methods: This was a cross-over interventional trial. Inclusion criteria were: age over 8 years, diagnosis of HbSS and ability to give informed consent and use an iPad. Evidence of overnight hypoxia and/or OSA was not necessary for inclusion in the trial. Each intervention was administered for a week in randomized order with a week of baseline data collection and a week of washout between the interventions. Tablet technology was used to collect daily pain scores and a detailed qualitative interview was performed after both interventions. These transcripts were analysed manually by two researchers using content analysis. Physiological and safety data included blood tests (routine hematology and biochemistry testing), urine protein measurements, oximetry, quality of life (using PedsQL), spirometry and lung volume measurements, which were measured at baseline and after each intervention. Adherence data was downloaded from the APAP machine and was self-reported for NOT. Results: Ten adults (3 female, mean age 31.7 years, 4 on hydroxyurea) and eleven children (5 female, mean age 11.9 years, 7 on hydroxyurea) were enrolled. APAP adherence data was available on 8 adults who completed 3 to 7 nights of APAP for a mean of 6.13 hours (range 4.49-7.76). Data was not available on 2 patients. One patient completed 3 days of APAP and was admitted two days later with a painful crisis and subsequent acute chest syndrome, they were subsequently withdrawn from the trial. One adult developed a pain crisis on day 2 of NOT which was self managed at home. Data on APAP adherence was available on nine children who completed APAP therapy for 3-7 nights for a mean of 5.9 hours (range 1.94-9.05), there was no data on 1 child and one did not tolerate APAP and stopped after one night. This child was admitted with a pain crisis three days after stopping APAP. Detailed quantitative interviews were completed on 19 participants. The majority of participants showed a preference for APAP because the machine was smaller, easier to handle and less noisy and noted that they slept better when using the APAP machine and were less fatigued, but some participants found the mask uncomfortable. Patients reported that NOT had a calming effect on them but they also reported that it was very noisy and caused dry nose, throat and mouth. There was no significance difference in hemoglobin, reticulocyte count, creatinine, erythropoietin, albumin creatinine ratio, bilirubin or lactate dehydrogenase at baseline and after either intervention. One patient showed a decrease in absolute reticulocyte count from 128x109 l to 53x 109/l after NOT therapy, with no change in hemoglobin. Mean overall pain days per week were 2.31 at baseline, 1.57 during APAP, 1.47 during NOT and 2.08 during washout. There was no difference in spirometry and lung volume measurements between baseline and post intervention. Pulse oximetry and Quality of Life was unchanged between baseline and after both interventions Conclusion: There were no safety concerns, in particular there was no evidence of erythroid suppression or rebound pain after 7-day application of APAP or nocturnal oxygen therapy. Tablet technology was acceptable to patients with satisfactory levels of completion. In view of patient preference for APAP the steering group has decided to proceed with a phase 2b randomized trial of six months therapy with APAP versus standard care to assess its effects on pain, quality of life and cognitive function. Disclosures Howard: Pfizer: Consultancy; Novartis: Consultancy, Other: Travel Grant; Aes-Rx: Consultancy.