Ondansetron and metoclopramide as second-line antiemetics in women with nausea and vomiting in pregnancy: the EMPOWER pilot factorial RCT

Background Around one-third of pregnant women suffer from moderate to severe nausea and vomiting, causing physical and emotional distress and reducing their quality of life. There is no cure for nausea and vomiting in pregnancy. Management focuses on relieving symptoms and preventing morbidity, and often requires antiemetic therapy. National guidelines make recommendations about first-, second- and third-line antiemetic therapies, although care varies in different hospitals and women report feeling unsupported, dissatisfied and depressed. Objectives To determine whether or not, in addition to intravenous rehydration, ondansetron compared with no ondansetron and metoclopramide compared with no metoclopramide reduced the rate of treatment failure up to 10 days after drug initiation; improved symptom severity at 2, 5 and 10 days after drug initiation; improved quality of life at 10 days after drug initiation; and had an acceptable side effect and safety profile. To estimate the incremental cost per treatment failure avoided and the net monetary benefits from the perspectives of the NHS and women. Design This was a multicentre, double-dummy, randomised, double-blinded, dummy-controlled 2 × 2 factorial trial (with an internal pilot phase), with qualitative and health economic evaluations. Participants Thirty-three patients (who were < 17 weeks pregnant and who attended hospital with nausea and vomiting after little or no improvement with first-line antiemetic medication) who attended 12 secondary care NHS trusts in England, 22 health-care professionals and 21 women participated in the qualitative evaluation. Interventions Participants were randomly allocated to one of four treatment groups (1 : 1 : 1: 1 ratio): (1) metoclopramide and dummy ondansetron; (2) ondansetron and dummy metoclopramide; (3) metoclopramide and ondansetron; or (4) double dummy. Trial medication was initially given intravenously and then continued orally once women were able to tolerate oral fluids for a maximum of 10 days of treatment. Main outcome measures The primary end point was the number of participants who experienced treatment failure, which was defined as the need for further treatment because symptoms had worsened between 12 hours and 10 days post treatment. The main economic outcomes were incremental cost per additional successful treatment and incremental net benefit. Results Of the 592 patients screened, 122 were considered eligible and 33 were recruited into the internal pilot (metoclopramide and dummy ondansetron, n = 8; ondansetron and dummy metoclopramide, n = 8; metoclopramide and ondansetron, n = 8; double dummy, n = 9). Owing to slow recruitment, the trial did not progress beyond the pilot. Fifteen out of 30 evaluable participants experienced treatment failure. No statistical analyses were performed. The main reason for ineligibility was prior treatment with trial drugs, reflecting an unpredicted change in prescribing practice at several points along the care pathway. The qualitative evaluation identified the requirements of the study protocol, in relation to guidelines on anti-sickness drugs, and the diversity of pathways to care as key hurdles to recruitment while the role of research staff was a key enabler. No important adverse events or side effects were reported. Limitations The pilot trial failed to achieve the recruitment target owing to unforeseen changes in the provision of care. Conclusions The trial was unable to provide evidence to support clinician decisions about the best choice of second-line antiemetic for nausea and vomiting in pregnancy. Trial registration Current Controlled Trials ISRCTN16924692 and EudraCT 2017-001651-31. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 63. See the NIHR Journals Library website for further project information.

Immediate oral versus immediate topical versus delayed oral antibiotics for children with acute otitis media with discharge: the REST three-arm non-inferiority electronic platform-supported RCT

Background Acute otitis media is a painful infection of the middle ear that is commonly seen in children. In some children, the eardrum spontaneously bursts, discharging visible pus (otorrhoea) into the outer ear. Objective To compare the clinical effectiveness of immediate topical antibiotics or delayed oral antibiotics with the clinical effectiveness of immediate oral antibiotics in reducing symptom duration in children presenting to primary care with acute otitis media with discharge and the economic impact of the alternative strategies. Design This was a pragmatic, three-arm, individually randomised (stratified by age < 2 vs. ≥ 2 years), non-inferiority, open-label trial, with economic and qualitative evaluations, supported by a health-record-integrated electronic trial platform [TRANSFoRm (Translational Research and Patient Safety in Europe)] with an internal pilot. Setting A total of 44 English general practices. Participants Children aged ≥ 12 months and < 16 years whose parents (or carers) were seeking medical care for unilateral otorrhoea (ear discharge) following recent-onset (≤ 7 days) acute otitis media. Interventions (1) Immediate ciprofloxacin (0.3%) solution, four drops given three times daily for 7 days, or (2) delayed ‘dose-by-age’ amoxicillin suspension given three times daily (clarithromycin twice daily if the child was penicillin allergic) for 7 days, with structured delaying advice. All parents were given standardised information regarding symptom management (paracetamol/ibuprofen/fluids) and advice to complete the course. Comparator Immediate ‘dose-by-age’ oral amoxicillin given three times daily (or clarithromycin given twice daily) for 7 days. Parents received standardised symptom management advice along with advice to complete the course. Main outcome measure Time from randomisation to the first day on which all symptoms (pain, fever, being unwell, sleep disturbance, otorrhoea and episodes of distress/crying) were rated ‘no’ or ‘very slight’ problem (without need for analgesia). Methods Participants were recruited from routine primary care appointments. The planned sample size was 399 children. Follow-up used parent-completed validated symptom diaries. Results Delays in software deployment and configuration led to small recruitment numbers and trial closure at the end of the internal pilot. Twenty-two children (median age 5 years; 62% boys) were randomised: five, seven and 10 to immediate oral, delayed oral and immediate topical antibiotics, respectively. All children received prescriptions as randomised. Seven (32%) children fully adhered to the treatment as allocated. Symptom duration data were available for 17 (77%) children. The median (interquartile range) number of days until symptom resolution in the immediate oral, delayed oral and immediate topical antibiotic arms was 6 (4–9), 4 (3–7) and 4 (3–6), respectively. Comparative analyses were not conducted because of small numbers. There were no serious adverse events and six reports of new or worsening symptoms. Qualitative clinician interviews showed that the trial question was important. When the platform functioned as intended, it was liked. However, staff reported malfunctioning software for long periods, resulting in missed recruitment opportunities. Troubleshooting the software placed significant burdens on staff. Limitations The over-riding weakness was the failure to recruit enough children. Conclusions We were unable to answer the main research question because of a failure to reach the required sample size. Our experience of running an electronic platform-supported trial in primary care has highlighted challenges from which we have drawn recommendations for the National Institute for Health Research (NIHR) and the research community. These should be considered before such a platform is used again. Trial registration Current Controlled Trials ISRCTN12873692 and EudraCT 2017-003635-10. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 67. See the NIHR Journals Library website for further project information.

Stakeholder perspectives on barriers and enablers to recruiting anxious children undergoing day surgery under general anaesthetic: a qualitative internal pilot study of the MAGIC randomised controlled trial

Background The ‘Melatonin for Anxiety prior to General anaesthesia In Children’ (MAGIC) trial was designed to compare midazolam and melatonin as pre-medications for anxious children (aged five to fourteen), undergoing day-case surgical procedures under general anaesthesia. Low recruitment is a challenge for many trials, particularly paediatric trials and those in ‘emergency’ settings. A qualitative study as part of MAGIC aimed to gather stakeholder perspectives on barriers and enablers to recruitment. Methods Sixteen stakeholders from six sites participated in semi-structured interviews about their experiences of setting up the MAGIC trial and recruiting patients as part of the internal pilot. Data was analysed using framework analysis. Results Participants identified barriers and enablers to recruitment. Barriers and enablers related to the study, participants, the population of anxious children, practitioners, collaboration with other health professionals, ethics, specific settings and the context of surgical day units and the wider health system. Attempting to recruit anxious children from a surgical day unit is particularly challenging for several reasons. Issues include the practicalities of dealing with a child experiencing anxiety for parents/guardians; professional unwillingness to make things more difficult for families and clinicians and nurses valuing predictability within a busy and time-sensitive setting. Conclusions Multi-site RCTs face recruitment barriers relating to study-wide and site-specific factors. There are multiple barriers to recruiting anxious children due to undergo day-case surgery. Barriers across domains can interrelate and reinforce each other, reflecting challenges relating to populations and settings. For example, in the case of anxious children, parents and other health professionals are concerned about exacerbating children’s anxiety prior to surgery. They may look for ways to keep things predictable and avoid the uncertainty of an RCT. Pre-trial engagement work could help address concerns among collaborating health professionals. Using rapid ethnography during set-up or an internal pilot to focus on how the protocol will be or has been operationalised in practice may help identify issues. Allowing time to reflect on the findings of internal pilots and implement necessary changes could facilitate higher recruitment during the main phase of a trial. Trial registration NIHR Trial Registration Number: ISRCTN18296119. Registered on October 01, 2019.

Internal pilot insertion for polar codes

Two internal pilot insertion methods are proposed for polar codes to improve their error correction performance. The presented methods are based on a study of the weight distribution of the given polar code. The insertion of pilot bits provided a new way to control the coding rate of the modified polar code on the basis of the Hamming weight properties without sacrificing the code construction and the related channel condition. Rate control is highly demanded by 5G channel coding schemes. Two short-length polar codes were considered in the work with successive cancellation list decoding. The results showed that advantages in the range of 0.1 to 0.75 dB were obtained in the relative tolerance of the modified coded signal to the additive white Gaussian noise and fading channels at a bit error rate of 10⁻⁴. The simulation results also revealed that the performance improvements were possible with a careful insertion of the pilots. The modified polar code with pilot insertion provided performance improvement and offered the control of the coding rate without any added complexity at both the encoder and the decoder.

Meaning-centered group psychotherapy in Portuguese cancer patients: A pilot exploratory trial

Objective To describe the feasibility of a meaning-centered group psychotherapy (MCGP) adaptation in a sample of Portuguese cancer patients. Method The study was carried out according to four steps: 1st — Transcultural adaptation and validation (focus groups); 2nd — Preliminary study with MCGP original version (to test its feasibility); 3rd — Adaptation of MCGP original version to a 4-session version (and internal pilot study); and 4th — Pilot exploratory trial (MCGP-4 session version), implemented between January 1, 2018 and December 31, 2019. Inclusion criteria were >18 years, psychological complaints, and difficulty to adapt to cancer. Allocation was according to participants’ preference: MCGP vs. care as usual (CAU). Primary outcomes were: MCGP adapted version improved quality of life (QoL) and spiritual well-being; secondary outcomes were improvement of depression, anxiety, and distress. Assessments were done at baseline (T1) and 1 month after (T2), with self-report socio-demographic and clinical questionnaires, Distress Thermometer (DT), McGill Quality of Life Questionnaire (MQOL), Functional Assessment of Chronic Illness Therapy — Spiritual Well-Being Scale (FACIT-Sp-12), Hospital Anxiety and Depression Scale, and its subscales (HADS — HADS-D, HADS-A). Results In the 1st step, and through focus groups, the manual was reformulated and tested. The preliminary study (2nd step) with MCGP original version showed a high number of dropouts which could jeopardize the study and, after reframing the sessions content, MCGP was adapted to a 4-session version, and its feasibility was tested by an internal pilot study (3rd step). The pilot exploratory trial (4th step) had 91 participants. Most socio-demographic and clinical characteristics between the groups (51: MCGP; 40: CAU) had no statistically significant differences. A comparison between the two groups at T2 showed that the MCGP group scored significantly higher in the general (U = 552.00, P < 0.001), and existential (U = 727.50, P = 0.018) domains and total score (U = 717.50, P = 0.015) of QoL, and CAU presented statistical higher levels in DT (U = 608.50, P = 0.001). Comparing the groups between T1 and T2, the MCGP group had a statistically significant improvement in the general (Z = −3.67, P < 0.001) and psychosocial (Z = −2.89, P = 0.004) domains and total score (Z = −2.71, P = 0.007) of QoL, and a statistically significant decrease in DT (Z = −2.40, P = 0.016). In terms of group effects, the MCGP group presented increased general (b = 1.42, P < 0.001, η2p = 0.179), and support (b = 0.80, P = 0.045, η2p = 0.048) domains and total score (b = 0.81, P = 0.013, η2p = 0.073) of QoL (small to elevated dimensions), and decreased levels of depression (b = −1.14, P = 0.044, η2p = 0.048), and distress (b = −1.38, P = 0.001, η2p = 0.127) (small to medium dimensions), compared with CAU. At T2, participants who attended ≥3 sessions (n = 38) had a statistically significant higher score in the general domain (U = 130.50, P = 0.009) of QoL, comparing with those who attended 1 or 2 sessions (n = 13). Significance of results This study supports the benefits of an MCGP adapted version in improving QoL and psychologic well-being. More studies are necessary to address the limitations of this pilot exploratory trial, as its small sample size.

Study protocol for randomised clinical trial comparing the effectiveness of side-lying sleep positioning to back-lying at reducing oxygen desaturation resulting from obstructive sleep apnoea in infants with cleft palate (SLUMBRS2)

IntroductionThe craniofacial abnormalities found in infants with cleft palate (CP) decrease their airway patency and increase their risk of obstructive sleep apnoea (OSA). We hypothesise that optimising sleep position in infants with CP may improve airway patency and offer a ‘low-cost, high-impact’ intervention to prevent the negative impacts of OSA. Because cleft centres give inconsistent advice about sleep position: some recommend back-lying and others side-lying, we will compare these in a randomised controlled trial.Methods and analysisThe aim is to determine the clinical effectiveness of side-lying as compared with back-lying sleep positioning in terms of reducing oxygen desaturation resulting from OSA in 244 infants aged 3–5 weeks of age, diagnosed with an isolated CP in/by UK cleft centres. Primary outcome is the 4% Oxygen Desaturation Index measured using pulse oximetry during sleep.Research plan1. Multicentre randomised controlled trial of side-lying compared with back-lying sleep positioning in reducing oxygen desaturation resulting from OSA in infants with CP at one month of age. 2. Internal pilot questionnaire-based study to support parents and clinicians regarding study participation, seeking to identify and address any barriers to recruitment. Monitoring data from the internal pilot will be used in the final analysis. 3. Co-development of new UK recommendations with Cleft Lip and Palate Association (CLAPA) regarding sleep position for infants with CP.Ethics and disseminationThe study protocol has received the favourable opinion of the West Midlands-South Birmingham Research Ethics Committee. Study results will be published on affiliated webpages and in peer-reviewed publications and conference contributions.Trial registration numberNCT04478201.

Impact of Remote Titration Combined With Telemonitoring on the Optimization of Guideline-Directed Medical Therapy for Patients With Heart Failure: Internal Pilot of a Randomized Controlled Trial

Background To improve health outcomes in patients with heart failure, guideline-directed medical therapy (GDMT) should be optimized to target doses. However, GDMT remains underutilized, with less than 25% of patients receiving target doses in clinical practice. Telemonitoring could provide reliable and real-time physiological data for clinical decision support to facilitate remote GDMT titration. Objective This paper aims to present findings from an internal pilot study regarding the effectiveness of remote titration facilitated by telemonitoring. Methods A 2-arm randomized controlled pilot trial comparing remote titration versus standard care in a heart function clinic was conducted. Patients were randomized to undergo remote medication titration facilitated by data from a smartphone-based telemonitoring system or standard titration performed during clinic visits. Results A total of 42 patients with new-onset (10/42, 24%) and existing (32/42, 76%) heart failure and a mean age of 55.29 (SD 11.28) years were randomized between January and June 2019. Within 6 months of enrollment, 86% (18/21) of patients in the intervention group achieved optimal doses versus 48% (10/21) of patients in the control group. The median time to dose optimization was 11.0 weeks for the intervention group versus 18.8 weeks for the control group. The number of in-person visits in the intervention group was 54.5% lower than in the control group. Conclusions The results of this pilot study suggest that remote titration facilitated by telemonitoring has the potential to increase the proportion of patients who achieve optimal GDMT doses, decrease time to dose optimization, and reduce the number of clinic visits. Remote titration may facilitate optimal and efficient titration of patients with heart failure while reducing the burden for patients to attend in-person clinic visits. Trial Registration ClinicalTrials.gov NCT04205513; https://clinicaltrials.gov/ct2/show/NCT04205513 International Registered Report Identifier (IRRID) RR2-10.2196/preprints.19705

Switching antipsychotic medication to reduce sexual dysfunction in people with psychosis: the REMEDY RCT

Background Sexual dysfunction is common among people who are prescribed antipsychotic medication for psychosis. Sexual dysfunction can impair quality of life and reduce treatment adherence. Switching antipsychotic medication may help, but the clinical effectiveness and cost-effectiveness of this approach is unclear. Objective To examine whether or not switching antipsychotic medication provides a clinically effective and cost-effective method to reduce sexual dysfunction in people with psychosis. Design A two-arm, researcher-blind, pilot randomised trial with a parallel qualitative study and an internal pilot phase. Study participants were randomised to enhanced standard care plus a switch of antipsychotic medication or enhanced standard care alone in a 1 : 1 ratio. Randomisation was via an independent and remote web-based service using dynamic adaptive allocation, stratified by age, gender, Trust and relationship status. Setting NHS secondary care mental health services in England. Participants Potential participants had to be aged ≥ 18 years, have schizophrenia or related psychoses and experience sexual dysfunction associated with the use of antipsychotic medication. We recruited only people for whom reduction in medication dosage was ineffective or inappropriate. We excluded those who were acutely unwell, had had a change in antipsychotic medication in the last 6 weeks, were currently prescribed clozapine or whose sexual dysfunction was believed to be due to a coexisting physical or mental disorder. Interventions Switching to an equivalent dose of one of three antipsychotic medications that are considered to have a relatively low propensity for sexual side effects (i.e. quetiapine, aripiprazole or olanzapine). All participants were offered brief psychoeducation and support to discuss their sexual health and functioning. Main outcome measures The primary outcome was patient-reported sexual dysfunction, measured using the Arizona Sexual Experience Scale. Secondary outcomes were researcher-rated sexual functioning, mental health, side effects of medication, health-related quality of life and service utilisation. Outcomes were assessed 3 and 6 months after randomisation. Qualitative data were collected from a purposive sample of patients and clinicians to explore barriers to recruitment. Sample size Allowing for a 20% loss to follow-up, we needed to recruit 216 participants to have 90% power to detect a 3-point difference in total Arizona Sexual Experience Scale score (standard deviation 6.0 points) using a 0.05 significance level. Results The internal pilot was discontinued after 12 months because of low recruitment. Ninety-eight patients were referred to the study between 1 July 2018 and 30 June 2019, of whom 10 were randomised. Eight (80%) participants were followed up 3 months later. Barriers to referral and recruitment included staff apprehensions about discussing side effects, reluctance among patients to switch medication and reticence of both staff and patients to talk about sex. Limitations Insufficient numbers of participants were recruited to examine the study hypotheses. Conclusions It may not be possible to conduct a successful randomised trial of switching antipsychotic medication for sexual functioning in people with psychosis in the NHS at this time. Future work Research examining the acceptability and effectiveness of adjuvant phosphodiesterase inhibitors should be considered. Trial registration Current Controlled Trials ISRCTN12307891. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 44. See the NIHR Journals Library website for further project information.

Ultrasound to identify lupus patients with inflammatory joint symptoms with a better response to therapy: The USEFUL longitudinal multicentre study

Objective To determine whether SLE patients with inflammatory joint symptoms and ultrasound-detected synovitis achieve better clinical responses to glucocorticoid compared to patients with normal ultrasound scans. Secondary objectives included identification of clinical features predicting ultrasound-synovitis. Methods A longitudinal muticentre study of SLE patients with physician-diagnosed inflammatory joint pain requiring treatment (intramuscular methylprednisolone 120mg) was undertaken. Clinical assessments, patient-reported outcome measures, and bilateral hands and wrist ultrasound data were collected at 0, 2 and 6 weeks post-glucocorticoid. The primary outcome (determined via internal pilot analysis) was EMS-VAS at 2 weeks, adjusted for the baseline value, comparing patients with positive (GS and/or PD) and negative ultrasound. Post-hoc analyses adjusting for fibromyalgia were performed. Results Of 133 patients recruited, 78/133 had positive ultrasound, but only 68% of these had ≥1 swollen joint. Of 66/133 patients with ≥1 swollen joint, 20% had negative ultrasound. Positive ultrasound was associated with joint swelling, symmetrical small joint distribution and active serology. In full analysis set (n=133) there was no difference in baseline-adjusted EMS-VAS at week 2 (-7.7mm 95% CI -19.0mm, 3.5mm, p=0.178). After excluding 32 fibromyalgia patients, response was significantly better in patients with positive ultrasound at baseline (baseline-adjusted EMS-VAS at 2 weeks -12.1 mm, 95% CI -22.2mm, -0.1mm, p=0.049). This difference was greater when adjusted for treatment (-12.8mm (95% CI -22mm, -3mm), p=0.007). Conclusions In SLE patients without fibromyalgia, those with positive ultrasound had a better clinical response to therapy. Imaging-detected synovitis should be used to select SLE patients for therapy and enrich clinical trials.

Developing a Bayesian Network Decision Support tool for low back pain: a pilot and protocol (Preprint)

BACKGROUND Low back pain (LBP) is an increasingly burdensome condition for patients and health professionals alike, with increasing persistent pain and disability consistently demonstrated. Previous decision support tools for LBP management have focussed on a subset of factors due to time constraints and ease of use for the clinician. With the explosion of interest in machine learning tools and the commitment from Western governments to introduce this technology, there are opportunities to develop intelligent decision support tools. We will do this for LBP using a Bayesian Network, which will entail constructing a clinical reasoning model elicited from experts. OBJECTIVE This paper proposes a method for conducting a modified RAND Appropriateness procedure to elicit the knowledge required to construct a Bayesian Network from a group of domain experts in LBP, and reports the lessons learned from the internal pilot of the procedure. METHODS We propose to recruit expert clinicians with a special interest in LBP from across a range of medical specialisms e.g. orthopaedics, rheumatology, sports medicine. The procedure will consist of four stages. Stage 1 is an online elicitation of variables to be considered by the model, followed by a face to face workshop. Stage 2 is an online elicitation of the structure of the model, followed by a face to face workshop. Stage 3 consists of an online phase to elicit probabilities to populate the Bayesian Network. Stage 4 is a rudimentary validation of the Bayesian Network. RESULTS Ethical approval has been gained from the Research Ethics Committee at Queen Mary University of London. An internal pilot of the procedure has been run with clinical colleagues from the research team. This showed that an alternating process of 3 remote activities and 2 in-person meetings were required to complete the elicitation without overburdening participants. Lessons learned have included the need for a bespoke, online elicitation tool to run between face-to-face meetings and for careful operational definition of descriptive terms even if widely clinically used. Further, tools are required to remotely deliver training about self-identification of various forms of cognitive bias and explain the underlying principles of a BN. The use of the internal pilot was recognised as being a methodological necessity. CONCLUSIONS We have proposed a method to construct Bayesian Networks that are representative of expert clinical reasoning, in this case for a musculoskeletal condition. We have tested the method with an internal pilot to refine the process prior to deployment, which indicates the process can be successful. The internal pilot has also revealed the software support requirements for the elicitation process, in order that clinical reasoning can be modelled for a range of conditions. CLINICALTRIAL