Pneumococcal conjugate vaccination schedules in infants—acquisition, immunogenicity, and pneumococcal conjugate and yellow fever vaccine co-administration study

Background Pneumococcal conjugate vaccines (PCVs) effectively prevent pneumococcal disease, but the global impact of pneumococcal vaccination is hampered by its cost. The evaluation of reduced dose schedules of PCV includes measurement of effects on immunogenicity and carriage acquisition compared to standard schedules. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where the introduction of PCV resulted in good disease control but where transmission of vaccine-type pneumococci persists. We designed a large cluster-randomised field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. We will also conduct a sub-study to evaluate the individual-level effect of the two schedules on carriage acquisition, immunogenicity, and co-administration of PCV with yellow fever vaccine, the PVS-AcqImm trial. Methods PVS-AcqImm is a prospective, cluster-randomised trial of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. alternative ‘1+1’ schedule) compared to three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. standard ‘3+0’ schedule). Sub-groups within the alternative schedule group will receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 9 to 14 months of age, (b) geometric mean concentration of vaccine-type pneumococcal IgG at 18 months of age, and (c) proportions with yellow fever neutralising antibody titre ≥8 four weeks after administration of yellow fever vaccine. Participants and field staff will not be masked to group allocation while the measurement of laboratory endpoints will be masked. Approximately equal numbers of participants will be resident in each of 28 geographic clusters (14 clusters in alternative and standard schedule groups); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. Discussion Analysis will account for potential non-independence of measurements by cluster and so interpretation of effects will be at the individual level (i.e. a population of individuals). PVS-AcqImm will evaluate whether acquisition of vaccine-type pneumococci is reduced by the alternative compared to the standard schedule, which is required if the alternative schedule is to be effective. Likewise, evidence of superior immune response at 18 months of age and safety of PCV co-administration with yellow fever vaccine will support decision-making regarding the use of the alternative 1+1 schedule. Acquisition and immunogenicity outcomes will be essential for the interpretation of the results of the large field trial comparing the two schedules. Trial registration International Standard Randomised Controlled Trial Number 72821613.

Minimising Young Children’s Anxiety through Schools (MY-CATS): Protocol for a Cluster Randomised Controlled Trial to Evaluate the Effectiveness and Cost-effectiveness of an Online Parent-led Intervention Compared With Usual School Practice for Young Children Identified as at-risk for Anxiety Disorders

BackgroundIdentifying and supporting young children who are at-risk of developing anxiety disorders would benefit children, families, and wider society. Elevated anxiety symptoms, inhibited temperament, and high parental anxiety are established risk factors for later anxiety disorders, but it remains unclear who is most likely to benefit from prevention and early intervention programmes. Delivering an online intervention through schools to parents of young children who have one or more of these risks could maximise reach.The primary aim of this trial is to evaluate the effectiveness and cost-effectiveness of delivering an online parent-led intervention, compared with usual school provision only, for children (aged 4-7) identified as at-risk for anxiety disorders on the basis of at least one risk factor. We also aim to identify the characteristics of children who do and do not benefit from intervention and mechanisms of change from the intervention.MethodsThe design will be a parallel group, superiority cluster randomised controlled trial, with schools (clusters) randomised to intervention or usual school practice arms in a 1:1 ratio stratified according to level of deprivation within the school. The study will recruit and randomise at least 60 primary/infant schools in England, and on the basis of recruiting 60 schools, we will recruit 1080 trial participants (540 per arm). Parents of all children (aged 4-7) in sampled Reception, Year 1, and Year 2 classes will be invited to complete screening questionnaires. Children who screen positive on the basis of anxiety symptoms, and/or behavioural inhibition, and/or parent anxiety symptoms will be eligible for the trial. Parents/carers of children in schools allocated to the intervention arm will be offered a brief online intervention; schools in both arms will continue to provide any usual support for children and parents throughout the trial. Assessments will be completed at: screening, baseline (before randomisation), 6-weeks, 12-weeks, and 12-months post randomisation. The primary outcome will be the absence/presence of an anxiety disorder diagnosis at 12-months. DiscussionThe trial will determine if delivering an online intervention for parents of young children at-risk of anxiety disorders identified through screening in schools is effective and cost-effective. Trial registration: ISRCTN 82398107. Prospectively registered on 14.1.2021. https://www.isrctn.com/ISRCTN82398107

Design and protocol for a cluster randomised trial of enhanced diagnostics for tuberculosis screening among people living with HIV in hospital in Malawi (CASTLE study)

Background People living with HIV (PLHIV) have a high risk of death if hospitalised in low-income countries. Tuberculosis has long been the leading cause of admission and death, in part due to suboptimal diagnostics. Two promising new diagnostic tools are digital chest Xray with computer-aided diagnosis (DCXR-CAD) and urine testing with Fujifilm SILVAMP LAM (FujiLAM). Neither test has been rigorously evaluated among inpatients. Test characteristics may be complementary, with FujiLAM especially sensitive for disseminated tuberculosis and DCXR-CAD especially sensitive for pulmonary tuberculosis, making combined interventions of interest. Design and methods An exploratory unblinded, single site, two-arm cluster randomised controlled trial, with day of admission as the unit of randomisation. A third, smaller, integrated cohort arm (4:4:1 random allocation) contributes to understanding case-mix, but not trial outcomes. Participants are adults living with HIV not currently on TB treatment. The intervention (DCXR-CAD plus urine FujiLAM plus usual care) is compared to usual care alone. The primary outcome is proportion of participants started on tuberculosis treatment by day 56, with secondary outcomes of mortality (time to event) measured to to 56 days from enrolment, proportions with undiagnosed tuberculosis at death or hospital discharge and comparing proportions with enrolment-day tuberculosis treatment initiation. Discussion Both DCXR-CAD and FujiLAM have potential clinical utility and may have complementary diagnostic performance. To our knowledge, this is the first randomised trial to evaluate these tests among hospitalised PLHIV.

Changing antibiotic prescribing practices in outpatient primary care settings in China: Study protocol for a health information system-based cluster-randomised crossover controlled trial

Background The overuse and abuse of antibiotics is a major risk factor for antibiotic resistance in primary care settings of China. In this study, the effectiveness of an automatically-presented, privacy-protecting, computer information technology (IT)-based antibiotic feedback intervention will be evaluated to determine whether it can reduce antibiotic prescribing rates and unreasonable prescribing behaviours. Methods We will pilot and develop a cluster-randomised, open controlled, crossover, superiority trial. A total of 320 outpatient physicians in 6 counties of Guizhou province who met the standard will be randomly divided into intervention group and control group with a primary care hospital being the unit of cluster allocation. In the intervention group, the three components of the feedback intervention included: 1. Artificial intelligence (AI)-based real-time warnings of improper antibiotic use; 2. Pop-up windows of antibiotic prescription rate ranking; 3. Distribution of educational manuals. In the control group, no form of intervention will be provided. The trial will last for 6 months and will be divided into two phases of three months each. The two groups will crossover after 3 months. The primary outcome is the 10-day antibiotic prescription rate of physicians. The secondary outcome is the rational use of antibiotic prescriptions. The acceptability and feasibility of this feedback intervention study will be evaluated using both qualitative and quantitative assessment methods. Discussion This study will overcome limitations of our previous study, which only focused on reducing antibiotic prescription rates. AI techniques and an educational intervention will be used in this study to effectively reduce antibiotic prescription rates and antibiotic irregularities. This study will also provide new ideas and approaches for further research in this area. Trial registration ISRCTN, ID: ISRCTN13817256. Registered on 11 January 2020.

Evaluation of the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine in a cluster-randomised trial

Background In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial (FinIP, ClinicalTrials.gov NCT00861380, NCT00839254), we assessed the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes. Methods Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009―2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010―2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years (5―7 years for TTP and outpatient antimicrobial prescriptions), and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010. Results From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years. Conclusions This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms.

GP-delivered medication review of polypharmacy, deprescribing, and patient priorities in older people with multimorbidity in Irish primary care (SPPiRE Study): A cluster randomised controlled trial

Background There is a rising prevalence of multimorbidity, particularly in older patients, and a need for evidence-based medicines management interventions for this population. The Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care (SPPiRE) trial aimed to investigate the effect of a general practitioner (GP)-delivered, individualised medication review in reducing polypharmacy and potentially inappropriate prescriptions (PIPs) in community-dwelling older patients with multimorbidity in primary care. Methods and findings We conducted a cluster randomised controlled trial (RCT) set in 51 GP practices throughout the Republic of Ireland. A total of 404 patients, aged ≥65 years with complex multimorbidity, defined as being prescribed ≥15 regular medicines, were recruited from April 2017 and followed up until October 2020. Furthermore, 26 intervention GP practices received access to the SPPiRE website where they completed an educational module and used a template for an individualised patient medication review that identified PIP, opportunities for deprescribing, and patient priorities for care. A total of 25 control GP practices delivered usual care. An independent blinded pharmacist assessed primary outcome measures that were the number of medicines and the proportion of patients with any PIP (from a predefined list of 34 indicators based predominantly on the STOPP/START version 2 criteria). We performed an intention-to-treat analysis using multilevel modelling. Recruited participants had substantial disease and treatment burden at baseline with a mean of 17.37 (standard deviation [SD] 3.50) medicines. At 6-month follow-up, both intervention and control groups had reductions in the numbers of medicines with a small but significantly greater reduction in the intervention group (incidence rate ratio [IRR] 0.95, 95% confidence interval [CI]: 0.899 to 0.999, p = 0.045). There was no significant effect on the odds of having at least 1 PIP in the intervention versus control group (odds ratio [OR] 0.39, 95% CI: 0.140 to 1.064, p = 0.066). Adverse events recorded included mortality, emergency department (ED) presentations, and adverse drug withdrawal events (ADWEs), and there was no evidence of harm. Less than 2% of drug withdrawals in the intervention group led to a reported ADWE. Due to the inability to electronically extract data, primary outcomes were measured at just 2 time points, and this is the main limitation of this work. Conclusions The SPPiRE intervention resulted in a small but significant reduction in the number of medicines but no evidence of a clear effect on PIP. This reduction in significant polypharmacy may have more of an impact at a population rather than individual patient level. Trial registration ISRCTN Registry ISRCTN12752680.

CHoosing Active Role Models to INspire Girls (CHARMING): protocol for a cluster randomised feasibility trial of a school-based, community-linked programme to increase physical activity levels in 9–10-year-old girls

Background In the UK, there is evidence that girls’ physical activity tends to decline to a greater extent than boys as they enter adolescence. ‘Role models’ could play a vital role in inspiring girls to become or remain physically active. The CHARMING Programme is a primary school-based community linked role-model programme, co-developed in 2016, with children, parents, schools and wider stakeholders. It involves different types of physical activity delivered for 1-h each week by a community provider and peer role models (e.g. older girls from secondary schools) joining in with the sessions. The programme ultimately aims to increase and sustain physical activity levels among 9–10-year-old girls. This study aims to assess the feasibility and acceptability of the CHARMING Programme and of evaluating it using a randomised trial. Methods This study is a feasibility cluster randomised controlled trial, with embedded process evaluation and health economic evaluation. Approximately 90 Year 5 (i.e. 9–10-year-old) girls will be recruited across six primary schools in Mid-South Wales. Participating schools will be allocated to the programme: control on a 2:1 basis; four intervention schools will run the CHARMING Programme and two will continue with usual practice. A survey and accelerometer will be administered at baseline and repeated at 12 months. Interviews and focus groups will be conducted post-intervention delivery. The primary aim is to assess feasibility of a future randomised trial via the recruitment of schools, participants and role models; randomisation; retention; reach; data collection completion rates; programme adherence; and programme fidelity, views on intervention acceptability and programme barriers and facilitators. Secondary aims are to evaluate established physical activity outcome measures for children plus additional health economic outcomes for inclusion in a future full-scale trial. Discussion The results of this study will inform decisions on whether and how to proceed to a full-scale evaluation of the effectiveness and cost-effectiveness of the CHARMING Programme to improve or sustain physical activity. Trial registration ClinicalTrials.gov ISRCTN36223327. Registered March 29, 2021