Multicentre stepped-wedge cluster randomised controlled trial of an antimicrobial stewardship programme in residential aged care: protocol for the START trial

IntroductionAntimicrobial resistance is a growing global health threat, driven by increasing inappropriate use of antimicrobials. High prevalence of unnecessary use of antimicrobials in residential aged care facilities (RACFs) has driven demand for the development and implementation of antimicrobial stewardship (AMS) programmes. The Stepped-wedge Trial to increase antibiotic Appropriateness in Residential aged care facilities and model Transmission of antimicrobial resistance (START) will implement and evaluate the impact of a nurse-led AMS programme on antimicrobial use in 12 RACFs.Methods and analysisThe START trial will implement and evaluate a nurse-led AMS programme via a stepped-wedge cluster randomised controlled trial design in 12 RACFs over 16 months. The AMS programme will incorporate education, aged care-specific treatment guidelines, documentation forms, and audit and feedback strategies that will target aged care staff, general practitioners, pharmacists, and residents and their families. The intervention will primarily focus on urinary tract infections, lower respiratory tract infections, and skin and soft tissue infections. RACFs will transition from control to intervention phases in random order, two at a time, every 2 months, with a 2-month transition, wash-in period. The primary outcome is the cumulative proportion of residents within each facility prescribed an antibiotic during each month and total days of antibiotic use per 1000 occupied bed days. Secondary outcomes include the number of courses of systemic antimicrobial therapy, antimicrobial appropriateness, antimicrobial resistant organisms, Clostridioides difficile infection, change in antimicrobial susceptibility profiles, hospitalisations and all-cause mortality. Analyses will be conducted according to the intention-to-treat principle.Ethics and disseminationEthics approval has been granted by the Alfred Hospital Human Research Ethics Committee (HREC/18/Alfred/591). Research findings will be disseminated through peer-reviewed publications, conferences and summarised reports provided to participating RACFs.Trial registration numberNCT03941509.

Multisystemic therapy compared with management as usual for adolescents at risk of offending: the START II RCT

Background The Systemic Therapy for At Risk Teens (START) trial is a randomised controlled trial of multisystemic therapy (MST) compared with management as usual (MAU). The present study reports on long-term follow-up of the trial (to 60 months). Objectives The primary objective was to compare MST and MAU for the proportion of young people in each group with criminal convictions up to 60 months post baseline. Secondary outcomes included group comparisons of psychological and behavioural factors. An economic analysis was carried out to determine the cost-effectiveness of MST compared with MAU. Two qualitative studies were conducted to better understand the subjective experiences of the participants. Design Primary outcomes (collected up to 60 months) were collected using a centralised police database. Secondary outcomes were evaluated using self-report questionnaires completed by both young people and parents or carers at the 24-, 36- and 48-month follow-ups. Research assistants were blind to treatment allocation. Setting Participants were recruited from participating MST sites in nine areas of England. Secondary outcomes were typically collected within the family home. Participants A total of 684 families were recruited into the START trial and allocated randomly to a treatment group. Of these, 487 remained in the second phase of the trial. Young people were aged, on average, 13.8 years at baseline, with 63% male and 37% female. Interventions MST is a manualised programme for young people exhibiting antisocial behaviour and their families that uses principles from cognitive–behavioural and family therapy to provide an individualised approach. MAU content was not prespecified, but consisted of the standard care offered to young people who met eligibility for the trial. Main outcome measures Young people’s offending was evaluated using the Police National Computer. Secondary measures included validated self-report measures completed by both the young person and their parent or carer. The economic evaluation took a broad perspective and outcomes were assessed in terms of quality-adjusted life-years and offending. Results No significant differences were found in the proportion of offending between the groups (hazard ratio 1.03, 95% confidence interval 0.84 to 1.26; p = 0.78). No differences were found between the groups on secondary outcome measures, with a few exceptions that did not hold up consistently across the follow-up period. The economic analysis did not find evidence to support the cost-effectiveness of MST compared with MAU. Outcomes from the qualitative studies suggest that families mostly felt positive about MST, and that MST was associated with greater maturity in young men. Limitations Some intended evaluations were not possible to deliver. Selective attrition may have influenced the nature of the sample size. It is also unclear how representative the MAU services were of reality. Future research Recommendations are made for the evaluation of MST in populations with more severe behavioural problems, as well as for identifying and testing new moderators. Conclusions The results of the second phase of the START trial do not support the long-term superiority of MST to MAU, but elements of the intervention may be adapted successfully. Trial registration Current Controlled Trials ISRCTN77132214 and London South-East REC registration number 09/H1102/55. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 23. See the NIHR Journals Library website for further project information.

The Safe Start trial to assess the effect of an infant hygiene intervention on enteric infections and diarrhoea in low-income informal neighbourhoods of Kisumu, Kenya: a study protocol for a cluster randomized controlled trial

Background Symptomatic and asymptomatic enteric infections in early childhood are associated with negative effects on childhood growth and development, especially in low and middle-income countries, and food may be an important transmission route. Although basic food hygiene practices might reduce exposure to faecal pathogens and resulting infections, there have been few rigorous interventions studies to assess this, and no studies in low income urban settings where risks are plausibly very high. The aim of this study is to evaluate the impact of a novel infant food hygiene intervention on infant enteric infections and diarrhoea in peri-urban settlements of Kisumu, Kenya. Methods This is a cluster randomized control trial with 50 clusters, representing the catchment areas of Community Health Volunteers (CHVs), randomly assigned to intervention or control, and a total of 750 infants recruited on a rolling basis at 22 weeks of age and then followed for 15 weeks. The intervention targeted four key caregiver behaviours related to food hygiene: 1) hand washing with soap before infant food preparation and feeding; 2) bringing all infant food to the boil before feeding, including when reheating or reserving; 3) storing all infant food in sealed containers; and, 4) using only specific utensils for infant feeding which are kept separate and clean. Results The primary outcome of interest is the prevalence of one or more of 23 pre-specified enteric infections, determined using quantitative real-time polymerase chain reaction for enteric pathogen gene targets. In addition, infant food samples were collected at 33 weeks, and faecal indicator bacteria (Enterococcus) isolated and enumerated to assess the impact of the intervention on infant food contamination. Conclusion To our knowledge this is the first randomized controlled trial to assess the effect of an infant food hygiene intervention on enteric infections in a high burden, low income urban setting. Our trial responds to growing evidence that food may be a key pathway for early childhood enteric infection and disease and that basic food hygiene behaviours may be able to mitigate these risks. The Safe Start trial seeks to provide new evidence as to whether a locally appropriate infant food hygiene intervention delivered through the local health extension system can improve the health of young children. Trial registration The trial was registered at clinicaltrial.gov on March 16th 2018 before enrolment of any participants (https://clinicaltrials.gov/ct2/show/NCT03468114).

A randomized evaluation of on-site monitoring nested in a multinational randomized trial

Background: Evidence from prospectively designed studies to guide on-site monitoring practices for randomized trials is limited. A cluster randomized study, nested within the Strategic Timing of AntiRetroviral Treatment (START) trial, was conducted to evaluate on-site monitoring. Methods: Sites were randomized to either annual on-site monitoring or no on-site monitoring. All sites were centrally monitored, and local monitoring was carried out twice each year. Randomization was stratified by country and projected enrollment in START. The primary outcome was a participant-level composite outcome including components for eligibility errors, consent violations, use of antiretroviral treatment not recommended by protocol, late reporting of START primary and secondary clinical endpoints (defined as the event being reported more than 6 months from occurrence), and data alteration and fraud. Logistic regression fixed effect hierarchical models were used to compare on-site versus no on-site monitoring for the primary composite outcome and its components. Odds ratios and 95% confidence intervals comparing on-site monitoring versus no on-site monitoring are cited. Results: In total, 99 sites (2107 participants) were randomized to receive annual on-site monitoring and 97 sites (2264 participants) were randomized to be monitored only centrally and locally. The two monitoring groups were well balanced at entry. In the on-site monitoring group, 469 annual on-site monitoring visits were conducted, and 134 participants (6.4%) in 56 of 99 sites (57%) had a primary monitoring outcome. In the no on-site monitoring group, 85 participants (3.8%) in 34 of 97 sites (35%) had a primary monitoring outcome (odds ratio = 1.7; 95% confidence interval: 1.1–2.7; p = 0.03). Informed consent violations accounted for most outcomes in each group (56 vs 41 participants). The largest odds ratio was for eligibility violations (odds ratio = 12.2; 95% confidence interval: 1.8–85.2; p = 0.01). The number of participants with a late START primary endpoint was similar for each monitoring group (23 vs 16 participants). Late START grade 4 and unscheduled hospitalization events were found for 34 participants in the on-site monitoring group and 19 participants in the no on-site monitoring group (odds ratio = 2.0; 95% confidence interval: 1.1–3.7; p = 0.02). There were no cases of data alteration or fraud. Based on the travel budget for on-site monitoring and the hours spent conducting on-site monitoring, the estimated cost of on-site monitoring was over US$2 million. Conclusion: On-site monitoring led to the identification of more eligibility and consent violations and START clinical events being reported more than 6 months from occurrence as compared to no on-site monitoring. Considering the nature of the excess monitoring outcomes identified at sites receiving on-site monitoring, as well as the cost of on-site monitoring, the value to the START study was limited.

Role of Inflammatory Biomarkers in the Prevalence and Incidence of Hypertension Among HIV-Positive Participants in the START Trial

BACKGROUND The association between hypertension (HTN) and inflammatory biomarkers (interleukin-6 [IL-6] and high-sensitivity C-reactive protein [hsCRP]) in HIV-positive persons with CD4+ count >500 cells/mm3 is unknown. METHODS We studied HTN in participants of the Strategic Timing of AntiRetroviral Treatment (START) trial of immediate vs. deferred antiretroviral therapy (ART) in HIV-positive, ART naive adults with CD4+ count > 500 cells/mm3. HTN was defined as having a systolic blood pressure (BP) ≥140 mmHg, a diastolic BP ≥90 mmHg, or using BP-lowering therapy. Logistic and discrete Cox regression models were used to study the association between baseline biomarker levels with prevalent and incident HTN. RESULTS Among 4,249 participants with no history of cardiovascular disease, the median age was 36 years, 55% were nonwhite, and the prevalence of HTN at baseline was 18.9%. After adjustment for race, age, gender, body mass index (BMI), diabetes, smoking, HIV RNA and CD4+ levels, associations of IL-6 and hsCRP with HTN prevalence were not significant (OR per twofold higher:1.10, 95% confidence interval [CI]: 0.99, 1.20 for IL-6 and 1.05, 95% CI: 0.99, 1.10 for hsCRP). Overall incidence of HTN was 6.8 cases/100 person years. In similarly adjusted models, neither IL-6 (Hazard ratios [HR] per twofold higher IL-6 levels: 0.97, 95% CI: 0.88, 1.08) nor hsCRP (HR per twofold higher hsCRP levels: 0.97, 95% CI: 0.92, 1.02) were associated with risk of incident HTN. Associations did not differ by treatment group. Age, race, gender, and BMI were significantly associated with both the prevalence and incidence of HTN. CONCLUSIONS Traditional risk factors and not baseline levels of IL-6 or hsCRP were associated with the prevalence and incidence of HTN in START.