Evaluation of a package of risk-based pharmaceutical and lifestyle interventions in patients with hypertension and/or diabetes in rural China: A pragmatic cluster randomised controlled trial.

BACKGROUND: Primary prevention of cardiovascular disease (CVD) requires adequate control of hypertension and diabetes. We designed and implemented pharmaceutical and healthy lifestyle interventions for patients with diabetes and/or hypertension in rural primary care, and assessed their effectiveness at reducing severe CVD events. METHODS AND FINDINGS: We used a pragmatic, parallel group, 2-arm, controlled, superiority, cluster trial design. We randomised 67 township hospitals in Zhejiang Province, China, to intervention (34) or control (33). A total of 31,326 participants were recruited, with 15,380 in the intervention arm and 15,946 in the control arm. Participants had no known CVD and were either patients with hypertension and a 10-year CVD risk of 20% or higher, or patients with type 2 diabetes regardless of their CVD risk. The intervention included prescription of a standardised package of medicines, individual advice on lifestyle change, and adherence support. Control was usual hypertension and diabetes care. In both arms, as usual in China, most outpatient drug costs were out of pocket. The primary outcome was severe CVD events, including coronary heart disease and stroke, during 36 months of follow-up, as recorded by the CVD surveillance system. The study was implemented between December 2013 and May 2017. A total of 13,385 (87%) and 14,745 (92%) participated in the intervention and control arms, respectively. Their mean age was 64 years, 51% were women, and 90% were farmers. Of all participants, 64% were diagnosed with hypertension with or without diabetes, and 36% were diagnosed with diabetes only. All township hospitals and participants completed the 36-month follow-up. At 36 months, there were 762 and 874 severe CVD events in the intervention and control arms, respectively, yielding a non-significant effect on CVD incidence rate (1.92 and 2.01 per 100 person-years, respectively; crude incidence rate ratio = 0.90 [95% CI: 0.74, 1.08; P = 0.259]). We observed significant, but small, differences in the change from baseline to follow-up for systolic blood pressure (-1.44 mm Hg [95% CI: -2.26, -0.62; P < 0.001]) and diastolic blood pressure (-1.29 mm Hg [95% CI: -1.77, -0.80; P < 0.001]) in the intervention arm compared to the control arm. Self-reported adherence to recommended medicines was significantly higher in the intervention arm compared with the control arm at 36 months. No safety concerns were identified. Main study limitations include all participants being informed about their high CVD risk at baseline, non-blinding of participants, and the relatively short follow-up period available for judging potential changes in rates of CVD events. CONCLUSIONS: The comprehensive package of pharmaceutical and healthy lifestyle interventions did not reduce severe CVD events over 36 months. Improving health system factors such as universal coverage for the cost of essential medicines is required for successful risk-based CVD prevention programmes. TRIAL REGISTRATION: ISRCTN registry ISRCTN58988083.

Long-term outcomes of an educational intervention to reduce antibiotic prescribing for childhood upper respiratory tract infections in rural China: Follow-up of a cluster-randomised controlled trial.

BACKGROUND: Inappropriate antibiotic prescribing causes widespread serious health problems. To reduce prescribing of antibiotics in Chinese primary care to children with upper respiratory tract infections (URTIs), we developed an intervention comprising clinical guidelines, monthly prescribing review meetings, doctor-patient communication skills training, and education materials for caregivers. We previously evaluated our intervention using an unblinded cluster-randomised controlled trial (cRCT) in 25 primary care facilities across two rural counties. When our trial ended at the 6-month follow-up period, we found that the intervention had reduced antibiotic prescribing for childhood URTIs by 29 percentage points (pp) (95% CI -42 to -16). METHODS AND FINDINGS: In this long-term follow-up study, we collected our trial outcomes from the one county (14 facilities and 1:1 cluster randomisation ratio) that had electronic records available 12 months after the trial ended, at the 18-month follow-up period. Our primary outcome was the antibiotic prescription rate (APR)-the percentage of outpatient prescriptions containing any antibiotic(s) for children aged 2 to 14 years who had a primary diagnosis of a URTI and had no other illness requiring antibiotics. We also conducted 15 in-depth interviews to understand how interventions were sustained. In intervention facilities, the APR was 84% (1,171 out of 1,400) at baseline, 37% (515 out of 1,380) at 6 months, and 54% (2,748 out of 5,084) at 18 months, and in control facilities, it was 76% (1,063 out of 1,400), 77% (1,084 out of 1,400), and 75% (2,772 out of 3,685), respectively. After adjusting for patient and prescribing doctor covariates, compared to the baseline intervention-control difference, the difference at 6 months represented a 6-month intervention-arm reduction in the APR of -49 pp (95% CI -63 to -35; P < 0.0001), and compared to the baseline difference, the difference at 18 months represented an 18-month intervention-arm reduction in the APR of -36 pp (95% CI -55 to -17; P < 0.0001). Compared to the 6-month intervention-control difference, the difference at 18 months represented no change in the APR: 13 pp (95% CI -7 to 33; P = 0.21). Factors reported to sustain reductions in antibiotic prescribing included doctors' improved knowledge and communication skills and focused prescription review meetings, whereas lack of supervision and monitoring may be associated with relapse. Key limitations were not including all clusters from the trial and not collecting returned visits or sepsis cases. CONCLUSIONS: Our intervention was associated with sustained and substantial reductions in antibiotic prescribing at the end of the intervention period and 12 months later. Our intervention may be adapted to similar resource-poor settings. TRIAL REGISTRATION: ISRCTN registry ISRCTN14340536.

Analysis of loss to follow-up in 4099 multidrug-resistant pulmonary tuberculosis patients.

Loss to follow-up (LFU) of ≥2 consecutive months contributes to the poor levels of treatment success in multidrug-resistant tuberculosis (MDR-TB) reported by TB programmes. We explored the timing of when LFU occurs by month of MDR-TB treatment and identified patient-level risk factors associated with LFU.We analysed a dataset of individual MDR-TB patient data (4099 patients from 22 countries). We used Kaplan-Meier survival curves to plot time to LFU and a Cox proportional hazards model to explore the association of potential risk factors with LFU.Around one-sixth (n=702) of patients were recorded as LFU. Median (interquartile range) time to LFU was 7 (3-11) months. The majority of LFU occurred in the initial phase of treatment (75% in the first 11 months). Major risk factors associated with LFU were: age 36-50 years (HR 1.3, 95% CI 1.0-1.6; p=0.04) compared with age 0-25 years, being HIV positive (HR 1.8, 95% CI 1.2-2.7; p<0.01) compared with HIV negative, on an individualised treatment regimen (HR 0.7, 95% CI 0.6-1.0; p=0.03) compared with a standardised regimen and a recorded serious adverse event (HR 0.5, 95% CI 0.4-0.6; p<0.01) compared with no serious adverse event.Both patient- and regimen-related factors were associated with LFU, which may guide interventions to improve treatment adherence, particularly in the first 11 months.

Cost-effectiveness analysis of a multi-dimensional intervention to reduce inappropriate antibiotic prescribing for children with upper respiratory tract infections in China.

BACKGROUND: We developed a multifaceted intervention to reduce antibiotic prescription rate for children with upper respiratory tract infections (URTIs) among primary care doctors in township hospitals in China. The intervention achieved a 29% (95% CI 16-42) absolute risk reduction in antibiotic prescribing. This study was to assess the cost-effectiveness of our intervention at reducing antibiotic prescribing in rural primary care facilities as measured by the intervention's effect on the antibiotic prescription rates for childhood URTIs. METHODS: We took a healthcare provider perspective, measuring costs of consultation (time cost of doctor), prescription monitoring process and peer-review meetings (time cost of participants) and medication costs. Costs on provider side were collected through a bespoke questionnaire from all 25 township hospitals in December 2016, while medication costs were collected prospectively in the trial. Incremental cost-effectiveness ratios were calculated by dividing the mean difference in cost of the two trial arms by the mean difference in antibiotic prescribing rate. RESULTS: This showed an incremental cost of $0.03 per percentage point reduction in antibiotic prescribing. In addition to this incremental cost, the cost of implementing the intervention, including training and materials delivered by township hospitals, was $390.65 (SD $145.68) per healthcare facility. CONCLUSIONS: This study shows that a multifaceted intervention programme, when embedded into routine practice, is very cost-effective at reducing antibiotic prescribing in primary care facilities and has the potential of scale up in similar resource limited settings.

Impact of China's essential medicines scheme and zero-mark-up policy on antibiotic prescriptions in county hospitals: a mixed methods study.

OBJECTIVE: To evaluate the impact of the national essential medicines scheme and zero-mark-up policy on antibiotic prescribing behaviour. METHODS: In rural Guangxi, a natural experiment compared one county hospital which implemented the policy with a comparison hospital which did not. All outpatient and inpatient records in 2011 and 2014 were extracted from the two hospitals. Primary outcome indicator was antibiotic prescribing rate (APR) among children aged 2-14 presenting in outpatients with a primary diagnosis of upper respiratory tract infection (URTI). We organised independent physician reviews to determine inappropriate prescribing for inpatients. Difference-in-difference analyses based on multivariate regressions were used to compare APR over time after adjusting potential confounders. We conducted 12 in-depth interviews with paediatricians, hospital directors and health officials. RESULTS: A total of 8219 and 4142 outpatient prescriptions of childhood URTIs were included in the intervention and comparison hospitals, respectively. In 2011, APR was 30% in the intervention and 88% in the comparison hospital. In 2014, the intervention hospital significantly reduced outpatient APR by 21% (95% CI:-23%, -18%), intravenous infusion by 58% (95% CI: -64%, -52%) and prescription cost by 31 USD (95% CI: -35, -28), compared with the controls. We collected 251 inpatient records, but did not find reductions in inappropriate antibiotic use. Interviews revealed that the intervention hospital implemented a thorough antibiotics stewardship programme containing training, peer review of prescriptions and restrictions for overprescribing. CONCLUSION: The national essential medicines scheme and zero-mark-up policy, when implemented with an antimicrobial stewardship programme, may be associated with reductions in outpatient antibiotic prescribing and intravenous infusions.

Was the Maternal Health Cash Transfer Programme in Nigeria Sustainable and Cost-Effective?

Background: The Subsidy Reinvestment and Empowerment Programme (SURE-P), Maternal and Child Health (MCH) was introduced by the Nigerian government to increase the use of skilled maternal health services and reduce maternal mortality. The programme, funded out of a reduction in the fuel subsidy, was implemented between October 2012 and April 2015 and incorporated a conditional cash transfer to women to encourage use of facility based maternal services. We seek to assess the incremental cost effectiveness and long term impact of the conditional cash transfer element of the programme. Methods: An impact analysis and incremental cost-effectiveness analysis of conditional cash transfers (CCTs) is undertaken taking a health service perspective toward costs of the intervention. The study was undertaken in Anambra state, comparing areas that received only the investment in health services with areas that implemented the conditional cash transfer programme. An interrupted time series analysis of the programme outputs was undertaken. These were combined with a programme costing to determine the incremental cost per output. Findings: Maternal services provided to patients in conditional cash transfer areas accelerated rapidly from the middle of 2014 until after the programme in late 2015. The costs of providing services in each Primary Health Center facility was US $52,128 in the areas that only invested in health services compared to US $90,702 in facilities that also provided cash transfers. Much of the additional cost was in managing cash transfers. The incremental cost in the cash transfer areas was $572 for delivery care and $11 for antenatal care. If the programme was to be integrated as a regular service in the public health system, the cost of a delivery is estimated to fall to $389 and to $188 if 2015 levels of activity are assumed. Conclusion: Although the cost of CCTs as originally constituted as a vertical programme are relatively high compared to other similar programmes, these would fall substantially if integrated into the main health system. There is also evidence of sustained impact beyond the end of the funding suggesting that short term programmes can lead to a long-term change in patterns of health seeking behavior.

From Rags to Riches: Assessing poverty and vulnerability in urban Nepal.

Urbanisation brings with it rapid socio-economic change with volatile livelihoods and unstable ownership of assets. Yet, current measures of wealth are based predominantly on static livelihoods found in rural areas. We sought to assess the extent to which seven common measures of wealth appropriately capture vulnerability to poverty in urban areas. We then sought to develop a measure that captures the characteristics of one urban area in Nepal. We collected and analysed data from 1,180 households collected during a survey conducted between November 2017 and January 2018 and designed to be representative of the Kathmandu valley. A separate survey of a sub set of households was conducted using participatory qualitative methods in slum and non-slum neighbourhoods. A series of currently used indices of deprivation were calculated from questionnaire data. We used bivariate statistical methods to examine the association between each index and identify characteristics of poor and non-poor. Qualitative data was used to identify characteristics of poverty from the perspective of urban poor communities which were used to construct an Urban Poverty Index that combined asset and consumption focused context specific measures of poverty that could be proxied by easily measured indicators as assessed through multivariate modelling. We found a strong but not perfect association between each measure of poverty. There was disagreement when comparing the consumption and deprivation index on the classification of 19% of the sample. Choice of short-term monetary and longer-term capital approaches accounted for much of the difference. Those who reported migrating due to economic necessity were most likely to be categorised as poor. A combined index was developed to capture these dimension of poverty and understand urban vulnerability. A second version of the index was constructed that can be computed using a smaller range of variables to identify those in poverty. Current measures may hide important aspects of urban poverty. Those who migrate out of economic necessity are particularly vulnerable. A composite index of socioeconomic status helps to capture the complex nature of economic vulnerability.

Prevalence of Zika and malaria in patients with fever in secondary healthcare facilities in south-eastern Nigeria.

We describe the frequency of Zika and malaria among patients presenting with fever to secondary health facilities in Cross River State, Nigeria. Using a cross-sectional, stratified survey design, we randomly selected nine facilities and consecutively recruited 100 participants (aged ≥ 1 year) who presented with fever. On testing blood samples using Biocan qualitative lateral flow immuno-chromatographic cassettes for Zika IgG and IgM, 10% were seropositive for Zika virus (ZIKV) IgM, 12% for ZIKV IgG and 20% for ZIKV IgM, IgG or both. Following microscopy of thick films stained with Giemsa for malaria parasites, 55% were positive for malaria and 15% were positive for both malaria and ZIKV IgM, IgG or both. A moderately negative association between urban and rural household location and seropositivity for ZIKV IgM or IgG was found on logistic regression. Our results clearly indicate a high rate of probable ZIKV and malaria co-incidence in Cross River State. Given the high risk of serious fetal outcomes following ZIKV infection, further epidemiological research and surveillance systems for ZIKV are clearly required.

Correction to: Evaluating the impact of Marie Stopes International's digital family planning counselling application on the uptake of long-acting and permanent methods of contraception in Vietnam and Ethiopia: a study protocol for a multi-country cluster randomised controlled trial.

Following publication of the original article [1], the authors requested a correction be made, indicating L. Bates as the first author only. There is no joint first authorship.

Evaluating the impact of Marie Stopes International's digital family planning counselling application on the uptake of long-acting and permanent methods of contraception in Vietnam and Ethiopia: a study protocol for a multi-country cluster randomised controlled trial.

BACKGROUND: Maintaining quality of care in family planning (FP) counselling in low-resource settings is challenging. Job aids can help providers give more accurate and client-specific advice but require a provider to use them effectively and consistently. Marie Stopes International (MSI) have designed the tablet-computer based Digital Counselling Application (DCA), which prompts structured, supportive, client-specific and unbiased FP counselling. We hypothesise that a systematic exploration of clients' fertility intentions, medical eligibility and preferences will increase their uptake of long acting and permanent methods of contraception (LAPMs). METHODS/DESIGN: We will conduct a two-armed, parallel, cluster randomised control trial across all MSI clinics (clusters) in Ethiopia (24) and Vietnam (11), randomising 18 clinics to the intervention group and 17 to the control group. Intervention providers will attend a two-day DCA-use training programme, and use DCA in their FP counselling sessions. Usual care providers will counsel clients as before. We aim to recruit 75 clients who have had FP counselling per clinic (2625 total), following them up via two telephone interviews, initially within 2 days and then at 4 months. The primary outcome is defined as the proportion of clients who report choosing a LAPM following FP counselling and will include switchers (FP counselling clients who switch from using any other FP method) and adopters (FP counselling clients who adopt any FP method having not previously been using one). We will also collect secondary outcomes at the initial follow-up (including the proportion of clients reporting being recommended a LAPM by a provider and a range of measures of client experience and satisfaction) and at the 4-month follow-up (including a range of measures of continuation rates for different FP method types). In the intervention arm, we will also conduct mixed-methods sampling to assess how providers use DCA (using an observational survey of provider-client interactions), and understand users' experiences of receiving and giving DCA-based FP counselling (through in-depth interviews). DISCUSSION: This trial will provide novel information on the feasibility and acceptability of health worker delivered FP counselling using DCA, with robust evidence on its effectiveness at increasing the uptake of LAPMs in low-resource settings. TRIAL REGISTRATION: ISRCTN, ISRCTN11040557 . Registered on 2 March 2017 (retrospectively registered).

Implementation of a comprehensive intervention for patients at high risk of cardiovascular disease in rural China: A pragmatic cluster randomized controlled trial.

OBJECTIVE: This study aims to assess whether a standard intervention package of cardiovascular disease (CVD) care was being delivered effectively, and if it was associated with improved lifestyle and biomedical indicators. METHODS: In rural China, we implemented a pragmatic cluster randomized controlled trial for 12 months, randomized at the township hospital level, and compared with usual care. Intervention case management guideline, training and performance monitoring meeting and patient support activities were designed to fit within the job description of family doctors in the township hospitals and comprised: 1) prescription of a standardised package of medicines targeted at those with hypertension or diabetes; 2) advice about specific lifestyle interventions; and 3) advice about medication adherence. Participants were 50-74 years old, had hypertension and CVD risk scores >20% or diabetes, but were excluded if a history of severe CVD events. We also randomly selected 100 participants from six selected clusters per arm as a panel to collect intermediate biomedical indicators over time. RESULTS: A total of 28,130 participants, in 33 intervention and 34 control township hospitals, were recruited. Compared with the control arm, participants in the intervention arm had substantially improved prescribing rates of anti-hypertensives, statins and aspirin (P<0.001), and had higher medication taking rates of aspirin and statins (P<0.001). Mean systolic and diastolic blood pressures were similar across both arms (0.15 mmHg, P = 0.79, and 0.52 mmHg, P = 0.05, respectively). In the panel, (950) rates of smoking (OR = 0.23, P = 0.02) and salt intake (OR = 2.85, P = 0.03) were significantly reduced in the intervention versus control arms, but there were no statistically significant improvement over the 12 month follow-up period in biomedical indicators (P>0.05). CONCLUSION: Implementation of the package by family doctors was feasible and improved prescribing and some lifestyle changes. Additional measures such as reducing medication costs and patient education are required. TRIAL REGISTRATION: Current Controlled Trials ISRCTN58988083.

Effect of a training and educational intervention for physicians and caregivers on antibiotic prescribing for upper respiratory tract infections in children at primary care facilities in rural China: a cluster-randomised controlled trial.

BACKGROUND: Inappropriate antibiotic prescribing contributes to the generation of drug resistance worldwide, and is particularly common in China. We assessed the effectiveness of an antimicrobial stewardship programme aiming to reduce inappropriate antibiotic prescribing in paediatric outpatients by targeting providers and caregivers in primary care hospitals in rural China. METHODS: We did a pragmatic, cluster-randomised controlled trial with a 6-month intervention period. Clusters were primary care township hospitals in two counties of Guangxi province in China, which were randomly allocated to the intervention group or the control group (in a 1:1 ratio in Rong county and in a 5:6 ratio in Liujiang county). Randomisation was stratified by county. Eligible participants were children aged 2-14 years who attended a township hospital as an outpatient and were given a prescription following a primary diagnosis of an upper respiratory tract infection. The intervention included clinician guidelines and training on appropriate prescribing, monthly prescribing peer-review meetings, and brief caregiver education. In hospitals allocated to the control group, usual care was provided, with antibiotics prescribed at the individual clinician's discretion. Patients were masked to their allocated treatment group but doctors were not. The primary outcome was the antibiotic prescription rate in children attending the hospitals, defined as the cluster-level proportion of prescriptions for upper respiratory tract infections in 2-14-year-old outpatients, issued during the final 3 months of the 6-month intervention period (endline), that included one or more antibiotics. The outcome was based on prescription records and analysed by modified intention-to-treat. This study is registered with the ISRCTN registry, number ISRCTN14340536. FINDINGS: We recruited all 25 eligible township hospitals in the two counties (14 hospitals in Rong county and 11 in Liujiang county), and randomly allocated 12 to the intervention group and 13 to the control group. We implemented the intervention in three internal pilot clusters between July 1, 2015, and Dec 31, 2015, and in the remaining nine intervention clusters between Oct 1, 2016 and March 31, 2016. Between baseline (the 3 months before implementation of the intervention) and endline (the final 3 months of the 6-month intervention period) the antibiotic prescription rate at the individual level decreased from 82% (1936/2349) to 40% (943/2351) in the intervention group, and from 75% (1922/2548) to 70% (1782/2552) in the control group. After adjusting for the baseline antibiotic prescription rate, stratum (county), and potentially confounding patient and prescribing doctor covariates, this endline difference between the groups represented an intervention effect (absolute risk reduction in antibiotic prescribing) of -29% (95% CI -42 to -16; p=0·0002). INTERPRETATION: In China's primary care setting, pragmatic interventions on antimicrobial stewardship targeting providers and caregivers substantially reduced prescribing of antibiotics for childhood upper respiratory tract infections. FUNDING: Department of International Development (UKAID) through Communicable Diseases Health Service Delivery.

Harvested populations are more variable only in more variable environments.

The interaction between environmental variation and population dynamics is of major importance, particularly for managed and economically important species, and especially given contemporary changes in climate variability. Recent analyses of exploited animal populations contested whether exploitation or environmental variation has the greatest influence on the stability of population dynamics, with consequences for variation in yield and extinction risk. Theoretical studies however have shown that harvesting can increase or decrease population variability depending on environmental variation, and requested controlled empirical studies to test predictions. Here, we use an invertebrate model species in experimental microcosms to explore the interaction between selective harvesting and environmental variation in food availability in affecting the variability of stage-structured animal populations over 20 generations. In a constant food environment, harvesting adults had negligible impact on population variability or population size, but in the variable food environments, harvesting adults increased population variability and reduced its size. The impact of harvesting on population variability differed between proportional and threshold harvesting, between randomly and periodically varying environments, and at different points of the time series. Our study suggests that predicting the responses to selective harvesting is sensitive to the demographic structures and processes that emerge in environments with different patterns of environmental variation.

Study protocol: realist evaluation of effectiveness and sustainability of a community health workers programme in improving maternal and child health in Nigeria.

BACKGROUND: Achievement of improved maternal and child health (MCH) outcomes continues to be an issue of international priority, particularly for sub-Saharan African countries such as Nigeria. Evidence suggests that the use of Community Health Workers (CHWs) can be effective in broadening access to, and coverage of, health services and improving MCH outcomes in such countries. METHODS/DESIGN: In this paper, we report the methodology for a 5-year study which aims to evaluate the context, processes, outcomes and longer-term sustainability of a Nigerian CHW scheme. Evaluation of complex interventions requires a comprehensive understanding of intervention context, mechanisms and outcomes. The multidisciplinary and mixed-method realist approach will facilitate such evaluation. A favourable policy environment within which the study is conducted will ensure the successful uptake of results into policy and practice. A realist evaluation provides an overall methodological framework for this multidisciplinary and mixed methods research, which will be undertaken in Anambra state. The study will draw upon health economics, social sciences and statistics. The study comprises three steps: (1) initial theory development; (2) theory validation and (3) theory refinement and development of lessons learned. Specific methods for data collection will include in-depth interviews and focus group discussions with purposefully identified key stakeholders (managers, service providers and service users), document reviews, analyses of quantitative data from the CHW programme and health information system, and a small-scale survey. The impact of the programme on key output and outcome indicators will be assessed through an interrupted time-series analysis (ITS) of monthly quantitative data from health information system and programme reports. Ethics approvals for this study were obtained from the University of Leeds and the University of Nigeria. DISCUSSION: This study will provide a timely and important contribution to health systems strengthening specifically within Anambra state in southeast Nigeria but also more widely across Nigeria. This paper should be of interest to researchers who are interested in adapting and applying robust methodologies for assessing complex health system interventions. The paper will also be useful to policymakers and practitioners who are interested in commissioning and engaging in such complex evaluations to inform policies and practices.

Protocol for a pragmatic cluster randomised controlled trial for reducing irrational antibiotic prescribing among children with upper respiratory infections in rural China.

INTRODUCTION: Irrational use of antibiotics is a serious issue within China and internationally. In 2012, the Chinese Ministry of Health issued a regulation for antibiotic prescriptions limiting them to <20% of all prescriptions for outpatients, but no operational details have been issued regarding policy implementation. This study aims to test the effectiveness of a multidimensional intervention designed to reduce the use of antibiotics among children (aged 2-14 years old) with acute upper respiratory infections in rural primary care settings in China, through changing doctors' prescribing behaviours and educating parents/caregivers. METHODS AND ANALYSIS: This is a pragmatic, parallel-group, controlled, cluster-randomised superiority trial, with blinded evaluation of outcomes and data analysis, and un-blinded treatment. From two counties in Guangxi Province, 12 township hospitals will be randomised to the intervention arm and 13 to the control arm. In the control arm, the management of antibiotics prescriptions will continue through usual care via clinical consultations. In the intervention arm, a provider and patient/caregiver focused intervention will be embedded within routine primary care practice. The provider intervention includes operational guidelines, systematic training, peer review of antibiotic prescribing and provision of health education to patient caregivers. We will also provide printed educational materials and educational videos to patients' caregivers. The primary outcome is the proportion of all prescriptions issued by providers for upper respiratory infections in children aged 2-14 years old, which include at least one antibiotic. ETHICS AND DISSEMINATION: The trial has received ethical approval from the Ethics Committee of Guangxi Provincial Centre for Disease Control and Prevention, China. The results will be disseminated through workshops, policy briefs, peer-reviewed publications, local and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN14340536; Pre-results.