This study has two components: effectiveness and cost-effectiveness components. The effectiveness study will be conducted in three stages. The first stage will focus on pre-intervention surveys in Kintampo North Municipal and Pru East district. This will be followed by an intervention stage which will be conducted in either Kintampo North or Pru East district, depending on which of these districts has a higher prevalence of malaria, STH and schistosoma infections. The third stage will be a post-intervention cross-sectional survey in the communities where the intervention study is conducted.

First stage: During community sensitisation and engagement meetings with parents and caregivers of potentially eligible children living in Kintampo North Municipal and Pru East district, the Kintampo Health Research Centre (KHRC) study team will explain the need for this study, using a simple picture to illustrate the integration of SMC and anthelminthic drugs; the study rationale and informed consent procedure, and the risks and benefits of allowing their children to participate in the study. After these meetings, an investigator from KHRC will identify parents/caregivers of potential child participants to explain the study further to them on an individual basis. The parents/caregivers will be given a copy of the participant information sheet. Parents/caregivers who feel that the study is appropriate for their child will be visited at home at a mutually agreed time. For logistical purposes, written informed consent will be obtained from a parent/caregiver one day before the planned start date of the pre-intervention survey in both districts, along with positive assent from children aged ≥ 7 years, where required. Following this, an investigator will provide a pre-labelled stool collection container to the parent/caregiver at this visit and encourage them to collect stool from their child and keep this safely for the research team who will visit them the following day. Subsequently, the investigator will confirm the parent/caregiver's willingness to allow their child's continued participation in the study and administer a purpose-designed electronic questionnaire to the parents/caregivers. The questionnaire will cover information such as socio-demographic data, health and residence characteristics, history of de-worming and malaria treatment. Height/length (cm) and weight (kg) of each child will be measured and anthropometric indices height-for-age, weight-for-age, weight-for-height, and body mass index, will be calculated using the WHO AnthroPlus software (www.who.int/growthref/tools/en/). The study villages will be mapped by recording each study participant's household global-positioning system (GPS) coordinates with a hand-held GPS device.

Following administration of the questionnaire, finger-prick blood samples will be collected from each child participant for thick and thin smear examination for malaria microscopy, and blood spot filter papers will be collected for DNA isolation and PCR amplification for species determination. Haemoglobin concentrations will be measured using the Haemocue® method. Freshly voided urine samples will also be collected from all study children. Urine filtration test will be used to quantify S. haemotobium, according to standard laboratory guidelines. Parallel testing for circulating cathodic antigens (CCA) will be used to complement the filtration test.

Stool samples will be collected to detect intestinal helminths. Duplicate Kato-Katz thick smears will be prepared from the stool samples and examined by experienced technicians using light microscopy to determine the egg counts for S. mansoni and STH. The number of eggs per slide will be used to obtain a measure of the number of helminth eggs per gram of faeces (EPG). The intensity of the helminth infection will be categorised according to standard guidelines. A multiplex PCR assay will also be used for simultaneous detection of mixed infections of helminths. Quality control will be performed by re-examining at least 10% of randomly selected blood slides, urine filters and Kato-Katz smears by an experienced independent laboratory scientist. Laboratory staff performing the analyses will be masked to the origin of the samples.

Intervention stage: The intervention stage will be implemented during SMC campaign in Bono East Region. Results obtained from the laboratory analysis of the blood, stool and urine samples collected from the children enrolled in the pre-intervention surveys in Kintampo North and Pru East districts will be used to determine which of the districts will host the intervention stage of the study. Given that the focus of this project is to evaluate the effectiveness of the integrated SMC-NTD control programmes, the intervention stage of the study will be conducted in the district with a higher prevalence of malaria, STH and schistosomiasis. Also, the intervention stage will be implemented in conjunction with the SMC providers in the selected district. The first day of starting the intervention stage (Day 0) will correspond to the day prior to the commencement of the first cycle of SMC in the selected district. On that day, the communities in the selected district will be randomised at the community level and stratified on the basis of the malaria and helminth prevalence (obtained from the pre-intervention surveys) into two groups at a 1:1 ratio to receive either combined SMC and anthelminthic drugs (intervention arm) or SMC drugs only (control arm). Given that 4-aminoquinoline drugs are reported to have antagonistic pharmacological interactions with praziquantel, the SMC partner drugs, amodiaquine AQ (a 4-aminoquinoline derivative) and sulphadoxine-pyrimethamine (SP) will not be administered with anthelminthic drugs (albendazole and praziquantel) on the same day in this study. Therefore, eligible children randomised into the intervention communities will receive albendazole and praziquantel on Day 0 and those randomised into the control communities will receive Vitamin A and Zinc supplements as control drugs. On the following day which corresponds to the start (Day 1) of the first SMC cycle, the children in the control and intervention communities will receive AQ and SP according to the WHO and Ghana SMC implementation guidelines. This will be followed on the second and third day of the SMC cycle with all study children in the two groups receiving AQ, in line with the SMC guidelines. All children irrespective of the study arms will undergo safety assessment.

Post-intervention stage: All child participants enrolled in the intervention study will be evaluated one month after the last course of SMC cycles, which corresponds to the end of malaria transmission season, to measure their haemoglobin concentration and to obtain a further blood film, dried blood spot, stool and urine samples, to test for malaria-helminth co-infections using parasitological methods such as microscopy, Kato-Katz, urine filtration test and improved diagnostic tools including molecular methods (qPCR), as described above.

Data collection for the cost and cost-effectiveness analyses: The incremental financial and economic costs of delivering the integrated SMC-anthelminthic drugs programme in the intervention stage of this study will be estimated from a health service (Ministry of Health and donor) perspective, compared to the counterfactual of giving SMC drugs alone. Financial cost data (including all direct expenditures on the trial including salaries) and economic costs (donated goods or services, such as time of salaried health workers) will be collected through reviews of project records and semi-structured key informant interviews (KIIs) at district, health facility and community health workers (CHW) levels. Detailed costs will be captured for disaggregated cost categories, including SMC and MDA drugs; drug supply chain; CHW delivery of doses; supervision; training; planning meetings; sensitisation; and supplies. Incremental costs required for the integrated delivery of anti-helminth MDA with SMC above what would be required for SMC delivery alone will be identified. The cost of diagnosis and treatment of moderate and severe anaemia from the health service perspective will be estimated using a combination of primary and secondary data. Cost per outpatient visit and cost per inpatient day (excluding diagnosis and treatment) will be obtained from existing data sources. Costs of diagnostic tests, medicines and provider time for treating cases of moderate and severe anaemia will be captured through KIIs with health staff at facilities providing outpatient and inpatient services in the study area. These parameters will be used to estimate incremental cost savings due to cases of moderate and severe anaemia averted by SMC plus MDA compared to SMC alone.

For the cost-effectiveness analysis (CEA), the main measure of the effects will be disability-adjusted life-years (DALYs) averted. DALYs combine mortality (years of life lost, YLLs) and morbidity (years lived with disability, YLDs) into a single measure of effect, allowing the impact of SMC + MDA to be compared with the impact of different types of health interventions. The effect measure used to calculate DALYs will be moderate and severe anaemia cases averted (where anaemia is the primary outcome for the CEA which is where the main incremental health benefit from co-delivery is expected), derived from unadjusted results of the trial, calculated on the basis of intention-to-treat. DALYs will be modelled using a 3% discount rate in the base case, no age weighting, standard DALY weights and life tables, and other secondary data (e.g. duration of an episode of anaemia). The CEA results will be expressed as an incremental cost-effectiveness ratio (ICER). The ICER is calculated as the difference in costs between MDA + SMC versus SMC alone, divided by the difference in effects between those strategies.