The impact of providing rapid diagnostic malaria tests on fever management in the private retail sector in Ghana: a cluster randomized trial

Study site and population

The trial was carried out in Dangme West, a rural district with widespread poverty in Ghana with an estimated population of 142 633 in 2009 mid-year. The people live in scattered small communities and are mostly subsistence farmers or fishermen. Vehicular transport is unavailable in many parts of the district, making access to formal care difficult. Health services are organized around a three tier system at district level, with the district hospital as the referral level, the health centre at subdistrict level, and the Community Health and Planning and Services (CHPS) compounds, which deliver close-to-client services mostly at home, at community level. There is one district hospital, three health centres, 13 CHPS compounds, and five formal private health facilities. In addition, 56 chemical shops and six pharmacies sell pharmaceutical products (fig 1⇓); Licensed Chemical Sellers are the main outlet for antimalarials in Ghana.. Earlier studies carried out in the district showed that for presumed “malaria” in the household, the first action taken is, in order of the most common: home treatment, chemical shop, health centre, hospital, drug peddler, and traditional healer.12 35 36 The study was conducted across both the high and low transmission seasons.

Chemical sellers in Ghana are regulated by the Pharmacy Council. To be eligible, a person must possess a minimum of secondary school level qualification, with basic knowledge in healthcare delivery being an advantage. Applicants attend pre-licensing training, and the licenses are renewed annually. The shops are legally allowed to retail over-the-counter medicines to members of the public in communities that the Pharmacy Council considers poor. The authorized medicines include analgesics and antimalarials. The only antibiotic allowed is co-trimoxazole.

Trial design

A cluster randomized trial design was used, with a cluster defined as a community with at least one chemical shop. Twenty four communities, with one to five shops per community, were eligible for inclusion in the study. The trial was evaluated among clients reporting to a participating chemical shop complaining of fever or requesting an antimalarial medicine. Clients were excluded if they were pregnant, <6 months old, had signs of severe disease, a prescription from a health facility, or would be in the district for less than 28 days. Assessments for eligibility were carried out by the chemical sellers, who were trained to do so. Clients with severe disease or who were pregnant were referred to the nearest health centre or the district hospital by the chemical seller.

An initial baseline study was carried out involving a census, including Global Positioning System (GPS), of all chemical shops to document the location of each shop and antimalarials available. The results of the baseline informed the study design. As part of formative research, focus group discussions were held with community members and chemical sellers to find out how acceptable the idea of chemical sellers testing for malaria in shops was, to community members and the best way to introduce the intervention.

The intervention

Shops in communities randomised to the control arm were expected to dispense medicines without test results as per current practice, while those in the intervention arm carried out a test for malaria using an rapid diagnostic test before dispensing any medication. In positive malaria tests, rapid diagnostic tests form a coloured line in the test area. Tests generally take 15–20 minutes depending on the test kit. CareStart Malaria HRP2 (Pf) rapid diagnostic test kits, which fulfil all the WHO assessment criteria, were provided by the study team on a monthly basis and were free of charge to chemical sellers and clients. The study team carried out regular quality control procedures by picking a random sample of test kits from the shop for testing using standard positive blood samples. This was to ensure that the rapid diagnostic test kits continued to perform optimally under the storage conditions in the chemical shop.

All chemical sellers attended a three day training on malaria, covering topics that included the antimalarial drug policy of Ghana; causes, signs, and symptoms of malaria; signs of severe disease and indications for referral; how to take a blood sample and make a blood slide; blood safety and handling of sharps; infection prevention procedures; and standard operating procedures of the study. Sellers in the intervention arm attended an additional day of training, covering how to carry out and interpret rapid diagnostic tests for malaria and further management of clients with a negative rapid diagnostic test result. The training involved a demonstration by a laboratory technologist followed by practice sessions by chemical sellers on their colleagues. They practised how to take a blood sample safely and also tested for malaria with a rapid diagnostic test. Test kits, sharps bins, and documentation were introduced and used during the training. Lecture sessions were interspersed with group discussions, role plays, and individual exercises. Assignments were marked and discussed in class. A minimum of two attendants were trained per shop to ensure continuity of service. After the training, all chemical sellers were provided with reference charts for doses of artemisinin combination therapies. Whenever a trained shop attendant resigned and was replaced by a new one, training was carried out in the shop for the new attendant.

Since Ghana was one of the phase one countries benefitting from the Affordable Medicines Facility for malaria, subsidized artemisinin combination therapy was available at the lowest level of the private drug retail sector from mid-2011, and chemical sellers were encouraged to use their regular source of supply of antimalarials. Bins for disposal of sharps and a certificate identifying the seller as a trained provider of malaria testing were also provided. Fieldworkers and supervisors were also trained separately in taking of blood samples and rapid diagnostic tests and the standard operating procedures of the study to enable them to provide technical support to the chemical sellers.

Study outcomes

The primary outcome was the proportion of clients who tested negative for malaria by a double-read research blood slide and who received an artemisinin combination therapy or other antimalarial. Secondary outcomes included treatment with antibiotics by test outcome, treatment of patients with a negative rapid diagnostic test result, treatment with other antimalarials or alternative treatments, the operational sensitivity of the rapid diagnostic tests used by chemical sellers against research slide results, the safety of use of rapid diagnostic tests at community level, and the impact on numbers of referrals to formal medical care.

The presence of malaria was assessed through a blood slide, which was prepared by health centre laboratory staff from a blood sample taken by the chemical seller as part of the consultation with the client regardless of study arm. Slides were double-read in research laboratories, and discrepant slides were re-read by a third and senior microscopist. Information on the test results obtained, medications dispensed, and whether the client was referred were documented by the seller on a form designed specifically for the study. The accuracy of the records of drugs dispensed was validated by conducting random checks of the forms and through “mystery clients.”

The “mystery client” complained of symptoms for himself or his child at home and submitted to a test when it was offered, observing the procedure the chemical seller followed for later documentation using a checklist. To ensure that chemical sellers correctly conducted the rapid diagnostic tests and adhered to safety and infection control procedures, direct observation of interactions between chemical sellers and clients was carried out by the study team using a checklist on a weekly basis during the first month of evaluation and for a further week mid-way through the trial in both arms.

In both arms clients were assessed for eligibility and requested to provide written consent for participation in the study. Basic demographic details were collected from all consenting clients, and a blood sample was taken by the chemical seller for the research slide. Detailed directions to the client’s home were also collected for the purposes of follow-up. Chemical sellers had access to the subsidized green leaf logo artemisinin combination therapy from the open market via the Affordable Medicines Facility for malaria. In the control arm, services were provided to clients following usual practice without test results. The chemical sellers collected a blood sample in a “microtainer” for study testing but did not do rapid diagnostic test testing. Control chemical sellers used the same client record form as the intervention arm.

In the rapid diagnostic test arm consent provided by clients included consent for rapid diagnostic testing. If the test result was positive, chemical sellers were trained to encourage clients to purchase any of the three recommended artemisinin combination therapies; amodiaquine-artesunate, arthemeter-lumefantrine, or dihydroartemisinine-piperaquine. Clients with a negative test were recommended to be referred to a nearby health facility or a facility of their choice. Clients who refused consent for a rapid diagnostic test received presumptive treatment (current practice), and reasons for the refusal of consent were documented. Blood slide results were provided to all shops after three days; the results of the blood slide were therefore not used by the chemical seller for initial dispensing decisions. Patients who were slide-positive but who had not been given an antimalarial in the chemical shop were contacted within 24 hours and requested to return to the chemical shop for an antimalarial. Follow-up was carried out on day 28 after the visit to the shop for all research slide-positive patients to determine the clinical course and outcome of the illness and care seeking behaviour after the visit to the chemical seller.

Randomization and registration

Communities were allocated to intervention or control by a process of restricted randomisation to ensure balance in covariates expected to be important correlates of the primary outcome.37 38 Because of the differing number of shops in each community, the balance was restricted to a difference of two in the number of chemical shops per arm, the same number of communities containing only one shop per arm, and a maximum relative difference of 20% in the average number of cases per day. Randomisation used a program written in R (version 2.14.2) by a statistician not otherwise involved in the study. All chemical sellers from shops assigned to each arm were invited to a meeting with the study team, informed about their assignment, and enrolled into their study arm. Following this, community sensitization meetings and durbars (a large community meeting usually hosted by the traditional leaders of the community during which issues important to the community are discussed and consensus reached) were carried out to explain the intervention to community members.

Those preparing and reading the blood slides were blind to the study allocation and rapid diagnostic test result.

Permission was given by the Ghana Pharmacy Council for chemical shop involvement. The trial received ethical clearance from the Ethical Review Committee of the Ghana Health Service and the ethics committee of the London School of Hygiene & Tropical Medicine. It was registered on ClinicalTrials.gov NCT01907672 before July 2011, although, because of a technical misunderstanding, there was a delay in releasing the protocol until September after trial start. (Formal release of the protocol was after randomization but before any outcome data were collected or analyzed, and no major changes were made between the attempt to register the study and the date when registration was complete.)

Statistical methods

After sample size calculations, the aim was for 24 communities (12 per arm) to be included. Calculations were conducted to determine a trial size sufficient to detect a 25% relative reduction in the primary outcome from 60% in the control arm among adults and 50% among children. Using methods for cluster randomised trials and assuming a coefficient of variation between clusters of 0.2, 80 adults and 114 children per community were required to detect the specified reductions with 80% power at the 5% significance level.39

Data were double entered and validated using Epidata 6.1, and analyzed using STATA version 12.0 (STATA Corporation, College Station, Texas). The effect of the intervention was analyzed using published methods suitable for cluster randomized trials with fewer than 20 clusters per arm.38 39 The observed proportion with the primary outcome was calculated for each community (cluster). Within each arm, a weighted average of the cluster proportions was taken with weights provided by the sample size for each cluster, to give the prevalence of the primary outcome in each arm. Due to the skewness in the distribution of the cluster proportions, a log transformation was applied and the mean of the log-proportions over clusters (log of the geometric mean) was estimated in each arm. The unadjusted risk ratio was then computed from exponentiation of the log of the ratio of these geometric means. The pooled variance of the log-proportions over clusters within each arm was calculated and used to obtain 95% confidence intervals and carry out formal hypothesis testing using a t test on the logarithm of the risk ratio. Adjustment for covariates was made by firstly fitting a standard logistic regression model to the individual-level data, including terms for the covariates of interest, but excluding the intervention effect. From the fitted model, the expected number of events in each cluster was computed. The ratio of the observed to expected number of events in each cluster was used to calculate cluster-specific ratio residuals. The next stage of analysis was to compare the residuals between study arms using the above methods for estimating the risk ratios and 95% confidence intervals as well as hypothesis testing with the residuals replacing cluster-level proportions. Analysis by age group and analyses of secondary outcomes were conducted using the same methods.