Study 13: Implementation
After 2 years of preparation, the first patient was enrolled in August 2000 in the Kassena-Nankana District of Ghana, in October 2000 in Chittagong District of Bangladesh, January 2001 in Kilosa District and extended to Handeni District in April 2002.
During the trial, there was reinforcement of training, supervision and community awareness to improve and follow referral advice to hospitals. Some sites were very inaccessible, especially in the rainy season. Motorcycles of field supervisors broke down, as did cars, watches, and other equipment. Poor light at night sometimes caused a problem. Nobody reported meeting a lion but a clinical officer was shot in the chest with a shotgun when robbers demanded his bike; he complied but they shot him anyway. He later recovered.
There was support from the communities and health professionals for the study. The existing quality of service was improved, necessary antimalarials and related medications and equipment were monitored by the study team and some referral facilities had round the clock coverage by staff. There was constant referral of study patients to the nearest hospital.
In Ghana, high school leavers were hired to be village-based recruiters in the study. In Tanzania, the village health workers who were already residing in the study villages were used as village-based recruiters. Bangladesh had a mixture of the two systems, using existing health workers in some villages and new hired village workers in other villages.
In Bangladesh, the Ward is the lowest geographical administrative unit and usually comprises 2 - 3 villages. One fieldworker was deployed for each Ward, consequently there were 149 recruiters and 34 supervisors supervising them. In Tanzania there were 2 village health workers in each village who were trained as recruiters. In Ghana there were 35 communities with 45 recruiters and 6 field supervisors in charge of them; the larger communities had more than one recruiter.
Altogether therefore, locally resident village recruiters (268 in Africa, 149 in Bangladesh), most with little prior medical knowledge and no research experience, underwent training and recruited patients in their community on the basis of clinical symptoms. They conducted the study with supervisory visits every few days from field supervisors.
Each village recruiter was trained in good history taking and the identification of signs and symptoms of malaria. Training focused on;
- assessment of whether a patient was eligible to be enrolled on the basis of clinical symptoms
- obtaining a parent’s or guardians’ written consent
- completing the enrolment form
- referring the patient to the hospital, health centre or dispensary for diagnosis and management
- following up the patient 7-30 days later
- they were also trained to take a blood slide prior to treatment
First the recruiters were given information about malaria, the study and their role. Then they were trained on specific elements - eg classification of a patient as unable to take oral medications. They were trained to use the case record form, which was constructed to be very simple (requiring a tick for most questions) and followed the normal sequence of patient assessment. They were also trained to take informed consent, to take a blood slide, to emphasize that the patient should be taken to the nearest health facility as without delay, and to follow up the patient and fill out the follow-up form.
The aim was to identify, as close to their homes as possible, young children (assessed age 6 months to 6 years, 5 years in Tanzania) with suspected severe malaria who could not take oral medication, to randomise them to receive rectal artesunate or an identical placebo, and then to refer them immediately to a medical facility for diagnosis and curative treatment. There was training emphasis on the inclusion/exclusion criteria for entry into the study for a patient to be eligible for treatment, training to take a blood slide - safely and well.
To make the randomisation process as easy and problem free as possible, previous experience from the Clinical trial Service Unit in Oxford was brought to bear to design a drug carton for the study. A special drug dispensing carton was prepared, which had 4 or 8 small boxes of artesunate or placebo in each carton. The study drug for each patient (either one 100mg artesunate or one identical placebo capsule for children or 400mg for older patients) was in a small box, along with peelable uniquely coded identification labels. Once a box was removed from an aperture in the dispensing carton, the next one dropped to fill its place, ready for use.
Data safety monitoring committee and endpoint review committee
The data were provided to the Data Safety Monitoring Committee (DSMC) for review at intervals of approximately one year. In mid-2002, the statistician reporting to the DSMC visited the study site in Tanzania to assess the conduct of the study. The DSMC reviewed the data and communicated to the Study Director their recommendations - invariably that there was no reason for the findings to be unblinded or for the trial protocol to be modified.
During the study an Endpoint Review Committee (ERC) was set up to review the written narratives of the events leading to each death and to each report of neurological damage and to judge, blinded to treatment allocation, whether that death or adverse outcome might have been influenced by the patient having received rectal artesunate. At its first meeting, the ERC requested that long-term clinical follow-up of all unresolved neurological damage be instituted to establish whether the damage was persistent. The ERC also requested, for all deaths, information on time to death, time to hospitalization and whether there had been a definite hospital diagnosis other than malaria.