Investigators

Background:

The CDA study is a multi-centre study carried out in about seven (7) other African sites including Burkina Faso, Ghana, Kenya, Nigeria, and Tanzanian. The broad aim of the study is to obtain a safe, effective and affordable Artemisinin-based Combination Therapy for the treatment of uncomplicated P. falciparum malaria in Africa.

Chlorproguanil-dapsone (LAPDAP) has been approved for the treatment of uncomplicated Plasmodium falciparum malaria across a number of sub-Saharan African countries. The combination of chlorproguanil-dapsone-artesunate (CDA) is developed as an alternate drug to Artemether-lumefantrine (Coartem) which is the only available fixed-dose Artemisinin-based Combination Therapy available and considered as the gold standard for the treatment of P.falciparum malaria.

Objectives:

Primary Objective:

• To demonstrate that CDA is non-inferior to artemether-lumefantrine when comparing efficacy at day 28.

Secondary Objectives:

• To compare the efficacy of CDA verses artemether-lumefantrine at day 14 and 42.
• To compare the asexual parasite densities over time and the parasitological clearance time (PCT) of CDA verses artemether-lumefantrine.
• To compare the fever clearance time (FCT) of CDA verses artemether-lumefantrine.
• To compare gametocyte densities over time of CDA verses artemether-lumefantrine.
• To report the safety and tolerability of CDA.
• To describe the population pharmacokinetics profile of Chorproguanil, Chlorcycloguanil, Dapsone, Artesunate and Dihydroartemisinin in the CDA treatment group.

Primary endpoint

• Parasitological cure rate, PCR corrected, at day 28 in the PP population. The intent  to treat population is a key supportive analysis.

Secondary endpoints

• Parasitological cure rate, PCR corrected, at day 14 and 42.
• Adequate Clinical Parasitological Response (ACPR) and ACPR Polymerase Chain Reaction corrected at day 14, 28 and 42.
• Summary of asexual parasite densities on days 0, 1, 2, 3,7,14, 28 and 42 by treatment group.
• Parasite Clearance Time and Fever Clearance Time by treatment group.
• Summary of gametocyte densities on days 0, 1, 2, 3,7,14, 28 and 42 by treatment group.
• Safety assessments, including adverse events and serious adverse events reporting, laboratory results and Glucose-6-phosphate-dehydrogenase (G6PD) status.
• Population pharmacokinetics parameters.

Study Design

The study is a multi- centre, parallel group, double-blind, double-dummy, randomized controlled trial of CDA verses artemether-lumefantrine. Each subject is randomized to receive CDA or artemether-lumefantrine in the ratio of 2:1 respectively. Subjects are screened and randomized on day 0 (day of enrolment) and closely monitored until day 2 (third day after enrolment). Subjects are dosed once daily with CDA and twice daily with Coartem for three successive days (days 0, 1 and 2). Subjects are then seen at home by a field-worker on days 4, 5 and 6 then sent to the health facility on days 7, 14, 28 and 42 on follow up visits and any additional day on request. During the study period, subjects are also expected to report to the facility when ill. The study population comprises children and young adolescents from 12 months of age to 14 years who have uncomplicated malaria.

The randomization schedule is generated by a Registration and Randomization Ordering System (RAMOS). This system operates from a central base by GSK and involves providing information on an eligible subject at a time to get him/her registered. The entire RAMOS process on site is facilitated by a mobile phone communication system.

Data for this trial from the source documents were entered into an electronic case report form (CRF) online.

The RAMOS and online electronic CRF were being tried in the Centre for the first time and quite challenging.  The phone network was sometimes out of service and this made it impossible to enroll subjects although they qualified to be enrolled. The internet was also slow and lost connectivity.

Kintampo Health Research Centre was expected to enroll one hundred (100) subjects out of a total sample size of one thousand, three hundred and ninety-five thousand (1,395) subjects.

Activities carried out so far.

Preparatory activities for the study were put in place in the course of the previous year. Being a drug trial, approval to carry out the study was sought from the Ghana Food and Drugs Board. Ethical
approvals were also obtained from the Ghana Health Service Ethical Review Board, Kintampo Health Research Centre Ethics Committee and London School of Hygiene and Tropical Medicine Ethics Committee.

All study staff including clinicians, fieldworkers, data managers and data entry clerks were trained on the study procedures and data collection tools. Community entry activities involving consultation with chiefs and opinion leaders, and community members were also carried out. Facility-based screening of study participants started in the previous year.  

The first subject was enrolled on 9th January, 2007. Fieldworkers were stationed in the various communities to identify potential study participants and facilitate their transportation to the hospital for screening and subsequent enrollment into the study if qualified. Other functions of field workers were to follow and monitor the condition of subjects within the follow-up period, and to pick any adverse or serious adverse events for referral to the study clinician as soon as possible. Field supervisors visited the fieldworkers regularly to supervise them and also offer assistance where required.  Follow-up schedules were also provided to field staff to facilitate follow-up visits and referrals.

External monitors from World Health Organization (WHO) and GlaxoSmithKline (GSK) visited the centre to monitor the progress of work and ensure adherence to the study protocol and patient safety.

The study lasted for ten (10) months.

Compliance was high due to the cooperation of care-givers and community members in all aspects of the study.  A total number of five hundred and forty (540) subjects were screened out of which one hundred and ninety-three (193) were successfully enrolled into the study.
One hundred and eighty-eight (188) enrolled subjects reported for all scheduled follow-up visits. Only five (5) subjects were absent at different periods of follow-up. All five subjects traveled out of the study area during these follow-up visits.
Four (4) subjects were admitted during the study period for further observation as a result of enteric fever, persistent vomiting, and hemolytic anemia. Further data cleaning was carried out to finalize the study’s results.

At the end of fieldwork, community exit meetings were held with chiefs and opinion leaders to express appreciation for their co-operation and support.

Sponsors: GlaxoSmithKline (GSK), Medicines for Malaria Venture (MMV), World Health Organization (WHO-TDR) and Ghana Health Service (GHS)

Contact: Livesy Abokyi