Efficacy of Chloroquine-Primaquine Treatment for Uncomplicated Plasmodium Vivax Malaria

Overview

The study was designed to evaluate the current efficacy of this combination therapy against P. vivax, given the possibility of misuse or inadequate adherence to the regimen due to its lengthy treatment duration, in one of a vivax-endemic area in southwest Ethiopia. A 42-day in vivo drug efficacy study was carried out as an open, two arm clinical trial involving 192 patients with uncomplicated P. vivax mono infection. Participants were allocated into two groups: supervised (n = 96) and unsupervised (n = 96). Both groups received CQ, 25 mg/kg over 3 days) and PQ, 0.25 mg/kg/day for 14 days). In the supervised group, treatment was administered under direct monitoring by healthcare providers and follow up was scheduled according to the World Health Organization (WHO) recommended drug efficacy testing protocol. Whereas patients in the unsupervised group were instructed to take their medication at home without direct monitoring and were advised to adhere to the treatment regimen. Their medication adherence and malaria episodes were monitored through scheduled phone follow ups.

The study area The study was conducted at a health center in Jimma Town, Oromia Regional State, South-west Ethiopia. Jimma lies 352 km southwest of Addis Ababa, the capital city of Ethiopia. In this region, malaria transmission is seasonal, peaking during and after the rainy season, with P. falciparum and P. vivax co-endemic. Study Participants and Eligibility Patients of all ages presenting with uncomplicated P. vivax malaria who fulfilled the inclusion criteria were recruited following the WHO protocol for antimalarial efficacy testing. Sample Size Sample size was calculated assuming a 5% treatment failure rate for CQ plus PQ, with ±5% precision at 95% confidence, as per the standard of WHO anti-malarial efficacy testing guideline. After adjusting for 20% loss to follow-up, 96 participants were required per arm, yielding a total of 19. Study Design An open-label, two-arm clinical trial was conducted. The patients' recruitment to the study was started on 01 December, 2024 and ended on November 30, 2025. Hence, the symptomatic vivax malaria patients were enrolled and randomly assigned to one of two treatment groups: supervised and unsupervised. The supervised group received CQ (250 mg, batch no. 33342, Addis Pharmaceutical Factory PLC) and PQ (7.5 mg, batch no. 110701, Remedica Ltd., Cyprus) under direct observation, following national guidelines (CQ 25 mg/kg over 3 days; PQ 0.25 mg/kg daily for 14 days). Patients were monitored for 30 minutes post-dose; those vomiting once were re-treated, while those vomiting twice were excluded from the study. The unsupervised group received the same regimen from the health facility pharmacy, self-administered at home (mimicking the routine malaria treatment practice in Ethiopian health facilities), and participated in scheduled telephone follow-ups (days 2, 3, 7, 14, 21, 28, 35, 42). These calls were to distantly monitor medication adherence, incidence of malaria-like symptoms, and reasons for missed doses, in case of non-adherence. Then the adherence was classified as: (i) Probably adherent (adherent) (ii) Probably non-adherent (iii) Certainly, non-adherent (non-adherent) Clinical and Laboratory Assessments An in vivo drug efficacy test was conducted following WHO-recommended procedure. Accordingly, for the supervised group, on day 0, blood samples were collected from a pricked finger for parasite identification and quantification after thin and thick smears were prepared. Hemoglobin levels were measured at baseline and on days 7, 14, and 42. The participants attended scheduled visits on days 1, 2, 3, 7, 14, 28, 35, and 42 to monitor recurrence of parasitemia in their blood and to assess the resolution of some adverse effects, and also unscheduled visits were permitted for any interim illness. Safety and tolerability data were collected during the first 14 days. Hemolysis was visually assessed only in the supervised group using the Hillmen Colour Chart. Quality Assurance Microscopy was performed independently by two technicians, with discrepancies resolved by a third reader. Equipment such as haemoglobin meters and thermometers was calibrated before data collection. In addition, all P. vivax-positive slides collected on the day of admission, a random 10% sample of negative slides prepared during follow-up, and all slides from the follow-up were re-examined by a senior laboratory technician. All staff received training to ensure protocol adherence. All health care providers who participated in the study received training before data collection to ensure strict adherence to the study protocol, and daily verification of recorded data was performed. All drugs used for patient treatment were supplied by the Ethiopian Pharmaceuticals Supply Service, with guaranteed quality assurance. Ethical Approval and Consideration The study received ethical clearance from the Jimma University Institutional Review Board (IRB) (RSG/149/2024) before data collection began. Written informed consent was obtained from each participant, and none of the participants had consent waived. In case of patients under 18 years of age, including infants and children, the guardian signed written consent, and all signed forms were documented at Jimma University. Before enrolment, the ethical procedures and detailed study protocol were thoroughly explained to all patients. Only those who volunteered or met the inclusion criteria were enrolled in the study. All the study procedures were carried out in accordance with the Declaration of Helsinki.