Published: August 30, 2025
Degaga, Tamiru Shibiru and Pasaribu, Ayodhia Pitaloka and Tripura, Rupam and Ghanchi, Najia and Rajasekhar, Megha and Adhikari, Bipin and Ley, Benedikt and Bamboro, Samuel Alemu and Jabbar, Fareeha Abdul and Hasibuan, Nurfadhilah and Tego, Tedla Teferi and Zehra, Shane and Qurashi, Bushra and Mnjala, Hellen and Lee, Grant and Li, Peixuan and Kazi, Momin and Safitri, Widaya and Yulita, Yulita and Siagian, Dedi Sahat Parningotan and Syahputra, Deni and Hadi, Halik and Muhammad, Taj and Ibrahim, Amna and Syed, Nasreen and Dost, Khuda and Puspitasari, Agatha Mia and Kariodimedjo, Pinkan Pertiwi and Rai, Anjana and Rumaseb, Angela and Sutanto, Edwin and Ean, Mom and Khan, Asia and Sokha, Meas and Commons, Robert James and Weston, Sophie and Noviyanti, Rintis and Peto, Tom and Callery, James J. and Ali, Umair and Mehmood, Tariq and Dondorp, Arjen M. and Devine, Angela and Setiawan, Ery and Mwaura, Muthoni and Cassidy-Seyoum, Sarah A. and Annose, Rodas Temesgen and Abate, Dagimawie Tadesse and Erjabo, Eyerusalem Beyene and Gessa, Geremew Gashaw and Kiros, Fitsum Getahun and Usmani, Muhammad Imran and Raza, Ali and Woyessa, Adugna and Mekuria, Asrat Hailu and Simpson, Julie A. and Karahalios, Amalia and Beg, Mohammad Asim and von Seidlein, Lorenz and Lek, Dysoley and Auburn, Sarah and Price, Ric N. and Thriemer, Kamala, Effectiveness and Safety of High Dose Primaquine and Tafenoquine in Plasmodium vivax Patients (EFFORT) – A Multi-Centre, Open Label, Superiority Randomised Controlled Trial. Available at SSRN: https://ssrn.com/abstract=5409116 or http://dx.doi.org/10.2139/ssrn.5409116
Background: Shorter courses of primaquine and single dose tafenoquine have potential to improve effectiveness in preventing recurrent Plasmodium vivax infection, but there are limited data on their comparative effectiveness when provided unsupervised.
Methods: We conducted a multi-centre, open-label randomised controlled superiority trial in Ethiopia, Pakistan, Indonesia and Cambodia. Adult patients with uncomplicated P. vivax infection and glucose-6-phosphate dehydrogenase (G6PD) activity of 70% or greater were eligible for enrolment. Patients were treated with blood schizontocidal drugs (chloroquine in Ethiopia and Pakistan, dihydroartemisinin-piperaquine in Indonesia and artesunate-pyronaridine in Cambodia) and randomly assigned (1:1:1) to receive 7 days of unsupervised high-dose primaquine (total dose 7mg/kg), single dose tafenoquine (300mg) or 14 days low-dose primaquine (total dose 3.5mg/kg). Assignment was done by an independent statistician using randomly permuted blocks of varying sizes. The primary endpoint was the cumulative incidence of any P. vivax parasitaemia within 6 months. The study was registered at ClinicalTrials.gov (NCT04411836).
Findings: Between April 2021 and September 2024, a total of 960 patients were enrolled. The cumulative incidence of P. vivax recurrence at 6 months was 13·0% (95% CI 9·4-17·7) in the 7-day-high-dose primaquine arm and 18·5% (95% CI 14·3-23·8) in the 14-day-low-dose primaquine arm (Hazard Ratio (HR) =0·66; 95% CI 0·43-1·02, p=0·063). The corresponding incidence in the tafenoquine arm was 12·6% (95% CI 9·2-17·2), with an HR of 0·96 (0·60-1·55, p=0·875) compared with the 7-day-high-dose primaquine arm.Of the adverse events occurring before day 42, 43% (24/56) were reported as drug related in the 7-day-high-dose primaquine arm, compared to 22% (16/72) in the tafenoquine arm and 34% (13/38) in the 14-day-low-dose primaquine arm. Two drug related serious adverse events occurred in the 7-day-high-dose primaquine arm.
Interpretation: Both unsupervised 7-day-high-dose primaquine and tafenoquine were well tolerated in G6PD normal patients and reduced the risk of P. vivax recurrence compared to 14-day-low-dose primaquine. Our findings support the geographic extension of the current tafenoquine recommendation with chloroquine to high burden areas such as Ethiopia and Pakistan. The effectiveness of tafenoquine when co-administered with artemisinin combination therapies (ACTs) in Cambodia and Indonesia challenges current recommendations and warrants further clinical evaluation.
Tamiru Degaga | Kamala Thriemer | Megha Rajasekhar | Benedikt Ley | Hellen Mnjala | Peixuan Li | Anjana Rai | Angela Rumaseb | Edwin Sutanto | Rob Commons | Angela Devine | Muthoni Mwaura | Sarah A. Cassidy-Seyoum | Ery Setiawan | Julie Simpson | Emily Karahalios | Sarah Auburn | Ric Price
