Parasite clearance, cure rate, post-treatment prophylaxis and safety of standard 3-day versus an extended 6-day treatment of artemether-lumefantrine and a single low-dose primaquine for uncomplicated Plasmodium falciparum malaria in Bagamoyo district, Tanzania: a randomized controlled trial

Lwidiko E Mhamilawa, Billy Ngasala, Ulrika Morris, Eliford Ngaimisi Kitabi, Rory Barnes, Aung Paing Soe, Bruno P Mmbando, Anders Björkman, Andreas Mårtensson, Lwidiko E Mhamilawa, Billy Ngasala, Ulrika Morris, Eliford Ngaimisi Kitabi, Rory Barnes, Aung Paing Soe, Bruno P Mmbando, Anders Björkman, Andreas Mårtensson

Abstract

Background: Artemisinin-based combination therapy (ACT) resistant Plasmodium falciparum represents an increasing threat to Africa. Extended ACT regimens from standard 3 to 6 days may represent a means to prevent its development and potential spread in Africa.

Methods: Standard 3-day treatment with artemether-lumefantrine (control) was compared to extended 6-day treatment and single low-dose primaquine (intervention); in a randomized controlled, parallel group, superiority clinical trial of patients aged 1-65 years with microscopy confirmed uncomplicated P. falciparum malaria, enrolled in Bagamoyo district, Tanzania. The study evaluated parasite clearance, including proportion of PCR detectable P. falciparum on days 5 and 7 (primary endpoint), cure rate, post-treatment prophylaxis, safety and tolerability. Clinical, and laboratory assessments, including ECG were conducted during 42 days of follow-up. Blood samples were collected for parasite detection (by microscopy and PCR), molecular genotyping and pharmacokinetic analyses. Kaplan-Meier survival analyses were done for both parasite clearance and recurrence.

Results: A total of 280 patients were enrolled, 141 and 139 in the control and intervention arm, respectively, of whom 121 completed 42 days follow-up in each arm. There was no difference in proportion of PCR positivity across the arms at day 5 (80/130 (61.5%) vs 89/134 (66.4%), p = 0.44), or day 7 (71/129 (55.0%) vs 70/134 (52.2%), p = 0.71). Day 42 microscopy determined cure rates (PCR adjusted) were 97.4% (100/103) and 98.3% (110/112), p = 0.65, in the control and intervention arm, respectively. Microscopy determined crude recurrent parasitaemia during follow-up was 21/121 (17.4%) in the control and 14/121 (11.6%) in the intervention arm, p = 0.20, and it took 34 days and 42 days in the respective arms for 90% of the patients to remain without recurrent parasitaemia. Lumefantrine exposure was significantly higher in intervention arm from D3 to D42, but cardiac, biochemical and haematological safety was high and similar in both arms.

Conclusion: Extended 6-day artemether-lumefantrine treatment and a single low-dose of primaquine was not superior to standard 3-day treatment for ACT sensitive P. falciparum infections but, importantly, equally efficacious and safe. Thus, extended artemether-lumefantrine treatment may be considered as a future treatment regimen for ACT resistant P. falciparum, to prolong the therapeutic lifespan of ACT in Africa. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017 https://ichgcp.net/clinical-trials-registry/NCT03241901.

Keywords: Artemether–lumefantrine; Drug resistance; Malaria; Plasmodium falciparum; Tanzania.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow of patients through the study
Fig. 2
Fig. 2
Parasite clearance by microscopy and fever clearance within treatment arms. a Percent of patients in each treatment arm positive by microscopy during first 72 h of treatment. b Percent of patients in each arm that remained febrile after initiation of artemether–lumefantrine during the first 72 h
Fig. 3
Fig. 3
Kaplan–Meier cumulative survival curve; time to microscopy determined recurrent parasitaemia (crude cure rates)
Fig. 4
Fig. 4
Proportion of P. falciparum detected by PCR among 81 patients for 20 sampling time points. Out of the 81 patients, 35 had recurrent parasitaemia by microscopy and 46 did not have recurrent parasitaemia during the 42-day follow-up period
Fig. 5
Fig. 5
Dot plot of qPCR determined parasite densities for 81 patients for 20 sampling time points. Out of the 81 patients, 35 had recurrent parasitaemia by microscopy and 46 did not have recurrent parasitaemia during the 42-day follow-up period
Fig. 6
Fig. 6
Bar plot modelling distribution of lumefantrine concentration at days 2–42 after treatment across treatment arms

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