AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial

Abstract

SummaryBackgroundChloroquine was used for malaria treatment until resistant Plasmodium falciparum was identified. Because 4-aminoquinolines with modified side chains, such as AQ-13, are active against resistant parasites, we compared AQ-13 against artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria.MethodsWe did a randomised, non-inferiority trial. We screened men (≥18 years) with uncomplicated malaria in Missira (northeast Mali) and Bamako (capital of Mali) for eligibility (≥2000 asexual P falciparum parasites per μL of blood). Eligible participants were randomly assigned to either the artemether plus lumefantrine group or AQ-13 group by permuting blocks of four with a random number generator. Physicians and others caring for the participants were masked, except for participants who received treatment and the research pharmacist who implemented the randomisation and provided treatment. Participants received either 80 mg of oral artemether and 480 mg of oral lumefantrine twice daily for 3 days or 638·50 mg of AQ-13 base (two oral capsules) on days 1 and 2, and 319·25 mg base (one oral capsule) on day 3. Participants were monitored for parasite clearance (50 μL blood samples twice daily at 12 h intervals until two consecutive negative samples were obtained) and interviewed for adverse events (once every day) as inpatients during week 1. During the 5-week outpatient follow-up, participants were examined for adverse events and recurrent infection twice per week. All participants were included in the intention-to-treat analysis and per-protocol analysis, except for those who dropped out in the per-protocol analysis. The composite primary outcome was clearance of asexual parasites and fever by day 7, and absence of recrudescent infection by parasites with the same molecular markers from days 8 to 42 (defined as cure). Non-inferiority was considered established if the proportion of patients who were cured was higher for artemether plus lumefantrine than for AQ-13 and the upper limit of the 95% CI was less than the non-inferiority margin of 15%. This trial is registered at ClinicalTrials.gov, number NCT01614964.FindingsBetween Aug 6 and Nov 18, 2013, and between Sept 18 and Nov 20, 2015, 66 Malian men with uncomplicated malaria were enrolled. 33 participants were randomly assigned to each group. There were no serious adverse events (grade 2–4) and asexual parasites were cleared by day 7 in both groups. 453 less-severe adverse events (≤grade 1) were reported: 214 in the combination group and 239 in the AQ-13 group. Two participants withdrew from the AQ-13 group after parasite clearance and three were lost to follow-up. In the artemether plus lumefantrine group, two participants had late treatment failures (same markers as original isolates). On the basis of the per-protocol analysis, the AQ-13 and artemether plus lumefantrine groups had similar proportions cured (28 [100%] of 28 vs 31 [93·9%] of 33; p=0·50) and AQ-13 was not inferior to artemether plus lumefantrine (difference −6·1%, 95% CI −...

A Phase II Pilot Trial to Evaluate CoBaT-Y017 Safety and Efficacy against Uncomplicated Falciparum Malaria versus Artemether‐Lumefantrine in Benin Subjects

“…which comes after the headaches in terms of frequencies. Similar data were obtained in another comparative study in which headache accounted for a higher proportion of adverse events followed by fatigue in patients treated with AL [22]. e main interest of this work was that we started from the realities of field.…”

Therapeutic efficacy of artemether-lumefantrine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali, 2015–2016

“…We assessed the post-treatment prophylactic effects of the ACTs by including new infections in the denominator of the uncorrected e cacy estimations. Kaplan Meier estimates were calculated for the uncorrected e cacy, the PCR-corrected e cacy for risk of recrudescence (per WHO guidelines [11]), and the PCR-corrected e cacy for reinfections only (using an approach described in [18]. ).…”

In Vivo and In Vitro Activities and ADME-Tox Profile of a Quinolizidine-Modified 4-Aminoquinoline: A Potent Anti-P. falciparum and Anti-P. vivax Blood-Stage Antimalarial

“…This is the case for ferroquine and for AQ-13, in which a ferrocenyl moiety or a short diethylaminopropyl group replaced the side chain of chloroquine, respectively [ 16 , 29 , 30 ]. Both compounds successfully completed phase I studies [ 19 , 20 ] in human volunteers and in asymptomatic patients, and are presently under phase II efficacy studies, either alone or in combination ( , ).…”

“…Over the years, several compounds active also in CQ-resistant strains have been synthesized and some of them, including one from our group, reached pre-clinical testing [ 13 , 14 , 15 ]. Ferroquine and AQ 13, for example, are in advanced clinical phase II evaluation [ 16 , 17 , 18 , 19 , 20 ].…”