Mefliam Plus (artesunate/mefloquine) / Cipla, Oswaldo Cruz Foundation, DNDi - LARVOL DELTA

DeTACT-Africa: A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combina-tions of 2 Anti-malarial Drugs. (clinicaltrials.gov) - P3 | N=2583 | Completed | Sponsor: University of Oxford | Recruiting ➔ Completed

Head-to-Head • Trial completion • Infectious Disease • Malaria

WITHDRAWN Monitoring the susceptibility of Plasmodium falciparum to Artesunate-Mefloquine in malaria-endemic regions of Vietnam (ASTMH 2025) - "Therefore, artesunate-mefloquine remains a highly effective, safe, and well-tolerated alternative in areas affected by dihydroartemisinin-piperaquine treatment failure. Given the high prevalence of artemisinin-resistant parasites, ongoing surveillance of treatment efficacy is crucial to prevent further resistance spread, maintain ACT effectiveness, and guide regional malaria control policies."

Infectious Disease • Malaria • ABCB1

Transplacental Transfer of Lumefantrine, Mefloquine, and Piperaquine: A Comparison of Concentrations in Mothers, Neonates, and Cord Blood. (PubMed, Clin Infect Dis) - "Antimalarial drugs crossed the placenta variably. Neonatal concentrations ranged from less than half (lumefantrine, mefloquine) to near maternal equivalence (piperaquine). Collection of neonatal capillary samples at birth should be considered in future studies.SummaryWe compared antimalarial blood concentrations in mothers, neonates, and cords. Neonatal drug concentrations ranged from near maternal equivalence (piperaquine) to less than half (lumefantrine, mefloquine). Cord concentrations may underestimate neonatal exposure. Future studies should consider neonatal capillary sampling."

Journal • Infectious Disease • Malaria

Finally - evidence-based regimens for single, low dose primaquine for transmission blocking. How did we do it? (ASTMH 2025) - "The ACTs were dihydroartemisinin piperaquine, artesunate pyronaridine, artesunate amodiaquine (ASAQ), artesunate mefloquine, artemether lumefantrine (AL), and the triple ALAQ. These regimens offer flexibility for malaria control programmes and guidance for drug manufacturers wishing to coblister SLDPQ with ACTs. The WHO should reinstate the 3.75 mg for prequalification and determine which of these regimens should be incorporated into their treatment guidelines to advance malaria elimination."

Infectious Disease • Malaria

Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria. (PubMed, Cochrane Database Syst Rev) - "Pyronaridine-artesunate was efficacious against uncomplicated P falciparum malaria; achieved a PCR-adjusted treatment failure rate of less than 8% at days 28 and 42; and may be at least as good as artesunate-amodiaquine and artesunate-mefloquine (based on 1 RCT per drug) and may be at least as good as, or better than, artemether-lumefantrine. Pyronaridine-artesunate increases the risk of episodes of abnormally raised ALT and AST compared to other studied therapeutics."

Clinical • Journal • Review • Hepatology • Infectious Disease • Liver Failure • Malaria

Single low dose primaquine to block the transmission of Plasmodium falciparum-proposed stand-alone and ACT-adapted regimens. (PubMed, BMC Med) - "These regimens offer flexibility for malaria control programmes and guidance for drug manufacturers wishing to co-blister SLDPQ with ACTs. The WHO should reinstate the 3.75 mg tablet for prequalification and determine which regimens should be incorporated into their treatment guidelines to advance malaria elimination."

Journal • Hematological Disorders • Infectious Disease • Malaria • Metabolic Disorders

Efficacy and safety of praziquantel plus artemisinin-based combinations versus praziquantel in the treatment of Kenyan children with Schistosoma mansoni infection: open-label, randomized, head-to-head, non-inferiority trial. (PubMed, Antimicrob Agents Chemother) - "Participants were randomly assigned (1:1:1:1:1) via a computer-generated block randomization procedure to receive a single oral dose of praziquantel (PZQ) (40 mg/kg/day) alone or in combination with a 3-day course (4 mg/kg of artesunate) of artesunate plus sulfalene-pyrimethamine (As + SP), artesunate plus amodiaquine (As + AQ), artesunate plus mefloquine (As + MQ) or dihydroartemisinin-piperaquine (DHAP). Alternatives to praziquantel should include praziquantel plus artesunate-mefloquine or praziquantel plus dihydroartemisinin-piperaquine. However, further multicentre trials are needed in different epidemiological settings and population groups to confirm these findings.CLINICAL TRIALSThis study is registered with the Pan-African Clinical Trials Registry under PACTR202001919442161."

Head-to-Head • Journal • Infectious Disease • Pain

The safety, tolerability and efficacy of artemether-lumefantrine+amodiaquine and artesunate+mefloquine+piperaquine against uncomplicated malaria in eight African countries. (ASTMH 2024) - No abstract available

Clinical • Infectious Disease • Malaria

2 - Can We Expect Triple/Multiple Artemisinin-Based Combination Therapies for Malaria in the Near Future? (ASTMH 2024) - "Artemether-lumefantrine (AL) is the most widely used ACT, accounting for >70% of ACT use...New antimalarial drugs may not come to the market within the next 5 years and one of the leading candidates, ganaplacide, is currently combined with lumefantrine...The Development of Triple Artemisinin-based Combination Therapies (DeTACT project), the ArteSunate-Amodiaquine-Atovaquone-Proguanil (ASAAP) consortium and the Multi-drug combination therapies to prevent Malaria drug resistance (MULTIMAL) consortium have been working TACTs and MDACTs to be primarily deployed in pediatric populations in African countries...The DeTACT clinical trial is complete and final results on safety, tolerability and efficacy of AL+amodiaquine (AL+AQ) and artesunate-mefloquine+piperaquine from eight African countries will be presented...The ASAAP consortium’s evaluation of clinical efficacy and transmission blocking potential of AL+atovaquone-proguanil in five African countries will be presented...."

Combination therapy • Infectious Disease • Malaria • Pediatrics

EFFECTS OF AL-BASED AND ASMQ-BASED DRUGS ON CARDIAC PARAMETERS: INSIGHTS FROM HEART RATE, ECG WAVEFORMS, AND REPOLARIZATION (CHEST 2024) - "PURPOSE: This study aimed to assess and compare the effects of two commonly used antimalarial drugs, Artemether-Lumefantrine (AL) and Artesunate-Mefloquine (ASMQ), on cardiac parameters in patients with uncomplicated malaria. The study highlights potential effects of AL and ASMQ on heart rate, ECG waveforms, and repolarization. These findings underscore the importance of close cardiac monitoring during antimalarial treatment, particularly in patients with pre-existing cardiac conditions or arrhythmia risk factors. Further research is needed to elucidate the long-term clinical significance of these changes."

Cardiovascular • Infectious Disease • Malaria

Intermittent preventive treatment for forest goers by forest malaria workers: an observational study on a key intervention for malaria elimination in Cambodia. (PubMed, Lancet Reg Health West Pac) - "In the second phase, a monthly artesunate-mefloquine IPTf was implemented by trained forest malaria workers who were former FGs conducting interviews, blood collection, and IPTf administration...Cambodia's National Malaria Program has acknowledged this strategy as essential for malaria elimination intervention, endorsing forest-specific approaches to meet the 2025 goal of eradicating all human malaria species in Cambodia. The study received funding from the French 5% Initiative (Initiative Canal 2-17SANIN205)."

Journal • Observational data • Infectious Disease • Malaria

DeTACT-Africa: A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combina-tions of 2 Anti-malarial Drugs. (clinicaltrials.gov) - P3 | N=3240 | Recruiting | Sponsor: University of Oxford | Trial completion date: Dec 2023 ➔ Sep 2024 | Trial primary completion date: Dec 2023 ➔ Mar 2024

Combination therapy • Head-to-Head • Trial completion date • Trial primary completion date • Infectious Disease • Malaria • ABCB1 • KCNH2 • KCNQ1OT1

Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combination. (PubMed, Front Cell Infect Microbiol) - "Here, we have used whole genome sequencing to characterize the genetic variation in the experimentally evolved Plasmodium chabaudi parasite clone AS-ATNMF1, which is resistant to artesunate + mefloquine. The mutation in the 26S proteasome subunit may therefore contribute to altering oxidation-dependent ubiquitination of the MDR-1 and/or K13 proteins and/or other targets, resulting in changes in protein turnover. In light of the alarming increase in resistance to artemisin derivatives and ACT partner drugs in natural parasite populations, our results shed new light on the biology of resistance and provide information on novel molecular markers of resistance that may be tested (and potentially validated) in the field."

Journal • Infectious Disease • Malaria • Targeted Protein Degradation • ABCB1

DeTACT-ASIA: A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combinations of 2 Anti-malarial Drugs (Asia) (clinicaltrials.gov) - P3 | N=103 | Completed | Sponsor: University of Oxford | Recruiting ➔ Completed | N=1368 ➔ 103

Combination therapy • Enrollment change • Head-to-Head • Trial completion • Infectious Disease • Malaria • ABCB1 • KCNH2 • KCNQ1OT1

Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial. (PubMed, Nat Med) - P3 | "Multicentric trials in different populations and epidemiological settings are needed to confirm these findings. ClinicalTrials.gov identifier: NCT03893097 ."

Journal • Infectious Disease

Myositis-specific autoantibodies in a non-traveler, patient from a non-endemic country, with Plasmodium vivax malaria. (PubMed, J Infect Dev Ctries) - "Malaria would not normally be considered during the initial diagnostic workup in a non-traveler and a patient from a non-endemic country. However, a thorough parasitic evaluation in patients presenting with a broad range of autoantibodies might be of particular importance."

Journal • Allergy • Fibrosis • Hematological Disorders • Immunology • Infectious Disease • Inflammation • Inflammatory Arthritis • Lupus • Malaria • Musculoskeletal Pain • Myositis • Pain • Scleroderma • Systemic Lupus Erythematosus • Systemic Sclerosis • CRP

Malaria and the Intermittent Preventative Treatment for Forest-Goers in Cambodia: Preliminary Results and Lessons Learned (ASTMH 2023) - "For example, due to reports of persistent side effects, CNM shifted from artesunate-mefloquine to artesunate-pyronaridine starting in August 2022. Despite the low uptake of IPTf, LME villages in Kampong Speu and Kratie implementing the full package of interventions have seen P. falciparum and mixed infections decrease by 82% over the last two years and there are ongoing analyses to ascertain whether this decrease was due, in part, to the distribution of IPTf. As Cambodia approaches elimination, documenting and sharing lessons learned and identifying which programs are truly accelerating elimination will be instrumental in aiding both Cambodia and the region in reaching their elimination targets."

Infectious Disease • Malaria

Mapping the epidemiology of drug-resistant Plasmodium falciparum strains in the Greater Mekong Subregion through cross-border genetic surveillance (ASTMH 2023) - "In Cambodia, where artesunate-mefloquine has been selected as frontline treatment, there is currently no indication of emerging resistance to mefloquine. Our results indicate that cross-border genetic surveillance is a strategic knowledge tool to inform elimination interventions."

Clinical • Infectious Disease • Malaria

Elucidating the interactions of pfcrt and plasmepsins 2/3 in modulating fitness and resistance in Plasmodium falciparum to piperaquine and other artemisinin partner drugs (ASTMH 2023) - "PPQ resistance-associated novel mutations in the P. falciparum chloroquine resistance transporter (pfcrt) including F145I or M343L, have also emerged on KEL1/PLA1 parasites expressing the Southeast Asian Dd2 pfcrt allele. Overall, our findings suggest that PPQ selects for pm2/3 amplification in mutant pfcrt parasites, and the poor fitness associated with multicopy pm2/3 may explain the loss of pm2/3 amplification in clinical isolates upon the switch from DHA+PPQ to artesunate+mefloquine. Furthermore, we demonstrate higher sensitivity of PPQ-resistant pfcrt alleles to lumefantrine and mefloquine, thus reinforcing their appeal as effective ACT drugs in Southeast Asia."

Infectious Disease • Malaria

Primaquine dose and the risk of haemolysis in patients with uncomplicated Plasmodium vivax malaria: a systematic review and individual patient data meta-analysis. (PubMed, Lancet Infect Dis) - "Treatment of patients with G6PD activity of 30% or higher with 0·25-0·5 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0·25-1 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses."

Journal • Retrospective data • Review • CNS Disorders • Hematological Disorders • Infectious Disease • Malaria • Psychiatry • Schizophrenia

Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis. (PubMed, Lancet Infect Dis) - "Increasing the total dose of primaquine from 3·5 mg/kg to 7 mg/kg can reduce P vivax recurrences by more than 50% in most endemic regions, with a small associated increase in gastrointestinal symptoms."

Journal • Retrospective data • Review • CNS Disorders • Gastrointestinal Disorder • Infectious Disease • Malaria • Psychiatry • Schizophrenia

Artesunate-mefloquine therapy for uncomplicated Plasmodium falciparum malaria: an updated systematic review and meta-analysis of efficacy and safety. (PubMed, Trans R Soc Trop Med Hyg) - "The incidence of serious adverse effects, such as seizure, encephalopathy and cardiac arrhythmia, was infrequent in both the ASMQ group and the comparison groups. After including new evidence, ASMQ is still recommended as a first-line treatment of uncomplicated malaria caused by P. falciparum, although local aspects need to be considered."

Clinical • Journal • Retrospective data • Review • Atrial Fibrillation • Cardiovascular • CNS Disorders • Epilepsy • Infectious Disease • Malaria

Preventing antimalarial drug resistance with triple artemisinin-based combination therapies. (PubMed, Nat Commun) - "Using two independent individual-based models of Plasmodium falciparum epidemiology and evolution, we evaluated whether introduction of either artesunate-mefloquine-piperaquine or artemether-lumefantrine-amodiaquine resulted in lower long-term artemisinin-resistance levels and treatment failure rates compared with continued ACT use. We show that introduction of TACTs could significantly delay the emergence and spread of artemisinin resistance and treatment failure, extending the useful therapeutic life of current antimalarial drugs, and improving the chances of malaria elimination. We conclude that immediate introduction of TACTs should be considered by policy makers in areas of emerging artemisinin resistance."

Combination therapy • Journal • Infectious Disease • Malaria

DeTACT-ASIA: A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combinations of 2 Anti-malarial Drugs (Asia) (clinicaltrials.gov) - P3 | N=1368 | Recruiting | Sponsor: University of Oxford | Trial completion date: Mar 2023 ➔ Dec 2023

Trial completion date • Infectious Disease • Malaria

DeTACT-Africa: A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combina-tions of 2 Anti-malarial Drugs. (clinicaltrials.gov) - P3 | N=3240 | Recruiting | Sponsor: University of Oxford | Trial completion date: Mar 2023 ➔ Dec 2023 | Trial primary completion date: Oct 2022 ➔ Dec 2023

Combination therapy • Head-to-Head • Trial completion date • Trial primary completion date • Infectious Disease • Malaria