Pharmacokinetics, safety, and efficacy of a single co-administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without Wuchereria bancrofti infection in Côte d'Ivoire.

BACKGROUND: A single co-administered dose of ivermectin (IVM) plus diethylcarbamazine (DEC) plus albendazole (ALB), or triple-drug therapy, was recently found to be more effective for clearing microfilariae (Mf) than standard DEC plus ALB currently used for mass drug administration programs for lymphatic filariasis (LF) outside of sub-Saharan Africa. Triple-drug therapy has not been previously tested in LF-uninfected individuals from Africa. This study evaluated the pharmacokinetics (PK), safety, and efficacy of triple-drug therapy in people with and without Wuchereria bancrofti infection in West Africa. METHODS: In this open-label cohort study, treatment-naïve microfilaremic (>50 mf/mL, n = 32) and uninfected (circulating filarial antigen negative, n = 24) adults residing in Agboville district, Côte d'Ivoire, were treated with a single dose of IVM plus DEC plus ALB, and evaluated for adverse events (AEs) until 7 days post treatment. Drug levels were assessed by liquid chromatography and mass spectrometry. Persons responsible for assessing AEs were blinded to participants' infection status. FINDINGS: There was no difference in AUC0-inf or Cmax between LF-infected and uninfected participants (P>0.05 for all comparisons). All subjects experienced mild AEs; 28% and 25% of infected and uninfected participants experienced grade 2 AEs, respectively. There were no severe or serious adverse events. Only fever (16 of 32 versus 4 of 24, P<0.001) and scrotal pain/swelling in males (6 of 20 versus 0 of 12, P = 0.025) were more frequent in infected than uninfected participants. All LF positive participants were amicrofilaremic at 7 days post-treatment and 27 of 31 (87%) remained amicrofilaremic 12 months after treatment. CONCLUSIONS: Moderate to heavy W. bancrofti infection did not affect PK parameters for IVM, DEC or ALB following a single co-administered dose of these drugs compared to uninfected individuals. The drugs were well tolerated. This study confirmed the efficacy of the triple-drug therapy for clearing W. bancrofti Mf and has added important information to support the use of this regimen in LF elimination programs in areas of Africa without co-endemic onchocerciasis or loiasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02845713.

Comparison of azithromycin plus chloroquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in children in Africa: a randomized, open-label study.

BACKGROUND: This randomized, open-label study was conducted to establish the non-inferiority of a combination of azithromycin (AZ) and chloroquine (CQ) to artemether-lumefantrine (AL) for treatment of uncomplicated malaria in children from six sites in sub-Saharan Africa. METHODS: Children with uncomplicated Plasmodium falciparum malaria between six and 59 months of age were randomized 1:1 to either AZCQ (30 mg/kg AZ + 10 mg/kg CQ base) or AL per prescribing information for three days (Days 0, 1, 2). Each site could enrol in the study population once the treatment of uncomplicated malaria in five children five to 12 years of age was deemed to be effective and well tolerated. The primary efficacy evaluation was the proportion of subjects in both the modified intent-to-treat (MITT) and per-protocol (PP) populations with an adequate clinical and parasitological response (PCR corrected) at Day 28. Non-inferiority was concluded if the lower bound of the 95% confidence interval comparing the two groups was 10 percentage points or greater. RESULTS: A total of 255 children were enrolled in the efficacy analysis (AZCQ, n = 124; AL, n = 131). The PCR corrected clearance rates were 89% (AZCQ) versus 98% (AL) for MITT, a difference of -9.10 (95% confidence interval; -16.02, -2.18) and 93% (AZCQ) versus 99% (AL) for PP, a difference of -6.08 (-12.10, -0.05). Early and late treatment failures were more common in subjects receiving AZCQ. Adverse events were more common in subjects treated with AZCQ. Drug concentrations obtained at specified time points following AZCQ administration had a large coefficient of variation partially due to sparse sampling with sample collection time window. CONCLUSIONS: In this study, non-inferiority of AZCQ to AL was not demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov NCT00677833 .

Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial.

BACKGROUND: Children are most vulnerable to malaria. A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria. METHODS: This phase III, multi-center, comparative, open-label, parallel-group, controlled clinical trial included patients aged ≤12 years, bodyweight ≥5 to <25 kg, with a reported history of fever at inclusion or in the previous 24 h and microscopically-confirmed uncomplicated P. falciparum malaria. Patients were randomized (2:1) to pyronaridine-artesunate granules (60/20 mg) once daily or artemether-lumefantrine crushed tablets (20/120 mg) twice daily, both dosed by bodyweight, orally (liquid suspension) for three days. RESULTS: Of 535 patients randomized, 355 received pyronaridine-artesunate and 180 received artemether-lumefantrine. Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using polymerase chain reaction (PCR) genotyping (per-protocol population) was 97.1% (329/339; 95% CI 94.6, 98.6) for pyronaridine-artesunate; 98.8% (165/167; 95% CI 95.7, 99.9) for artemether-lumefantrine. The primary endpoint was achieved: pyronaridine-artesunate PCR-corrected day-28 ACPR was statistically significantly >90% (P < .0001). Pyronaridine-artesunate was non-inferior to artemether-lumefantrine: treatment difference -1.8% (95% CI -4.3 to 1.6). The incidence of drug-related adverse events was 37.2% (132/355) with pyronaridine-artesunate, 44.4% (80/180) with artemether-lumefantrine. Clinical biochemistry results showed similar mean changes versus baseline in the two treatment groups. From day 3 until study completion, one patient in each treatment group had peak alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and peak total bilirubin >2xULN (i.e. within the Hy's law definition). CONCLUSIONS: The pyronaridine-artesunate pediatric granule formulation was efficacious and was non-inferior to artemether-lumefantrine. The adverse event profile was similar for the two comparators. Pyronaridine-artesunate should be considered for inclusion in paediatric malaria treatment programmes. TRIAL REGISTRATION: ClinicalTrials.gov: identifier NCT00541385.

Pyronaridine-artesunate versus mefloquine plus artesunate for malaria.

BACKGROUND: Pyronaridine-artesunate is an artemisinin-based combination therapy under evaluation for the treatment of Plasmodium falciparum and P. vivax malaria. METHODS: We conducted a phase 3, open-label, multicenter, noninferiority trial that included 1271 patients between 3 and 60 years of age from Asia (81.3%) or Africa (18.7%) with microscopically confirmed, uncomplicated P. falciparum malaria. Patients underwent randomization for treatment with a fixed-dose combination of 180 mg of pyronaridine and 60 mg of artesunate or with 250 mg of mefloquine plus 100 mg of artesunate. Doses were calculated according to body weight and administered once daily for 3 days. RESULTS: Pyronaridine-artesunate was noninferior to mefloquine plus artesunate for the primary outcome: adequate clinical and parasitologic response in the per-protocol population on day 28, corrected for reinfection with the use of polymerase-chain-reaction (PCR) genotyping. For this outcome, efficacy in the group receiving pyronaridine-artesunate was 99.2% (743 of 749 patients; 95% confidence interval [CI], 98.3 to 99.7) and that in the group receiving mefloquine plus artesunate was 97.8% (360 of 368 patients; 95% CI, 95.8 to 99.1), with a treatment difference of 1.4 percentage points (95% CI, 0.0 to 3.5; P=0.05). In the intention-to-treat population, efficacy on day 42 in the group receiving pyronaridine-artesunate was 83.1% (705 of 848 patients; 95% CI, 80.4 to 85.6) and that in the group receiving mefloquine plus artesunate was 83.9% (355 of 423 patients; 95% CI, 80.1 to 87.3). In Cambodia, where there were 211 study patients, the median parasite clearance time was prolonged for both treatments: 64 hours versus 16.0 to 38.9 hours in other countries (P<0.001, on the basis of Kaplan-Meier estimates). Kaplan-Meier estimates of the recrudescence rate in the intention-to-treat population in Cambodia until day 42 were higher with pyronaridine-artesunate than with mefloquine plus artesunate (10.2% [95% CI, 5.4 to 18.6] vs. 0%; P=0.04 as calculated with the log-rank test), but similar for the other countries combined (4.7% [95% CI, 3.3 to 6.7] and 2.8% [95% CI, 1.5 to 5.3], respectively; P=0.24). Elevated levels of aminotransferases were observed in those receiving pyronaridine-artesunate. Two patients receiving mefloquine plus artesunate had seizures. CONCLUSIONS: Fixed-dose pyronaridine-artesunate was efficacious in the treatment of uncomplicated P. falciparum malaria. In Cambodia, extended parasite clearance times were suggestive of in vivo resistance to artemisinin. (Funded by Shin Poong Pharmaceutical Company and the Medicines for Malaria Venture; ClinicalTrials.gov number, NCT00403260.).

Comparative efficacy of uncontrolled and controlled intermittent preventive treatment during pregnancy (IPTp) with combined use of LLTNs in high resistance area to sulfadoxine-pyrimethamine in Côte d'Ivoire.

INTRODUCTION: In recent years, intermittent preventive treatment for pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) has become policy in much of sub-Saharan Africa. But resistance to SP has been spreading across sub-Saharan Africa and thus the effectiveness of IPTp-SP has been questioned. The present study therefore sought to assess the incidence of placental malaria, low birth weight, and anemia of two IPTp-SP approaches (directly observed treatment scheme versus no directly observed treatment) in Anonkoua-Kouté and Samo, Côte d'Ivoire where the reported prevalence of dfr single mutant 108 was 62% and 52.2%, respectively. METHODS: The study was a longitudinal design involving pregnant women and was conducted in Anonkoua-Kouté, a suburban area, and Samo, a rural area, from January 2008 through March 2009. Women of a pregnancy less than 28 weeks duration were randomized to receive SP (1.5 g/0.075 g SP) in a single intake twice and were followed up monthly until delivery. Doses were administered under supervision in the controlled IPTp group, while SP was given free to women in the uncontrolled IPTp group with a recommendation to take it at home. The primary end point was the proportion of low birth weight infants (body weight < 2500 g) and the secondary end point was the rate of severe anemia and placental malaria detected at delivery. RESULTS: A total of 420 pregnant women were enrolled (212 and 208, respectively, in the controlled and uncontrolled groups). Delivery outcome was available for 378 women. In the modified intention-to-treat analysis, low birth weight infants were born from 15.5% of women of the uncontrolled IPTp group and from 11.9% of women in the controlled IPTp group (P = 0.31). The per-protocol population analysis showed consistent results. The proportion of women with placental malaria infection, moderate anemia (hemoglobin < 11 g/dL), and severe anemia (hemoglobin < 8 g/dL) at delivery were similar between the two groups (P > 0.05). CONCLUSION: The study showed that the two approaches were equivalent, suggesting that unsupervised IPTp-SP free of charge should be used in areas where implementation of the directly observed treatment scheme suffers from many constraints.

Artesunate/mefloquine paediatric formulation vs. artemether/lumefantrine for the treatment of uncomplicated Plasmodium falciparum in Anonkoua kouté, Côte d'Ivoire.

OBJECTIVES: To test the hypothesis that Artesunate-mefloquine paediatric (AS+MEF) is as effective as Artemether-lumefantrine (AL) in treating acute uncomplicated malaria in children. METHODS: In an open label, randomized controlled clinical trial, children aged 6-59 months were randomized to receive AS+MEF or AL. Both drug regimens were given for 3 days, and follow-up was for 28 days. The primary endpoint was the 28-day cure rate and was defined as proportion of patients with PCR-corrected cure rate after 28 days of follow-up. RESULTS: One hundred and fifty-six patients with confirmed uncomplicated P. falciparum malaria were randomly assigned to receive AS+MEF (n = 77) or AL (n = 79). PCR-corrected day 28 cure rates for per protocol (PP) populations were 99% for AS+MEF and 97% (P = 1) for AL. For the intention to treat (ITT) population, cure rates were 96% for AS+MEF and 92% (P = 0.49) for AL. Both regimens were well tolerated. CONCLUSION: AS+MEF is as effective as AL, and both combinations were efficacious and safe.

A comparative, randomized clinical trial of artemisinin/naphtoquine twice daily one day versus artemether/lumefantrine six doses regimen in children and adults with uncomplicated falciparum malaria in Côte d'Ivoire.

BACKGROUND: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination anti-malarial therapy, including artemisinins, has been advocated to improve efficacy and limit the spread of resistance. The fixed combination of oral artemether-lumefantrine (AL) is highly effective and well-tolerated. Artemisinin/naphtoquine (AN) is a fixed-dose ACT that has recently become available in Africa. The objectives of the study were to compare the efficacy and safety of AN and AL for the treatment of uncomplicated falciparum malaria in a high transmission-intensity site in Ivory Coast. METHODS: We enrolled 122 participants aged 6 months or more with uncomplicated falciparum malaria. Participants were randomized to receive either artemisinin/naphtoquine or artemether/lumefantrine with variable dose according to their weight. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection. RESULTS: Among 125 participants enrolled, 123 (98.4%) completed follow-up. Clinical evaluation of the 123 participants showed that cumulative PCR-uncorrected cure rate on day 28 was 100% for artemisinin/naphtoquine and 98.4% for artemether/lumefantrine. Both artemisinin-based combinations effected rapid fever and parasite clearance. INTERPRETATION: These data suggest that Arco could prove to be suitable for use as combination antimalarial therapy. Meanwhile, pharmacokinetic studies and further efficacy assessment should be conducted before its widespread use can be supported.