A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria

Abstract

Background: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia.

Methods: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure-response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored.

Results: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures.

Conclusion: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://ichgcp.net/clinical-trials-registry/NCT02497612?term=NCT02497612&draw=2&rank=1.

Keywords: C580Y; Combination treatment; Exposure–response; Ferroquine; Kelch-13 mutation; Parasite clearance; Pharmacokinetics/pharmacodynamics; Resistance; Vomiting.

Conflict of interest statement

FM, MHCR, ACM, TW, FW, and DL are employed by MMV. BL is a consultant for MMV and was paid for his work on the FALCI Study. AJ, CC and RB are employed by Sanofi. AJ holds shares in the company. The other authors declare that they have no competing interests.

Figures

Fig. 1

Patient disposition by treatment arm. All doses of artefenomel and ferroquine are expressed as adult-equivalent doses

Fig. 2

Study analysis sets. 1 Safety analyses were conducted in the overall Safety Set, including all randomized patients who received at least one dose or part of a dose of the study drug, regardless of age and region (n = 373). In addition, safety analyses were also performed in the 3 separate Safety Subsets including the African patients ≤ 5 years, the African patients > 5 years and the Asian patients, respectively. 2 The primary efficacy analysis was conducted in the PP Set at Day 28 (African patients ≤ 5 years only). Note: three African sites had quality issues related to the reading of the slides by microscopy. For one site, issues were detected before database lock and the patients were excluded from the PP Sets. All doses of artefenomel and ferroquine are expressed as adult-equivalent doses

Fig. 3

PCR-adjusted ACPR at Day 28 by age (African patients) and by region (PP Sets). All doses of artefenomel and ferroquine are expressed as adult-equivalent doses. n: number of patients in each category achieving ACPR. r: total number of patients in the relevant analysis set with a defined response of Cure or Failure (i.e. patients evaluable for the outcome considered). 95% CI L: lower limit of 95% confidence interval; 95% CI U: upper limit of 95% confidence interval

Fig. 4

PCR-adjusted ACPR at Day 28 in African patients ≤ 5 years by a age group and b body weight band (PP Set). All doses of artefenomel and ferroquine are expressed as adult-equivalent doses. n: number of patients in each category achieving ACPR. r: total number of patients in the relevant analysis set with a defined response of Cure or Failure (i.e. patients evaluable for the outcome considered). 95% CI L: lower limit of 95% confidence interval; 95% CI U: upper limit of 95% confidence interval

Fig. 5

Kaplan–Meier cumulative incidence curve for time to a re-emergence, b recrudescence and c re-infection in African patients aged ≤ 5 years (mITT Set). Kaplan–Meier estimates below each graph are estimates of the cumulative incidence rates. All doses of artefenomel and ferroquine are expressed as adult-equivalent doses. Patients with no event were censored at the time of study completion, premature study discontinuation, including switch to established anti-malarial treatment or start of any other treatment with anti-malarial activity, whichever was earliest

Fig. 6

Relationship between parasite clearance half-life and kelch-13 genotype by region (PP Sets). Only patients with both genotyping and PCt1/2 results were included (n = 240). The patient with the mixed infection including the E556G mutation was not included due to the lack of a PCt1/2 result. PC half-life: parasite clearance half-life; mixed WT: mixed wild type (presence of mutants and wild type); true WT: true wild type (no mutations at any of the tested loci)

Fig. 7

Estimated Day 7 concentrations of artefenomel (a) and ferroquine (b) by treatment arm and region/age group. All doses of artefenomel and ferroquine are expressed as adult-equivalent doses. The boxplots show the sample medians, with the first and third quartiles. The whiskers represent the lowest/largest values no further than 1.5 times the interquartile range. Circles and triangles are individual patient values. Blue lines represent the median Cday7 in the exposure–response dataset: artefenomel 5.3 ng/mL and ferroquine 55 ng/mL. The PK Sets included all patients who received each study drug and had at least one evaluable blood sample for PK (n = 364 for artefenomel; n = 367 for ferroquine)

Fig. 8

Estimated Day 7 concentrations of artefenomel (a) and ferroquine (b) across the treatment arms by body weight band (excluding vomiters). The boxplots show the sample medians, with the first and third quartiles. The whiskers represent the lowest/largest values no further than 1.5 times the interquartile range. Circles are individual patient values of non-vomiters (n = 280 for artefenomel and 276 for ferroquine)

Fig. 9

Estimated Day 7 concentrations of artefenomel and ferroquine in individual patients grouped by vomiting status and PCR-adjusted ACPR at Day 28 (African patients ≤ 5 years). All African patients ≤ 5 years with PCR-adjusted ACPR at Day 28 and exposure to both drugs were included (n = 231). The scatter plot displays the relationship between exposures to ferroquine (X axis) and artefenomel (Y axis) in African patients ≤ 5 years. Four quadrants were then defined according to the median artefenomel and ferroquine exposures, and the PCR-adjusted ACPR at Day 28 is provided for the patients belonging to each quadrant

Fig. 10

Logistic regression result for PCR-adjusted ACPR at Day 28. All patients with PCR-adjusted ACPR at Day 28 and exposure to both drugs were included in the analysis (n = 298). Note: 'Africa Flagged' refers to the three African sites where quality issues related to the reading of the slides by microscopy were detected

Fig. 11

Isobolograms for various levels of PCR-adjusted ACPR at Day 28 in African patients, regardless of age (baseline parasitaemia = 30,000/μL). The figure shows the isobolograms for African patients for various probabilities of achieving ACPR at Day 28 with a baseline parasitaemia of 30,000 parasites/μL, which was the median baseline parasitaemia observed in African children ≤ 5 years