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Am J Trop Med Hyg. 2017 Aug;97(2):514-525. doi: 10.4269/ajtmh.16-0731. Epub 2017 Jul 19.

Phase 2a, Open-Label, 4-Escalating-Dose, Randomized Multicenter Study Evaluating the Safety and Activity of Ferroquine (SSR97193) Plus Artesunate, versus Amodiaquine Plus Artesunate, in African Adult Men with Uncomplicated Plasmodium falciparum Malaria.

Author information

1
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.
2
Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon.
3
Département de Parasitologie-Mycologie, Faculté de Médecine, Université des Sciences de la Santé, Libreville, Gabon.
4
Sanofi-Aventis, Paris, France.
5
Walter Reed Project (Kisumu), U.S. Army Medical Research Unit (USAMRU)-Kenya, Kenya Medical Research Institute, Nairobi, Kenya.

Abstract

Artemisinin-based combination therapies are recommended as first-line agents for treating uncomplicated Plasmodium falciparum malaria. Ferroquine, a 4-aminoquinolone, is a novel long-acting combination partner for fast-acting drugs like artesunate (AS). We did a small phase 2a, multicenter, open-label, safety-focused dose-ranging randomized study of ferroquine at three African hospitals: two Gabonese and one Kenyan. We recruited adult men with symptomatic uncomplicated P. falciparum monoinfection. Four escalating doses of ferroquine (100, 200, 400, and 600 mg) were assessed in sequence, versus an amodiaquine comparator. After a 2:1 randomization (block size three, equating to N = 12 for each ferroquine dose and N = 6 for each of four amodiaquine comparator groups) patients received daily for three consecutive days, either ferroquine + AS (200 mg/day) or amodiaquine (612 mg/day) + AS (200 mg/day). Safety, electrocardiograms, parasite clearance times, efficacy, and pharmacokinetics were assessed to day 28. Seventy-two patients were randomized. Ferroquine + AS showed generally mild increases (Grade 1 toxicity) in alanine aminotransferase (ALT) levels with a dose trend starting at 400 mg. There were two Grade 2 ALT events: one patient receiving 200 mg (3.8 upper limit of normal [ULN], day 7) and one receiving 600 mg (3.3 ULN, day 14), both without increased bilirubin. One ferroquine 100 mg + AS patient after one dose was withdrawn after developing a QTcF interval prolongation > 60 milliseconds over baseline. Parasitemias in all patients cleared quickly, with no recurrence through day 28. Hepatic, as well as cardiac, profiles should be monitored closely in future trials. (ClinicalTrials.gov: NCT00563914).

PMID:
28722611
PMCID:
PMC5544076
DOI:
10.4269/ajtmh.16-0731
[Indexed for MEDLINE]
Free PMC Article

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