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

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 One ferroquine 100 mg + AS patient after one dose was withdrawn after developing a QTcF interval prolongation 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).

Figure 1.

Consort diagram.

Figure 2.

Mean alanine aminotransferase (ALT) raw values expressed by upper limit of normal (ULN), by visit and by treatment. A dose–response trend occurred in doses of 400 and 600 mg ferroquine, approximately days 5–9 (box). There was no relation between ferroquine C_max and maximum ALT elevations (Figure 3).

Figure 3.

Ferroquine C_max (drug exposure) and maximum changes from baseline for upper limit of normal (ULN) of alanine aminotransferase (ALT). There was no trend between the two factors.

Figure 4.

A ferroquine 200 mg patient had a Grade 2 alanine aminotransferase (ALT) adverse event, maximum level was 3.8 × upper limit of normal (ULN) on day 14. The median ferroquine blood concentration in the 200-mg ferroquine group trended higher than the Grade 2 ALT patient.

Figure 5.

A ferroquine 600 mg patient had a Grade 2 alanine aminotransferase (ALT) adverse event, maximum level was 3.3 × upper limit of normal (ULN) on day 7. The median ferroquine blood concentration in the 600-mg ferroquine group trended closely with the Grade 2 ALT patient.

Figure 6.

Day 0-3, mean changes from baseline in QTcF intervals (left), raw heart rates (right) and ferroquine blood levels (lower). By day 3, a dose–response trend for mean QTcF interval prolongation was noted in 600-mg ferroquine and amodiaquine (AQ) groups (box, left), and AQ heart rates trended lowest (box, right). One 100-mg ferroquine patient developed > 60 milliseconds QTcF elongation, day 1, and was withdrawn.

Figure 7.

Days 0–28, mean changes from baseline in QTcF intervals (left), raw heart rates (right), and ferroquine blood levels (lower). By day 3, a dose–response trend for QTcF interval elongation was noted in 600-mg ferroquine and amodiaquine (AQ) groups (box, left). By day 5, there was a trend of lower heart rates in AQ (box, right).

Figure 8.

Raw QTcF values, days 0–3, left, and days 0–28, right. By day 9, note trend for 600 mg ferroquine, right, toward lower QTcF values (box), supporting the notion of lack of a dose response with changes in QTcF.

Figure 9.

Ferroquine C_max (drug exposure) and maximum changes from baseline for QTcF. There was no trend between the two factors. One 100-mg ferroquine patient developed > 60 milliseconds QTcF interval, day 1, and was withdrawn.

Figure 10.

A ferroquine 100 mg patient had a serious adverse event (SAE), > 60 milliseconds QTcF change from baseline, day 1, 12 hours after dose one. The median ferroquine blood concentration in the 100-mg ferroquine group trended higher than the SAE patient.