MALARONE was evaluated for prophylaxis of P. falciparum malaria in 5 clinical trials in malaria‑endemic areas and in 3 active‑controlled trials in non‑immune travelers to malaria‑endemic areas.

Three placebo‑controlled trials of 10 to 12 weeks’ duration were conducted among residents of malaria‑endemic areas in Kenya, Zambia, and Gabon. The mean age of subjects was 30 (range: 17 to 55), 32 (range: 16 to 64), and 10 (range: 5 to 16) years, respectively. Of a total of 669 randomized patients (including 264 pediatric patients aged 5 to 16 years), 103 were withdrawn for reasons other than falciparum malaria- or drug‑related adverse events (55% of these were lost to follow‑up and 45% were withdrawn for protocol violations). The results are listed in Table 6.

In another study, 330 Gabonese pediatric patients (weighing 13 to 40 kg and aged 4 to 14 years) who had received successful open‑label radical cure treatment with artesunate, were randomized to receive either MALARONE (dosage based on body weight) or placebo in a double‑blind fashion for 12 weeks. Blood smears were obtained weekly and any time malaria was suspected. Nineteen of the 165 children given MALARONE and 18 of 165 patients given placebo withdrew from the study for reasons other than parasitemia (primary reason was lost to follow-up). One out of 150 evaluable patients (<1%) who received MALARONE developed P. falciparum parasitemia while receiving prophylaxis with MALARONE compared with 31 (22%) of the 144 evaluable placebo recipients.

In a 10‑week study in 175 South African subjects who moved into malaria‑endemic areas and were given prophylaxis with 1 MALARONE tablet daily, parasitemia developed in 1 subject who missed several doses of medication. Since no placebo control was included, the incidence of malaria in this study was not known.

Two active-controlled trials were conducted in non‑immune travelers who visited a malaria‑endemic area. The mean duration of travel was 18 days (range: 2 to 38 days). Of a total of 1,998 randomized patients who received MALARONE or controlled drug, 24 discontinued from the study before follow-up evaluation 60 days after leaving the endemic area. Nine of these were lost to follow-up, 2 withdrew because of an adverse experience, and 13 were discontinued for other reasons. These trials were not large enough to allow for statements of comparative efficacy. In addition, the true exposure rate to P. falciparum malaria in both trials is unknown. The results are listed in Table 7.

A third randomized, open‑label study was conducted which included 221 otherwise healthy pediatric patients (weighing ≥11 kg and aged 2 to 17 years) who were at risk of contracting malaria by traveling to an endemic area. The mean duration of travel was 15 days (range: 1 to 30 days). Prophylaxis with MALARONE (n = 110, dosage based on body weight) began 1 or 2 days before entering the endemic area and lasted until 7 days after leaving the area. A control group (n = 111) received prophylaxis with chloroquine/proguanil dosed according to WHO guidelines. No cases of malaria occurred in either group of children. However, the study was not large enough to allow for statements of comparative efficacy. In addition, the true exposure rate to P. falciparum malaria in this study is unknown.

Causal Prophylaxis

In separate trials with small numbers of volunteers, atovaquone and proguanil hydrochloride were independently shown to have causal prophylactic activity directed against liver‑stage parasites of P. falciparum. Six patients given a single dose of atovaquone 250 mg 24 hours prior to malaria challenge were protected from developing malaria, whereas all 4 placebo‑treated patients developed malaria.

During the 4 weeks following cessation of prophylaxis in clinical trial participants who remained in malaria‑endemic areas and were available for evaluation, malaria developed in 24 of 211 (11.4%) subjects who took placebo and 9 of 328 (2.7%) who took MALARONE. While new infections could not be distinguished from recrudescent infections, all but 1 of the infections in patients treated with MALARONE occurred more than 15 days after stopping therapy. The single case occurring on Day 8 following cessation of therapy with MALARONE probably represents a failure of prophylaxis with MALARONE.

The possibility that delayed cases of P. falciparum malaria may occur sometime after stopping prophylaxis with MALARONE cannot be ruled out. Hence, returning travelers developing febrile illnesses should be investigated for malaria.