Table 4 Pooled analyses of data on the six-dose AL regimen

Mueller et al 2006 [40]

11 randomized clinical trials conducted in Thailand, India, Europe, China, Bangladesh in adolescents and adults aged >12 years

Almost every patient reported at least one AE during treatment. The rate and type of AEs were generally comparable between the 6- and four-dose groups. Most AEs were reported during the first 3 days of treatment and were of mild or moderate severity. Severe AEs were infrequent (5.9% for the six-dose group, 3.8% for the four-dose group). The most common AEs reported for AL included headache, asthenia, dizziness, myalgia, arthralgia, nausea, anorexia and fatigue; all of these could have been disease-related. Only a small proportion of patients reported AEs that were suspected to be drug-related and these occurred less frequently with the six-dose AL group than in the four-dose group. Drug-related AEs were more frequent for most comparator treatments than six-dose AL regimen, and for MAS, these were higher than the rates seen in both the six-dose and four-dose groups.

Six-dose AL (n = 598)

Four-dose AL (n = 770)

Comparators included:

Mefloquine (n = 126)

Quinine/SP (n = 114)

Chloroquine (n = 90)

MAS (n = 335)

Halofantrine (n = 52)

SAEs were reported by 0.6% of patients in the six-dose group and 0.8% of patients in the four-dose group. No SAEs in patients in the six-dose group (dyspnoea, febrile coma, pulmonary oedema, typhoid fever) were considered to be drug-related. SAEs in the four-dose group included (one each of) abnormal laboratory values, anaemia, falciparum malaria, malaria relapse, severe malaria, and two cases of hepatitis; only the reports of anaemia and malaria relapse were suspected to be drug-related. For the comparators, one SAE was reported in each of the MAS and chloroquine groups.

There was no difference in neurotoxicity between any of the groups, apart from paresthesia, which was only present in the four-dose AL group and the MAS group. Headache and dizziness were the most frequently reported neurological AEs. Decreased hearing (hypoacusis) was reported by 1.6% of patients in the four-dose group; there were no reports in the six-dose group. All cases of hypoacusis were mild, apart from one case of moderate severity and only two were considered to be drug-related. For the comparators, only patients in the MAS group reported hypoacusis (6.3%).

Makanga et al 2006 [41]

8 clinical trials in Gambia, Tanzania, Kenya, Nigeria and Thailand in children (5-25 kg)

The majority of patients reported at least one AE after dosing; these were generally mild or moderate in severity. Severe AEs were infrequent (5.2% for the six-dose and 7.0% for the four-dose AL groups). The most commonly reported AEs included cough, anaemia, anorexia, vomiting, hepato-/splenomegaly, headache, and diarrhoea, with most of these possibly related to malaria. The proportion of patients with AEs was similar between the 5 to <10, 10 to <15, and 15-25 kg body weight groups for both dosing groups. There were some differences between body weight groups for certain AEs such as headache and dizziness. These subjective AEs appeared less commonly in very small infants, but this may have been related to the patients' limited ability to verbalize symptoms and as such is not considered clinically relevant. Drug-related AEs were only reported for a small number of patients and occurred more frequently in the six-dose group.

Six-dose AL (n = 343)

Four-dose AL (n = 201)

Only three patients (0.9%) in the six-dose group reported SAEs (convulsion, urticaria, viral hepatitis) compared with one patient (0.5%) in the four-dose group (pneumonia). Of these SAEs, only the case of severe urticaria, which required hospitalisation, was considered drug-related. In addition to these SAEs, one patient died, but this was from causes unrelated to study treatment. Fewer patients in the six-dose than in the four-dose group reported AEs that were related to the central nervous system; headache (9.9% vs. 40.3%, respectively) and dizziness (3.8% vs. 16.4%, respectively) were the most commonly reported events. Other neurological AEs reported in the six-dose and four-dose groups included clonus (3.8% vs. 1.0%, respectively), hyperreflexia (1.7% vs. 0.5%, respectively), and convulsions (0.3% vs. 1.0%). Patients in the six-dose group failed to report the following AEs which were seen in the four-dose group: nystagmus, ataxia, and coordination abnormal (all 1.0-1.5%) and decreased hearing (1.5%). The cases of decreased hearing were not considered to be drug-related.

For cardiac safety assessments, the incidence of QTc changes within specific ranges was comparable between groups, and it is unlikely that there is an increased cardiac risk in the paediatric patients included in this analysis. Clinical laboratory parameters showed no major differences between the groups; findings were consistent with acute malaria.