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Table 2 Published studies with the six-dose AL regimen in Africa

From: Safety profile of Coartem®: the evidence base

Authors Country Design and patient population Comparators (no. of patients) Results
Bukirwa et al 2006 [12] Uganda Randomized, single-blind, single centre in children (1-10 years) AL (n = 204) ASAQ (n = 204) Overall, 261 (65%) of participants experienced AEs of moderate or severe intensity and there was no difference between the two treatment groups. SAEs were uncommon with both regimens, with one occurring in each group and judged to be unrelated to study medication (ASAQ) or unlikely to be related to study medication (AL). No abnormalities in hearing or fine finger dexterity were detected.
Dorsey et al 2007 [13] Uganda Single-blind, randomized, single centre in children (1-10 years) AL (n = 103 and202 treatments) AQSP (n = 111 and 253 treatments) ASAQ (n = 113 and 232 treatments) All study regimens appeared to be safe and generally well tolerated. In the first 14 days, anorexia and weakness occurred more commonly in children treated with AQSP than those receiving ASAQ or AL. A total of 45 SAEs were reported in 38 patients, but none of these were considered probably or definitely related to study medication.
Gürkov et al 2008 [14] Ethiopia Single centre in adults and children >5 years of age AL (n = 30) Quinine (n = 35) Atovaquone/proguanil (n = 32) The first randomized clinical trial to directly compare ototoxicity of AL with other anti-malarial drugs. Pure tone audiometry and distortion product otoacoustic emission levels revealed transient significant cochlear hearing loss in patients treated with quinine but not in those treated with AL or atovaquone/proguanil. Transitory evoked otoacoustic emission could be elicited in all examinations, except for three patients in the quinine group on day 7, who suffered a transient hearing loss greater than 30 dB. There was no evidence of drug-induced brain stem lesions by brain stem evoked response audiometry. There was no detrimental effect of AL on peripheral hearing or brainstem auditory pathways; however, transient hearing loss is common after quinine therapy due to temporary outer hair cell dysfunction.
Kamya et al 2007 [15] Uganda Single-blind, randomized, single centre in children (6 months to 10 years) AL (n = 210) DP (n = 211) Both drugs were well tolerated and reported AEs were of mild or moderate severity and consistent with symptoms of malaria. There were 6 SAEs reported in this study and all were judged unrelated to study medications.
Mårtensson et al 2005 [16] Zanzibar Multicenter, randomized, open-label in children (6-59 months) AL (n = 200) ASAQ (n = 208) Both drugs were well tolerated and most AEs were of mild severity. Similar proportions of moderate or severe AEs were reported by the two groups (10% for AL vs. 12% for ASAQ). All severe AEs were associated with malaria and were not attributed to the study drugs. No significant differences were seen in the mean counts of white blood cells and neutrophils during follow-up. Significant and similar increases in mean haemoglobin levels from baseline to day 42 were seen in both groups.
Mohamed et al 2006 [17] Sudan Two-centre, open-label in children and adults AL (n = 72) ASSP (n = 71) No AEs were recorded for patients given ASSP and 11 were recorded for patients given AL (5 cases of gastric disturbance, 5 of excessive sleepiness and 1 of dizziness). All were mild and self-limited and no patients withdrew from the study because of an AE.
Yeka et al 2008 [18] Uganda Randomized, single centre, single-blinded study in children aged 6 months to 10 years AL (n = 199) DP (n = 215) Most AEs were of mild or moderate severity and consistent with symptoms of malaria. The most commonly reported AEs in both groups were cough, coryza, abdominal pain, anorexia, weakness, diarrhoea and pruritus and there were no significant differences between groups. A total of 7 SAEs were reported (2.3% after DP and 1% after AL), but all were judged unrelated to study medication.
Mulenga et al 2006 [19] Zambia Randomized, open-label, multicentre in adults AL (n = 485) SP (n = 486) AL and SP were generally well tolerated. SAEs were observed in 2 patients treated with SP and one patient treated with AL. Eleven patients (5 on AL and 6 on SP) had various symptoms possibly related to the study drugs but none were serious enough to interrupt the treatment.
Adjei GO et al 2008 [20] Ghana Randomized, open label in children (6 months to 14 years) AL (n = 111) ASAQ (n = 116) The majority of AEs were mild in intensity, overlapped with known malaria symptomology, and were mostly classified as unrelated to study medication. Drug-related AEs were rare. Possibly related AEs were pruritus (2 patients on ASAQ and 1 patient on AL) and fatigue/excessive sleepiness (5 patients on ASAQ and 4 patients on AL). Neurological examinations were conducted on 168 children (n = 92 for ASAQ; n = 76 for AL). Nystagmus was observed in two patients (1 per group), but both had a history of admission to a neonatal intensive care unit and either excessive emotional liability or cognitive impairment. One child in the AL group had a positive Romberg's test (indicative of sensory ataxia) on day 3, but also had a history of cognitive impairment. No other neurological abnormalities were observed during the 28-day follow-up, at monthly visits or in patients who took multiple courses of treatment. Audiometry was assessed in 72 patients (n = 37 for ASAQ; n = 35 for AL). Hearing thresholds were significantly elevated in treated patients compared with age- and sex-matched controls up to and including day 28, but there were no differences after 9 to 12 months. (Note: full audiometry results are presented elsewhere).
Falade et al 2008 [21] Nigeria Randomized, open label, single centre in children (6 months to 10 years) AL (n = 66) ASAQ (n = 66) Both drugs were well tolerated according to clinical and laboratory parameters. The most common AEs were vomiting, anaemia, cough and abdominal pains and are frequent clinical findings among patients with malaria. No child was withdrawn because of an AE.
Faye et al 2007 [22] Senegal Randomized, open-label, multicentre in children and adults ASAQ (n = 360) AQSP (n = 161) MAS (n = 145) Six-dose AL (n = 149) Four-dose AL (n = 140) The side-effects of treatments were minor and consisted mainly of mild gastralgia, dizziness, pruritus, asthenia, and vomiting. These disappeared at the end of treatment and did not require any specific treatment. No SAEs were observed and there were no severe alterations in renal or hepatic function for any of the drug combinations.
Koram et al 2005 [23] Ghana Two-centre, randomized, open-label in children (6-59 months) AL (n = 51) CQ (n = 36) SP (n = 27) ASAQ (n = 54) Some patients were withdrawn from the study due to AEs: 2 patients on day 1 due to lethargy/inability to eat, (1 each for the CQ and SP groups), 3 patients due to excessive vomiting/lethargy (all after ASAQ) and 1 patient due to excessive vomiting and diarrhoea (this patient in the AL group had a concomitant hookworm infection).
Owusi-Agyei et al 2008 [24] Ghana Randomized, open label in children aged 6 months to 10 years AL (n = 223) ASAQ (n = 228) ASCD (n = 178) The incidence of AEs was comparable between the groups although a history of body pain was more frequently reported in the ASAQ group compared with the AL or ASCD groups (14.0% vs. 5.7% vs. 5.1%, respectively; p = 0.01).
Sagara et al 2006 [25] Mali Randomized, single centre, open-label study in children (≥ 6 months) and adults AL (n = 303) AS plus sulphamethoxypyrazine plus pyrimethamine (n = 303) AL and AS plus sulphamethoxypyrazine plus pyrimethamine were both well tolerated. The total number of reported AEs and the number of patients reporting any symptom/signs in the first week after treatment was similar in the groups. Diarrhoea occurred more frequently after AL compared with AS plus sulphamethoxypyrazine-pyrimethamine (3.6% vs. 1.0%, respectively; p = 0.03). No SAEs occurred.
Sowunmi et al 2007 26] Nigeria Randomized, open-label, single centre, in children (≤ 10 years) AL (n = 90) AQ plus sulphalene plus pyrimethamine (n = 91) AEs within the first week of treatment were reported by 21 children (9 after AL and 12 after AQ plus sulphalene plus pyrimethamine). There was no significant difference in the proportions of patients reporting AEs in both groups. Pruritus and weakness were significantly more frequent in the AQ plus sulphalene plus pyrimethamine group, and vomiting was significantly more frequent in the AL group. No child was withdrawn because of drug intolerance.
Sutherland et al 2005 [27] Gambia Randomized, single centre, single-blind, in children (1-10 years) AL (n = 406) CQSP (n = 91) Minor complaints noted at the day 7 laboratory visit included headache (12% and 11% in the CQSP and AL groups, respectively), anorexia (12% and 16%), diarrhoea (7% and 4%), abdominal pain (5% and 5%), and pruritus (1% and 1%). No SAEs occurred in either group, and there were no deaths among children in the study.
Zongo et al 2007 [28] Burkina Faso Multicentre, randomized, open-label in children (6 months to 10 years) AL (n = 261) AQSP (n = 260) Both drugs were well tolerated. AEs did not differ between groups apart from pruritus, which was more common with AQSP than AL (16% vs. 3%, p < 0.0001). Only 2 SAEs (both haemoglobin levels below 50 g/L) were reported; 1 SAE was due to early treatment failure after AQSP and 1 SAE was due to late clinical failure after AL.
Zongo et al 2007 [29] Burkina Faso Multicentre, randomized, open-label in children (≥ 6 months) AL (n = 188) AQSP (n = 184) DP (n = 187) All drugs were well tolerated. However, abdominal pain was reported more often in the AQSP and AL groups than in the DP group (24% and 20% vs. 9%, respectively), headache was more common in the AL group than in the AQSP and DP groups (21% vs. 14% and 10% respectively) and pruritus was more common in the AQSP group than in the AL and DP groups (18% vs. 6% and 3%, respectively). No SAEs were reported in this study.
Fanello et al 2007 [30] Rwanda Randomized, open-label, 2-centre in children (12-59 months) AL (n = 251) AQSP (n = 249) AEs concomitant with the administration of the study drug were reported by 251 patients (52.21% after AQSP and 48.21% after AL). AEs that were possibly or probably related to the study drug were reported by 22.73% of patients after AQSP and 14.47% after AL (p = 0.06). The most frequently reported AEs after AQSP were fatigue, anorexia, vomiting and abdominal pain and the AEs most frequently reported after AL were cough and diarrhoea.
Ndayiragije et al 2004 [31] Burundi Multicentre, randomized, open-label in children (<5 years) AL (n = 142) ASAQ (n = 153) AEs were similar in the two groups, although vomiting on days 1 and 2 was more frequent in the ASAQ group (13.1% and 5.3%, respectively) than in the LA group (5% and 0.7%, respectively).
Van den Broek et al 2006 [32] Republic of Congo Randomized, single centre, open-label study in children (6-59 months) AL (n = 106) ASAQ (n = 101) ASSP (n = 91) The most frequent AEs reported during the 3 days of treatment were vomiting, diarrhoea, abdominal pain and anorexia. The frequency of these AEs was low (around 10% of children) and did not differ among the groups. There were two cases of urticaria (1 after ASAQ and 1 after ASSP), but these developed after completion of the treatment. No SAEs were reported.
  1. AL: Artemether/lumefantrine; CQ: Chloroquine; SP: Sulphadoxine/pyrimethamine; CQSP: Chloroquine/sulphadoxine/pyrimethamine; AS: Artesunate; AQ: Amodiaquine; ASAQ: Amodiaquine/artesunate; AQSP: Amodiaquine/sulphadoxine/pyrimethamine; DP: dihydroartemisinin/piperaquine; MAS: mefloquine/artesunate