Table 4.

Description of major characteristics of studies included.

Reference	Methodology	Participants	Intervention	Outcomes measured	Researchers' finding and conclusion	Reviewer's comments
Adam et al., 2010 [29]	Study design: RCT    Country: Sudan    Setting: Elmouraf Health Centre in Sinnar    Malaria transmission rate of area: moderate    Participant allocation:  it was by block randomization and concealment of allocation was by use of sealed opaque envelopes containing treatment	Mean age: DP group: 9.8 years; AL group: 8.4 years.   Sample size at start of study: 160 patients (80 in each group)    Final analysis: it was based on 149 patients (75 in DP and 74 in AL); attrition rate was 6.9%    Inclusion criteria: patients aged ≥6 months; axillary temperature ≥37.5°C; monoinfection with P. falciparum; informed consent and ability of patient to take oral medications  Exclusion criteria: signs of severe malaria; presence of other febrile illness; patients who were allergic to any of study drugs; pregnant women and patients who had used the study drug in preceding 28 days	Experimental group:   oral treatment with DP (Duocotexin)/40 mg D/320 mg P tablet for adults and 20 mg D/160 mg P for children were given according to weight as follows: 5–9 kg: half tablet; 10–19.9 kg: one tablet; 20–40 kg: two tablets; or >40 kg: three “adult” tablets or two“child” tablets (once daily for 3 days)    Control group:  oral AL (Coartem) tablets 20 mg A/120 mg L were used according to weight as follows: 5–14 kg: one tablet; 15–24 kg: two tablets; 25–34 kg: three tablets; and >35 kg: four tablets (twice daily for 3 days)	Primary outcome:  adequate clinical and parasitological response (ACPR) by day 28    Secondary outcome:  frequencies of early treatment failure (ETF) by day 3 of treatment; late clinical response (LCR) by day 28; late parasitological response (LPR) by day 28; gametocyte carriage; adverse events recorded during treatment	The cure rate of participants by day 28 was found to be 100% for DP and 98.7% for AL   This implies that both DP and AL were effective and safe for treating uncomplicated P. falciparum malaria but the DP might be preferred to AL due to its simple once daily dosing regimen compared to twice daily dose required for AL	Strengths: ethical clearance was acquired; written consent was obtained from guardians; random allocation process was used to allocate participants into study groups with concealment of allocation process to prevent selection bias; the two study groups were reported to be similar before start of study; both study groups were treated equally and differ only in study drugs served; all treatments were served at the health centre to ensure compliance; attrition rate was 6.9% which is deemed to be insignificant to affect internal validity of study results. Length of followup was 28 days which is in consonance with the WHO standards for efficacy studies on antimalaria drugs. All outcome measures were also according to the WHO protocol. Weaknesses: (1) there was no information in the paper indicating that power calculation was done which would ascertain sample size adequacy. This means that there is the likelihood that type II error could have been committed, that is, the inability to detect differences in the efficacy of the two drugs even if it existed. (2) No information was given in the paper on blinding of outcome assessors; hence there is likelihood of measurement bias in this study.
Kamya et al., 2007 [30]	Study design: RCT     Country:   Uganda     Malaria transmission status of area: very high intensity     Participant allocation:   it was by random allocation using random list generated by off-site investigator using computer and concealment of allocation was ensured using sealed opaque envelopes containing treatment groups	Mean age: 1.8 years for DP group and 1.5 years for AL group     Sample size at start of study: 421 (211 in DP group and 210 in AL group)     Number included in final analysis: 417 (99%) (209 in DP and 208 in AL)     Inclusion criteria: children between 6 months and 10 years old; weight ≥5 kg; history of fever in last 24 hrs or axillary temperature ≥37.5°C; no allergy to study medications; no concomitant febrile illness; informed consent; no sign of severe malaria and infection with P. falciparum only	Experimental group:    DP (Duocotexin 40 mg D/320 mg P) tablets were administered as 6.4 and 51.2 mg/kg of D and P, respectively, given in daily doses for 3 days. Control group:   AL (Coartem 20 mg, Artemether/120 mg, and Lumefantrine) tablets were administered according to weight as follows: one (5–14 kg), two (15–24 kg), three (25–34 kg), or four tablets (≥35 kg). Served twice daily for 3 days	Primary outcome   Early treatment failure (ETF) by day 3   Late clinical failure (LCF) by day 28 and 42   Late parasitological failure (LPF)   Adequate clinical and parasitological response by day 42    Secondary outcomes  Serious adverse events  Common adverse events   Fever clearance by day 3	Risk of recurrent falciparum infection was significantly lower for patients treated with DP compared to AL by day 28 [11% versus 29%; RD = 18%; 95% CI (11%–26%)] and by day 42 [43% versus 53%; RD = 9.6%; 95% CI: 0%–19%]. The conclusion was that DP was superior to AL in reducing risk for recurrent falciparum infection	Strengths: ethical clearance was acquired; written consent was obtained from guardians; participants were allocated into study groups by random allocation process and allocation process was also concealed to prevent selection bias by use of sealed opaque envelopes; power calculation was done and hence adequacy of sample was ascertained to prevent type II error; no significant difference between the study groups before start of study; both study groups were treated equally and differ only in study drugs served; attrition rate was 0.95% which is insignificant to affect study result validity. Length of followup was 42 days and was within the WHO standards. All outcome measures were according to the WHO protocol and outcome assessors were kept blind to the treatment groups of the participants. Weaknesses: care givers (nurses) were not blinded to treatments of participants which could be a source of performance bias
Mens et al., 2008 [31]	Design:   RCT     Country:   Kenya     Malaria transmission status of area: high     Participant allocation:     it was by random allocation using computer generated random list with concealment of allocation process ensured with sealed opaque envelops which contained treatment group	Mean age: DP group: 60 months; AL group: 52 months    Sample size at start of study: 146 (73 for AL and 73 for DP)    Sample included in final analysis: 134 (92%)-67 for AL; 67 for DP    Inclusion criteria: children between 6 months and 12 years; uncomplicated P. falciparum infection; axillary temperature ≥37.5°C or history of fever. Exclusion criteria: infection with other Plasmodium spp.; severe malaria; presence of other underlying infectious conditions	Experimental group: oral DP tablet of 20 mg D/160 mg P (paediatric formulation) was used and was given according to weight as follows: between 4–7 kg: half a tablet; 7–13 kg: one tablet; 13–24 kg: 2 tablets; 24–35 kg: four tablets. Tablets were given daily for 3 days    Control group:   oral AL tablet, 20 mg Artemether/120 Lumefantrine was served according to bodyweight: 5–14 kg: one tablet; 15–24: two tablets; and 25–34 kg: three tablets; drug was served twice daily for 3 days	Early treatment failure at day 3  Fever clearance  Adverse events  Gametocyte carriage  Haemoglobin level	Rate of parasite clearance for the first 3 days was slower in patients treated with DP than those who received AL, but after day 28, there was no difference between the two drugs	Strengths: ethical clearance was obtained; written consent was obtained from guardians; participants were allocated into study groups by process of random allocation; there was no significant difference between the study groups before start of study; both study groups were treated equally and differ only in study drugs served; attrition rate was very low (7.6%) which is deemed insignificant to affect study results. Length of followup was 28 days and was within the WHO standards. Outcome assessors were kept blind to the treatment groups of the participants  Weaknesses: (1) no description of concealment of allocation process was given in the paper implying there could be selection bias; power calculation was not mentioned and hence adequacy of sample could not be ascertained hence there is likelihood of type II error committed in the study, that is, inability to detect differences between study treatments
Bassat et al., 2009 [32]	Design: Noninferiority trial    Countries: Burkina Faso, Kenya Mozambique, Uganda, and Zambia     Malaria transmission status of areas: high for all sites     Participant allocation:   it was done by random allocation process using computer generated stratified random list and allocation concealment ensured using sealed opaque envelops	Sample size at start of study: 1,548 (1038 in DP group and 510 in AL group)  Final analysis: it was based on 1468 (94.8%) (986 for DP group and 482 for AL group) for day 28 as against 1451 (93.7%) (977 versus 474 for the groups, resp.) for day 42. Inclusion criteria: children between 6 and 59 months; weight >5 kg; microscopically confirmed P. falciparum monoinfection; history of fever in the preceding 24 hours or axillary temperature ≥37.5°C; informed consent  Exclusion criteria: severe malaria; acute malnutrition; any contraindication to receive study drugs; current treatment with any antimalaria drug; presence of any concomitant infectious disease	All participants received directly observed treatment for 3 days  DP group: two different formulations of Eurartesim tablet (20 mg D + 160 mg P or 40 mg D + 320 mg P) were used and administered according to standard bodyweight dosage of 2.25 mg/kg and 18 mg/kg of D and P, respectively     AL group: Coartem (AL) tablet (20 mg Artemether + 120 mg Lumefantrine) was given according to bodyweight twice daily for 3 days as follows: 5–14 kg: one tablet per dose, 15–24 kg: two tablets per dose, 25–34 kg: three tablets per dose	Primary outcome  Adequate clinical and parasitological response (ACPR) by days 28 and 42   Early treatment failure (ETF) by day 3  Late treatment failures (LTF) by days 28 and 42    Secondary outcomes  Fever clearance rate   Haemoglobin level   Adverse events	The PRC-corrected cure rate by day 28 was 90.4% for patients who received DP and 90.0% for those treated with AL (P = 0.820), meaning the difference was not statistically significant. They concluded that both drugs have comparable efficacies in treating uncomplicated malaria in children from different settings in Africa	Strengths: ethical clearance was acquired; written consent was obtained from guardians; participants were allocated into study groups by process of random allocation; there was no significant difference between the study groups before start of study; both study groups were treated equally and differ only in study drugs served; attrition rate was very low (7.6%) which is insignificant to affect study results. Length of followup was 42 days and was within the WHO standards. Outcome assessors were kept blind to the treatment groups of the participants to avoid measurement bias   Weaknesses: (1) the different settings involved might have introduced some level of difference (heterogeneity) in the result and affect their combination
Yavo et al., 2011 [33]	Study design: RCT     Country: Cameroon, Cote d'Ivoire, and Senegal (multicentric)     Malaria transmission status of sites: high     Participant allocation:   it was by random allocation, using computer generated random list with concealment ensured by use of sealed opaque envelopes containing treatment group controlled by an independent nurse	Mean age:   experimental group: 15.6 years; control group: 13.5 years     Sample size at start of study: 384 (187 in AL arm and 197 in DP arm)   Final analysis: it was based on 374 patients (183 in AL and 191 in DP)    Inclusion criteria: patient with P. falciparum monoinfection; fever with axillary temperature ≥37.5; patient must be ≥2 years old; informed consent; no history of allergy to study drugs; no concomitant febrile illness; no severe malaria; no treatment with an antimalaria drug in previous 3–7 days; not pregnant or nursing; and no ongoing antimalaria treatment	Control group: Coartem tablets (20 mg Artemether + 120 mg Lumefantrine) were administered twice daily for 3 days according to weight as follows: 5–14 kg: one tablet per dose; 15–24 kg: two tablets per dose; 25–34 kg: three tablets per dose; and ≥35 kg: four tablets per dose     Experimental group: Duocotexin tablets (40 mg D + 320 mg P) were administered daily for 3 days per bodyweight: 5–9 kg: half tablet per dose; 10–14 kg: 3/4 tablet per dose; 15–19 kg: 1 tablet per dose; 20–24 kg: 1 + 1/4 tablet per dose; 25–29 kg: 1 + 1/2 tablet per dose; 30–34 kg: 1 + 3/4 tablet per dose; 35–39 kg: 2 tablets per dose; 40–44 kg: 2 + 1/4 tablet per dose; 45–49 kg: 2 + 1/2 tablet per dose; and >50 kg: 3 tablets per dose	Primary outcome  Recovery rate by day 28  Early clinical failure by day 3  Late clinical failure (LCF)    Secondary outcome  Rate of fever clearance; rate of parasite clearance, and adverse clinical and laboratory events	Adjusted recovery rate was 99.5% for patients treated with DP and 98.9% for those who received AL but the difference was not statistically significant (P = 0.538). No early treatment failures were recorded. The investigators concluded that DP was as efficacious as AL in treatment of uncomplicated falciparum malaria and added that DP may be preferred by patients because of its simple daily dose regimen	Strengths: ethical clearance was acquired; written consent was obtained from guardians; participants were allocated into study groups by process of random allocation; all the study groups were comparable before start of treatment; both groups were treated equally and differ only in study drugs served; attrition rate was very low (2.6%) which is deemed insignificant to affect study results. Length of followup was 28 days in line with the WHO standards. Outcome assessors were kept blind to the treatment groups of the participants to present objective measurement of outcomes   Weaknesses: (1) the different treatment sites and country could introduce variation in participants and affect homogeneity
Sawa et al., 2013 [34]	Study design: RCT    Country: Kenya    Malaria transmission status of area: moderate intensity    Patient allocation: it was by random allocation using computer generated random list and concealment was ensured using opaque sealed envelopes containing treatment groups controlled by an independent nurse.	Median age in years: experimental group: 5 (3–8); control group: 5 (3–7)     Sample size at start of study: 298 (experimental. group: 145; control group: 153)    Sample size in analysis: 284 by day 28 (137 for exp. and 147 for control); 279 by day 42 (134 in exp. and 145 in control).   Inclusion criteria: children between 6 months and 10 years old; history of fever in last 24 hours or tympanic temperature of ≥37.5°C; confirmed infection with P. falciparum parasite; informed consent    Exclusion criteria: patient haemoglobin level <5 g/dL; presence of other febrile illness; infection with other Plasmodium species; history of adverse reaction to study drugs; signs of severe malaria	Experimental group:   DP (Duocotexin) tablets (40 mg D + 320 mg P) were administered at a target total dose of 6.4 mg and 51.2 mg of D and P, respectively, in 3 equally divided daily doses for 3 days     Control group:   AL (Coartem) tablets (20 mg Artemether + 120 mg Lumefantrine) were administered as half a tablet per 5 kg bodyweight twice daily for 3 days.	Primary outcome:  adequate clinical response by day 28 and 42  Early treatment failure (ETF) by day 3  Late treatment failure (LTF) by day 28 and 42    Secondary outcomes  Gametocyte prevalence at days 28 and 42  Parasite clearance by day 3	Adequate clinical recovery by day 28 was 100% in patients treated with DP compared to 93.2% in those treated with AL with difference being statistically significant (P = 0.002). The cumulative risk for recurrent infection on day 42 was 3.7%; 95% CI (1.2–8.5) for DP and 20.7%; 95% CI (14.4–28.2); the difference was statistically significant. Their conclusion was that treatment with DP was associated with longer prophylactic efficacy than AL	Strengths: ethical clearance was acquired; written consent was obtained from guardians; the study with robust design generally. Efforts were made to reduce systematic bias: participants were allocated into study groups by process of random allocation; all the study groups were comparable with no significant differences before start of treatment; both groups were treated equally and differ only in study drugs served; attrition rate was very low and insignificant to affect study results. Length of followup was 28 days, in line with the WHO standards. Outcome assessors were kept blind to the treatment groups of the participants to ensure objective measurement of outcomes.    Weaknesses: (1) no description or mention was made of concealment of allocation process and therefore could not be ascertained. There is, therefore, a high possibility of selection bias if concealment was not ensured
Yeka et al., 2008 [35]	Study design: RCT    Country: Uganda    Setting:   Kihihi Health Centre in Kanungu    Malaria transmission status of area: high     Patient allocation: it was by random allocation using computer generated random list done by an off-site investigator Concealment was done by use of sealed opaque envelopes containing treatment groups	Mean age:     experimental group: 2 years;     control group: 2 years    Sample size at start of trial: 414 (experimental group: 215 and control group: 199)    Sample during analysis: 408 (3 participants lost in each study group)    Inclusion criteria: children between 6 months and 10 years, monoinfection of P. falciparum parasite, no presence of other febrile illness, informed consent    Exclusion criteria: haemoglobin level <5 g/dL, presence of signs of severe malaria	Experimental group:   Received DP (Duocotexin) tablets (40 mg D + 320 mg P) for a target total dose of 6.4 and 51.2 mg of D and P, respectively, in 3 equally divided daily doses for 3 days. DP patients were given placebo in the evening to mimic the twice dosing for AL group    Control group:    Received AL (Coartem) tablets (20 mg Artemether + 120 mg Lumefantrine) twice daily for 3 days according to body weight as follows: 5–14 kg: one tablet per dose; 15–24 kg: two tablets per dose; 25–34 kg: three tablets per dose; and ≥35 kg: four tablets per dose  All medications were served with water and patients were given milk afterwards to improve absorption	Primary outcome  Early treatment failure by day 3  Late clinical failure at days 28 and 42  Late parasitological failure by days 28 and 42    Secondary outcome  Rate of fever clearance Rate of parasite clearance Adverse event Presence of gametocyte	Risk for recurrent infection in patients treated with DP was significantly lower than those treated with AL (12.2% versus 33.2%), respectively. Risk difference (RD) = 20.9%; 95% CI (13.0–28.8%); P < 0.0001. The researchers concluded that treatment of uncomplicated malaria with DP was highly efficacious and could also be preferred more to AL because of its simple daily dosing regimen	Strengths: all ethical requirements were satisfied; efforts were made to reduce systematic bias as follows: participants were allocated into study groups by process of random allocation; all the study groups were similar in terms participant characteristics before start of treatment; both groups were treated equally and differ only in study drugs served; attrition rate was very low and insignificant to affect study results. Length of followup was 42 days in line with the WHO standards. All outcome assessors were kept blind to the treatment groups of the participants to present objective measurement of outcomes   Weaknesses: (1) nurses who provided care and administered study drugs were not blinded which may be a likely source of performance bias