Does the Use of Dihydroartemisinin-Piperaquine in Treating Patients with Uncomplicated falciparum Malaria Reduce the Risk for Recurrent New falciparum Infection More Than Artemether-Lumefantrine?
Table 4
Description of major characteristics of studies included.
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.
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
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
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
The PRC-corrected cure rate by day 28 was 90.4% for patients who received DP and 90.0% for those treated with AL (), 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
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: tablet per dose; 25–29 kg: tablet per dose; 30–34 kg: tablet per dose; 35–39 kg: 2 tablets per dose; 40–44 kg: tablet per dose; 45–49 kg: 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 (). 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
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 (). 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
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%); . 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
