Conceived and designed the experiments: MSS AD SC HFJ OKD. Performed the experiments: MSS AD HT MD BT DK BN MD BK AT AB AT. Analyzed the data: MSS OBT. Contributed reagents/materials/analysis tools: MSS SC HFJ OKD. Wrote the paper: MSS AD SC HFJ OKD.
SC and JFH declare that they are employed by Dafra Pharma, the organisation sponsoring this study and manufacturing the trial interventions. JFH is a member of the Board of Directors of Dafra Pharma.
This study was conducted to determine the efficacy of the antimalarial artemisinin-based combination therapy (ACT) artesunate +sulfamethoxypyrazine/pyrimethamine (As+SMP), administered in doses used for malaria, to treat
The study was conducted in Djalakorodji, a peri-urban area of Bamako, Mali, using a double blind setup in which As+SMP was compared with praziquantel (PZQ). Urine samples were examined for
The study demonstrates that PZQ was more effective than As+SMP for treating
ClinicalTrials.gov NCT00510159
An estimated 200 million individuals worldwide are living with schistosomiasis, the second parasitic disease after malaria in terms of socioeconomic and public health importance
Artemether and artesunate, derivates of artemisinin (the Chinese drug
In this study, the safety and effect of the ACT Co-Arinate FDC® (combination of artesunate with sulfamethoxypyrazine and pyrimethamine (As+SMP)) and praziquantel (PZQ) on the cure rate and egg reduction rate of
The protocol for this trial and supporting CONSORT checklist are available as supporting information; see
The trial was carried out between August 2007 and October 2007 in Djalakorodji, a peri-urban area of Bamako, the capital of Mali. The village is situated to the north of Bamako and has 28,000 inhabitants. Numerous temporary streams, created by seasonal rains, intersect the village in several locations. Although these streams dry up after the rainy season (March - April) they are used by the population for multiple activities such as laundry, dishwashing, fishing, bathing and recreation. They constitute an excellent breeding place for snails, the intermediate hosts necessary for completion of the
This is a double-blind, controlled clinical trial in children, aged 6 to 15 years. The study was designed to determine the efficacy of the antimalarial ACT As+SMP, administered in doses used for malaria, to treat
The cure rate for the PZQ group was assumed to be 75% (60–95%), while the cure rate in the As+SMP treatment group was estimated at +10% in comparison to the PZQ group. With 90% power and a two-sided type 1 (α) error of 5%, we calculated that 354 patients were needed in each of the treatment arms. 46 additional children were included in each arm to correct for loss to follow-up and non compliance. A total number of 800 children were enrolled in the trial, with 400 children randomized into each arm. Block randomization was used to allocate the patients to the two treatment arms, and was blinded to the treating physician and his team, as well as to the patient.
One arm of the study received PZQ (treatment B) on the first day of treatment and As+SMP matched placebo (treatment D) on the second day of treatment. The second arm received PZQ matched placebo (treatment A) on the first day of treatment and As+SMP (treatment C) on the second day of treatment.
Treatment allocation was carried out using an envelope system, containing either “treatment A/C” or “treatment B/D”. All tablets were administered under direct medical supervision, which assures compliance to the treatment. The random allocation sequence was computer generated in Belgium. The participants were enrolled by the clinical investigators and they were assigned to their treatment group by the study pharmacist on site (Djalakorodji, Mali).
Co-Arinate FDC® was administered as a 24 hour therapy with 3 tablets. Each tablet contains 100 mg artesunate +250 mg sulfamethoxypyrazine/12.5 mg pyrimethamine. This drug is now being introduced in many African countries for the treatment of malaria. Doses administered in this trial were equal to the doses that are used for the treatment of malaria. The drug's safety and efficacy for treating malaria has been demonstrated in several studies, most recently in a large multicenter trial carried out in 4 different regions throughout Africa
At screening, each child provided one urine sample. A second sample was collected the following day before inclusion in the trial. Samples were taken between 10 am and 2 pm, and children were asked to run 3 laps before donating their samples. Appearance (macroscopic aspect) of the urine samples was reported and haematuria was checked (Hemastix®, Siemens Diagnostics, Belgium). At screening and at day 28 blood were obtained to measure White Blood cell Count 103/µL (WBC), Red Blood cell Count 103/µL (RBC), Haemoglobine g/dl (Hgb), Haematocrit % (Ht), Mean Corpuscular Volume fl (MCV), Mean Corpuscular Haemoglobin Concentration g/dl (MCHC), Mean Corpuscular Haemoglobin pg (MCH), Platelets 103/µL, Lymphocytes 103/µL, Alanine Aminotransferase U/L (ALT), Aspartate Aminotransferase U/L (AST) and creatinine µM/L).
Quantitative urine analysis was performed, using a filter technique with Whatman® filters. Two separate microscope filters were prepared for each sample, and evaluated by 2 independent, experienced microscopists. Data quality control for inter-observer variability was addressed by re-reading 10% of all the slides, picked out at random. If the first reading was positive and the second reading positive with a difference of less than 20%, mean number of eggs per 10 mL urine was calculated. If there was a difference between the two readers of 20% or more, a third reader was assigned to re-read the slides.
Infected children who were excluded from the study due to any of the above mentioned exclusion criteria, were treated at a standard recommended dose of 40 mg/kg PZQ.
Children were asked to come back and visit the team for treatment evaluation on 28 and 29 days after drug administration. Children who were not present on the evaluation days were actively searched for and brought to the centre by local guides. Two urine samples were collected from each child. If eggs were still present in these urine samples, a viability check was carried out. This test consists of checking for moving organelles of the miracidium inside the egg shell, hatching miracidia (in case of rupture of the egg shell) or beating of flame cellular. All dark eggs were considered as non viable. If all eggs in a sample were determined to be non viable (dark eggs or eggs without any of the viability characteristic listed above), the samples were considered to be egg negative.
Study primary outcome was measured by treatment cure rate and egg reduction rate. Egg reduction rate was calculated as: [1 - (geometric mean of egg counts per 10 mL of urine after treatment divided by geometric mean of egg counts per 10 mL of urine before treatment)] ×100. Secondary outcomes were measured by (1) changes in urine appearance (before mixing the urine sample with the staining solution, the visual appearance of each urine sample was noted as being clear, cloudy or blood stained) before and after treatment, (2) changes in haematuria (using Hemastix®) before and after treatment and (3) patients' opinion towards the different treatment arms. The patient's opinion on the treatment was evaluated by using a short questionnaire. All adverse events were recorded following the days of treatment, all children were invited to come to the centre for two days of active follow-up, as well as at any time during the study period for adverse events (sign or symptoms). Investigators were permanently present at the study site. Adverse events are considered drug related if the same adverse events were not reported at the first presentation to the clinic during screening and the clinician did not find another explanation.
Data were double entered, validated using Microsoft ACCESS and analyzed with SPSS 12.0 for Windows. The intention-to-treat (ITT) analysis included all the randomized patients, excluding one case who received both investigational drugs. The ITT analysis was used for analysis of baseline comparison and adverse events. Per-protocol (PP) analysis was used for baseline comparison and for efficacy evaluation. Pearson Chi-square test, Yates Chi-square test or Fisher Exact tests were used to compare categorical variables. Mann-Whitney U test and Unpaired Student t-test were used to assess differences between treatment arms in the means for continuous variables. The McNemar paired chi-square test was used to compare the frequency of haematuria and the proportion of biological parameter normal values before and after treatment in each treatment arm. Wilcoxon T test was used to compare laboratory values before and after treatment administration.
Out of a total of 3033 children (age range 6–15 years) screened for infection, 2233 children did not meet our inclusion criteria. A total of 392 children completed the study in the As+SMP treatment arm. Three children were lost to follow-up, in 3 other cases the protocol was violated, and 2 patients chose to withdraw from the study. In the PZQ treatment arm, one patient received both medications and was withdrawn from analysis. Six children were lost to follow-up, 1 patient voluntarily withdrew from the study, and the protocol was violated in 4 children. A total of 389 children completed the study in the PZQ treatment arm (
Out of a total of 3033 children (age range 6–15 years) screened for infection, 2233 children did not meet inclusion. A total of 392 children completed the study in the As/SMP treatment arm. Three children were lost to follow-up, in 3 cases the protocol was violated, and 2 patients chose to withdraw from the study. One patient assigned to the PZQ treatment arm received both medications and was withdrawn from analysis. Six children were lost to follow-up, 1 patient voluntarily withdrew from the study, and the protocol was violated in 4 children. A total of 389 children completed the study in the PZQ treatment arm (
At enrolment, the two study treatment groups were similar with regard to age, sex, ethnicity, weight, height and egg count per 10 mL of urine, p>0.05. The mean age was 10.45 years, and 35.8% of all the patients were female (
As+SMP N = 392 | PZQ N = 389 | |
Mean Age ± SD | 10.4±2.4 | 10.5±2.5 |
Range (Min, Max) | 9.4 (6, 15.4) | 9.2 (6, 15.2) |
Median | 10.2 | 10.5 |
Sex Male | 251 | 252 |
Sex Female | 141 | 137 |
Bambara | 211 | 220 |
Sarakole | 41 | 30 |
Malinke | 27 | 39 |
Peulh | 24 | 23 |
Dogon | 16 | 16 |
Senoufo | 12 | 11 |
Dafing | 11 | 13 |
Bobo | 16 | 7 |
Sonrhaï | 13 | 14 |
Kakolo | 8 | 5 |
Others | 13 | 11 |
Mean Weight ± SD | 27.7±7.5 | 28.0±7.3 |
Range (Min, Max) | 33 (17, 50) | 34 (16, 50) |
Median | 26.0 | 27 |
Mean Height ± SD | 133.5±12.5 | 133.7±11.8 |
Range (Min, Max) | 58 (108, 166) | 61 (108, 169) |
Median | 133.0 | 133.0 |
Geometric Mean Eggs | 40.9 | 41.4 |
Range (Min, Max) | 1458 (2, 1460) | 1382 (2, 1384) |
Median | 42.2 | 41.2 |
Haematuria + | 324 | 339 |
Haematuria − | 66 | 48 |
Total | 390 | 387 |
Hematic + | 160 | 177 |
Hematic − | 232 | 212 |
Total | 392 | 389 |
Mann-Whitney U test.
Microscopic haematuria and macroscopic aspect of urine did not significantly differ between the two treatment groups (Per protocol analysis) before as well as after the treatment with PZQ or As+SMP.
The geometric mean of egg count in each group before treatment was comparable 42.2 in As+SMP group and 41.2 in PZQ group (
As+SMP | PZQ | |||
without viability testing | with viability testing | without viability testing | with viability testing | |
– |
172 | 319 | 206 | 380 |
220 | 73 | 183 | 9 | |
Cure Rate % | 43.9 | 81.4 | 53.0 | 97.7 |
Total number of children treated | 392 | 389 |
The egg reduction rate without viability test under PZQ treatment was 95.6% in comparison to 92.8% under As+SMP treatment Chi-square = 2.76, p = 0.096.
The geometric mean of egg counts after viability test was comparable: 1.1 for As+SMP versus 1.0 for PZQ. The egg reduction rate after viability test under PZQ treatment was 97.6% in comparison to 97.4% under As+SMP treatment, Chi-square = 0.05, p = 0.829.
Both treatments were found to be easy to use and patient opinion on the number of tablets to be taken, treatment intake and administration of drugs between the two treatments did not vary significantly between the two treatment arms.
After treatment, the proportion of participants who experienced adverse events related to medication was 0.5% (2/400) in the As+SMP treatment arm versus 2.3% (9/399) in the PZQ group, Chi-square = 4.53, p-value = 0.033. Abdominal pain and vomiting were the most frequent adverse events for both treatment arms. Dizziness and headache were also observed in the PZQ group. All adverse events were mild (
As+SMP | PZQ | |||||
R | NR | Tot | R | NR | Tot | |
1 | 73 | 74 | 1 | 49 | 50 | |
0 | 17 | 17 | 3 | 17 | 20 | |
0 | 61 | 61 | 1 | 62 | 63 | |
1 | 104 | 105 | 4 | 30 | 34 | |
0 | 1 | 1 | 0 | 4 | 4 | |
0 | 3 | 3 | 0 | 0 | 0 | |
0 | 1 | 1 | 0 | 0 | 0 | |
0 | 1 | 1 | 0 | 1 | 1 | |
0 | 1 | 1 | 0 | 0 | 0 | |
0 | 28 | 28 | 0 | 24 | 24 | |
0 | 1 | 1 | 0 | 0 | 0 | |
0 | 4 | 4 | 0 | 4 | 4 | |
0 | 9 | 9 | 0 | 8 | 8 | |
0 | 1 | 1 | 0 | 0 | 0 | |
0 | 1 | 1 | 0 | 1 | 1 | |
0 | 7 | 7 | 0 | 5 | 5 | |
0 | 1 | 1 | 0 | 1 | 1 | |
0 | 3 | 3 | 0 | 1 | 1 | |
0 | 0 | 0 | 0 | 2 | 2 | |
0 | 1 | 1 | 0 | 0 | 0 | |
0 | 12 | 12 | 0 | 9 | 9 | |
0 | 1 | 1 | 0 | 2 | 2 | |
0 | 3 | 3 | 0 | 5 | 5 | |
0 | 1 | 1 | 0 | 1 | 1 | |
0 | 4 | 4 | 0 | 7 | 7 | |
Comparison of biological parameters between the two treatment arms shows that all the parameters (White Blood cell Count 103/µL (WBC), Red Blood cell Count 103/µL (RBC), Haemoglobine g/dl (Hgb), Haematocrit % (Ht), Mean Corpuscular Volume fl (MCV), Mean Corpuscular Haemoglobin Concentration g/dl (MCHC), Mean Corpuscular Haemoglobin pg (MCH), Platelets 103/µL, Lymphocytes 103/µL, Alanine Aminotransferase U/L (ALT), Aspartate Aminotransferase U/L (AST) and creatinine µM/L) were similar on day 0. After treatment (Day 28) only the mean WBC increased significantly under As+SMP treatment (7.7±2.6 in As+SMP, versus 7.1±2.0 in the PZQ group), p = 0.007.
As+SMP | PZQ | p |
|||||||
Mean±SD | Med | Min Max | NAV | Mean±SD | Med | Min Max | NAV | ||
Day 0 | 7.3±2.1 | 6.9 | 3.4, 17.6 | 46 | 7.3±2.1 | 7 | 2.8, 18.0 | 43 | |
Day 28 | 7.7±2.6 | 7.2 | 3.0, 17.9 | 78 | 7.1±2.0 | 6.8 | 3.1, 20.6 | 43 | |
Day 0 | 4.5±1.1 | 4.4 | 2.8, 24.0 | 26 | 4.4±0.5 | 4.4 | 1.8, 6.9 | 24 | |
Day 28 | 4.4±0.4 | 4.4 | 3.2, 5.7 | 15 | 4.4±0.4 | 4.4 | 3.0, 6.1 | 22 | |
Day 0 | 11.2±1.4 | 11.4 | 7.4, 13.9 | 64 | 11.1±1.5 | 11.4 | 3.7, 14.3 | 63 | |
Day 28 | 11.4±0.9 | 11.4 | 7.9, 14.5 | 18 | 11.3±0.9 | 11.4 | 7.4, 13.4 | 17 | |
Day 0 | 35.5±3.1 | 35.6 | 25.3, 44.3 | 21 | 35.3±3.3 | 35.6 | 14.9, 43.0 | 18 | |
Day 28 | 35.1±2.6 | 35.3 | 27.3, 42.6 | 10 | 34.9±2.6 | 35 | 26.9, 41.8 | 11 | |
Day 0 | 80.8±5.7 | 80.8 | 60.9, 98.2 | 20 | 80.3±6.4 | 81.2 | 57.1, 99.2 | 38 | |
Day 28 | 80.2±5.6 | 80.5 | 60.0, 94.0 | 23 | 80.2±6.0 | 81.1 | 56.9, 95.5 | 32 | |
Day 0 | 31.5±2.8 | 32.3 | 21.7, 35.5 | 100 | 31.4±3.1 | 32.2 | 21.1, 50.3 | 102 | 0.61 |
Day 28 | 32.3±1.2 | 32.4 | 26.3, 36.1 | 33 | 32.4±1.2 | 32.4 | 26.4, 35.4 | 31 | 0.486 |
0.038 | <0.001 | ||||||||
Day 0 | 25.4±3.0 | 25.9 | 14.9, 31.7 | 60 | 25.3±3.5 | 26 | 13.1, 41.7 | 73 | 0.827 |
Day 28 | 25.9±2.4 | 26.3 | 15.8, 39.1 | 27 | 25.9±2.4 | 26.4 | 16.8, 31.2 | 33 | 0.557 |
0.527 | 0.003 | ||||||||
Day 0 | 364.2±90.2 | 359 | 36.0, 804.0 | 53 | 363.3±96.7 | 354 | 142.0, 1000 | 54 | 0.522 |
Day 28 | 338.6±85.6 | 330 | 94.0, 799.0 | 30 | 347.6±91.2 | 338.5 | 83.0, 965.0 | 46 | 0.206 |
<0.001 | <0.001 | ||||||||
Day 0 | 2.9±0.8 | 2.7 | 1.2, 6.3 | 2.8±0.8 | 2.8 | 1.2, 7.3 | 0.911 | ||
Day 28 | 2.9±0.8 | 2.8 | 1.3, 5.6 | 2.9±1.0 | 2.8 | 1.1, 14.1 | 0.403 | ||
0.63 | 0.169 | ||||||||
Day 0 | 29.8±16.5 | 25 | 6.0, 146.3 | 31 | 28.8±15.8 | 23.7 | 9.1, 118.5 | 31 | 0.172 |
Day 28 | 26.4±17.3 | 23.1 | 6.2, 274.7 | 14 | 26.1±13.6 | 22.9 | 3.6, 138.7 | 18 | 0.682 |
<0.001 | 0.004 | ||||||||
Day 0 | 43.1±26.6 | 38.4 | 15.2, 451.0 | 40.4±22.3 | 36.3 | 9.7, 398.0 | 0.109 | ||
Day 28 | 43.9±20.9 | 39.3 | 14.7, 194.2 | 44.3±20.8 | 39.1 | 9.9, 173.6 | 0.973 | ||
0.165 | 0.016 | ||||||||
Day 0 | 75.8±34.1 | 72 | 10.3, 621.0 | 374 | 73.7±18.9 | 70.9 | 37.2, 148.1 | 377 | 0.52 |
Day 28 | 84.7±24.6 | 82.3 | 26.0, 313.1 | 385 | 86.9±26.8 | 83.2 | 35.8, 228.9 | 383 | 0.59 |
<0.001 | <0.001 |
The efficacy and safety of the antimalarial ACT As+SMP, administered in the doses used for the treatment of malaria, were compared to the efficacy and safety of PZQ, the standard treatment for schistosomiasis, in children aged 6 to 15 years. As+SMP induced a egg reduction rate of 92.8% compared to 95.6% obtained with PZQ. The cure rate without viability test was 43.9% in the As+SMP group versus 53% in the PZQ group (Chi2 = 6.44, p = 0.011), meaning that PZQ was more effective than As+SMP for treating
In this study, PZQ was more efficacious to reduce haematuria during
The safety and tolerability profile of As+SMP was similar to the profile seen with PZQ. All clinical adverse events were graded mild and were resolved during the 2 active follow-up days. No serious adverse event was recorded with any one of the treatments administered, as documented in previous studies
Overall, the means of all laboratory parameters were normal on days 0 and 28, except for the creatinine for both treatment arms. This can be explained by the effect of
Although the safety and tolerability profiles of both treatment arms are similar, PZQ was more effective than As+SMP in this clinical set up. However, the doses of As+SMP that were used in this trial are doses commonly used for the treatment of malaria. Further research into correct dosing for this specific indication may be recommendable. It will be interesting to evaluate the efficacy and safety of As+SMP on other
CONSORT Checklist
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Trial Protocol
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The authors thank all the children from Djalakorodji who participated in the study, and the parents for permitting their children to take part. Kati District Health Center, Djalakorodji Community leaders, Local Community Health Center and School Directors are also thanked for granting permission to conduct the study in Djalakorodji. Thanks are addressed to Miss Djimdé Fanta Guindo, president of Community Health Center Association, the Director of National Schistosomiasis Programme and all our local guides for all the help they provided to better organize the conduct of the study.