English
中文1. Background
Despite efforts to contain the disease, Schistosomiasis remains one of the severe debilitating illnesses in millions of people. Although it has a relatively low mortality rate, it has a high morbidity rate, causing schistosomiasis to often be a chronic illness that can cause liver and intestinal damage. The disease is mainly found in tropical countries in Africa, Caribbean, eastern South America, East Asia and in the Middle East. The World Health Organisation estimates that about 207 million people have the disease, 120 million symptomatic. There are five species of flatworms that cause schistosomiasis. Each type is prevalent in different parts of the world. S. haematobium, is the most virulent parasite in Africa and the Middle East.
Due to the absence of accurate epidemiological data, estimates must still be used to determine the possible burden of infection due to schistosomiasis. For this purpose, the estimates of Utroska et al. (1989) on the average prevalence of infection and the proportion of the population at risk of infection for each country have been applied to the 1995 population (World Bank, 1997) to calculate the number of people at risk of infection and those infected. Based on these calculations, 85% of the estimated number of infected people is on the African continent.
Drugs that are currently prescribed for the prophylaxis of schistosomiasis include praziquantel. Unfortunately, with the use praziquantel, there is a high chance that those people who have been chemotherapeutically cured may rapidly become reinfected, as infected snails and cercaria will still be present in their water supplies, and costly re-treatment campaigns must be maintained. It is thus not an optimum treatment for people living in endemic areas. Consequently there remains an urgent need for new, safe and effective, anti schistosomiasis chemoprophylactic drugs or combination therapies.
Artesunate is part of the artemisinin group of drugs that is used to treat malaria and that has been found by De Clercq et al. (2002) to be effective in the treatment of schistosomiasis caused by the strain, S. haematobium as well. However, there is a high risk that treatment with artesunate may result in the malaria parasites found in the area to become resistant to the drug.
The aim of this field study was to compare the efficacy, safety and tolerance of a combination therapy comprising praziquantel and artesunate and single drug therapy artesunate for the chemoprophylaxis of S. haematobium schistosomiasis in children school children in Lampsar, Northern Senegal.
2. Study area
A village, Lampsar, located along the Lampsar river in the delta of the SRB, was selected for this study. Lampsar, where rice irrigation had been introduced just after the Second World War, is known to be a S. haematobium focus for over 30 years (Chaine and Malek, 1983; Vercruysse et al., 1985) and until 1986 it was considered the only focus in the Delta. Three seasons can be distinguished in the North of Senegal. The rainy season, hot with irregular rains, runs from July to September/October; the cold season, dry and cool (12-30 °C) from November to February, and the hot season, hot and dry, from March to June. Two study groups will be used to remove the influence of transmission season on treatment outcome. The first cohort will be examined and treated with the relavant drug (praziquantel and artesunate or artesunate only) during the season with high transmission, February/Mach and the second cohort will be examined and treated during the low transmission season, in July approximately 5 months later. The present study should preferably be run in Lampsar from February to October.
3. Subject Selection
This is a double- blind, placebo-controlled, randomized, two-arm, parallel group trial. Ethical permission for the study is to be obtained from the Re´gion Me´dicale in Saint-Louis, Ministry of Public Health to which the protocol of the study has to be presented. Before the study begins, months have to be spent in the Lampsar to provide the possible participants, their family, village authorities, health representatives and schoolteachers with the background and purposes of the study. Participation in the survey is subject to the informed consent from the heads of the households to which the children belong. It is vital that the children fully understood the study prior to participating. Children should be screened using ultrasonography. Children found to be presented with macro-haematuria or severe pathology detected by ultrasonography (large masses, pseudo-polyps or hydronephrosis/hydroureter) at the 6 months follow-up examination will be treated with praziquantel and excluded in the data analysis.
To allow for dropouts, approximately two hundred primary schoolchildren (between 7 and 14 years old) are to be examined. To minimise confounding factors in the clinical study, the children are to be tested for other diseases that are prevalent in the region or the village of Lampsar. For example, the possible presence of Amoebiasis, Hookworm disease, Leishmaniasis and Malaria may be determined prior to selecting the participants to carry out the study.
4. Study design
Baseline sampling
Study participants are to be clinically examined at the beginning to ensure they are sufficiently fit to take part and to survive the study. Baseline values of prevalence of S. haematobium in the population and mean parasite intensity in each individual have to be determined. In summary, mean parasite intensity may be determined by sampling the urine on three consecutive days around noon at the time of maximum egg excretion (Feldmeier and Poggensee, 1993). 10 ml of urine is to be filtered on Nuclepore® filters and the eggs are to be counted microscopically. A Geometric Mean (GM) is to be calculated for the three samples. The GM was calculated as the antilogarithm minus one of the mean of all log-transformed egg count plus 1. The reduction percentages in egg counts were calculated as (1−(GM of eggs counted per 10 ml after treatment/GM of eggs counted per 10 ml before treatment))×100 (De Clercq et al., 2002). Parasite sampling will take place at the laboratories in the local university and a few of the urine samples will be preserved in 10% formalin and taken back to Kingston University to check identification of S. haematobium eggs. It is vital that the participants are informed of this. Only those children, in whom S. haematobium eggs are found during this baseline survey, were further considered.
Randomization of subjects and double blinding of experiment
Following an initial screening visit, all eligible volunteers are to be systematically allocated into 3 groups with one group receiving a single dose of 40 mg/kg artesunate (Mediplantex, Hanoi) and the other with a single dose of combination therapy comprising half the dose of artesunate (Mediplantex, Hanoi) used in treatment of malaria (i.e. 4 tablets of 50 mg over 5 days, i.e. 3, 2, 1, 1, 1) and 20 mg/kg praziquantel (Pharmamed, Malta). The third group should receive the placebo drug. Placebo consisted of an identical-appearing tablet composed primarily of lactose. All drugs should be administered at the same time and should be physically identical to ensure that neither the investigator nor the subjects know which treatment the subject gets. Medication should be taken under direct super vision of trained field workers and compliance should be further confirmed by a tablet count.
The scientist who collates the results with the codes on the different drugs at the end of the experiments is not part of the actual study team. Information on codes is only revealed when the data has been collected and requires analysis. This ensures the experiment remains double blind.
In-treatment and post-treatment sampling
Three consecutive midday urine samples should be examined 5 weeks post-treatment to determine the cure rate and at weeks 12 and 24 weeks after treatment to observe re-infection patterns. Again, GM values should be calculated for the three samples to obtain the most accurate results. The results will help determine as to which is the most effective drug to be used on the treatment of S. haematobium schistosomiasis in schoolchildren specific to Lampsar.
Studies have shown that the ingestion of food increases the bioavailability of atovaquone17 and consequently all treatment regimens should be administered within 45 min of a small meal.
Observations of side effects
Body temperature and adverse events since the last visit should be recorded on a weekly basis. Blood samples should be taken for routine haematology, clinical chemistry and plasma drug level determination
Side effects to look out for include gastric pain, nausea, pollakiuria, vertigo, tinnitus, diarrhoea and fever.
5. Subject compliance
It is vital that the participant complies with the trial and follows the treatment protocol. As mentioned above, medication should be taken under direct super vision of trained field workers and compliance should be further confirmed by a tablet count. The administration of the drug can be done in the school compounds. The trained field workers may visit the classes in which the participants are studying and administer the drugs. Or to ensure that the drugs are taken at the same time, the field workers may employ the services of the schoolteachers. It is best to have the participants of the trial take the drug at school, instead of at home where it may be impossible to monitor the intake of the drug.
6. Health and safety
All safety data should be listed highlighting clinical laboratory values outside the normal range. A COSHH form is attached for the use of formalin.
