55
TRANSACTIONS OF THE ROYALSOCIETY OF Tnor~cnr. MEDICINEAND HYGIENE(1990)84, 55-57
Proguanil-sulph.onamide
for malaria
prophylaxis
Jerome J. Kanvacki, G. Dennis Shanks, Nipon Limsomwong Research Institute of Medical Sciences, Bangkok, Thailand Abstract There are few safe, effective chemoprophylactic regimens for preventing Plasmodium falciparum infection in south-east Asia. In two randomized placebocontrolled trials, combinations of proguanil and sulphonamide were tested for chemoprophylactic activity in schoolchildren, aged 6-15 years, living near the Thai-Burmese border. Proguanil at an equivalent adult dose of 200 mg/d was combined with sulphafurazole (=sulfisoxazole) at 25 mg/kg/d or sulnhamethoxazole at 25 and 10 me/kc/d. Combinatie-ns of daily prop;uanil/sulpKafrazole and proguanil/sulph&n&ho&zole were equally effective (>75%‘, against both falcioarum and vivax malaria &hen ihe” sulphonamide ‘component was used at 25 mg/kg/d. Proguanil and sulphamethoxazole at 10 mg/kg/d was ineffective. Approximately 1% of the children had sulphonamide-related skin rasheswhich resolved when treatment stopped. ProguanUsulphonamide is a possible alternative chemoprophylactic regimen in areas with multiple drug-resistant P. falciparum .
Introduction The emergence and spread of multiple drugresistant Plasmodium fakiparum in south-east Asia has made the treatment of malaria increasingly difficult (HOFFMAN, 1986). No less difficult has been the selection of appropriate chemoprophylactic agents (CDC, 1988). In a recent report from this laboratory, a proguanil and sulphafurazole (=sulfisoxazole)* combination was shown to provide effective chemoprophylaxis when either drug alone failed (PANG et al.. 1989). Further studies were then carried out to determink if other sulphonamides and other doses could be used successfully. This report details 2 separate clinical trials. The first was an equivalent dose comparison of pronuanivsulphafurazole and proguanilisulphamethoxa~ole. Suiphamethoxazole was chosen because its half-life of 10-12 h more closely approximated that of proguanil. The second trial compared 2 separate doses of proguanil/sulphamethoxazole in order to find a minimum effective dose of the sulphonamide component. Materials and Methods Study subjects
The trials were conducted in Bonoklo, an ethnic The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Informed consent was obtained from the participant’s parents or guardians. Guidelines for human experimentation of the Department of Defense were followed in the conduct of the clinical research. ‘Sulphafurazole B.P.=sulfisoxazole U.S.P.; in this paper, the British name has been used (ed.).
and Pricha Singharaj
Armed Forces
Karen village located along the Thai-Burmese border in Thailand’s Tak Province. Schoolchildren aged 6-15 years were eligible for participation after a minimum of 2 negative malaria smears and if there was no history of intolerance to any of the study drugs. Available subjects were stratified by age and spleen size as an estimate of prior experience of malaria, and then grouped according to a computer generated random number list. All participants’ parents or guardians gave informed consent before enrohnent. Explanations and informed consent statements were all in the native language of the parents. Protocols were approved by the AFRIMS Ethical Review Committee and bv the Karen Committee, Mae Sod, Thailand. ’ Medication
Assigned drugs were administered daily by a registered nurse. Drug administration was not ‘blind’, to-prmit rapid evaluation of sulphonamide reaction. In the first trial sulnhafurazole (suffisoxazole: Gantrisin, Roche Laboiatories) and sulphamethoxazole (Gantanol, Roche Laboratories) were used at 25 mgi kg/d. In the second trial only sulphamethoxazole was used at dosesof both 10 and 25 mn/kg. Multi-vitamin tablets were used as placebos. P&g&nil (Paludrine, ICI Pharmaceuticals1 was used in both trials at a maximum daily doge of 200 mg. Study subjects weighing 20 kg or less received 100 mg and those over 20 kg received 200 mg. Clinical and parasitological examinations
All participants were questioned daily about symptoms and specific side-effects. A physician examined any ill children; any children not present during daily drug administration were usually located through a search of the village. Medications were re-administered to children who vomited within one hour. Participants were examined for malaria weekly or whenever they exhibited symptoms compatible with malaria. The laboratory technicians who examined blood smearswere unaware of the drug assignments. A casewas defined as a person with malaria parasites seenin a Giemsa-stained thick blood smearwhich was made after uninterrupted daily medication. A smear was declared negative if no parasites were seen upon microscopical examination of 200 oil-immersion fields by an experienced technician. Subjects contracting P. falciDarum were treated with mefloquine/sulp~adoxi~elp~rimethamine (Fansimef. Hoffman La Rachel under the suoervision of a primary care clinic opera&d by a vohmieer organization. P. vivax was treated with 4 dosesof chloroquine concurrent with a 14 d course of primaquine. After completing treatment or returning from a period of absence, subjects were re-entered into their original drug group upon demonstration of a negative malaria smear.
56
calculated according to cases and man-weeks of participation (KLEINBAUMet al., 1982). For example, in study 1 the ID ratio of 0.11 indicates 89% protection compared to placebo. In study 2, proguaniUsulphamethoxazole at 25 mglkgid remained better than placebo. However, there was no difference between proguaniysulphamethoxazole at 10 mg/kg/d and placebo except with P. vivax. The statistical power is small due to the general decreasein malaria that occurred over time in the entire village. The ID ratio for the 10 mg/kg sulphamethoxazole group was greater than 1, indicating a failure to protect against falciparum malaria. Due to the relatively low malaria attack rate in study 2, the power of this study was low. However, results for the samedoseregimen can be pooled since both studies were performed sequentially in the same population. The combined results of the 25 mg/kg dose of sulphamethoxazole show 78% protection with a 95% confidence interval of 73-83%. The resulting
Data analysis
The system of weekly malaria testing and re-entry after absenceor infection allowed the compilation of the data in the form of infections per man-week. Analysis was by the incidence density method using standard formulas (KLEINBAUMet al., 1982). Laboratory tests before and after both trials were compared by paired t tests. Results
The patient groups were comparable with respect to age, sex and markers of previous malaria (Table 1). The actual drug dose given varied only minimahy despite the limitations of subdividing tablets. Five children were removed due to skin rashes thought to be due to sulphonamides. None of these were serious and all resolved within days of discontinuation of the drug. Follow-up for all daily appointments was 97%. Breakthrough malaria casesare shown in Table 2. The incidence density (ID) ratio is a relative risk Table
1. Comparability
of drug groups upon entry
Subjects
Average age (ye&
Sex Wf)
116 119 118
9.47 9.38 9.52
60156 46173 50168
i:
;:;
27
-
26.4 26.8 -
102 1;:
9.45 9.15 9.21
41/61 50147 44157
1X
6.6 6.6 -
10.3 24.8 -
Study 1’ PRO/SXZZS PRO/SMX-25 Placebo Study 2’ PRO/SMX-10 PRO/SMX-25 Placebo
Spleena
Drug dose (mg/kg)b Proguanil Sulpha
7
“Spleen=number of subjects with palpable spleen. bAverage dose administered. ‘PRO=proguanil 200 mg adult-equivalent dose/d; SXZ=sulphafurazole at stated dose (mg/kg/d); SMX=sulphamethoxazole at stated dose (mgikg/d); Placebo=daily multi-vitamin. Table
2. Malaria
cases and incidence
density ratio according P . falciparum
Cases Study lb PRO/SXZZS
ID ratio
to malaria species P. &ax
Man-weeks
Cases
ID ratioa 0.21 (0.16-0.28)
TRANSACTIONS OF THE ROYALSOCIETY OF Tnor~cnr. MEDICINEAND HYGIENE(1990)84, 55-57
Proguanil-sulph.onamide
for malaria
prophylaxis
Jerome J. Kanvacki, G. Dennis Shanks, Nipon Limsomwong Research Institute of Medical Sciences, Bangkok, Thailand Abstract There are few safe, effective chemoprophylactic regimens for preventing Plasmodium falciparum infection in south-east Asia. In two randomized placebocontrolled trials, combinations of proguanil and sulphonamide were tested for chemoprophylactic activity in schoolchildren, aged 6-15 years, living near the Thai-Burmese border. Proguanil at an equivalent adult dose of 200 mg/d was combined with sulphafurazole (=sulfisoxazole) at 25 mg/kg/d or sulnhamethoxazole at 25 and 10 me/kc/d. Combinatie-ns of daily prop;uanil/sulpKafrazole and proguanil/sulph&n&ho&zole were equally effective (>75%‘, against both falcioarum and vivax malaria &hen ihe” sulphonamide ‘component was used at 25 mg/kg/d. Proguanil and sulphamethoxazole at 10 mg/kg/d was ineffective. Approximately 1% of the children had sulphonamide-related skin rasheswhich resolved when treatment stopped. ProguanUsulphonamide is a possible alternative chemoprophylactic regimen in areas with multiple drug-resistant P. falciparum .
Introduction The emergence and spread of multiple drugresistant Plasmodium fakiparum in south-east Asia has made the treatment of malaria increasingly difficult (HOFFMAN, 1986). No less difficult has been the selection of appropriate chemoprophylactic agents (CDC, 1988). In a recent report from this laboratory, a proguanil and sulphafurazole (=sulfisoxazole)* combination was shown to provide effective chemoprophylaxis when either drug alone failed (PANG et al.. 1989). Further studies were then carried out to determink if other sulphonamides and other doses could be used successfully. This report details 2 separate clinical trials. The first was an equivalent dose comparison of pronuanivsulphafurazole and proguanilisulphamethoxa~ole. Suiphamethoxazole was chosen because its half-life of 10-12 h more closely approximated that of proguanil. The second trial compared 2 separate doses of proguanil/sulphamethoxazole in order to find a minimum effective dose of the sulphonamide component. Materials and Methods Study subjects
The trials were conducted in Bonoklo, an ethnic The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Informed consent was obtained from the participant’s parents or guardians. Guidelines for human experimentation of the Department of Defense were followed in the conduct of the clinical research. ‘Sulphafurazole B.P.=sulfisoxazole U.S.P.; in this paper, the British name has been used (ed.).
and Pricha Singharaj
Armed Forces
Karen village located along the Thai-Burmese border in Thailand’s Tak Province. Schoolchildren aged 6-15 years were eligible for participation after a minimum of 2 negative malaria smears and if there was no history of intolerance to any of the study drugs. Available subjects were stratified by age and spleen size as an estimate of prior experience of malaria, and then grouped according to a computer generated random number list. All participants’ parents or guardians gave informed consent before enrohnent. Explanations and informed consent statements were all in the native language of the parents. Protocols were approved by the AFRIMS Ethical Review Committee and bv the Karen Committee, Mae Sod, Thailand. ’ Medication
Assigned drugs were administered daily by a registered nurse. Drug administration was not ‘blind’, to-prmit rapid evaluation of sulphonamide reaction. In the first trial sulnhafurazole (suffisoxazole: Gantrisin, Roche Laboiatories) and sulphamethoxazole (Gantanol, Roche Laboratories) were used at 25 mgi kg/d. In the second trial only sulphamethoxazole was used at dosesof both 10 and 25 mn/kg. Multi-vitamin tablets were used as placebos. P&g&nil (Paludrine, ICI Pharmaceuticals1 was used in both trials at a maximum daily doge of 200 mg. Study subjects weighing 20 kg or less received 100 mg and those over 20 kg received 200 mg. Clinical and parasitological examinations
All participants were questioned daily about symptoms and specific side-effects. A physician examined any ill children; any children not present during daily drug administration were usually located through a search of the village. Medications were re-administered to children who vomited within one hour. Participants were examined for malaria weekly or whenever they exhibited symptoms compatible with malaria. The laboratory technicians who examined blood smearswere unaware of the drug assignments. A casewas defined as a person with malaria parasites seenin a Giemsa-stained thick blood smearwhich was made after uninterrupted daily medication. A smear was declared negative if no parasites were seen upon microscopical examination of 200 oil-immersion fields by an experienced technician. Subjects contracting P. falciDarum were treated with mefloquine/sulp~adoxi~elp~rimethamine (Fansimef. Hoffman La Rachel under the suoervision of a primary care clinic opera&d by a vohmieer organization. P. vivax was treated with 4 dosesof chloroquine concurrent with a 14 d course of primaquine. After completing treatment or returning from a period of absence, subjects were re-entered into their original drug group upon demonstration of a negative malaria smear.
56
calculated according to cases and man-weeks of participation (KLEINBAUMet al., 1982). For example, in study 1 the ID ratio of 0.11 indicates 89% protection compared to placebo. In study 2, proguaniUsulphamethoxazole at 25 mglkgid remained better than placebo. However, there was no difference between proguaniysulphamethoxazole at 10 mg/kg/d and placebo except with P. vivax. The statistical power is small due to the general decreasein malaria that occurred over time in the entire village. The ID ratio for the 10 mg/kg sulphamethoxazole group was greater than 1, indicating a failure to protect against falciparum malaria. Due to the relatively low malaria attack rate in study 2, the power of this study was low. However, results for the samedoseregimen can be pooled since both studies were performed sequentially in the same population. The combined results of the 25 mg/kg dose of sulphamethoxazole show 78% protection with a 95% confidence interval of 73-83%. The resulting
Data analysis
The system of weekly malaria testing and re-entry after absenceor infection allowed the compilation of the data in the form of infections per man-week. Analysis was by the incidence density method using standard formulas (KLEINBAUMet al., 1982). Laboratory tests before and after both trials were compared by paired t tests. Results
The patient groups were comparable with respect to age, sex and markers of previous malaria (Table 1). The actual drug dose given varied only minimahy despite the limitations of subdividing tablets. Five children were removed due to skin rashes thought to be due to sulphonamides. None of these were serious and all resolved within days of discontinuation of the drug. Follow-up for all daily appointments was 97%. Breakthrough malaria casesare shown in Table 2. The incidence density (ID) ratio is a relative risk Table
1. Comparability
of drug groups upon entry
Subjects
Average age (ye&
Sex Wf)
116 119 118
9.47 9.38 9.52
60156 46173 50168
i:
;:;
27
-
26.4 26.8 -
102 1;:
9.45 9.15 9.21
41/61 50147 44157
1X
6.6 6.6 -
10.3 24.8 -
Study 1’ PRO/SXZZS PRO/SMX-25 Placebo Study 2’ PRO/SMX-10 PRO/SMX-25 Placebo
Spleena
Drug dose (mg/kg)b Proguanil Sulpha
7
“Spleen=number of subjects with palpable spleen. bAverage dose administered. ‘PRO=proguanil 200 mg adult-equivalent dose/d; SXZ=sulphafurazole at stated dose (mg/kg/d); SMX=sulphamethoxazole at stated dose (mgikg/d); Placebo=daily multi-vitamin. Table
2. Malaria
cases and incidence
density ratio according P . falciparum
Cases Study lb PRO/SXZZS
ID ratio
to malaria species P. &ax
Man-weeks
Cases
ID ratioa 0.21 (0.16-0.28)
