A double-blind clinical trial of a combination of mefloquine, sulfadoxine and pyrimethamine in symptomatic falciparum malaria

Bulletin ofthe World Hlealth Organization, 63 (2): 339-343 (1985) +< World Health Organization 1985 A double-blind clinical trial of a combination of mefloquine, sulfadoxine and pyrimethamine in symptomatic falciparum malaria J. M. KOFI EKUE,' O. 0. SIMOOYA, U. K. SHETH,3 W. H. WERNSDORFER, & E. K. NJELESANI5 Fansimef is a combination of 250 mg of mefloquine, 500 mg of sulfadoxine, and 25 mg ofpyrimethamine per tablet. A total of 150 adult male Zambian patients who had symptomatic Plasmodium falciparum parasitaemia were treated in a double-blind randomized fashion with either one, two or three tablets of Fansimef. All patients in the three treatment groups showed an S-type response. The rates of clearance ofparasitaemia andfever were similar in all treatment groups. Tolerance was good at all dose levels. The main side-effects were abdominal discomfort, weakness and lassitude, dizziness, and pruritus, but these were mild, transient and required no specific treatment. Vomiting occurred only in 4% of patients given the highest dose of three tablets. The results of various haematological and biochemical investigations and urinalysis were not adversely altered by the administration of Fansimef. Mefloquine, administered orally in doses of 750-1000 mg, has been shown to be effective in the treatment of both chloroquine-resistant and chloroquine-sensitive acute falciparum malaria (1, 2). However, it is feared that the use of mefloquine alone in clinical practice may soon lead to the development of resistance, since studies in mice and rats have already demonstrated that resistance of Plasmodium berghei to mefloquine could be induced relatively quickly and easily (3-5). The emergence of resistance could be delayed by the administration of antimalarials in combination (6). Fansidara is a fixed 20:1 ratio combination of sulfadoxine and pyrimethamine, which has been used for many years for the successful treatment and sup- pression of malaria (7). It is a second-line drug of choice in the management of chloroquine-resistant falciparum malaria (8, 9). Unfortunately, increasing resistance of P.falciparum to sulfadoxine/pyri- Clinical Pharmacologist, Tropical Diseases Research Centre (TDRC), P.O. Box 71769, Ndola, Zambia. 2 Staff Development Fellow (Clinical Pharmacology), TDRC, Ndola, Zambia. 3WHO Consultant Clinical Monitor, Malaria Action Programme, World Health Organization, Geneva, Switzerland. 4Chief, Research and Technical Intelligence, Malaria Action Programme, World Health Organization, Geneva, Switzerland. Director, TDRC, Ndola, Zambia. Hoffmann-La Roche and Co. Ltd, Basel, Switzerland. methamine has been reported from Brazil and Thailand and has also emerged in Africa (10, 11, J. M. K. Ekue et al., unpublished observations, 1983-84). Fansimef,a a combination of 250 mg of mef- loquine, 500 mg of sulfadoxine, and 25 mg of pyri- methamine per tablet, was introduced in the hope that it would not only be effective in drug-resistant P.falciparum malaria but also delay the emergence of resistance to mefloquine. In phase I studies, Fansimef was found to be well tolerated in healthy adult male volunteers in Zambia; adequate blood levels of each of the components were achieved after administration of three tablets to volunteers (J. M. K. Ekue et al., unpublished obser- vations, 1982). The present study was carried out to assess the tolerance and effectiveness of Fansimef at three dose levels in adult male Zambians with symptomatic P.falciparum parasitaemia. MATERIALS AND METHODS The study was carried out in the clinical trials wards of the Tropical Diseases Research Centre, Ndola, Zambia. The transmission of malaria is not possible in the mosquito-free hospital environment. The protocol for the trial was approved by the 4530 -339- J. M. KOFI EKUE ET AL. Zambian Ethical Committee as well as by the World Health Organization Secretariat Committee on Research involving Human Subjects. All the patients who entered the trial were aged 12 years or over, and were recruited from the out- patients' department of Ndola Central Hospital. The trial was prospective, randomized, and double- blind. Each patient was kept under observation in hospital from day 0 (when the drugs were adminis- tered) to day 35. A total of 150 patients with proven symptomatic asexual P.falciparum parasitaemia gave informed consent to participate in the trial. Patients with serious infections or other com- plications needing parenteral treatment were excluded from the study. Each patient was assigned to one of three groups, in a random double-blind manner. Tablets of Fansimef, together with identical placebo tablets, were adminis- tered as follows: patients in group 1 received one Fansimef plus two placebo tablets; those in group 2, two Fansimef plus one placebo tablet; and those in group 3 were given three Fansimef tablets. The patients were treated with other drugs such as analgesics (aspirin), sedatives (diazepam), and anthel- minthics only upon advice of the clinicians; any such medication was noted on the patient's record form. A history was taken from each patient and a detailed clinical examination was carried out according to a standard protocol. Clinical measure- ments and various laboratory investigations were also carried out serially. The patients were examined on day 0 before the administration of the trial drugs and daily on days 1-7, then once a week until day 35. Clinical features such as symptoms, pulse rate, body temperature, and respiration were recorded daily. Blood pressure was measured daily on days 0 to 7 and then weekly up to day 35. The electrocardiogram, chest X-ray, measurement of height and body weight, the Dill-Glazko urine test for chloroquine, a quali- tative urine test for glucose-6-phosphate dehydro- genase (G6PD), and determination of haemoglobin genotype were performed on day 0. The electrocar- diogram was repeated on days 1, 4, 7, 14, 28, and 35 and the patients were reweighed on day 35. A series of haematological and biochemical investigations was carried out on days 0, 1, 4, 7, 14, 28, and 35. Urinalysis was performed daily on days 0 to 7 and also on days 14, 28, and 35. Stools were examined for blood and parasites on day 0. Blood smears were prepared and examined for malarial parasites daily from day 0 to day 7, then weekly until day 35. RESULTS Each of the three treatment groups comprised 50 patients aged between 12 and 49 years. Two patients dropped out from each group (in total six patients) for reasons that were not related to the administration of the trial drugs. One patient in group 3 could not be assessed as he was found to have gametocytes only. Therefore, results were available for 48 patients in each of groups 1 and 2, and 47 in group 3. The mean body weight in group I was 53.5 kg on day 0, and there was an average weight gain of 2.4 kg by day 35. The mean body weight in group 2 was 53.9 kg on day 0, with a mean weight gain of 1.3 kg by day 35. The equivalent values for group 3 were 54.3 kg and 3.3 kg. There were wide individual variations in weight but there was no significant difference in mean weight among the three groups during the period of observation. Clinicalfindings In all cases, the blood pressure and respiratory system were normal and remained normal after administration of the trial drug. Mild sinus brady- cardia occurred in 6 patients from group 1, 5 patients from group 2, and 6 patients from group 3. There were no clinical symptoms and the pulse rate reverted to normal without any specific treatment. Sinus tachycardia, associated with pyrexia, was seen in 22 patients in group 1, 22 patients in group 2, and 28 patients in group 3 before the administration of the trial drugs on day 0. First-degree atrioventricular block was seen before treatment in three patients (two in group 2 and one in group 3) and developed between day 7 and day 35 in one patient in group 3. Before treatment, a Wolff- Parkinson-White syndrome was seen in one patient in group 2, a suspected myocarditis in one patient in group 3, and a generalized electrocardiographic T- wave inversion in one patient in group 3. None of these patients showed any adverse effects after drug administration. Only one patient had neuropsychiatric symptoms after the administration of the trial drug; the patient in question developed an acute anxiety reaction on days 3 to 7, and was treated with diazepam and chlorpromazine. His relatives took him out of the hospital on day 8 against medical advice. Follow-up investigations revealed that the patient was under severe mental stress before he developed the attack of acute malaria. There was splenomegaly in 20-22 patients in each group on day 0. The numbers with splenic enlarge- ment on day 35 were 3 in group 1, 2 in group 2, and 4 in group 3. Five patients (three in group 1 and one each in groups 2 and 3) had slight hepatomegaly on day 0; in most cases, liver size soon reverted to normal. One patient in group 1 developed slight hepatomegaly between days 2 and 35. 340 CLINICAL TRIAL OF MEFLOQUINE/SULFADOXINE/PYRIMETHAMINE Laboratory investigations In all three groups, the values for haemoglobin, erythrocyte volume fraction (haematocrit), red and white blood cell counts, differential white blood cell counts, and reticulocytes were comparable before treatment. No drug-related adverse changes were seen. Erythrocyte sedimentation rate was high in all three groups on day 0, and returned gradually to normal values. On day 0, the mean rates were 27.3 mm/h, 29.0 mm/h, and 26.1 mm/h, respec- tively, for groups 1, 2 and 3; the corresponding values on day 35 were 7.4 mm/h, 8.8 mm/h, and 6.8 mm/h. Eosinophil counts were elevated in a number of patients; this was probably related to a high rate of helminth infection in this population (30-50% of subjects in all groups on day 0). No significant drug-related changes were seen in the results of urinalysis, in any of the three groups. Fasting serum glucose, plasma urea, serum bili- rubin, aspartate aminotransferase, alanine amino- transferase, alkaline phosphatase, serum calcium, serum sodium, serum potassium, serum creatinine, and serum proteins were generally within the normal range and were not modified in any undesirable manner after administration of the trial drug. Parasitological response Table 1 shows the details of clearance of parasit- aemia and mean parasite counts in the three treatment groups. Group 1 (one tablet). Of the 48 cases, only one was positive for P.falciparum asexual forms by day 3. From day 4 to day 35, no cases were positive. The mean parasite clearance time was 2.5 ± 0.6 days. Group 2 (two tablets). Of the 48 cases who were evaluated, only two were positive for P.falciparum on day 3. From day 4 to day 35, no cases were positive. The mean parasite clearance time was 2.5 ± 0.6 days. Group 3 (three tablets). All 47 cases were positive for P.falciparum on day 0, 3 cases on day 3, and 2 cases on day 4. From day 5 to day 35, all cases remained negative. The mean parasite clearance time was 2.4 ± 0.8 days. Body temperature The numbers of patients who had fever before treatment on day 0 were 39 in group 1, 48 in group 2, and 38 in group 3. Similar mean rates of clearance of fever were seen in the three groups: 1.9 ± 1.0 days for group 1, 2.2 ± 1.0 days for group 2, and 2.3 ± 1.2 days for group 3. Differences between the groups were not significant. Side-effects The main subjective side-effects that could be attributed to the trial drugs were abdominal discom- fort or pain, dizziness, weakness and lassitude, and pruritus (Table 2). The incidence of these side-effects was similar in all three groups. The incidence of dizzi- ness appeared to be dose-related, but the numbers were too small to permit statistical analysis. Vomiting was observed only in two patients in group 3. The differences between the dosage groups regarding the incidence of side-effects were not statistically signi- ficant. The side-effects were mostly mild and of short duration, and required no specific treatment. DISCUSSION The objective of this study was to compare the clinical effectiveness, safety and tolerance of three Table 1. Clearance of parasitaemia and mean parasite counts (per mm3 of blood) in patients given sulfadoxine/pyri- methamine/mefloquine Group 1 Group 2 Group 3 Day of treatment No. % Mean No. % Mean No. % Mean positive positile parasite positive positive parasite positive positive parasite count count count 0 48 100 10004 48 100 11 953 47 100 9 596 1 46 9'.8 10 301 48 100 15 961 45 95.7 11 527 2 26 54 99 22 45.8 199 16 34 452 3 1 2 3.7 2 4.2 2 4 8.5 12.9 4 0 0 0 0 0 0 2 4.2 10.6 5-7 0 0 0 0 0 0 0 0 0 341 J. M. KOFI EKUE ET AL. Table 2. The incidence of side-effects after administration of sulfadoxine/pyrimethamine/mefloquine Side-effect Group 1 M%) Group 2 (%) Group 3 %) Nausea 0 6 4 Vomiting 0 0 4 Abdominal pain 12 14 4 Diarrhoea 4 2 4 Dizziness 10 14 22 Weakness/lassitude 18 14 14 Pruritus 10 8 6 Rash 0 0 2 doses of Fansimef (a combination of 250 mg of mefloquine, 500 mg of sulfadoxine, and 25 mg of pyrimethamine per tablet). One, two, or three tablets were given as a single oral dose to patients with P.falciparum malaria. The cure rate (S-response) was 100% in all treat- ment groups. The mean rate of clearance of P.falciparum parasitaemia was 2.5 days, and similar rates were seen in all treatment groups (2.5, 2.5, and 2.4 days, respectively). By day 3, the extent of clearance of parasitaemia was 97.9% for group 1, 95.8/o for group 2, and 95.7% for group 3. The rates of clearance of fever in the three groups were also similar: 1.9 days for group 1, 2.2 days for group 2, and 2.3 days for group 3. Tolerance was good at all dose levels. Side-effects were mild and transient and showed similar incidence in all treatment groups. The main side-effects were abdominal discomfort, weakness and lassitude, dizzi- ness, and pruritus. During a previous study, meflo- quine produced vomiting in 11.9% of cases (1). In the present study with Fansimef, the incidence of vomiting was low and occurred only in the group given the highest dose (407). Haematological and biochemical investigations and urinalysis did not reveal any adverse effects after the administration of Fansimef at any of the three dose levels. Fansimef was found to be well tolerated, safe, and effective in the treatment of symptomatic falciparum malaria in a single oral dose of one, two, or three tablets. Similar responses were seen at all three dosage levels. In Zambia, where the emergence of drug- resistant malaria is not yet a major problem and where most of the malarial parasites are sensitive to standard doses of chloroquine, a dose of two tablets would appear to be appropriate for the treatment of falciparum malaria; this will ensure a margin of safety for cases that may require slightly higher blood drug concentrations. The sensitivity of P.falciparum to antimalarials is changing rapidly (12) and it is important to ensure the rational use and deployment of new drugs. Attention is drawn to the recommendations of a WHO Scientific Group (13), that the use of mefloquine and its combinations by communities in endemic areas should be restricted to the treatment of acute malaria attacks that are likely to be due to multiple drug- resistant P.falciparum, and that fully curative doses should be used at all times. ACKNOWLEDGEMENTS We thank Sister R. A. Kishombe and the TDRC nursing staff for their excellent cooperation. We are also grateful to the staff of the TDRC parasitology, haematology and biochemistry laboratories. This study received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases. 342 CLINICAL TRIAL OF MEFLOQUINE/SULFADOXINE/PYRIMETHAMINE 343 RESUME ESSAI CLINIQUE A DOUBLE INSU D'UNE ASSOCIATION DE MEFLOQUINE, SULFADOXINE ET PYRIMETHAMINE DANS LE PALUDISME SYMPTOMATIQUE A P. FALCIPARUM Un total de 150 adultes zambiens de sexe masculin, presentant une parasitemie a Plasmodium falciparum symptomatique, ont e traites par une unique adminis- tration orale d'un, de deux ou de trois comprimes de Fansimef (contenant chacun 250 mg de mefloquine, 500 mg de sulfadoxine et 25 mg de pyrimethamine). Il s'agissait d'une etude prospective, randomisee, a double insu. Tous les malades ont et choisis parmi les sujets frequentant la consultation externe de l'h6pital central de Ndola. Ils ont &et inclus apres avoir donne leur consentement eclaire et ont ete gardes en observation pendant 35 jours en milieu hospitalier a I'abri des moustiques. Le taux de guerison (reponse S) a e de 100% dans tous les groupes de traitement. Les taux de disparition de la parasitemie et de la fievre ont e similaires. La tolerance a ete bonne pour les trois doses. Les effets secondaires etaient benins, transitoires et n'ont demande aucun traitement specifique. Les plus courants etaient: douleur abdominale, vertige, faiblesse et fatigue ainsi que prurit. Les vomisse- ments etaient rares (4%o) et n'ont e observes que chez les malades recevant la dose la plus elevee. La frequence des effets secondaires a e la meme pour les trois doses. REFERENCES 1. EKUE, J. M. K. ET AL. Bulletin of the World Health Organization, 61: 713-718 (1983). 2. HARINASUTA, T. ET AL. Bulletin of the World Health Organization, 61: 299-305 (1983). 3. PETERS, W. J. & ROBINSON, B. L. 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