640 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE (1991) 85, 64&643
A placebo-controlled double-blind trial for the treatment filariasis with ivermectin or diethylcarbamazine M. Sabry’, H. Gamal*, N. El-Masry’ and M. E. Kilpatrick’ No. 3 (NAMRU-3),
Cairo, Egypt;
*Abbassia Fever Hospital,
Abstract Theraoeutic efficacv and clinical side-effects of ivermectm (single dose of 100 pg/kg) and diethylcarbamazine (DEC) (3 mgikg for one day, then 6 mgikg dailv for 12 d) were evaluated for microfilaricidal effect in Bancroftian filariasis. Seventy-one microfilaraemic consenting adult male patients (2100 microfilariae (mf)/ml)~were randomiy assigned to receive ivermectin. DEC or nlacebo and kent in hosuital for 15 d. Those receiving placebo were treated with ivermectin on day 9. Ivermectin (19 ‘double-blinded’ and 22 ‘unblinded’ patients) caused an abrupt reduction in mf count to 1.5% of the pre-treatment level 12 h after drug administration and to 0.06% on day 14, with recrudescence to 1.8% after one month and to 9.2% after 3 months. DEC (30 patients) caused a gradual drop in mf count to 1.1% of the pre-treatment level on day 14, which increased to 2.4% after one and 3 months. The total scores of side-effects were 77 (l%), 305 (2.1%) and 311.5 (3.0%) for placebo, ivermectin and DEC respectively; the differences between DEC or ivermectin and placebo were statistically significant. Ivermectin produced lower sidereaction scores than DEC and the differences were highly significant at the 95% confidence level. Sideeffects were mainly headache and body aches in the ivermectin patients, which appeared as early as 4 h after drug administration, resolved within 36 to 48 hours, and were significantly related to mf densities. Side-effects in DEC patients were mainly testicular and epididymal pain and swelling, unrelated to mf densities, which began at day 2 and continued to day 7. Single dose ivermectin was more effective in reducing microfilaraemia in Bancroftian filariasis than a 13 d course of DEC for a period of about 2 months after treatment, and side effects were of shorter duration. Introduction Lvmuhatic filariasis is endemic in trouical and subtroiical countries with approximately 965 million people at risk of infection, and 90.2 million people already infected; 81.6 million with Wuchereria bancrofti and 8.6 million with Brugia malayi and B. timori (WHO. 1984). Diethylcardamazine (DEC), a piperazine derivative, has remained the drug of choice for the past 40 years, but because of its side-reactions, mainly testicular and epididymal pain and swelling, many patients refuse treatment (SASA et al., 1963; SUNDARAM
et al.,
1974; HAWKING, 1979). Ivermectin,
a
Requests for offprints: Research Publications Branch, US NAMRU-3, FPO New York 09527-1600,USA. Attn. Code 101
of Bancroftian
I United States Naval Medical Research Unit Ministry of Health, Cairo, Egypt
semi-synthetic macrocyclic lactone derived from
Streptomyces avermitilis, was extremely successful in
the treatment of onchocerciasis at 150 pg/kg single dose. The objective of the present study was to evaluate efficacv and side-effects of ivermectin and DEC in a ‘double-blinded’, placebo-controlled trial infected with W. bancrofti. Patients and Methods Patients
Eighty male Egyptians (aged 15-55 years) volunteered to participate in the study. They were initially identified by surveys conducted in the Qulyubia and Dakahlyia governorates, 2 areasendemic for Bancroftian filariasis. All had microfilariae (mf) counts 215 per 20 mm3 of finger prick blood (2100 mfiml of venous blood) and were admitted to hospital for 15 d in Abbassia fever hospital, Cairo. None of the individuals was symptomatic before admission and all denied any antifilarial treatment during the past 2 years. Informed consent was obtained from each individual after the study was explained to them. Treatment
Ivermectin (100 pglkg single dose on day 1, then placebo for 12 d), DEC (3 mgikg on day 1, then 6 mgikg daily for 12 d), and placebo were each prepared as identical capsules in separate 13 d coded treatment kits in dosagesappropriate for body weight ranges. Patients were randomly and ‘blindly’ assigned to one of the 3 treatment groups. Since all study individuals were infected, those patients assigned to placebo were identified by an independent monitor on day 8 of therapy and treated with a single 100 pg/kg dose of ivermectin on day 9, without disclosing their identity to the associateinvestigators, and they were observed for efficacv of treatment and side-effects for 6 d. All medication was given before breakfast on days 1-13 and patients were observed to swallow the
capsules. Methods
Blood samples (5 ml) were collected in ethylenediaminetetraacetic acid from all studv individuals between 2200 and 2400 h on days 0, 1; 2, 8 and 14; the placebo patients had samples taken on days 0, 1, 2, 8, 9, 10 and 14. After discharge similar samples
were taken at 1 month and 3 months, and further follow-up sampleswill be taken at 69 and 12months. Mf counts were made by filtering 1 ml aliquots through Nuclepore@membrane filters, mounting the filter on a slide, staining with Giemsa stain solution diluted 1: 10 in phosphate buffer, and counting the mf at 100x magnification. Complete blood cell counts,
641 determination of serum creatinine, alkaline phosphatase, aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT) and bilirubin, and urinalysis were performed on each individual on days 0, 8 and 14. Side effects Patients were questioned and examined daily for signs and symptoms of possible drug side effects. Any untoward effects were recorded on the individual’s clinical file and scored on a scale of 0 to 3 (nil, mild, moderate or severe). Blood pressure was recorded 3 times daily. Fever was scored on a scale of 1 to 3: 1, 37.6”C to 38.X; 2, 38.6 to 39.X; and 3, >39.6”C. Statistical analysis Student’s t test was used to determine the significance of differences between the means of 2 samples of unequal sizes (using their pooled variance) and the Wilcoxon test was used as a non-parametric alternative (SNEDECOR & COCHRAN, 1967). Results Seventy-five patients completed the 15 d in hospital; 5 were discharged earlier, one for refusing to give a blood sample on day 1, one because he vomited on day 1; and 3 for family reasons. Another 4 patients were excluded from the analysis of drug efficacy and side-effects because their admission blood specimen (on day 0) contained no mf, although they had been positive in the survey before admission and all denied having received any antifilarial drug before admission to hospital. Of the 71 patients evaluated, 30 received DEC, 19 received ivermectin, and 22 received placebo until day 8 and ivermectin on day 9. At the one and 3 month follow-up examinations 69 and 68 individuals were evaluated respectively. Mf counts from days 0, 1 and 2 for the ivermectin group were combined with the days 8,9 and 10 counts of the placebo group (who were then treated with Table 1. Microfilariae examinationsa’b
ivermectin on day 9). Side-effects of ivermectin treatment were also combined in these 2 groups. This was possible because days 0 and 8 were before treatment, and days 1, 2 and 9, 10 were after treatment. The results are shown in Table 1, which indicates that there was no significant difference in mf counts among the 3 treatment groups on day 0. On days A, 2 and 8, both the ivermectin and DEC groups had srgnificantly lower mf counts than the placebo group (P
A placebo-controlled double-blind trial for the treatment filariasis with ivermectin or diethylcarbamazine M. Sabry’, H. Gamal*, N. El-Masry’ and M. E. Kilpatrick’ No. 3 (NAMRU-3),
Cairo, Egypt;
*Abbassia Fever Hospital,
Abstract Theraoeutic efficacv and clinical side-effects of ivermectm (single dose of 100 pg/kg) and diethylcarbamazine (DEC) (3 mgikg for one day, then 6 mgikg dailv for 12 d) were evaluated for microfilaricidal effect in Bancroftian filariasis. Seventy-one microfilaraemic consenting adult male patients (2100 microfilariae (mf)/ml)~were randomiy assigned to receive ivermectin. DEC or nlacebo and kent in hosuital for 15 d. Those receiving placebo were treated with ivermectin on day 9. Ivermectin (19 ‘double-blinded’ and 22 ‘unblinded’ patients) caused an abrupt reduction in mf count to 1.5% of the pre-treatment level 12 h after drug administration and to 0.06% on day 14, with recrudescence to 1.8% after one month and to 9.2% after 3 months. DEC (30 patients) caused a gradual drop in mf count to 1.1% of the pre-treatment level on day 14, which increased to 2.4% after one and 3 months. The total scores of side-effects were 77 (l%), 305 (2.1%) and 311.5 (3.0%) for placebo, ivermectin and DEC respectively; the differences between DEC or ivermectin and placebo were statistically significant. Ivermectin produced lower sidereaction scores than DEC and the differences were highly significant at the 95% confidence level. Sideeffects were mainly headache and body aches in the ivermectin patients, which appeared as early as 4 h after drug administration, resolved within 36 to 48 hours, and were significantly related to mf densities. Side-effects in DEC patients were mainly testicular and epididymal pain and swelling, unrelated to mf densities, which began at day 2 and continued to day 7. Single dose ivermectin was more effective in reducing microfilaraemia in Bancroftian filariasis than a 13 d course of DEC for a period of about 2 months after treatment, and side effects were of shorter duration. Introduction Lvmuhatic filariasis is endemic in trouical and subtroiical countries with approximately 965 million people at risk of infection, and 90.2 million people already infected; 81.6 million with Wuchereria bancrofti and 8.6 million with Brugia malayi and B. timori (WHO. 1984). Diethylcardamazine (DEC), a piperazine derivative, has remained the drug of choice for the past 40 years, but because of its side-reactions, mainly testicular and epididymal pain and swelling, many patients refuse treatment (SASA et al., 1963; SUNDARAM
et al.,
1974; HAWKING, 1979). Ivermectin,
a
Requests for offprints: Research Publications Branch, US NAMRU-3, FPO New York 09527-1600,USA. Attn. Code 101
of Bancroftian
I United States Naval Medical Research Unit Ministry of Health, Cairo, Egypt
semi-synthetic macrocyclic lactone derived from
Streptomyces avermitilis, was extremely successful in
the treatment of onchocerciasis at 150 pg/kg single dose. The objective of the present study was to evaluate efficacv and side-effects of ivermectin and DEC in a ‘double-blinded’, placebo-controlled trial infected with W. bancrofti. Patients and Methods Patients
Eighty male Egyptians (aged 15-55 years) volunteered to participate in the study. They were initially identified by surveys conducted in the Qulyubia and Dakahlyia governorates, 2 areasendemic for Bancroftian filariasis. All had microfilariae (mf) counts 215 per 20 mm3 of finger prick blood (2100 mfiml of venous blood) and were admitted to hospital for 15 d in Abbassia fever hospital, Cairo. None of the individuals was symptomatic before admission and all denied any antifilarial treatment during the past 2 years. Informed consent was obtained from each individual after the study was explained to them. Treatment
Ivermectin (100 pglkg single dose on day 1, then placebo for 12 d), DEC (3 mgikg on day 1, then 6 mgikg daily for 12 d), and placebo were each prepared as identical capsules in separate 13 d coded treatment kits in dosagesappropriate for body weight ranges. Patients were randomly and ‘blindly’ assigned to one of the 3 treatment groups. Since all study individuals were infected, those patients assigned to placebo were identified by an independent monitor on day 8 of therapy and treated with a single 100 pg/kg dose of ivermectin on day 9, without disclosing their identity to the associateinvestigators, and they were observed for efficacv of treatment and side-effects for 6 d. All medication was given before breakfast on days 1-13 and patients were observed to swallow the
capsules. Methods
Blood samples (5 ml) were collected in ethylenediaminetetraacetic acid from all studv individuals between 2200 and 2400 h on days 0, 1; 2, 8 and 14; the placebo patients had samples taken on days 0, 1, 2, 8, 9, 10 and 14. After discharge similar samples
were taken at 1 month and 3 months, and further follow-up sampleswill be taken at 69 and 12months. Mf counts were made by filtering 1 ml aliquots through Nuclepore@membrane filters, mounting the filter on a slide, staining with Giemsa stain solution diluted 1: 10 in phosphate buffer, and counting the mf at 100x magnification. Complete blood cell counts,
641 determination of serum creatinine, alkaline phosphatase, aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT) and bilirubin, and urinalysis were performed on each individual on days 0, 8 and 14. Side effects Patients were questioned and examined daily for signs and symptoms of possible drug side effects. Any untoward effects were recorded on the individual’s clinical file and scored on a scale of 0 to 3 (nil, mild, moderate or severe). Blood pressure was recorded 3 times daily. Fever was scored on a scale of 1 to 3: 1, 37.6”C to 38.X; 2, 38.6 to 39.X; and 3, >39.6”C. Statistical analysis Student’s t test was used to determine the significance of differences between the means of 2 samples of unequal sizes (using their pooled variance) and the Wilcoxon test was used as a non-parametric alternative (SNEDECOR & COCHRAN, 1967). Results Seventy-five patients completed the 15 d in hospital; 5 were discharged earlier, one for refusing to give a blood sample on day 1, one because he vomited on day 1; and 3 for family reasons. Another 4 patients were excluded from the analysis of drug efficacy and side-effects because their admission blood specimen (on day 0) contained no mf, although they had been positive in the survey before admission and all denied having received any antifilarial drug before admission to hospital. Of the 71 patients evaluated, 30 received DEC, 19 received ivermectin, and 22 received placebo until day 8 and ivermectin on day 9. At the one and 3 month follow-up examinations 69 and 68 individuals were evaluated respectively. Mf counts from days 0, 1 and 2 for the ivermectin group were combined with the days 8,9 and 10 counts of the placebo group (who were then treated with Table 1. Microfilariae examinationsa’b
ivermectin on day 9). Side-effects of ivermectin treatment were also combined in these 2 groups. This was possible because days 0 and 8 were before treatment, and days 1, 2 and 9, 10 were after treatment. The results are shown in Table 1, which indicates that there was no significant difference in mf counts among the 3 treatment groups on day 0. On days A, 2 and 8, both the ivermectin and DEC groups had srgnificantly lower mf counts than the placebo group (P
