Albendazole: placebo-controlled study in 870 patients with intestinal helminthiasis

TRANSACT~NS

OF THE ROYAL SOCIETY OF TROPICAL MEDICINE

Albendazole

University

AND HYGIENE, VOL. 77, No. 5, 707-711 (1983)

: placebo-controlled study in 870 patients intestinal helminthiasis

JEAN FRANCOIS ROSSIGNOL AND HERVE MAISONNEUVE of South Alabama Medical College, Dept. of Medicine, Mobile,

AL

36688,

707

with

USA

Summary

A total of 870patients, both malesandfemales,from 3 to 79yearsold, receivedeither albendazole or a placebofor the treatmentof nematodeand cestodeinfections. Eachpatient wasinterviewed and underwent a completephysicalexaminationon the initial visit. In addition, completeblood count, clinical blood chemistry valuesand routine urinalysiswere performedbefore and at least24 hours after the last treatment. Stool examinationswere performed before, 7 and 21 days after treatment. Direct examination,an eggcount usingthe Kato techniqueandfaecalconcentrationwerecarried out for eachpatient. In ancylostomiasis and strongyloidiasis,faeceswere cultured by the Harada-Mori technique. Albendazole,asa single400 mg oral dose,washighly effective againstAscaris lumbricoides, Necator americanus, Ancylostoma duodenale and Trichuris trichiura; efficacy againstStrongyloides stercoralis was observedafter three consecutivedays of treatment at the samedaily doselevel. Efficacy against Hmlepis nunuwas fair. Basedon both clinical signsand biologicalvalues, albendazoledid not produce any significant side effects. Introduction

Single-drug treatment of the four major soiltransmitted helminthiases-ascariasis, ancylostomiasiscausedby Necator americanus and Ancylostoma duodenale, trichuriasis and strongyloidiasis-hasremained difficult in the last 15 years. Pyrantel and levamisolearequite effective againstroundwormsand hookworms, whereasmebendazoleis, in addition, highly effective againstwhipworms. Thiabendazole, which is weakly active againstthesethree nematodes, remains the drug of choice in strongyloidiasis. However, none of these drugs has shown a total spectrumof effectivenessagainstall four speciesof soil-transmittedhelminths. Albendazole, one of the newest benzimidazole carbamates,has been shown to be effective against these four parasitesduring a multi-centre, doubleblind, placebo-controlledstudy in 870 cases. Patients

and Methods

Patients

1,100 patients, all harbouring nematodesand cestodes,were included in the study. Only 870 completed the trial and were selected from 11 countries-France, Morocco, Mali, Senegal,Nigeria, CentralAfrican Republic, Kenya, Brazil, Peru, Mexico and the Philippines;they remainedout-patientsof hospitalsor dispensariesthroughout the study. Of thesepatients, 296 (140 malesand 156females)were Caucasians from Europeand Latin America, 517(353 malesand 164 females)were Africans from North, East and West Africa. and 57 (32 malesand 25 females)were Filipinos: Their agesrangedfrom-3 to 79 years, 604of them being between10and 29 years old. Patientsreceiving or who had receivedanthelmintics during the 21 days beforecommencingthe study were excluded, as were those with an acute illness

(with or without fever), pregnant females,nursing mothers,children under threeyearsof age,diagnosed epilepsy casesand personswith generalizedactive skin conditions.In general,patientswho experienced high sensitivity to any drug or those receiving long-term therapy or having chronic illnessesor proteinuria also were excluded. Drug therapy

Albendazoleor placebotabletsweremadeavailable to patientsaccordingto randomizednumbersunder a code establishedby the manufacturer. Tablets containing 100mg of active ingredientor of placebowere administeredmorning and eveningfor oneday in the presenceof the physician,except in casesof strongyloidiasiswhere the treatment was administeredfor three consecutive days. Adult patients received 200mg twice daily; children under 12 years old received 100mg twice daily. Tablets were swallowed or chewed,and the mouth wasinspectedafter dosing. When mouth inspectionwasimpossiblein the eve6 inn (in 49% of the total number of cases).the daily d&e. was administeredonce as a 400 mg dose for adultsand 200 mg dosefor children. No fasting was required. Clinical

assessment

Each patient was interviewed and underwent a complete physical examination on the initial visit, including a complete blood count, serum analysis (SCOT, SGPT, BUN, creatinine) and urinalysis (glucose,protem, bilirubin, urobilinogen). A pregnancy test was conducted in all women of childbearing potential before they were included in the study. The samephysicalexaminationand laboratory investigationswerecarriedout 24to 72 hoursafter the last treatment, and each patient was carefully questioned about side effects.

708 Table

ALBENDAZOLE:

I-Albendazole

Eggcyt

STUDY

IN

870

efficacy in relation Age

group*

A. lumbricoideti

No. of cases**

Light

58 7

Moderate

40

Heavy

PATIENTS

to degree

WITH

INTESTINAL

HELMINTHIASIS

of infection

No. of patients cured

Mean egg count (eggs/gfaeces)

Mean egg reduction (%)

15 44 34

56 (965%) 7 (100-O%) 38 (95.0%) 12 (80*00/o) 39 (88.6%) 33 (973%)

754 796 4,621 4,869 32,601 38,121

18 5 20 2 1

17 (94.4%) 3 (-) 19 (95.0%) 2 (-) I(-)

834 774 4,687 2,328 15,864

144 33 14 6 3

117 (81.2%) 16 (48.4%)

557 637 3,865 4,445 30,927

92-s

481 759 3,383 2,939 7,670 6,048

89.2 73.9

99.9

100.0 E 99.9 99.9

A. dwdenal~

Light Moderate Heavy

98.4

73.1 92-2 100.0 100.0

N. americanus-t

Light Moderate Heavy T. trichiuratt

Light Moderate Heavy

A C A C

c”

132 39 8 5 :

91 16 3 1 2 0

S . stercoralis

47 7

(68.9%) (41.0%) (375%) C-1 (40.0%) C-1

-

84.2 99.2 98.7 98.9

87.0 79.2 95.0 87.0 -

= adults; C = children. **multiple infections included. tLight = lessthan 2,000 eggs/gfaeces(e.p.g.); moderate= 2,000-10,000 e.p.g.; heavy = more than 10,000 e.p.g. ttlight = less than 2,000 e.p.g.; moderate= 2,00&5,000 e.p.g.; heavy = more than 5,000 e.p.g. *A

Parasitic

assessment

Statistical

anabsis

At the initial visit, andagainon days7 and 21 after treatment, faecalexaminationswere carried out on a singlestool specimen.Patientsshowingpositive egg countsby the Kato techniqueand one of the various well known concentrationtechniques(Faust, Kitchie, Junod) were included in the study. In casesof ancylostomiasisand strongyloidiasis,faecal cultures usingthe Harada-Mori techniqueweredone. Patients were consideredcured when the faecal examination carried out on day 21 was negative. At the end of the study, all patients received mebendazole,100mg b.i.d. for three consecutive days.

Statisticalanalysisof toleranceandefficacy between albendazoleand placebogroupswascarriedout using the x2 test or Student’s ‘t’ test. Results

Of the 870 patientstreated, 457 receivedalbendazole and 413receiveda placebo,479had oneparasite,

235 two parasites, 144 three parasites, 11 four parasitesand only onehad five parasites.446patients receivedthe active drug or the placebotwice daily, while the remaining424 received a singledose. In adult patientswho received400 mg,,albendazolewas effective against Ascaris lumbricotdes, Ancylostoma duodenale, Nectar americanus and light mfectionswith Trichuris trichiura. (Table I). Albendazolewaseffective againstStrongyloides stercoralis (81% cure rate) in patientswho received400 mg daily for three consecutive days. No difference betweenb.i.d. and single dosewere recorded. In childrenwho receivedhalf of the adult dose,i.e., 200mg or for three consecutivedays,albendazolewas much lesseffective than in the adult group (Table I). Hymenolepis nana was found in 58 and Taenia saginara in six patients. Of the 17 patientswith H. nana infection who received 400mg of albendazole daily for three consecutivedays, only five (29%)were cured. A 21-day stool follow-up is consideredinadequateto draw any conclusionsregardingcure in patients passing T. saginata proglottides (DAVIS, 1973).

J.

Table

II-Cure

rates in adult

F.

ROSSIGNOL

cases: comparison

AND

H.

between

MAISONNEUVE

albendazole

Albendazole

and placebo

groups

Placebo

No. of cured patients

No. of cases

709

No. of

cases

No. of cured patients

x2 test

A. lumbricoides*

Light Moderate Heavy

56 (97%)

ii 44

49 41 38

P
A. duodenale*

Light Moderate Heavy

23 15 3

4 (17%) 3 (20%) 0 (0%)

P
125 11 1

20 (16%)

P
114 12 6 53

17 (15%) 0 (0%) 0 (0%) 17 (32%)

P
N. americanus*

Light Moderate Heavy T. trichiura**

Light Moderate Heavy S . stercoralis

144 14 3

1:; ig”:oj 2 (lo)

132 t

91 (69%) 3 (38%) 2(-l 38 (81%)

47

P
*Light = lessthan 2,000 eggs/gfaeces(e.p.g.); moderate= 2,OWlO,OOOe.p.g.; heavy = more than 10,000 e.p.g. ** Light = lessthan 2,000 e.p.g.; moderate= 2,000-5,000 e.p.g.; heavy = more than 5,000 e.p.g. Table III-Side effects reported albendazole or placebo*

by patients

taking

significantdifferencesbetweenthe two groups were found (Table IV). Discussion

Side effects Dizziness Headache Epigastric pain geyermouth Pruritus Vomiting Diarrhoea

Albendazole ii 30 : 22 8

Total 55 *x2 = 0.415, not significant.

Placebo 5 :20 0 1 : 4 44

Eggsof Enterobius vermicularis were found in the faecesof 21 patients. However, neither the Kato nor the concentrationtechniquesare adequateto assess the presenceof Enterobius eggssincethey are rarely found in faeces.Graham’s Scotch tape technique, which is the most reliable test for enterobiasis,was not used during this study. In the placebogroup, spontaneouscures of light to moderate infections occurredfrequently. However, albendazolewassignificantly more effective than the placebo (Table II). The incidenceof clinical sideeffectsin the albendazole and placebogroupsis shownin Table III. There wasno significantdifference betweenthe number of signsreported in the two groups(x2 = 0.415, N.S.). Mean valuesof haematologyand clinical chemistry were establishedfor each parameterand compared betweenthe albendazoleand the placebogroupsfor values obtained before and after treatment. These mean values were subjected to statistical analysis (Student’s ‘t’ test) to detect any variations. No

There are few reports in the literature of clinical trials comparinganthehninticswith a placebo.DAVIS (1973)mentionedthe needfor suchtrials in order to evaluate the real value of any new drug. In our placebogroup the ratesof spontaneous cure for light and moderateascariasis, ancylostomiasis and trichuriasis seemto be comparableto those observedby other authors. POND et al. (1970)reported a 43.3% cure rate in 133casesof ascariasis receiving a placebo (egg count not done). THIENPONTet al. (1960) observeda 6% cure rate in 87 casesof ascari&isand 27% cure rate in 41 casesof ancylostomiasisin a placebogroup. FARAHMANDIANet al. (1972) found a 10% cure rate in 50 casesof untreated ascariasis (averageStoll eggcount 15,130eggs/gfaeces(e.p.g.) and a 16% cure rate in 50 casesof Ancylostoma duodenale infection (average Stall egg count 1,661 e.p.g.). In the later study, they observeda curerate of 44% for Ascaris lumbricotdes (averageStall egg count 3,737 e.p.g.) and 12.5% for Ancylostoma duodewle, infection (averageStoll egg count 523e.p.g.) among an untreated group of 48 patients (FARAHMANDIAR et al., 1977). JUNG& MCCROAN(1960) reported a 25.6% cure rate in 39 casesof ancylostomiasis receiving a placebo. Our cure ratesare basedon the resultsof the faecal examinationcarried out on day 21. We believe that resultsof the examinationdone on day 7 reflect late eliminationof eggs,ashasbeenreported by MARTIN (1965): beadswere recoveredfor up to 10 days after administration in volunteers and were randomly dispersedin the faeces. Albendazole appearedto be effective as a single dose against Ascaris, hookworms and whipworms,

710 Table

ALBENDAZOLE:

IV-Biological

Parameter

values:

STUDY

IN

870 PATIENTS

WITH

INTESTINAL

mean values before and after treatment

Albendazole

HELMINTHIASIS

for albendazole

and placebo

Placebo

groups

Before

After

Student’s t test

Before

After

Student’s t test

R.B.C.

4,582

4,540

N.S.

4,739

4,432

N.S.

(103 x mm3) W.B.C.

6,798

6,432

N.S.

6,769

6,878

N.S.

5.96

5.80

N.S.

6.79

7.00

N.S.

(m3) B.U.N. (m.mol/l) Creatinine (WOW S.G.O.T. (ui/l) S.G.P.T. (ui/l)

67.0

68.6

N.S.

65.0

67.4

N.S.

15.4

15.5

N.S.

14.5

13.4

N.S.

19.2

17.5

N.S.

19.1

17.2

N.S.

although its effect in moderateto heavy trichuriasis remainsunclear. Mebendazolehasalsobeenreported to be highly effective againstAscark and to a lesser extent whipworms after a single dose of 600 mg (CARERAet al., 1980; KAN, 1983), but its effect against hookworms after such a short treatment remainsrelatively undocumented. Abendazoleseemsto be effective and well tolerated asa three-day treatment of strongyloidiasis,basedon stoolexaminationsdoneup to 21 daysafter treatment. Stool examinationsover a longer period of time are difficult to undertakein endemicareas,wherereinfectionsare frequent. There was,however,a statistically significantcure rate in patientswho receivedthe drug in connection with those who received the placebo. In other trials, children receiving a single400mg dose of albendazolehad cure rates comparableto thoseobservedfor adults (COULAUD& ROSSIGNOL, 1983).Albendazoleshouldtherefore be administered at the samedosagein adults and children. Albendazole, like mebendazoleor flubendazole,is very well tolerated, but all three drugs belongto the benzimidazolecarbamateswhich are known to produce embryotoxicity and teratogenicity in a number of animal species(DELATOURet al., 1976). There is little doubt that the benzimidazolesare highly effective in treating a broad spectrum of intestinal nematodeinfections, producing high cure rates. The impact of treatment on the number of e.p.g. taeces is also important, decreasingthe rate of infection by decreasingthe soil pollution (STOLL, 1962).Albendazole, therefore, which producessatisfactory cure rates and egg count reductions is certainly very interesting asa singledosetreatment. Acknowledgements We are grateful to Dr. A. Davis, Chief of the Department of Schistosomiasis and Other Helminthic Diseases, WHO, Geneva, for the great help we received in designing the protocol and reviewing our results. We are grateful to Drs. M. C. Baranski, N. 0. Bwibo, L. Camilo-Coura, J. P. Coulaud, E. Garcia, J. P. Garin, H. Lumbreras Cruz, M. Mojon, A. B. 0.0. Oyediran, P. Pene and P. M. Salazar Schettino, participating in the albendazole

clinical research group, who kindly communicated their individual results: We are also grateful to Smith Kline & French Laboratories and their area medical directors, Drs. M. Botey, B. Dickson and D. L. Ovedoff for their help during this multi-centre study and for making available 100 mg albendazole and placebo tablets. Albendazole is marketed as ZentelR.

References Carera, B. D., Valdez, E. V. & Go, T. G. (1980). Clinical trials of broad spectrum anthehnintics against soiltransmitted helminthiasis. Southeast Asian Journal of Tropical

Medicine

& Public

Health,

II,

502-506.

Coulaud, J. P. & Rossignol, J. F. (1983). Evaluation of albendazole in Europe, West-Africa and Asia as a single dose anthelmintic. Report on 1,455 cases. Actu Tropica (in press). Davis, A. (1973). Drug rreeatmentin intesrinaf helminthiasis. World Health Organization. Geneva, Switzerland. Delatour, P., Lorgue, P., Lapras, M. & Richard, Y. (1976). Proprietes embryotoxiques et antimitotiques du parbendazole, du mebendazole et du cambendazole. Compte Rendus de PAcademie des Sciences de Paris, Serie D, 282, 517-518. Farahmandian, I., Sahba, G. H., Arfaa, F. & Jalali, H. (1972). Comparative evaluation of the therapeutic effects of pyrantel pamoate and bephenium hydroxynaphtoate on Ancyloswma duodenale and other intestinal hehninths. Journal

of Tropical

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Farahmandian, I., Arfaa, F., Jalali, H. & Reza, M. (1977). Comparative studies on the evaluation of the effects of new anthehnintics on various intestinal hehninths in Iran. Chemotherapy, 23, 98-105. Jung, R. C. & McCroan, J. E. (1960). Efficacy of bephenium and tetrachlorethylene in mass treaunent of hookworm infections. American 3ouwtal of Tropical Medicine and Hygiene, 9, 492-495. Kan, S. P. (1983). Efficacy of single doses of mebendazole in the treatment of Trichuris trichiura infection. American Journal of Tropical Medicine and Hygiene, 32, 118-122. Martin, L. K. (1965). Randomness of particle distribution in humans faeces and the resulting influence of hehninth egg counting. American 3oumal of Tropical Medicine and Hygiene,

14, 747-759.

Pont, N. S., Bokat, R. B., Johnson, J. P., Knight, J. L., Healy, G. R., Gleason, N. N. & Hall, E. C. (1970). Mass treatment for ascariasis. Southeastern MedicalJournal, 63, 599-602.

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Stall, N. R. (1962). Helminthic infections. Biological Council Symposium on Drugs, Parasites and Hosts. Goodwin, L. G. & Nimmo-Smith, R. H. (Editors). London: J. & A. Churchill Ltd., pp. 3-14. Thienpont, D., Brugmans, J., Abadi, K. & Tanamal, S. (1960). Tetramisole in the treatment of nematode infec-

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1983

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AND

H.

711

MAISONNEUVE

tions in man. American Hygiene, 18, 520-525.

Accepted

Journal

for publication

30th

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March,

Medicine

1983.

Fellows Mulchandani, R., India Mdla, A. F., Zambia Neville, L. O., Britain Nyazeme, N. F., Zimbabwe Parrinello, A. E., Italy Phillips, R. E., Thailand Rajvenshi, H. K,., Libya Ray, P. R., In&a Reddy, Y. J. V., India Reid, H. F. M., Trinidad Roy, P. P., India Ryan, L., Britain Saha, D., India Sarkar, R. K., India Sarkar, S., India Schiller, R. A., Federal German Republic Siddiqui, H. J., Dubai Sil, R. K., India Vernes, A. France Yazbak, A. Dubai Elected

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and