DTIC ADA267890: Placebo-Controlled Double-Blind Study to Determine the Efficacy of Topical Niclosamide 1% Lotion in the Prevention of Naturally Occurring Schistosoma haematobium Infection in Egyptian Farmers

108 Pages·3.5 MB·English

by  Defense Technical Information Center

890
AD-A267
TECHNICAL REPORT
Placebo-controlled double-blind study to determine
the efficacy of topical niclosamide 1% lotion in the
prevention of naturally occurring Schistosoma
haematobium infection in Egyptian farmers
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ITIC
ELECTE
-AUG 12 1993 imtO!E
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-- t--This' d-cumaew has been approved
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lo t reulleia s(cid:127)e and sazle; its
-- / (cid:127)t4 uto is unliminted. ,By
I ' R.R. Abu-Elyazeed, MD. PhD.
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• T.K. "Podgore, D.O.
Form Approved
REPORT DOCUMENTATION PAGE I
OMB No. 0704-o08
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1. AGENCY USE ONLY (Leave blank) 2. REPORT DATE 3. REPORT TYPE AND DATES COVERED
1993 Final, 01 APR 92 -30 OCT 92
4. TITLE AND SUBTITLE 5. FUNDING NUMBERS
Placebo-Controlled Double-Blind Study to Determine the Efficacy of Topical PE- 64758A
Niclosamide 1% Lotion in the Prevention of Naturally Occurring Schistosoma WU- 3M464758D849.EB
haematobium Infection in Egyptian Farmers.
6. AUTHOR(S)
Abu-Elyazeed, R.R. and Podgore, J.K.
7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) B. PERFORMING ORGANIZATION
U.S. Naval Medical Research Unit No. 3 REPORT NUMBER
PSC 452, Box 5000 TR 2/93
FPO AE 09835-0007
9. SPONSORING/ MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSORING / MONITORING
Naval Medical Research and Development AGENCY REPORT NUMBER
Command, National Naval Medical Center
Building 1, Tower 12
Bethesda, MD 20889-5044
11. SUPPLEMENTARY NOTES
Technical Report: Conducted under I~vestigational New Drug Application Number 33,272 in Effect with the U.S.
Food and Drug Administration, Sponsored by the Surgeon General, Department of the Army.
12a. DISTRIBUTION / AVAILABILITY STATEMENT 12b. DISTRIBUTION CODE
Approved for public release;
Distribution is unlimited.
13. ABSTRACT (Maximum200 words) * ,audu,,ted douulo-uituu ;! L It n ayuum, r! O u .!i©
efficacy of twice-weekly application of 1 % niclosamide lotion to prevent S. haematobium re-infection. Farmers aged 18-4
years were treated by praziquantel to cure their S. haematobium infection. Subjects were randomly assigned to receive
niclosamide or placebo lotion which was self-applied, under observation, to limbs, neck and torso twice weekly for 26
weeks. Subjects were exposed to schistosomal infested water during routine irrigation activities from April to October
1992. Urine specimens were evaluated by te Nucleopore filtration method monthly during and 4 month following the
lotion application period. Those included in the statistical analysis were free from S. haematobium ova in urine in the firs
4 months after the start of lotion application. Three hundred and fifty subjects met the inclusion criteria and completed thi
trial, 169 (48.3%) in the niclosamide group and 181 (51.7 %) in the placebo group. The subjects assigned to the
niclosamide group were comparable to those in the placebo group in age (27.2 vs 27.8 years), total water contact (101.9 V,
109.0 hours), reported 98-100% lotion application compliance (93.5% vs 90.6%) and reported no water contact involving
whole body (94.7 % vs 96.7 %). The re-infection rate of S. haematobium based on the presence of ova in urine up to 12
weeks after cessation of lotion application was 30.8% in the niclosamide and 28.2% in the placebo group. The re-infectio
rates up to 16 weeks were 37.3% and 32.0% in the niclosamide and placebo groups, respectively. Niclosamide lotion
applied to the limbs and truck twice weekly did not prevent S. haematobium re-infection. Previous studies in monkeys
with both S. haematobium and §. manso and in humans with I. mansoni showed that 1% niclosamide was effective in
preventing re-infection. A more rigorous application regimen may be indicated.
14. SUBJECT TERMS 15. NUMBER OF PAGES
Field trial; Randomized double-blind study; Water contact exposure; 78
Schistosoma haematobium; Niclosamide 1%; Farmers; Fayoum, Egypt. 16. PRICE CODE
17. SECURITY CLASSIFICATION 18. SECURITY CLASSIFICATION 19. SECURITY CLASSIFICATION 20. LIMITATION OF ABSTRACT
OF REPORT OF THIS PAGE OF ABSTRACT
UNCLASSIFIED UNCLASSIFIED UNCLASSIFIED
%SN 7540-iV-280-i5ii) Stanilard 'nrm 298 ýqev 2-89)
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* TECHNICAL REPORT
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Placebo-controlled double-blind study to determinee
the efficacy of topical niclosamide 1% lotion in the
prevention of naturally occurring Schistosoma
haematobium infection in Egyptian farmers
* By
R.R. Abu-Elyazeed, MD. PhD.
J.K. Podgore, D.O. Acce~ion
NTIS Cp. ,_
QT!C f,,r
United States Naval Medical Research Unit No.3 u .";.o,-c.ed
Cairo, Egypt J., cttfoW.c.. ..
FPO, AE 09835-0007 By
FAX [phone] y ..........
i Di-.t ibi~tion I
May, 1993 Availability Cojes
Avail a3;d (21r
Dist Special
I ?DTIC QUALITY INSPECTED 3
Conducted under Investigational New Drug application number 33, 272 in effect with
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the U.S. Food and Drug Administration.
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Sponsor: The Surgeon General, Departnment of the Army
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_ Sum m ary . .. .. ..... ......... .......... .. ... .. .. . .. .. 7
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Introduction ........................................... 9
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Statement of Purpose .................................. . . 14
Materials and Methods ................................... 15
Study D esign ....................................... 15
Study Area ...... .................................... 15
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Study Population.. ..................................... 16
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Study Medication .. .................................... 19
Assignment of Study Medications ............................ 19
D.
Dosage Ranged ... ..................................... 21
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Dosage Schedule........................................ 21
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Application of Study Medication ............................ 21
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Concomitant Medications . ............................... 22
Duration of the Study ................................... 22
Study Procedures ...................................... 23
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Clinical Evaluations ..................................... 24
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Field Evaluation . ..................................... 26
Laboratory Evaluations ...... ........................... 28
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Statistical Evaluation .................................. ... 31
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M onitoring of Study ................................... .. 32
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Protection of Human Subjects ............................ ... 33
Ethical Aspects ...................................... ... 34
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Disposition of Study Materials ............................ . 35
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Results ............................................... 36
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Discussion ......................................... .... 39
References ......................................... ... 41
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List of Tables
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Table 1. Individuals participating in field operations . . . . . . . . . . . . . 44
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Table 2. The status of the 600 subjects participating
in the study .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. 45
Table 3. Reasons for exclusion and discontinuation of the subjects
in study villages
the . . . . . . . . . . . . . . . . . . . . . . . .... . . 58
Table 4. List of subjects included in the statistical analysis . . . . . . . . . 59
Table 5. Distribution of subjects by study villages ....... .67
. . . . . . .
* Table 6. Distribution of subjects by study medication among the
four villages .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. 68
Table 7. Subject's mean age and standard deviation in years by study
medication in the four villages . . . . . . . . . . . . . . . . . . . . . . 69
* Table 8. Lotion application compliance among study groups in
the four villages ............................... 70
* Table 9. Lotion application observation by study monitors among
study groups in the four villages .................... 71
Table 10. Mean and Standard Deviation of infested water contact
in hours reported during the entire study period by study
medication in the four villages ...................... 72
Table 11. Water contact episodes involving non lotion-appliaction areas
reported by the study groups in the four villages .......... 73
Table 12. S. haematobium Reinfection Rates based on live and dead
ova in urine up to 12 weeks after cessation of lotion
application among the study groups in the four villages ...... 74
Table 13. S. haematobium Reinfection Rates based on live and dead
ova in urine up to 16 weeks after cessation of lotion
application among the study groups in the four villages ..... 75
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Table 14. S. haematobium Reinfection Rates based on live ova in
urine up to 12 weeks after cessation of lotion application
among the study groups in the four villages ............. 76
Table 15. S. haematobium Reinfection Rates based on live ova in
urine up to 16 weeks after cessation of lotion application
among the study groups in the four villages ............. 77
List of Figures
Figure 1. Description of study subjects ........................ 78
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List of Appendices
Appendix 1. Medical Forms
a. Report of Medical Examination
b. Record of Medical Care
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Appendix 2. Dermal/Systemic Reaction Record
Appendix 3. Adverse Reaction Report (Form FDA No. 1639)
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Appendix 4. Dates for Specimen Collection
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Appendix 5. NAMRU-3 SOP for the detection of S. haematobium ova in urine
specimens
Appendix 6. Laboratory Validation
Appendix 7. Informed Consent Forms
a. English Version
b. Arabic Version
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Appendix 8. Subject Daily Log (Case Report Forms)
a. English Form
b. Arabic Form
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Summary
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A randomized double-blind t, al was conducted in Fayoum, Egypt, to assess the
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efficacy -' twice-weekly application of 1% niclosamide lotion to prevent
S.haematobium re-infection. Farmers aged 18-40 years were treated by praziquantel
to cure their S. haematobium infection. Subjects were randomly assigned t6 receive
II niclosamide or placebo lotion which was self-applied, under observation, to limbs,
I
neck and torso twice weekly for 26 weeks. Subjects were exposed to schistosomal
I
infested water during routine irrigation activities from April to October 1992. Urine
specimens were evaluated by the Nuclepore filtration method monthly during and
4 months following the lotion application period. Those included in the statistical
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analysis were free from S. haematobium ova in urine in the first 4 months after the
start of lotion application. Three hundred and fifty subjects met the inclusion criteria
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and completed the trial, 169 (48.3%) in the niclosamide group and 181 (51.7%) in
the placebo group. The subjects assigned to the niclosamide group were comparable
io those in the placebo group in age (27.2 vs 27.8 years), total water contact (101.9
vs 109.0 hours), reported 98-100% lotion application co(cid:127)mpliance (93.5% vs 90.6%)
and reported no water contact involving whole body (94.7% vs 96.7%). The re-
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infection rate of S. haematobium based on the presence of ova in urine up to 12
weeks after cessation of lotion application was 30.8% in the niclosamide and 28.2%
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in the placebo group. The reinfection rates up to 16 weeks were 37.3% and 32.0%
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in the niclosamide and placebo groups, respectively. Niclosamide lotion applied to
the limbs and trunk twice weekly did not prevent S. haematobium reinfection.
Previous studies in monkeys with both S. haematobium & S. mansoni and in humans
with S. mansoni showed that 1 % niclosamide was effective in preventing re-infection.
A more rigorous application regimen may be indicated.
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