Efficacy and Safety of a Multi-dose Regimen of Mebendazole Against Hookworm in Children

Study Overview
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Brief Summary
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This study is a double-blind randomized clinical trial which aims at providing evidence on the efficacy and safety of two regimens of mebendazole in school-aged children. Thus, our primary objective is to assess the efficacy and safety of: i) 100 mg solid tablets twice a day for 3 days, and ii) one dose of 500 mg solid tablets of mebendazole in participants aged 6-12, inclusive, infected with hookworm. The primary endpoint of the trial is the cure rate (CR) of the 3-day regimen of mebendazole against hookworm and a single dose mebendazole treatment. The secondary objectives are to determine if the multi-dose regimen is superior to the single dose regimen, evaluate the efficacy against concomitant soil-transmitted helminth infections, and assess the safety of both mebendazole regimens. After obtaining informed consent from children's caregiver, the medical history of the participating individuals will be assessed with a standardized questionnaire, in addition to a clinical examination carried out by the study physician on the treatment day. Enrollment will be based on two stool samples which will be collected, if possible, on two consecutive days or otherwise within a maximum of 5 days apart. All stool samples will be examined with duplicated Kato-Katz thick smears by experienced laboratory technicians. Randomization of participants into the two treatment arms will be stratified according to intensity of infection. Participants will be interviewed before treatment for clinical symptoms and 3 hours after every morning treatment and 24 hours after every morning treatment about the occurrence of adverse events. The efficacy of the treatment will be determined 14-21 days post-treatment by collecting another two stool samples. The primary analysis will include all participants with primary end point data (available case analysis). Supplementary, two sensitivity analyses will be conducted imputing all missing endpoint data as treatment failures or all as treatment success. CRs will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment. CRs will be compared by using unadjusted logistic regression. To assess model robustness with respect to covariates, adjusted logistic regressions (adjustment for age, sex, school, weight and strata) will be performed. Geometric and arithmetic mean egg counts will be calculated for the different treatment arms before and after treatment to assess the corresponding ERRs. Bootstrap resampling method with 5,000 replicates will be used to calculate 95% confidence intervals (CIs) for ERRs and the difference of the ERRs.

Official Title
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Efficacy and Safety of a Single-dose Regimen and a Multi-dose Regimen of Mebendazole Against Hookworm Infections in School Children: a Randomized Controlled Trial

Conditions
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Hookworm

Intervention / Treatment
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* Drug: Treatment with one of the two regimens of mebendazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent signed by parents and/or caregiver; and oral assent by participant. Able and willing to be examined by a study physician at the beginning of the study. Able and willing to provide two stool samples at the beginning (baseline) and approximately three weeks after treatment (follow-up). Positive for hookworm eggs in the stool (≥ 100 EPG and at least two Kato-Katz thick smears slides with more than one hookworm egg). Absence of major systemic illnesses, e.g. diabetes, severe anemia (HB<8.0 g/l) as assessed by a medical doctor at school, upon initial clinical assessment. No known or reported history of chronical illness as cancer, diabetes, chronic heart, liver or renal disease. No recent anthelminthic treatment (within past 4 weeks). No known allergy to study medications (mebendazole and albendazole). Exclusion Criteria: No written informed consent by parents and/or caregiver; no oral assent by participant. Menarche, based on self-report Presence of major systemic illnesses, e.g. diabetes, severe anemia (HB<8.0 g/l) as assessed by a medical doctor, upon initial clinical assessment. History of acute or severe chronic disease. Recent use of anthelminthic drug (within past 4 weeks). Attending other clinical trials during the study. Negative diagnostic result for hookworm eggs in the stool (< 100 EPG (total of the four slides) and/or only one Kato-Katz thick smear slide with more than one hookworm egg).

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Single dose of mebendazole<br>In day 1 each child in this treatment arm will receive a 500 mg tablet of mebendazole plus one 100 mg placebo tablet in the morning. In the afternoon of day 1 they will only receive the placebo. In day 2 and 3 each child will receive one placebo twice a day (in the morning and in the evening) | Drug: Treatment with one of the two regimens of mebendazole<br>* Once in the morning and once in the evening for 3 consecutive days<br>|
| Active Comparator: Multiple dose of mebendazole<br>In day 1 each child in this treatment arm will receive a 100 mg tablet of mebendazole plus one 500 mg placebo tablet in the morning. In the afternoon of day 1 they will only receive the 100 mg tablet of mebendazole. In day 2 and 3 each child will receive one 100 mg tablet of mebendazole twice a day (in the morning and in the evening). | Drug: Treatment with one of the two regimens of mebendazole<br>* Once in the morning and once in the evening for 3 consecutive days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure Rate (CR) of Mebendazole Against Hookworm | Cure rates (CRs) will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment. | baseline (before treatment) and 18 to 22 days post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Egg Reduction Rate (ERR) of the Two Regimens of Mebendazole Against Hookworm | Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. The egg reduction rate (ERR) is calculated as follows: ERR = (1-(geometric mean EPG at follow-up/geometric mean EPG at baseline))*100). Note: in contrast to the publication the outcome measure entry mask requires the complementary percentage: (geometric mean at follow-up/geometric mean at baseline)*100). | baseline (before treatment) and 18 to 22 days post-treatment | 
| CR of Both Mebendazole Regimens Against Trichuris Trichiura | Cure rates (CRs) will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment. | baseline (before treatment) and 18 to 22 days post-treatment | 
| Geometric ERR of Both Mebendazole Regimens Against Trichuris Trichiura | Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. The egg reduction rate (ERR) is calculated as follows: ERR = (1-(geometric mean EPG at follow-up/geometric mean EPG at baseline))*100). Note: in contrast to the publication the outcome measure entry mask requires the complementary percentage: (geometric mean at follow-up/geometric mean at baseline)*100). | baseline (before treatment) and 18 to 22 days post-treatment | 
| Cure Rate (CR) of Both Mebendazole Regimens Against Ascaris Lumbricoides | Cure rates (CRs) will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment. | baseline (before treatment) and 18 to 22 days post-treatment | 
| Geometric ERR of Both Mebendazole Regimens Against Ascaris Lumbricoides. | Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. The egg reduction rate (ERR) is calculated as follows: ERR = (1-(geometric mean EPG at follow-up/geometric mean EPG at baseline))*100). Note: in contrast to the publication the outcome measure entry mask requires the complementary percentage: (geometric mean at follow-up/geometric mean at baseline)*100). | baseline (before treatment) and 18 to 22 days post-treatment | 
| Arithmetic ERR of the Two Regimens of Mebendazole Against Hookworm | Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. The egg reduction rate (ERR) is calculated as follows: ERR = (1-(arithmetic mean EPG at follow-up/arithmetic mean EPG at baseline))*100). Note: in contrast to the publication the outcome measure entry mask requires the complementary percentage: (arithmetic mean at follow-up/arithmetic mean at baseline)*100). | baseline (before treatment) and 18 to 22 days post-treatment | 
| Arithmetic ERR of Both Mebendazole Regimens Against Trichuris Trichiura | Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. The egg reduction rate (ERR) is calculated as follows: ERR = (1-(arithmetic mean EPG at follow-up/arithmetic mean EPG at baseline))*100). Note: in contrast to the publication the outcome measure entry mask requires the complementary percentage: (arithmetic mean at follow-up/arithmetic mean at baseline)*100). | baseline (before treatment) and 18 to 22 days post-treatment | 
| Arithmetic ERR of Both Mebendazole Regimens Against Ascaris Lumbricoides | Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. The egg reduction rate (ERR) is calculated as follows: ERR = (1-(arithmetic mean EPG at follow-up/arithmetic mean EPG at baseline))*100). Note: in contrast to the publication the outcome measure entry mask requires the complementary percentage: (arithmetic mean at follow-up/arithmetic mean at baseline)*100). | baseline (before treatment) and 18 to 22 days post-treatment |