Clinical trial NCT03245398: Efficacy and Safety of a Multi-dose Regimen of Mebendazole Against Hookworm in Children
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hookworm
Lead sponsor: Swiss Tropical & Public Health Institute
Sponsor class: OTHER
Collaborators: name: PATH
name: Public Health Laboratory Ivo de Carneri
First posted: 2017-08-10
Enrollment: 186
Sex: ALL
Minimum age (years): 6
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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).

Primary outcomes:
measure: Cure Rate (CR) of Mebendazole Against Hookworm
timeFrame: baseline (before treatment) and 18 to 22 days post-treatment
Secondary outcomes:
measure: Geometric Mean Egg Reduction Rate (ERR) of the Two Regimens of Mebendazole Against Hookworm
timeFrame: baseline (before treatment) and 18 to 22 days post-treatment
measure: CR of Both Mebendazole Regimens Against Trichuris Trichiura
timeFrame: baseline (before treatment) and 18 to 22 days post-treatment
measure: Geometric ERR of Both Mebendazole Regimens Against Trichuris Trichiura
timeFrame: baseline (before treatment) and 18 to 22 days post-treatment
measure: Cure Rate (CR) of Both Mebendazole Regimens Against Ascaris Lumbricoides
timeFrame: baseline (before treatment) and 18 to 22 days post-treatment
measure: Geometric ERR of Both Mebendazole Regimens Against Ascaris Lumbricoides.
timeFrame: baseline (before treatment) and 18 to 22 days post-treatment
measure: Arithmetic ERR of the Two Regimens of Mebendazole Against Hookworm
timeFrame: baseline (before treatment) and 18 to 22 days post-treatment
measure: Arithmetic ERR of Both Mebendazole Regimens Against Trichuris Trichiura
timeFrame: baseline (before treatment) and 18 to 22 days post-treatment
measure: Arithmetic ERR of Both Mebendazole Regimens Against Ascaris Lumbricoides
timeFrame: baseline (before treatment) and 18 to 22 days post-treatment
Other outcomes:
measure: Comparison of the Sensitivity of Kato Katz to Quantitative Polymerase Chain Reaction (PCR) Assays
timeFrame: 1 year
measure: Prevalence of Genetic Resistance Markers Among Participants
timeFrame: 2 years
measure: Distribution of Hookworm Species Among Participants
timeFrame: 1 year
Locations:
city: Chake Chake
country: Tanzania
facility: Public Health Laboratory Ivo de Carneri, P.O. Box 122
state: Pemba
Study officials:
affiliation: Swiss Tropical & Public Health Institute
name: Jennifer Keiser, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Palmeirim MS, Ame SM, Ali SM, Hattendorf J, Keiser J. Efficacy and Safety of a Single Dose versus a Multiple Dose Regimen of Mebendazole against Hookworm Infections in Children: A Randomised, Double-blind Trial. EClinicalMedicine. 2018 Jul 11;1:7-13. doi: 10.1016/j.eclinm.2018.06.004. eCollection 2018 Jul.