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

Primary Purpose

Hookworm

Status
Completed
Phase
Phase 4
Locations
Tanzania
Study Type
Interventional
Intervention
Treatment with one of the two regimens of mebendazole
Sponsored by
Jennifer Keiser
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hookworm

Eligibility Criteria

6 Years - 12 Years (Child)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Public Health Laboratory Ivo de Carneri, P.O. Box 122

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Single dose of mebendazole

Multiple dose of mebendazole

Arm Description

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)

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).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).
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.
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).
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.
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).
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).
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).
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).

Full Information

First Posted
July 22, 2017
Last Updated
March 14, 2019
Sponsor
Jennifer Keiser
Collaborators
PATH, Public Health Laboratory Ivo de Carneri
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1. Study Identification

Unique Protocol Identification Number
NCT03245398
Brief Title
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

2. Study Status

Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
July 25, 2017 (Actual)
Primary Completion Date
September 15, 2017 (Actual)
Study Completion Date
September 15, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jennifer Keiser
Collaborators
PATH, Public Health Laboratory Ivo de Carneri

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hookworm

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Participants, physicians, nurses and investigators will all be blinded. Based on the randomization list, individual envelopes with the correct combination of mebendazole tablets and placebos will be prepared. The randomization code is then sealed in an envelope. Unblinding will only occur in case of a SAE, SUSAR or other kind of emergency.
Allocation
Randomized
Enrollment
186 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Single dose of mebendazole
Arm Type
Active Comparator
Arm Description
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)
Arm Title
Multiple dose of mebendazole
Arm Type
Active Comparator
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Treatment with one of the two regimens of mebendazole
Intervention Description
Once in the morning and once in the evening for 3 consecutive days
Primary Outcome Measure Information:
Title
Cure Rate (CR) of Mebendazole Against Hookworm
Description
Cure rates (CRs) will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Time Frame
baseline (before treatment) and 18 to 22 days post-treatment
Secondary Outcome Measure Information:
Title
Geometric Mean Egg Reduction Rate (ERR) of the Two Regimens of Mebendazole Against Hookworm
Description
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).
Time Frame
baseline (before treatment) and 18 to 22 days post-treatment
Title
CR of Both Mebendazole Regimens Against Trichuris Trichiura
Description
Cure rates (CRs) will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Time Frame
baseline (before treatment) and 18 to 22 days post-treatment
Title
Geometric ERR of Both Mebendazole Regimens Against Trichuris Trichiura
Description
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).
Time Frame
baseline (before treatment) and 18 to 22 days post-treatment
Title
Cure Rate (CR) of Both Mebendazole Regimens Against Ascaris Lumbricoides
Description
Cure rates (CRs) will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Time Frame
baseline (before treatment) and 18 to 22 days post-treatment
Title
Geometric ERR of Both Mebendazole Regimens Against Ascaris Lumbricoides.
Description
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).
Time Frame
baseline (before treatment) and 18 to 22 days post-treatment
Title
Arithmetic ERR of the Two Regimens of Mebendazole Against Hookworm
Description
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).
Time Frame
baseline (before treatment) and 18 to 22 days post-treatment
Title
Arithmetic ERR of Both Mebendazole Regimens Against Trichuris Trichiura
Description
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).
Time Frame
baseline (before treatment) and 18 to 22 days post-treatment
Title
Arithmetic ERR of Both Mebendazole Regimens Against Ascaris Lumbricoides
Description
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).
Time Frame
baseline (before treatment) and 18 to 22 days post-treatment
Other Pre-specified Outcome Measures:
Title
Comparison of the Sensitivity of Kato Katz to Quantitative Polymerase Chain Reaction (PCR) Assays
Description
Two aliquots (about 1 g of stool each) of positive samples will be stored in ethanol and transported to the Swiss Tropical Public Health Institute for subsequent DNA extraction and diagnostic.
Time Frame
1 year
Title
Prevalence of Genetic Resistance Markers Among Participants
Description
The same two aliquots of stool will be used in this section.. Additionally, a Harada Mori culture will be prepared from one of the stool samples of each child at baseline and at follow-up to extract hatched larvae. Larvae will be stored in ethanol. Both stool and larvae samples will undergo an assessment of drug resistance-associated single-nucleotide polymorphisms.
Time Frame
2 years
Title
Distribution of Hookworm Species Among Participants
Description
Genetic differentiation between Necator americanus and Ancylostoma duodenale using PCRs will allow us to identify which of the species is most prevalent.
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jennifer Keiser, PhD
Organizational Affiliation
Swiss Tropical & Public Health Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Public Health Laboratory Ivo de Carneri, P.O. Box 122
City
Chake Chake
State/Province
Pemba
Country
Tanzania

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
31193620
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.
Results Reference
derived

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

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