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

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03245398

Enrollment

186

Registered

2017-08-10

Start date

2017-07-25

Completion date

2017-09-15

Last updated

2019-06-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hookworm

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.

Interventions

DRUGTreatment with one of the two regimens of mebendazole

Once in the morning and once in the evening for 3 consecutive days

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes 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.

Eligibility

Sex/Gender

ALL

Age

6 Years to 12 Years

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).

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Cure Rate (CR) of Both Mebendazole Regimens Against Ascaris Lumbricoides	baseline (before treatment) and 18 to 22 days post-treatment	Cure rates (CRs) will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Arithmetic ERR of the Two Regimens of Mebendazole Against Hookworm	baseline (before treatment) and 18 to 22 days post-treatment	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	baseline (before treatment) and 18 to 22 days post-treatment	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	baseline (before treatment) and 18 to 22 days post-treatment	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).
Geometric Mean Egg Reduction Rate (ERR) of the Two Regimens of Mebendazole Against Hookworm	baseline (before treatment) and 18 to 22 days post-treatment	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	baseline (before treatment) and 18 to 22 days post-treatment	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	baseline (before treatment) and 18 to 22 days post-treatment	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).
Geometric ERR of Both Mebendazole Regimens Against Ascaris Lumbricoides.	baseline (before treatment) and 18 to 22 days post-treatment	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).

Other

Measure	Time frame	Description
Distribution of Hookworm Species Among Participants	1 year	Genetic differentiation between Necator americanus and Ancylostoma duodenale using PCRs will allow us to identify which of the species is most prevalent.
Prevalence of Genetic Resistance Markers Among Participants	2 years	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.
Comparison of the Sensitivity of Kato Katz to Quantitative Polymerase Chain Reaction (PCR) Assays	1 year	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.

Countries

Tanzania

Participant flow

Participants by arm

Arm	Count
Single 500 mg Dose of Mebendazole In the morning of day 1 each child in this treatment arm received a 500 mg tablet of mebendazole plus one 100 mg placebo tablet. In the afternoon of day 1 they only received the placebo. In day 2 and 3 each child received one placebo tablet twice a day (in the morning and in the evening). Treatment with one of the two regimens of mebendazole: Once in the morning and once in the evening for 3 consecutive days	93
Multiple (Bid for 3 Days) Dose of 100 mg Mebendazole In the morning of day 1 each child in this treatment arm received a 100 mg tablet of mebendazole plus one 500 mg placebo tablet. In the afternoon of day 1 they only received the 100 mg tablet of mebendazole. In day 2 and 3 each child received one 100 mg tablet of mebendazole twice a day (in the morning and in the evening). Treatment with one of the two regimens of mebendazole: Once in the morning and once in the evening for 3 consecutive days	93
Total	186

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Travelled to another island	1	0

Baseline characteristics

Characteristic	Multiple (Bid for 3 Days) Dose of 100 mg Mebendazole	Total	Single 500 mg Dose of Mebendazole
Age, Continuous	10.1 years STANDARD_DEVIATION 1.6	10.1 years STANDARD_DEVIATION 1.6	10.1 years STANDARD_DEVIATION 1.6
EPG A. lumbricoides (geometric mean)	4095.9 EPG	3349 EPG	2691.2 EPG
EPG hookworm (geometric mean)	234 EPG	226 EPG	219 EPG
EPG T. trichiura (geometric mean)	725.7 EPG	693 EPG	661.8 EPG
Heavy A. lumbricoides infection (≥50,000 EPG)	3 Participants	7 Participants	4 Participants
Heavy hookworm infection (≥4000 EPG)	0 Participants	1 Participants	1 Participants
Heavy T. trichiura infection (≥10,000 EPG)	0 Participants	0 Participants	0 Participants
Infected with A. lumbricoides	51 Participants	98 Participants	47 Participants
Infected with hookworm	93 Participants	186 Participants	93 Participants
Infected with T. trichiura	91 Participants	179 Participants	88 Participants
Light A. lumbricoides infection (1-4999 EPG)	20 Participants	48 Participants	28 Participants
Light hookworm infection (1-1999 EPG)	90 Participants	179 Participants	89 Participants
Light T. trichiura infection (1-999 EPG)	56 Participants	115 Participants	59 Participants
Mean height (cm)	131.8 cm STANDARD_DEVIATION 9.6	131.9 cm STANDARD_DEVIATION 9.9	132.0 cm STANDARD_DEVIATION 10.2
Mean weight (kg)	26.2 kg STANDARD_DEVIATION 5.1	26.4 kg STANDARD_DEVIATION 5.2	26.7 kg STANDARD_DEVIATION 5.3
Median EPG hookworm	222 Eggs per gram (EPG)	222 Eggs per gram (EPG)	222 Eggs per gram (EPG)
Moderate A. lumbricoides infection (5000-49,999 EPG)	28 Participants	43 Participants	15 Participants
Moderate hookworm infection (2000-3999 EPG)	3 Participants	6 Participants	3 Participants
Moderate T. trichiura infection (1000-9999 EPG)	35 Participants	65 Participants	30 Participants
Race/Ethnicity, Customized Black	93 Participants	186 Participants	93 Participants
Region of Enrollment Tanzania	93 participants	186 participants	93 participants
Sex: Female, Male Female	46 Participants	85 Participants	39 Participants
Sex: Female, Male Male	47 Participants	101 Participants	54 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 93	0 / 93
other Total, other adverse events	2 / 93	8 / 93
serious Total, serious adverse events	0 / 93	0 / 93

Outcome results

Primary

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.