Albendazole Dose Finding and Pharmacokinetics in Children and Adults

Study Overview
=================
Brief Summary
-----------------
This study is a single-blind randomized clinical trial conducted in rural Côte d'Ivoire. This study aims at providing evidence on the dose-response of increasing oral albendazole dosages against whipworm (T. trichiura) and hookworm infections in preschoolers (2-5 years), school-aged children (6-12 years) and adults (≥ 21 years). The primary objective is to determine cure rates (primary end point, i.e. conversion from being egg positive pre-treatment to egg negative post-treatment). Secondary objectives involve the determination of egg reduction rates (the reduction in the number of excreted eggs from baseline (prior to treatment) to follow-up) and the assessment of safety of ascending dosages of albendazole (secondary end points). In addition, key pharmacokinetic parameters will be determined from blood samples collected with a micro-sampling device (secondary end point).

Detailed Description
-----------------
This study is a single-blind randomized clinical trial conducted in Côte d'Ivoire. This study aims at providing evidence on the efficacy and safety of ascending oral albendazole dosages in children and adults infected with T. trichiura and hookworm. In preschool-aged children (2-5 years) (i) 200 mg, (ii) 400 mg and (iii) 600 mg; in schoolchildren (6-12 years) and adults (≥ 21 years) (i) 200 mg (only for hookworm infections), (ii) 400 mg, (iii) 600 mg and (iv) 800 mg will be administered and efficacy, safety and pharmacokinetic parameters will be assessed. The primary objective is to determine the dose-response based on cure rates of albendazole in preschool-aged children (2-5 years), school-aged children (6-12 years) and adults (≥ 21 years) infected with T. trichiura and hookworm. The secondary objectives of the trial are to determine the efficacy based on egg reduction rates of albendazole in preschool-aged children, school-aged children and adults, to determine an exposure (including length of time that the drug concentration is above the MIC, Cmax, AUC)-response correlation of albendazole in preschool-aged children, school-aged children and adults, to evaluate the safety and tolerability of albendazole in preschool-aged children, school-aged children and adults, and to determine the efficacy against concomitant soil-transmitted helminthiasis (Ascaris lumbricoides). After obtaining informed consent from individual/parents and/or caregiver, the medical history of the participants will be assessed with a standardized questionnaire, in addition to a clinical examination and venipuncture to examine biochemical parameters in the blood carried out by the study physician before treatment. Enrollment will be based on two stool samples that will be collected, if possible, on two consecutive days or otherwise within a maximum of 5 days. All stool samples will be examined with duplicated Kato-Katz thick smears by experienced laboratory technicians. Randomization of participants into the treatment arms will be stratified according to intensity of infection. All participants will be interviewed before treatment, 3 and 24 hours and 3 weeks after treatment about the occurrence of adverse events. Children and adults will be sampled using finger pricking for micro-blood sampling at 0, 1, 2, 3, 4, 6, 8, 24 hours post-dosing. The primary analysis will include all participants with primary end point data (available case analysis). Supplementary, a per-protocol analysis and an intention-to-treat analysis will be conducted. CRs will be calculated as the percentage of egg-positive subjects at baseline who become egg-negative after treatment. Differences among CRs will be analysed by using crude logistic regressions and adjusted logistic regressions (adjustment for age, sex, and height). 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 2,000 replicates will be used to calculate 95% confidence intervals (CIs) for differences in ERRs. Noncompartmental and nonlinear mixed-effects (NLME) modeling will be used to determine PK parameters.

Official Title
-----------------
Efficacy and Safety of Ascending Dosages of Albendazole Against T. Trichiura and Hookworm in Preschool- and School-aged Children and Adults: a Randomized Controlled Trial

Conditions
-----------------
Trichuriasis, Hookworm Infections

Intervention / Treatment
-----------------
* Drug: Albendazole
* Drug: Albendazole
* Drug: Albendazole
* Drug: Albendazole
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female adults (≥21 years), preschool-aged children (2-5 years) and school-aged children (6-12 years) infected with T. trichiura/hookworm Written informed consent/assent signed from parent/guardian Positive for T. trichiura/hookworm by at least two slides of the quadruple Kato-Katz thick smears and infection intensities of at least 100 eggs per gram of stool (EPG) Agree to comply with study procedures, including provision of two stool samples at the beginning (baseline) and approximately three weeks after treatment (follow-up). Exclusion Criteria: Presence of acute or uncontrolled systemic illnesses (e.g. severe anemia, infection, clinical malaria) as assessed by a medical doctor, upon initial clinical assessment and liver function tests. Known or reported history of chronic illness such as HIV, acute or chronic hepatitis, cancer, diabetes, chronic heart disease or renal disease. Prior treatment with anthelmintics (eg, diethylcarbamazine [DEC], suramin, ivermectin, mebendazole or albendazole) within 4 weeks before planned test article administration. Received any investigational drugs or investigational devices within 4 weeks before administration of test article that may confound safety and/or efficacy assessments. Known or suspected allergy to benzimidazoles. Pregnant (urine testing) or breastfeeding women

Ages Eligible for Study
-----------------
Minimum Age: 2 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 200 mg albendazole<br>against T. trichiura in preschool-aged children or against hookworm infections in preschool-aged children, school-aged children and adults | Drug: Albendazole<br>* Single dose of albendazole (200mg, dependent on treatment cohort)<br>* Other names: Zentel®;|
| Experimental: 400 mg albendazole<br>against T. trichiura in preschool-aged children, school-aged children and adults or against hookworm infections in preschool-aged children, school-aged children and adults | Drug: Albendazole<br>* Single dose of albendazole (400mg, dependent on treatment cohort)<br>* Other names: Zentel®;|
| Experimental: 600 mg albendazole<br>against T. trichiura in preschool-aged children, school-aged children and adults or hookworm infections in preschool-aged children, school-aged children and adults | Drug: Albendazole<br>* Single dose of albendazole (600mg, dependent on treatment cohort)<br>* Other names: Zentel®;|
| Experimental: 800 mg albendazole<br>against T. trichiura in school-aged children and adults or against hookworm infections in school-aged children and adults | Drug: Albendazole<br>* Single dose of albendazole (800mg, dependent on treatment cohort)<br>* Other names: Zentel®;|
| Placebo Comparator: Placebo<br>against T. trichiura in preschool-aged children, school-aged children and adults or hookworm infections in preschool-aged children, school-aged children and adults | Drug: Placebo<br>* Matching placebo tablets will be obtained from Fagron, Germany.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure Rate Against T. Trichiura and Hookworm Infections | The conversion from being egg positive pre-treatment to egg negative post-treatment, or cure rate (CR). | 14-21 days after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Egg-reduction Rate (ERR) Against T. Trichiura and Hookworm Infections, Respectively | Percent change in geometric mean eggs per gram of stool from before to after treatment | 14-21 days after treatment | 
| Maximum Concentration (Cmax) of Albendazole Sulphoxide | To determine maximum drug concentration (Cmax) of albendazole and its metabolites in adults (≥ 21 years), preschool-aged (2-5 years) and school-aged children (6-12 years). Albendazole sulfoxide will be quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Drug concentrations will be calculated by interpolation from a calibration curve with a foreseen limit of quantification of approximately 1-5 ng/ml. | 0, 1, 2, 3, 4, 6, 8, 24 hours post-dosing | 
| Time to Reach Cmax (Tmax) of Albendazole Sulphoxide | To determine time to reach Cmax (tmax) of albendazole and its metabolites in adults (≥ 21 years), preschool-aged (2-5 years) and school-aged children (6-12 years). Albendazole sulfoxide was quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Drug concentrations will be calculated by interpolation from a calibration curve with a foreseen limit of quantification of approximately 1-5 ng/ml. | 0, 1, 2, 3, 4, 6, 8, 24 hours post-dosing | 
| Area Under the Curve (AUC) of Albendazole Sulphoxide | To determine the area under the curve (AUC) of albendazole sulphoxide in adults (≥ 21 years), preschool-aged (2-5 years) and school-aged children (6-12 years). Albendazole and its metabolites (albendazole sulfoxide and albendazole sulfone) will be quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Drug concentrations will be calculated by interpolation from a calibration curve with a foreseen limit of quantification of approximately 1-5 ng/ml. | 0, 1, 2, 3, 4, 6, 8, 24 hours post-dosing |