Validating Egg-based Diagnostics and Molecular Markers for the Spread of Anthelmintic Resistance

NCT03465488 | Completed

• 1 other identifier: OPP1120972
• Study Type: interventional
• Target: 1,000
• Locations: 4 countries
• Sites: 4

Brief Summary

Soil-transmitted helminths (STHs) are a group of parasitic worms that infect millions of children in sub-tropical and tropical countries, resulting in malnutrition, growth stunting, intellectual retardation and cognitive deficits. To control the morbidity due to these worms, school-based deworming programs are implemented, in which anthelminthic drugs are administered to children without prior diagnosis. The continued fight against these worms is aided by the London declaration on neglected tropical diseases, which helps sustain and expand global drug donation program, resulting in an unprecedented growth of deworming programs. However, the high degree of drug pressure makes deworming programs vulnerable to the development of anthelmintic resistance because they only rely on one drug with sometimes suboptimal efficacy and there is no availability of alternative drugs. Moreover, at present, there is no surveillance system to monitor the emergence and spread of anthelmintic resistance. It remains unclear to what extent the efficacy of drugs may have dropped and whether anthelmintic resistance is already present. This project aims to strengthen the monitoring and surveillance of drug efficacy and anthelmintic resistance in STH programs. As such, it will support deworming programs in their quest to eliminate STHs as a public health problem. The specific objectives of the first work package are to validate diagnostic tools to monitor drug efficacy and the spread of anthelmintic resistance, and to validate molecular markers for benzimidazole resistance. This study will be conducted at four different sites (Ethiopia, Tanzania, Lao PDR and Brazil) and will focus on school-aged children (age 5-14). At baseline subjects will be asked to provide a recent stool sample which will be processed using 3 different microscopic techniques (KK, Mini-Flotac and FECPAKG2). All children will be treated with a single-oral dose of albendazole (ALB) 400 mg and 14-21 days after treatment, a second stool sample will be collected from all children to again determine the fecal egg counts. At each sampling, stool is stored in preservative. Stored stool will be shipped to Belgium for DNA extraction and quantitative PCR (qPCR) analysis. A subset of the samples will be analysed by pyrosequencing to evaluate the single nucleotide polymorphisms in the b-tubulin gene. Pooling of the stored samples will also be performed to compare with the values obtained from analysing individual samples.

Conditions

Soil-transmitted Helminth Infections

Keywords

parasitology; helminth infections; diagnosis; drug resistance; albendazole; benzimidazole drugs; Ascaris; Trichuris; hookworm; qPCR; microscopy

Outcome Measures

Primary Outcomes (3)

• Validation of the performance of FECPAKG2 to assess drug efficacy

  We will validate the performance of the FECPAKG2 as well as its ability to assess drug efficacy by means of egg reduction rates.

  up to 12 months

• In depth evaluation of the FECPAKG2 technique to assess drug efficacy

  We will check the variation in egg counts obtained in repeated measurements and by different technicians and make a cost assessment.

  up to 12 months

• Validation of b-tubulin gene as a molecular marker for benzimidazole resistance

  This will be done through assessment of the polymorphisms at the b-tubulin gene using a pyrosequencing approach. We will compare results obtained from the 4 different study sites which have a varying MDA history as well as results obtained from responders, poor responders and non-responders within each different site.

  up to 24 months

Secondary Outcomes (2)

• Comparing the sensitivity of quantitative PCR with traditional diagnostic tools (Kato-Katz, Mini-FLOTAC and FECPAKG2) for the detection of soil-transmitted helminth infections.

  up to 12 months

• Comparing the use of individual and pooled stool samples to assess polymorphisms in the β-tubulin gene.

  up to 24 months

Study Arms (1)

Subjects

EXPERIMENTAL

All participants that meet all inclusion criteria and none of the exclusion criteria will be enrolled in the study and receive a subject identifier (SubjectID). At baseline, all participants will receive a single treatment of albendazole 400mg and their stool will be examined for helminth eggs. Two to three weeks after treatment a follow-up examination of their stool is performed.

Drug: Albendazole Pill 400mg (GSK)

Interventions

Albendazole Pill 400mg (GSK) DRUG

One single dose of 400mg Albendazole is provided at baseline.

Also known as: Albendazole 400mg form GlaxoSmithKline (Batch Nr: 335726)

Subjects

Eligibility Criteria

• Age: 5 Years - 18 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Subject, male or female, is 5-14 years of age
• Subject is otherwise in an healthy condition (medical history and physical examination)
• Parent(s)/guardians of subjects (or their legally-accepted representatives) signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to have their child participate in the study.
• Subject of ≥6 years has assented (agreed) to participate in the study.
• Subject of ≥12 has signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
• The subject swallowed the entire drug (ALB 400 mg) under supervision
• Subject provides a stool sample of at least 9 grams

You may not qualify if:

• Subject has active diarrhea (defined as the passage of 3 or more loose or liquid stools per day) at baseline or follow-up
• Subject has any acute medical condition or is experiencing a severe concurrent medical condition
• Subject has a known hypersensitivity to benzimidazole drugs
• Subject has received an anthelminthic treatment within 90 of the start of the treatment.
• Subject vomited within 4 hours after drug administration
• Subject is unable to provide a stool sample at follow-up

Sponsors & Collaborators

• University Ghent: lead
• Swiss Tropical & Public Health Institute: collaborator

Study Sites (4)

Fiocruz - Research institute of Renê Rachou

Belo Horizonte, Minas Gerais, Brazil

Location

Jimma University

Jimma, Ethiopia

Location

National Institute of Public Health

Vientiane, Laos

Location

The Public Health Laboratory - Ivo de Carneri (PHL-IdC)

Chake Chake, Pemba, Tanzania

Location

Related Publications (5)

• Coffeng LE, Vlaminck J, Cools P, Denwood M, Albonico M, Ame SM, Ayana M, Dana D, Cringoli G, de Vlas SJ, Fenwick A, French M, Kazienga A, Keiser J, Knopp S, Leta G, Matoso LF, Maurelli MP, Montresor A, Mirams G, Mekonnen Z, Correa-Oliveira R, Pinto SA, Rinaldi L, Sayasone S, Steinmann P, Thomas E, Vercruysse J, Levecke B. A general framework to support cost-efficient fecal egg count methods and study design choices for large-scale STH deworming programs-monitoring of therapeutic drug efficacy as a case study. PLoS Negl Trop Dis. 2023 May 17;17(5):e0011071. doi: 10.1371/journal.pntd.0011071. eCollection 2023 May.

  PMID: 37196017 DERIVED

• Walker M, Cools P, Albonico M, Ame SM, Ayana M, Dana D, Keiser J, Matoso LF, Montresor A, Mekonnen Z, Correa-Oliveira R, Pinto SA, Sayasone S, Vercruysse J, Vlaminck J, Levecke B. Individual responses to a single oral dose of albendazole indicate reduced efficacy against soil-transmitted helminths in an area with high drug pressure. PLoS Negl Trop Dis. 2021 Oct 19;15(10):e0009888. doi: 10.1371/journal.pntd.0009888. eCollection 2021 Oct.

  PMID: 34665810 DERIVED

• Vlaminck J, Cools P, Albonico M, Ame S, Ayana M, Cringoli G, Dana D, Keiser J, Maurelli MP, Matoso LF, Montresor A, Mekonnen Z, Mirams G, Correa-Oliveira R, Pinto SA, Rinaldi L, Sayasone S, Thomas E, Vercruysse J, Verweij JJ, Levecke B. Therapeutic efficacy of albendazole against soil-transmitted helminthiasis in children measured by five diagnostic methods. PLoS Negl Trop Dis. 2019 Aug 1;13(8):e0007471. doi: 10.1371/journal.pntd.0007471. eCollection 2019 Aug.

  PMID: 31369562 DERIVED

• Cools P, Vlaminck J, Albonico M, Ame S, Ayana M, Jose Antonio BP, Cringoli G, Dana D, Keiser J, Maurelli MP, Maya C, Matoso LF, Montresor A, Mekonnen Z, Mirams G, Correa-Oliveira R, Pinto SA, Rinaldi L, Sayasone S, Thomas E, Verweij JJ, Vercruysse J, Levecke B. Diagnostic performance of a single and duplicate Kato-Katz, Mini-FLOTAC, FECPAKG2 and qPCR for the detection and quantification of soil-transmitted helminths in three endemic countries. PLoS Negl Trop Dis. 2019 Aug 1;13(8):e0007446. doi: 10.1371/journal.pntd.0007446. eCollection 2019 Aug.

  PMID: 31369558 DERIVED

• Vlaminck J, Cools P, Albonico M, Ame S, Ayana M, Bethony J, Cringoli G, Dana D, Keiser J, Maurelli MP, Montresor A, Mekonnen Z, Mirams G, Correa-Oliveira R, Prichard R, Rashwan N, Rinaldi L, Sayasone S, Thomas E, Verweij JJ, Vercruysse J, Levecke B. Comprehensive evaluation of stool-based diagnostic methods and benzimidazole resistance markers to assess drug efficacy and detect the emergence of anthelmintic resistance: A Starworms study protocol. PLoS Negl Trop Dis. 2018 Nov 2;12(11):e0006912. doi: 10.1371/journal.pntd.0006912. eCollection 2018 Nov.

  PMID: 30388108 DERIVED

Related Links

• Project website
• Laboratory website

MeSH Terms

Conditions

Trematode Infections; Disease; Ancylostomiasis

Interventions

Albendazole; halofantrine

Condition Hierarchy (Ancestors)

Helminthiasis; Parasitic Diseases; Infections; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Hookworm Infections; Strongylida Infections; Secernentea Infections; Nematode Infections

Intervention Hierarchy (Ancestors)

Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Bruno Levecke, PhD

  University Ghent

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 16, 2018
• First Posted: March 14, 2018
• Study Start: August 15, 2016
• Primary Completion: January 1, 2018
• Study Completion: September 1, 2019
• Last Updated: October 21, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: A general overview of the project is already published on our project website. The specific study protocol for work-package 1 of the project is currently being submitted for publication. Once final data is collected, De-identified data will be available through the project website as well. No specific time-frame will be applied.
• Access Criteria: Free access for all

Locations

TA (1); BR (1); LA (1); ET (1)