Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04177654 |
| Other study ID # |
OPP1120972_WP2 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 15, 2019 |
| Est. completion date |
December 31, 2022 |
Study information
| Verified date |
August 2023 |
| Source |
University Ghent |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial 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 overall aim of this study is to pilot a surveillance system to assess
anthelmintic drug efficacy and the emergence of AR in 9 countries were drug pressure has been
high over a long period of time.
The specific objectives are to:
1. Assess the prevalence of moderate/heavy intensity infections of the different STH
2. Assess the drug efficacy of a single dose of BZ drugs against STH infections in these
countries
3. Assess the frequency of the ß-tubulin SNPs linked to BZ resistance
4. Identify implementation-related barriers and opportunities for monitoring drug efficacy
and AR in national PC programs for STH.
5. Expand the Starworms repository of STH field samples
Description:
Soil-transmitted helminths (STHs) include Ascaris lumbricoides, Trichuris trichiura, and two
hookworm species, namely Necator americanus and Ancylostoma duodenale. They are responsible
for the highest burden among all neglected tropical diseases (NTDs). Recent global estimates
indicate that in 2010 more than 1.4 billion people were infected with at least one of the
four STH species, resulting in a global burden of approximately 3.3 million
disability-adjusted life years (DALYs). To control the morbidity caused by STHs, preventive
chemotherapy (PC) is the main strategy. This entails the periodical administration of a
single-oral dose of albendazole (ALB; 400 mg) or mebendazole (MEB; 500 mg) to at-risk
populations (ie., preschool-aged (preSAC), school-aged children (SAC) and women of
reproductive age) (WHO, 2017). Accelerated by the London Declaration on NTDs, the global
coverage of children in PC programs has increased from ~30% in 2011 to 63.6% in 2016, with
the goal of covering at least 75% of children by 2020. The laudable long-term aim is to
eliminate STHs as a public health problem (<1% moderate/heavy intensity infections), and to
eventually declare targeted geographical areas free of infections.
This high level of drug pressure makes PC programs highly vulnerable to the development of
anthelmintic resistance (AR). First, the community relies on two drugs (ALB and MEB) of the
same class (benzimidazole (BZ) drugs), and with the same mode of action (the inhibition of
the polymerization of microtubules). Hence the emergence of AR is likely to occur as drug
donations expand. This has been substantiated in veterinary medicine, where AR has developed
within a decade of the introduction of every anthelmintic class. Moreover, the development of
AR against one BZ drug would most likely be accompanied by poor anthelmintic drug efficacy of
the other BZ drug. Second, drugs are administered in single doses. Although a single dose is
operationally justified, it never achieves 100% efficacy. Consequently, this practice may
further select for the development of AR when suboptimal doses are widely applied over a
significant period. Finally, only few anthelmintic drugs are licensed for the treatment of
STH infections in humans Thus, should AR against BZ drugs eventually emerge and spread,
PC-based control of STHs will be even more limited than at present with few acceptable
alternative options. Hence, this re-enforces the urgent necessity for increased accessibility
of anthelmintic drugs of different anthelmintic classes and thoroughly designed surveillance
systems that allow detection of any changes in anthelmintic drug efficacy arising through the
evolution of AR in these helminths.
Currently, any global surveillance system to monitor both drug efficacy and emergence of AR
is lacking, and as a consequence it remains unclear to what extent the efficacy of drugs may
have dropped and whether AR is already present. One of the main reasons for this lack of
monitoring systems is the absence of a framework that guides and supports healthcare decision
makers in planning, performing and reporting surveys. The development of such a framework is
not straightforward. Moreover, PC programs typically operate in resource-limitedsettings, and
therefore it is indispensable that health-care decision makers have some pliancy to minimize
both financial and technical resources, while assuring a reliable assessment of the drug
efficacy and spread of AR.
To conclude, AR is a real threat for PC programs targeting human STHs. To establish a
surveillance system, and to hence further ensure the efficacy of the administered drugs,
there is a need for diagnostic methods that effectively mitigate important obstacles of
performing, analysing and reporting drug efficacy surveys in resource poor settings, and a
validated molecular marker to detect emergence of AR at an early stage. Subsequently, a
surveillance system should be established to assess global patterns of drug efficacy and AR.
Finally, tools for planning routine AR monitoring, and for following up the global changes in
drug efficacy and spread of AR over time should be made available.
The overall aim of this study is to pilot a surveillance system to assess anthelmintic drug
efficacy and the emergence of AR in 11 countries were PC coverage has been high over a long
period of time. The specific objectives are to:
1. Assess the prevalence of moderate/heavy intensity infections of the different STH
2. Assess the drug efficacy of a single dose of BZ drugs against STH infections in these
countries
3. Assess the frequency of the ß-tubulin SNPs linked to BZ resistance
4. Measure the costs related to monitoring drug efficacy and AR in national PC programs for
STH.
5. Expand the Starworms repository of STH field samples
A series of drug efficacy trials will be performed in 9 STH endemic countries (Lao PDR,
Bangladesh, Vietnam, Cambodia, Senegal, Ghana, Rwanda, Haiti) during their national PC
program. These trials were designed to correctly classify the efficacy of a single oral dose
of BZ drugs against STH infections in SAC into 'normal', 'doubtful' and 'reduced'. The study
will focus on SAC (age 5-14) since they are the major target population of PC programs
against STH, and they usually represent the group with highest intensity of infection for A.
lumbricoides and T. trichiura. At baseline, SAC will be asked to provide a fresh stool
sample. All children that meet all inclusion criteria and none of the exclusion criteriawill
be enrolled in the study. They will be treated with a single oral dose of BZ drug under
supervision. The choice of BZ drug will depend on the drug used in the STH program. The drug
used in the study will be provided by the national PC program.
All collected stool samples at baseline will be processed to determine the fecal egg counts
(FECs; expressed in eggs per gram of stool (EPG)) for each STH using a duplicate Kato-Katz
thick smear. Positive baseline samples will be preserved for further molecular analysis.
Fourteen to 21 days after drug administration, a second stool sample will be collected from
all the children that were excreting eggs of any STH at baseline. These stool samples will
again be examined by a duplicate Kato-Katz thick smear. All follow-up samples will be
preserved for further molecular analysis.
