Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05306067 |
| Other study ID # |
GenMoz |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
October 12, 2021 |
| Est. completion date |
February 2024 |
Study information
| Verified date |
December 2023 |
| Source |
Centro de Investigacao em Saude de Manhica |
| Contact |
Alfredo Mayor, Professor |
| Phone |
+34 686444183 |
| Email |
alfredo.mayor[@]isglobal.org |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Mozambique is among the ten countries with the highest burden of malaria worldwide, with an
estimated 9.3 million cases in 2018, and constitutes a core target for the World Health
Organization (WHO) and the Roll Back Malaria Partnership to End Malaria's country-led 'high
burden to high impact' initiative. At the same time, the National Malaria Control Program
(NMCP) of Mozambique seeks to accelerate elimination in the south, where transmission is
lowest. NMCP is currently working with partners (Malaria Consortium, PMI, Global Fund) to set
up a high-resolution surveillance system that can drive decision-making across all
transmission strata through strengthening of routine data quality, data use and data to
action packages. However, decisions become more complex as control reveals heterogeneity and
better tools are required for a strategic use of information to drive impact. The overall
objective of the study is to operationalize a functional malaria molecular surveillance (MMS)
system that generates reliable and reproducible genomic data over time for programmatic
decisions. The integration of genomic data into routine surveillance activities has the
potential to increase the actionable intelligence for making programmatic decisions on the
optimal mix of control and elimination measures in Mozambique by:
1. Informing drug and diagnostic choices through the monitoring of antimalarial drug
resistance and diagnostic resistance (hrp2/3 deletions);
2. Targeting the reservoirs sustaining transmission through the use of transmission network
models to quantify parasite importation, identify sources and characterize local
transmission in near-elimination settings;
3. Improving stratification, monitoring and impact evaluations in different epidemiological
and health system contexts through the use of measures of P. falciparum genetic
diversity (routinely from positive cases) to supplement traditional surveillance,
especially where it is sparse;
4. Using alternative, cost-effective, approaches targeting easy-access populations (e.g.
pregnant women at antenatal care clinics) to monitor transmission and
antimalarial/diagnostic resistance.
Description:
Genomic data constitutes a valuable adjunct to routine surveillance that can guide
programmatic decisions to reduce the burden of infectious diseases. However, genomic
capacities remain low in Africa. This study aims to operationalize a functional malaria
molecular surveillance system in Mozambique that generates reliable and reproducible genomic
data over time for malaria control and elimination. This prospective surveillance study seeks
to generate P. falciparum genetic data to 1) monitor molecular markers of drug resistance and
deletions in rapid diagnostic test targets; 2) characterize transmission sources
(imported/introduced or indigenous) in low transmission settings; and 3) quantify
transmission levels and the effectiveness of antimalarial interventions.
Nine provinces were identified through consultation with the NMCP for inclusion in the study:
Maputo, Maputo City, Gaza, Inhambane, Niassa, Manica, Nampula, Zambezia and Sofala. Selection
of study sites will be stratified by transmission intensity into two major strata: A) low
transmission (Maputo province and Maputo City, where individual case notification is in
effect for the purpose of a complete interruption of transmission), and B) medium-to-high
transmission areas (Gaza, Inhambane, Niassa, Manica, Nampula, Zambezia and Sofala provinces,
targeted by control (non-elimination) strategies). The provinces were selected to provide a
range of low and medium-to-high transmission intensity, geographies, climatic conditions,
malaria interventions mixes and populations (symptomatic, household contacts and sentinel
groups). In the low transmission areas, districts and locations will be sampled based on
historic surveillance data. Additionally, in Maputo province, the Ponta d'Ouro border post
will be included to capture potential imported cases of malaria.
Dried blood spot samples and rapid diagnostic tests will be collected across the study
districts through a combination of dense (all malaria cases) and targeted (a selection of
malaria cases) sampling of malaria symptomatic cases in low malaria transmission and
medium-to-high malaria transmission areas, respectively. In medium-to-high malaria
transmission areas a second, non-HRP2 based test will be carried out and discrepant results
suggestive of pfhrp2/3 deletions will be recorded and further analysed. Pregnant women
attending their first antenatal care visit will be also included to assess their value as
sentinel populations for molecular surveillance. Written informed consent will be sought from
all survey participants before surveys and blood sample collections are conducted. In that
case, information about the purpose of the sample collection will be explained, any questions
will be clarified, and written informed consent will be obtained. The information sheet and
consent form will also include text explaining informed consent for future use of biological
specimens. In case of minors, consent will be sought from parents or guardians. The field
worker or nurse will read the informed consent form to adults or the child's parent/guardian
and will ask them if he/she agree his/her child to participate in the study. A witness will
be required to sign the informed consent in case parent/guardian of the participant is
illiterate. The consent will be available in Portuguese and translated into local language
spoken at the study areas. The information sheet includes a brief description of the study,
the data collection procedure, the blood sample collection procedure, the potential harm to
participants, the expected benefits and the voluntary nature of participation at all stages
of the interview and blood sampling. Two copies will be signed by the participant and the
study team member obtaining the consent. One copy will be given to the participant and the
other copy will be kept in the study file at the CISM office.
Sample size per sampling domain has been estimated taking into account antimalarial and
diagnostic resistance as a primary use case, considering the negligible carriage of molecular
markers of artemisinin resistance and pfhrp2/3 deletions in Mozambique, and setting 5% as the
warning threshold. Assuming a 10% of loss of samples or uninterpretable analysis, a sample
size of up to 500 per sampling domain would be adequate to: a) estimate a proportion of 0.05
(markers of drug resistance or pfhrp2 deletion) with 0.026 absolute precision and 95%
confidence and b) achieve a power of 80% for detecting an increase of genetic marker
(resistance or deletion) from 0 ‰ to 5% at a two-sided p-value of 0.01. It is estimated that
up to 500 participants will be recruited among all ages for the study in each sampling unit
(i.e. province) across those accessing APEs and health facilities (except Maputo city and
Maputo province where continuous collections may exceed this number and household contact
sample collection may increase this further). We will target up 500 RDT-positive pregnant
women attending ANC clinics in all medium-to-high transmission districts and in low
transmission areas each year for a period of three years. A flexible and adaptive sampling
scheme will be followed, where a) estimates generated during the first half of the project
will inform subsequent sampling schemes and b) not all the samples collected will be analysed
(some of them will be stored as reference materials or for confirmation of findings).
The project will also leverage from intervention studies and surveillance activities being
conducted in Mozambique between 2021 and 2024, namely: the Malaria Indicator Survey
(2022-2023) in southern Mozambique; the Therapeutic Efficacy Survey (2022) in sentinel sites
in the country (Cabo Delgado, Tete, Sofala, Zambézia and Inhambane); reactive surveillance
activities (Maputo province); a Phase III cluster-randomized, open-label, clinical trial to
study the safety and efficacy of ivermectin mass drug administration to reduce malaria
transmission (Zambezia; 2022); a large-scale implementation development project aiming at
maximising the delivery and uptake of intermittent preventive treatment in infancy (IPTi)
(Inhambane; 2022-2024); a hybrid effectiveness-implementation study to evaluate the
feasibility and effectiveness of seasonal malaria chemoprevention (SMC) with
sulfadoxine-pyrimethamine and amodiaquine (Nampula; 2022); and a programmatic delivery of a
population-based mass drug administration with dihydroartemisinin-piperaquine (Gaza Province;
2022-2023).
Molecular analysis will be conducted at CISM. Initial planned genomic analyses of parasite
DNA are as follows, though it is possible that improved technologies, protocols, and/or
additional parasite genomic targets of interest may become apparent during the course of this
project, in part from lessons learned from the data generated herein. Informative SNPs and
short haplotypes will be targeted using multiplexed primers on flanking sequences, with a
range of amplicon size of ~150-250 bp (covered by a paired end read). Targeted amplicons
obtained by PCR on genomic DNA using universal tags, Illumina-specific adaptors and
sample-specific barcode will be pooled to create a single product library, which will be
sequenced (paired-end 150-bp) on an Illumina MiSeq or NextSeq. Alternative molecular
approaches will be used if the single multiplexed amplicon approach does not provide the
expected results. Samples will be also used for other molecular analysis of programmatic
interest, such as the detection of Plasmodium species, parasite antigens, serological markers
of parasite exposure (antibodies)and parasite RNA-based markers (i.e., gametocytes). For
quality control purposes, up to 5% of the analysed samples will be transported to UCSF (USA)
and/or ISGlobal (Spain) for secondary analysis.
Sequences generated through the analysis of samples collected (from Mozambique and
neighbouring countries) will be integrated into a curated catalogue of genomic data together
with relevant clinical and epidemiological information. These databases will be made publicly
available in open access repositories such as the European Nucleotide Archive (ENA) and
MalariaGen Resource Center. In order to facilitate data accessibility and use, and to obtain
a meaningful integration with other sources of surveillance data, genetic information will be
incorporated into the DHIS2-based Integrated malaria information storage system (iMISS),
which is currently being rolled out. The iMISS includes: case data, focus investigations,
entomological surveillance data and intervention data. Data visualizations, and dashboards
will be defined in collaboration with all users and stakeholders and aligned with the current
work led by WHO GMP regarding standardization of malaria dashboards. We will establish risk
profile algorithms and interpretation components that are capable of generating outputs on a)
country-wide antimalarial resistance profiles (rolling-basis); b) in very low transmission
areas, genetic connectivity and case classification (together with travel history and other
parameters obtained from case-based notification tools); and c) "high burden to high
impact"-specific analysis (i.e., stratification and trend analyses for exploring the
potential impact of intervention mixes implemented), to be agreed in consultation with WHO
and the SM&E TWG.
