Adjunctive Ivermectin Mass Drug Administration for Malaria Elimination: A cluster randomized trial

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Infectious and Tropical Diseases

Abstract

This trial will be the first to investigate the impact of adding ivermectin (IVM) to mass drug administration (MDA) with an efficacious antimalarial (eg dihydroartemisinin-piperaquine (DP)) to reduce malaria transmission in a seasonal low-transmission setting. Additive IVM MDA will be compared to DP-only MDA (with treatment daily for three days during the three months of peak malaria transmission (July-September)) in combination with standard programmatic interventions for malaria control (long-lasting insecticidal nets (LLIN) and intermittent preventative treatment in pregnancy (IPTp)) in a cluster-randomized community-based trial. Primary outcome measures will be population-based Plasmodium falciparum (malaria infection) prevalence (estimated using ultra-sensitive PCR tests) and Anopheles gambiae (malaria vector) survival (measured using parity estimated by dissection of Anopheles ovaries). Data on MDA coverage, acceptability and feasibility of the intervention and a cost-effectiveness analysis will be included. We have established field infrastructure on the Bijagós Archipelago (including trained field entomologists and field laboratory technicians) and have detailed recent baseline data on the burden of disease caused by malaria and other neglected tropical diseases (NTDs) and vector populations on the islands. This 'natural laboratory' island setting provides an unparalleled opportunity to understand transmission and its interruption using a combined MDA strategy through investigating the impact of imported infections (through an expanded community-based CDSAT (case detection screen and treat) intervention which we will include in both arms), using serological (immune) markers in the blood to define transmission dynamics and estimate entomological inoculation rate (EIR) and monitoring the effect of IVM MDA on confined vector populations over time.

Technical Summary

This trial will be the first to investigate the impact of adjunctive IVM MDA to reduce malaria transmission in a seasonal low-transmission setting. Adjunctive IVM MDA will be compared to DP-only MDA (with treatment daily for three days during the three months of peak malaria transmission (July-September)) in combination with standard programmatic interventions (long-lasting insecticidal nets (LLIN) and intermittent preventative treatment in pregnancy (IPTp)) in a cluster-randomized community-based trial. Primary outcome measures will be population-based Pf prevalence (estimated using ultra-sensitive PCR) and Anopheles gambiae survival (measured using parity). Data on MDA coverage, acceptability and feasibility of the intervention and a cost-effectiveness analysis will be included. We have established field infrastructure on the Bijagós Archipelago (including trained field entomologists and field laboratory technicians) and have detailed recent baseline data on malaria and NTD epidemiology and vector populations on the islands. This island setting provides an unparalleled opportunity to understand transmission and its interruption using a combined MDA strategy through investigating the impact of imported infections (through an expanded community-based CDSAT (case detection screen and treat) intervention in both arms), using serological markers to define transmission dynamics and estimate entomological inoculation rate (EIR) and monitoring the effect of IVM MDA on confined vector populations over time (parity, sporozoite rate, resistance to pyrethroids and IVM and population genomic diversity).

Planned Impact

There is increasing interest in the potential of ivermectin (IVM) mass drug administration (MDA) tailored to local transmission patterns to complement vector control strategies, particularly where existing strategies such as long lasting insecticidal nets (LLIN) and indoor residual spraying (IRS) have been maximized. Moreover, new tools for reduction in malaria transmission are required as both pyrethroid and antimalarial resistance emerges. There is growing evidence that adjunctive IVM MDA used in this context will be a useful new tool in reducing malaria transmission, and even eliminating malaria in some settings, but there is currently a lack of cluster randomized trials investigating its utility and efficacy. The public health impact of adjunctive IVM MDA to MDA with an efficacious antimalarial is not known and there have not been any trials to date designed to answer this research question specifically. Results from the proposed trial will be important in addressing some of the outstanding questions. The design of the trial will allow us to quantify the impact of adjunctive IVM MDA as a malaria control strategy. The confined nature of the islands will allow us to estimate the impact on vector density and survival and measure the effect of imported infection and population movement on MDA strategies for malaria control and elimination. The results will be generalizable in other settings of similar endemicity in Africa.

The results of this trial will contribute to information relevant to malaria control programmes of the efficacy of IVM MDA in in combination with dihydroartemesinin-piperaquine (DP) MDA as part of a community-based intervention strategy for malaria elimination. If DP+IVM MDA is shown to be feasible and cost-effective this strategy may be important in the acceleration of elimination of malaria which would have a significant beneficial impact on health. The results of this trial may also contribute knowledge towards the integrated elimination of IVM-susceptible Neglected Tropical Diseases (NTDs) such as lymphatic filariasis (LF), soil-transmitted helminths (STH) (such as Strongyloides) and scabies alongside malaria elimination in co-endemic settings. This study will enhance our knowledge of sustainable surveillance and feasible and equitable access to MDA. The results of this study will inform malaria (and NTD) control policies in Guinea Bissau and elsewhere in Africa with similar geography or malaria endemicity and could have a major impact on the burden of these diseases in West Africa and beyond. The Bissau-Guinean Ministry of Public Health (MoPH) (including the National Malaria Control Programme (PNLCP) and the National Programme for Neglected Tropical Diseases (PNDTN)) and the National Institute for Public Health (INASA) in Bissau will be able to use these data to define and implement these strategies on the islands. This trial is complementary to the MASSIV trial, currently underway, which is investigating a similar strategy for malaria transmission reduction in The Gambia. The combined data from both of these trials will be a powerful data set that will enhance the knowledge of these interventions and their implementation.

Publications

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Jones RT (2021) The use of islands and cluster-randomized trials to investigate vector control interventions: a case study on the Bijagós archipelago, Guinea-Bissau. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

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Kositz C (2022) Broadening the range of use cases for ivermectin - a review of the evidence. in Transactions of the Royal Society of Tropical Medicine and Hygiene

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McGregor D (2021) The Epidemiology of Plasmodium falciparum Malaria in the Bijagos Islands of Guinea-Bissau in The American Journal of Tropical Medicine and Hygiene

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The Ivermectin Roadmappers (2020) A Roadmap for the Development of Ivermectin as a Complementary Malaria Vector Control Tool. in The American journal of tropical medicine and hygiene

 
Title Promoting public health research by the London School of Hygiene and Tropical Medicine 
Description Lyrics and music composition by a Guinean artist to reflect work done by the London School of Hygiene and Tropical Medicine on the Bijagos Archipelago of Guinea Bissau; focus on public health, infectious disease control with tribute to our field research team. Music has been used in publicity and celebratory events and was streamed on social media. 
Type Of Art Composition/Score 
Year Produced 2018 
Impact Local publicity resulting in local interest in working on our research projects; increased recruitment in Guinea Bissau. Increased prominence of London School projects and boosted field research team morale. 
 
Description MRC London Intercollegiate Doctoral Training Partnership Scheme
Amount £96,415 (GBP)
Funding ID MR/N013638/1 
Organisation London School of Hygiene and Tropical Medicine (LSHTM) 
Sector Academic/University
Country United Kingdom
Start 01/2021 
End 09/2024
 
Description Wellcome Trust PhD Training Fellowship for Clinicians
Amount £368,396 (GBP)
Funding ID 222991/Z/21/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2021 
End 08/2024
 
Description Collaboration with Bandim Health Project 
Organisation Bandim Health Project (BHP)
Country Denmark 
Sector Charity/Non Profit 
PI Contribution We have created in-country links with our Bissau-based partners such that their mobile field teams can link into our field infrastructure on the Bijagos Islands. We offer support to their mobile team requirements and also provide links with MRCG. We have provided educational sessions at their centre and have disseminated our research findings to them as collaborating partners. We pay overheads for services used. One of the co-investigators on our current grant is the head of research at BHP.
Collaborator Contribution BHP have been very supportive with initial logistic set-up of all our projects. They have also provided in country logistic/operational and administrative support and cold storage facilities for samples.
Impact We have disseminated results from our studies in an educational forum for both Danish and Bissau-Guinean colleagues. We have also provided the opportunity for research students and trainees to undertake research placement with our projects.
Start Year 2010
 
Description Collaboration with MRC The Gambia Unit 
Organisation Medical Research Council (MRC)
Department MRC Unit, The Gambia
Country Gambia 
Sector Public 
PI Contribution MATAMAL is an important cluster randomized placebo controlled trial to evaluate the impact of adjunctive ivermectin for malaria control in West Africa. The study site is well suited for a cluster randomized trial of this nature, allowing us to minimize contamination effects between clusters. The study is a natural continuation of a recent cluster randomized trial (MASSIV) conducted by the unit and is of significant interest to our unit-based co-investigators. This project has facilitated MRC The Gambia in improving their support for operational research in the West African sub-region, which is a major long term capacity-building aim of the unit. This project has facilitated capacity-building within the disciplines of laboratory diagnostics and entomology and collaboration with Guinean co-investigators. This grant has notably improved and mobilised the development of a serological diagnostics 'hub' for the sub-region in collaboration with several other research grants led by Chris Drakeley at LSHTM and Umberto D'Alessandro et al at MRCG. This 'hub' represents a long term aim of the unit and our research team and this award will contribute significantly towards its development and launch. This partnership will contribute towards the sustainability of serological diagnostics for epidemiological and clinical trial research into programmatic use. This project also provides financial support for multidisciplinary staff at MRCG who are involved in procurement, logistics support, investigational medicinal product preparation and storage for the trial.
Collaborator Contribution Our partnership with MRCG is important scientifically; MATAMAL is a natural progression from the MASSIV trial (PI Umberto D'Alessandro). It has been important to include Umberto D'Alessandro and colleagues as co-investigators on MATAMAL to ensure comparability of results between trials to promote a solid evidence base for this strategy for malaria control. This is augmented by LSHTM and MRCG participation in an international 'Ivermectin Roadmap' collaboration between a number of international institutions and investigators to harmonise trials and collectively contribute to the evidence base. The collaboration with MRCG has been critical in providing laboratory services to support MATAMAL, where in-country (Guinea Bissau) laboratory services are lacking and beyond the scope of the current award to develop. To this end, in collaboration with MRCG we have been able to support training of Guinean field and laboratory staff in GCP, laboratory diagnostics and entomology. Where facilities are lacking in Guinea Bissau, MRCG has been able to provide significant logistic support, from independent pharmacists in the handling of IMP, to specialist logistics to facilitate transfer of temperature-controlled IMP and essential materials and consumables imported for research from Europe. The standing and experience of the unit has benefitted our collaboration significantly and it is our and MRCG's aim to build capacity and provide support within the region, particularly for Guinea Bissau, in the context of research.
Impact Multidisciplinary: Clinical, Epidemiological, Laboratory Services, Clerical/Logistics services, Clinical Trial Support
Start Year 2016
 
Description Collaboration with the National Research Institute (Instituto Nacional de Estudos e Pesquisa (INEP)), Bissau, Guinea-Bissau 
Organisation Instituto Nacional de Estudos e Pesquisa
Country Guinea-Bissau 
Sector Public 
PI Contribution Our research has provided the opportunity for social scientists from Guinea-Bissau to collaborate with LSHTM and improve their academic CVs through training and publication of peer-reviewed articles resulting from collaborative research. We are developing this collaboration to provide academic support for social scientists at different stages in their career through our field research projects. This award includes funding to support their training and involvement in MATAMAL.
Collaborator Contribution We have benefited from the partnership with Guinean social scientists who have been able to assist and guide our social science research within MATAMAL and previous projects. The real-time evaluation of intervention access, acceptability and feasibility is crucial to the success of MATAMAL and to any potential downstream programmatic application. Working with our colleagues from INEP has allowed an appropriate and in-depth evaluation, which is mutually beneficial to LSHTM and INEP. The aim is for this collaboration to continue with future operational research and clinical trials.
Impact Previous collaborative publication (doi: 10.1016/j.socscimed.2019.03.019)
Start Year 2017
 
Description ASTMH Symposium 2020 Ivermectin and Antimalarial Mass Drug Administration for Malaria Control and Elimination: Preliminary Field Trial Results and Trial Designs (Session 65) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Ivermectin mass drug administration (MDA) to humans and/or livestock has been proposed as potential vector control tools to accelerate malaria elimination efforts. The mainstays of malaria vector control, insecticide-treated nets and indoor residual spraying with insecticides, have been very effective at reducing the global malaria burden but efforts are beginning to stall and even reverse in some areas. Thus, novel vector control tools are needed, particularly methods that can target vectors outside the home. Ivermectin treatment makes human or animal blood lethal to feeding Anopheles, and this measure can directly target outdoor and early evening biting Anopheles. Ivermectin MDAs to humans in West Africa have been shown to reduce the survival, shift the population age structure, and reduce the sporozoite rate of wild Anopheles gambiae, which in turn reduces malaria parasite transmission to humans. Ivermectin alone will not clear treated persons of their malaria infections, so efforts have been made to assess the safety of ivermectin and antimalarial drugs. Two clinical trials administering ivermectin and dihydroartemisinin-piperaquine in Kenya and Thailand demonstrated the safety, tolerability, and pharmacokinetic interaction that caused increased ivermectin concentrations when co-administered with dihydroartemisinin-piperaquine, and subsequent enhanced mosquito-lethal effect. MDAs with ivermectin alone combined with mass ivermectin treatment of livestock are planned for Mozambique and Tanzania. MDAs with ivermectin and dihydroartemisinin-piperaquine are being evaluated in The Gambia and Guinea-Bissau in two large cluster-randomized trials. Modeling indicates that the addition of ivermectin to dihydroartemisinin-piperaquine will reduce the number of rounds and time necessary to achieve malaria elimination. Seasonal Malaria Chemoprevention (SMC) is the monthly administration of sulfadoxine-pyrimethamine plus amodiaquine during the malaria transmission season to children 3-59 months old in the Sahel of Africa. Modeling indicates that combining SMC with ivermectin MDA to eligible persons = 5 years old would be extremely impactful, and this combination is being assessed in Burkina Faso. Ivermectin-only treatments in low transmission areas outside of Africa where it is more common for malaria vectors to feed outdoors, such as the Greater Mekong Subregion, may be more impactful as few people will harbor malaria parasites, reducing justification for combining ivermectin with antimalarial drugs, and this is being assessed in Thailand. Preliminary results or trial designs from each of these trials will be presented here.
Year(s) Of Engagement Activity 2020
URL https://www.abstractsonline.com/pp8/#!/9181/session/39
 
Description Community event and debriefing workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Study participants or study members
Results and Impact This is a planned event to coincide with the imminent MDA in MATAMAL and closely linked with the interactive and reactive social science component on MATAMAL that will evaluate in real-time accessibility, acceptability and feasibility of the MDA regime in MATAMAL. There will be a community event centred around community perceptions of malaria and MDA for malaria, using the Photo Voice modality, allowing participants to share their individual stories. This will be alongside a workshop with debrief and feedback for study team members, to reflect on the MDA and with the aim of improving implementation and coverage in subsequent MDA. This will promote discussion and allow viewpoints to be shared.
Year(s) Of Engagement Activity 2021
 
Description Informal Expert Consultation on Trachoma Elimination 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Present as part of an expert group to decide on changes to trachoma control programme surveillance and intervention in hard to reach populations and in regions where trachoma has not been eliminated.

Considerations linked to current research on a WT Collaborative award evaluating strategies for trachoma elimination through a cluster randomised controlled trial (Stronger SAFE).
Year(s) Of Engagement Activity 2021
 
Description Ivermectin Roadmap (Expert Group) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact "A roadmap for the development of ivermectin as a complementary vector control tool" was conceived and written by a group of experts led by Regina Rabinovich and Carlos Chaccour at the Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain. The development process began with a kick-off meeting at the ASTMH conference in November 2017, in Baltimore, USA, followed by a series of specific consultations with different stakeholders, and a synthesis meeting held in June 2018, in Sitges, Spain. A preliminary version of the manuscript (see Publications) was presented during a symposium at the ASTMH conference, 2018, in New Orleans and published in 2020 in AJTMH. The Ivermectin Roadmapper group is working closely with relevant stakeholders to ensure that real-time data from the first wave of clinical trials evaluating ivermectin MDA for malaria is used promptly and appropriately to allow timely translation into policy and practice.
Year(s) Of Engagement Activity 2017,2018,2020,2021
 
Description MATAMAL sensitisation radio broadcasts 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A series of broadcasts with information about MATAMAL, FAQs and introduction to the study team prior to the MDA intervention. Broadcasts are being delivered in Kriolu (lingua franca) and Bijogo (local dialect) languages, in two formats. Firstly, as part of a Public Health Broadcast slot and secondly, delivered in the form of Bijogo poetry, which is commonly used for community communication. Our field research team has worked closely with the local radio station to develop the content of these broadcasts.
Year(s) Of Engagement Activity 2021
 
Description Media interview about infectious diseases (malaria) on the Bijagos Archipelago 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This was a publicity piece for the BBC on the unique research setting of the Bijagos Islands, and their relevance in operational research towards disease elimination, particularly for the current MATAMAL trial where vector control in malaria is one of the key objectives. This piece was wide-reaching and promoted discussion, contact and questions, most notably by post-graduate students, many of whom have undertaken their research projects with our research team, resulting in several peer-reviewed publications (see Publications section).
Year(s) Of Engagement Activity 2018
URL https://www.bbc.co.uk/news/world-africa-46077299
 
Description Obi nha historia - A photo dialogue from frontline community health workers in Guinea Bissau 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact The overall aim of this public engagement activity is to give the ASCs (community health workers) a greater voice to share their experiences and ideas around mass drug administration campaigns (MDA), to document their journey distributing MDA for MATAMAL and to provide the opportunity for them to act as ambassadors for malaria control within their communities.

Activities and Outputs:
Twelve ASCs from three different islands will use PhotoVoice - a qualitative participatory research method involving photography to document activities, objects and people associated with key themes of interest - to capture their daily experiences during MDA delivery.

Prior to the final MDA round in 2021, the ASCs attended a one-day training composed of two workshops. The first workshop will cover research ethics (consent, voluntary participation, etc.), the purpose and use of the PhotoVoice method. International and local ethical approvals for use of PhotoVoice as part of the MATAMAL trial are already in place. The second workshop covered use of cameras, photography composition, and storytelling and narrative development. The ASCs took photos to document their experiences during the final MDA round in 2021.

The photos taken were developed and will be returned to the photographers during a series of three Focus Group Discussions (one per island) where the events prompting the taking of specific images will be discussed. The ASCs will be asked to develop verbal and/or written narratives to accompany 5 to 10 photographs of their choice highlighting successes and challenges of the MDA implementation.

Dissemination of findings will be organized after the final MDA delivery in two formats:
• A one-day community dissemination event will be organised on Bubaque to provide ASCs with the opportunity to share their photos and narratives with selected peers, community members and leaders, and the regional health authorities. The event will be kicked-off by the PhotoVoice participants and a presentation of key findings. Group discussions on emerging topics will be facilitated at different tables to generate ideas on mitigation strategies and suggestions to improve the different MDA processes. The workshop will end with a 'harvesting' session to synthetize findings for the group and to provide recommendations and learnings for the 2022 MATAMAL MDA and other programmatic campaigns.
• A road-show aboard the MATAMAL 'Codewa' ('Healing') pirogue (local sea transport canoe) will be visiting the PhotoVoice participants' islands to engage with other local ASCs, community members, leaders and nurses. A small exhibition of selected photos and narratives will be installed at the health centre. Following a similar format as the dissemination event, emerging topics around MDA will be presented and discussed with the community and their representatives to generate ideas and recommendations to improve subsequent MDA campaigns. The roadshow will provide PhotoVoice participants with the opportunity to engage with their own communities around MDA experiences and processes using additional communication channels of their choice (music, dance, poetry, etc.).

A short illustrated report will be compiled based on the main learnings from the dissemination event to be widely shared with all ASCs on the Archipelago, local (nurses), regional (Dr. Jose Nakutum) and national (INEP, MINSAP, INASA) decision-makers and the wider scientific community.
Year(s) Of Engagement Activity 2022
 
Description Poster Presentation - Evaluating the entomological effects of adjunctive ivermectin mass drug administration for malaria control in the Bijagos archipelago, Guinea-Bissau: A cluster-randomised trial (MATAMAL) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The Global Strategic Framework for Integrated Vector Management, set out by the World Health Organization (WHO), advocates the use of a range of interventions, used collaboratively and synergistically, to help control the transmission of vector-borne diseases. Ivermectin (IVM) has the capacity to not only be integrated into existing control measures for malaria but also into existing control measures for other vector-borne diseases, leading to more cohesion between programmes. Ivermectin could work alongside indoor residual spraying and long-lasting insecticidal net (LLIN) distribution programmes in seasonal malaria transmission areas. Our trial will be the first to investigate the impact of adding IVM to a MDA with an efficacious antimalarial (Dihydroartemisinin-Piperaquine (DP)) to reduce malaria transmission in a seasonal low-transmission setting. The Bijagos archipelago is situated off the coast of Guinea-Bissau. These islands will be the site for the cluster-randomised trial of adjunctive IVM mass drug administration (MDA). The islands will be randomly assigned to either the DP-only or DP+IVM arm (10 clusters per arm). The intervention will be implemented for two years consecutively. To investigate the effect of IVM on the mosquito population we will assess the age or parity of the mosquitoes. Collecting from indoor CDC light traps and dissecting in our field laboratory. In collaboration with the MRC the Gambia at LSHTM, we will also monitor the mosquito populations' species composition, density, susceptibility to IVM and insecticide resistance during the trial. Multivariate random effects logistic regression or generalised estimating equation modelling (adjusting for the effects of clustering) will be used to analyse the parity of the mosquito populations. Linear regression models will be used to analyse continuous outcomes (with transformation as appropriate to approximate to the normal distribution) such as mosquito density. Potential confounding factors such as LLIN coverage and use, access to health care facilities and equity bias will be included in our data collection and used to adjust the analysis. This sparked discussion and debate in the session and subsequently during the conference.
Year(s) Of Engagement Activity 2020
URL https://www.abstractsonline.com/pp8/#!/9181/presentation/3202