Intermittent screening and treatment or intermittent preventive therapy for control of malaria in pregnancy in Indonesia

Lead Research Organisation: Liverpool School of Tropical Medicine
Department Name: UNLISTED

Abstract

FIGHTING MALARIA IN PREGNANCY IN INDONESIA
The control of malaria in pregnancy in Indonesia, where approximately 10% of pregnant women get infected with malaria, could receive a potential boost through a new study conducted by the Eijkman Institute for Molecular Biology and the Timika Research Facility in Indonesia. Together with experts from the Liverpool School of Tropical Medicine in the UK, they are going to test two new methods of preventing malaria and the harmful effects in pregnancy.

When pregnant women contract malaria this can have devastating consequences for pregnancy, resulting in fever which may trigger preterm onset of labour or even pregnancy loss. It is also possible for women to be infected without showing any outward signs or symptoms, yet if these infections are undetected and left untreated, they can cause anaemia in the mother and can interfere with the growth of the fetus leading to low birth weight, which increases the risk of babies dying during infancy.

The new project will provide malaria testing to women with or without the symptoms of malaria on every scheduled antenatal visit using a rapid diagnostic test (RDT). The RDT is simple to perform, uses a single drop of blood and gives results within 15 minutes. Those women testing positive will be treated with an artemisinin combination drug called dihydroartemisinin-piperaquine (DHP), which is the treatment of choice in the 2nd and 3rd trimester of pregnancy in Indonesia. A second method called intermittent preventive treatment, which is used in most countries in Africa but not yet in Asia, will also be tested. With this method women without symptoms of malaria will be selected to receive the same drug but without prior blood testing.

Both methods will be compared with the existing policy in Indonesia, where all pregnant women are tested for malaria on the first antenatal visit only, and those with a positive result are treated with DHP. During subsequent antenatal visits, women are only tested if they have symptoms of malaria such as fever. This means that some infections will go undetected. It is anticipated that the two new methods will either detect infections much earlier than the current approach, or prevent them altogether.

The findings of this study, together with an assessment of feasibility and cost effectiveness of each method, will be used to inform malaria prevention policy for pregnant women in Indonesia and other parts of South East Asia.

Technical Summary

BACKGROUND:
Malaria in Pregnancy (MiP) can have devastating consequences to mother and newborn, yet the harmful effects are entirely preventable. Annually, 70% of 125.2 million pregnancies in malaria endemic regions occur in the Asia-Pacific region, and cost-effective prevention strategies are urgently needed in this region which has predominantly low-intensity falciparum and vivax transmission. Indonesia is the first country in Asia to introduce systematic screening at first antenatal visit (Single Screening and Treatment: SSTp). SSTp may not detect subsequent infections. A proposed extension is intermittent screening and treatment (ISTp) consisting of repeated screening with rapid diagnostic tests (RDTs) as part of focused antenatal care and treating the RDT positive women with long-acting drugs that also provides several weeks of post-treatment prophylaxis. Screening strategies however may miss low density PCR-positive infections, not detectable by RDT or microscopy. Recently completed surveys in Asia have shown an unexpectedly high prevalence of these infections in asymptomatic pregnant women. Under these circumstances, intermittent preventive therapy (IPTp) is another approach, not yet evaluated in Asia though widely used in sub-Saharan Africa.

OBJECTIVES AND METHODS:
Open-label three-arm parallel-group multicentre cluster-randomised controlled superiority trial conducted in two rural sites in Eastern Indonesia comparing the efficacy, safety and cost-effectiveness of IPTp and ISTp with the current SSTp strategy. Dihydroartemisinin-piperaquine will be used in all three arms. The study is designed to detect 50% reduction in malaria infection at birth from 10% to 5%; Unit of randomization: antenatal clinics. Sample size: 23 clusters of 41 women per arm (N=3198) (Power 90%, alpha 0.025, ICC 0.002, allowing for 20% loss-to-follow-up and 13% efficiency loss due to varying cluster sizes). Secondary endpoints include clinical malaria, maternal anaemia, preterm birth, low birthweight and safety endpoints. Enrolled women of all parities in the 2nd trimester make 3 or 4 scheduled ANC visits 6-8 weeks apart. Infant follow-up is 42 days. Sub-studies of the cost-effectiveness, acceptability/feasibility studies will be conducted alongside the main clinical trial.

PARTNERS AND PRODUCT:
The project builds on an existing MiP research collaborations between the Liverpool School of Tropical Medicine (trial sponsor), the Eijkman Institute in Jakarta (coordinating Institute) and between the Timika Research Facility in Indonesia, and the Menzies School of Health Research, Australia and is designed to inform national, regional and global policy. It is designed in close collaboration with the policy makers and main implementers in Indonesia, notably the MoH, WHO and UNICEF-Indonesia.

The project will take 3.5 years.

Publications

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Title STOPMIP study logo 
Description An abstract art STOPMIP logo was created which represented a pregnant woman, the drug dihydroartemisinin-piperaquine used for malaria preventive treatment and a RDT for intermittent screening test. The logo contributed to creating STOPMIP branding . 
Type Of Art Image 
Year Produced 2013 
Impact The STOPMIP logo was used in similar trials conducted in Africa. 
 
Description APMEN Meeting 10 October 2017.
Geographic Reach Asia 
Policy Influence Type Participation in a advisory committee
Impact APMEN MIP 10 October 2017, Bali, Indonesia Summary: As a direct result of this STOPMIP study, Indonesia is now going to pilot the implementation of IPTp with DHA-piperaquine in one moderate transmission district in Papua Indonesia in 2018 with an API of >100. If this is successful the Indonesian Government plans to expand this to other similar transmission districts in Papua with an API >100. Five such districts exist in Indonesia, with a population of about 500,000. The Indonesian malaria control program agreed that there might be challenges with acceptance by women of giving antimalarials without prior testing. In Indonesian Papua, there are difficulties with access as well. It was agreed that roll out would be easier if linked with the country's ANC schedule, rather than monthly dosing, so a consideration was to link it with 'every scheduled visit', similar to WHO's current recommendations for IPTp with SP in Africa. Brief meeting overview: On 10-12 Oct 2017, approximately 110 representatives from 18 malaria endemic countries including malaria researchers in the Asia-Pacific region and elsewhere came together for a 2.5-day meeting in Bali, Indonesia as part of the Asia-Pacific Malaria Elimination Network (APMEN). One full day was dedicated to malaria in pregnancy (MiP) to discuss the results of recent prevention studies that were completed in the region with potentially policy relevant findings. Results were presented of 3 prevention trials conducted India, Papua New Guinea and Indonesia. The latter included the STOPMIP Indonesia trial funded by the JGHT MRC/DFID/WT. These were the first trials assessing the safety and efficacy of new approaches to controlling malaria in pregnancy using single screen and treat strategies (SST), monthly intermittent screening and treatment (IST) and monthly intermittent preventive therapy (IPTp) in this region. STOPMIP Indonesia: The results of this large 3-arm cluster randomised trial conducted in two sites (SW Sumba and Papua) in Indonesia were presented by Dr Rukhsana Ahmed and Dr Jeanne Rini Poespoprodjo. The session was chaired by Prof ter Kuile. The study compared the current policy in Indonesia consisting of single screening and treatment (SST) at antenatal booking (enrolment) with IST and IPTp. All arms used DHA-piperaquine. The study found that IST did not detect more infections than SST, but IPTp resulted in marked reduction in the incidence of malaria during pregnancy and a halving of the risk of placental malaria, but only in Papua, the site with moderate malaria transmission, and not in Sumba, which had low malaria transmission. In the discussion break-out sessions that followed there was one group that mapped the current strategies for malaria prevention in pregnancy in the region. Countries included Indonesia, Laos, Malaysia, PNG, Vanuatu and Solomon Islands. Long Lasting Insecticide Nets (LLINs) distribution has been the main focus of malaria prevention programs in pregnancy in all countries represented in the group. IPT is policy in a single country, Papua New Guinea, and uses SP. In Vanuatu and Solomon Islands, weekly chloroquine is given to pregnant women. Indonesia's National Policy includes single screening and treatment for pregnant women in low to moderate malaria endemic area. Malaysia is screening all pregnant women at risk on their first ANC visit and after delivery (those with vivax malaria) will be given primaquine for radical cure following G6PD testing. Migrants in Malaysia and Laos are also screened at first ANC visit and treated according to the National Guidelines. Importantly, there were also discussions about whether SST, IST and IPTp should be considered for policy and in which areas. Most countries in this region were already applying single screen and treat strategies (i.e. the control arm in the Indonesia trial). The suggestion was to use SST in areas where the malaria transmission is above an API (the most commonly available measure for malaria transmission intensity in low transmission areas) of 1 in India (suggested by India) or 5 in other countries. As a direct result of this STOPMIP study, Indonesia is now going to pilot the implementation of IPTp with DHA-piperaquine in one moderate transmission district in Papua Indonesia in 2018 with an API of >100. If this is successful the Indonesian Government plans to expand this to other similar transmission districts in Papua with an API >100. Five such districts exist in Indonesia, with a population of about 500,000. The Indonesian malaria control program agreed that there might be challenges with acceptance by women of giving antimalarials without prior testing. In Indonesian Papua, there are difficulties with access as well. It was agreed that roll out would be easier if linked with the country's ANC schedule, rather than monthly dosing, so a consideration was to link it with 'every scheduled visit', similar to WHO's current recommendations for IPTp with SP in Africa.
URL http://apmen.org/events/annual-meeting/67/vivax-working-group-annual-meeting-2017.html
 
Description Attendance at APMEN meeting to disseminate STOPMIP rfindings
Geographic Reach Asia 
Policy Influence Type Participation in a advisory committee
 
Description Malaria in pregnancy first trimester treatment policy in Indonesia
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Gave evidence to a government review
 
Description Ministry of Health, Malaria sub-directorate meeting 11 August 2017-co-PI attended to present STOPMIP findings
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description Newborn examination
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description RBM-MiP WG 18-20 September 2017, Geneva, Participated to disseminate STOPMIP findings
Geographic Reach Asia 
Policy Influence Type Participation in a advisory committee
 
Description WHO-MiP ERG meeting in 12-14 July 2017, Geneva, Switzerland
Geographic Reach Asia 
Policy Influence Type Membership of a guideline committee
 
Description WHO-MiP ERG meeting in July 2017
Geographic Reach Asia 
Policy Influence Type Membership of a guideline committee
 
Description Pharmacovigilence and drug safety
Amount € 432,867 (EUR)
Funding ID PO17/00456 
Organisation Medicines for Malaria Venture (MMV) 
Sector Charity/Non Profit
Country Switzerland
Start 09/2017 
End 06/2019
 
Description UNICEF awards
Amount $99,999 (USD)
Funding ID #43144958 
Organisation UNICEF 
Sector Public
Country Global
Start 08/2013 
End 07/2015
 
Title Data Management Plan 
Description A detailed Data Management Plan was developed including the use of Teleform for data entry. 
Type Of Material Biological samples 
Provided To Others? No  
Impact This has contributed to the capacity development of Data Managers and Data Assistants of the collaborating institute 
 
Title Malaria risk map 
Description Baseline data on malaria risk and clinic size are required for matched randomization in the main trial. Retrospective Health systems data from 2010 and 2011 on clinic visits due to clinical malaria in the general population (all ages, all genders) were collected from all potential village clusters in Timika and South West-Sumba. In addition annual malaria surveillance data was obtained from the District Health Offices at the two sites. Complete data was available on the monthly incidence rate of smear confirmed clinical malaria using census data as the denominator. A malaria risk map was produced for each of the two study sites, with the support of Dr Iqbal Elyazar from the Eijkman Institute who works closely with the Malaria Atlas Project (MAP). As anticipated, the data shows marked heterogeneity in malaria risk and stresses the potential value of matching cluster for randomization. Baseline data on the risk of asymptomatic malaria in pregnant women obtained from the existing ANC screening program (Single screening and treatment [SSTp]) was also available, but not from all clusters. Since the risk is strongly correlated with the risk of clinical malaria in the population, the latter will be used for matching. 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact Impact: The risk maps were provided to the District Health Offices in the two study sites, SW Sumba and Timika which shows the distribution of malaria at village level and helps the decision process of DHO on malaria control activities. 
 
Title Open Source Reporting Service (OSRS) 
Description The OSRS is a web based data reporting dashboard developed by the STOPMiP data managers. The data viewed on the dashboard include recruitment information, performance and management of laboratory data and study data. Each chart generated can be saved in an image or .pdf format for further reporting needs. This current dashboard is developed specifically for the clinical trial STOPMIP. 
Type Of Material Data handling & control 
Year Produced 2016 
Provided To Others? Yes  
Impact Although the OSRS is developed for the STOPMIP, considering that the need for visibility of study data and data management performance are increasing as the data driven decisions increase, this system could be applied to other studies in the future. 
 
Description First Trimester DHP exposure in pregnancy ( pharmacovigilence and drug safety study) 
Organisation Medicines for Malaria Venture (MMV)
Country Switzerland 
Sector Charity/Non Profit 
PI Contribution Assessing the safety and pregnancy outcome of women exposed to DHP in early pregnancy which will have major policy implications in first trimester treatment of malaria
Collaborator Contribution Provides assistance in executing the study and financial support.
Impact None yet.
Start Year 2017
 
Description High-Sensitivity RDT study-FIND 
Organisation Foundation for Innovative New Diagnostics (FIND)
Country Switzerland 
Sector Charity/Non Profit 
PI Contribution We have received a new grant from FIND to evaluate the performance of high sensitivity RDT for detection of malaria during pregnancy in low-moderate transmission settings. This grant is a direct result of capacity and infrastructure developed during the STOPMiP trial on the grant awarded by JGHT/MRC/DFID/WT. The field work will be done in Papua Indonesia and LSTM staff together with collaborators at the Eijkman Institute, Jakarta will be involved in conducting the study.
Collaborator Contribution FIND had contributed in kind Loop Mediated Isothermal Amplification ( LAMP) kits for molecular analysis blood samples in STOPMIP trial. The new HS-RDT study is result of this initial partnership and capacity and infrastructure development during STOPMIP. The data collected in this study will enable the design of a large prospective study to evaluate different HS-RDT implementation strategies during antenatal care.
Impact none yet.
Start Year 2016
 
Description LAMP study for screening malaria in pregnancy 
Organisation Foundation for Innovative New Diagnostics (FIND)
Country Switzerland 
Sector Charity/Non Profit 
PI Contribution Samples collected during STOPMIP study were tested with LAMP, a new molecular diagnostic for assessing the performance of LAMP in pregnant women and are being used. The performance is compared against PCR, the current (but more labour intensive) standard.
Collaborator Contribution the LAMP kits and technical expertise to build local capacity in Indonesia were provided by FIND
Impact the collaboration contributed to molecular testing of STOPMIP samples. A manuscript is being drafted based on these outcomes, showing that LAMP can be a use friendly alternative to PCR.
Start Year 2014
 
Description Pharmacokinetic study, Mahidol University, Thailand 
Organisation Wellcome Trust
Department Mahidol University-Oxford Tropical Medicine Research Programme
Country Thailand 
Sector Academic/University 
PI Contribution We expanded the partnership between our collaborating institute in Indonesia and Mahidol-Oxford Research Unit ( MORU). The data generated will be shared with MORU, and would be used in PhD studentship thesis development. As result we have contributed towards capacity strengthening of this partnership and our collaborating institute in Indonesia.
Collaborator Contribution Our collaborating Institute in Indonesia does not have the capacity or expertise to do the pharamcokinetic analysis on blood samples collected in the STOPMIP study. MORU performed the analysis of these samples and at the same time gave an opportunity for the Research Assistant in our collaborating institute in Indonesia to visit and have a short training. This contributed to capacity development of our collaborating institute in Indonesia. In addition the data will be used to generate reports and manuscript for publication to disseminated results.
Impact Not yet.
Start Year 2016
 
Description SSA-UNICEF: RDT comparison study 
Organisation UNICEF
Department UNICEF Indonesia
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Before the main STOPMiP trial could start, the optimal rapid diagnostic tests (RDT) needed to be identified. We therefore conducted a comparative study to evaluate four different HRP2,- and pLDH-based combination RDTs involving 950 women attending antenatal clinics and 200 deliveries in Sumba (one of the two study sites for the main trial) in 2012. Two of the four RDTs ( SDBioline and Parascreen) are currently used in Indonesia, and the other two are the two top performing RDTs in the latest FIND-TDR-WHO report (Carestart and FirstResponse). PCR was conducted on all samples and analysis is currently ongoing.
Collaborator Contribution UNICEF has provided financial support and facilitates collaboration activities required through Ministry of Health, Jakarta for the conduct of STOPMiP trial.
Impact The result of this work will help in selecting the best performing RDT out of the four RDTs evaluted which will benefit the current national malaria control programme and the STOPMIP trial. If test accuracy (using composite measures of sensitivity and specificity) does not differentiate the RDTs (there is no pre-set cut-off), then other factors such as cost, ease of use, and familiarity in the Indonesian context will be taken into account. Publication: doi: 10.1186/s12936-015-0943-5
Start Year 2011
 
Description UNICEF Indonesia-MiP Study 
Organisation UNICEF
Department UNICEF Indonesia
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Evaluated four different malaria Rapid Diagnostic Tests (RDTs), two of which are already being used in Malaria in pregnancy programmes in Indonesia and two RDTs that were rated high in the WHO-FIND testing. The work enabled us to select an RDT that had high sensitivity and was user friendly for our trial.
Collaborator Contribution Financial contribution and salary support for the study co-ordinator
Impact The collaboration enabled us to do baseline data collection and helped us select the RDT to use for malaria screening in the trial.
Start Year 2013
 
Description University of Melbourne and Menzies School of Health Research, Darwin, Australia; drug safety in early pregnancy 
Organisation Menzies School of Health Research
Country Australia 
Sector Academic/University 
PI Contribution We have received an new award from MMV (Medicine for Malaria Venture) to look at drug safety in early pregnancy in Indonesia. The award is a direct result of the infrastructure and capacity development that was build with the support received through the original grant from JGHT MRC/DFID/WT funding (Intermittent screening and treatment or intermittent preventive therapy for control of malaria in pregnancy in Indonesia). The new study involves field work in Indonesia that will be conducted by LSTM in partnership with our collaborators in Indoneisa. The data will be shared with the collaborator in Melbourne for analysis
Collaborator Contribution This group in Melbourne has specific expertise in this type of specialised data analyses that involves statistical methods that would take up several months to develop de novo. This is part of a new grant that we received from MMV (Medicine for Malaria Venture) to look at the drug dihydroartemisinin-piperaquine safety in early pregnancy in Indonesia. The award is a direct results of the infrastructure that was build with the support received through the original grant from JGHT MRC/DFID/WT funding (Intermittent screening and treatment or intermittent preventive therapy for control of malaria in pregnancy in Indonesia).
Impact not yet
Start Year 2017
 
Description University of Melbourne and Menzies School of Health Research, Darwin, Australia; drug safety in early pregnancy 
Organisation University of Melbourne
Department School of Psychological Sciences
Country Australia 
Sector Academic/University 
PI Contribution We have received an new award from MMV (Medicine for Malaria Venture) to look at drug safety in early pregnancy in Indonesia. The award is a direct result of the infrastructure and capacity development that was build with the support received through the original grant from JGHT MRC/DFID/WT funding (Intermittent screening and treatment or intermittent preventive therapy for control of malaria in pregnancy in Indonesia). The new study involves field work in Indonesia that will be conducted by LSTM in partnership with our collaborators in Indoneisa. The data will be shared with the collaborator in Melbourne for analysis
Collaborator Contribution This group in Melbourne has specific expertise in this type of specialised data analyses that involves statistical methods that would take up several months to develop de novo. This is part of a new grant that we received from MMV (Medicine for Malaria Venture) to look at the drug dihydroartemisinin-piperaquine safety in early pregnancy in Indonesia. The award is a direct results of the infrastructure that was build with the support received through the original grant from JGHT MRC/DFID/WT funding (Intermittent screening and treatment or intermittent preventive therapy for control of malaria in pregnancy in Indonesia).
Impact not yet
Start Year 2017
 
Title DHP for IPTp 
Description Dihydroartemisinin-piperaquine (DHP), the drug combination that will be used in this trial, is part of artemisinin containing combination therapies (ACTs). ACTs are now the standard for treatment of P.falciparum malaria in non-pregnant individuals and in the 2nd and 3rd trimester of pregnancy, including in Indonesia, where DHP is now first line treatment in the second and third trimesters of pregnancy in malaria endemic areas. Globally, there is now considerable experience with artemisinin derivatives in the 2nd and 3rd trimesters of pregnancy. A systematic review of the efficacy and safety of ACTs for the treatment of malaria in non-pregnant adults and children conducted to inform the 2nd edition of the malaria treatment guidelines by WHO, showed that DHP is very effective and provides long durations of post-treatment prophylaxis similar to mefloquine and longer durations than amodiaquine (AQ-artesunate, or AQ-SP), artemether-lumefantrine (Coartem®) based antimalarial combinations. A GMP formulation of DHP has recently become available as Eurartesim, manufactured by Sigma-Tau, Italy and approved in October 2011 by the European Medicine Agency (EMEA) for treatment of malaria 
Type Management of Diseases and Conditions
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2011
Development Status Actively seeking support
Impact The primary purpose of the trial is to inform policy makers on selecting suitable interventions for the prevention of malaria at national, regional and global levels. Indonesia has extensive experience with DHP, and is the first country to have made DHP the treatment of choice in the 2nd and 3rd trimesters of pregnancy. Indonesia is also the first country to introduce screening as the national MiP policy as part of antenatal care. In these settings ISTp with DHP is therefore a logical extension of the existing SSTp strategy. Because the large Island nation of Indonesia has one of the most diverse malaria epidemiology globally, a one-size-fits-all policy (as currently recommended for Africa), will not be appropriate for Indonesia. Information on both new interventions (ISTp and IPTp) is therefore needed; e.g. IPTp may be considered in the low-medium transmission intensity regions, such as parts of Papua, whereas ISTp may be the better option in lower transmission areas and SSTp in areas with the lowest transmission. Indonesia has been a regional pioneer with the development of its current SSTp strategy to control MiP and thus the data of this proposed trial would have relevance to other Asian countries in deciding on MiP control programmes. This study, together with two other ongoing prevention trials in India and Papua New Guinea (PNG), will potentially have important policy implications for most malaria endemic countries in Asia and possibly Latin America. 
 
Description IPT or IST with dihydroartemisinin-piperaquine for malaria in pregnancy in Indonesia: an open label cluster randomised controlled trial; Rukhsana Ahmed 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Dr R Ahmed presented the findings of the study to an audience of researchers, policy makers and industry at the First World Malaria Congress held in Melbourne, Australia 1-4 July 2018, There were discussions around which of the strategies ( IST or IPT) was more suitable for Asia region for the control of malaria in pregnancy.
Year(s) Of Engagement Activity 2018