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HS#2017-3512, Adaptive Interventions for Optimizing Malaria Control: A Cluster-Randomized SMART Trial

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ClinicalTrials.gov Identifier: NCT04182126
Recruitment Status : Recruiting
First Posted : December 2, 2019
Last Update Posted : July 1, 2021
Sponsor:
Information provided by (Responsible Party):
University of California, Irvine

Brief Summary:
In the past decade, massive scale-up of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) have led to significant reductions in malaria mortality and morbidity. Nonetheless, malaria burden remains high, and a dozen countries in Africa show a trend of increasing malaria incidence over the past several years. The high malaria burden in many areas of Africa underscores the need to improve the effectiveness of intervention tools by optimizing first-line intervention tools and integrating newly approved products into control programs. Vector control is an important component of the national malaria control strategy in Africa. Because transmission settings and vector ecologies vary among countries or among districts within a country, interventions that work in one setting may not work well in all settings. Malaria interventions should be adapted and re-adapted over time in response to evolving malaria risks and changing vector ecology and behavior. The central objective of this application is to design optimal adaptive combinations of vector control interventions to maximize reductions in malaria burden based on local malaria transmission risks, changing vector ecology, and available mix of interventions approved by the Ministry of Health in each target country. The central hypothesis is that an adaptive approach based on local malaria risk and changing vector ecology will lead to significant reductions in malaria incidence and transmission risk. The aim of this study is to use a cluster-randomized sequential, multiple assignment randomized trial (SMART) design to compare various vector control methods implemented by the Ministry of Health of Kenya in reducing malaria incidence and infection, and develop an optimal intervention strategy tailored toward to local epidemiological and vector conditions.

Condition or disease Intervention/treatment Phase
LLIN, PBO LLIN, IRS, Larviciding Other: Regular long-lasting insecticidal nets Other: LLIN plus Piperonyl butoxide-treated LLIN Other: Long-lasting microbial larvicide Other: Indoor residual spraying with micro-encapsulated pirimiphos-methyl Not Applicable

Detailed Description:

In the past decade, massive scale-up of long-lasting insecticide-treated nets (LLINs) and indoor residual spraying (IRS) in Africa have led to significant reductions in malaria mortality and mobility. However, current first-line interventions are not sufficient to eliminate malaria in most countries. The widespread use of pyrethroid insecticides has resulted in resistant vector populations, and high coverage of LLINs and IRS has led to increased outdoor human feeding behavior and resting behavior. These changes in vector ecology and behaviors have significantly limited the effectiveness of current first-line interventions that target indoor biting and resting mosquitoes. Furthermore, as a result of ecological changes and intervention measures, malaria risk in a locality is dynamic, and the utility of malaria intervention tools may vary as new tools are being approved and introduced and the cost of each tool differs among locations and over time. Such variations in malaria risk, vector ecology, and utility of intervention tools exemplify the need to develop optimal adaptive interventions tailored to local malaria risks, vector ecology and supply chains. The central objective of this application is to design optimal adaptive combinations of vector control interventions to maximize reductions in malaria burden based on local malaria transmission risks, changing vector ecology, and available mix of interventions approved by the Ministry of Health in each target country. The central hypothesis is that an adaptive approach based on local malaria risk and changing vector ecology will lead to significant reductions in malaria incidence and transmission risk. To accomplish this objective, we propose the following three specific aims:

  1. Measure malaria incidence and predict risk using environmental, biological, social, and climatic features with machine learning approaches. Hypothesis: Malaria risk prediction can be improved through the use of machine learning techniques that include environmental, biological, socio-economic, and climatic features. Approach: Each site will measure malaria incidence, prevalence and social economic factors through community surveys. Classification-based and regression-based approaches will be used to develop malaria risk predictive models, and model performance will be validated. Outcome: This Aim will establish improved malaria risk prediction models and lay an important foundation for developing intervention strategies adaptive to local vector ecology and future malaria risks using reinforced machine learning approaches.
  2. Use a cluster-randomized sequential, multiple assignment randomized trial (SMART) design to develop an optimal adaptive intervention strategy. Hypothesis: Malaria control interventions that are adapted to local malaria risk and vector ecology and are cost effective can be identified using a cluster-randomized SMART design. Approach: Cluster-randomized SMART design will be used in a high transmission areas in Kenya to evaluate the impact of adaptive interventions that involve sequential and combinational use of next-generation nets, indoor spraying of non-pyrethroid insecticides, and larval source management for malaria control.
  3. Evaluate the cost-effectiveness and impact of an adaptive intervention approach on secondary endpoints related to malaria risk and transmission. Hypothesis: Intervention strategies adapted to local malaria risk and vector ecology will be more cost-effective in reducing malaria incidence and transmission risk than the currently-used LLIN intervention. Approach: The economic costs of individual interventions or combinations thereof will be assessed from both a provider and societal perspective using standard economic evaluation methodologies. Cost-effectiveness will be measured in terms of cost per person protected. The study will examine changes in drug and insecticide resistance and infection prevalence attributable to the adaptive interventions.

Malaria interventions adapted to rapidly changing malaria risk and vector ecologies are critically needed to improve the effectiveness of malaria control measures. This study will use new techniques, including machine learning and a novel cluster-randomized SMART design, to develop optimal adaptive malaria intervention strategies.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 122872 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: This study will use a longitudinal sequential multiple assignment randomized trial design. It will include multiple stages, at each stage, clusters are assigned to different arms (interventions) using an adaptive strategy. Therefore, number of arms vary from stage to stage.
Masking: Triple (Care Provider, Investigator, Outcomes Assessor)
Masking Description: This study partially masking participants, because by design some participants will receive PBO treated long-lasting insecticidal nets (LLINs) and others will not receive such bed nets, therefore, those who receives the PBO LLINs can not be masked.
Primary Purpose: Prevention
Official Title: Environmental Modifications in Sub-Saharan Africa: Changing Epidemiology, Transmission and Pathogenesis of Plasmodium Falciparum and P. Vivax Malaria
Actual Study Start Date : December 1, 2019
Estimated Primary Completion Date : March 31, 2024
Estimated Study Completion Date : March 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Placebo Comparator: Regular long-lasting insecticidal nets
All participants will have LLIN coverage through routine MoH distribution of long-lasting insecticidal nets (LLINs), no other interventions will be applied. Regular LLIN: Olyset nets containing 2% permethrin or PermaNet 2.0 containing 1.8 and 1.4 g/kg, respectively, for 75 and 100 denier yarn.
Other: Regular long-lasting insecticidal nets
Olyset nets: containing 2% permethrin or PermaNet 2.0 containing 1.8 and 1.4 g/kg, respectively, for 75 and 100 denier yarn
Other Name: LLIN

Experimental: Piperonyl butoxide-treated LLIN

All participants will received piperonyl butoxide-treated LLINs (PBO-LLINs) at Stage 1 and Stage 2 interventions provided that PBO-LLINs are effective at Stage 1 interventions. Each household will be provided on PBO-LLIN per two people with appropriate eduction.

PBO-LLIN: Olyset Plus, containing 2% permethrin and 1% PBO.

Other: LLIN plus Piperonyl butoxide-treated LLIN
Olyset Plus: containing 2% permethrin and 1% PBO
Other Name: PBO-LLIN

Experimental: PBO-LLIN plus larval source management
All participants will received piperonyl butoxide-treated LLINs (PBO-LLINs) at Stage 1, however, Stage 1 intervention is not effective. All participants will received PBO-LLINs plus larval source management (LSM) at Stage 2. LSM will be implemented in selected clusters, including both physical and chemical methods by physical filling or removal of temporary larval habitats and larviciding of semi-permanent and permanent habitats, per the National Malaria Strategic Plan of Kenya. We will use the long-lasting microbial larvicides manufactured by Central Life Sciences. Semi-permanent and permanent habitats will be treated with FourStar® 180-day Briquets using the recommended dosage of 100 ft2 water surface per briquet.
Other: LLIN plus Piperonyl butoxide-treated LLIN
Olyset Plus: containing 2% permethrin and 1% PBO
Other Name: PBO-LLIN

Other: Long-lasting microbial larvicide
Semi-permanent and permanent habitats will be treated with FourStar® 180-day Briquets using the recommended dosage of 100 ft2 water surface per briquet
Other Name: FourStar® 180-day Briquets

Experimental: PBO-LLIN plus enhanced methods
All participants will received piperonyl butoxide-treated LLINs (PBO-LLINs) at Stage 1, however, Stage 1 intervention is not effective. All participants will received PBO-LLINs plus an enhanced intervention at Stage 2. The enhanced intervention is determined by machine learning method.
Other: LLIN plus Piperonyl butoxide-treated LLIN
Olyset Plus: containing 2% permethrin and 1% PBO
Other Name: PBO-LLIN

Experimental: LLIN plus indoor residual spraying
All participants will received regular LLINs plus indoor residual spraying (IRS) (LLIN+IRS) at Stage 1 and Stage 2 interventions provided that LLIN+IRS is effective at Stage 1 interventions. For LLIN+IRS clusters, each dwelling's interior walls and ceilings will be sprayed with micro-encapsulated pirimiphos-methyl (Actellic 300CS) at the recommended dosage of 1g/m² and at the recommended frequency of once a year.
Other: Regular long-lasting insecticidal nets
Olyset nets: containing 2% permethrin or PermaNet 2.0 containing 1.8 and 1.4 g/kg, respectively, for 75 and 100 denier yarn
Other Name: LLIN

Other: Indoor residual spraying with micro-encapsulated pirimiphos-methyl
each dwelling's interior walls and ceilings will be sprayed with micro-encapsulated pirimiphos-methyl at the recommended dosage of 1g/m² and at the recommended frequency of once a year
Other Name: Actellic 300CS

Experimental: LLIN+IRS+LSM
All participants will received regular LLINs plus IRS at Stage 1, provided that LLIN+IRS is not effective. LSM will be added on these clusters at Stage 2 interventions. LSM at Stage 2 will be the long-lasting microbial larvicides manufactured by Central Life Sciences. Semi-permanent and permanent habitats will be treated with FourStar® 180-day Briquets using the recommended dosage of 100 ft2 water surface per briquet.
Other: Regular long-lasting insecticidal nets
Olyset nets: containing 2% permethrin or PermaNet 2.0 containing 1.8 and 1.4 g/kg, respectively, for 75 and 100 denier yarn
Other Name: LLIN

Other: Long-lasting microbial larvicide
Semi-permanent and permanent habitats will be treated with FourStar® 180-day Briquets using the recommended dosage of 100 ft2 water surface per briquet
Other Name: FourStar® 180-day Briquets

Other: Indoor residual spraying with micro-encapsulated pirimiphos-methyl
each dwelling's interior walls and ceilings will be sprayed with micro-encapsulated pirimiphos-methyl at the recommended dosage of 1g/m² and at the recommended frequency of once a year
Other Name: Actellic 300CS

Experimental: LLIN+IRS plus enhanced method
All participants will received regular LLINs plus IRS at Stage 1, provided that LLIN+IRS is not effective. Enhanced method will be added on these clusters at Stage 2 interventions.The enhanced intervention is determined by machine learning method.
Other: Regular long-lasting insecticidal nets
Olyset nets: containing 2% permethrin or PermaNet 2.0 containing 1.8 and 1.4 g/kg, respectively, for 75 and 100 denier yarn
Other Name: LLIN

Other: Indoor residual spraying with micro-encapsulated pirimiphos-methyl
each dwelling's interior walls and ceilings will be sprayed with micro-encapsulated pirimiphos-methyl at the recommended dosage of 1g/m² and at the recommended frequency of once a year
Other Name: Actellic 300CS




Primary Outcome Measures :
  1. Annual clinical malaria incidence rate [ Time Frame: Clinical malaria will be monitored for up to 60 months ]
    To compare clinical malaria incidence rates among different intervention arms


Secondary Outcome Measures :
  1. Malaria infection prevalence [ Time Frame: Infection prevalence will be monitored for up to 60 months ]
    To compare infection prevalence rates among different intervention arms using microscopic, RDT and molecular diagnostic methods

  2. Malaria vector density [ Time Frame: Vector density will be monitored for up to 60 months ]
    To compare malaria vector densities between different intervention arms

  3. Malaria transmission intensity [ Time Frame: Entomological inoculation rate will be examined for up to 60 months ]
    To compare entomological inoculation rates between different intervention arms



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Household inclusion criteria:

  • Households with residents at the time of survey
  • Agreement of the adult resident to provide informed consent for the intervention and survey

Study subjects inclusion criteria:

  • Passive case detection by health facilities will include all residents in the study clusters; active case detection will include residents of >6 months
  • Agreement of parent/guardian to provide informed consent and minors to provide assent.

Household exclusion criteria:

  • Household vacant
  • No adult resident home on more than 3 occasions

Study subjects exclusion criteria:

• Participants not home on day of survey


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04182126


Contacts
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Contact: Guiyun Yan, Ph.D. 19498240175 guiyuny@uci.edu
Contact: Guiyun Yan 19498240175 guiyuny@uci.edu

Locations
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United States, California
Program in Public Health Active, not recruiting
Irvine, California, United States, 92697
Kenya
Tom-Mboya University College, Maseno University Recruiting
Homa Bay, Homa Bay County, Kenya
Contact: Harrysone E Atieli, Ph.D.    +254 721 347 437    etemesi2012@yahoo.com   
Contact: John Githure, Ph.D.       jgithure@gmail.com   
Sub-Investigator: Andrew K Githeko, Ph.D.         
Sub-Investigator: Gordon Okomo, Ph.D.         
Sponsors and Collaborators
University of California, Irvine
Investigators
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Principal Investigator: Guiyun Yan, Ph.D. University of California at Irvine
Study Director: John Githure, Ph.D. Tom-Mboya University, Kenya
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of California, Irvine
ClinicalTrials.gov Identifier: NCT04182126    
Other Study ID Numbers: U19AI129326-03S1 ( U.S. NIH Grant/Contract )
First Posted: December 2, 2019    Key Record Dates
Last Update Posted: July 1, 2021
Last Verified: June 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of California, Irvine:
Adaptive intervention
Multiple assignment randomized trial (SMART)
Cluster-randomized SMART trial
Optimal intervention strategy
Clinical malaria incidence
Cost-effectiveness
Additional relevant MeSH terms:
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Malaria
Protozoan Infections
Parasitic Diseases