Efficacy of Three Novel Bi-treated Long Lasting Insecticidal Nets

Efficacy of Three Different Bi-treated Long Lasting Insecticidal Nets and Deployment Strategy for Control of Malaria Transmitted by Pyrethroid Resistant Vectors: A Randomised Controlled Trial

The massive scale-up of Long Lasting Insecticidal Nets (LLIN) has led to a major reduction in malaria burden (up to 50%) in many sub-Saharan African countries. This progress is threatened by the wide scale selection of insecticide resistant malaria vectors. New types of LLIN combining a mixture of two insecticides or an insecticide and a synergist have been developed to control resistant mosquitoes.

The efficacy of three bi-treated LLIN are compared to a standard LLIN in a four-arm, single blinded, cluster-randomized trial in Misungwi district, Tanzania. The arms are; 1/ Royal Guard, a net combining pyriproxyfen (PPF), which is known to disrupt female reproduction and fertility of eggs, and the pyrethroid alpha-cypermethrin, 2/Interceptor G2, LLIN incorporating a mixture of two adulticides with different modes of action; chlorfenapyr and a pyrethroid (alpha-cypermethrin), and 3/ Olyset Plus an LLIN which incorporates a synergist, piperonyl butoxide (PBO), to enhance the potency of pyrethroid insecticides, and 4/ The control arm: Interceptor treated a standard LLIN treated with alpha-cypermethrin.

The primary outcome of the trial will be cross-sectional community prevalence of malaria infection (by RDT) in children aged 6 months to 14 years at 12 and 24 months post-intervention.

Study Overview

• Status: Completed
• Conditions: Malaria; Anaemia
• Intervention / Treatment: Other: pyriproxyfen LLIN; Other: Chlorfenapyr LLIN; Other: Piperonyl butoxide LLIN; Other: Standard LLIN

• Study Type: Interventional
• Enrollment (Actual): 4200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Tanzania
  • Mwanza
    • Misungwi, Mwanza, Tanzania
      • District Misungwi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 14 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• At least one child between 6 months to 14 years old having permanent residence in selected household
• Having an adult caregiver willing to provide written consent for the household and clinical survey

Exclusion Criteria:

• Dwelling not found or vacant during the survey
• No adult caregiver capable to give informed consent
• Children severely ill

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pyriproxyfen LLIN; Royal Guard® (Disease Control Technologies, LLC) is a Long Lasting Insecticidal Net made of polyethylene incorporating a mixture of 225 mg/m2 pyriproxyfen and 261mg/m2 alpha-cypermethrin. This LLIN will be distributed to all the households in 21 clusters on a 1 LLIN per two household residents basis.	Other: pyriproxyfen LLIN; Dual active ingredient Long Lasting Insecticidal Net
Experimental: Chlorfenapyr LLIN; Interceptor® G2 (BASF corporation) is a LLIN made of polyester coated with a wash-resistant formulation of 200 mg/m2 chlorfenapyr and 100 mg/m2 alpha-cypermethrin. This LLIN will be distributed to all the households in 21 clusters on a 1 LLIN per two household residents basis.	Other: Chlorfenapyr LLIN; Dual active ingredient Long Lasting Insecticidal Net
Experimental: Piperonyl butoxide LLIN; Olyset® Plus (Sumitomo Chemicals) is a LLIN combining Piperonyl butoxide (400mg/m2) and the repellent pyrethroid permethrin (800 mg/m2) incorporated into the polyethylene fibres. This LLIN will be distributed to all the households in 21 clusters on a 1 LLIN per two household residents basis.	Other: Piperonyl butoxide LLIN; Combination insecticide and synergist Long Lasting Insecticidal Net
Active Comparator: Standard LLIN; Interceptor® (BASF Corporation) is a single pyrethroid-treated LLIN with alpha-cypermethrin (coated onto filaments) at a target dose of 200 mg/m2 of polyester fabric. This LLIN will be distributed to all the households in 21 clusters on a 1 LLIN per two household residents basis.	Other: Standard LLIN; Standard Long Lasting Insecticidal Net with one insecticide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Malaria infection prevalence in children 6 months to 14 years	Malaria prevalence will be assessed using Malaria Rapid Diagnostic test (CareStart Malaria histidine-rich protein 2 (HRP2)/plasmodium lactate dehydrogenase (pLDH) Combo, DiaSys, UK)	24 months post intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of malaria cases in children 6 months to 10 years	Malaria incidence cases will be assessed using Malaria Rapid Diagnostic test (CareStart)	Two years post intervention follow up
Prevalence of anaemia in children under 5 years old	Hemoglobin (Hb) concentration will be tested to assess anaemia (<8 g/dL) using HemoCue Hb 201+.	12, 18, 24, 30, 36 months post intervention
Indoor Anopheles density	Anopheles density per house per night will be assess every quarter in 8 houses per cluster using light trap. Anopheles density and sporozoite rate will be used to estimate the entomological inoculation rate (EIR)	Three years post intervention follow up
Sporozoite rate	A sub-samples of Anopheles collected indoor will be tested for Plasmodium falciparum circumsporozoite protein using an ELISA test. Sporozoite rate will be used to estimate the EIR with Anopheles density.	Three years post intervention follow up
Insecticide content in Long Lasting Insecticidal Net (LLIN)	30 LLINs will be collected at yearly interval and Insecticide content in g/kg assessed with High-performance liquid chromatography (HPLC)	at 0, 12, 24, 30, 36 months post intervention
Mortality in Anopheles after one hour exposure to every study LLIN	30 LLINs will be sampled every 6 months and tested in cone bio assay or tunnel test using resistant Anopheles and susceptible Kisumu Anopheles to assess for bio efficacy. 24, 48 and 72 hours mortality post exposure will be recorded.	at 0, 6, 12, 18, 24, 30, 36 months post intervention
LLIN usage	The proportion of study participant declaring sleeping under a LLIN the previous night will be assessed during household survey every 6 months using a questionnaire.	at 6, 12, 18, 24, 30, 36 months post intervention
Malaria infection prevalence in children 6 months to 14 years	Malaria prevalence will be assessed using Malaria Rapid Diagnostic test (CareStart Malaria histidine-rich protein 2 (HRP2)/plasmodium lactate dehydrogenase (pLDH) Combo, DiaSys, UK)	12 months post intervention
Malaria infection prevalence in children 6 months to 14 years	Malaria prevalence will be assessed using Malaria Rapid Diagnostic test (CareStart Malaria histidine-rich protein 2 (HRP2)/plasmodium lactate dehydrogenase (pLDH) Combo, DiaSys, UK)	18 months post intervention
Malaria infection prevalence in children 6 months to 14 years	Malaria prevalence will be assessed using Malaria Rapid Diagnostic test (CareStart Malaria histidine-rich protein 2 (HRP2)/plasmodium lactate dehydrogenase (pLDH) Combo, DiaSys, UK)	30 months post intervention
Malaria infection prevalence in children 6 months to 14 years	Malaria prevalence will be assessed using Malaria Rapid Diagnostic test (CareStart Malaria histidine-rich protein 2 (HRP2)/plasmodium lactate dehydrogenase (pLDH) Combo, DiaSys, UK)	36 months post intervention
Cost & DALYs of each type of bi-treated LLIN	Cost of each intervention will be gathered and used to calculate cost per malaria case averted and cost per DALY averted	Three years post intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insecticide resistance intensity in wild Anopheles population	Twice a year insecticide resistance will be assessed in wild Anopheles. 24 hours mortality will be recorded in Anopheles exposed to different concentrations of insecticides in CDC bottle assay or WHO test	Three years post intervention follow up
P450 over-expression in wild Anopheles population	P450 genes involved in pyrethroid insecticide resistance will be monitored in the 4 arms once a year using reverse-transcription quantitative polymerase chain reaction (PCR)	Three years post intervention follow up
Frequency of Vgsc mutation in wild Anopheles population	A sub sample of mosquitoes collected in the 4 arms will be tested for the Vgsc mutation involved in pyrethroid resistance using Taq Man PCR.	Three years post intervention follow up

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: University of Ottawa; National Institute for Medical Research, Tanzania; Kilimanjaro Christian Medical Centre, Tanzania

Publications and helpful links

General Publications

• Protopopoff N, Mosha JF, Lukole E, Charlwood JD, Wright A, Mwalimu CD, Manjurano A, Mosha FW, Kisinza W, Kleinschmidt I, Rowland M. Effectiveness of a long-lasting piperonyl butoxide-treated insecticidal net and indoor residual spray interventions, separately and together, against malaria transmitted by pyrethroid-resistant mosquitoes: a cluster, randomised controlled, two-by-two factorial design trial. Lancet. 2018 Apr 21;391(10130):1577-1588. doi: 10.1016/S0140-6736(18)30427-6. Epub 2018 Apr 11.
• Ranson H, N'guessan R, Lines J, Moiroux N, Nkuni Z, Corbel V. Pyrethroid resistance in African anopheline mosquitoes: what are the implications for malaria control? Trends Parasitol. 2011 Feb;27(2):91-8. doi: 10.1016/j.pt.2010.08.004. Epub 2010 Sep 16.
• Asidi A, N'Guessan R, Akogbeto M, Curtis C, Rowland M. Loss of household protection from use of insecticide-treated nets against pyrethroid-resistant mosquitoes, benin. Emerg Infect Dis. 2012 Jul;18(7):1101-6. doi: 10.3201/eid1807.120218.
• Ochomo EO, Bayoh NM, Walker ED, Abongo BO, Ombok MO, Ouma C, Githeko AK, Vulule J, Yan G, Gimnig JE. The efficacy of long-lasting nets with declining physical integrity may be compromised in areas with high levels of pyrethroid resistance. Malar J. 2013 Oct 24;12:368. doi: 10.1186/1475-2875-12-368.
• N'Guessan R, Odjo A, Ngufor C, Malone D, Rowland M. A Chlorfenapyr Mixture Net Interceptor(R) G2 Shows High Efficacy and Wash Durability against Resistant Mosquitoes in West Africa. PLoS One. 2016 Nov 16;11(11):e0165925. doi: 10.1371/journal.pone.0165925. eCollection 2016.
• Ngufor C, N'Guessan R, Fagbohoun J, Todjinou D, Odjo A, Malone D, Ismail H, Akogbeto M, Rowland M. Efficacy of the Olyset Duo net against insecticide-resistant mosquito vectors of malaria. Sci Transl Med. 2016 Sep 14;8(356):356ra121. doi: 10.1126/scitranslmed.aad3270.
• Mosha JF, Kulkarni MA, Messenger LA, Rowland M, Matowo N, Pitt C, Lukole E, Taljaard M, Thickstun C, Manjurano A, Mosha FW, Kleinschmidt I, Protopopoff N. Protocol for a four parallel-arm, single-blind, cluster-randomised trial to assess the effectiveness of three types of dual active ingredient treated nets compared to pyrethroid-only long-lasting insecticidal nets to prevent malaria transmitted by pyrethroid insecticide-resistant vector mosquitoes in Tanzania. BMJ Open. 2021 Mar 8;11(3):e046664. doi: 10.1136/bmjopen-2020-046664.
• Mosha JF, Kulkarni MA, Lukole E, Matowo NS, Pitt C, Messenger LA, Mallya E, Jumanne M, Aziz T, Kaaya R, Shirima BA, Isaya G, Taljaard M, Martin J, Hashim R, Thickstun C, Manjurano A, Kleinschmidt I, Mosha FW, Rowland M, Protopopoff N. Effectiveness and cost-effectiveness against malaria of three types of dual-active-ingredient long-lasting insecticidal nets (LLINs) compared with pyrethroid-only LLINs in Tanzania: a four-arm, cluster-randomised trial. Lancet. 2022 Mar 26;399(10331):1227-1241. doi: 10.1016/S0140-6736(21)02499-5.
• Martin JL, Messenger LA, Mosha FW, Lukole E, Mosha JF, Kulkarni M, Churcher TS, Sherrard-Smith E, Manjurano A, Protopopoff N, Rowland M. Durability of three types of dual active ingredient long-lasting insecticidal net compared to a pyrethroid-only LLIN in Tanzania: methodology for a prospective cohort study nested in a cluster randomized controlled trial. Malar J. 2022 Mar 19;21(1):96. doi: 10.1186/s12936-022-04119-4.

Helpful Links

• WHO, Conditions for deployment of mosquito nets treated with a pyrethroid and piperonyl butoxide, G.M. Programme, Editor. 2017, World Health Organization: Geneva.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2019
• Primary Completion (Actual): February 28, 2022
• Study Completion (Actual): February 1, 2023

Study Registration Dates

• First Submitted: April 26, 2018
• First Submitted That Met QC Criteria: May 31, 2018
• First Posted (Actual): June 13, 2018

Study Record Updates

• Last Update Posted (Actual): March 21, 2023
• Last Update Submitted That Met QC Criteria: March 20, 2023
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Malaria; Vector Control; Long lasting Insecticidal Net
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria
• Other Study ID Numbers: ITDCZN11

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: all IPD that underlie results in each publication will be shared and accessible in the LSHTM repository.
• IPD Sharing Time Frame: June 2023
• IPD Sharing Access Criteria: Upon request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No