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

Jacklin F Mosha, Manisha A Kulkarni, Louisa A Messenger, Mark Rowland, Nancy Matowo, Catherine Pitt, Eliud Lukole, Monica Taljaard, Charles Thickstun, Alphaxard Manjurano, Franklin W Mosha, Immo Kleinschmidt, Natacha Protopopoff, Jacklin F Mosha, Manisha A Kulkarni, Louisa A Messenger, Mark Rowland, Nancy Matowo, Catherine Pitt, Eliud Lukole, Monica Taljaard, Charles Thickstun, Alphaxard Manjurano, Franklin W Mosha, Immo Kleinschmidt, Natacha Protopopoff

Abstract

Introduction: The massive scale-up of long-lasting insecticidal nets (LLINs) has led to major reductions in malaria burden in many sub-Saharan African countries. This progress is threatened by widespread insecticide resistance among malaria vectors. This cluster-randomised controlled trial (c-RCT) compares three of the most promising dual active ingredients LLINs (dual-AI LLINs), which incorporate mixtures of insecticides or insecticide synergists to standard LLINs in an area of pyrethroid insecticide resistance.

Methods: A four-arm, single-blinded, c-RCT will evaluate the effectiveness of three types of dual-AI LLINs (1) Royal Guard, combining two insecticides, pyriproxyfen and the pyrethroid alpha-cypermethrin; (2) Interceptor G2, combining chlorfenapyr and alpha-cypermethrin; (3) Olyset Plus, an LLIN combining a synergist, piperonyl butoxide and the pyrethroid permethrin, compared with; (4) Interceptor LN, a standard LLIN containing the pyrethroid alpha-cypermethrin as the sole AI. The primary outcomes are malaria infection prevalence in children aged 6 months-14 years and entomological inoculation rate (EIR), as a standard measure of malaria transmission at 24 months postintervention and cost-effectiveness.

Ethics and dissemination: Ethical approval was received from the institutional review boards of the Tanzanian National Institute for Medical Research, Kilimanjaro Christian Medical University College, London School of Hygiene and Tropical Medicine, and University of Ottawa. Study findings will be actively disseminated via reports and presentations to stakeholders, local community leaders, and relevant national and international policy makers as well as through conferences, and peer-reviewed publications.

Trial registration number: NCT03554616.

Keywords: epidemiology; health economics; infection control; infectious diseases; parasitology; public health.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Secondary objectives. Dual-AI-LLINs, dual active ingredients LLINs; EIR, entomological inoculation rate; LLINs, long-lasting insecticidal nets; py-PBO-LLINs, pyrethroid-piperonyl butoxide LLINs; py-PPF-LLINs, pyrethroid-pyriproxyfen LLINs; s-LLINs, standard pyrethroid LLINs
Figure 2
Figure 2
Trial study design. CDC, Centers for Disease Control and Prevention.
Figure 3
Figure 3
Study area. Map showing Misungwi study area in Mwanza region, North Tanzania (A), the 85 study clusters identified with core and buffer area and intervention allocation (B). (C) Closer map on the minimum 600 000 m area between houses in adjacent clusters.

References

    1. WHO . World malaria report Geneva. Switzerland, 2018.
    1. WHO . World malaria report. Geneva, Switzerland, 2019.
    1. Asidi A, N'Guessan R, Akogbeto M, et al. . Loss of household protection from use of insecticide-treated nets against pyrethroid-resistant mosquitoes, Benin. Emerg Infect Dis 2012;18:1101–6. 10.3201/eid1807.120218
    1. Ochomo EO, Bayoh NM, Walker ED, et al. . The efficacy of long-lasting nets with declining physical integrity may be compromised in areas with high levels of pyrethroid resistance. Malar J 2013;12:368. 10.1186/1475-2875-12-368
    1. Kleinschmidt I, Bradley J, Knox TB, et al. . Implications of insecticide resistance for malaria vector control with long-lasting insecticidal nets: a WHO-coordinated, prospective, international, observational cohort study. Lancet Infect Dis 2018;18:640–9. 10.1016/S1473-3099(18)30172-5
    1. Lindblade KA, Mwandama D, Mzilahowa T, et al. . A cohort study of the effectiveness of insecticide-treated bed nets to prevent malaria in an area of moderate pyrethroid resistance, Malawi. Malar J 2015;14:31. 10.1186/s12936-015-0554-1
    1. Ochomo E, Chahilu M, Cook J, et al. . Insecticide-Treated nets and protection against insecticide-resistant malaria vectors in Western Kenya. Emerg Infect Dis 2017;23:758–64. 10.3201/eid2305.161315
    1. Protopopoff N, Mosha JF, Lukole E, et al. . 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;391:1577–88. 10.1016/S0140-6736(18)30427-6
    1. WHO . Report of the 12th WHOPES Working group meeting. Geneva, Switzerland: World Health Organization, 2008: 41–75.
    1. WHO . Conditions for use of long-lasting insecticidal nets treated with a pyrethroid and piperonyl butoxide. World Health Organization, 2015.
    1. WHO . Conditions for deployment of mosquito nets treated with a pyrethroid and piperonyl butoxide. Geneva: World Health Organization, 2017.
    1. Staedke SG, Gonahasa S, Dorsey G, et al. . Effect of long-lasting insecticidal nets with and without piperonyl butoxide on malaria indicators in Uganda (LLINEUP): a pragmatic, cluster-randomised trial embedded in a national LLIN distribution campaign. Lancet 2020;395:1292–303. 10.1016/S0140-6736(20)30214-2
    1. N'Guessan R, Odjo A, Ngufor C, et al. . A Chlorfenapyr mixture net Interceptor® G2 shows high efficacy and wash durability against resistant mosquitoes in West Africa. PLoS One 2016;11:e0165925. 10.1371/journal.pone.0165925
    1. Ngufor C, N'Guessan R, Fagbohoun J, et al. . Efficacy of the Olyset duo net against insecticide-resistant mosquito vectors of malaria. Sci Transl Med 2016;8:356ra121. 10.1126/scitranslmed.aad3270
    1. Djènontin A, Ahoua Alou LP, Koffi A, et al. . Insecticidal and sterilizing effect of Olyset Duo®, a permethrin and pyriproxyfen mixture net against pyrethroid-susceptible and -resistant strains of Anopheles gambiae s.s.: a release-recapture assay in experimental HUTS. Parasite 2015;22:27. 10.1051/parasite/2015027
    1. Koffi AA, Ahoua Alou LP, Djenontin A, et al. . Efficacy of Olyset® duo, a permethrin and pyriproxyfen mixture net against wild pyrethroid-resistant Anopheles gambiae s.s. from Côte d'Ivoire: an experimental HuT trial. Parasite 2015;22:28. 10.1051/parasite/2015028
    1. Kawada H, Dida GO, Ohashi K, et al. . A small-scale field trial of pyriproxyfen-impregnated bed nets against pyrethroid-resistant Anopheles gambiae s.s. in Western Kenya. PLoS One 2014;9:e111195. 10.1371/journal.pone.0111195
    1. Bayili K, N'do S, Namountougou M, et al. . Evaluation of efficacy of Interceptor® G2, a long-lasting insecticide net coated with a mixture of chlorfenapyr and alpha-cypermethrin, against pyrethroid resistant Anopheles gambiae s.l. in Burkina Faso. Malar J 2017;16:190. 10.1186/s12936-017-1846-4
    1. Camara S, Ahoua Alou LP, Koffi AA, et al. . Efficacy of Interceptor® G2, a new long-lasting insecticidal net against wild pyrethroid-resistant Anopheles gambiae s.s. from Côte d'Ivoire: a semi-field trial. Parasite 2018;25:42. 10.1051/parasite/2018042
    1. Ngufor C, Fagbohoun J, Critchley J, et al. . Which intervention is better for malaria vector control: insecticide mixture long-lasting insecticidal nets or standard pyrethroid nets combined with indoor residual spraying? Malar J 2017;16:340. 10.1186/s12936-017-1987-5
    1. Ngufor C, Agbevo A, Fagbohoun J, et al. . Efficacy of Royal guard, a new alpha-cypermethrin and pyriproxyfen treated mosquito net, against pyrethroid-resistant malaria vectors. Sci Rep 2020;10:12227. 10.1038/s41598-020-69109-5
    1. Tiono AB, Ouédraogo A, Ouattara D, et al. . Efficacy of Olyset duo, a bednet containing pyriproxyfen and permethrin, versus a permethrin-only net against clinical malaria in an area with highly pyrethroid-resistant vectors in rural Burkina Faso: a cluster-randomised controlled trial. The Lancet 2018;392:569–80. 10.1016/S0140-6736(18)31711-2
    1. WHO . Report of the 20th WHOPES Working group meeting. Geneva: WHO, 2017: 4–46.
    1. Tungu P, Kirby M, Malima R, et al. . Interceptor® long-lasting insecticidal net: phase III evaluation over three years of household use and calibration with phase II experimental HuT outcomes. Parasit Vectors 2016;9:204. 10.1186/s13071-016-1490-9
    1. WHO . Design of epidemiological trials for vector control products: report of a who expert Advisory group. Geneva, Switzerland: WHO, 2017.
    1. Kabula B, Tungu P, Matowo J, et al. . Susceptibility status of malaria vectors to insecticides commonly used for malaria control in Tanzania. Trop Med Int Health 2012;17:742–50. 10.1111/j.1365-3156.2012.02986.x
    1. Kisinza WN, Nkya TE, Kabula B, et al. . Multiple insecticide resistance in Anopheles gambiae from Tanzania: a major concern for malaria vector control. Malar J 2017;16:439. 10.1186/s12936-017-2087-2
    1. Matiya DJ, Philbert AB, Kidima W, et al. . Dynamics and monitoring of insecticide resistance in malaria vectors across mainland Tanzania from 1997 to 2017: a systematic review. Malar J 2019;18:102. 10.1186/s12936-019-2738-6
    1. NBS . National Bureau of statistics, demographic and health survey and malaria indicator survey 2015-2016. Dar Es Salaam, Tanzania: National Bureau of Statistics, 2016.
    1. Katureebe A, Zinszer K, Arinaitwe E, et al. . Measures of malaria burden after long-lasting insecticidal net distribution and indoor residual spraying at three sites in Uganda: a prospective observational study. PLoS Med 2016;13:e1002167. 10.1371/journal.pmed.1002167
    1. WHO . Guidelines for laboratory and field-testing of long-lasting insecticidal nets. World Health Organization, 2013.
    1. Chan A-W, Tetzlaff JM, Altman DG, et al. . Spirit 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200–7. 10.7326/0003-4819-158-3-201302050-00583
    1. National Bureau of Statistics N . The 2012 population and housing census (PHC) for the United Republic of Tanzania Dar ES Salaam. Tanzania, 2012.
    1. . Early warning system rainfall estimate (rfe), 2020. Available:
    1. Nkya TE, Mosha FW, Magesa SM, et al. . Increased tolerance of Anopheles gambiae s.s. to chemical insecticides after exposure to agrochemical mixture. Tanzan J Health Res 2014;16:329–32. 10.4314/thrb.v16i4.10
    1. PMI . Tanzania malaria operational plan FY 2018, 2018. Available:
    1. Hayes RJ, Moulton LH. Chapter 6: Randomisation procedures. : Cluster randomised trials. London: Chapman & Hall/CRC, 2009: 149–62.
    1. Tanzania MoHaSW . National malaria strategic plan 2014-2020, 2014.
    1. Harris C, Lwetoijera DW, Dongus S, et al. . Sterilising effects of pyriproxyfen on Anopheles arabiensis and its potential use in malaria control. Parasit Vectors 2013;6:144. 10.1186/1756-3305-6-144
    1. Lwetoijera D, Harris C, Kiware S, et al. . Effective autodissemination of pyriproxyfen to breeding sites by the exophilic malaria vector Anopheles arabiensis in semi-field settings in Tanzania. Malar J 2014;13:161. 10.1186/1475-2875-13-161
    1. Raghavendra K, Barik TK, Sharma P, et al. . Chlorfenapyr: a new insecticide with novel mode of action can control pyrethroid resistant malaria vectors. Malar J 2011;10:16. 10.1186/1475-2875-10-16
    1. Measure D, PMI, RBM, UNICEF, WHO . Household survey indicators for malaria control. Geneva: World Health Organization, 2018.
    1. West PA, Protopopoff N, Wright A, et al. . Enhanced protection against malaria by indoor residual spraying in addition to insecticide treated nets: is it dependent on transmission intensity or net usage? PLoS One 2015;10:e0115661. 10.1371/journal.pone.0115661
    1. Gillies MTC M. A supplement to the Anophelinae of Africa South of the Sahara (Afrotropical region, 1987.
    1. Detinova TS, Gillies MT. Observations on the determination of the age composition and epidemiological importance of populations of Anopheles gambiae Giles and Anopheles funestus Giles in Tanganyika. Bull World Health Organ 1964;30:23.
    1. Wirtz RA, Zavala F, Charoenvit Y, et al. . Comparative testing of monoclonal antibodies against Plasmodium falciparum sporozoites for ELISA development. Bull World Health Organ 1987;65:39–45.
    1. Durnez L, Van Bortel W, Denis L, et al. . False positive circumsporozoite protein ELISA: a challenge for the estimation of the entomological inoculation rate of malaria and for vector incrimination. Malar J 2011;10:195. 10.1186/1475-2875-10-195
    1. Bass C, Williamson MS, Field LM. Development of a multiplex real-time PCR assay for identification of members of the Anopheles gambiae species complex. Acta Trop 2008;107:50–3. 10.1016/j.actatropica.2008.04.009
    1. Vezenegho SB, Bass C, Puinean M, et al. . Development of multiplex real-time PCR assays for identification of members of the Anopheles funestus species group. Malar J 2009;8:282. 10.1186/1475-2875-8-282
    1. Bass C, Nikou D, Donnelly MJ, et al. . Detection of knockdown resistance (KDR) mutations in Anopheles gambiae: a comparison of two new high-throughput assays with existing methods. Malar J 2007;6:111. 10.1186/1475-2875-6-111
    1. Brogdon WG, Chan A. Guideline for evaluating insecticide resistance in vectors using the CDC bottle bioassay. Altlanta, USA: Centers for Disease Control and Prevention, 2012.
    1. WHO . Test procedures for insecticide resistance monitoring in malaria vector mosquitoes. Second ed. Geneva, Switzerland: World Health organization, 2016.
    1. Matowo J, Kitau J, Kaaya R, et al. . Trends in the selection of insecticide resistance in Anopheles gambiae s.l. mosquitoes in northwest Tanzania during a community randomized trial of longlasting insecticidal nets and indoor residual spraying. Med Vet Entomol 2015;29:51–9. 10.1111/mve.12090
    1. Mavridis K, Wipf N, Medves S, et al. . Rapid multiplex gene expression assays for monitoring metabolic resistance in the major malaria vector Anopheles gambiae. Parasit Vectors 2019;12:9. 10.1186/s13071-018-3253-2
    1. Charlwood JD, Rowland M, Protopopoff N, et al. . The Furvela tent-trap MK 1.1 for the collection of outdoor biting mosquitoes. PeerJ 2017;5:e3848. 10.7717/peerj.3848
    1. Georgios Gkountouras JAL, Stanciole A, Stenberg K. Estimation of unit costs for general health services: updated WHO-CHOICE estimates. WHO department of Health Systems Financing, 2011.
    1. Organization WH . Life tables, 2020.
    1. GBD 2017 DALYs and HALE Collaborators . Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet 2018;392:1859–922. 10.1016/S0140-6736(18)32335-3
    1. Hayes RJ, Bennett S. Simple sample size calculation for cluster-randomized trials. Int J Epidemiol 1999;28:319–26. 10.1093/ije/28.2.319
    1. West PA, Protopopoff N, Wright A, et al. . Indoor residual spraying in combination with insecticide-treated nets compared to insecticide-treated nets alone for protection against malaria: a cluster randomised trial in Tanzania. PLoS Med 2014;11:e1001630. 10.1371/journal.pmed.1001630
    1. Kasza J, Hemming K, Hooper R, et al. . Impact of non-uniform correlation structure on sample size and power in multiple-period cluster randomised trials. Stat Methods Med Res 2019;28:703–16. 10.1177/0962280217734981
    1. Proschan MA, Waclawiw MA. Practical guidelines for multiplicity adjustment in clinical trials. Control Clin Trials 2000;21:527–39. 10.1016/S0197-2456(00)00106-9
    1. Wilkinson T, Sculpher MJ, Claxton K, et al. . The International decision support initiative reference case for economic evaluation: an aid to thought. Value Health 2016;19:921–8. 10.1016/j.jval.2016.04.015
    1. Husereau D, Drummond M, Petrou S, et al. . Consolidated health economic evaluation reporting standards (cheers) statement. BMJ 2013;346:f1049. 10.1136/bmj.f1049
    1. Evaluation IfHMa . Global burden of disease results tool. Seattle, USA: University of Washington, 2017.
    1. Fenwick E, Claxton K, Sculpher M. Representing uncertainty: the role of cost-effectiveness acceptability curves. Health Econ 2001;10:779–87. 10.1002/hec.635
    1. Ochalek J, Lomas J, Claxton K. Estimating health opportunity costs in low-income and middle-income countries: a novel approach and evidence from cross-country data. BMJ Glob Health 2018;3:e000964. 10.1136/bmjgh-2018-000964
    1. Marseille E, Larson B, Kazi DS, et al. . Thresholds for the cost-effectiveness of interventions: alternative approaches. Bull World Health Organ 2015;93:118–24. 10.2471/BLT.14.138206
    1. WHO . Test procedures for insecticide resistance monitoring in malaria vector mosquitoes. Geneva, Switzerland: World Health organisation, 2016.
    1. Rao X, Huang X, Zhou Z, et al. . An improvement of the 2ˆ(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostat Bioinforma Biomath 2013;3:71–85.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit