{"paper_id":"04d8755a-28a0-4cdd-8a1c-0ccb57b58175","body_text":"1 \n \nEffectiveness and safety of reactive foca l mass drug administration (rfMDA) using dihydroart emisinin-1 \npiperaquin e to r educ e malaria transmis sion in very l ow-ende mic setting of Eswatini: a pragmatic 2 \ncluster rando mised c ontrolle d trial  3 \n 4 \nSibonakaliso Vilakati 1 * , Non tokozo Mng a di 2 *, Jad e Benjamin-Chung 3,4 *, Nomcebo  Dlamini 1 , Mi-Suk Kang 5 \nDufour 3,5 , Brooke Whit temor e 6 , Khayelihl e Bhangu 1 , Lisa M. Prach 4 , Kimberly Balt z ell 7 , Nomcebo 6 \nNhlaba thi 1 , Calisile Malamb e 1 , Bongani D lamini 2 , Danica Helb 5 , Bryan G reen house 5 , Gugu Maphalal a 8 , 7 \nDeepa Pindolia, 2  Muhind o Kalungero 9 , G etahun Tesfa 10 , Roly Gosling 4 , Nyasa tu N t shalintshali 2 , Simon 8 \nKunene 1‡ , Mich elle S. Hsia ng 4,6,11†  9 \n 10 \nAffiliations  11 \n1 Eswatini Nation al Mala ria Program, Ma nzini, Eswatini  12 \n2 Clinton Health Access Initia tive, Mb aban e, Eswatini  13 \n3 Division of Epidemiology & Biostatistics,  University of California, Berk eley, USA  14 \n4 Malaria Eliminati on Ini tiative , Glob al He alth G roup, UCSF  15 \n5 Departmen t of Medicine, University of California, San F rancisco (UCSF), USA 16 \n6 Departmen t of Pediatrics, Unive rsity of Texas Sout hweste rn Medic al Cente r, Dall as, USA  17 \n7 Departmen t of Family Health Care Nursi ng, UCSF 18 \n8 Departmen t of Medicine N atio nal Clinical Laborat ory Services, Mb abane , Eswati ni 19 \n9 Good Sheph erd Hospi tal, Si teki, Eswatin i 20 \n10 Raleigh Fitkin Memori al Hospital , Manz ini, Eswatini 21 \n11 Department of Pedia trics, UCSF  22 \n 23 \n* contributed equ ally  24 \n‡ Deceased Augus t 3, 2019 25 \n† Correspond ence t o: Michell e Hsiang M D MSc, Departmen t of Pediatrics, Unive r sity of Texas 26 \nSouthwest ern M edical Cent er, 5323 Har r y Hines Blvd., Dallas, TX, USA, +1-214-648-2228, 27 \nmichelle.hsiang@uts outhwes tern .edu  28 \n 29 \nAbstrac t word count : 298 30 \nManuscript word cou nt: 4485  31 \n 32 \n  33 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n2 \n \nWhat is already known? 34 \n• Reactive case d et ection (RACD), or malar ia testing an d tre atme nt in th e vicinity of passively 35 \ndetec ted mala ria cases, is a st andard of c are int erven tion used in low and very lo w transmission 36 \nsettings aiming for malari a eliminat ion.  37 \n• Despite th e use of RACD, progress t owar d malaria elimina tion has st alled in many  countries and 38 \nnew strat egies ar e need ed.  39 \n• Reactive focal mass drug administ rati on (rfMDA) is a transmission reducing stra te gy that has 40 \nbeen shown to b e effective in a low tra nsmission setting, but the re a re no t rial da t a from a very 41 \nlow transmission set ting.  42 \n 43 \nWhat are the new findings? 44 \n• In a pragmatic, clus ter-r andomised con tr olled tri al of rfMDA using dihydroart emisinin-45 \npiperaqui ne compar ed to R ACD, we found that rfMDA was safe.  46 \n• rfMDA result ed in lower cumulative incid ence, but we we re unabl e to confirm its effectiveness 47 \ncompared t o RACD, poten tially due to in sufficient power (we expec ted 63 to tal cl usters would 48 \nhave incident cases , but obs erved 47).  49 \n 50 \nWhat do the new findings imply?  51 \n• When implemen ted in a real-world , very low transmission set ting, rMDA was safe but evidence 52 \nregarding its effective ness to r educe t ran smission was weak.  53 \n• The challenge t o show a statis tically significant impact of a targe ted communi ty-based 54 \ninterven tion in a very low tr ansmission setting highlights the ne ed for such tri als t o be multi-site , 55 \nadaptive, and consider us e of compleme ntary int erventi ons.  56 \n 57 \n  58 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n3 \n \nAbstract 59 \n 60 \nIntroduction  61 \nTo reduce malari a tr ansmission in very low-endemic settings, scre ening and t rea t ment nea r inde x cases 62 \n(reactive case de tec tion (RACD)), is widely practiced, but the r apid diagnos tic test s (RDTs ) u sed miss low -63 \ndensity infections . Presumptive t rea tme nt near ind ex cas es (reactive focal mass drug administra tion 64 \n(rfMDA)) may be safe and more effective . 65 \n 66 \nMethods 67 \nWe conduct ed a cluste r-randomis ed con trolle d trial in Eswatini , a very low-ende mic setting. 77 cluste rs 68 \nwere rand omised to rfMDA using dihydr oart emisin-pipera quine (DP) or RACD inv olving RDTs and 69 \nartem eth er lumefan trine (AL). Int erven ti ons were deliver ed by the loc al program me. An int enti on-to-70 \ntrea t analysis was used to compa re clust er-level cumulative confirme d malaria in cidence among cluste rs 71 \nwith cases. Second ary outcomes includ e d safety and adhe rence .  72 \n 73 \nResults  74 \nFrom Sept 2015– Aug 2017, 220 index cas es from 47 clusters trigger ed 49 RACD events and 68 rfMDA 75 \nevents. R ACD and rfMDA were deliver ed to 1696 and 1932 individuals, resp ectivel y. Index cas e and 76 \ntarge t popula tion in terven tion cover ages  for both arms were 75 .6%–81.4% and a dherenc e to DP was 77 \n98.7%. For rfMDA versus RACD, cumulati ve incidences (per 1000 person-yea rs) of all malaria wer e 2.11 78 \n(95% CI 1.73–2.59) and 1.97 (1.57–2.47), respectively; and of locally acquired mala ria, th ey were 1.29 79 \n(95% CI 1.00–1.67) and 0.97 (0.71–1.34), respectively . Adjusting for imbalance in b aseline incide nce, 80 \nincidence ra te ra tio (aIR R) for rfMDA versus  RACD was 0.93 (9 5% CI 0.54–1.60) fo r all malaria and 0 .77 81 \n(95% CI 0.38–1.56) for locally acquired malaria . No seri ous adverse events occur re d.  82 \n 83 \nConclusion  84 \nIn a very low-endemic, rea l-world set ting, this trial is t he first t o evalua te rfMDA u sing DP. rfMDA was 85 \nsafe and resul ted in lower cumula tive inc idence compar ed to R ACD, but we were unable t o confirm its 86 \neffectiveness, po ten tially due to insuffici ent power . To assess impact of int erventi ons in very low-87 \nendemic set tings, multi-site , adap tive tri als and use of complement ary inte rventi ons may be needed .  88 \n 89 \nKeywords 90 \nPlasmodium, Swaziland, low transmissio n, malaria elimin ation , active case d etec t ion, reac tive case 91 \ndetec tion, an timala rial, dihydro ar temisin -piperaquin e, cluste r rand omized cont rol led trial  92 \n 93 \n  94 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n4 \n \nBackground  95 \nSince 2000, many countries have scal ed up effective malaria con trol in terven tion s, resulting in 96 \nreductio ns in malaria bur den and a rene wed goal to er adicat e malaria worl dwide  by 2050.(1) When the 97 \ngoal is to inte rrup t tra nsmission, it may be necessary to tre at no t only symptomati c malaria but also 98 \nasymptomatic infections which pe rpe tua te ongoing tr ansmission and re pres ent a n increasing propo rtio n 99 \nof all infections in low transmission se tti ngs.(2, 3)  100 \nTo address asymptoma tic infections, on e  widely practiced str ategy is active case d etec tion in 101 \nhousehold memb ers and neighb ours of symptomatic cases rec ently rep ort ed fro m health faciliti es, also 102 \nknown as reactive case d etec tion (RACD).(4) Since malaria infections clust er in sp ace and time ,(3) RACD 103 \ncan targe t limited r esourc es to ar eas a t highest risk of infection. I n set tings with substanti al import ed 104 \nmalaria cases th at may seed loc al transm ission, RACD also serves as a focal outbr e ak response .(4) 105 \nHowever, th e effectiveness of RACD is limited by the low sensit ivity of currently available poin t-of-care 106 \ndiagnostics to de tec t low-density and no n-falciparum infections. Mol ecular testi n g such as polymerase 107 \nchain reacti on (PCR) or loop-mediated is otherm al amplification (LAMP) improves sensitivity but is not 108 \npractical given costs, logistic al challenges  of specimen collection and transpo rt , an d turn-arou nd time 109 \nrequir ed for labor ato ry testi ng and re tur n visits to tre at t est-posi tive individuals. I n addition, mass 110 \nscreening and t rea tmen t, which is similar to RACD but deliver ed community-wide,  has not sustain ably 111 \nreduced incid ence in prio r studies .(5) As such, the Wo rld Heal th O rganiza tion (W HO) does not 112 \nrecommend RACD as a stra tegy to r educ e or int errup t tr ansmission.  113 \n Mass drug administra tion (MDA), or th e trea tmen t all individuals within a specifie d area with an 114 \neffective antimala rial ir respec tive of infection sta tus,(6, 7) may address some of the challenges of RACD. 115 \nMDA was a component of many malaria elimination p rogrammes in th e mid-twen tieth c entury bu t fell 116 \nout of favor due to conce rns rega rding it s effectiveness, sustain ability, cost , and fear of accele rating 117 \ndrug resistanc e. Mo re r ecent evidence s uggests that whe n implement ed in ar eas  of low endemicity and 118 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n5 \n \nin combination with o the r inte rventio ns, MDA has the po ten tial to sus tainably int errup t tr ansmission.(6, 119 \n7)  Maximizing coverage and adh erenc e may also help to mitiga te risks of drug re sistance.(8) MDA has 120 \nrecen tly been r ecommended by th e WH O in areas a pproaching in ter rupti on of tr ansmission where th ere 121 \nis good access to tre atme nt, effective im plement ation of vecto r contr ol and surve illance, and minimal 122 \nrisk of re-introduc tion of infection .(9) However, a dea rth of definitive evidence on  its effectiveness, 123 \nsafety, and feasibili ty remains.(10)  124 \nEswatini (formerly Swaziland) is among 21 countries worldwide tha t were id entifi ed by WHO as 125 \nthe most likely to reach ze ro indigen ous cases by 2020.(11) However, several of these count ries 126 \nincluding Eswatini continue to ex peri enc e persist ent local transmission an d resur gence. As a mala ria 127 \nelimination-sp ecific strat egy, the Eswatin i Nation al Mala ria Programme (NMP) has implemented R ACD 128 \nsince 2009. Prior studies have confirm ed that asympt omatic infectio ns cluster a ro und passively detect ed 129 \nindex cases, wit h the high est risk within 200 meters of the in dex cas e.(12) However, in Eswatini RACD 130 \nusing RDTs missed two-thirds of infections and 40% of hotspots compared to mo re sensitive mol ecular 131 \nmethods.(12) Due to logistical chall enges , att empts to us e more sensi tive molecul ar methods to dir ectly 132 \ninform trea tmen t have be en unsuccessful (N. Dlamini, personal communica tion).  133 \nReactive focal MDA (rfMDA) is an altern a tive inte rventio n tha t builds on RACD for targe ting 134 \nhigh-risk populations r esiding near ind ex cases. rfMDA ent ails mass drug administr ation withou t t esting 135 \nin household membe rs and neighbo urs o f recent inde x cases.(13) A recen t tr ial of rfMDA using 136 \nartem eth er-lumefant rine (AL) from a low transmission set ting (infection pr evalenc e 1–10%(14)) with 137 \nminimal importa tion in Namibi a repo rt e d safe administra tion and rfMDA r educe d locally acquired 138 \nmalaria incidenc e by approxim ately 50% compared t o RACD.(13) However, ther e are no t rials of rfMDA 139 \nfrom very low transmission settings (infe ction preval ence >0 but <1%(14)) with a high level of 140 \nimporta tion, which charac teri zes most n ear-elimina tion se ttings. rfMDA may be more appr opria te th an 141 \nblanket MDA in low-end emic settings, si nce it targ ets popul ations whe re mala ria has been r ecently 142 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n6 \n \nintroduc ed. Also , the re a re no t rials of rfMDA using dihydroart emisinin-piper aqui ne (DP), which 143 \ncompared t o standa rd ar temisinin-combi nation t her apies such as AL, has favorabl e charact eristics for 144 \nMDA (less frequent dosing and long er pe riod of prot ection), bu t safety concerns a bout ra re QT-inte rval 145 \nprolongati on leadi ng to arry thmia and sudden dea th e xist.(15) 146 \nOur objective in this trial was t o evalua te  the effectiven ess of rfMDA using DP, co mpared to 147 \nRACD, for reducing malaria t ransmission in the very low transmission se tting of Eswatini. Bo th th e 148 \nrfMDA and RACD interven tions were embedded within the Eswatini Nati onal Mal aria Programme; as 149 \nsuch, this pragmatic t rial assess ed real-w orld effectiveness of th ese int erven tions when delivered wit hin 150 \nan existi ng surveillance and respons e pro gramme.  151 \n 152 \nMethods  153 \nStudy design and  participants  154 \nWe conduct ed a pragma tic open-lab el, cl uster-ra ndomised con troll ed tria l(16) between Sept ember 2015 155 \nand June 2017 in th e Kingdom of Eswatini, a low middle-income country in sout he rn Africa. 156 \nAppro ximat ely 30% of the populatio n lives in the e aste rn malaria- endemic ar ea, which borders 157 \nMozambique . Plasmodium falciparum is responsible for ove r 99% of malaria case s in Eswatini. Malari a 158 \ntransmission is unstab le and occurs main ly between Oc tobe r and May.(12) Annua l case loads are 159 \nrepor ted from July to Ju n e each year .  160 \nAfter major d eclines in malari a transmiss ion from annual par asite incid ence (API) of 3.9 to 0.07 161 \nper 1000 popula tion from 1999 to 2009, the NMP r eorie nte d its str ategy from control t o elimina tion of 162 \ntransmission by 2020. Since implemen ta t ion of the elimina tion pr ogramme and until ju st prior to this 163 \ntrial, API h as remain ed <1 pe r 1000 population . In 2014–2015, th e tr ansmission se ason prior to th e trial , 164 \nther e were 604 r epor ted cases, of which 50% were classified as imported .(17) 165 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n7 \n \nThis pragmatic cluster-r andomised con tr olled tri al was designed to compa re rfM DA and RACD 166 \neffectiveness as implemen ted by th e Eswatini Na tiona l Malari a Programme (NMP) and in the cont ex t of 167 \nother ongoing inte rventio ns including case managemen t, vector con trol , surveilla nce, and informa tion, 168 \ncommunication and ed ucation . 77 malari a endemic localiti es or clust ers, with a to tal of 209085 169 \nindividuals residing in 431 enumer ation a reas, wer e eligible for inclusion . Of th e 77 clusters, 63 had 170 \nmalaria cases in th e thr ee yea rs prior to t he trial ; th e remaind er did no t have case s but had prior 171 \nhistorical risk of malaria transmission . W e randomised clus ters with a 1:1 allocati on ratio to rec eive 172 \nRACD, including rapid diagnostic t esting with Pf- specific First Response (Premier Medical Corpor atio n 173 \nLtd, Mumbai, In dia) and tr eatm ent of po sitives with AL (Coartem, Nova rtis Pharm aceuticals, Kemp ton 174 \nPark, South Africa) or rfMDA with pr esu mptive tre atmen t using DP (Eurartesim, Sigma Tau, Italy) (Figure 175 \n1). Inclusion and exclusi on crite ria ar e sh own in Appendix 1 . Briefly, microscopy- or RDT-confirmed index 176 \ncases repor ted from any he alth facility in  Eswatini were classified as local, impor t ed, or unknown base d 177 \non travel hist ory. RACD or rfMDA was tri ggered if the inde x case r esided within a study cluster. If RACD 178 \nwas conducted in th e prior 5 weeks of th e index cas e repo rt, i t was not re pea ted . Following the 179 \nmanufacture r’s recommen dati on tha t DP not be rep eat ed within 8 weeks, nor ta ken more tha n twice in 180 \na year, rfMDA was not r epea ted if th ese criteri a were me t. O the r exclusio n crite ri a for DP included: age 181 \n< 9 months; weight < 7 kg; pr egnancy and breastfe eding, all ergy to DP, acute illne ss including severe 182 \nmalaria, und erlying kidney or hepa tic pro blems, person al or family history of QT prolongati on, or r ecen t 183 \ntrea tmen t with QT-prolonga ting medicat ions.  184 \nRandomisation and masking  185 \nTo ensure th at t he baseli ne risk of malari a was balanced be tween in terven tion a r ms, we utilized block-186 \nstratifie d randomisa tion . We assigned th e 77 localities or clus ters to rand omisatio n blocks by separating 187 \nthem into thre e risk groups based on incidence in th e thr ee years p rior t o the trial  and prior hist orical 188 \nrisk according to NMP. W e furth er str atif ied each block by whethe r the siz e of the  population at risk was 189 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n8 \n \nabove or below 650 individuals. A statis ti cian at UC San Francisco (MKD) generate d the rand om 190 \nallocation s equenc e using SAS (version 9. 4m2) to randomly assign 0 or 1 to each cluster within each 191 \nblock and strat um, and th e NMP flipped a coin to de termin e which interven tion c orrespo nded t o 0 and 192 \n1. The inte rventio n delivery t eam and st udy investigators wer e not blind ed to in t erventi on assignment 193 \ndue to th e na ture of int erven tions.  194 \n 195 \nProcedur es  196 \nPrior to th e study, individuals r esiding in endemic are as receive d indoor r esidual s praying (IRS) per 197 \nstandar d procedu res by the NMP. During  the study, mala ria cases who pres ent ed at surveillanc e sites 198 \nwere confirmed using RDT or microscopy. Inde x cases trigge red in terven tions if th ey lived within the 199 \nstudy area . The surveillanc e te am att em pted t o visit index cas es’ homes within 4 8 hours to administ er a 200 \nquestionn aire a bout travel his tory and vector con trol me asures .  201 \nIn the R ACD arm, consistent wit h NMP st andard pr actices, all cons enting individuals residing 202 \nwithin 500m of the index cas e (the “targ et popul ation” for RACD) received RDT te sting, and a dri ed 203 \nblood spot (DBS) was collected for subse quent molecul ar t esting. RDT-positive in dividuals were 204 \ntranspo rt ed to t he ne ares t heal th facility  for trea tment . The study aimed to delive r interve ntions within 205 \n7 days of index case prese nta tion, but all owed u p to 5 weeks.  206 \nIn the rfMDA a rm, individuals residing wi thin 200m of the inde x case, bu t ex tendi ng beyond 207 \n200m to reach a minimum of 30 individuals (the “targe t popula tion” for rfMDA) were ta rget ed for drug 208 \nadministra tion using DP. A radius of 200 meters with a minimum 30 individuals was chosen because 209 \nprior RACD studies showed tha t the maj ority of infections nea r an inde x case cou ld be captur ed within 210 \nthis targ et popul ation .(12) Field staff assessed wheth er it was safe to administe r DP to enrolled eligibl e 211 \nindividuals. Individuals inel igible to r ecei ve DP received RDT testing, and a DBS was collected for 212 \nsubsequen t molecular testi ng. RDT-positi ve individuals were tr anspor ted t o the n eares t heal th facility 213 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n9 \n \nfor trea tmen t. Eligible individuals r eceive d the first dose of DP under directly obse rved ther apy and 214 \ndoses for day 2 and day 3 for self-administrati on. In dividuals ineligible for DP were screen ed using RDTs 215 \nand transp ort ed to the n eares t heal th fa cility for trea tmen t if they test ed posi tive . Participan ts were 216 \ninstruct ed to go to the n ear est he alth fac ility if they expe rienced any illness after t aking DP, and they 217 \nwere instruc ted to cont act an on-call stu dy nurse that was availa ble at all hours. T o assess adher ence, 218 \nthe study t eam re turn ed to a subsampl e of participan ts (all participan ts of the firs t inte rvention for each 219 \nrfMDA cluster) 7-10 days after enrollm en t to conduct pill cou nts.  220 \nIn both a rms, study te ams retu rned a sec ond and thir d day to rec ruit individuals w ho were 221 \ninitially absen t. The study aimed to achi e ve at least 80% int erven tion coverage of index cases and 80% 222 \ncoverage of the targe t popula tion .  223 \n 224 \nLaboratory m ethods  225 \nRDT testing was performed using th e Firs t Response P. falciparum  HRP-2 Detecti o n Test (Premier 226 \nMedical Corpor atio n Ltd.). DNA e xt ractio n from DBS for LAMP testing was conducted as pr eviously 227 \ndescribed (Loopamp Mal aria Pan and Pf Detectio n Kits, Eiken Chemical Co., Ltd.).( 12) LAMP results were 228 \nused for rese arch purpos es only.  229 \n 230 \nOutcomes 231 \nThe primary outcome of th e tri al was the  cumulative incidence of malari a cases b y study cluster over 232 \ntwo-years of follow-up. Secondary ou tco mes repor ted h ere includ e safety and ad herenc e (acceptabili ty 233 \nhas been r epor ted els ewher e(18)). Infection prevalenc e and ser opreval ence a t two-year follow-up were 234 \noriginally also seconda ry outcomes but t he endline cr oss-sectional su rvey was not conducted du e to a 235 \nshift in prioriti es within th e Minist ry of Health .  236 \n 237 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n10 \n \nStatistical Analysis  238 \nWe estima ted the minimum det ecta ble d ifference in cumulative incide nce per p o pulation a t-risk 239 \nbetwee n arms. Bas ed on surveillanc e dat a from 2012–2015 in areas wher e RACD was conducted, we 240 \nassumed an annual incid ence of 4 per 10 00 individuals, coefficient of variation of 0.9, and type I err or of 241 \n0.05. We assum ed the p opula tion at-risk (the tot al popula tion of census enum era t ion areas that 242 \nrepor ted incid ent cases within each clust er) was 55 928 individuals in at least 63 o f the 77 total clus ter . 243 \nThere was 80% statistica l power t o det ec t a 50% percent reducti on be tween a rms if at least 63 of 77 244 \nclusters had a t leas t one ind ex case .(19) 245 \nThe cumulative incidence in each cluste r was calculated as th e number of passivel y detect ed 246 \nmalaria cases divided by th e produc t of populatio n and follow-up time in each clu ster, st ar ting on the 247 \ndate of first ind ex case d etec tion. Th e first index case in each cluste r was exclude d from incidence 248 \ncalculations since in terven tions wer e deli vered afte r initial ind ex cas e det ection in  each cluster . Mala ria-249 \nfree survival was compared, and the assu mption of propor tion al hazar ds was assessed using Schoenfeld 250 \nresiduals t esting.(20)  251 \nTo estimat e inte rventio n effects, we use d an inten tion-to- tre at (ITT) approach th at exclud ed 252 \nlocalities with no incid ent cases during th e stu dy period since thes e localiti es did n ot receive 253 \ninterven tions . The primary analysis used negative binomial regressio n models wit h an offset for 254 \npopulati on size to estima te incidenc e rat e ratios in each cluste r over th e study pe riod. Mod els adjuste d 255 \nfor baseline covari ates that we re associa ted with th e outcom e using a likelihood r atio t est (p-value < 256 \n0.2) and that ha d a Pearson cor rela tion c oefficient with th e outcom e ≥  0.3.(21) Ba selines covaria tes 257 \nincluded: incidenc e (2014–2015), propor tion of import ed cases, pr opor tion of ho uses receiving IRS in 258 \nthe pas t year, mon thly average e nhance d vegetati on inde x, monthly aver age rain fall, monthly average 259 \nland surface temp era tur e, and el evation .   260 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n11 \n \nMalaria transmission is highly het erogen eous in lower t ransmission set tings(22), and tre nds in 261 \nmonthly incidence differed b etwe en arm s in the thr ee yea rs prior t o the trial . To a ccount for thes e pre-262 \ntrial differe nces, we used a synth etic con trol analysis to minimiz e pre-t rial differe nces in incidence 263 \nbetwee n arms (Appendi x 2).(23)  We the n estimat ed th e difference-in-differenc es  for RACD vs rfM DA 264 \nand the synth etic RACD vs rfMDA. This analysis was not pre-specified.  265 \nTo assess poten tial cont aminati on due t o  a lack of buffer zones between clus ters, we identified 266 \nall clusters with con tiguous neighbou ring clusters and plo tt ed the incid ence in eac h cluster agains t 267 \nincidence in th e neighbour ing cluster . The small number of contiguous clust ers pr ecluded th e use of 268 \nformal statis tical tes ting to assess cor rela tions betw een incidenc es in contiguous c lusters .  269 \n 270 \nResults  271 \nBetwe en Sep tembe r 2015 and June 2017 , 22 of the 38 clusters ran domly assigned  to RACD had 99 272 \nrepor ted cas es; 56 of these cases we re c overed by forty-nine RACD events . Twenty-five of the 39 273 \nclusters ran domly assigned to rfMDA ha d 121 report ed cases; 89 of th ese cases were covered by 68 274 \nrfMDA events. The r emaining cases did n ot receive reac tive inte rventio ns due to s taff limitations, fuel 275 \nshortages , or wea ther condi tions compli cating transp ort (Figure 2). Of th e 2134 individuals eligible to 276 \nreceive RACD, 1696 (79%) were tes ted b y RDTs. Five RDT -positive cases, of which three we re LAMP 277 \npositive), were r eferr ed for tr eatm ent wi th AL. The most common re ason for non- receip t of RACD was 278 \nnot pres ent (n=398, 18.7%); only 1.5% (n=33) refused. Of th e 2623 individuals eligible to r eceive rfMDA, 279 \n1932 (74% ) received DP. The most comm on reasons for non-r eceip t of rfMDA wer e not pr esent (n=302 , 280 \n11.5%) and ineligibility of receive DP (n=313, 11.9%) mainly due to repor ted po te ntial for medica tion 281 \ninter action . Seventy-six (2.9%) of eligible individuals refused to p articip at e. Data o n medication typ e 282 \nwere incomple te as nurs es repo rte d sens itivities ar ound par ticipan ts disclosing use of antire trovir als 283 \n(ARVs). No RDT nor LAMP-positive individuals were iden tified among rfMDA ineli gibles. In to tal, 117 284 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n12 \n \ninterven tion eve nts were impl ement ed i n the tri al and 3941 individuals in 47 clusters wher e 285 \ninterven tions wer e conduct ed were inclu ded in primary outcom e analyses. Adhe r ence to in terven tion 286 \nassignment was incomplet e: 20 RACD int erventi ons were delive red in rfMDA a rea s (14 clusters), and 5 287 \nrfMDA interven tions wer e deliver ed in R ACD areas (four clusters).  288 \nNot t aking into accoun t clusteri ng, index cases had a similar distri bution of age, se x, case origin 289 \n(e.g. local, impor ted, o r unknown), occupation, a nd bed ne t ownership b etwe en st udy arms (Appendix 290 \n3). The percent age of index cas es tha t re porte d having had thei r home spraye d in the past yea r was 291 \nhigher in rfMDA clusters than RACD clust ers (28.6% vs 5.3%). For target popul atio n receiving study 292 \ninterven tions, ther e was a similar distrib ution of age, occupa tion, a nd vector con t rol coverage . A higher 293 \npropor tion in th e rfMDA arm (1.4%) worked in manufacturing compar ed to R ACD (0.1%). In all study 294 \nclusters, an ave rage of 35.7% of index ca ses and 2.8% of the ta rget po pulati on re porte d inte rna tional 295 \ntravel in th e prio r 8 weeks during the st u dy period.  296 \nTaking into account clust ering, th ere was  imbalance in baselin e tra nsmission inten sity. 297 \nCumulative incidence of all malari a in th e thre e years pr eceding th e tri al was higher in th e rfMDA arm 298 \ncompared t o the R ACD arm (6.30 vs 4.17 per 1000, resp ectively) with a similar tre nd seen for local cases 299 \nonly, and for all and local cases only in 2 014–2015, the yea r prec eding the trial (Table 1, App endix 4a). 300 \nThe percen tage of cases classified as imp orted in each cluste r in the ye ars prio r to  the tri al was higher in 301 \nthe RACD arm compare d to th e rfMDA ar m (35.8% v s 28.1% for 2012–2015, and 48.7% vs 32.2% for  302 \n2014–2015). Mean popul ation siz e and e cological factors including rainfall, e nhan ced vegeta tive index , 303 \nelevatio n, and daytim e land surface t em pera ture we re bala nced be tween a rms at baseline (Table 1).  304 \nIndex cas e and t arget p opula tion int erve ntion coverag e in the R ACD arm was 80.1% and 75.6%, 305 \nrespectively, compa red t o 77.0% and 81. 4%, respectively, in th e rfMDA arm (Table 2). Total coverage 306 \n(including both index cases a nd the targe t popula tion ar ound each ind ex case) wa s 60.0% in RACD and 307 \n68.8% in rfMDA. For all coverage me asur es, 95% confidence inte rvals for each ar m overlapped 308 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n13 \n \nsubstanti ally. The median numb er of days between ind ex case repo rt and in terve ntion resp onse was 7 309 \n(range: 2, 27) in the RACD arm and 11 (range: 3, 52) in the rfMDA arm. I n the rfM DA arm, two clusters 310 \nhad respons e times of 40 and 52 days; ex cluding those cluste rs, th e range was 3 t o 21. 311 \nDuring follow-up, the cumulative inciden ce decreas ed from baselin e levels in bot h the RACD and 312 \nrfMDA arms, with rfMDA having fewer cases during the final mon ths (Janua ry to May) of the second 313 \ntransmission seas on (Figure 3, Appe ndix 4b). The cumulative incidence from 2015 –2017 was 2.11 per 314 \n1000 in the rfMDA arm compare d to 1.9 7 in the RACD arm (Table 3) (N = 47 clusters in both a rms). In the 315 \ninten tion-to-t rea t analysis, crud e and adj usted incidenc e rat e ra tios (IRRs) were 1. 01 (95% CI 0.58, 1.73) 316 \nand 0.93 (95% CI 0.54, 1.60), respectively  (Table 3). Restricting to loc al cases only, the adjust ed IRR was 317 \n0.77 (95% CI 0.38, 1.56). 318 \nCumulative malaria-fre e survival for all cases was similar betwe en arms (Figure 4 a). Restric ting 319 \nto local cases only, cumulative su rvival was higher in the rfMDA arm until app roxi mately 9 months afte r 320 \nstudy initiati on, and subs equen tly it was higher in the R ACD arm throughou t th e second high 321 \ntransmission seas on (13–18 months afte r study initia tion) (Figure 4b). The Schoe nfeld residual t est 322 \nindicated that su rvival was proportio nal betwee n arms for all cases (rho = -0.04, p-value = 0.308) but not 323 \nfor local cases (rho = 0.12, p-value = 0 .032). 324 \nIn the synth etic cont rol ana lysis accounti ng for pre-trial differ ences in incidence b etween arms, 325 \nther e was no difference in incidenc e of all malaria cases be tween the rfMDA arm and the synth etic 326 \nRACD arm (Appendix 5 and 6). When co mparing incidence in each clus ter t o inci dence in contiguous 327 \nneighbouring clust ers, clust er-level incid ence was not associa ted with incid ence i n contiguous 328 \nneighbouring clust ers, suggesting th at th e risk of contaminati on in this tri al was minimal (Appendix 7).  329 \nField staff conducted 1114 pill coun ts an d recorde d complet e adhe rence to th e 3-day DP 330 \nregimen in 1099 (98.7%) individuals.  Adverse even ts were e xpe rienc ed by 68 individuals in the rfMDA 331 \narm (49 in year 1, 19 in year 2). Based on  the WHO s everity scale , 54 (80%) events  were mild and 14 332 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n14 \n \n(20.6%) were as moderate . The most co mmon complaints were he adache , nause a/vomiting, and 333 \nabdominal pain . Of five individuals with adverse even ts who did not comple te t h e course of DP, all 334 \nrecovere d. On e had difficulty brea thing a nd chest tightn ess tha t could be consist e nt with DP-associated 335 \narrythmia bu t the accompanying diarroh ea is less consisten t (Appendi x 8 and 9). During the study 336 \nperiod, ther e was only one reco rded mal aria dea th in th e study ar ea. The infec tio n was locally acquired 337 \nand the pa tien t lived in an rfMDA cluste r , though rfMDA had no t previously be en conducted in th e 338 \ntarge t are a. N o AEs were r epor ted in t he RACD arm. 339 \n 340 \nDiscussion  341 \nIn this pragma tic, cluste r-randomised tri al conducted in a very low tr ansmission malaria elimina tion 342 \nsetting, rfMDA clust ers had lowe r locally acquired mala ria incidenc e during th e whole study peri od 343 \ncompared t o RACD clusters, pa rticula rly during the secon d high transmission se ason of the study peri od, 344 \nbut overall , evidence was weak. I nte rven tion coverage was lowe r than e xpec ted, and malaria occur red 345 \nin fewer clusters th an plann ed in the sa mple size calculatio n. Adh ere nce to p res umptive tre atme nt with 346 \nDP was high, and as reported els ewher e,  acceptabili ty was high.(18) Importantly, ther e were no s erious 347 \nadverse even ts (SAEs).   348 \nProgress towards th e 2030 eliminat ion goal in southe rn Africa has slowed d espit e  coordinat ed 349 \nregional effor ts and delivery of stand ard interven tions, including pr e-season ind o or residual sp raying, 350 \nsymptomatic case manageme nt, an d RA CD.(11)  While RACD aims in part to add r ess asymptomatic 351 \nreservoirs of t ransmission, ra pid diagnos tic tests use d in low transmission se tting s have poor sensitivity 352 \nand miss many low-density infections.(24) While blanket MDA would r each all as ymptomatic infections, 353 \nit is logistically difficult to implement a t s cale, inefficient in pop ulati ons with few, highly clustered 354 \ninfections, and i t may not be safe or acc e ptable .(7)  355 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n15 \n \nA few trials have evalua ted focal MDA de livered to ho tspo ts at th e village or sub-village level in 356 \nlow transmission set tings and resul ts ar e mixed.(25-28) In Zanzibar, which most re sembles our sit e due 357 \nto high coverage of stand ard in terven tio ns, very low transmission intensi ty, and h igh rates of 358 \nimporta tion, n egative findings of focal MDA effectiveness were hypot hesize d to b e rela ted t o 359 \nsuboptimal timing and the numbe r of MDA rounds, and r e-introd uction of malari a through 360 \nimporta tion.(27) The reac tive appro ach e mployed in our tri al sought to address th ese issues by targe ting 361 \nthe focal MDA to a time and plac e when transmission risk was highest (e.g. whe re  there we re r ecent 362 \nimported o r local cases).  363 \nThis trial is one of thr ee t hat evaluat ed rfMDA. Resu lts from a low t ransmission se tting in Zambia 364 \ntrial ar e forthcoming .(25) A trial in a low transmission se tting in Namibi a evalua te d rfMDA alone and in 365 \ncombination with r eactive vect or cont rol  in comparison to RACD.(13) Compared t o RACD, rfMDA 366 \nreduced local mal aria incid ence by 48%, and rfMDA with additi onal re active vecto r control r educed 367 \nincidence by 74%. There ar e sever al key differences be tween t he Namibi a tri al an d this trial . First , the 368 \nNamibia t rial had a highe r baselin e annual malaria incidenc e (30 per 1000 compared to 3 pe r 1000 in 369 \nthis trial) and a lowe r propo rtio n of imported mala ria (3% compared to 40% in thi s trial), both of which 370 \nmay facilitate higher impac t of focal MDA.(26) Second, the Namibia t rial was larg ely implemente d by a 371 \nresea rch team , while the Eswatini trial w as pragmatic and la rgely implement ed b y the local malaria 372 \ncontrol pr ogramme.(16) Coverage in the Namibia t rial was also higher compa red t o this trial (study ar ea 373 \nindex and targe t popula tion cover age we re >84% and >85%, compar ed to 78.5% a nd 78.7% in this trial).  374 \nThis trial faced several cha llenges uniqu e  to very low incidence set tings including strong 375 \nspatiot empor al clusteri ng and import ed malaria.(22) The number of cluste rs with  at least o ne inde x case 376 \nduring follow-up was lower than ex pect e d (we expecte d 63 but observe d 47). Thus, the t rial was not 377 \npowered t o det ect t he hypoth esized inci dence red uction of ≥ 50%, no r smaller r e ductions, with 378 \nprecision. S econd, t hough the s tudy was cluster-ran domised, bas eline mala ria inci dence and t he 379 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n16 \n \npercen tage of import ed cases was higher  in the rfMDA arm th an the R ACD arm. The lower th an 380 \nexpec ted numb er of clusters p er arm like ly contribut ed to t hese imbal ances. Thou gh analyses adjusted 381 \nfor these fact ors, it r emains possible that  unmeasured fact ors affecting malaria tr ansmission differed 382 \nbetwee n arms. To furth er add ress baseli ne imbalance, we conduc ted a synth etic control an alysis, which 383 \nproduced similar r esults to th e primary a nalysis. However, th e synthe tic contr ol a nalysis did not 384 \ncompletely accoun t for pre-int erven tion differences in incidence b etwe en arms, li kely because few 385 \nclusters (<25 per a rm) had incident cases  during follow-up, and cluster-level incid ence varied . When 386 \noutcomes ar e rar e and clust ered , tri als r equire very la rge cluste r numbers t o have sufficient statis tical 387 \npower and basel ine bala nce.(27, 28)  388 \nImplemen tatio n factors may have influe nced effect estima tes . First, tot al covera ge was lower 389 \nthan th e tri al’s goal of 80%, and imbalan ced across arms (60% for RACD and 68.8% for rfMDA). 390 \nLimitations r elat ed to st affing and transp ort compromise d index cas e level covera ge and particip ants no t 391 \nbeing presen t compromised targe t popul ation cover age. Of no te, 12% of the rfM DA target p opula tion 392 \nwas ineligible to r eceive DP, with the mo st common reason b eing poten tial medic ation int erac tion with 393 \nARVs. Alth ough saquinavir, t he only ARV contraindic ate d for use with DP, is not available in Eswatini, 394 \nnurses exp ressed conc ern th at adve rse e vents could be int erpr et ed by the pa rtici pant as due to ARV, 395 \nand thus compromise A RV adher ence. W here A RV use is common, such as Eswatini which has the 396 \nhighest worldwide incide nce of human immunodeficiency virus (HIV),(29 ) better strat egies to a ddress 397 \nsafety concerns rega rding drug-drug int e raction will be ne eded . The use of less st ringent e xclusion 398 \ncriteri a (e.g. inclusion of pregn ant wome n, young children, individuals with cer tai n morbidities) as has 399 \nbeen safely prac ticed by othe rs(30) could also improve coverage . However, cove rage was not associa ted 400 \nwith incidence, suggesting t hat differ enc es in coverage be tween a rms were unlik ely to affect study 401 \nfindings. Second, int erven tion resp onse t ime was substantially highe r for two rfM DA clusters compare d 402 \nto the R ACD arm. It is possible tha t the re  was greater mal aria t ransmission be twe en index cas e 403 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n17 \n \ndetec tion and in terve ntion d elivery in th e rfMDA arm than the RACD arm. Third , study clusters wer e not 404 \nsepara ted by geograp hic buffer zones to minimize contamina tion, which can occu r due to vect ors or 405 \nhuman movement. H owever, clust er-lev el incidence was not co rrela ted b etwe en contiguous cluste rs, 406 \nsuggesting that the chance of con tamina tion in this t rial was low.   407 \nImport antly, our s tudy is the first t o sho w the safety of rfMDA using DP. The Namibia trial used 408 \nAL and in comparison, DP may be prefer able for MDA due t o ease of use and lon ger prot ective pe riod 409 \n(once versus twice daily, and 4–6 weeks versus a few days, due to th e half-life). Rarely, DP-associated 410 \nQT-interval prolo ngation may lea d to sud den dea th (1/~200 000), and in very low- endemic set tings the 411 \nrisk-to-benefit r atio may not favor DP.(15) Here, one pa rticipa nt had symptoms t hat could be consis tent 412 \nwith arrythmia , and tr ea tment was stop ped. Pharmacovigilance pr ovided by nurs es through follow-up 413 \nvisits and their on-call avail ability likely helped t o preven t SAEs.  414 \n 415 \nConclusions  416 \nThis study is the first trial to compar e rfMDA and RACD in a very low malaria-endemic setting . As 417 \ninterven tions wer e embedd ed within an existing na tional mal aria pr ogramme, i t provides such evidence 418 \nin realistic implem enta tion condi tions. W e found tha t rfMDA was safe. Alth ough rfMDA clusters had 419 \nlower cumulative incidenc e during th e st udy period, we wer e unable to confirm e ffectiveness of rfMDA 420 \ncompared t o RACD, poten tially due to in sufficient power. Fo r rfMDA to be mor e effective than R ACD, 421 \nimproved coverage and/o r the a ddition of complementary int erven tions, such as  IRS, may need t o be 422 \ndelivered in tandem .(13) To improve stat istical power t o det ect impact of int erve ntions in very low-423 \nendemic set tings, futur e trials may re qui re multi-site d esigns, large r sample sizes,  or alte rnatively, 424 \nsmaller units of rand omisation (e .g. a nei ghborhood), or ad aptive d esigns that a djust featur es such as 425 \nthe sample siz e and alloca tion ra tio .(31, 32) Such evidence will be critical to guide  countries in th eir 426 \nquest to move from very low to no trans mission. 427 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n18 \n \n 428 \nList of abbreviations 429 \n 430 \naITT  adjusted int enti on to t rea t  431 \nARV  antir etr ovirals  432 \nDP   dihydroar temisinin-pipe raquin e  433 \nHIV  human immunodeficiency virus 434 \nITT   inten tion to tre at  435 \nIRS   indoor resi dual spraying  436 \nLAMP  loop mediat ed isoth ermal amplifica tion  437 \nMDA  mass drug administrat ion  438 \nNMP  Natio nal Mala ria Programme  439 \nPCR  polymerase chain r eacti on  440 \nRACD  reactive cas e det ection  441 \nrfMDA  reactive focal mass drug administ rati on  442 \nRDT rapid diagnostic test  443 \nSAE  serious advers e events  444 \nWHO  World He alth O rganiza tion  445 \n 446 \n 447 \n 448 \n 449 \n 450 \nDeclarations  451 \n 452 \nEthics approval an d co nsent to partici pate 453 \nEthics approval was given by Eswatini Ministry of Health (MH/599C) and by University of California San 454 \nFrancisco Human Rese arch Prot ection Pr ogram & IRB (Formerly Committe e on Hu man Research) (14-455 \n15226). Writt en informed conse nt was o btained from individual p articip ants . For children less th an 18 456 \nyears, writ ten informed cons ent from a p aren t or guardi an was requir ed, as was writt en assen t for 457 \nchildren 12–17 years .  458 \nTrial registration  459 \nClinicalTrials.gov, NCT02315690 (registra tion dat e: Decemb er 8, 2014) 460 \nConsent for publication   461 \nNot applic able  462 \n 463 \nAvailability of data and materials  464 \nThe data t hat supp ort the findings of this  study are availabl e from Eswatini Minist ry of Health but 465 \nrestric tions apply to the availa bility of th ese dat a, which were used und er licens e for the curr ent st udy, 466 \nand so are no t publicly available . Data ar e however availabl e from the au tho rs upon reason able r eques t 467 \nand with permission of Eswatini Minist ry of Health.  468 \n 469 \nCompeting inter ests 470 \nThe autho rs declar e tha t th ey have no competing inte res ts.  471 \n 472 \nFunding  473 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n19 \n \nThis study was supported by the Bill & M elinda G ates Fo undati on (A122394) and the Horchow Family 474 \nFund (5300375400). The funders of the study had no rol e in study design, dat a col lection, d ata an alysis, 475 \ndata in terp ret atio n, or writi ng of the rep ort.  476 \n 477 \nPatient and Public Involvem ent  478 \nAs assessed formally (through Knowledg es Atti tudes a nd Practices surveys) and informally (during 479 \nmalaria progr amme activiti es including r eactive case d etec tion), th e public’s conc erns abou t malaria and 480 \ntheir eagern ess for the coun try to achi eve its goal of malaria elimin ation info rme d the res earch qu estion 481 \nand study design. As incide nt malari a cas es were th e trigge r for recrui tmen t (targ eting househ old 482 \nmembers and neighb ors of index cas es) and the prim ary outcome , thes e aspec ts of the study reli ed on 483 \npatien ts seeking car e when ill and rec eiving malaria tes ting. To elicit o ngoing feed back regarding th e 484 \nconduct and burd en of the s tudy interve ntion, pa tien ts and th e public were enga ged in an ongoing basis 485 \nthrough focus group discussions, th e res ults of which are published els ewher e.(1 8)  486 \n 487 \nAuthors’ co ntributions  488 \nMSH, SK, and RG conc eptua lised and d esigned the stu dy. NN , ND, and KB contr ib uted t o study design. 489 \nNM led th e tri al coordin ation . KB, BD, DH, LMP, and CM additionally suppor ted tri al coordina tion. ND led 490 \nthe field implemen ta tion. SV led the da ta  collection. MK and GT oversaw clinical a nd safety aspects of 491 \nthe t rial. KB overs aw data collec tion and analysis of acceptability assessmen t. NN led the la bora tory 492 \nactivities with oversigh t from DH, BG, an d GM. SV and BW l ed dat a managemen t and support ed da ta 493 \nanalyses. MSKD, JBC, and MSH l ed th e da ta analysis. R G and DP advised on the da t a analyses. J BC and 494 \nMSH wrote the manuscrip t. N N and SK p rovided oversight of local implem enta tio n. MSH provided 495 \noverall oversight of th e study. All auth ors  read and app roved th e final manuscript .  496 \nAcknowledgements  497 \nThe autho rs would like to th ank the r esid ents of Eswatini who support ed th e stud y through thei r 498 \nparticipa tion and in puts. We th ank the fi eld and labo rato ry staff. We t hank Alema yehu for collecting 499 \necological dat a. W e thank Ad am Soble, Manik Saini, Charlo tt e Lejeune, a nd Tho mas How at CHAI for 500 \ntheir supp ort in adminis tra tion and loc al coordina tion. W e th ank Justin Cohe n, Ar naud LeMenach , Hugh 501 \nSturrock, Joell e Nadl e, Immo Kleinschmi dt, and Rob er t Haley for th eir inpu ts on t rial design. W e thank 502 \nthe Minis try of Health , Eswatini Pharmac ovigilance committe e, and th e Eswatini Malaria Elimina tion 503 \nAdvisory Group for their supp ort a nd ove rsight.  504 \n 505 \n 506 \nFigure lege nds 507 \nFigure 1. Map of th e study ar ea  508 \nAbbrevia tions: rfMDA, react ive focal mass drug administra tion; R ACD, reactive cas e det ection .  509 \n 510 \nFigure 2. Trial pr ofile showing randomisa tion and en rolmen t  511 \nAbbrevia tions: rfMDA, react ive focal mass drug administra tion; R ACD, reactive cas e det ection ; RDT, 512 \nrapid diagnostic test ; LAMP, loop-media t ed isothe rmal amplification ; AL, ar teme t her-lumefant rine ; DP, 513 \ndihydroar temisinin-pipe raquin e  514 \n*not cover ed due to staff limitati ons, fue l shortages, o r weath er condi tions compl icating transp ort  515 \n†RDT testing conduct ed in 262 of DP ineligibles. As none test ed positive , none we re refe rred for 516 \ntrea tmen t with AL  517 \n 518 \nFigure 3. Mon thly incidence in e ach stud y arm prior to and du ring the in terve ntio n period.  519 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n20 \n \nRACD, reactive case d etec tion; rfMDA, re active focal mass drug administra tion  520 \n 521 \nFigure 4. Mala ria-fre e survival curves for the ou tcomes of a) all incident mala ria cases, and b) local 522 \nincident mala ria cases. R ACD, reactive ca se detec tion; rfMDA, reac tive focal mass drug administra tion . 523 \nHigh transmission seasons occur red from  follow-up months 1-5 and 13-18.   524 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n21 \n \nReferences  525 \n1. Feachem RG A, Chen I, Akbari O , Ber tozzi- Villa A, Bhat t S, Binka F, e t al. Malari a era dication 526 \nwithin a gener ation : ambitio us, achievab le, and nec essary. Lance t. 2019;394(10203):1056-112. 527 \n2. Okell LC, Bousema T, Griffin JT, Ou edra o go AL, Ghani AC, Drakel ey CJ. Factors d et ermining the 528 \noccurrence of submicroscopic mala ria infections and their r elevance for con trol . N at Commun. 529 \n2012;3:1237.  530 \n3. Sturrock HJ , Hsiang MS, Cohen JM, Smith  DL, Greenhous e B, Bous ema T, et al . Tar geting 531 \nasymptomatic malari a infections: active surveillance in cont rol and elimin ation . PLoS Med. 532 \n2013;10(6):e1001467. 533 \n4. Moonen B , Cohen JM , Snow RW, Slutske r L, Drakeley C, Smith DL, et al. Op era tion al stra tegies to 534 \nachieve and maint ain malari a eliminat io n. Lancet . 2010;376(9752):1592-603. 535 \n5. WHO. W HO Evidence R eview Group on mass drug administrat ion, mass scree nin g and 536 \ntrea tmen t and focal scree ning and tr eat ment for malari a. G eneva, Swit zerl and: World He alth 537 \nOrganiza tion; 2015 .  538 \n6. Poirot E, Skarbinski J, Sincl air D, Kachur S P, Slutsker L, Hwang J. Mass drug admini strati on for 539 \nmalaria. Cochr ane Data base Syst Rev. 20 13(12):C D008846. 540 \n7. Newby G, Hwang J, Koit a K, Chen I, G ree nwood B, von Seidlein L, e t al. R eview of mass drug 541 \nadministra tion for mala ria and its op era ti onal challenges . Am J Trop M ed Hyg. 2015;93(1):125-34. 542 \n8. White NJ . Does antimala rial mass drug a dministrati on incre ase or d ecreas e the ri sk of 543 \nresistanc e? Lancet Infect Dis. 2017;17(1):e15-e20.  544 \n9. WHO. M ass drug administr ation for falci parum malaria . G eneva, Switz erlan d: Wo rld Healt h 545 \nOrganiza tion; 2017 .  546 \n10. Eisele TP, Benne tt A, Silumb e K, Finn TP, Chalwe V, Kamuliwo M, et al. Shor t-t erm  Impact of 547 \nMass Drug Administra tion Wi th Dihydroa rtemisinin Plus Piperaquin e on Mal aria in  Souther n Province 548 \nZambia: A Cluster-Ran domized Cont rolle d Trial. The Jou rnal of infectious dis eases . 2016;214(12):1831-9. 549 \n11. Programme WGM . Wo rld Mala ria Rep ort  2019. Geneva : World H ealt h Organiz atio n; 2019.  550 \n12. Hsiang MS, Ntsha lintshali N, Kang Dufour MS, Dlamini N, Nhlab athi N , Vilakati S, e t al. Active 551 \ncase-finding for malaria: A t hre e-year na t ional evalua tion of optimal a pproach es t o detec t infections an d 552 \nhotspots through r eactive cas e det ection  in the low transmission se tting of Eswati ni. Clin Infect Dis. 553 \n2019. 554 \n13. Hsiang MS, Ntuku H, R ober ts KW, Dufour  MK, Whitt emore B , Tambo M, e t al. Effe ctiveness of 555 \nreactive focal mass drug administ rati on a nd reactive focal vecto r cont rol to r educ e malaria t ransmission 556 \nin the low malaria- endemic set ting of Na mibia: a cluster- randomised con troll ed, open-label , two-by-two 557 \nfactorial design t rial. Lanc et. 2020 ;395(10233):1361-73. 558 \n14. WHO. A fr amework for malaria eliminati on. G eneva: W orld He alth O rganiza tion; 2017. 559 \n15. WHO. The ca rdiot oxicity of antim alarials .   WHO Evidence Review Gr oup Me eting; Octobe r 13 to 560 \n14; Gen eva, Switze rland: World H ealth O rganizati on; 2016.  561 \n16. Ford I, N orri e J. Pragma tic Trials. N Engl J Med. 2016;375(5):454-63. 562 \n17. Programme SNMC. N ation al Mala ria Con trol Programme A nnual Re por t 2014-2015. In: He alth 563 \nMo, edi tor. Mbaban e, Swaziland2015 .  564 \n18. Baltz ell KA, Maglior A, Bangu K, Mngadi N, Prach LM, Whit temo re B, e t al. \"W e were afrai d of 565 \nthe lion t hat has r oar ed ne xt t o us\"; com munity response to re active focal mass drug administra tion for 566 \nmalaria in Eswatini (formerly Swaziland). Malaria jour nal. 2019;18(1):238.  567 \n19. Hayes R, Moult on L. Cluster Ra ndomised Trials: CRC Press; 2009. 568 \n20. Grambsch PM, Thern eau TM. Propo rtio n al hazards t ests and di agnostics based o n  weighted 569 \nresiduals. B iomet rika. 1994;81(3):515–26 . 570 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n22 \n \n21. Pocock SJ, Assmann SE, Enos LE, Kasten LE. Subgroup analysis, covaria te adjus tme nt and 571 \nbaseline compa risons in clinical trial repo rting: curr ent p ractice a nd probl ems. Sta t Med. 572 \n2002;21(19):2917-30.  573 \n22. Bousema T, Griffin JT, Sau erwein R W, Sm ith DL, Churcher TS, Takken W, et al . Hit ti ng hotspots: 574 \nspatial t arge ting of malaria for cont rol an d elimination . PLoS Med. 2012;9(1):e100 1165. 575 \n23. Rehkopf DH, Basu S. A N ew Tool for Case Studies in Epidemiology-the Syn the tic Control M eth od. 576 \nEpidemiology. 2018;29(4):503-5. 577 \n24. Newby G, Harva rd K, Cotte r C, Roh M, Be nnet t A, Chen I, et al . Scree n and tr ea t st rategi es for 578 \nmalaria elimina tion : a review of evidence , A Background Paper commissione d by the Bill and Meli nda 579 \nGat es Founda tion . San Francisco: Th e Gl obal Heal th Gr oup, Ins titu te for Global H ealth Scie nces, 580 \nUniversity of California, San Fr ancisco. ht tp://www.shrinkingthemalari amap.o rg/resources-581 \npublications/scre en-and-tr eat-s tra tegies- malaria-elimina tion-r eview-evidence ; 20 18. 582 \n25. Bridges DJ, Mille r JM, Chalwe V, Mo onga  H, Hamainza B, S teke tee R , et al . Community-led 583 \nResponses for Eliminati on (CoRE): a study protocol for a community rand omized controll ed tri al 584 \nassessing the effectiven ess of community-level, reactive focal drug adminis tra tio n for reducing 585 \nPlasmodium falciparum infection preval e nce and incidence in Sou the rn Province, Zambia. Trials. 586 \n2017;18(1):511. 587 \n26. von Seidlein L, Peto TJ, Landi er J , Nguyen  TN, Tripura R, Phommasone K, e t al. Th e  impact of 588 \ntarge ted mala ria elimina tion with mass d rug administra tions on falciparum mala ri a in Southe ast Asia : A 589 \ncluster ra ndomised t rial. PLoS Med . 2019;16(2):e1002745. 590 \n27. Lipsitch M, Eyal N. Improving vaccine tri a ls in infectious disease em ergencies . Scie nce. 591 \n2017;357(6347):153-6.  592 \n28. Lang T. Adaptive t rial design: could we us e this appr oach to improve clinical trials i n the field of 593 \nglobal healt h? Am J Trop M ed Hyg. 2011; 85(6):967-70.  594 \n29. Justman J , Ree d JB, Bic ego G, Donnel l D, Li K, Bock N, et al. Swazilan d HIV Incidenc e 595 \nMeasur ement Su rvey (SHIMS): a prospec tive nation al cohor t study. Lance t HIV. 2 017;4(2):e83-e92. 596 \n30. Gutman J, Kovacs S, Dorsey G, St ergachis  A, Ter Kuile FO . Safety, t oler ability, and efficacy of 597 \nrepea ted d oses of dihydroar temisinin-pi peraquin e for preve ntion a nd tr eatm ent of malaria: a 598 \nsystematic review and me ta-analysis. La ncet Infect Dis. 2017;17(2):184-93.  599 \n 600 \n  601 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n23 \n \nTables  602 \nTable 1. Baseline cha ract eristics of cluste rs (localities) included in the trial  603 \nCluster-level cha racteristic  Overall  \nn=77  \nRACD  \nn=38  \nrfMDA \nn=39  \nTransmission intensity and  cont rol  measures, mea n (95% CI)  \nSept 201 2–June 2 015     \nCumulative inc idence  of  all  cases 5.25 (3.7 6 – 6.74)  4.17 (2.9 1 – 5.43)  6.30 (3.5 9 – 9.01)  \nCumulative inc idence  of  loca l cases 4.02 (3.2 1 – 4.82)  3.31 (2.1 5 – 4.47)  4.70 (3.5 7 – 5.83)  \nPropo rtio n of  cases classified as impo rted a  31.9 (2 5.0 – 38.7)  35.8 (2 4.5 – 47.2)  28.1 (1 9.9 – 36.3)  \nJuly 20 14–June  20 15     \nCumulative inc idence  of  all  cases 2.99 (2.0 9 – 3.88)  2.59 (1.3 6 – 3.82)  3.38 (2.0 4 – 4.72)  \nCumulative inc idence  of  loca l cases 2.44 (1.5 6 – 3.32)  1.80 (0.6 1 – 2.99)  3.06 (1.7 5 – 4.38)  \nPropo rtio n of  cases classified as impo rted b  40.1 (2 9.2 – 51.0)  48.7 (3 1.3 – 66.2)  32.2 (1 8.3 – 46.0)  \nPopulati on c haracter istics, mean ( 95% CI)  \nSize 2715  (22 75 –  31 56)  2752  (20 86 –  34 18)  2680  (20 70 –  32 89)  \nEcol ogical  factors , media n (ra nge) \nRainfa ll, mm c  65.9 (3 6.9 – 92.6)  64.8 (3 9.6 – 92.6)  66.7 (3 6.9 – 89.0)  \nEVI c  0.29 (0.1 9 – 0.44)  0.28 (0.2 1 – 0.39)  0.29 (0.1 9 – 0.44)  \nElevation , m  368 ( 147  – 8 52)  377 ( 170  – 5 89)  355 ( 147  – 8 52)  \nDaytime LST, °C c  31.2 (2 8.3 – 35.7)  31.4 (2 8.4 – 35.2)  31.1 (2 8.3 – 35.7)  \nIncidences are cases per  10 00 p opu latio n  604 \nAbbreviatio ns: RACD, reactive case detection;  rfM DA, reactive fo cal mass dr ug admin istration ; E VI, e nhanced vegetative index; 605 \nLST, land su rface temperatu re  606 \na  Sample size (n ) fo r Overa ll , RACD, an d r fMDA were 74 , 3 6,  and 38 c lusters, respectively  607 \nb Samp le size (n)  fo r Overal l,  RACD, and  rfMDA we re 52 , 2 5,  and 27 c lusters, respectively  608 \nc  Mean month ly values Sept 20 15–June  20 17  609 \n 610 \n 611 \n  612 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n24 \n \nTable 2. Inte rvention cove rage and r espo nse time  613 \n Overall  \nn=47 a  \nRACD  \nn=22 a  \nrfMDA \nn=25 a  p-value  \nIndex case coverage b , mean % ( 95% CI) 78.5 (6 9.9 – 87.0)  80.1 (6 7.3 – 92.9)  77.0 (6 4.8 – 89.2)  0.72  \nTarget popu latio n coverage c , mean % \n(95% CI) \n78.7 (7 1.1 – 86.3)  75.6 (6 1.8 – 89.5)  81.4 (7 2.6 – 90.1)  0.45  \nTotal c overage d , mean  % (95% CI)  64.6 (5 6.4-7 2.9)  60.0 (4 6.0-7 4.0)  68.8 (5 8.6-7 9.1)  0.86  \nResponse time, med ian ( range) \nDays between index case report \nand i ntervention response  \n8 (3 –  52)  7 (2 –  27)  11 (3  – 5 2)  0.37  \nAbbreviatio ns: RACD, reactive case detection;  rfM DA, reactive fo cal mass dr ug admin istration  614 \na  Sample size (n ) fo r Overa ll , RACD, an d r fMDA were 41 , 2 0,  and 21 c lusters, respectively for  target populat ion coverage, total  615 \ncoverage, and t ime to intervention , an d respo nse time 616 \nb  Index case coverage was defined  as the perce ntage of eligi ble index cases that received a n i ntervention averaged acr oss study 617 \narm clusters.  618 \nc  Target pop ulati on c overage was defined as the p ercentage of the target po pulati on w ithin  20 0m z ones arou nd each  in dex case 619 \nthat received an interventio n averaged acr oss study arm cl usters.  620 \nd  T otal c overage was defined as the p rod uct o f i nd ex case coverage and target popu lation  coverage 621 \n 622 \n  623 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n25 \n \nTable 3. Adjusted incidenc e rat e ra tios (I RRs) in 2015–2017 comparing clusters as signed to RACD versus 624 \nrfMDA   625 \nStudy Arm N \nclusters \nIncidence (cases \nper 1 000  person -\nyears) \nCrude IRR  p-\nvalue Adjusted IRR* p-\nvalue \nAll cases \nRACD  22  1.97  \n(1.57 – 2.47)  1 (Ref)  \n0.99  \n1 (Ref)  \n0.80  \nrfMDA  25  2.11  \n(1.73 – 2.59)  \n1.01  \n(0.58 – 1.73)  \n0.93  \n(0.54 – 1.60)  \nLocal cases on ly \nRACD  22  0.97  \n(0.71 – 1.34)  1 (Ref)  \n0.85  \n1 (Ref)  \n0.47  \nrfMDA  25  1.29  \n(1.00 – 1.67)  \n1.06  \n(0.57 – 1.98)  \n0.77  \n(0.38 – 1.56)  \nAbbreviatio ns: RACD, reactive case detection;  rfM DA, reactive fo cal mass dr ug admin istration  626 \n95% Conf idence intervals f or inc idence  were estimated using the W ilson  method. Inci dence rate ra tios (IRRs) compa red l ocal ity-627 \nlevel inc idence  in  the r fMDA arm to the RACD arm  using an intentio n-to-t reat appr oach a nd negativ e bin omial  mode ls.   628 \n*Adjusted for baseline covariates that were associ ated with the outc ome: inc idence in 201 4–15  (al l cases model on ly), loca l 629 \ninci dence in 2 014– 15 ( loca l cases model  on ly). 630 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n77 Localities in study area \n(total population 209 085)\nRACD\n38 localities (total population 104 584) \nrfMDA\n39 localities (total population 104 501)\n121 cases reported in 25 localities (population 97 142)99 cases reported in 22 localities (population 66 575)\n2 134 eligible individuals \n(44/event)\n33 refusals (1.5%)\n398 not present (18.7%)\n7 not done (0.33%)\n1 696 RDTs done\n(34.6 individuals/event)\n76 refusals (2.9%)\n302 not present (11.5%)\n313 DP ineligible (11.9%)†\n87 potential medication interaction\n51 reported pregnancy\n13 possibly pregnant\n35 with heart, kidney, or liver problems \n14 less than 9 months\n8  weight <7 kg\n7 with fever or feeling ill \n8 family history of heart problems or sudden death\n4 allergic to DP \n86 unknown reason1 932 received DP\n(28.4 individuals/event)\nRANDOMISATIONTRIGGERING \nINDEX CASESCOMMUNITY INTERVENTION RESPONSE\n49 reactive intervention events covering 56 cases in 22 localities 68 rfMDA intervention events covering 89 cases in 25 localities\n43 cases not covered* 32 cases not covered*\n2,623 eligible individuals \n(39/event)\n1 691 RDT negative \n(10/1644 tested LAMP \npositive)\n5 RDT positive (3/5 tested \nLAMP positive)\n5 referred for treatment \nwith AL \n355 localities in Eswatini\n775 cases reported from 78 health facilities\n537 cases reside outside study area\n15 found in RACD\n3 false positives by microscopy\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint \n\nA B\n0.995\n0.996\n0.997\n0.998\n0.999\n1.000\n0 4 8 12 16 20\nMonths since study start\nProportion without malaria infectionRACD fMDA\nRACD 95% CI fMDA 95% CI High Low\nA) All cases\n24474 24469 24461 24455 24449 24417\n31927 31920 31910 31901 31886 31854\nRACD\nfMDA\n0 4 8 12 16 20\nMonths since study start\nNumber at risk\n0.997\n0.998\n0.999\n1.000\n0 4 8 12 16 20\nMonths since study start\nProportion without malaria infectionRACD fMDA\nRACD 95% CI fMDA 95% CI High Low\nB) Local cases only\n21791 21785 21785 21783 21780 21763\n31464 31463 31458 31451 31440 31422\nRACD\nfMDA\n0 4 8 12 16 20\nMonths since study start\nNumber at risk\n0.995\n0.996\n0.997\n0.998\n0.999\n1.000\n0 4 8 12 16 20\nMonths since study start\nProportion without malaria infectionRACD fMDA\nRACD 95% CI fMDA 95% CI High Low\nA) All cases\n24474 24469 24461 24455 24449 24417\n31927 31920 31910 31901 31886 31854\nRACD\nfMDA\n0 4 8 12 16 20\nMonths since study start\nNumber at risk\n0.997\n0.998\n0.999\n1.000\n0 4 8 12 16 20\nMonths since study start\nProportion without malaria infectionRACD fMDA\nRACD 95% CI fMDA 95% CI High Low\nB) Local cases only\n21791 21785 21785 21783 21780 21763\n31464 31463 31458 31451 31440 31422\nRACD\nfMDA\n0 4 8 12 16 20\nMonths since study start\nNumber at risk\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 12, 2021. ; https://doi.org/10.1101/2021.03.12.21252721doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}