Statistical analysis plan for the control of blood pressure and risk attenuation-rural Bangladesh, Pakistan, Sri Lanka (COBRA-BPS) trial: A cluster randomized trial for a multicomponent intervention versus usual care in hypertensive patients

UPDATE Open Access S a is ical analysis plan o he con ol o blood p essu e and isk a enua ion- u al Bangladesh, Pakis an, S i Lanka (COBRA- BPS) ial: a clus e andomized ial o a mul icomponen in e en ion e sus usual ca e in hype ensi e pa ien s Mihi Gandhi 1,2,3 , P yseley Nkouibe Assam 1,2* , Elizabe h L. Tu ne 4,5 , Donald E. Mo isky 6 , Edwin Chan 7 , Tazeen H. Ja a 5,8* , on behal o he COBRA-BPS S udy G oup Abs ac Backg ound: In u al sou h Asia, hype ension emains a signi ican public heal h issue wi h sub-op imal blood p essu e (BP) con ol a es. The goal o he ial is o e alua e he e ec i eness and cos -e ec i eness o a mul icomponen in e en ion (MCI) compa ed o usual ca e on lowe ing BP among adul s wi h hype ension in u al sou h-Asian communi ies. This a icle desc ibes he s a is ical analysis plan o he p ima y and seconda y objec i es ela ed o in e en ion e ec i eness based on clinical and pa ien - epo ed endpoin s. Me hods/Design: The s udy is a clus e andomized ial which will en oll 2550 pa icipan s aged ≥40 yea s wi h hype ension om u al communi ies in Bangladesh, Pakis an, and S i Lanka. The uni o andomiza ion is a clus e de ined by 250–300 households. Thi y clus e s, 10 om each coun y, a e andomized in a 1:1 a io o ei he MCI o usual ca e, s a i ied by coun y and hei dis ance om he clinic. All pa icipan s will be assessed e e y six mon hs o e a wo-yea pe iod a e baseline wi h measu emen s o sys olic and dias olic BP, an ihype ensi e and s a in medica ion use, medica ion adhe ence, physical ac i i y le el, an h opome ic pa ame e s, smoking s a us, and die a y habi s. The p ima y objec i e is o assess he e ec i eness o MCI as compa ed wi h usual ca e in e ms o mean change in sys olic BP om baseline o inal ollow-up a wo yea s. The p ima y ou come will be modelled using a gene alized linea mixed-model o epea ed measu es based on a pa icipan -le el analysis. The model will include clus e andom-e ec s and will use a non-independence esidual co ela ion ma ix o accoun o epea ed measu es on he same pa icipan . Sensi i i y analyses o he p ima y endpoin will be based on mul iple impu a ion as well as pa e n mix u e model ipping poin analyses. Seconda y ou comes will be analyzed using he same modeling app oach as o he p ima y ou come, wi h app op ia e dis ibu ions wi hin he exponen ial amily and co esponding link unc ions. (Con inued on nex page) * Co espondence: [email p o ec ed]; azeen.ja [email p o ec ed] 1 Depa men o Bios a is ics, Singapo e Clinical Resea ch Ins i u e, #02-01, Nanos, 31 Biopolis Way, Singapo e, Singapo e 5 Duke Global Heal h Ins i u e, Duke Uni e si y, T en Hall, 310 T en D i e, Du ham, NC, USA Full lis o au ho in o ma ion is a ailable a he end o he a icle © The Au ho (s). 2018 Open Access This a icle is dis ibu ed unde he e ms o he C ea i e Commons A ibu ion 4.0 In e na ional License (h p://c ea i ecommons.o g/licenses/by/4.0/), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided you gi e app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e Commons license, and indica e i changes we e made. The C ea i e Commons Public Domain Dedica ion wai e (h p://c ea i ecommons.o g/publicdomain/ze o/1.0/) applies o he da a made a ailable in his a icle, unless o he wise s a ed. Gandhi e al. T ials (2018) 19:658 h ps://doi.o g/10.1186/s13063-018-3022-8 (Con inued om p e ious page) Discussion: The a p io i s a is ical analysis plan will a oid epo ing bias and da a-d i en analysis o he p ima y and key seconda y ou comes. The esul s o he s udy will p o ide e idence o he bene i s and isks o he MCI o BP con ol in u al communi ies in sou h Asian coun ies wi h low- esou ced public heal h in as uc u e. T ial egis a ion: Clinical ials.go , NCT02657746. Regis e ed on 14 Janua y 2016. Keywo ds: Clus e andomized ial, Hype ension, S a is ical analysis plan, Blood p essu e In oduc ion The con ol o blood p essu e and isk a enua ion- u al Bangladesh, Pakis an, S i Lanka (COBRA-BPS) ial is a clus e andomized clinical ial o compa e a mul icom- ponen in e en ion (MCI) o usual ca e. The o e all goal is o e alua e he e ec i eness and cos -e ec i eness o MCI in adul s aged ≥40 yea s wi h hype ension who eside in u al communi ies o Bangladesh, Pakis an, and S i Lanka. MCI comp ises he ollowing i e compo- nen s: (1) home heal h educa ion (HHE) by go e nmen communi y heal h wo ke s (CHWs); (2) blood p essu e (BP) moni o ing and s epped-up e e al o a ained gene al p ac i ione (GP) using a checklis ; (3) ained public and p i a e p o ide s in managemen o hype en- sion and using a checklis ; (4) designa ed hype ension iage coun e and hype ension ca e coo dina o s in go e nmen clinics; and (5) a inancing model o compen- sa e o addi ional heal h se ices and p o ide subsides o low-income indi iduals wi h poo ly con olled hype en- sion. A de ailed desc ip ion o he COBRA-BPS ial p o ocol has al eady been published [1]. I con ained a b ie desc ip ion o he p ima y e ec i eness analysis. The cu en a icle desc ibes a mo e de ailed s a is ical analysis plan o he p ima y and seconda y objec i es o he in e en ion e ec i eness based on clinical and pa ien - e- po ed ou comes. A he ime o w i ing, no pos -baseline ou comes o e ec i eness has been analyzed in he ial. The a p io i s a is ical analysis plan will a oid epo ing bias and da a-d i en analysis. This a icle does no include an analysis plan o o he objec i es such as e alua ing cos -e - ec i eness o he in e en ion and pa ien s’expe ience du - ing he cou se o in e en ion h ough quali a i e da a. These opics will be co e ed in sepa a e pape s. Randomiza ion The ial is conduc ed in Bangladesh, Tangail Dis ic (popula ion 3.2 million), and Munshiganj Dis ic (popu- la ion 1.4 million); Pakis an, Tha a Dis ic (popula ion 1.5 million); and S i Lanka, Pu alam Dis ic (popula ion 1.6 million). The uni o andomiza ion was a clus e de ined by 250–300 households as de ined by local admin- is a ion acco ding o CHW ca chmen a ea (each se ed by 1–2 CHWs). These clus e s we e g ouped in geog aph- ically con iguous adminis a i e uni s (AUs) as de ined by he local go e nmen s (12 sub-dis ic s in Tangail, six subdis ic s in Munshignaj, 30 union councils in Tha a, 12 medical o ice s o he heal h di ision in Pu alam Dis ic ) such ha each uni is se ed by one go e nmen clinic. Fi s , in he selec ed dis ic o each coun y, 10 adminis a i e uni s we e delibe a ely sampled, and he espec i e go e nmen clinic was de e mined. Wi hin each AU in each coun y, eligible clus e s we e iden i ied (one clus e is de ined as a illage o Bangladesh, 2–5 neigh- bo ing illages o Pakis an, and wo G ama Niladha i [GN] di isions o S i Lanka). Each coun y measu ed he dis ance o clus e s om he espec i e go e nmen clinic by a GPS de ice. In each AU, clus e s we e s a i ied in o wo s a a acco ding o hei dis ance o espec i e go e nmen clinic: FAR and NEAR (a dis ance o ≤2km was de ined as NEAR and > 2 km as FAR). In each a m (usual ca e o MCI), h ee o he i e AUs we e andomly sampled o be NEAR AUs so ha he emaining wo we e FAR. Then, one NEAR clus e om each NEAR AU and one FAR clus e om each FAR AU we e andomly selec ed o pa icipan ec ui men . A minimum dis ance o 10 km be ween andomized clus e s we e ensu ed. Figu e 1shows a schema ic diag am o clus e selec ion c i e ia. In summa y, andomiza ion was s a i ied by coun y as well as by he dis ance om he go e nmen clinic, and AUs (equi alen ly, he sampled clus e s) we e andomized in a 1:1 a io o ei he MCI o usual ca e wi hin he six s a a de ined by he combina ion o coun y and dis ance (NEAR e sus FAR) using a com- pu e -gene a ed andomiza ion p og am a Singapo e Clinical Resea ch Ins i u e, Singapo e. S udy assessmen s S udy assessmen s a e summa ized in Table 1.Themajo i y o he assessmen will be pe o med a six-mon hly home isi s up o wo yea s om he baseline. The accep able ole ance in he six-mon hly isi s is ± 2 mon hs. All assessmen s will be pe o med by independen assesso s (masked o andomiza ion s a us). Mo e de ails o s udy assessmen o ms, ques ionnai es, and checklis s a e a ail- able in he published p o ocol [1]. Sample size The planned sample size is 2550 pa icipan s wi h hype - ension, co esponding o a a ge sample size o 85 hype ensi e pa icipan s pe clus e o each o he 10 Gandhi e al. T ials (2018) 19:658 Page 2 o 11 clus e s pe coun y in each o he h ee coun ies. Based on indings om a p e ious easibili y s udy in u al Bangladesh, Pakis an, and S i Lanka [2], a conse a i e in aclass co ela ion coe icien (ICC) o 0.02 was conside ed. Assuming 80% pa icipan e en ion a e pe clus e a wo yea s a e baseline (68 hype ensi e pa icipan s pe clus e ) and a wo-sided ype I e o a e o 5%, he ial will p o ide > 99% powe o he o e all es o de ec a di e ence be ween a ms in SBP educ ion as small as 4 (SD 11) mm Hg [3–5]. The s udy will use 5 mmHg as he clinically meaning ul di e ence be ween he wo a ms o educ ion in SBP. Pe aining o he e ogenei y in he in e en ion e ec among he h ee coun ies, we assume ha < 3 mmHg di e ence in SBP is no clinically meaning ul. The e o e, he in e en ion e ec will be conside ed he e ogeneous among coun ies i he di e ence in SBP educ ion be ween any wo coun ies is ≥3 mmHg (SD 11) ( o example, a educ ion in SBP o 3 mmHg in one coun y and 9 mmHg in he o he wo coun ies; o educ ion in SBP is 3 mmHg in one coun y, 6 mmHg he in second, and 9 mmHg in he hi d). The planned sample size p o- ides > 80% powe o de ec he e ogenei y (as de ined abo e) in in e en ion e ec s based on he ollowing assump ions: ICC o 0.02 and ype I e o a e o 0.16% Fig. 1 Schema ic diag am o clus e selec ion c i e ia in he andomiza ion Mul icomponen in e en ion clus e ; Usual ca e clus e ; Go e nmen clinic nea es o he andomized clus e ; Non- andomized clus e ; Go e nmen clinic ou side 10 km adius o andomized clus e . Rec angles ep esen adminis a i e uni s. Do ed line su ounding a clus e ep esen s a 10-km adius o he clus e . Do ed line su ounding a go e nmen clinic ep esen s a 2-km adium o he clinic. No usual ca e clus e s a e wi hin a 10-km adius o MCI clus e s. Any usual ca e clus e should no be nea e o a MCI go e nmen clinic han i s own; simila ly, any MCI clus e should no be nea e o a usual ca e go e nmen clinic han i s own Table 1 S udy assessmen s schedule Assessmen s S udy isi s Sc eening Baseline 6-mon hly (un il 2 yea s om baseline) In o med consen ✓ Demog aphics cha ac e is ics ✓ Sys olic and dias olic blood p essu es a ✓✓✓ Cu en blood p essu e medica ions ✓ Socioeconomic cha ac e is ics ✓ Medical his o y ✓ Concomi an medica ions ✓✓ Family medical his o y ✓ Tobacco smoking s a us ✓✓ In e na ional physical ac i i y ques ionnai e ✓✓ Die a y ques ionnai e ✓✓ EQ-5D-5L ques ionnai e ✓✓ b MMAS-8 o an ihype ensi e medica ion adhe ence ✓✓ MMAS-8 o s a ins adhe ence ✓ Adiposi y measu es (BMI, wais ci cum e ence) ✓✓ Labo a o y es s ✓✓ b Se um c ea inine Fas ing blood glucose To al choles e ol High densi y lipop o ein choles e ol Low densi y lipop o ein choles e ol T iglyce ides U ine spo albumin U ine spo sodium U ine spo c ea inine Ad e se/se ious ad e se e en s ✓✓ Dea h ✓ a Only measu emen s aken by independen assesso s who will be masked o andomiza ion will be used o he analysis b To be assessed only a inal ollow-up isi Gandhi e al. T ials (2018) 19:658 Page 3 o 11 (based on a Bon e oni adjus men o h ee pai wise compa isons). In addi ion o his, he ial has > 80% powe o de ec a di e ence o 4 mmHg (SD 11) in SBP educ ion be ween he MCI and usual ca e a ms o each coun y sepa a ely, o an ICC o 0.02, a wo-sided ype I e o a e o 5%, and 10 clus e s o size 85 pa icipan s pe coun y wi h 80% pa icipan e en ion a e pe clus e a wo yea s pos baseline (68 pa icipan s pe clus e ) (Fig. 2). Fu he mo e, he high powe also ensu es ha he main e ec is adequa ely powe ed e en a e adjus ing o d opou s. The e o e, he s udy is no o e -powe ed o he e ogenei y o d opou s (missing da a). Powe and Sample Size (PASS) e sion 14 so wa e was used o he powe calcula ions. Based on ou p e ious wo k in u ban Pakis an, and expec ing a somewha lowe a i ion a e in u al a eas, he a i ion a e is likely o be < 15% a he end o wo yea s in he o e all s udy; he e o e, ou assump ions abou ollow-up a es a e conse a i e [4]. S udy objec i es P ima y e ec i eness objec i e To assess he e ec i eness o MCI compa ed o usual ca e in e ms o mean change in sys olic blood p essu e (SBP) om baseline o inal ollow-up a wo yea s pos baseline. Seconda y e ec i eness objec i es To compa e mean change om baseline, o p opo ion, a he inal ollow-up a wo yea s pos baseline be ween MCI and usual ca e a m o he ollowing ou comes: BP con olled o a ge (SBP < 140 mmHg and dias olic blood p essu e [DBP] < 90 mmHg) Response (SBP < 140 mmHg and dias olic BP < 90 mmHg, o ≥5 mmHg educ ion in SBP a wo yea s om he baseline) Poo ly con olled BP (SBP ≥160 mmHg o DBP ≥100 mmHg) DBP An i-hype ension and s a in medica ions use An i-hype ensi e medica ion and s a ins adhe ence sco e assessed by he eigh -i em Mo isky Medica ion Adhe ence Scale (MMAS-8) Physical ac i i y sco e assessed by In e na ional Physical Ac i i y Ques ionnai e (IPAQ) Ca dio ascula e en s isk sco e assessed by INTERHEART “Choles e ol”modi iable isk sco e Heal h- ela ed quali y o li e assessed by 5-Le el Eu oQol-5 Dimension (EQ-5D-5L) ques ionnai e Body mass index (BMI) Wais ci cum e ence Cu en smoking s a us F equency o ege ables and ui s in ake pe week Fig. 2 S a is ical powe o indi idual coun y and o e all s udy a he planned sample size Gandhi e al. T ials (2018) 19:658 Page 4 o 11 Sal in ake assessed by u ine spo sodium- o- c ea inine a io and 24-h u ine sodium Inciden diabe es Choles e ol le el assessed by o al choles e ol, high densi y lipop o ein choles e ol, low densi y lipop o ein choles e ol, and iglyce ides Es ima ed glome ula il a ion a e (eGFR) U ine albumin exc e ion Table 2lis s de ini ions o he abo e ou comes a a pa icula isi . Explo a o y e ec i eness objec i es To compa e mean change in SBP a he inal ollow-up a wo yea s pos baseline be ween MCI and usual ca e a ms o he ollowing sub-g oups de ined acco ding o baseline cha ac e is ics: Table 2 Ou come de ini ions o e ec i eness objec i es Ou come Measu emen and de ini ion Sys olic and dias olic blood p essu e (SBP/DBP) Measu ed using a calib a ed au oma ed de ice (Om on HEM-7300 Blood P essu e Moni o ) wi h he indi idual in he si ing posi ion. Th ee eading a e aken a leas 3 min apa . Mean o las wo eadings will be used as he inal measu emen . Blood p essu e con olled o a ge SBP (mean o las 2 o 3 eadings) is < 140 mmHg and DBP (mean o las 2 o 3 eadings) is < 90 mmHg. Response SBP (mean o las 2 o 3 eadings) is < 140 mmHg and DBP (mean o las 2 o 3 eadings) is < 90 mmHg, o change in mean o las wo eadings om he mean o las wo eadings om he baseline is ≥5 mmHg. Poo ly con olled blood p essu e SBP (mean o las 2 o 3 eadings) is ≥160 mmHg o DBP (mean o las 2 o 3 eadings) is ≥100 mmHg. An i-hype ensi e and s a in medica ion usage In o ma ion on any ongoing an i-hype ensi e and s a in medica ions will be classi ied in o one o he ollowing medica ion classes: Angio ensin II Recep o Blocke o Angio ensin-Con e ing Enzyme Inhibi o , Be a Blocke , Calcium Channel Blocke , diu e ics, and s a ins. Eigh -i em Mo isky Medica ion Adhe ence Scale (MMAS-8) sco es Sel - epo ed medical adhe ence is measu ed by he MMAS-8, sepa a ely o an i-hype ensi e medica ion and s a ins [13–16]. MMAS-8 sco es a e calcula ed by summing all coded answe s. In e na ional Physical Ac i i y Ques ionnai e (IPAQ) sco es To al physical ac i i y sco e (MET-min/week) and ac i i y classi ica ion (Inac i e, Minimally Ac i e, and Highly Ac i e) a e de i ed acco ding o he IPAQ sco ing guideline [17]. Ca dio ascula e en s isk sco e The INTERHEART “Choles e ol”modi iable isk sco e p o ides a comp ehensi e nume ic assessmen o isk ac o s o ca dio ascula e en s [18]. The sco e is he sum o poin s o ques ions co esponding o ca ego ies o hese isk ac o s. Fi e-le el Eu oQol-5 Dimension (EQ-5D-5L) ques ionnai e index The EQ-5D-5L is adminis e ed o assess a pa icipan ’s heal h s a us on he day o assessmen . In addi ion, i has a isual analogue scale (VAS) measu ing heal h on a scale o 0 (The wo s heal h you can imagine) o 100 (The bes heal h you can imagine) [19]. The EQ-5D-5L index summa izing heal h s a us o he pa icipan s is calcula ed using he EQ-5D-5L alue se o England [20]. Cu en ly, he e is no alue se a ailable o Bangladesh, Pakis an, o S i Lanka. Howe e , i any mo e sui able alue se becomes a ailable be o e he inal da a analysis, i will be used. The EQ-5D-5L VAS is also conside ed as an addi ional heal h- ela ed quali y-o -li e measu e. Body mass index Calcula ed as weigh (kg) di ided by heigh 2 (m). Heigh is measu ed using s anda dized Po able S adiome e (Model SECA 213) in cm wi h g adua ion o 1 mm. Weigh is measu ed using s anda dized OMRON Digi al Weigh Scale (Model HN-286). Wais ci cum e ence Measu ed as pe he WHO STEPS p o ocol [21]. The measu emen o wais ci cum e ence is made a he app oxima e midpoin be ween he lowe ma gin o he las palpable ib and he op o he iliac c es . Cu en smoking s a us Indi iduals smoking obacco on a daily basis, including ciga e e, pipes, ciga s, che oo s, ciga illos, and wa e pipe smoking sessions, a e conside ed cu en smoke s. F ui s and ege ables in ake A die a y ques ionnai e is adminis e ed o collec in o ma ion on die a y habi s ela ed o ui s and ege ables in ake. A leas one in ake pe week will be conside ed an indica o o each ype o die a y in ake. Sal in ake Measu ed in e ms o u ine spo sodium- o-c ea inine a io and 24-h u ine sodium es ima ion by Kawaskai o mula [22]. (Chemis y analyze [u ine spo sodium]: Beckman Synch on Cx-7 by Ion Elec ode; Regen [u ine spo sodium]: aluminum silica e; Chemical analyze [u ine spo c ea inine]: Synch on Cx-7/Del a; Regen [u ine spo c ea inine]: THC2) Inciden diabe es The use o hypoglycemic agen s o as ing blood glucose ≥126 mg/dL a any ime du ing he wo-yea ollow-up pe iod o all pa icipan s wi hou p e alen diabe es a en ollmen . (Chemis y analyze : Beckman Synch on Cx-7/Del a; Reagen : GLUCm) Choles e ol le el Measu ed in e ms o o al choles e ol, high densi y lipop o ein choles e ol, low densi y lipop o ein choles e ol, and iglyce ides. (Chemis y analyze : Roche Hi achi 912; Reagen : Roche eagen s) Es ima ed glome ula il a ion a e Es ima ed using CKD-EPI equa ion [23]. U ine albumin exc e ion Measu ed in e ms o u ine albumin- o-c ea inine a io de ined as a a io o spo u ine albumin di ided by spo u ine c ea inine exp essed as mg/g. (Chemis y analyze : Beckman Synch on Cx-7/Del a; Regen : Py ogallol ed plus sodium molybda e) Gandhi e al. T ials (2018) 19:658 Page 5 o 11 Pa icipa ing coun y (Bangladesh, Pakis an, S i Lanka) Clus e dis ance om he p ima y ca e clinic (Fa , Nea ) Gende (Male, Female) Cu en ly on an i-hype ensi e medica ion (Yes, No) Poo ly con olled BP (SBP ≥160 mmHg o DBP ≥ 100 mmHg) Socioeconomic le el (Poo , Non-poo ) Addi ional explo a o y analysis may be pe o med o e alua e he in e en ion e ec o o he ou comes o he abo emen ioned sub-g oups. Sa e y objec i es To compa e he MCI and usual ca e a ms a he inal ollow-up a wo yea s pos andomiza ion o he ollowing endpoin s: P opo ion o pa icipan s who expe ienced any se ious ad e se e en (SAE) P opo ion o pa icipan s who expe ienced any SAE o special in e es (dea h [all cause], hospi al admission due o co ona y hea disease, hea ailu e, o s oke) On e en o an AE, he si e in es iga o will decide i s ca ego y and sys em o gan class and also e alua e whe he an AE is an SAE i i leads o o is classi ied in o one o mo e o ollowing ca ego ies: dea h; li e- h ea ening; disabili y o pe manen damage; hospi aliza ion (excludes eme gency oom isi s); p olonga ion o hospi al s ay (≥ 24 h); equi ed in e en ion o p e en pe manen impai - men o damage; o he SAEs. Table 3lis s he p ede ined ca ego ies and sys em o gan class o AEs. SAEs epo ed wi h an onse da e be o e he baseline isi o a e he inal assessmen isi a wo yea s will no be included in he analysis. Po en ial co a ia es The ollowing baseline a iables may be conside ed as po en ial co a ia es in he suppo i e analyses: Age (in yea s) Gende (male, emale) Educa ion le el (no o mal educa ion, o mal educa ion) Ma i al s a us (single [ne e ma ied, di o ced, sepa a ed, widowed], no single [ma ied]) Socioeconomic le el (poo , middle, high) BMI (obese/o e weigh [≥23.5 kg/m 2 BMI], non-obese/no -o e weigh [< 23.5 kg/m 2 BMI]) [6] Wais ci cum e ence Diabe es (yes, no) Ch onic diseases (yes [hea disease, ch onic kidney disease, s oke], no) Cu en ly using an an i-hype ensi e medica ion (yes, no) Cu en smoking s a us (yes, no) Physical ac i i y sco e (inac i e/minimally ac i e, highly ac i e) Sal in ake ○U ine spo sodium- o-c ea inine a io ○24-h u ine sodium Choles e ol le el ○To al choles e ol ○High densi y lipop o ein choles e ol ○Low densi y lipop o ein choles e ol ○ iglyce ides Kidney unc ion ○Es ima ed glome ula il a ion a e (eGRF) ○U ine spo albumin- o-c ea inine a io Po en ial mode a o s The ollowing a iables eco ded o e ime may be conside ed as po en ial mode a o s in he suppo i e analyses: BMI Wais ci cum e ence Adhe ence o an i-hype ensi e medica ion Cu en smoking s a us Physical ac i i y le el Popula ions In en - o- ea (ITT) popula ion The ITT popula ion consis ed o all en olled pa icipan s wi h a baseline isi (i.e. assessed o he p ima y and seconda y ou comes). Pa icipan s om he MCI clus e s will be included in he MCI a m e en i hey did no ecei e he MCI. Simila ly, pa icipan s om he usual ca e clus e s will be included in he usual ca e a m e en i hey a e exposed o he MCI. Table 3 P ede ined ca ego ies and sys em o gan classes o ad e se e en s Ca ego ies Sys em o gan classes Angioedema and anaphylac ic eac ion Pe iphe al edema Hypo ension Co ona y hea disease Hea ailu e S oke o ansien ischemic a ack Headache, dizziness, o ligh headedness Flushing Cough a e ini ia ing an ihype ensi e Abdominal pain Muscle pain Falls and auma O he Sys emic eac ions Ca dio ascula sys em Ne ous sys ems Skin and appendages Respi a o y sys em Gas oin es inal and hepa obilia y sys em O he Gandhi e al. T ials (2018) 19:658 Page 6 o 11 T ea ed popula ion The MCI a m includes all en olled pa icipan s who ha e a ended a leas one in e iew on HHE o is- i ed ained GPs (i.e. based on eceip o physician’s managemen checklis ) as a pa o he MCI in e en ion. The usual ca e a m includes all en olled pa icipan s. Pa icipan s om an MCI clus e who a e conside ed o ha e no been “ ea ed”(i.e. ha e no a ended any in e - iew on HHE and ha e no isi ed a ained GP as a pa o he MCI in e en ion) will be analyzed wi h he usual ca e a m. Pe -p o ocol popula ion The pe -p o ocol popula ion consis s o all en olled pa icipan s who do no ha e any signi ican p o ocol de ia ions (desc ibed below). Signi ican p o ocol iola ion/de ia ions including hose which could ha e an impac on he p ima y e ec i eness measu es, hose which p esen a sa e y isk o he pa ici- pan s, and/o hose ha a e o e hical conce n will be iden i ied du ing a blinded da a e iew be o e da abase lock. Gene al signi ican p o ocol iola ion/de ia ion c i e ia a e lis ed below: Eligibili y de ia ions (included in he s udy despi e mee ing ollowing c i e ia) 1) W ong hype ensi e diagnosis: nei he has pe sis en ly uncon olled BP (SBP ≥140 mmHg o DBP ≥90 mmHg) no on an i-hype ensi e medica ions. 2) Unde age: aged < 40 yea s. On-s udy de ia ions (con inued he s udy despi e mee ing ollowing c i e ia) 1) P egnancy 2) Any majo medical sys emic illness which p ecludes con inua ion 3) E o in in e en ion assignmen : pa icipan s ea ed wi h in e en ion a m di e en om he assigned clus e ’s in e en ion a m. 4) Wi hd aw consen o los o ollow-up The abo e lis o signi ican p o ocol de ia ion c i e ia may be ex ended as app op ia e. All e ec i eness analyses will be pe o med using he ITT popula ion. Howe e , conside ing he na u e o he s udy (communi y-based clus e andomized ial wi h da a collec ion in u al pa s o h ee de eloping coun ies), he e is a chance ha a small p opo ion o pa icipan s mayno p o ideany ollow-upda aandhence heywillno con ibu e o he e alua ion o in e en ion e ec i eness. I his p opo ion o pa icipan s is sizable, pa icipan dispos- i ion, and demog aphic and baseline pa icipan cha ac e is- ics will be analyzed using he ITT popula ion, as well as excluding pa icipan s who ha e no con ibu ed in he e ec i eness analyses. The ITT and pe -p o ocol popu- la ions may be used o addi ional suppo i e analysis o e ec i eness endpoin s. S udy in e en ion exposu e and sa e y analyses will be pe o med using he ea ed popula ion. The ITT popula ion may also be used o suppo i e sa e y analyses. S a is ical analyses Gene al me hods and da a handling ules All obse ed da a will be included in he ITT popula ion, wi h he excep ion o da a collec ed ou side he accep able assessmen window (± 2 mon hs) o each ime poin and pa icipan s wi h no ollow-up da a. The equency dis i- bu ion o he e ec i eness ou comes will be e iewed, e.g. using boxplo s and his og ams. Con inuous a iables wi h excessi e skewness and/o ku osis will be analyzed using app op ia e me hods o asymme ic da a o conside ed o ans o ma ion. All p alues will be wo-sided. A p alue < 0.05 o he p ima y analysis will be conside ed s a is ically signi ican , in line wi h he p especi ied le el used in he sample size calcula ion. All con idence in e - als (CI) will be a he 95% le el. All s a is ical analyses will be ca ied ou using SAS so wa e (SAS Ins i u e, NC, USA). A e he s a is ical plan has been w i en and signed o , and a e he da abase o he inal analysis has been locked, he indi idual clus e ’s assigned in e en ion will be made known o he s udy eam. T ial p o ile The numbe o pa icipan s en olled in o he s udy a sc eening, easons o sc eening ailu e, numbe o pa ici- pan s en olled, numbe o pa icipan s who comple ed he baseline and ollow-up isi s, mean and SD o clus e size a each isi will be summa ized by in e en ion a m using he CONSORT low cha [7]. The dis ibu ion o baseline cha ac e is ics will be summa ized by: (1) in e en ion a m; and (2) coun y and in e en ion a m, wi h desc ip- i e s a is ics o he ITT popula ion. In e en ion exposu e MCI exposu e is e alua ed using he HHE session deli e y a e, physician e e al a e, and physician’s e alua ion a e. Table 4de ines hese ideli y measu es. The ideli y measu es a e es ima ed along wi h co esponding 95% CI o coun y o he MCI a m based on he ea ed popula ion. Exposu e and adhe ence o an i-hype ensi e medica ions is summa ized as seconda y ou comes. P ima y e ec i eness analysis This p ima y analysis will be pe o med on he ITT popula ion. Change in SBP a wo yea s om baseline is he p ima y ou come. The ou six-mon hly change- Gandhi e al. T ials (2018) 19:658 Page 7 o 11 om-baseline measu emen s (six mon hs, 12 mon hs, 18 mon hs, and 24 mon hs) om all pa icipan s will be modelled simul aneously using a likelihood-based gene al- ized linea mixed-model o epea ed measu es (MMRM) based on a pa icipan -le el analysis, inco po a ing a clus e andom-e ec , using Gaussian dis ibu ion and iden i y link unc ion [8,9]. App op ia e dis ibu ions wi hin he exponen ial amily and co esponding link unc ions will be employed o he p ima y ou come in case o non-no mali y. An uns uc u ed ma ix will be used o model he esidual a iance-co a iance s uc u e wi hin pa icipan . I his model ails o con e ge, he e ogeneous oepli z, he e ogeneous au o eg essi e o o de one, au o- eg essi e o o de one, and compound symme y s uc- u es will be conside ed in he speci ied o de o model he co ela ion be ween ime poin s om he same pa ici- pan . MMRM accoun s o missing da a and is alid unde he missing a andom (MAR) assump ion. All p ima y analysis models will include ixed e ec s o baseline SBP, coun y, indica o o dis ance om clinic ( a o nea ), age, gende , in e en ion a m, isi numbe , and he in e en ion a m-by- isi numbe in e - ac ion. The p ima y ou come o in e es a wo yea s om baseline will be es ima ed wi h co esponding 95% CIs using he app op ia e con as a he inal isi . We will employ es ic ed/ esidual maximum likelihood wi h he be ween-wi hin app oxima ion o deg ee o eedom es ima ion [10]. Suppo i e e ec i eness analyses A MMRM model will be pe o med o SBP simila o he p ima y analysis men ioned abo e including in e ac ions o coun y, in e en ion g oup, and ime o de e mine whe he he e ec s di e by coun y. I he in e ac ion e ec is ound o be clinically meaning ul, a MMRM model simila o he p ima y analysis model will be pe o med sepa a ely o each coun y. The coun y-speci ic analyses will use Bon e oni co ec ed p alues and CIs o e alua ing in e en ion e ec i eness. Fu he analysis will be pe - o med simila o he p ima y analysis wi h each po en ial con ounde a a ime as ixed e ec (sepa a e model o each con ounde ) as well as all (o selec ed) po en ial con ounde s a he same ime as ixed e ec s (single model including mul iple con ounde s). The inal lis o con ounde s will be decided conside ing s a is ical signi i- cance (p< 0.1), e ec size, and clinical impo ance. A MMRM model will be pe o med o SBP simila o he p ima y analysis men ioned abo e, including each mode - a o a a ime as ixed e ec as well as all mode a o s a he same ime as ixed e ec s using he ITT popula ion. Fu he suppo i e analysis may be pe o med using he ITT and pe -p o ocol popula ions. Seconda y e ec i eness analyses Seconda y e ec i eness ou comes will be analyzed using a simila s a egy applied o he p ima y endpoin . Tha is, using a MMRM wi h an uns uc u ed a iance-co a i- ance ma ix. App op ia e dis ibu ions wi hin he expo- nen ial amily and co esponding link unc ions will be employed o each ou come. Analysis o inciden diabe es ( o hose wi hou p e alen diabe es a baseline), sal in- ake, and choles e ol le el will be based on only wo ime-poin s (baseline and wo yea s) using simila MMRM models. All seconda y analyses will be pe o med on he ITT popula ion. Suppo i e analyses may be pe o med using he ea ed and pe -p o ocol popula ions. Addi ional suppo i e analyses may be pe o med o e alua ed in e - en ion e ec a e adjus ing o po en ial con ounde s. Explo a o y e ec i eness analyses A MMRM model will be pe o med o SBP simila o he p ima y analysis men ioned abo e including a ixed e ec e m o cu en ly an i-hype ensi e medica ion (yes/no) a baseline and i s in e ac ions wi h in e en ion g oup and ime o de e mine whe he he in e en ion e ec di e s by an i-hype ensi e medica ion use s a us a baseline. Simila analysis will be pe o med o clus e dis ance om he p ima y ca e clinic, gende , poo ly con olled BP s a us, and socioeconomic s a us a base- line. I he in e ac ion e ec is ound o be clinically meaning ul, a MMRM model simila o he p ima y analysis model will be pe o med sepa a ely o each sub-g oup. These analyses will be pe o med on he ITT popula ion. Table 4 In e en ion ideli y measu es Fideli y measu e De ini ion Home heal h educa ion (HHE) session deli e y a e Calcula ed as he o al numbe o h ee-mon hly HHE sessions deli e ed a he household le el using he Communi y Heal h Wo ke s Moni o ing and Home Heal h Educa ion Checklis di ided by he o al numbe o planned HHE sessions un il he s udy discon inua ion/comple ion, mul iplied by 100. Physician e e al a e Calcula ed as he o al numbe o imes hey a e e e ed o ained physicians by CHWs using he Gene al P ac i ione Re e al Checklis di ided by he o al numbe o imes pa icipan s iden i ied wi h ha ing poo ly con olled BP (SBP ≥160 mmHg o DBP ≥100 mmHg) du ing s udy isi s un il he s udy discon inua ion/comple ion, mul iplied by 100. Physician’s e alua ion a e Calcula ed as he o al numbe o imes hey a e e alua ed by ained physicians using he Gene al P ac i ione Managemen Checklis di ided by he o al numbe o imes pa icipan s iden i ied wi h ha ing poo ly con olled BP du ing s udy isi s un il he s udy discon inua ion/comple ion, mul iplied by 100. Gandhi e al. T ials (2018) 19:658 Page 8 o 11 Handling o missing da a in he e ec i eness analyses The p ima y analysis is planned wi h no impu a ion o missing da a. The p ima y analysis, based on a likelihood- based MMRM, is alid unde he MAR assump ion [11]. The MAR assump ion means ha missingness is inde- penden o he unobse ed ou come alues a e accoun - ing o he app op ia e obse ed da a and co a ia es in he model. In o de o e alua e he obus ness o he indings o he MAR assump ion, sensi i i y analyses will be pe - o med unde a ying assump ions o da a conside ed likely o be missing unde MAR, as well as missing no a andom (MNAR). MNAR means ha missingness de- pends on he unobse ed alues and canno be p edic ed solely based on he pa icipan ’s obse ed da a. Se e al ypes o s a is ical models ha e been p oposed o analyze clinical s udy da a unde such assump ions. We will use wo possible app oaches o e alua e he impac o missingness. The i s app oach ha will be implemen ed o his s udy is he use o mul iple impu a ions and MMRM o he p ima y ou come. Using MI da a o change in SBP pos baseline (six mon hs, 12 mon hs, 18 mon hs, and 24 mon hs om baseline measu emen s) om all pa ic- ipan s will be modelled simul aneously using MMRM model same as he p ima y analysis. I is expec ed ha he majo i y o missing da a will be caused by pa icipan s discon inuing om he s udy p ema u ely. The esul ing missing da a will ha e a mono one pa e n, meaning ha once a pa icipan has missing da a o a isi , da a will be missing o all subse- quen isi s. I is also expec ed ha a small amoun o non-mono one missing da a (when pa icipan s skip in e media e isi s bu e u n o e alua ions a subse- quen isi s) will be p esen . The in e mi en missing da a will be impu ed using he Mon e Ca lo Ma ko Chain (MCMC) me hod o mul iple impu a ion be o e he impu a ion o he mono one missing da a [8]. The second app oach is he use o pa e n mix u e models (PMMs) and mul iple impu a ions, which will be implemen ed i he amoun o missingness on he p ima y ou come is > 25% o he di e ence in pe cen age o missing da a be ween he in e en ion a ms is ≥15% [8]. PMMs ha e he ad an ages o allowing anspa en and clinically in e p e able o mula ions o heassump ions ega ding unobse ed da a [11,12]. PMMs wi h del a (δ)adjus men s will be used and impu a ions will be based on an MNAR clinical assump ion ha pa icipan s om he MCI a m who discon inue a a gi en ime poin would ha e, on a e - age, hei unobse ed e icacy sco e wo se by some amoun , δ, compa ed wi h he obse ed e icacy sco e o pa icipan s who con inue o he nex assessed ime poin . Fo pu poses o he sensi i i y analyses, pa icipan s who discon inue om he usual ca e a m a e ea ed as i hey would ha e exhibi ed he same e olu ion o he disease and same bene i om in e en ion wi h usual ca e as pa ici- pan s ha s ayed on he s udy. Del a alues will be based on he es ima ed in e en ion e ec aken om he p ima y analysis in he ITT popula ion whe e alues will a y om 0 o he es ima ed in e en ion di e ence in inc emen s o 0.5 mmHg, so ha one can assess a which poin he s udy conclusions change om a o able o un a o able, ha is, so ha onecan inda ippingpoin .Thesewillbebasedon 10 impu a ions δ- alue. The magni ude o he ipping poin will hen be in e p e ed clinically and he obus ness o he s udy conclusions o missingness e alua ed. Sa e y analysis All on-s udy SAEs epo ed on SAE epo ing o ms will be summa ized by in e en ion a m, using he ea ed popula ion. The pe cen age and equency o pa icipan s who e e epo ed each ype o SAE and SAE o special in e es along wi h sys em o gan class will be abula ed. A simila sa e y analysis may be pe o med on he ITT popula ion. All dea hs, oge he wi h easons, will be summa ized using coun s by in e en ion a m based on he ITT popula ion. In e im analyses Planned in e im sa e y analyses a e o occu a e e y six mon hs om he s a o he s udy. The in e im ana- lyses will summa ize pa icipan baseline cha ac e is ics and on-s udy sa e y da a by andomized g oup, as well as pooled o e all andomized g oups, o he ea ed popula- ion. The by andomized g oup analysis is e iewed by an independen da a sa e y and moni o ing boa d. The s udy eam, excep s a is icians in ol ed in pe o ming he in e im analyses, is blinded o hese esul s. The pooled analysis (combined o andomized g oups) is p esen ed o he s udy eam. Discussion The COBRA-BPS ial is a p agma ic, mul i-coun y, clus e andomized, con olled ial o a MCI wi h po en- ial o implemen i on a wide scale na ionally in he pa icipa ing coun ies and beyond. The s udy aims o e alua e he bene i s o he MCI and moni o po en ial sa e y conce ns o BP con ol in he u al communi ies in sou h-Asian coun ies wi h low- esou ced public heal h in as uc u es. The clus e andomized s udy design is a p agma ic s udy o mimic how he p oposed in e en ion can be ollou p ima ily using he exis ing in as uc u e in coun ies wi h di e en ypes o heal hca e sys ems and a ailabili y o esou ces. The e o e, i helps o e alua e no jus he e ec i eness o he in e en ion in he eal-li e se ing bu also i s easibili y in implemen a ion wi h an es ima e o equi ed esou ces, ime and cos s. Gandhi e al. T ials (2018) 19:658 Page 9 o 11