Background There is a large treatment gap with few community services for people with schizophrenia in low income

countries largely due to the shortage of specialist mental healthcare human resources. Community based rehabilitation (CBR), involving lay health wor ers, has been shown to be feasible, acceptable and more effective than routine care for people with schizophrenia in observational studies. The aim of this study is to evaluate whether a lay health wor er led, Collaborative Community Based Care (CCBC) intervention, combined with usual !acility Based Care (!BC), is superior to !BC alone in improving outcomes for people with schizophrenia and their caregivers in "ndia. Methods/Design This trial is a multi#site, parallel group randomised controlled trial design in "ndia. The trial will be conducted concurrently at three sites in "ndia where persons with schizophrenia will be screened for eligibility and recruited after providing informed consent. Trial participants will be randomly allocated in a $%& ratio to the CCBC'!BC and !BC arms respectively using an allocation se(uence pre#prepared through the use of permuted bloc s, stratified within site. The structured CCBC intervention will be delivered by trained lay community health wor ers (C)*s) wor ing together with the treating +sychiatrist. *e aim to recruit $,$ persons with schizophrenia. The primary outcomes are reduction in severity of symptoms of schizophrenia and disability at &$ months. The study will be conducted according to good ethical practice, data analysis and reporting guidelines. Discussion "f the additional CCBC intervention delivered by front line C)*s is demonstrated to be effective and cost#effective in comparison to usually available care, this intervention can be scaled up to e-pand coverage and improve outcomes for persons with schizophrenia and their caregivers in low income countries. Trial registration The trial is registered with the "nternational .ociety for the Registration of Clinical Trials and the allocated uni(ue "/ number is ".RCT0 12,334&5.

Background
.chizophrenia is a severe mental disorder that usually has an onset in early adulthood and is often associated with persistent or relapsing symptoms and a range of other adverse outcomes 6&,$7. 8ven though a low prevalence disorder, schizophrenia contributes an estimated &.&9 of the total /isability :d;usted <ife =ears (/:<=>s) and ?.19 of the total /:<=>s attributable to the neuropsychiatric disorders 657 in .outh 8ast :sia ma ing it a priority public health concern for the region. There is international consensus that care for people with schizophrenia should largely be delivered in community settings for the best outcomes6@7. *hile in high resource countries, community care is the norm, in low income countries, the availability of community services is the e-ception617. Thus, for the ma;ority of persons with schizophrenia and their caregivers in low income countries, including in "ndia, there is little access to any care 627. :ddressing this >treatment gap> by scaling up accessible, acceptable and effective community based services for persons with schizophrenia is an urgent public health and ethical priority in countries li e "ndia637. .caling up of community services in low income countries faces challenges li e the paucity of specialist resources and the lac of evidence around the effectiveness, costs and processes involved in delivering community based interventions. Ane method that specifically addresses the challenges of the lac of specialist resources, accessibility and ine(uity in care provision is the Community Based Rehabilitation (CBR) strategy for persons with disabilities# a health and social intervention that is largely implemented by appropriately trained, lay persons within community settings6,7. "n addition, the CBR method has a strong focus on empowerment of service users, social inclusion, livelihood support and e(ualising of opportunities for people with disabilitiesB all of these are of particular relevance to persons with schizophrenia. : non#randomised controlled study from rural "ndia showed that CBR using trained lay community wor ers was feasible and improved outcomes for people with schizophrenia, compared with routine outpatient care 6?7. : more recent study from the same site has described the impact of specific components of the comple- intervention on long# term outcomes in people with schizophrenia6&47. These encouraging results need to be rigorously tested through a randomized controlled trial. "f demonstrated to be clinically effective and affordable in comparison to usually available care (i.e. facility based care) alone, such interventions can be scaled up e-pand coverage and improve outcomes of persons

with schizophrenia and their caregivers in low income countries by using available and low cost human resources. Objectives The ob;ectives of the trial are% firstly, to test the hypotheses that usual, !acility#Based Care (!BC), when combined with a Collaborative Community#Based Care intervention (CCBC), will be superior to !acility#Based Care alone in improving a range of outcomes in people with schizophrenia and their caregivers and, secondly, to determine if the CCBC intervention is cost effective in "ndia. The primary ob;ectives of the trial are to determine whether the !BC'CCBC intervention will be superior to !BC alone in% i) reducing symptoms of schizophrenia at &$ months, and ii) reducing disability related to schizophrenia over &$ months. "n persons with schizophrenia, the secondary ob;ectives are to determine whether, !BC'CCBC will be more effective than !BC alone, in% C improving adherence to antipsychotic treatment C reducing e-periences of stigma and discrimination !or caregivers of people with schizophrenia, the secondary ob;ectives are to determine whether, !BC' CCBC will be superior to !BC alone, in% C improving their nowledge and attitudes about the illness C reducing their burden of caring C reducing e-periences of stigma and discrimination. The health economic ob;ective is to compare the costs and assess the cost#effectiveness and cost#utility of the !BC' CCBC intervention compared to !BC alone.

The CA+." trial is a collaborative effort between multiple institutions and individual +sychiatrists at the "ndian sites. The lead institution is the "nstitute of +sychiatry ("o+), Dings> College, <ondon, while the partner organizations are the <ondon .chool of )ygiene and Tropical Eedicine (<.)TE), .angath in Foa, the .chizophrenia Research !oundation (.C:R!) in Chennai, the 0ational "nstitute of Eental )ealth and 0euroscience (0"E):0.) in Bangalore and +arivartan and 0irmittee in .atara. "n Foa and in .atara, the individual collaborators are +sychiatrists wor ing in the private sector.

Methods/Design
Study design 8ffectiveness, parallel group, randomised controlled trial design with une(ual allocation of participants between arms. The two arms of the study (allocation ration $%&) will compare people with schizophrenia allocated to receive% (i) !BC' CCBC, or (ii) !BC only, with follow up over &$ months. Setting The trial will be conducted in three sites in "ndia# in four rural bloc s or sub#districts in the southern "ndian state of Tamil 0adu and in two sites in western "ndia, # across the state of Foa and in .atara in the state of Eaharashtra. The relevant details of the sites are summarized in Table &. These three sites have been chosen to reflect a diversity of health system conte-ts, to strengthen the generalisability of the study findings and to meet trial recruitment targets within the allocated timeframe. Table 1. The characteristics of the CA+." trial sites. Description of the nterventions The collaborative co!!unity based care "##B#$ intervention The CCBC intervention is underpinned by three ey principles% C firstly, the intervention is planned and implemented for each participant in close collaboration between the person with schizophrenia, the primary care giver(s) and the

treatment team members (comprising the lay C)*, a supervising +sychiatric .ocial *or er and the treating +sychiatrist)B C secondly that the intervention is provided in a fle-ible manner that reflects the uni(ue needs of the person with schizophrenia and their caregivers andB C thirdly, that the intervention will promote respect, autonomy and dignity for the person with schizophrenia and caregivers. The inclusion of the specific treatment components within the treatment pac age have been guided by% C evidence that the treatment is locally feasible, acceptable and potentially of low costB C evidence for the effectiveness of the treatment in low and middle income settings andB C evidence that it can be delivered by lay health wor ers The CCBC intervention will be coordinated and delivered by lay C)*s who have completed at least &4 years of schooling and have been systematically trained at each site over 2 wee s. The training is based on the intervention manual that follows a modular structure covering various aspects of the illness, specific components of the intervention and the operational re(uirements of the trial related documentation and supervision

http%GGwww.sangath.comGdetails.phpHnavIidJ24 webcite. The C)*s will be closely supervised at each site by +sychiatric .ocial *or ers wor ing as designated "ntervention Coordinators. They will coordinate the overall delivery of the intervention and assure the (uality and fidelity of the intervention at the site. The treating +sychiatrists will provide clinical leadership for the community care teams and ongoing supervision to maintain safety and (uality standards. Averall, the continued supervision of the C)*s through ;oint onsite visits, wee ly group meetings and in scheduled meetings with the +sychiatrist is an essential component of the CCBC intervention. The treatments included in the intervention pac age are%

C structured psycho-educational information about various issues related to the understanding and proactive management of the illness for the participant and the care givers as well as specific efforts to identify and address e-periences of stigma and discrimination C adherence management strategies to reduce the rates of non#adherence to treatments C health promotion strategies to improve the physical health status of people with schizophrenia C .pecific rehabilitation strategies to improve the personal, social and vocational functioning of participants C <in age to self help groups and other methods of user led support C /eveloping networks with community agencies to address social problems in the family li e poverty or interpersonal disputes and facilitate a supportive framewor for participants to see employment and access to social and legal benefits The intervention is delivered in three phases. "n the initial, 5 month intensive engagement phase, the ey tas s will include developing a positive therapeutic alliance with the person with schizophrenia and care givers, conducting the needs assessment and generating the collaborative individual treatment plan. There will also be a focus on identifying and addressing familial social difficulties that have an adverse impact on the person with schizophrenia, adherence management and structured psycho#education sessions. *e anticipate that C)*s will conduct 2#, home based (or other convenient location nominated by the person and care givers) sessions during this phase. "n the second, stabilization phase during months @#3, the C)*s will conduct a total of 2#, fortnightly sessions. "n this phase, the focus will be on addressing the unmet or partially met needs from the first phase, reinforce psycho#education and adherence, and introduce other components li e health promotion, rehabilitation needs assessment and interventions (for e-ample, improving activities of daily living s ills and social s ills training), and improving social interactions within and outside of the family.

"n the final, maintenance phase during months ,#&$, the C)*s will conduct 2 sessions. "n this phase we intend to reinforce the progress made, discuss strategies to deal with distressing symptoms, discuss ways of dealing with e-periences of stigma and discrimination, focus on restoration of social and economic roles, generate a relapse prevention plan and address remaining unmet needs, to the e-tent possible before a carefully planned termination. "n total, we anticipate that each participant in the CCBC arm will receive a ma-imum of $$ planned contacts during the &$ months of the intervention, and that each C)* will carry a ma-imum case load of $1 people with schizophrenia at any one time. "n evaluating the intervention, we have set an a priori definition of >minimum ade(uate> as being &$ sessions of the CCBC sessions delivered over &$ months. :ll informational materials meant for the use of participants and caregivers has been systematically translated into the five regional languages used across the trial sites. The intervention has been systematically piloted at each of the sites. Based on the results of the field testing, the final content and process of the phase specific delivery of the intervention has been manualised, as mentioned earlier. %acility based #are "%B#$ >!acility Based Care> is the care usually provided by mental health practitioners for persons with schizophrenia and their families. "n two of the sites i.e. Foa and .atara, +sychiatrists in the private sector are the primary care providers with trained assistants recording essential socio demographic details in some of these clinics. "n rural Tamil 0adu, a team of three persons are involved in the clinics. : trained assistant records essential socio demographic details of all persons who come to the clinic. : brief clinical history is then elicited by the +sychiatric .ocial wor er (+.*) who then presents the findings to the clinic +sychiatrist for detailed assessment and treatment planning. "n Foa and in .atara, the +sychiatrists are the first point of contact and, for the most part, conduct all necessary procedures themselves. :cross all settings, consultations last from &1#@1 minutesB persons with schizophrenia presenting for the first time are reviewed once or twice a month while those who are clinically stable are reviewed more fle-ibly# once a month# 5 months. :lmost all persons with schizophrenia in these facilities are prescribed psychotropic medications with the newer

antipsychotic medications being preferred (as in "ndia, these newer drugs are cost comparable with the older antipsychotic drugs) while the use of antidepressants, anticholinergic, sedatives and modified 8lectroconvulsive treatment (8CT) is based on individual clinical needs. :ll psychiatrists also provide specific information about the illness, encourage adherence and discuss other specific concerns that the person with schizophrenia or their family members haveB all of these are provided on an >as needed> basis. The salient difference between the two arms is that in the CCBC arm, a comple- psychosocial intervention, tailored towards individual needs, will be delivered in an accessible (home based) and structured manner by a dedicated C)*. There will be no guidelines or protocols made available to +sychiatrists for the medical treatment of participants as this is more representative of usual care in "ndia. !BC will continue to be available to participants in both study arms and treating +sychiatrists will be unblinded while providing care for participants. Selection of participants CA+." is an effectiveness trial and to improve the generalisability of the study results, we will% C recruit persons with schizophrenia into the trial from those who present to routine, >real life> treatment settings and C include those persons with schizophrenia for whom community based care is ;ustified even in low resource countries. Thus, the inclusion criteria for participating in the trial are% C Trial participants must be between the ages of &2#24 years C )ave a primary diagnosis of schizophrenia as per "C/#&4 /CR criteria 6&&7 C )ave had an illness duration of at least &$ months and an overall moderate severity of the illness based on the Clinical Flobal "mpression#.chizophrenia(CF"#.C)) scale 6&$7 rating. This reflects the threshold at which additional community care is warranted in resource constrained settings where community based care can realistically be offered only for those with high needs.

C Be residing within the study catchment area for the ne-t &$ months. "n the Tamil 0adu site, participants will be selected from those identified through a community survey in the study area and will then be referred to community clinics for assessment by the +sychiatrists. "n Foa and .atara, participants will be approached for recruitment from the clinical practices of the collaborating +sychiatrists. "n these settings, we anticipate two pathways for recruitment% (a) people with schizophrenia from within the e-isting caseloads at each of the sites who meet inclusion criteriaB and (b) people with schizophrenia who have presented for care for the first time and meet all inclusion criteria. The flo& of participants in the trial The collaborating +sychiatrists will identify all persons with a primary diagnosis of "C/ &4# /CR schizophrenia in their setting by using a chec list. :ll persons with schizophrenia will be assigned a uni(ue identification number and the +sychiatrist will fill out an initial screening form to confirm eligibility and record other basic socio#demographic and clinical details. !rom this >universe> of persons with schizophrenia, for those who meet all inclusion criteria, the +sychiatrists will provide a brief overview of the trial together with a standard flier outlining the purpose of the trial (that is translated to all relevant local languages) and as the person and the caregiver (s) whether they are interested in participating in the trial. "f the person or the caregiver does not agree to proceed further, the +sychiatrist will briefly record their reasons for their not agreeing, whenever possible. !or those who have refused, the +sychiatrist has the option of revisiting their participation during the course of the recruitment period. "f both are interested to continue, the +sychiatrist will then fill out additional clinical details and ta e written (for non literate persons, their left thumb impression will be ta en) assent for the independent consent procedure. .ubse(uently, an independent, trained researcher will conduct the informed consent interview. The consent procedure has been specially designed to provide ade(uate information about the trial in a manner that is matched to the literacy levels of the participant and caregiver and to minimize the cognitive difficulties that persons with schizophrenia commonly face in processing information for ma ing an informed decision6&57. :fter the procedure, the participant and the caregivers ma e an informed choice to participate or not.

:t this stage, the researcher will record the reasons for participation or refusal, whenever possible. Ance informed consent has been obtained, trained researchers will complete the baseline (uantitative assessments for both the participant and the caregiver(s) who are then assigned a uni(ue trial "/. !rom this overall sample of participants, a purposively selected sub sample of &$ participant and their caregivers will be chosen at each of the three sites for the additional baseline (ualitative interviews. Ance all baseline assessments have been completed, participants will be randomly assigned to either of the $ arms of the study for the ne-t &$ months. The identification, registration and subse(uent flow of participants in the trial will be governed by the trial standard operational protocol (.A+) at all sites. This will be monitored closely using a set of process indicators and any deviations from the protocol and the reasons for the same will be carefully recorded. The flow of participants during the conduct of the trial, illustrated in !igure &, will be monitored and reported in compliance with the recent CA0.ART recommendations6&@7.

%igure 1. %lo& of participants during the conduct of the trial 'ando!isation (enerating the allocation list Three lists have been generated independently by the Trial .tatistician in <ondon, one for each site, and transmitted to the site /ata Eanagers prior to the commencement of the recruitment for the trial. The pre determined allocation se(uence cannot be altered during the recruitment of participants in the trial. )llocation conceal!ent The site /ata Eanagers will be entrusted with eeping the allocation list secure (through password protected files). The matching of the study numbers of the recruited participants with their randomization numbers and the concealment of randomization from interviewers

will also be managed by the central /ata Eanager to ensure that no one has access to the allocation list. !ple!entation !or logistic reasons, the site /ata Eanagers will be responsible for assigning the uni(ue trial "/ for each randomized participant in the trialB if the participant is assigned to the CCBC arm, the /ata Eanager will notify the site intervention coordinator and pass on the re(uired contact information. !or participants in both arms, the /ata Eanager will also ensure that treating +sychiatrists are provided with the specially designed clinical boo let to record treatment details for the ne-t &$ months. !or statistical reasons (see >sample size estimation> below) there will be une(ual allocation, with a larger number in the intervention arm. The rationale for the une(ual randomization is the additional source of variability in the intervention arm # the effect of individual community health wor ers which is built into the analysis and allowed for in the sample size as recommended in the recent CA0.ART guidelines for non pharmacological trial design and reporting6&17. "t is difficult to precisely estimate the magnitude of this e-tra variability (the intra#class correlation), but the value chosen for the intervention arm of 4.& is conservative% a recent review of a large number of primary care variables found the inter# (uartile range to be 4 to 4.45$6&27. !or practical reasons, the ratio of numbers in the two arms was fi-ed at a whole numberB for the study this has been chosen to be $%&. The method of allocation will be through the use of permuted bloc s, with random bloc sizes chosen from 5, 2 and ? using the >ralloc> routine in .tata. Outcome assessments 1. Quantitative assessments !or the primary outcome assessments, we will record the symptoms of schizophrenia at baseline and at &$ months, with the +ositive and 0egative .yndrome .cale (+:0..) 6&37. !or measuring the change in disability, we will use the "ndian /isability 8valuation and :ssessment .cale ("/8:.)6&,7 at baseline, 2 and &$ months to generate information on the time course of the effect of the intervention.

!or the secondary outcome assessment for persons with schizophrenia, we will measure% C Adherence with antipsychotic medication% !or each participant, we will assess adherence at baseline (if on treatment) and at 2 and &$ months using a 1 point ordinal scale developed for the study. C !or measuring various dimensions of the experience of stigma and discrimination , we will use the /iscrimination and .tigma .cale (/".C)6&?7 at baseline and at &$ months. C :n item on willingness to disclose mental illness 6$47 will be used for participants at baseline and at &$ months to assess their readiness to disclose their illness. C The :lienation subscale of the "nternalized .tigma of Eental "llness (".E") scale6$&7 will be used to measure the subjective experience of internalized stigma of participants at baseline and at &$ months. C !inally, to estimate the Quality Adjusted Life Years QALY!, we will use the widely used 8uro(ol (8K#1/) 6$$7 at baseline and at &$ months. The secondary outco!e !easure for the primary care givers are% C The family burden of caring will be measured at baseline and at &$ months by using the Burden :ssessment .chedule (B:.) which has been developed and used widely in "ndia6$57. C The knowledge and attitudes of family members about schizophrenia will be assessed at baseline and at &$ months by using the Dnowledge about .chizophrenia "nterview (D:.") 6$@7 C : section of the >!amily "nterview .chedule> (!".) developed for the "nternational .tudy of .chizophrenia (".A.)6$17 and previously used in a study in "ndia6$27 will be employed to assess the experiences of stigma and discrimination experienced by the primary caregivers. C The item on willingness to disclose mental illness 6$47will be used for caregivers after suitable modification.

C The caregiver summary assessment of the participant"s degree of adherence will be rated by using the same 1 point ordinal scale used for participants. To improve the validity of adherence ratings, we will complete a systematic assessment of medication use for the last $ months (to minimize recall bias over the 2 month period)B this $ month adherence will be e-trapolated for the last 2 months. !or the economic aspects of the study, we will as caregivers to complete the Cost of "llness .chedule (C".) that has been developed and used in "ndia in community studies before6$37 at baseline, 2 and &$ months. "n addition, we will record the type, dosage and duration of medications prescribed by treating +sychiatrists during each of the contacts with participants as well as the number of inpatient days for each participant # this data will be available from the +sychiatrists> structured records. .ervice costs will be calculated by attaching locally calculated unit costs to these data. "n addition, we will use the 8uro(ol 8K#1/ with participants for assessing Kuality of <ife =ears at baseline and at &$ months. The adherence measures and the C". will be repeated at 2 months, as will the "/8:.. !or the C". and adherence measures, the rationale is to minimize recall bias. The "/8:. will be used at 2 months to have an interim measure for one of the primary outcomes that is brief and easy to complete. Table $ describes the data collection details of the study. Table *. .ummary table of data collection in CA+.". !inally, we will record other presence of co#morbid mental and physical disorders and relevant socio# demographic information about the participant, the primary caregiver and the family during the baseline assessment. Outcome evaluation/masking The outcome evaluation of symptoms using the +:0.. will be carried out by mental health professionals who will be trained, certified and supervised by e-perts. :ll other outcome measurements will be conducted by trained graduate researchers. The selected researchers will be trained in a structured manner across the sites to ensure ade(uate inter#rater reliability for all scale items across the sites. To maintain blinding of these assessments, all outcome

measures will be administered by researchers who are independent of the intervention and blind to the allocation of treatment. .ince neither the participant nor the family caregivers will be blind to their allocation status at the time of the 2 and &$ month interviews, we intend to minimize the chances of unmas ing during the outcome assessments by instituting the following measures% C The intervention and research teams at the sites will not have any interactions during the trial with separate physical location and administrative management. C The researchers are told that they are evaluating two interventions and that there is genuine e(uipoise about which one is better C Arient the families prior to each assessment that they should not disclose whether or not they are receiving home visits from the C)* and C Complete the primary outcome measures (+:0.. and the "/8:.) first. 2. Qualitative Data Collection The purpose of (ualitative data collection within the trial is to describe the e-periences of participants and caregivers in the two arms relating to the care received (including acceptability and perceived effect), the impact of the illness and e-periences of stigma and discrimination. *e also intend to describe changes in these domains over the follow#up period, e-plore attributions of changes and to compare outcomes between the two arms of the trial. *e intend to recruit appro-imately 52 participants and 52 primary caregivers (J 52 participant # caregiver dyads) at each site for the in#depth#interviews at baselineB however, numbers may be increased if indicated by ongoing analyses. .eparate consent will be obtained from participants and caregiver(s) for these (ualitative interviews. The same participants and caregivers who are interviewed at baseline will be approached for follow#up interviews &$ months later after the final (uantitative outcome assessments are completed. The sampling strategy is purposive, ta ing into account participant>s gender and the degree to which stigma is a concern to the participant as assessed by (uantitative measures. 8fforts will

be made to purposively interview outliers. .ampling will further aim to ensure sample variability at each research site with regards to severity of illness, highest education levels in the household, type of relationship of caregiver to patient and other themes that may emerge as important from ongoing analyses. "n addition, we propose to conduct in#depth#interviews with +sychiatrists and C)*s at endpoint to ascertain their satisfaction with wor , the ade(uacy of training and supervision and their impressions on the impact of the program. Quality assurance and fidelity management To ensure that the CCBC intervention is of ade(uate fidelity, we will collate the intervention process indicators related to the delivery of the intervention (Table $) every month from each site. This will be monitored to chec for significant divergence from per protocol norms between the sitesB any such divergence will lead to suitable corrective action to harmonize the intervention across the sites. !or (uality assurance purposes, ey CCBC sessions at each site (needs assessment, 5 and 2 month reviews and termination session) will be rated by intervention coordinators during ;oint home visits with the C)*s. !eedbac for improving the methods and delivery of the intervention will be provided to all C)*s to achieve and maintain pre determined (uality benchmar s during the trial. .ystematic efforts will be made to ensure that both (uantitative outcome measurements as well as (ualitative interviews will be of ade(uate (uality across the sites. The researchers will be supervised in a wee ly group meeting with the study coordinators at each site. "n addition, 19 of all interviews at each site will be assessed through ;oint onsite visits with the coordinator who will provide feedbac using a specially designed assessment form to confirm that the overall pre#set (uality benchmar s are achieved and maintained during the trial. !or the (ualitative data, there will be regular supervision available for researchers at each site with regular group and individual supervision related to interview methods, data translation and transcription.

To ensure the safety of the researchers while conducting interviews at the homes of participants, all initial visits will be made by a team of $ researchers who will have notified the Coordinators about their location. Researchers have also been trained to recognize possible dangers and threats and respond to them appropriately (seating arrangements, non confrontational interview techni(ues). :ll researchers will also have access to mobile phones to discuss any potentially difficult situation with their supervisor. "n case of any untoward incident, researchers will have provision for debriefing and a review of the safety arrangements. Statistical issues Sample size estimation Based on the data from the earlier non randomized study6?7, it was assumed that a difference of at least $49 reduction on the +:0.. total score of 21 (sd &4) i.e. &5 points to 1$, would be highly clinically significant. The estimated pre#post correlation was 4.@ (reducing the effective sd to ? after ad;usting for baseline). The intra#class correlation within the three sites in the control arm was set at 4.41B in the intervention arm (which would include within#C)* as well as within#site effects) it was set at a higher level of 4.&B alpha was set as 4.41. Lsing the method of Roberts and Roberts6$,7 with the .tata routine cluspower will give us ?,9 power to detect this difference. This is e(uivalent to a large standardised effect size, &.@@. !or effect sizes of & (? +:0.. units) and 4., (3.$ +:0.. units) the power would be appro-imately ?49 and ,49 respectively. The re(uired sample size of $@& was increased to $,$ to allow for &19 attrition and rounded up to allow for a $%& randomisation within each site. The total number of participants was then divided slightly une(ually between sites for reasons of feasibility. : total of &,, persons with schizophrenia will be allocated to the CCBC arm while ?@ persons will be allocated to the !BC arm. Data management and analysis !indings will be reported according to the revised CA0.ART guidelines6&@7. 0o interim analyses are planned apart from baseline comparisons. The statistical pac age .tata will be

used for the (uantitative analysis. "n accordance with good trial practices, data will be retained for 3 years after completion of the trial. /escriptive summaries of socio#demographic and clinical data will be provided for all trial participants at baseline, and for outcome measures at baseline, 2#month and &$#month follow up pointsB this will include means and standard deviations, or proportions, in the two arms, as appropriate. .cale and subscale totals with missing items will be pro#rated (i.e. based on the mean of those items that are present) if $49 or fewer items are missing. The +:0.. and the "/8:. will be summarised in terms of the total score, the separate sub scores of the different domains and the proportion of patients improving by M$49 from baseline. )istograms within each arm will be used to assess normality of the distribution of the data, to identify any outliers and chec for data errors. The proportion of participants who are fully, partially or non# adherent to antipsychotic treatment (derived from the adherence ratings of primary caregivers) will be reported for both arms. C)* characteristics such as completed years of education and caseload will also be described. The data will be analysed under intention#to#treat assumptions (i.e. all those with at least one follow up measurement will be analysed in arms as randomised). The &$#month +:0.. total score, ad;usted for +:0.. scores at baseline and site (using analysis of covariance), and including clustering effects of C)*s, will be used for determining the comparative effects of the two arms on this primary outcome of the study. The disability score generated by the "/8:. will be similarly analysedB in addition, a longitudinal analysis including both 2# and &$#month outcomes will also be performed using a F88 or random effects model including a time - treatment term allowing for modelling changes over time. Residual analysis will be performed to chec the distribution of the data and to detect outliers. <ogistic regression analysis with M$49 reduction in +:0.. at &$ months as the dependent variable will be performed. .econdary outcomes at &$ months will be treated in a similar way to the primary outcomeB of the secondary outcomes, adherence will be measured at the 2#month point as well as the &$#month point. : number of sensitivity analyses for the primary outcome are planned to be carried out. Regression models will be re#estimated including possible confounders such as participant characteristics that differ at baseline and may be associated with outcome (e.g. age, gender,

duration of illness, socioeconomic status and education) and C)* characteristics li e education and caseloadB imputation of missing baseline covariates will be performed if there are more than &49 missing and analyses will be repeated. .ubgroup analyses will include site and gender as interactions with treatment arm to estimate differential effects, and further analyses will investigate the effect of engagement with the interventions on outcome. "n addition to the primary intention#to#treat analysis, the effect of participants in the CCBC arm receiving the minimum effective number of sessions as defined in the protocol will also be estimated. +ower for these subgroup analyses has not been specifically allowed for, and so they will be treated as e-ploratory. Analysis plan for economic data .ervice costs will be calculated by combining the service use data with appropriate local unit costs. Cost comparisons will be made using bootstrapping methods to account for s ewed data. Cost#effectiveness will be assessed by combining costs with outcomes in the form of incremental cost#effectiveness ratios which will show the e-tra cost incurred (if any) to produce a unit improvement in the main outcomes (symptoms and disability) as well as K:<=s (measured using the 8K#1/ combined with appropriate utility weights). Lncertainty around cost#effectiveness estimates will be e-plored using cost#effectiveness planes and interpretation will be aided using cost#effectiveness acceptability curves. Analyses plan of ualitative data :nalyses of interview data will commence as data collection is ongoing and will involve importing interview transcripts into (ualitative analysis software (0Nivo,) for coding and identification of ey themes. :nalyses of the baseline (ualitative data will e-plore illness e-periences of people with schizophrenia and their caregivers, with a particular focus on e-periences of stigma and discrimination. :s part of the &$#month follow#up (ualitative analyses, treatment arms will be compared with regards to themes such as the impact of the illness on persons with schizophrenia and caregivers including e-periences of stigma and discrimination, met and unmet needs and other themes that emerge as important from the data. There will also be a focus on

understanding the e-periences of care received, including their acceptability and perceived effect, perceptions of interactions with staff and attributions of changes from entry into the trial to endpoint. 8-amples of possible unintended or even negative conse(uences of CCBC will be sought out. .taff interviews will concentrate on staff>s perspectives on the impact of the intervention on the study outcomes. !rial management and monitoring The CA+." study will be conducted according to the good clinical practice guidelines recommended for conducting multi site randomized controlled trials. There will be a dedicated Trial Coordinator who will coordinate the recruitment and progress of the trial in con;unction with each of the site +ro;ect Eanagement Committees set up for this purpose. "t#ical considerations 8ven though there is observational evidence from uncontrolled studies about the effectiveness of community based interventions, there is genuine clinical e(uipoise regarding the (uestion of the effectiveness and affordability of community care in <ow and Eiddle "ncome Countries (<:E"C). This trial is ;ustified in this conte-t of paucity of evidence from such conte-ts, derived from rigorous controlled studies, about the clinical and cost effectiveness of community services for people with schizophrenia. Lnderpowered trials are unethical and we have made provisions to have ade(uate power in the CA+." study. *e have calculated the sample size in a systematic fashion at several levels. This includes having a threshold of ?19 power (using alpha J 4.41) for detecting a clinically significant difference in the primary outcome measure between the two arms. *e have also specifically addressed the issue of clustering effects within treatment sites and C)*s delivering the intervention in calculating our sample size. Based on these assumptions, we feel the study is ade(uately powered to detect differences in a robust manner to generate valid results. *e will ensure that the rights of participants are protected during the conduct of the trial in accordance with good practice ethical obligations. To address the problems associated with obtaining consent from people with schizophrenia who are symptomatic and sometimes non#

literate, the consent procedure will be carried out using non technical language and, in a manner designed to enhance the inta e and retention of information. This includes the use of a specially designed flipchart illustrating the ey components of the information relevant to informed decision ma ing. "rrespective of the decision to participate or not, no person with schizophrenia will be deprived of any treatment sGhe will ordinarily receive. +articipants will be free to withdraw from the study at any stage without compromising their usual clinical care. !inally, informed consent to participate in the trial will be recorded by using a form that is in compliance with the )elsin i /eclaration and Food Clinical +ractice (FC+) guidelines6$?7B these have been approved by regulatory bodies. :rrangements will be made to comply with suggested FC+ guidelines in related to protecting the confidentiality of personal data principally through procedures to separate study data and participant identifiable data. !or the (uantitative data, the data gathered in the palmtops for each participant and the family at baseline will be chec ed by the /ata Eanager who will remove all personal identification items (to be ept as a separate file with restricted password protected access to the /ata Eanager only) and assign a uni(ue Trial "/. :ll future data will be collected and collated using only the "/ number. Regarding the (ualitative data set, participant and caregiver files will be ept in loc ed cabinets with only the interviewers and the research coordinator having access. :ll identifying information (i.e. name, socio# demographic data etc) will be removed from the interview data and ept separately. Both the individuals and caregivers will be given uni(ue "/ codes (i.e. not having nameGany other identifying information). .oft copies of transcriptions will be ept in password protected files in a secure computer. Transcriptions will have no identifying information. !ormal ethical approval for conducting the trial has been sought and obtained from the ethics committees at the Dings> College, <ondon (+0EG4,G4?#&$&), the <ondon .chool of )ygiene and Tropical Eedicine (approval number 113?) and from the respective "nstitutional Review Boards at .C:R! and .angath. The trial is registered with the "nternational .ociety for the Registration of Clinical Trials and the allocated uni(ue "/ number is ".RCT0 12,334&5. The trial will be regulated by an independent Trial Eonitoring Committee (TEC) represented by e-perts and user representatives who have reviewed and formally approved the protocol before commencing recruitment. The TEC will be provided with (uarterly updates

describing the trial progress during the recruitment period and every 2 months thereafter. : critical incident register will be maintained during the study to record four specific serious adverse events# death, suicide attempt, hospitalization (from any cause) and serious medication side effects li e neuroleptic malignant syndrome, tardive dys inesia, a athisia and tremors for participants in both arms of the studyB these are in accordance with the recommendations of the TEC. :cross both arms, these adverse events will be recorded by the treating +sychiatrists as they occur and by the researchers who will be collecting (uantitative data at 2 and &$ months. !or participants in the CCBC arm, the concerned C)* will also report these events. The reporting and per protocol action ta en for each adverse event will be made available the TEC during the updates. The TEC is also empowered to independently review the ethical and data management procedures of the trial as per established good practice norms. The TEC can e-amine the unblinded outcome and adverse event data during the planned annual review meetings and will be consulted before the public reporting of the results of the study. Lpdates will be provided to all concerned ethics committees of ma;or changes in the protocol, if necessary.

Discussion
+roviding community based services for greater numbers of people with schizophrenia in low and middle income countries is an urgent public health priority. The CA+." randomized controlled trial builds on previous observational evidence of the feasibility, acceptability and effectiveness of CBR programs that incorporated lay community health wor ers as the front line service providers. This trial is designed to provide (uality evidence about the clinical effectiveness of the intervention and the economic implications of the community intervention. Fiven the >real life> sample of sub;ects and the diversity of the sites where the study will be conducted, we believe that the results of the study will be generalisable beyond the study population. "f the results confirm the hypotheses and CCBC intervention has additional clinical benefits and is cost effective, this can have significant impact on health policy related to the scaling up community care for people with schizophrenia in "ndia and other <:E"C.

The results of the trial will be used to inform policy ma ers and practitioners about the benefits, necessary human resources and costs of a community based intervention that can be fronted by non#specialist wor ers (wor ing in tandem with specialists), involve the person with schizophrenia and the family and engage proactively with the local community in promoting recovery and social inclusion. !inally, through the detailed e-ploration of e-periences of stigma and discrimination and evaluation of the intervention on stigma outcomes, the study will also contribute to the limited evidence on felt e-periences and effective interventions to reduce stigma and discrimination for people with severe mental disorders in <:E"C.

#o!peting interests
The authors declare that they have no competing interests.

)uthors+ contributions
.C, E/ was responsible for the initial drafting of the paper and for coordinating the revisions leading to the final paper for submission. E<, +h/ and DF, E.c, E+) provided specific inputs for the statistics section of the paper. ED ERC+sych, is a *ellcome Trust Clinical Research !ellow and provided specific inputs for drafting the (ualitative data rationale and analysis plan aspects of the paper. +E, +h/ specifically contributed to the drafting of the economic aspects of the paper. .O, E:, Research Coordinator, .0, B..c Research Coordinator, )/, /0B and EB, E:, E.c, and formerly pro;ect coordinator, helped with the sections on flow of participants, data management and description of usual care of the paper. EN, E/ and +rofessor, /epartment of +sychiatry, 0"E):0., RT, E/, +h/, and /irector, .C:R!, N+, +h/, +rofessor of "nternational Eental )ealth P *ellcome Trust .enior Clinical Research !ellow in Tropical Eedicine and FT, +h/, +rofessor and )ead of )ealth .ervice and +opulation Research /epartment, "nstitute of +sychiatry were closely involved in providing feedbac and the overall guidance and mentoring for the drafting of the paper. :ll authors have read the paper and are in agreement with the contents.

)ckno&ledge!ents

*e greatly appreciate the support provided by Ram rishna )egde, E/, +undali R. +ai Da ode, E/, Eelvin Chagas .ilva3, E/, :ssistant +rofessor, +eter Castelino, E/, +rasanna /abhol ar, E/, :nimish Chavan,, E/ and Ra;shree /eshpande, E/ who are members of the CA+." authors> groupQ. :ll of them were involved in the overall drafting of the paper, providing specific inputs for the description of sites and for the section on usual care facilities. The CA+." trial is supported by a *ellcome Trust pro;ect grant. *e would li e to ac nowledge the valuable suggestions and contributions made by members of the Trial Eonitoring Committee. The TEC is chaired by +rofessor Eohan "saac from the !aculty of Eedicine and /entistry at the Lniversity of *estern :ustralia. The other members are% C +rofessor R. Raguram, )ead of the /epartment of +sychiatry, Dempegowda "nstitiute of Eedical .ciences, Bangalore, "ndia. C +rofessor +. Chandra, /epartment of +sychiatry, 0"E):0., Bangalore, "ndia. C :dditional +rofessor D. Thennarasu, /epartment of Biostatistics, 0"E):0., Bangalore, "ndia. C Es B. :hluwalia is the user representative on the committee.