Study design
A pragmatic parallel arms cluster randomized controlled trial (c RCT) with two arms will be conducted from January 2012 to December 2016 with a duration of 60 months.
The proposed cluster randomized controlled trial will evaluate the effects of delivering quality HTN-CVD care, through enabled private health care facilities, to achieve better adherence and hypertension control also blood glucose and serum cholesterol control. The trial will have two arms (Figure 1).
Interventions
Intervention arm
Quality care will be delivered to adult hypertension patients, through enabled private healthcare facilities. The inputs for delivering quality care at enabled facilities will include: a) context sensitive operational guidelinesb, b) supplement equipment and communication, c) training and supervisory support, d) patient education materials. The care delivery dimensions to be addressed will include: a) enhanced screening and diagnosis, b) standardized prescription, c) interactive education of patient and family, d) follow-up and adherence, e) recording, reporting and monitoring, f) referral linkage with respective district hospital, g) district health office engagement and support, and h) technical support for in-country research uptake.
Control arm
The control for comparison is the current care practices (for hypertension and associated conditions) at the private health care facilities. The only addition will be a) enhanced screening and diagnosis, b) introduction of HTN-CVD register for collecting core data set on patients attending these control facilities. In ‘current practice’, each practitioner manages HTN-CVD cases, as per his/her self-determined regimen and without reference to any specific guidelines and/or tools.
The health staff at a facility will offer the same care package to all its HTN-CVD cases, regardless of their social strata and other preferences. This will reduce the chances of intra-cluster contamination as well as strengthen and simplify the implementation of prospective evaluation. All trial patients will be asked to arrange their prescribed drugs, so that the trial reflects the real life practice in private health care delivery system.
Study setting
Sargodha is the tentatively proposed district for implementing the research. About one-third of the district population lives in urban areas (i.e. 1 million out of 3.1 million). About 38% of the urban population is above 25 years of age (i.e. 380,000), and about a quarter of these are expected to be hypertensives (95,000).
In Sargodha, the Association has actively been engaged in supporting the implementation of various disease control interventions through district health systems. These include communicable diseases like TB-DOTS and sexually transmitted infection (STI) control, tobacco cessation, public-private partnership, advocacy-communication and social mobilization for disease control, drug management enhancement etc. This experience-based understanding and trust with the district health office would help partners to implement the proposed public-private partnership innovation.
Study population
In these two districts, 12 private health facilities will be selected into the trial.
Identifying participants
A group of private facilities has already been selected for TB-PPM intervention in the district. These facilities have been selected on basis of objective functioning and willingness criteria. The private facilities for HTN-CVD trial will be identified from the already functioning facilities in the district.
The individuals attending the outpatients will be identified and screened for HTN and subsequently for type 2 diabetes, hypercholesterolemia and smoking, as per agreed care delivery guidelines.
Approaching participants
The eligible facilities will be approached through district health office for possible inclusion in the trial. Through respective health facility, communal consent will be arranged from the respective catchment populations. The facilities where both staff and the catchment population consent to participate will be selected in the trial.
Inclusion/exclusion criteria
Among these private facilities ,all newly diagnosed hypertensive (systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg) male and female patients aged 25 years or more from the catchment population of the respective facility will be included, after an informed consent. The patients to be excluded from the trial are: a) pregnant women, b) persons with advanced chronic disease, c) person with conditions that cause secondary hypertension, d) person with known history of hypertension and/or CVD treatment in the past, e) person not likely to stay in the area for the required follow-up period of 15 months.
Patients who are pregnant and have hypertension will be referred to a gynecologist, patients with advanced chronic disease to a general medical practitioner, and those with a known history of hypertension and/or CVD treatment in the past will be referred to a cardiologist. Only patients who are new cases of hypertension are included in the trial. People with known hypertension are excluded from the trial as they would already be on some sort of antihypertensive drug regimen which may mask the effects of our intervention.
Recruiting participants
The eligible for inclusion patients will be informed and offered to participate (see inclusion/ exclusion criteria above). The patient is recruited only if he/she consents to participate.
Once recruited, each patient in the:
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control arm will be offered standardized diagnosis and care as per current practice, whereas intervention arm will be offered an enhanced HTN-CVD care including standardized diagnosis, prescription, follow-up, and monitoring.
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intervention arm will also be educated on life style modifications recommended for the individual, whereas control arm patients will receive information brochure.
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both arms will be asked to arrange the prescribed medicine through their own sources. However, access to baseline BP, HbA1c, cholesterol examination will be facilitated, for both arms, through trial resources.
Both arms will be requested to adhere to the treatment protocols.
Data management procedures
Most of the data will be collected as a part of the care delivery process by doctors and paramedics on the ‘CVD card’. Other data related especially to trial will be recorded on the ‘trial registration form (TRF). Research assistant (RA) will visit the identified Lab on monthly basis and will collect test results. RA will visit each centre on monthly basis and will i) check each TRF for completeness and correctness, and those found with missing data will be acted upon accordingly. ii) correlate the Lab results with entries on TRF iii) check for drugs and supplies and reimburse for gaps. RA will send a copy of TRF and Lab test results to the central office i) at test one i.e. baseline ii) at test two i.e. final outcome, for data entry, cleaning and analysis.
Data confidentiality and data entry
Each form will be sent as mentioned above by a registered courier service in a sealed envelope. The forms will be kept under lock and key in the central ASD office with only the PI and project coordinator having access to them. Data entry will be done twice by two independent data entry operators to minimize typing errors. Data will be entered on SPSS 20.
Statistical considerations
Sample size
A total of twelve clustersc (i.e. six clusters in each trial arm) will be included in the study, with a minimum of 76 patients recruitment in each cluster and a total of 912 patients in the trial. The assumptions are: a) an intra-class correlation coefficient (ICC) of 0.02, b) design effect of 2.5 [4], c) and standard deviation of blood pressure as 11 mm [5] d) lost to follow-up of 25%. This sample size will give 94% power using 5% level of significance for detecting an assumed difference in the mean change of systolic blood pressure of 6 mm Hg between the intervention and the control arm [6, 7].
For a sub group analysis of hypertensive patients with concomitant type-II diabetes, the main assumption is that 27.6% of the recruited hypertensive will have type-II diabetes i.e. 21 patients out of 76 hypertensive recruited at each clinic will be have diabetes [3]. The proposed sample size will give 86% power using 5% level of significance for detecting an assumed difference in mean change of HbA1c of 1% [8, 9] between the intervention and the control arms. The assumed standard deviation of HbA1c is 2% [10], and intra-cluster correlation is 0.02 [6, 7].
For a sub group analysis of hypertensive patients with concomitant hyper-cholesteremia, the main assumption is that 39.3% of the recruited hypertensive will have hyper-cholesteremia i.e. 30 patients out of 76 hypertensive recruited at each clinic will be have hyper-cholesteremia [3]. The proposed sample size will give 100% power using 5% level of significance for detecting an assumed difference of 4.9 mg/dl [11] between the group means. The assumed standard deviation is 2.9 mg/dl [11], and intra-cluster correlation is 0.02 [6, 7].
For a sub group analysis those hypertensive patients who smoke, the main assumption is that 34.5% of the recruited hypertensive will be tobacco smokers i.e. 27 out of 76 hypertensive recruited at each clinic will be smokers [3]. The proposed sample size will give 100% power using 5% significance level for detecting a difference between the group proportions of 0.33 when the intra-cluster correlation is 0.02 [6, 7].
Planned analysis
The results in each cluster would be analyzed on the basis of “intention to treat”. This means the quality of care and service utilization outcomes of each patient will be counted in the intervention for the cluster, regardless of their actually accepting or availing the offered services.
Planned statistical tests
Cluster and individual level analysis will be done on SPPS version 17. Histograms will be made for the continuous variables e.g. age, systolic blood pressure, diastolic blood pressure, fasting blood glucose, HbA1c etc.
Descriptive statistics will be computed: proportion for categorical variables, mean and standard deviation for continuous variables having normal distribution, median and inter quartile range for continuous variables having skewed distribution.
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a.
Difference of mean systolic blood pressure at baseline and then at 15 months of follow up between the intervention and the control arm will be measured by independent t-test. Difference of mean systolic blood pressure at baseline and at 15 months of follow up in the intervention arm/control arm will be measured by the paired sample t-test. Mean change of systolic blood pressure between intervention and the control arm will be measured by t-test. P-value of < 0.05 will be considered significant.
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b.
Difference of mean HBA1c at baseline and then at 15 months of follow up between the intervention and the control arm will be measured by independent t-test. Difference of mean HBA1c at baseline and at 15 months of follow up in the intervention arm/control arm will be measured by the paired sample t-test. Mean change of HBA1c between intervention and the control arm will be measured by t-test. P-value of < 0.05 will be considered significant.
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c.
Difference of mean total cholesterol levels at baseline and then at 15 months of follow up between the intervention and the control arm will be measured by independent t-test. Difference of mean total cholesterol levels at baseline and at 15 months of follow up in the intervention arm/control arm will be measured by the paired sample t-test. Mean change of total cholesterol levels between intervention and the control arm will be measured by t-test. P-value of < 0.05 will be considered significant.
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d.
Proportions of adult Type 2 diabetes patients having htn control (<140/90) in the two arms will be compared by conducting chi-square test. P-value of < 0.05 will be considered significant.
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e.
Residual confounding will be taken care of by multivariable regression (MLR)analysis. Strartified MLR will be done with the different groups of medications being as different strata eg, Beta blockers, ACE inhibitors, ARBs, Calcium channel blockers etc. being as different strata. Results will be presented in a stratified analysis. This will take care of confounding my different effects on BP from different groups of anti hypertensive drugs.
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f.
Incremental cost and effect will be calculated for the intervention and the control arms and subsequently cost: effect ratio will be calculated.
Phases of the trial
The trial will have the following three phases: Refer to Figure 2.
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1)
Inception & piloting phase. The main purpose of the two-year phase is to develop, pilot and refine the care delivery guidelines/ materials and trial design/ protocols before embarking upon the trial registration.
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The piloting experiences and results will enable the research team to:
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Assess the feasibility and acceptability, and then accordingly modifythe process for health facility selection (i.e. facility assessment, providers’ and communal consent for the trial etc.) and management support (logistic supplement, reporting, monitoring etc.)
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Assess the feasibility and acceptability, and then accordingly modifythe case management guidelines i.e. diagnosis, treatment, record keeping, follow-up etc.
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Assess the feasibility and robustness of the research protocols, then accordingly modify, the protocols for case inclusion/ exclusion, recruitment rate, and periodic assessment (research related).
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Revisit the assumed proportion of diabetics, dyslipidemic and smoker patients among adult hypertensive patients in local context.
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Revisit the assumptions about sample size calculation to meet the power of the study such as mean change (± standard deviation) in systolic blood pressure, glycaemic and cholesterol control, and tobacco cessation between intervention and control arms.
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Assess and modify, if needed, the proposed statistical methods to analyze the trial data.
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The qualitative interviews with providers (± patients) for assessing the feasibility during the trial piloting will also be adapted subsequently for the trial assessment. In short the trial piloting will inform the decision to implement the trial to get optimal results and valid evidence.
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2)
Trial Implementation phase
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In the first 03 months of the trial implementation phase, the following arrangements will be made before start registering cases in the trial.
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Refine the case management guidelines/ materials Assess and shortlist the health facilities for possible inclusion in the trial. Randomization :The ASD central trial unit, under the supervision of Trial Steering Committee, will then randomize the facilities into two trial arms. Randomization preformed will be simple randomization. Each participating facility (cluster) will be given a unique ID which the investigators will be blinded to.12 different sheets of paper will be taken and the unique ID of each cluster will be written on the paper, which will be folded and sealed into an envelop.12 such sealed envelopes will be made. Then by a simple procedure, 6 sealed envelopes will be selected by hand picking them randomly from the pile of 12 sealed envelopes.6 will be hand picked for the intervention arm and 6 sealed envelopes for the control arm. The Steering committee will consist of a director, two people from ASD and two people from in-country (PMRC) and international partners (WHO).
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At least two doctors and two paramedics from each participating facility will be trained. The intervention facility staff will be trained on enhanced case management guidelines and materials including recording reporting and enhanced follow-up and referral, whereas the control facility staff will be trained only to register and report, use patient education brochure, and access HbA1c and cholesterol testing for trial patients.
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In the next 06 months of the trial implementation phase, the patients will be registered and enrolled in the trial, as per agreed protocols. During the period the baseline hypertension measurement will be validated by an external expert examination, kept blind to the trial arm as well as any previous measurements.
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The case management enhancement in the intervention arm will include: case management desk-guide for patient care, flip chart and brochure for patient education, mobile link for late patient retrieval, referral for advanced care (if needed), regular monitoring and support.
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Once the required number of trial patients is enrolled in the trial, the subsequent patients will receive HTN-CVD and associated care from the respective facility (as per prevailing case management protocols i.e. either intervention or control) but their results will not be included in the trial evaluation.
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The research team will closely monitor the inclusion and exclusion of trial patients, mainly to identify and respond to any deviation from the research protocols and/or case management processes.
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In the next 15 months of the trial implementation phase, the registered trial patients will be followed-up to measure the outcomes.
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All patients will pay for the case management services, as per facility protocols. However, the measurement of hypertension, HbA1c, serum cholesterol and carbon mono oxide in exhaled air will be paid from the project sources (as these measurements are being made solely for the trial evaluation). The referral to district headquarter hospital, as required, for specialist consultation (e.g. cardiology, ophthalmic examination, renal assessment, drug side effect) will be managed as per agreed guidelines for intervention arm and as per current routine in the control arm. The specialist facility will be encouraged to refer back patients to the respective referring facility, after providing the requested specialist care.
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The case management record on each patient will be maintained in the chronic disease register (to be developed and introduced through the trial inputs). The chronic disease register at each facility will provide the data for detailed analysis on case management experiences in the two trial arms.
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The modalities for periodically monitoring the participating facilities (including reviewing records and collecting reports) will be developed during the initial development phase (see section 12 below). The research team will ensure that each participating facility is monitored as per guidelines agreed for the respective facility (i.e. intervention and control).
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The research team will also supplement the logistic inputs at the participating facilities. This includes maintenance of BP apparatus, glucometer and supplies, print materials etc. at the participating facilities.
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3)
Intervention Evaluation and Research Take-up phase
Costing study
A costing analysis will be designed and conducted to inform programmatic decisions by managers and policy makers for possible scaling-up in other districts with ongoing PPM for communicable disease control. The minimal is the incremental cost effectiveness ratio (ICER) analysis of the provider cost (i.e. health department and private facility). The ICER will focus mainly on cost of additional inputs (training, materials, monitoring etc.) at private facility level to achieve the outcomes. This analysis is more relevant for the health department decision makers to consider scaling-up the intervention. The main source of cost data will be records and key informant interviews. We will also explore the possibility of covering, to an extent possible, the patient perspective to the care for HTN and associated conditions. This might involve surveying the registered patients for costing and coping experiences.
Explanatory qualitative study
Qualitative interviews with selected care providers (6), and patients (12)d will help to better understand the experiences. A qualified anthropologist, with help of other members, will develop the interview schedules and conduct the semi-structured interviews with various individual categories of interest. The study would collect data on a range of social, economic, service access and quality etc. factors from care providers as well as patients and their families to assess the social and administrative feasibility of said interventions in the programme context and inform refinements before scaling-up to other parts of the country.
Dissemination
The results/experiences and products of research will also be shared with wider stakeholders through: a) existing partner networks (e.g. COMDIS,), b) presentations at national and international conferences (e.g. White Ribbon Alliance, World Federation of Public Health Associations), and c) access to resource centers/websites more widely used e.g. WHO.
The scientific papers, based on results of the trial and associated studies, will be submitted to international and national peer-reviewed journals. The potential journals to target includes: BMC cardiovascular disease, Lancet, British Medical Journal, WHO Bulletin, BMC Implementation Science-process evaluation study(s); Health Policy and Planning, Reproductive Health Matters-social science (qualitative studies).