Urinary Proteomics Combined With Home Blood Pressure Telemonitoring for Health Care Reform

Study Overview
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Brief Summary
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UPRIGHT-HTM will compare risk stratification, treatment efficiency and health economic outcomes of a diagnostic approach based on home blood pressure telemonitoring combined with urinary proteomic profiling with home blood pressure telemonitoring alone

Detailed Description
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Hypertension is by far the dominant reversible risk factor dwarfing most others in the pathogenesis of chronic kidney disease (CKD) and diastolic left ventricular dysfunction (DVD), two archetypes of chronic age-related diseases, which are rampant in ageing societies in epidemiological transition. Home blood pressure telemonitoring (HTM) is a recommended approach in the diagnosis and management of hypertension. Urinary peptidomic profiling (UPP) holds great promise in individualising prevention and treatment of CKD and DVD and associated complications, such as coronary heart disease. Making use of these modern technologies, UPRIGHT-HTM is an investigator-initiated randomised clinical trial with a patient-centred design, for the first time, comparing HTM combined UPP (experimental group) to HTM alone (control group) in risk profiling and as guide to starting or intensifying management of risk factors to prevent established disease. The trial will run in Europe, sub-Saharan Africa and South America. Eligible patients, aged 55-75 years old, are asymptomatic, but have three or more CKD- or DVD-related risk factors, preferably including hypertension, type 2 diabetes mellitus, or both, and do have internet skills. The primary endpoint consists of a composite of new-onset intermediate endpoints (microalbuminuria, progression of CKD, diabetic or hypertensive retinopathy, electrocardiographic or echocardiographic left ventricular hypertrophy or DVD and hard outcomes (cardiovascular mortality and non-fatal complications, including myocardial infarction, heart failure and stroke). Secondary objectives are demonstrating that combining HTM with UPP is feasible and cost-effective in a multicultural context, defining the molecular signatures of early CKD and DVD, and with help of stakeholders educating and empowering patients. Assuming an accrual time of 1 year, a median follow-up of 4 years, a 10% dropout rate, a 20% risk of the primary endpoint in the control group and 30% risk reduction in the experimental group, requires 1000 patients to be randomised in a 1:1 proportion with the two-sided alpha level and power set 0.05 and 0.80, respectively. The expected outcome is proving the superiority in terms of efficiency and cost-effectiveness of HTM combined with UPP vs HTM alone, which should lead to redesigning the clinical workflow, putting greater emphasis on preventing rather than curing established disease.

Official Title
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Urinary Proteomics Combined With Home Blood Pressure Telemonitoring for Health Care Reform: a Randomised Controlled Trial

Conditions
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Protein Deregulation, Blood Pressure, Health Care Utilization, Cost Effectiveness, Patient Empowerment

Intervention / Treatment
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* Diagnostic Test: In-vitro urinary diagnostic test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have at least three additional guideline-defined risk factors, preferably including hypertension, type 2 diabetes mellitus (T2DM), or both; Patients should be willing patients to engage for the duration of the study in home blood pressure telemonitoring (1 reading per day); Patients must have an email address and internet access via smartphone, tablet, or laptop or desktop computer; Patients should comply with the study protocol during the run-in phase. Exclusion Criteria: Type 1 diabetes mellitus; Absence of a practicable echocardiographic window; Previous or concurrent severe cardiovascular or non-cardiovascular disease; Cancer within 5 years of enrolment; Suspected substance abuse; Psychiatric illness; Use of nephrotoxic drugs; Particpation in another clinical study.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel group design
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HTM plus UPP<br>Urinary proteomic profiling administered on top of home blood pressure telemonitoring and guideline-endorsed non-pharmacological and pharmacological management of risk factors | Diagnostic Test: In-vitro urinary diagnostic test<br>* Urinary proteomic profiling (UPP) using established multidimensional urinary markers for progression to CKD (CKD273), left ventricular dysfunction (HF1 and HF2) and coronary heart disease (CAD238 and ACSP75) - in-vitro test certified in Germany and by extension in the EU (DE/CA09/0829/IVD/001, DE/CA09/0829/IVD/005).<br>|
| Other: HTM alone<br>Home blood pressure telemonitoring administered on top of non-pharmacological and pharmacological management of risk factors | Diagnostic Test: In-vitro urinary diagnostic test<br>* Urinary proteomic profiling (UPP) using established multidimensional urinary markers for progression to CKD (CKD273), left ventricular dysfunction (HF1 and HF2) and coronary heart disease (CAD238 and ACSP75) - in-vitro test certified in Germany and by extension in the EU (DE/CA09/0829/IVD/001, DE/CA09/0829/IVD/005).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary composite endpoint | The primary endpoint is a composite of intermediary and hard cardiovascular-renal endpoints. The intermediate endpoints are diabetic nephropathy, progression to a higher CKD stage, doubling of serum creatinine, an eGFR decrease by 30% or more or eGFR declining below 45 ml/min/1.73 m2, new-onset hypertensive or diabetic retinopathy, electrocardiographic or echocardiographic left ventricle hypertrophy, and diastolic left ventricular dysfunction. The hard composite cardiovascular endpoint includes cardiovascular mortality, and nonfatal myocardial infarction, nonfatal hospitalised heart failure, and nonfatal stroke, not including transient ischemic attack. The hard renal outcomes include macroalbuminuria, the need for renal-replacement therapy, and death to renal causes. | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Change in serum creatinine (mg/dl) | The concentration of creatinine in serum, expressed in mg/dl, will be measured, using Jaffe's method with modifications () in certified laboratories applying isotope-dilution mass spectrometry for calibration (Clin Chem 2006; 52: 5-18). | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Change in eGFR (ml/min/1.73m2) | eGFR will be derived from the serum creatinine concentration by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Ann Intern Med 2009; 150: 604-612) and expressed in ml/min/1.73 m2. | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Progression of CKD | The National Kidney Foundation Kidney Disease Outcomes Quality Initiative guideline will be followed (Kidney Int Suppl 2013;3:1-150): eGFR ≥90, 60-89, 45-59, 30-44, 15-29 and <15 mL/min/1.73 m2 for Stage 1, 2, 3A, 3B, 4 and 5, respectively | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Incidence of diabetic nephropathy | Microalbuminuria of 30 microgram per gram creatinine or more in two of three morning urine samples collected on three consecutive days. | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Incidence of diabetic retinopathy | Non-proliferative diabetic retinopathy (NPDR): early NPDR, at least one microaneurysm ; moderate NDPR, characterized by multiple microaneurysms, dot-and-blot hemorrhages, venous beading, and/or cotton wool spots; severe NPDR, diffuse intraretinal hemorrhages and microaneurysms in four quadrants, venous beading in two or more quadrants, or severe intraretinal microvascular abnormalities Proliferative diabetic retinopathy (PDR): fibrovascular proliferation extending beyond the internal limiting membrane; vitreous hemorrhage; retinal detachment, macular edema (https:// https://webeye.ophth.uiowa.edu/eyeforum/tutorials/Diabetic-Retinopathy-Med-Students/Classification.htm) | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Incidence of hypertensive retinopathy | Grade 1: mild narrowing and tortuosity of the retinal arterioles; Grade 2: definite focal retinal arteriolar narrowing and arteriovenous nipping; Grade 3: retinal hemorrhages and cotton wool spots; Grade 4: papilledema | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Incidence of electrocardiographic LV hypertrophy | The Sokolow-Lyon index is the sum of the S-wave in V1 and the R wave in V5 or V6, whichever is greater; the threshold value is 3.5 mV (PMID 31352838, 19015402, 28789616); in regularly calibrated ECGs, 1 mV is 10 mm along the vertical axis; The Cornell product is the sum of RaVL and RV5 with 6 mV added for women, multiplied by the QRS duration in milliseconds; the cut-off value is 2440 mV × ms (PMID 31352838, 19015402, 28789616); Increased R-wave in aVL: the threshold values is 1.1 mV; ST segment down sloping in V4-V6 with T-top inversion. Based on these criteria the investigators will classify patients as having or not having electrocariographic LV hypertrophy | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Incidence of echocardiographic LV hypertrophy | Guidelines should be applied for acquisition and off-line analysis of the echocardiographic imaging studies (PMID 15452478, 19187853, 27037982); LV mass will be calculated using a formula validated by necropsy (PMID 2936235, 15452478); LVM = 0.8 × (1.04 × (EDD + IVS + LPW)3 - EDD)3) + 0.6; expressed in gram; LV mass will be indexed to body surface; the threshold values are ≥95/≥115 g/m2 in women/men. | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Incidence of diastolic LV dysfunction | Diastolic LV dysfunction will be defined as an abnormally low age-specific transmitral E/A ratio, indicative of impaired relaxation, or a mildly-to-moderately elevated left ventricular filling pressure (E/e' >8.5) with normal or decreased age-specific E/A ratio. The ejection fraction should be over 50% (Circ Heart Fail 2009;2: 105-112). | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Incidence of CV mortality | ICD10 codes I00-I99 | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Incidence of nonfatal myocardial infarction | ICD10 codes I21,I22 | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Incidence of nonfatal heart failure | ICD10 code I50 | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Incidence of nonfatal stroke | ICD10 codes I60-I63 | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 
| Incidence of CKD | ICD10 codes N17, N18 | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EQ-5D (scale ranging from 0 [worst possible] to 100 [best possible]) | Quality of life will be assessed using the EQ-5D quality of life questionnaire (http://www.euroqol.org) | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years. | 
| Health-economic analysis | For health-economic evaluation, the EQ-5D patient-administered questionnaire (https://www.euroqol.org) is of particular importance, as Quality Adjusted Life Years (QALYs) can be generated from this simple instrument | After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years. |