Urinary Proteomics Combined With Home Blood Pressure Telemonitoring for Health Care Reform (UPRIGHT-HTM)

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

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

Study Overview

• Status: Not yet recruiting
• Conditions: Blood Pressure; Health Care Utilization; Patient Empowerment; Cost Effectiveness; Protein Deregulation
• Intervention / Treatment: Diagnostic test: In-vitro urinary diagnostic test

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 1000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jan A Staessen, MD, PhD; Phone Number: +32 47 632 4928; Email: jan.staessen@med.kuleuven.be
• Study Contact Backup: Name: Zen-Yu Zhang, MD, PhD; Phone Number: +32 16 34 7104; Email: zhenyu.zhang@med.kuleuven.be

Study Locations

• Belgium
  • Brussels, Belgium, 1000
    • European Kidney Health Aliance
  • Gent, Belgium, 9000
    • Diabetes Liga
  • Mechelen, Belgium, 2800
    • Alliance for the Promotion of Preventive Medicine
• Denmark
  • Gentofte, Denmark, 2820
    • Steno Diabetes Center Copenhagen
    • Contact: Tine W Hansen, MD, PhD; Phone Number: +45 39 68 08 00; Email: tine.willum.hansen@regionh.dk
• Germany
  • Hannover, Germany, D-30659
    • Mosaiques-Diagnoostics and Therapeutics AG
• Greece
  • Athens, Greece, 115 27
    • Biomedical Research Foundation of the Academy of Athens
• Nigeria
  • Abuja, Nigeria, NCT Airport Road
    • Department of Internal Medicine, Faculty of Clinical Sciences, College of Health Sciences, University of Abuja
    • Contact: Augustine N Odili, MD, PhD; Phone Number: +234 803 395 4983; Email: odilimercy@yahoo.com
• Poland
  • Gdańsk, Poland, 80-214
    • Department of Hypertension, Medical University of Gdańsk
    • Contact: Krzysztof Narkiewicz, MD, PhD; Email: krzysztof.narkiewicz@gumed.edu.pl
    • Contact: Mariana Smoluchowskiego; Phone Number: +58 584 44 40
    • Sub-Investigator: Natasza Gilis-Malinowska
  • Kraków, Poland
    • First Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College
    • Contact: Marek Raizer, MD, PhD; Phone Number: +4812 4002150; Email: marek.raizer@uj.edu.pl
    • Sub-Investigator: Katarzyna Stolarz-Skrzypek, MD, PhD
• Slovenia
  • Ljubljana, Slovenia, 1000
    • Department of Internal Medicine, Division of Hypertension, University Medical Centre Ljubljana
    • Contact: Jana Brguljan Hitij, MD, PhD; Phone Number: +386 1 522 50 50; Email: jana.brguljan-hitij@guest.arnes.si
• South Africa
  • Potchefstroom, South Africa, 2520
    • Hypertension in Africa Research Team, Medical Research Council Unit for Hypertension and Cardiovascular Disease, North-West University
    • Contact: Alta Schutte, MD, PhD; Phone Number: +27 18 299 1111; Email: alta.schutte@nwu.ac.za
    • Sub-Investigator: Carina Mels, MD, PhD
    • Sub-Investigator: Gontse Mokwatsi, MD, PhD
• Uruguay
  • Montevideo, Uruguay, 11600
    • Centro de Nefrología and Departamento de Fisiopatología, Hospital de Clínicas, Universidad de la República
    • Contact: José Boggia, MD, PhD; Phone Number: +598 2480 98 50; Email: ppboggia@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HTM plus UPP; 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; 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).
Other: HTM alone; Home blood pressure telemonitoring administered on top of non-pharmacological and pharmacological management of risk factors	Diagnostic test: In-vitro urinary diagnostic test; 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).

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: KU Leuven
• Collaborators: Alliance for the Promotion of Preventive Medicine
• Investigators: Principal Investigator: Lutgarde Thijs, MSc, University of Leuven

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2020
• Primary Completion (Anticipated): December 31, 2025
• Study Completion (Anticipated): July 31, 2026

Study Registration Dates

• First Submitted: March 2, 2020
• First Submitted That Met QC Criteria: March 5, 2020
• First Posted (Actual): March 6, 2020

Study Record Updates

• Last Update Posted (Actual): March 6, 2020
• Last Update Submitted That Met QC Criteria: March 5, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Other Study ID Numbers: UPRIGHT-HTM, version 4.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: A motivated request for data transfer for scientific purposes should be addressed to Prof Jan A. Staessen
• IPD Sharing Time Frame: Starting after completion of the trial for a duartion of 5 years
• IPD Sharing Access Criteria: Approval by the Ethics Committee of the University Hospitals Leuven
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No