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

• ClinicalTrials.gov Identifier: NCT04299529
• Recruitment Status: Not yet recruiting
• First Posted: March 6, 2020
• Last Update Posted: March 6, 2020
• Sponsor: KU Leuven
• Collaborator: Alliance for the Promotion of Preventive Medicine
• Information provided by (Responsible Party): Jan A. Staessen, KU Leuven

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Protein Deregulation; Blood Pressure; Health Care Utilization; Cost Effectiveness; Patient Empowerment	Diagnostic Test: In-vitro urinary diagnostic test	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1000 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Parallel group design
• Masking: Single (Outcomes Assessor)
• Masking Description: Caregivers will know the group to which their patients were randomly assigned. In the two groups, both patients and caregivers will have full access to the HTM data. In both treatment groups, caregivers will be informed about the UPP risk profile. However, in the experimental group, patients will be informed about their UPP risk profile shortly after randomisation and in the control group, only when they leave randomised follow-up or at the completion of the trial. The central study coordinating team will remain blinded to the primary endpoint and all of its components until completion of the trial and until all datasets have been cleaned and frozen for the final analysis.
• Primary Purpose: Diagnostic
• Official Title: Urinary Proteomics Combined With Home Blood Pressure Telemonitoring for Health Care Reform: a Randomised Controlled Trial
• Estimated Study Start Date: April 1, 2020
• Estimated Primary Completion Date: December 31, 2025
• Estimated Study Completion Date: July 31, 2026

Arms and Interventions

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).
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).

Outcome Measures

Primary Outcome Measures :

1. Primary composite endpoint [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]

   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.

2. Change in serum creatinine (mg/dl) [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
   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).
3. Change in eGFR (ml/min/1.73m2) [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
   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.
4. Progression of CKD [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
   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
5. Incidence of diabetic nephropathy [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
   Microalbuminuria of 30 microgram per gram creatinine or more in two of three morning urine samples collected on three consecutive days.
6. Incidence of diabetic retinopathy [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]

   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)

7. Incidence of hypertensive retinopathy [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
   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
8. Incidence of electrocardiographic LV hypertrophy [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]

   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

9. Incidence of echocardiographic LV hypertrophy [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
   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.
10. Incidence of diastolic LV dysfunction [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
    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).
11. Incidence of CV mortality [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
    ICD10 codes I00-I99
12. Incidence of nonfatal myocardial infarction [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
    ICD10 codes I21,I22
13. Incidence of nonfatal heart failure [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
    ICD10 code I50
14. Incidence of nonfatal stroke [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
    ICD10 codes I60-I63
15. Incidence of CKD [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years ]
    ICD10 codes N17, N18

Secondary Outcome Measures :

1. EQ-5D (scale ranging from 0 [worst possible] to 100 [best possible]) [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years. ]
   Quality of life will be assessed using the EQ-5D quality of life questionnaire (http://www.euroqol.org)
2. Health-economic analysis [ Time Frame: After a run-in period of 2 to 5 weeks to check the eligibility, patients will be randomized and followed up for 4 years. ]
   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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Jan A Staessen, MD, PhD; +32 47 632 4928; jan.staessen@med.kuleuven.be

Contact: Zen-Yu Zhang, MD, PhD; +32 16 34 7104; zhenyu.zhang@med.kuleuven.be

Locations

Belgium

European Kidney Health Aliance

Brussels, Belgium, 1000

Diabetes Liga

Gent, Belgium, 9000

Alliance for the Promotion of Preventive Medicine

Mechelen, Belgium, 2800

Denmark

Steno Diabetes Center Copenhagen

Gentofte, Denmark, 2820

Contact: Tine W Hansen, MD, PhD +45 39 68 08 00 tine.willum.hansen@regionh.dk

Germany

Mosaiques-Diagnoostics and Therapeutics AG

Hannover, Germany, D-30659

Greece

Biomedical Research Foundation of the Academy of Athens

Athens, Greece, 115 27

Nigeria

Department of Internal Medicine, Faculty of Clinical Sciences, College of Health Sciences, University of Abuja

Abuja, Nigeria, NCT Airport Road

Contact: Augustine N Odili, MD, PhD +234 803 395 4983 odilimercy@yahoo.com

Poland

Department of Hypertension, Medical University of Gdańsk

Gdańsk, Poland, 80-214

Contact: Krzysztof Narkiewicz, MD, PhD krzysztof.narkiewicz@gumed.edu.pl

Contact: Mariana Smoluchowskiego +58 584 44 40

Sub-Investigator: Natasza Gilis-Malinowska

First Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College

Kraków, Poland

Contact: Marek Raizer, MD, PhD +4812 4002150 marek.raizer@uj.edu.pl

Sub-Investigator: Katarzyna Stolarz-Skrzypek, MD, PhD

Slovenia

Department of Internal Medicine, Division of Hypertension, University Medical Centre Ljubljana

Ljubljana, Slovenia, 1000

Contact: Jana Brguljan Hitij, MD, PhD +386 1 522 50 50 jana.brguljan-hitij@guest.arnes.si

South Africa

Hypertension in Africa Research Team, Medical Research Council Unit for Hypertension and Cardiovascular Disease, North-West University

Potchefstroom, South Africa, 2520

Contact: Alta Schutte, MD, PhD +27 18 299 1111 alta.schutte@nwu.ac.za

Sub-Investigator: Carina Mels, MD, PhD

Sub-Investigator: Gontse Mokwatsi, MD, PhD

Uruguay

Centro de Nefrología and Departamento de Fisiopatología, Hospital de Clínicas, Universidad de la República

Montevideo, Uruguay, 11600

Contact: José Boggia, MD, PhD +598 2480 98 50 ppboggia@gmail.com

Sponsors and Collaborators

KU Leuven

Alliance for the Promotion of Preventive Medicine

Investigators

• Principal Investigator: Lutgarde Thijs, MSc; University of Leuven

More Information

• Responsible Party: Jan A. Staessen, Professor of Medicine, KU Leuven
• ClinicalTrials.gov Identifier: NCT04299529
• Other Study ID Numbers: UPRIGHT-HTM, version 4.0
• First Posted: March 6, 2020
• Last Update Posted: March 6, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: A motivated request for data transfer for scientific purposes should be addressed to Prof Jan A. Staessen
• Supporting Materials: Study Protocol; Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: Starting after completion of the trial for a duartion of 5 years
• Access Criteria: Approval by the Ethics Committee of the University Hospitals Leuven

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No