NT-proBNP Selected Prevention of Cardiac Events in Diabetic Patients

NCT02817360 | Recruiting Phase 4 DMC

• 1 other identifier: PONTIAC II
• Study Type: interventional
• Target: 2,400
• Locations: 5 countries
• Sites: 21

Brief Summary

Purpose and rationale The purpose of this study is to evaluate the effect of high dose Renin-Angiotensin System (RAS)-antagonists and beta-blocker treatment for the primary prevention of cardiac events in a population of patients with Type 2 diabetes mellitus (T2DM) with no evidence of a preexisting cardiac disease. An additional aim is to demonstrate an interaction between concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP as a surrogate of imminent cardiac risk) and treatment effects and the economic impact of the intervention overall and in the biomarker stratified subgroups. Primary objective Superiority of high dose treatment with RAS-antagonists and beta-blockers compared to conventional therapy regarding the reduction of unplanned hospitalization or death due to a cardiac event in T2DM patients with a NT-proBNP \> 125pg/ml. There is an additional eye-substudy for Viennese sites only. The purpose of this sub-study is to evaluate the effect of high dose RAS-antagonists and beta blocker treatment on early subclinical signs of diabetic micro-angiopathy and neuropathy. An additional aim will be the evaluation of the possible impact of the cardiovascular risk factor NT-proBNP on the onset and progression of diabetic retinopathy.

Conditions

Heart Diseases; Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (1)

• Number of patients with an unplanned cardiac hospitalization or death due to a cardiac event

  The combined endpoint of the number of patients with an unplanned cardiac hospitalization or death due to a cardiac event will be recorded throughout the study duration of 2 years.

  2 years

Other Outcomes (4)

• Number of patients hospitalised due to any cardiac reasons

  2 years

• Number of patients hospitalised due to heart failure

  2 years

• Number of patients hospitalised due to all causes

  2 years

Study Arms (2)

Intensive therapy

EXPERIMENTAL

RAS-antagonist and beta-blocker up-to maximal dosages as permitted and tolerated and following national guidelines.

Drug: RAS-antagonist and beta-blocker up-to maximal dosages

Conventional therapy

OTHER

No RAS-antagonist and beta-blocker or at stable dose as per study entrance. Changes in RAS-antagonist or beta-blocker therapy are not allowed in the control group during the study phase.

Other: RAS-antagonist and beta-blocker none or at stable dose

Interventions

RAS-antagonist and beta-blocker up-to maximal dosages DRUG

All patients have to be stable on their glucose lowering, lipid lowering and blood pressure lowering therapy at least for 3 months. RAS-antagonist and beta-blocker therapy at entrance is allowed. Patients receive a prescription and/or up-titration to maximum recommended or tolerated dose of RAS-antagonist and beta-blockers within three months of study entry. The Number of titration visits is up to the treating physician, but one visit should be performed at least at the end of titration.

Also known as: Enalapril 40mg/d, Ramipril 10mg/d, Lisinopril 40mg/d, Cilazapril 5mg/d, Perindopril 8mg/d, Captopril 150mg/d, Spirapril 24mg/d, Quinapril 40mg/d, Trandolapril 4mg/d, Zofenopril 60mg/d, Fosinopril 40mg/d, Candesartan 32mg/d, Valsartan 320mg/d, Irbesartan 300mg/d, Losartan 150mg/d, Eprosartan 800mg/d, Bisoprolol 10mg/d, Metoprololsuccinat 200mg/d, Carvedilol 50mg/d (100mg/d if weight is > 85kg), Nebivolol 10mg/d

Intensive therapy

RAS-antagonist and beta-blocker none or at stable dose OTHER

All patients have to be stable on their glucose lowering, lipid lowering and blood pressure lowering therapy at least for 3 months. RAS-antagonist and beta-blocker therapy at entrance is allowed. Changes in RAS-antagonist or beta-blocker therapy are not allowed in the control group during the study phase. If there is a vital indication for changes, this has to be argued and documented.

Conventional therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Type-2 diabetes for at least six months,
• ≥ 18 years of age, men or female,
• Written informed consent to participate in the study and ability to comply with all requirements.

You may not qualify if:

• History of hypersensitivity to any of the investigated drugs as well as known or suspected contraindications to the study drugs or previous history of intolerance to high dose of RAS-Antagonist or Beta-blocker in the absence of any other blood pressure lowering drugs.
• Patients already on maximum dose of RAS-antagonist or beta-blocker.
• Creatinine \> 2.5mg/dl.
• Symptomatic hypotension and/or systolic blood pressure (SBP) \< 100 mmHg at Visit 1.
• Symptomatic bradycardia and/or heart rate (HR) \< 60 bpm at Visit 1
• Signs of cardiac disease in the ECG such as atrial fibrillation; ST-T abnormalities or any bundle branch block / higher degree atrioventricular (AV) block.
• Abnormal echocardiography, defined as low ejection fraction \< 50%; wall motion abnormalities suggesting coronary artery disease (CAD), significant valve dysfunction \> grade I or other significant alteration.
• Coronary artery disease, defined by a history of myocardial infarction, known coronary stenosis \> 70% detected either by angiography or by CT-scan, significant defects in myocardial scintigraphy or positive stress-test echocardiography.
• A disease other than T2DM lowering the patient's life expectancy to less than two years.
• Chronic infections or malignancies.
• Systemic treatment with corticosteroids.
• Renal replacement therapy.
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum Follicle Stimulating Hormone (FSH) levels \> 40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy OR are using one or more of the following acceptable methods of contraception: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception (implantable, patch, and oral), and double-barrier methods (if accepted by local regulatory authority and ethics committee). Reliable contraception should be maintained throughout the study and for 7 days after study drug discontinuation.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive Human Chorionic Gonadotropin (hCG) laboratory test (\> 5 U/ml).
• History of noncompliance to medical regimes and patients who are considered potentially unreliable.

Sponsors & Collaborators

• Martin Huelsmann: lead

Study Sites (21)

Internistische Ordination

Mödling, Lower Austria, 2340, Austria

ACTIVE NOT RECRUITING

Klinischen Abteilung für Endokrinologie und Diabetologie MU Graz

Graz, Styria, 8036, Austria

RECRUITING

Konventhospital der Barmherzigen Brüder Abteilung für Innere Medizin

Linz, Upper Austria, 4021, Austria

RECRUITING

Krankenanstalt Rudolfstiftung, 1. Medizinische Abteilung

Vienna, 1030, Austria

COMPLETED

Zentrum für Klinische Studien

Vienna, 1060, Austria

TERMINATED

Medical University of Vienna Univ.Clinic for Internal Medicine II Department of Cardiology

Vienna, 1090, Austria

RECRUITING

Univ. Klinik für Innere Medizin III Med. Uni Wien

Vienna, 1090, Austria

RECRUITING

Universitätsklinik für Augenheilkunde und Optometrie Medizinische Universität Wien

Vienna, 1090, Austria

RECRUITING

Diabetes & Stoffwechselambulanz Gesundheitszentrum Wien Süd

Vienna, 1100, Austria

RECRUITING

3. Med. Abtlg., KH Hietzing mit Neurologischem Zentrum Rosenhügel

Vienna, 1130, Austria

TERMINATED

iMED19

Vienna, 1190, Austria

RECRUITING

Maastricht University Medical Center; Dep. Cardiology

Maastricht, 6202, Netherlands

ACTIVE NOT RECRUITING

Christchurch Heart Institute

Christchurch, 8140, New Zealand

RECRUITING

Hospital de la Santa Creu i Sant Pau, Unitat de Diabetis, Servei d'Endocrinologia i Nutrició, Universitat Autònoma de Barcelona

Barcelona, 8025, Spain

RECRUITING

Hospital Universitari Germans Trias i Pujol, l'Institut del Cor

Barcelona, 8916, Spain

RECRUITING

Ninewells Hospital, Diabetes Support Unit

Dundee, DD19SY, United Kingdom

RECRUITING

Queen Elisabeth University Hospital, Glasgow Clinical Research Facility

Glasgow, G514TF, United Kingdom

RECRUITING

North Manchester General Hospital, Diabetes centre

Manchester, M85RB, United Kingdom

RECRUITING

Nethergreen Surgery

Sheffield, S117EJ, United Kingdom

ACTIVE NOT RECRUITING

Ecclesfield Group Practice

Sheffield, S359XQ, United Kingdom

ACTIVE NOT RECRUITING

Woodseats Medical Centre

Sheffield, S8OSH, United Kingdom

ACTIVE NOT RECRUITING

MeSH Terms

Conditions

Heart Diseases; Diabetes Mellitus, Type 2

Interventions

Enalapril; Ramipril; Lisinopril; Cilazapril; Perindopril; Captopril; spirapril; Quinapril; trandolapril; zofenopril; Fosinopril; candesartan; Valsartan; Irbesartan; Losartan; eprosartan; Bisoprolol; Carvedilol; Nebivolol

Condition Hierarchy (Ancestors)

Cardiovascular Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Dipeptides; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pyridazines; Heterocyclic Compounds, 1-Ring; Indoles; Proline; Imino Acids; Amino Acids, Cyclic; Amino Acids; Tetrahydroisoquinolines; Isoquinolines; Phosphinic Acids; Organophosphorus Compounds; Organic Chemicals; Tetrazoles; Azoles; Valine; Amino Acids, Branched-Chain; Amino Acids, Essential; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Spiro Compounds; Polycyclic Compounds; Imidazoles; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines; Carbazoles; Heterocyclic Compounds, 3-Ring; Ethanolamines; Benzopyrans; Pyrans

Study Officials

• Martin Huelsmann, Doz.Dr.

  Univ.Clinic II, Medical University Vienna

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Martin Huelsmann, Doz.Dr.

CONTACT

+43 1 40400; martin.huelsmann@meduniwien.ac.at

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Univ.Doz. Dr.

Study Record Dates

• First Submitted: February 15, 2016
• First Posted: June 29, 2016
• Study Start: February 1, 2016
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2026
• Last Updated: March 14, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (11); NL (1); NZ (1); GB (6); ES (2)