E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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. |
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E.1.1.1 | Medical condition in easily understood language |
Diabetes mellitus Type II |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. Co-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 in the whole population
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E.2.2 | Secondary objectives of the trial |
Secondary objective: Dependency of treatment efficacy (reduction of unplanned hospitalization or death due to a cardiac event in T2DM patients) on the NT-proBNP concentration (interaction effect between NT-proBNP concentrations and treatment).
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
SUB-STUDY 1: Impact of high dose β-Blocker and ACE Inhibition on early retinal changes in diabetic subjects - a possible prevention of diabetic retinopathy? (PONTIAC 2 Eye Study), protocol version 1.3, dated 06.05.2019
1. Rationale The purpose of this study is to evaluate the effect of high dose RAS-antagonists and ß-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.
2. Study design Single center, masked longitudinal follow up
3. Study population 130 Type 2 diabetic patients that were already included in the PONTIAC II study and 30 healthy volunteers. Only patients from Viennese sites will be included. For comparison, 30 healthy volunteers will be investigated.
4. Primary objective Differences between both treatment arms in thickness-change in the retinal nerve fiber layer or outer nuclear layer measured in SD-OCT
5. Secondary objectives • Effect of high dose treatment with RAS Antagonists on subclinical changes in retinal morphology and retinal perfusion compared to standard care • Identification of biomarkers for early retinal changes in diabetic patients with application of computational algorithms • Development of disease specific algorithms for the identification of OCT biomarkers in all stages of diabetic retinopathy including supervised and unsupervised machine learning algorithms • Identification of biomarkers to distinguish between high risk and low risk patients in regard to micro-vascular and macro-vascular disease progression. • To validate methods for the evaluation of OCT-angiography images by comparison to ground truth manually annotated images. • Population analysis and disease modeling with regards to all available parameters for the potential identification of other biomarkers predictive for the development or progression of diabetic retinopathy
SUB-STUDY 2: Echocardiographic sub-study, protocol version 1.0, dated 2016-04-19
1. Rationale The principal aim of this sub-study is to comprehensively assess the long-term impact of intensified treatment with RAS-antagonists and ß-blockers on systolic and diastolic function and myocardial mechanics. Experimental data in mice suggests that inhibition of the RAS can prevent diabetes-induced cardiac dysfunction as assessed by echocardiography. However, there is little known about the effects of primary preventive use of intensive therapy with RAS antagonists and ß-blockers on echocardiographic measures of cardiac dysfunction in patients with diabetes.
2. Study Design PONTIAC 2 study centers, which also participate in the Echocardiographic sub-study have to be qualified to obtain and store their echocardiographies in sufficient quality, as defined by the study protocol. Echocardiography will be done only during the routinely investigation at baseline and after 2 years, as stated in the main protocol. However all requested loops for patients taking part in the sub-study, will be saved for later analysis by the core lab at the department of cardiology, Medical Univ. Vienna. By participating in the echocardiographic sub-study, there is no additional effort or risk for patients.
3. Study Population Out of qualified study centers, 600 consecutive patients, willing to participate, will be included. Exclusion criteria for participation in this sub-study will be inadequate echocardiographic imaging.
4. Primary objective Influence of high dose treatment with RAS-antagonists and ß-blockers compared to conventional therapy regarding a change in global longitudinal strain at 2-year follow up.
5. Secondary objective • Influence of high dose treatment with RAS-antagonists and ß-blockers compared to conventional therapy regarding the secondary endpoints. • Dependency of the primary and secondary endpoints on baseline NT-proBNP.
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E.3 | Principal inclusion criteria |
1) Type-2 diabetes mellitus for at least six months, 2) ≥ 18 years of age, men or female, 3) Written informed consent to participate in the study and ability to comply with all requirements.
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E.4 | Principal exclusion criteria |
1) History of hypersensitivity to any of the drugs investigated as well as known or suspected contraindications to the study drugs or previous history of intolerance to high dose of RAAS-antagonists or beta-blocker in the absence of any other blood pressure lowering drugs. 2) Patients already receiving a maximum dose of RAAS-antagonists or beta-blocker. 3) Creatinine > 2.5mg/dl. 4) Symptomatic hypotension and/or systolic blood pressure (SBP) < 100mmHg at visit 1. 5) Symptomatic bradycardia and/or heart rate (HR) < 60bpm at visit 1. 6) Signs of cardiac disease in the electrocardiogram such as atrial fibrillation; ST-T abnormalities or a bundle branch block/ higher degree AV block. 7) Abnormal echocardiography, defined as low ejection fraction < 50%; wall motion abnormalities suggesting coronary artery disease (CAD), significant valve dysfunction > grades I. 8) 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. 9) A disease other than diabetes lowering the patient’s life expectancy to less than two years. 10) Chronic infections or malignancies. 11) Systemic treatment with corticosteroids. 12) Renal replacement therapy. 13) 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 > 40mIU/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. 14) 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 ( > 5mIU/ml). 15) History of noncompliance to medical regimes and patients who are considered potentially unreliable. 16) Current double blind treatment in diabetic trials. 17) Participation in an investigational drug study at the time of enrollment or within the past 90 days.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint are unplanned hospitalization or death due to a cardiac event in T2DM patients with a NT-proBNP > 125pg/ml. The co-primary endpoint is whether high dose treatment with RAS-antagonists and beta-blockers is superior to conventional therapy regarding the reduction of unplanned hospitalization or death due to a cardiac event in T2DM patients in the whole population |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoints will be evaluated in the 2-years study period and will be further followed-up by telephone calls or registers. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints is an interaction effect between NT-proBNP concentrations and treatment efficacy. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary endpoints will be evaluated in the 2-years study period and will be further followed-up by telephone calls or registers. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
alternative antihypertensive therapy |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
New Zealand |
Austria |
Netherlands |
Spain |
Germany |
Italy |
Hungary |
Russian Federation |
United Kingdom |
Serbia |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |