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Efficacy and Safety Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure (CUPID)

19 sierpnia 2014 zaktualizowane przez: Celladon Corporation

A Phase 1/2 Trial of Intracoronary Administration of MYDICAR® (AAV1/SERCA2a) in Subjects With Heart Failure in Two Stages (Open-Label, Sequential Dose-Escalation Cohorts and Randomized, Double-Blind, Placebo-Controlled, Parallel Cohorts)

The study is divided into 2 parts. In the first part, the safety of the gene transfer agent MYDICAR® will be evaluated. In the second part, the ability of MYDICAR® to improve heart function will be studied.

Przegląd badań

Szczegółowy opis

The American Heart Association (AHA) 2006 update on heart disease reported that 5 million Americans are believed to have symptomatic heart failure (HF), and 550,000 patients are newly diagnosed each year. The estimated direct and indirect cost of HF in the United States (U.S.) for 2006 will be ~$29.6 billion. Heart failure is a disabling chronic disease and the most frequent discharge diagnosis for hospitalization among older adults. Despite the significant resources expended on the treatment of this disease, outcomes remain poor. The five-year survival for individuals diagnosed with heart failure is less than 50%, and in end-stage heart failure, the one-year survival may be as low as 25% regardless of medical therapy.

Recent studies suggest that the failing heart is not refractory to treatment, as was previously believed. For example, the observation that a small percentage of subjects with left ventricular assist devices (LVADs) can be permanently weaned from their device strongly suggests that damaged hearts are capable of recovering lost function.

Clinical studies of MYDICAR® have not yet been conducted in humans. Celladon Corporation (Celladon) proposes to investigate gene transfer as a method to restore SERCA2a function in heart failure (HF) patients using a recombinant adeno-associated viral vector (AAV), which consists of an AAV serotype 1 capsid and contains the human SERCA2a complementary DNA (cDNA) flanked by Inverted Terminal Repeats (ITR) derived from AAV serotype 2 (AAV1/SERCA2a). MYDICAR® refers to AAV1/SERCA2a drug product intended for administration by percutaneous delivery.

Typ studiów

Interwencyjne

Zapisy (Rzeczywisty)

51

Faza

  • Faza 2
  • Faza 1

Kontakty i lokalizacje

Ta sekcja zawiera dane kontaktowe osób prowadzących badanie oraz informacje o tym, gdzie badanie jest przeprowadzane.

Lokalizacje studiów

    • California
      • San Diego, California, Stany Zjednoczone, 92123
        • San Diego Cardiac Center
      • San Diego, California, Stany Zjednoczone, 92103
        • University of California at San Diego Medical Center
    • Florida
      • Gainesville, Florida, Stany Zjednoczone, 32608
        • Shands Hospital at University of Florida
    • Illinois
      • Chicago, Illinois, Stany Zjednoczone, 60611
        • Northwestern University
      • Chicago, Illinois, Stany Zjednoczone, 60637
        • University Of Chicago Medical Center
    • Missouri
      • Kansas City, Missouri, Stany Zjednoczone, 64111
        • Mid America Heart Institute, Saint Luke's Hospital
      • St. Louis, Missouri, Stany Zjednoczone, 63110
        • St. Louis University Hospital
    • New Jersey
      • Newark, New Jersey, Stany Zjednoczone, 07101
        • University of Medicine and Dentistry of New Jersey
    • New York
      • New York, New York, Stany Zjednoczone, 10029
        • Mount Sinai Medical Center
      • New York, New York, Stany Zjednoczone, 10032
        • Columbia University Hospital
    • North Carolina
      • Winston-Salem, North Carolina, Stany Zjednoczone, 27157
        • Wake Forest University
    • Ohio
      • Cincinnati, Ohio, Stany Zjednoczone, 45267
        • University of Cincinnati
      • Cleveland, Ohio, Stany Zjednoczone, 44109
        • MetroHealth Medical Center
      • Cleveland, Ohio, Stany Zjednoczone, 44195
        • Cleveland Clinic Foundation
    • Oregon
      • Portland, Oregon, Stany Zjednoczone, 97239
        • Oregon Health and Science University
    • Pennsylvania
      • Philadelphia, Pennsylvania, Stany Zjednoczone, 19104
        • Hospital of the University of Pennsylvania
      • Pittsburgh, Pennsylvania, Stany Zjednoczone, 15213
        • University of Pittsburgh Medical Center, Presbyterian-Shadyside Hospital
    • Tennessee
      • Tullahoma, Tennessee, Stany Zjednoczone, 37388
        • Tennessee Center for Clinical Trials & Harton Regional Medical Center
    • Texas
      • Dallas, Texas, Stany Zjednoczone, 75230
        • Cardiopulmonary Research Science and Technology Institute, Medical City Dallas Hospital
      • Houston, Texas, Stany Zjednoczone, 77030
        • Methodist Hospital
    • Utah
      • Murray, Utah, Stany Zjednoczone, 84157
        • Intermountain Medical Center
    • Wisconsin
      • Madison, Wisconsin, Stany Zjednoczone, 53792
        • University of Wisconsin

Kryteria uczestnictwa

Badacze szukają osób, które pasują do określonego opisu, zwanego kryteriami kwalifikacyjnymi. Niektóre przykłady tych kryteriów to ogólny stan zdrowia danej osoby lub wcześniejsze leczenie.

Kryteria kwalifikacji

Wiek uprawniający do nauki

18 lat do 75 lat (Dorosły, Starszy dorosły)

Akceptuje zdrowych ochotników

Nie

Płeć kwalifikująca się do nauki

Wszystko

Opis

Inclusion Criteria:

  • Chronic ischemic or non-ischemic cardiomyopathy. Subjects with ischemic cardiomyopathy must have at least one major coronary vessel with Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow.
  • Left ventricular ejection fraction (LVEF) ≤35%
  • Diagnosis of New York Heart Association (NYHA) Class III/IV heart failure for a minimum of 3 months prior to screening
  • Maximal oxygen consumption (VO2 max) ≤20 mL/kg/min within 90 days prior to enrollment
  • An implantable cardioverter defibrillator (ICD) implanted a minimum of 30 days prior to enrollment
  • Treatment with appropriate heart failure therapy as tolerated
  • All women of childbearing potential must have a negative urine pregnancy test prior to administration of investigational product and agree to use adequate contraception. Men capable of fathering a child must agree to use barrier contraception or limit activity to post-menopausal, surgically sterilized, or a contraception-practicing partner, for 3 months after administration of investigational product.
  • Ability to sign Informed Consent Form (ICF) and Release of Medical Information Form

Exclusion Criteria:

  • Any intravenous therapy with positive inotropes, vasodilators, or diuretics within 30 days prior to enrollment
  • Restrictive cardiomyopathy, obstructive cardiomyopathy, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease, or dyskinetic LV aneurysm
  • Cardiac surgery, percutaneous coronary intervention, or valvuloplasty within 30 days prior to enrollment
  • Clinically significant myocardial infarction (e.g., ST elevation MI [STEMI] or large non-STEMI) within 6 months prior to enrollment
  • Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), surgically implanted LVAD or cardiac shunt
  • Likely to receive cardiac resynchronization therapy, cardiomyoplasty, LVRS, heart transplant, conventional revascularization procedure, or valvular repair within 6 months following enrollment
  • Patients with prior coronary artery bypass graft(s) (CABG) will reviewed on a case-by-case basis
  • No evidence of functional or viable myocardium
  • Exercise capacity primarily limited by obesity, peripheral vascular disease, intrinsic pulmonary disease or orthopedic problems and not by underlying heart failure
  • Known hypersensitivity to octafluoropropane (component of the intravenous echocardiography contrast agent, DEFINITY®) or other contrast dyes used for angiography; history of, or likely need for, high dose steroid pretreatment prior to contrast angiography
  • A left ventricle that is difficult to image or high quality echocardiography is not obtainable at screening
  • Significant left main or ostial right coronary lumenal stenosis in the opinion of the investigator
  • Expected survival <1 year in the investigator's medical opinion
  • Suspected or active viral, bacterial, fungal, or parasitic infection within 48 hours prior to enrollment
  • Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase) >2x Upper Limit of Normal (ULN) within 30 days prior to enrollment or known intrinsic liver disease (e.g., cirrhosis, chronic hepatitis B or hepatitis C virus infection)
  • Current or likely need for hemodialysis within 12 months following enrollment
  • Bleeding diathesis or thrombocytopenia defined as platelet count <50,000 platelets/μL
  • Anemia defined as hemoglobin <10 g/dL
  • Known AIDS or HIV-positive status, or a previous diagnosis of immunodeficiency with an absolute neutrophil count <1000 cells/mm3
  • Previous participation in a study of gene transfer
  • Presence of neutralizing anti-AAV1 antibodies at titer ≥1:2 within 3 months of screening
  • Receiving investigational intervention or participating in another clinical study within 30 days or within 5 half-lives of the investigational drug administration prior to enrollment
  • Pregnancy or lactation
  • Recent history of psychiatric disease (including drug or alcohol abuse) that is likely to impair subject's ability to comply with protocol-mandated procedures, in the opinion of the investigator
  • Other concurrent medical condition(s) that, while not explicitly excluded by the protocol, could jeopardize the safety of the patient or objectives of the study

Plan studiów

Ta sekcja zawiera szczegółowe informacje na temat planu badania, w tym sposób zaprojektowania badania i jego pomiary.

Jak projektuje się badanie?

Szczegóły projektu

  • Główny cel: Leczenie
  • Przydział: Randomizowane
  • Model interwencyjny: Przydział równoległy
  • Maskowanie: Poczwórny

Broń i interwencje

Grupa uczestników / Arm
Interwencja / Leczenie
Eksperymentalny: MYDICAR Very Low Dose
Single dose of MYDICAR, a viral vector (adeno-associated virus serotype 1 [AAV1]) carrying the gene for sarcoplasmic reticulum Ca++-adenosine triphosphatase (SERCA2a), at a dose of 1.4x10e11 DNAase resistant particles administered by antegrade epicardial coronary artery infusion. Used in MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study) only.
MYDICAR administered by antegrade epicardial coronary artery infusion
Inne nazwy:
  • AAV1/SERCA2a
Eksperymentalny: MYDICAR Low Dose
Single dose of MYDICAR, a viral vector (adeno-associated virus serotype 1 [AAV1]) carrying the gene for sarcoplasmic reticulum Ca++-adenosine triphosphatase (SERCA2a), at a dose of 6x10e11 DNAase resistant particles administered by antegrade epicardial coronary artery infusion. Used in MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study) and MYDICAR Phase 2 (Placebo-controlled, Randomized Study)
MYDICAR administered by antegrade epicardial coronary artery infusion
Inne nazwy:
  • AAV1/SERCA2a
MYDICAR administered by antegrade epicardial coronary artery infusion
Inne nazwy:
  • AAV1/SERCA2a
Eksperymentalny: MYDICAR Mid Dose
Single dose of MYDICAR, a viral vector (adeno-associated virus serotype 1 [AAV1]) carrying the gene for sarcoplasmic reticulum Ca++-adenosine triphosphatase (SERCA2a), at a dose of 3x10e12 DNAase resistant particles administered by antegrade epicardial coronary artery infusion. Used in MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study) and MYDICAR Phase 2 (Placebo-controlled, Randomized Study).
MYDICAR administered by antegrade epicardial coronary artery infusion
Inne nazwy:
  • AAV1/SERCA2a
MYDICAR administered by antegrade epicardial coronary artery infusion
Inne nazwy:
  • AAV1/SERCA2a
Eksperymentalny: MYDICAR High Dose
Single dose of MYDICAR, a viral vector (adeno-associated virus serotype 1 [AAV1]) carrying the gene for sarcoplasmic reticulum Ca++-adenosine triphosphatase (SERCA2a), at a dose of 1x10e13 DNAase resistant particles administered by antegrade epicardial coronary artery infusion. Used in MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study) and MYDICAR Phase 2 (Placebo-controlled, Randomized Study).
MYDICAR administered by antegrade epicardial coronary artery infusion
Inne nazwy:
  • AAV1/SERCA2a
MYDICAR administered by antegrade epicardial coronary artery infusion
Inne nazwy:
  • AAV1/SERCA2a
Komparator placebo: Placebo infusion
A single dose of placebo (Sodium Chloride Injection, USP) administered by antegrade epicardial coronary artery infusion.
Saline; epicardial coronary artery infusion

Co mierzy badanie?

Podstawowe miary wyniku

Miara wyniku
Opis środka
Ramy czasowe
Phase 2: Incidence of Treatment-emergent Adverse Events (TEAE) at 12 Months
Ramy czasowe: 12 months
Includes all adverse events that occurred from the time of first infusion of the investigational product or placebo to the 12-month visit. The category of "TEAEs related to the investigational product (IP)" includes TEAEs considered by the investigator to be possibly, probably, or definitely related to the IP.
12 months
Phase 2: Length of Cardiovascular-related Hospitalizations at 6 Months
Ramy czasowe: 6 months
Mean number of days in the hospital for cardiovascular-related complications. All hospitalizations were evaluated and classified by the blinded Clinical Endpoints Committee.
6 months
Phase 2: Change in Symptomatic Efficacy Domains From Baseline to Month 6: New York Heart Association (NYHA) Class and Minnesota Living With Heart Failure Questionnaire (MLWHFQ) Score
Ramy czasowe: Baseline to 6 months

NYHA classification is a symptomatic assessment in which the investigator evaluates subjects on a scale ranging from Class I (subjects with no limitation of activities, no symptoms from ordinary activities) to Class IV (subjects who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest).

The MLWHFQ is a patient-reported quality of life (QoL) measure in which patients assess the impact of their heart condition on activities in the past month using a Likert scale ranging from 0 (no effect) to 5 (very much effect). Higher scores thus indicate a lower QoL. The maximum (worst) score is 105 and the minimum (best) score is 0.

For both measures, changes from baseline with positive values indicate a worsening in symptoms and changes from baseline with negative values indicate an improvement in symptoms.

Baseline to 6 months
Phase 2: Change in 6-minute Walk Test (6MWT) From Baseline to Month 6
Ramy czasowe: Baseline to 6 months
The 6MWT measures the distance walked in meters during a 6-minute test. Higher values indicate a better functional status. Changes from baseline with negative values indicate a worsening in function and changes from baseline with positive values indicate an improvement in function.
Baseline to 6 months
Phase 2: Change in Peak Maximum Oxygen Consumption (VO2) From Baseline to Month 6
Ramy czasowe: Baseline to 6 months
Peak VO2 is a measure of maximal oxygen consumption during cardiopulmonary exercise testing; this study used the modified Naughton treadmill protocol. Higher values indicate a better functional status. Changes from baseline with negative values indicate a worsening in function and changes from baseline with positive values indicate an improvement in function.
Baseline to 6 months
Phase 2: Change in Absolute Levels of N-terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) From Baseline to Month 6
Ramy czasowe: Baseline to 6 months
NT-proBNP is a biomarker for heart failure. Increased levels of this biomarker are associated with increased mortality and cardiovascular hospitalization in patients with heart failure.
Baseline to 6 months
Phase 2: Change in Percentage of Blood Ejected From the Left Ventricle (LV) (i.e., Left Ventricular Ejection Fraction [LVEF]) From Baseline to Month 6
Ramy czasowe: Baseline to 6 months
Contrast echocardiography was used to determine LVEF. Increases in LVEF are associated with reduced mortality. Changes from baseline with positive values indicate an improvement in heart function and changes from baseline with negative values indicate a worsening of heart function.
Baseline to 6 months
Phase 2: Change in Absolute Left Ventricular End Systolic Volume (LVESV) Frm Baseline to Month 6
Ramy czasowe: Baseline to 6 months
Contrast echocardiography was used to determine LVESV. Decreases in LVESV are associated with reduced mortality. Changes from baseline with positive values indicate a worsening in heart function and changes from baseline with negative values indicate an improvement in symptoms.
Baseline to 6 months

Inne miary wyników

Miara wyniku
Opis środka
Ramy czasowe
Phase 2: Length of Cardiovascular-related Hospitalizations at 12 Months
Ramy czasowe: 12 months
Mean number of days in the hospital for cardiovascular-related complications. All hospitalizations were evaluated and classified by the blinded Clinical Endpoints Committee.
12 months
Phase 2: Change in Symptomatic Efficacy Domains From Baseline to Month 12: New York Heart Association (NYHA) Class and Minnesota Living With Heart Failure Questionnaire (MLWHFQ) Score
Ramy czasowe: Baseline to 12 months

NYHA classification is a symptomatic assessment in which the investigator evaluates subjects on a scale ranging from Class I (subjects with no limitation of activities, no symptoms from ordinary activities) to Class IV (subjects who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest).

The MLWHFQ is a patient-reported quality of life (QoL) measure in which patients assess the impact of their heart condition on activities in the past month using a Likert scale ranging from 0 (no effect) to 5 (very much effect). Higher scores thus indicate a lower QoL. The maximum (worst) score is 105 and the minimum (best) score is 0.

For both measures, changes from baseline with positive values indicate a worsening in symptoms and changes from baseline with negative values indicate an improvement in symptoms.

Baseline to 12 months
Phase 2: Change in 6-minute Walk Test (6MWT) From Baseline to Month 12
Ramy czasowe: Baseline to 12 months
The 6MWT measures the distance walked in meters during a 6-minute test. Higher values indicate a better functional status. Changes from baseline with negative values indicate a worsening in function and changes from baseline with positive values indicate an improvement in function.
Baseline to 12 months
Phase 2: Change in Peak Maximum Oxygen Consumption (VO2) From Baseline to Month 12
Ramy czasowe: Baseline to 12 months
Peak VO2 is a measure of maximal oxygen consumption during cardiopulmonary exercise testing; this study used the modified Naughton treadmill protocol. Higher values indicate a better functional status. Changes from baseline with negative values indicate a worsening in function and changes from baseline with positive values indicate an improvement in function.
Baseline to 12 months
Phase 2: Change in Absolute Levels of N-terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) From Baseline to Month 12
Ramy czasowe: Baseline to 12 months
NT-proBNP is a biomarker for heart failure. Increased levels of this biomarker are associated with increased mortality and cardiovascular hospitalization in patients with heart failure.
Baseline to 12 months
Phase 2: Change in Percentage of Blood Ejected From the Left Ventricle (LV) (i.e., Left Ventricular Ejection Fraction [LVEF]) From Baseline to Month 12
Ramy czasowe: Baseline to 12 months
Contrast echocardiography was used to determine LVEF. Increases in LVEF are associated with reduced mortality. Changes from baseline with positive values indicate an improvement in heart function and changes from baseline with negative values indicate a worsening of heart function.
Baseline to 12 months
Phase 2: Change in Absolute Left Ventricular End Systolic Volume (LVESV) From Baseline to Month 12
Ramy czasowe: Baseline to 12 months
Contrast echocardiography was used to determine LVESV. Decreases in LVESV are associated with reduced mortality. Changes from baseline with positive values indicate a worsening in heart function and changes from baseline with negative values indicate an improvement in symptoms.
Baseline to 12 months
Phase 1 and Phase 2: All Subject Deaths Through 36 Months
Ramy czasowe: 36 months
All subject deaths that occurred during the 12-month study or the 24-month follow-up in subjects enrolled in either the Phase 1 or Phase 2 trial. Events occurring after early termination from the trial are listed as occurring during long-term follow-up, but may have been within 12 months. Specifically, two cardiovascular (CV) deaths in placebo subjects occurred following early study termination, but within 12 months of study initiation. These deaths are therefore included under "Deaths within 12 months" but also listed as "Cardiovascular deaths in long-term follow-up." Accordingly, the number of "Cardiovascular deaths in long-term follow-up" for the placebo group is greater than the number of "Deaths after 12 months," as 2 of the deaths occurred within 12 months but after early termination.
36 months

Współpracownicy i badacze

Tutaj znajdziesz osoby i organizacje zaangażowane w to badanie.

Śledczy

  • Główny śledczy: Randall Starling, MD, The Cleveland Clinic
  • Główny śledczy: Thomas Cappola, MD, ScM, University of Pennsylvania
  • Główny śledczy: Brian Jaski, MD, San Diego Cardiac Center
  • Główny śledczy: Stephen Archer, MD, University of Chicago
  • Główny śledczy: Donna Mancini, MD, Columbia University Hospital
  • Krzesło do nauki: Mariell Jessup, MD, University of Pennsylvania
  • Główny śledczy: Daniel Pauly, MD, Shands Hospital, University of Florida at Gainesville
  • Główny śledczy: Barry London, MD, University of Pittsburgh Medical Center
  • Główny śledczy: Barry Greenberg, MD, University of California at San Diego Medical Center
  • Główny śledczy: A. G. Kfoury, MD, Intermountain Medical Center
  • Główny śledczy: Andrew Kao, MD, Mid America Heart Institute, Saint Luke's Hospital
  • Główny śledczy: Paul J. Hauptman, MD, St. Louis University Hospital
  • Główny śledczy: Jill Kalman, MD, Icahn School of Medicine at Mount Sinai
  • Główny śledczy: Douglas W. Losordo, MD, Northwestern University
  • Główny śledczy: Eric J. Eichhorn, MD, FACC, Cardiopulmonary Research Science and Technology Institutte, Medical City Dallas Hospital
  • Główny śledczy: Stephanie H. Dunlap, DO, University of Cincinnati
  • Główny śledczy: Vinay Thohan, MD, Wake Forest University
  • Główny śledczy: Maryl R. Johnson, MD, University of Wisconsin, Madison
  • Główny śledczy: Mark Dunlap, MD, MetroHealth Medical Center
  • Główny śledczy: Joaquin E. Cigarroa, MD, Oregon Health and Science University
  • Główny śledczy: Dinesh K. Gupta, MD, Tennessee Center for Clinical Trials, Harton Regional Medical Center
  • Główny śledczy: Marc Klapholz, MD, University of Medicine and Dentistry of New Jersey
  • Główny śledczy: Guillermo Torre, MD, The Methodist Hospital Research Institute

Publikacje i pomocne linki

Osoba odpowiedzialna za wprowadzenie informacji o badaniu dobrowolnie udostępnia te publikacje. Mogą one dotyczyć wszystkiego, co jest związane z badaniem.

Publikacje ogólne

Daty zapisu na studia

Daty te śledzą postęp w przesyłaniu rekordów badań i podsumowań wyników do ClinicalTrials.gov. Zapisy badań i zgłoszone wyniki są przeglądane przez National Library of Medicine (NLM), aby upewnić się, że spełniają określone standardy kontroli jakości, zanim zostaną opublikowane na publicznej stronie internetowej.

Główne daty studiów

Rozpoczęcie studiów

1 marca 2007

Zakończenie podstawowe (Rzeczywisty)

1 sierpnia 2010

Ukończenie studiów (Rzeczywisty)

1 sierpnia 2012

Daty rejestracji na studia

Pierwszy przesłany

30 marca 2007

Pierwszy przesłany, który spełnia kryteria kontroli jakości

30 marca 2007

Pierwszy wysłany (Oszacować)

2 kwietnia 2007

Aktualizacje rekordów badań

Ostatnia wysłana aktualizacja (Oszacować)

20 sierpnia 2014

Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości

19 sierpnia 2014

Ostatnia weryfikacja

1 sierpnia 2014

Więcej informacji

Terminy związane z tym badaniem

Inne numery identyfikacyjne badania

  • CELL-001
  • CUPID Trial (Identyfikator rejestru: NCT00454818)

Te informacje zostały pobrane bezpośrednio ze strony internetowej clinicaltrials.gov bez żadnych zmian. Jeśli chcesz zmienić, usunąć lub zaktualizować dane swojego badania, skontaktuj się z register@clinicaltrials.gov. Gdy tylko zmiana zostanie wprowadzona na stronie clinicaltrials.gov, zostanie ona automatycznie zaktualizowana również na naszej stronie internetowej .

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