E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic advanced symptomatic heart failure secondary to ischemic cardiomyopathy |
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E.1.1.1 | Medical condition in easily understood language |
Advanced heart failure of ischemic origin |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010684 |
E.1.2 | Term | Congestive heart failure |
E.1.2 | System Organ Class | 100000004849 |
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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 |
The primary objective is to evaluate the efficacy of C3BS-CQR-1 by comparing the overall response to C3BS-CQR-1 relative to standard of care undergoing a sham procedure using a composite outcome of morbidity and mortality, changes in quality of life , six-minute walk distance, and left ventricular structure and function at 39 weeks (9 months) post-procedure. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess the safety of C3BS-CQR-1 by comparing the incidence of serious adverse events between study groups at 52 weeks (12 months) post-procedure and all cause mortality at 104 weeks (24 months) post-procedure. Additionally data will be collected to evaluate the safety and performance of the endoventricular injection catheter C-Cath® as a system for delivery of C3BS-CQR-1 into the left ventricular myocardium. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Eligible patients must meet all of the following inclusion criteria: 1. Age ≥ 18 and < 80 years. 2. Systolic dysfunction with LVEF ≤ 35% as assessed by echocardiography. 3. Ischemic heart failure without known need for revascularization. 4. Total MLHFQ score > 30. 5. Ability to perform a Six-Minute Walk Test > 100 m and ≤ 400 m. 6. History of hospitalization for HF within 12 months prior to screening or treatment in an out-patient clinic with intravenous vasoactive therapy (including vasodilators, positive inotropic agents and vasopressors) or diuretics for worsening HF within 12 months prior to screening. 7. Be or must have been within the previous 12 months in NYHA class III or IV or INTERMACS class 4, 5, 6 or 7, and at the time of inclusion, must be at least in NYHA class II or greater. 8. Use of ACE inhibitor and/or ARB; and beta blocker, for at least 3 months prior to screening visit, unless intolerant or contraindicated. 9. Stable dosing of ACE inhibitor, ARB, beta blocker, aldosterone blocker, and diuretics for at least one month prior to screening visit, defined as ≤50% change in total dose of each agent. 10. Willing and able to give written informed consent.
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E.4 | Principal exclusion criteria |
Eligible patients must meet none of the following exclusion criteria: 1. Women who are pregnant, confirmed by a positive urine or serum hCG laboratory test at screening. 2. Women of child-bearing potential without a negative serum or urine pregnancy test at screening or who are not practicing a reliable form of birth control. Women who are postmenopausal (12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH level > 40 IU/m or 6 weeks post surgical bilateral oophorectomy) or surgically sterile are not considered to be of child-bearing potential. Reliable contraception includes surgical sterilization, hormonal contraception, or double-barrier methods. 3. Men refusing to exercise a reliable form of contraception. 4. Myocardial infarction, unstable angina or percutaneous coronary intervention (PCI) within 90 days prior to screening, or CABG surgery within 180 days prior to screening. 5. Patient on a cardiac transplant list or previously received any solid organ transplant. 6. Previously underwent cardiac surgery with remodeling procedure, left ventricular assist device placement or cardiomyoplasty. This exclusion does not apply to patients who underwent ventricularplasty without placements device >1 year ago. 7. Patient has undergone cardiac resynchronization therapy (CRT) within 6 months (180 days) prior to screening. 8. Severe uncontrolled HF requiring need for intensive intravenous diuretics or inotropic support within 1 month prior to screening. 9. Inability to perform a Six-Minute Walk Test due to physical limitations other than HF including: a. Severe peripheral vascular disease b. Severe pulmonary disease or chronic obstructive pulmonary disease (COPD) limiting exercise c. Orthopedic limitations, severe muscular diseases, any other joint or muscular disease or neurological disorder (such as an old stroke or neuropathy) limiting the ability to walk for 6 minutes. 10. Dependence on chronic oral steroid therapy. 11. Stroke or transient ischemic attack leading to limitations in lower extremities or occurring within 180 days prior to screening. 12. Active myocarditis, constrictive pericarditis, restrictive, hypertrophic or congenital cardiomyopathy. 13. BMI < 19 or > 45. 14. Left ventricular thrombus. 15. Left ventricular wall thickness < 8mm visualized in more than 50% of LV, and defined as a “LV no-go zone 16. LV aneurysm or candidate for surgical aneurysmectomy. 17. Sustained VT or VF which led to AICD therapy (shock) within 3 months prior to screening. 18. Primary significant organic valvular heart disease. 19. Moderate to severe aortic valve disease precluding catheter entry into the LV. 20. Mechanical prosthetic valve in aortic or mitral position. 21. Chronic infection or active malignancy. 22. Patient has compromised renal function as reflected by a serum creatinine level >3.0 mg/dL (>0.265 mmol/l) or is currently on dialysis. 23. Hematocrit < 28%. 24. Atherosclerosis and/or tortuosity of the aorta, iliac or femoral arteries of a degree that could impede or preclude the safe retrograde passage of the delivery catheter. 25. Chronic immunosuppressive therapy due to inflammatory or systemic disease. 26. Patient tested positive for HIV 1 or 2, Hepatitis B or C, HTLV 1 or 2 (if requested by regulations) or syphilis. 27. Exposure to any previous experimental cell or angiogenic therapy and/or myocardial laser therapy and/or therapy with another investigational drug within 60 days prior to screening or enrollment in any concurrent study that may confound the results of this study. 28. Known drug or alcohol dependence or any other factors which will interfere with the study conduct or interpretation of the results or in the opinion of the investigator are not suitable to participate. 29. Any illness other than CHF which might reduce life expectancy to less than 2 years from screening. 30. Known and relevant allergies and/or hyper-sensitivities to Dextran or other plasma volume expanders to include Gentran, Hyskon and Macrodex. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will measure the efficacy of C3BS-CQR-1 injection at 39 weeks (9 months) based on a hierarchical composite of: 1. All-cause mortality. 2. Worsening of heart failure events defined as requiring unscheduled treatment for signs and symptoms of heart failure in an urgent outpatient setting or requiring hospital admission, as adjudicated by a Clinical Events Committee. 3. Change in MLHFQ total score. 4. Change in Six-Minute Walk Test (6MWT) 5. Change in LVESV as assessed by echocardiography 6. Change in LVEF as assessed by echocardiography.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At 39 weeks (9 months) post index procedure. |
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E.5.2 | Secondary end point(s) |
Safety endpoints will include the following: 1. The occurrence of the following clinical events: death and cause of death, re-admissions and cause of re-admission, cardiac transplantation, myocardial infarction, stroke. 2. Incidence of serious adverse events. 3. Incidence of non-serious adverse events.
Secondary efficacy endpoints will include the effect of C3BS-CQR-1 injection at 52 weeks (12 months) on: 1. Time to all cause mortality. 2. Worsening of heart failure events defined as requiring unscheduled treatment for signs and symptoms of heart failure in an urgent outpatient setting or requiring hospital admission, as adjudicated by a Clinical Events Committee. 3. Aborted sudden death events, defined as resuscitated sudden death or appropriate Automatic Implantable Cardioverter Defibrillator (AICD) therapy for severe ventricular tachyarrhythmias.
Tertiary (explorative) efficacy endpoints will include the effect of C3BS-CQR-1 injection on each of the components of the composite endpoint at 39, and 52 weeks (9 and 12 months) unless otherwise specified: 1. Time to all cause mortality. 2. Time to cardiovascular (CV) mortality. 3. Worsening of heart failure events defined as requiring unscheduled treatment for signs and symptoms of heart failure in an urgent outpatient setting or requiring hospital admission, as adjudicated by a Clinical Events Committee. 4. Aborted sudden death events, defined as resuscitated sudden death or appropriate AICD therapy for severe ventricular tachyarrhythmias. 5. Re-admissions for heart failure. 6. Total days alive out of hospital. 7. Change in Six-Minute Walk Test from pre-procedure. 8. Change in MLWHF Questionnaire from pre-procedure. 9. Change in LVESV, LVEDV, LVEF and Left Ventricular Mass Index assessed by echocardiography from pre-procedure to 6, 9 and 12 months. 10. Change in NT-pro-BNP level from pre-procedure to 9 months. 11. Changes in INTERMACS class from pre-procedure and proportion of patients with improved INTERMACS classification. 12. Changes in NYHA class from pre-procedure and proportion of patients with improved NYHA classification. 13. Change in blood cell counts, CRP, and renal function (Creatinine). 14. Total cost and healthcare utilization. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety endpoints (clinical events as defined in E.5.2 and serious adverse events): through 52 and 104 weeks (12 and 24 months) post index procedure. Safety endpoints (Non-serious adverse events): through 52 weeks (12 months) post index procedure. Secondary Efficacy endpoints: at 52 weeks (12 months) post index procedure. Tertiary efficacy endpoints: at 39 and 52 weeks (9 and 12 months) post index procedure. |
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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 | Yes |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Belgium |
Bosnia and Herzegovina |
Bulgaria |
Croatia |
Estonia |
France |
Hungary |
Ireland |
Israel |
Italy |
Latvia |
Lithuania |
Poland |
Romania |
Serbia |
Spain |
Sweden |
Switzerland |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |