| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008908 |
| E.1.2 | Term | Chronic 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 objectives of this study are to:
•determine whether transendocardial delivery of 150 M allogeneic human bone marrow-derived MPCs (rexlemestrocel-L) when administered during a single index cardiac catheterization and intracardiac mapping procedure is more effective than a scripted sham cardiac mapping and cell delivery procedure in patients with chronic HF due to LV systolic dysfunction who have received optimal medical/ revascularization therapy as assessed by the time to first HF–MACE.
For full list of primary objectives refer to section 2.2 of Protocol |
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| E.2.2 | Secondary objectives of the trial |
•time-to-recurrent non-fatal decompensated HF events in presence of terminal HF MACE
•total hospital admissions for decompensated HF after index cardiac catheterization (with or without intracardiac mapping and cell delivery)
•total hospital admissions or urgent HF visits for decompensated HF after index cardiac catheterization (with or without intracardiac mapping and cell delivery)
•length of in-hospital stay in intensive care unit for decompensated HF
•cardiac survival (captures only cardiac deaths)
•overall survival (captures all cause deaths)
•time-to-terminal HF-MACE (first of cardiac death, resuscitated cardiac death [including successful firing of an ICD for VF in patients who have an ICD or any implanted device capable of defibrillation], LVAD placement, heart transplant, artificial heart implantation);
•time to death from cardiovascular causes, non-fatal MI, non-fatal CVA, coronary artery revascularization or hospitalization for unstable angina, whichever comes first |
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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 |
Optional exploratory PGx substudy:
Blood samples will be collected from patients who provide informed consent for possible use in future PGx analyses for the assessment of possible associations between genetic polymorphisms and the response to rexlemestrocel-L therapy in patients with chronic HF. |
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| E.3 | Principal inclusion criteria |
1. The patient is 18 to 80 years of age, inclusive; both men and women will be enrolled.
2. The patient has a diagnosis of chronic HF of ischemic or nonischemic etiology for at least 6 months before the initiation of screening procedures, with NYHA Functional Class II or Functional Class III symptoms. Chronic HF of ischemic etiology includes epicardial CAD defined as documented stenosis of at least 50% in one or more major epicardial coronary arteries or documented prior MI.
3. The patient is on stable, optimally tolerated dosages of HF therapies including beta-blockers (approved for country-specific usage), ACE inhibitors or angiotensin-receptor blockers (ARBs), and/or aldosterone antagonists, without change in dose for at least 1 month prior to study intervention (ie, hospitalization on day 0 for index cardiac catheterization with or without intracardiac mapping and cell
delivery).
4. The patient is on a stable, outpatient, oral diuretic dosing regimen in which the patient remains clinically stable during the screening period (flexible diuretic dosing that allows the patient to titrate the dose or add a dose of a second diuretic during screening is permitted, provided that the dosing regimen is not further altered and the patient remains stable during this period) or the patient is not on a regular dose of diuretics but takes diuretics as needed based on daily weight or the appearance of symptoms.
5. The patient is not a candidate for either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery as determined by the principal investigator (or designee) during screening.
6. The patient may be on the cardiac transplant list. However, he/she must have low priority status with low probability of having a transplant procedure performed over the next 12 months (ie, cannot be UNOS status 1A or 1B).
7. The patient has a LVEF of 40% or less as measured by 2-D echocardiogram, or 35% or less as measured by RVG within 42 days prior to study intervention (ie, hospitalization on day 0 for index cardiac catheterization with or without intracardiac mapping and cell delivery).
8. The patient has 1 or more of the following:
•at least 1 HF hospitalization more than 1 month, but 9 months or less before initiation of screening procedures
•at least 1 outpatient visit requiring IV diuretic, vasodilator, and/or positive inotropic therapy more than 1 month, but 9 months or less before initiation of screening procedures
•plasma levels of NT-pro-BNP greater than 1000 pg/mL (1000 ng/L SI units; 118 pmol/L) or 1200 pg/mL (1200 ng/L SI units; 141.6 pmol/L) for patients with atrial fibrillation
9. If the patient has an ICD (or any implanted device capable of defibrillation) in place, the procedure must have occurred at least 1 month before initiation of screening procedures.
10. If the patient has had CRT, the procedure must have occurred at least 3 months before screening.
11. The patient has an LV diastolic wall thickness of at least 8 mm at the potential target site for cell injection.
12. Women must be surgically sterile, 1 year post-menopausal, or must have a negative urine pregnancy test at screening.
13.Women must be surgically sterile, 1 year post-menopausal, or, if of childbearing potential, currently using a medically accepted method of contraception, and must agree to continue to use this method of contraception after initiation of screening procedures and for 6 months after study intervention (ie, hospitalization on day 0 for
index cardiac catheterization with or without intracardiac mapping and cell delivery).
Acceptable methods of contraception refer Protocol
14. The patient must be willing to return for required follow-up visits.
15. Written informed consent is obtained for the study before any study-specific procedures are performed. A separate written informed consent for the exploratory PGx substudy is obtained before any PGx-specific procedures are performed. Participation in the PGx substudy is optional and consent may be collected at a later stage than screening (though preferred as early as possible). A patient will not be
excluded from participation in the study if he/she chooses not to provide consent for the additional procedures that are required as part of the exploratory PGx substudy.
16. Prior to the initiation of any procedures on day 0, the cell injection center will ensure that an institution-specific informed consent document is obtained, if applicable
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|
| E.4 | Principal exclusion criteria |
Subjects will not be enrolled into this study if they meet ANY of the following criteria:
1.The patient has NYHA Functional Class I or Functional Class IV symptoms.
2.The patient has had an acute MI within 1 month before initiation of the screening procedures.
3.The patient has unstable angina pectoris within 1 month before initiation of screening procedures; unstable angina is defined as the occurrence of chest pain more frequently than usual, pain at rest or upon minimal exertion, or protracted episodes of pain without any discernible trigger, and/or chest pain that persists despite use of vasodilatory therapy (eg, nitroglycerin) and or aggravation of stable angina or new onset angina.
4.The patient has peri-/postpartum cardiomyopathy.
5.The patient has ischemic or hemorrhagic stroke as diagnosed by CT or MRI within 3 months prior to study enrollment.
6.The patient has had coronary arterial or peripheral arterial revascularization procedure within 2 months before initiation of screening procedures.
7.The patient has had IV therapy with diuretic, vasodilator, and/or positive inotropes or aquapheresis within 1 month before initiation of screening procedures, and/or during the screening period.
8.The patient, who in the absence of an ICD (or any implanted device capable of defibrillation), has a history of malignant ventricular arrhythmia or sustained ventricular tachycardia (VT), with sustained VT demonstrated by QRS complexes wider than 120 milliseconds, lasting more than 30 seconds, and with a rate of more than 100 beats per minute on screening ECG or other data supporting this diagnosis.
9.The patient has restrictive, obstructive, or infiltrative CM, pericardial constriction, amyloidosis, or uncorrected thyroid disease.
10.The patient has moderate to severe aortic stenosis as determined by echocardiography-Doppler assessment with a valve area less than 1.0 cm2.
11.The patient requires valve or other cardiac (eg, pericardectomy) surgery.
12.The patient has had LV reduction surgery, implanted LVAD, or cardiac transplantation. The patient may be on the cardiac transplant list, but must have low probability of having a transplant procedure over the next 12 months.
13.The patient has an LV thrombus diagnosed by echocardiography, left ventriculogram, or other imaging.
14.The patient has cardiogenic shock that is dependent upon mechanical or inotropic support at the time of study intervention (ie, hospitalization on day 0 for index cardiac catheterization with or without intracardiac mapping and cell delivery), as defined by Killip Class IV physiology indicative of cardiogenic shock and/or requirement of intra-aortic balloon pump or IV inotropic support for the maintenance of mean arterial blood pressure at least 60 mmHg.
15.The patient is known to have unprotected left main coronary artery disease (CAD) greater than 50%.
16.The patient has known hypersensitivity to radiocontrast media or dimethyl sulfoxide (DMSO), murine, and/or bovine products, with the exception of patients with mild hypersensitivity to radiocontrast media or DMSO, who may be pretreated with corticosteroids and/or antihistamines
17.The patient has a known active malignancy within the past 3 years except for localized prostate cancer, cervical carcinoma in situ, breast cancer in situ, or nonmelanoma skin cancer that has been definitively treated.
18.The patient has acute bacterial or viral infectious disease, or acute exacerbation of a chronic infectious disease at the time that day 0 intervention is planned. However, patients with an upper respiratory infection diagnosed at screening that is cleared by day 0 (maximum of 42 days from signing of informed consent form) may undergo the procedure.
19.Patients with severe chronic obstructive pulmonary disease (COPD) or patients who require home oxygen for any kind of pulmonary disease; home oxygen use as part of CPAP (continuous positive airway pressure) for the indication of sleep apnea in patients living at high altitude is permitted, and as-needed home oxygen use solely as therapy for HF is permitted.
For full list of Exclusion criteria refer to section 4.2 of Protocol |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint for this study is time to first HF-MACE, with HF–MACE defined as a composite of terminal HF-MACE (cardiac death, resuscitated cardiac death [including successful firing of an ICD for VF in patients who have an ICD or any implanted device capable of defibrillation], LVAD placement, heart transplant, artificial heart implantation) or nonfatal decompensated HF event. The diagnosis of a non-fatal decompensated HF event requires signs and symptoms consistent with clinical decompensation of the patient’s HF state. These HF events require use of IV diuretics or aquapheresis during an in-hospital stay or during an outpatient visit. Adjudication of HF MACE will be performed by an independent, blinded CEC. For details on the role and responsibilities of the CEC, please see the CEC Manual of Operations.
For full details please refer to section 3.2 of the protocol |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| This is an event-driven study and the study duration will be determined by the number of HF MACE events. Patients are expected to participate in this study until the required number of HF MACE occurs. The last patient enrolled must be followed for a minimum of 6 months. |
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| E.5.2 | Secondary end point(s) |
The key secondary efficacy measures and endpoints of the study comprise the following:
•time-to-recurrent non-fatal decompensated HF events in the presence of terminal HF MACE
•total hospital admissions for decompensated HF after index cardiac catheterization with or without intracardiac mapping and cell delivery
•total hospital admissions or urgent HF visits for decompensated HF after index cardiac catheterization with or without intracardiac mapping and cell delivery
•length of in-hospital stay in intensive care unit for decompensated HF
•cardiac survival (captures only cardiac deaths)
•overall survival (captures all cause deaths)
•time-to-terminal HF-MACE (first of cardiac death, resuscitated cardiac death [including successful firing of an ICD for VF in patients who have an ICD or any implanted device capable of defibrillation], LVAD placement, heart transplant, artificial heart implantation); all terminal events will be accounted for
•time-to-death from cardiovascular causes, nonfatal MI, nonfatal CVA, coronary revascularization, or hospitalization for unstable angina, whichever comes first
For full list of secondary end points refer to the Protocol pages 66-67 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| This is an event-driven study and the study duration will be determined by the number of HF MACE events. Patients are expected to participate in this study until the required number of HF MACE occurs. The last patient enrolled must be followed for a minimum of 6 months. |
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Independent Clinical Endpoints Comittee will remain blinded to study treatment for duration of study |
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| 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 |
| Sham–procedure–controlled study |
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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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 |
| Austria |
| Belarus |
| Bulgaria |
| Canada |
| Czech Republic |
| Finland |
| France |
| Germany |
| Italy |
| Latvia |
| Lithuania |
| Netherlands |
| Poland |
| Russian Federation |
| Singapore |
| Slovenia |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
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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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| Because this study is endpoint driven, the actual duration of the study will be determined by the time required to achieve a minimum of 314HF MACE that have been positively adjudicated by the CEC. Patients are expected to participate in this study until the required number of HF MACE occurs. The last patient enrolled must be followed for a minimum of 6 months. |
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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 | 5 |
| 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 | 5 |
| 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 |
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