PercutaneOus StEm Cell Injection Delivery Effects On Neomyogenesis in Dilated CardioMyopathy (The POSEIDON-DCM Study) (PoseidonDCM)

• ClinicalTrials.gov Identifier: NCT01392625
• Recruitment Status: Completed
• First Posted: July 12, 2011
• Results First Posted: February 15, 2018
• Last Update Posted: February 15, 2018
• Sponsor: Joshua M Hare
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Joshua M Hare, University of Miami

Tracking Information

• First Submitted Date: June 29, 2011
• First Posted Date: July 12, 2011
• Results First Submitted Date: August 3, 2017
• Results First Posted Date: February 15, 2018
• Last Update Posted Date: February 15, 2018
• Actual Study Start Date: May 19, 2011
• Actual Primary Completion Date: August 28, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 10, 2014)

Incidence of Any Treatment-emergent Serious Adverse Events (TE-SAEs) [ Time Frame: One month post-catheterization ]

Incidence of TE-SAEs is defined as the composite of: death, non-fatal MI, stroke, hospitalization for worsening heart failure, cardiac perforation, pericardial tamponade, sustained ventricular arrhythmias (characterized by ventricular arrhythmias lasting longer than 15 seconds or with hemodynamic compromise), or any other potential late effects detected and corroborated by clinical presentation, laboratory investigations, image analysis and when necessary with biopsy from suspected target sites in the body.

Original Primary Outcome Measures (submitted: July 11, 2011)

Incidence of Any Treatment-emergent Serious Adverse Events (TE-SAEs) [ Time Frame: One month post-catheterization ]

Incidence of TE-SAEs is defined as the composite of: death, non-fatal MI, stroke, hospitalization for worsening heart failure, cardiac perforation, pericardial tamponade, sustained ventricular arrhythmias (characterized by ventricular arrhythmias lasting longer than 15 seconds or with hemodynamic compromise).

Current Secondary Outcome Measures (submitted: January 19, 2018)

• Measurement of Changes in Peak VO2 [ Time Frame: Baseline, 6 month and 12 month ]
  Measurement of Peak oxygen consumption (Peak VO2) by treadmill determination during the 12 month follow-up period.
• Measurement of Changes in 6 Minute Walk [ Time Frame: Baseline, 6 month and 12 month ]
  Measurement of Six-minute walk test during the 12 month follow-up period
• Measurement of Changes in Global Ejection Fraction [ Time Frame: Baseline, 6 month and 12 month ]
  Measurement of regional left ventricular function, end diastolic and end systolic volume, measured by MRI, and or CT, and echocardiogram.
• Measurement of Changes in New York Heart Association (NYHA) [ Time Frame: Baseline, 6 month and 12 month ]
  Measurement of New York Heart Association (NYHA) functional class during the 12 month follow-up period.
• Measurement of Changes in Minnesota Living With Heart Failure (MLHF) Questionnaire [ Time Frame: Baseline, 6 month and 12 month ]
  Measurement of Minnesota Living with Heart Failure (MLHF) Questionnaire during the 12 month follow-up period. It measures the effects of symptoms, functional limitations, and psychological distress on an individual's quality of life. The response scale for all 21 items on the MLHF is based on a 6-point. The Maximum possible scores being 126 and the minimum 0. Higher scores indicate a worse or worsening quality of life, while lower scores or decreasing scores indicate a better quality of life.

Original Secondary Outcome Measures (submitted: July 11, 2011)

Measurement of Changes in Regional Left Ventricular function [ Time Frame: Baseline, 6 month and 12 month ]

Measurement of regional left ventricular function, wall thickening, end diastolic and end systolic volume,including tissue perfusion measured by MRI, and or CT, and echocardiogram. Other measurements include: Peak VO2 (by treadmill determination),Six-minute walk test,NYHA functional class, Minnesota Living with Heart Failure (MLHF) Questionnaire, Incidence of the Major Adverse Cardiac Events (MACE) endpoint, defined as the composite incidence of (1) death, (2) hospitalization for worsening heart failure, (3) non-fatal recurrent MI, or (4) angina requiring hospitalization.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: PercutaneOus StEm Cell Injection Delivery Effects On Neomyogenesis in Dilated CardioMyopathy (The POSEIDON-DCM Study)
• Official Title: A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Non-ischemic Dilated Cardiomyopathy.

Brief Summary

The technique of transplanting progenitor cells into a region of damaged myocardium, termed cellular cardiomyoplasty1, is a potentially new therapeutic modality designed to replace or repair necrotic, scarred, or dysfunctional myocardium2-4. Ideally, graft cells should be readily available, easy to culture to ensure adequate quantities for transplantation, and able to survive in host myocardium; often a hostile environment of limited blood supply and immunorejection. Whether effective cellular regenerative strategies require that administered cells differentiate into adult cardiomyocytes and couple electromechanically with the surrounding myocardium is increasingly controversial and recent evidence suggests that this may not be required for effective cardiac repair. Most importantly, transplantation of graft cells should improve cardiac function and prevent adverse ventricular remodeling. To date, a number of candidate cells have been transplanted in experimental models, including fetal and neonatal cardiomyocytes5, embryonic stem cell-derived myocytes6, 7, tissue engineered contractile grafts8, skeletal myoblasts9, several cell types derived from adult bone marrow10-15, and cardiac precursors residing within the heart itself16. There has been substantial clinical development in the use of whole bone marrow and skeletal myoblast preparations in studies enrolling both post-infarction patients, and patients with chronic ischemic left ventricular dysfunction and heart failure. The effects of bone-marrow derived mesenchymal stem cells (MSCs) have also been studied clinically.

Currently, bone marrow or bone marrow-derived cells represent highly promising modality for cardiac repair. The totality of evidence from trials investigating autologous whole bone marrow infusions into patients following myocardial infarction supports the safety of this approach. In terms of efficacy, increases in ejection fraction are reported in the majority of the trials.

Non-ischemic dilated cardiomyopathy is a common and problematic condition; definitive therapy in the form of heart transplantation is available to only a tiny minority of eligible patients. Cellular cardiomyoplasty for chronic heart failure has been studied less than for acute MI, but represents a potentially important alternative for this disease.

Detailed Description

This is a Pilot Study, intended as a safety assessment prior to a full comparator study. In this Pilot Study, cells administered via the Biosense Webster MyoStar NOGA injection catheter system will be tested in 36 patients in two groups:

Group 1 (18 patients) Eighteen (18) patients will be treated with Auto-hMSCs: 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1 X 108 (100 million) Auto-hMSCs.

Group 2 (18 patients) Eighteen (18) patients will be treated with Allo-hMSCs: 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1 X 108 (100 million) Auto-hMSCs.

The first three (3) patients in each group (Group 1 and Group 2) will not be treated less than 5 days apart and will each undergo full evaluation for 5 days to demonstrate there is no evidence of a procedure induced myocardial infarction or myocardial perforation prior to proceeding with the treatment of further patients.

Patients will be randomized in a 1:1 ratio to one of the two groups.

Treatment Strategies: Autologous hMSCs vs. Allogeneic hMSCs. The Study Team will record and maintain a detailed record of injection locations.

If a patient is randomized to Groups 1 (Auto-hMSCs) and the Auto-hMSCs do not expand to the required dose of 1 X 108 cells, each injection will contain the maximum number of cells available.

The injections will be administered transendocardially during cardiac catheterization using the Biosense Webster MyoStar NOGA Catheter System.

For patients randomized to Group 1(Auto-hMSCs); the cells will be derived from a sample of the patient's bone marrow (obtained by iliac crest aspiration) approximately 4-6 weeks prior to cardiac catheterization. For patients randomized to Group 2 (Allo- hMSCs), the cells will be supplied from an allogeneic human mesenchymal stem cell source manufactured by the University of Miami. The Allo-hMSCs for patients in group 2 will be administered after all baseline assessments are completed with an expected range of 2 - 4 weeks post-randomization.

Following cardiac catheterization and cell injections, patients will be hospitalized for a minimum of 2 days then followed at 2 weeks post-catheterization, and at month 2, 3, 6, and 12 to complete all safety and efficacy assessments.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment
• Condition: Non-ischemic Dilated Cardiomyopathy

Intervention

• Biological: Autologous hMSCs

  Cells will be administered via the Biosense Webster MyoStar NOGA Injection Catheter System will be tested in 18 patients via transendocardial injection:

  Group 1 (18 patients) Eighteen (18) patients will be treated with Auto-hMSCs: 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1 x 108 (100 million) Auto-hMSCs.

  Other Name: Biosense Webster MyoStar NOGA Injection Catheter System.
• Biological: Allogeneic hMSCs

  Cells will be administered via the Biosense Webster MyoStar NOGA Injection Catheter System will be tested in 18 patients via transendocardial injection:

  Group 2 (18 patients) Eighteen (18) patients will be treated with Allo-hMSCs: 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1 x 108 (100 million) Auto-hMSCs.

  Other Name: Biosense Webster MyoStar NOGA Injection Catheter System.

Study Arms

• Active Comparator: Autologous hMSCs
  Group 1 (18 patients) Eighteen (18) patients will be treated with Auto-hMSCs: 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1 x 108 (100 million) Auto-hMSCs.
  Intervention: Biological: Autologous hMSCs
• Active Comparator: Allogeneic hMSCs
  Group 2 (18 patients) Eighteen (18) patients will be treated with allogeneic hMSCs (Allo-hMSCs): 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1 x 108 (100 million) Auto-hMSCs.
  Intervention: Biological: Allogeneic hMSCs

Publications *

• Williams AR, Trachtenberg B, Velazquez DL, McNiece I, Altman P, Rouy D, Mendizabal AM, Pattany PM, Lopera GA, Fishman J, Zambrano JP, Heldman AW, Hare JM. Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Circ Res. 2011 Apr 1;108(7):792-6. doi: 10.1161/CIRCRESAHA.111.242610. Epub 2011 Mar 17.
• Trachtenberg B, Velazquez DL, Williams AR, McNiece I, Fishman J, Nguyen K, Rouy D, Altman P, Schwarz R, Mendizabal A, Oskouei B, Byrnes J, Soto V, Tracy M, Zambrano JP, Heldman AW, Hare JM. Rationale and design of the Transendocardial Injection of Autologous Human Cells (bone marrow or mesenchymal) in Chronic Ischemic Left Ventricular Dysfunction and Heart Failure Secondary to Myocardial Infarction (TAC-HFT) trial: A randomized, double-blind, placebo-controlled study of safety and efficacy. Am Heart J. 2011 Mar;161(3):487-93. doi: 10.1016/j.ahj.2010.11.024.
• Hare JM, DiFede DL, Rieger AC, Florea V, Landin AM, El-Khorazaty J, Khan A, Mushtaq M, Lowery MH, Byrnes JJ, Hendel RC, Cohen MG, Alfonso CE, Valasaki K, Pujol MV, Golpanian S, Ghersin E, Fishman JE, Pattany P, Gomes SA, Delgado C, Miki R, Abuzeid F, Vidro-Casiano M, Premer C, Medina A, Porras V, Hatzistergos KE, Anderson E, Mendizabal A, Mitrani R, Heldman AW. Randomized Comparison of Allogeneic Versus Autologous Mesenchymal Stem Cells for Nonischemic Dilated Cardiomyopathy: POSEIDON-DCM Trial. J Am Coll Cardiol. 2017 Feb 7;69(5):526-537. doi: 10.1016/j.jacc.2016.11.009. Epub 2016 Nov 14.
• Premer C, Wanschel A, Porras V, Balkan W, Legendre-Hyldig T, Saltzman RG, Dong C, Schulman IH, Hare JM. Mesenchymal Stem Cell Secretion of SDF-1α Modulates Endothelial Function in Dilated Cardiomyopathy. Front Physiol. 2019 Sep 24;10:1182. doi: 10.3389/fphys.2019.01182. eCollection 2019.
• Tompkins BA, Rieger AC, Florea V, Banerjee MN, Natsumeda M, Nigh ED, Landin AM, Rodriguez GM, Hatzistergos KE, Schulman IH, Hare JM. Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy. J Am Heart Assoc. 2018 Jul 12;7(14). pii: e008460. doi: 10.1161/JAHA.117.008460.
• Mushtaq M, DiFede DL, Golpanian S, Khan A, Gomes SA, Mendizabal A, Heldman AW, Hare JM. Rationale and design of the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy (the POSEIDON-DCM study): a phase I/II, randomized pilot study of the comparative safety and efficacy of transendocardial injection of autologous mesenchymal stem cell vs. allogeneic mesenchymal stem cells in patients with non-ischemic dilated cardiomyopathy. J Cardiovasc Transl Res. 2014 Dec;7(9):769-80. doi: 10.1007/s12265-014-9594-0. Epub 2014 Oct 30.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 19, 2018): 37
• Original Estimated Enrollment (submitted: July 11, 2011): 36
• Actual Study Completion Date: August 28, 2017
• Actual Primary Completion Date: August 28, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Major Inclusion Criteria:

• Be ≥ 18 and < 95 years of age.
• Provide written informed consent.
• Diagnosis of nonischemic dilated cardiomyopathy.
• Be a candidate for cardiac catheterization within 5 to 10 weeks of screening.
• Been treated with appropriate maximal medical therapy for heart failure.
• Ejection fraction below 40% and either a left ventricular end diastolic diameter (LVEDD) > 5.9cm in male subjects, an LVEDD of > 5.6cm in female subjects or left ventricular end diastolic volume index > 125 mL/m2
• Be able to undergo an MRI or CT.

Major Exclusion Criteria:

• Baseline glomerular filtration rate equal or < 45 ml/min/1.73m2.
• Be eligible for or require standard-of-care surgical or percutaneous intervention for the treatment of nonischemic dilated cardiomyopathy.
• Presence of a prosthetic aortic valve or heart constrictive device.
• Presence of a prosthetic mitral valve.
• Previous myocardial infarction (MI) as documented by a clinical history that will include an elevation of cardiac enzymes and/or ECG changes consistent with MI.
• Diagnosis of nonischemic dilated cardiomyopathy due to valvular dysfunction, mitral regurgitation, tachycardia, or myocarditis.
• Previous treatment for post-infarction left ventricular dysfunction including PCI and thrombolytic therapy.
• Documented presence of a known LV thrombus, aortic dissection, or aortic aneurysm.
• Documented presence of epicardial stenosis of 70% or greater in one or more major epicardial coronary arteries.
• Documented presence of aortic stenosis (aortic stenosis graded as 1.5cm2 or less).
• Documented presence of moderate to severe aortic insufficiency (echocardiographic assessment of aortic insufficiency graded as ≥+2).
• Evidence of a life-threatening arrhythmia in the absence of a defibrillator (nonsustained ventricular tachycardia ≥ 20 consecutive beats or complete second or third degree heart block in the absence of a functioning pacemaker) or QTc interval > 550 ms on screening ECG.
• AICD firing in the past 30 days prior to the procedure
• Be eligible for or require coronary artery revascularization.
• Diabetic with poorly controlled blood glucose levels and/or evidence of proliferative retinopathy.
• Have a hematologic abnormality as evidenced by hematocrit < 25%, white blood cell < 2,500/ul or platelet values < 100,000/ul without another explanation.
• Have liver dysfunction, as evidenced by enzymes (ALT and AST) greater than three times the ULN.
• Have a coagulopathy condition = (INR > 1.3) not due to a reversible cause.
• Known, serious radiographic contrast allergy.
• Known allergies to penicillin or streptomycin.
• Organ transplant recipient.
• Have a history of organ or cell transplant rejection
• Clinical history of malignancy within 5 years (i.e., patients with prior malignancy must be disease free for 5 years), except curatively-treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma.
• Non-cardiac condition that limits lifespan to < 1 year.
• On chronic therapy with immunosuppressant medication.
• Serum positive for HIV, hepatitis BsAg, or viremic hepatitis C.
• Female patient who is pregnant, nursing, or of child-bearing potential and not using effective birth control.
• Have a history of drug or alcohol abuse within the past 24 months.
• Be currently participating (or participated within the previous 30 days) in an investigational therapeutic or device trial.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 95 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01392625
• Other Study ID Numbers: 20100968; 1R01HL110737-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Joshua M Hare, University of Miami
• Study Sponsor: Joshua M Hare
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Joshua M Hare, MD; University of Miami

• PRS Account: University of Miami
• Verification Date: January 2018