A Phase 1 Open-Label Study of the Safety of Intravenous Allogeneic Neonatal Mesenchymal Cells (nMSCs) in Young Adult (1A) and Pediatric (1B) Patients With Dilated Cardiomyopathy (DCM)

Dilated Cardiomyopathy Clinical Trial

Official title:

A Phase 1 Open-Label Study of the Safety of Intravenous Allogeneic Neonatal Mesenchymal Cells (nMSCs) in Young Adult (1A) and Pediatric (1B) Patients With Dilated Cardiomyopathy (DCM)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06464588
• Other study ID #: STUDY00004268
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: July 2024
• Est. completion date: July 2027

Study information

• Verified date: June 2024
• Source: Emory University
• Contact: William Mahle, MD
• Phone: 404-256-2593
• Email: wmahle[@]emory.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 1 study to determine the safety and efficacy of allogeneic neonatal mesenchymal stromal cells (nMSCs) for the treatment of Dilated Cardiomyopathy. The purpose of the study is to help doctors and scientists learn if allogeneic neonatal mesenchymal stromal cells (nMSCs) infusions are a safe and effective way to improve cardiac function and left ventricular ejection fraction.

Description:

This study is a single site open label study with 2 phases. The 2 phases will be broken into an adult group Phase 1A with group pediatric group Phase 1B. This study will enroll patients between the ages of 4 years and 30 years old. The investigators will be looking at the safety, feasibility, and maximum tolerated dose of allogeneic neonatal mesenchymal stromal cells (nMSCs) as defined by freedom from CTCAE or Grade 3 AE that is probably or definitely related to the IP throughout the duration of the study.

A minimum of 9 and a maximum of 18 patients will be enrolled into both Phase 1A adult groups and 1B pediatric groups. Phase 1A subjects will receive study products with doses defined by the study group and Phase 1B will begin after all adult subjects have completed Phase 1A infusions, FDA and a DSMC review. All pediatric subjects will receive study product dosed per body weight in the defined study group.

Allogeneic neonatal mesenchymal stromal cells (nMSCs) will be infused via IV every 15 days for a total of 3 infusions. A check-in will be scheduled the morning after each infusion for pediatric patients. There will be a baseline visit before allogeneic neonatal mesenchymal stromal cells (nMSCs) therapy is initiated, followed by a phone call 30 days after the last infusion. There will be in person visits at 3-month, 6 months, and 1 year mark. The total duration for each patient will be 14 months.

Labs will be collected at baseline, during nMSC infusions, and at in person follow up visits to assess cardiac function. Any leftover blood samples may be stored for future research by the sponsor of the study. Echocardiograms will be completed at baseline, and 3 month-, 6 month-, and 1-year visits to look at left ventricular ejection fraction and electrocardiograms will be completed to provide measures of cardiac rhythm or rhythm. Other assessments include physical exam, 6-minute walk test, Cardiac MRI, vital signs, PedsQL questionnaire for pediatrics and The Kansas City Cardiomyopathy Questionnaire for adults.

It is expected to recruit 18-36 participants through face-to-face encounters between participants and study staff during clinical encounters at Children's Healthcare of Atlanta and Emory Health care system, Clinicaltrials.gov registration, and Institutional Review Board approved advertisements to surrounding hospitals with cardiac programs. Patients will also be recruited through MyChart. If identified as eligible to participate, the study team will seek approval by the subjects' primary cardiologist and consent and/or assent with the permission of the parent or legally authorized representative, will occur in person during a baseline visit.

After allogeneic neonatal mesenchymal stromal cells (nMSCs) infusions, pediatric patients will be provided an overnight stay at Ronald McDonald House, or a hospital affiliated hotel in case of any unanticipated effects and follow up visits the next morning. This is so pediatric patients are near the hospital for such events. Adults will not be required to stay overnight for a follow-up visit. There will be financial compensation for each study visit, and patients will be reimbursed for parking.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 36
• Est. completion date: July 2027
• Est. primary completion date: July 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years to 30 Years

Eligibility

Inclusion Criteria

• Phase 1A: Age greater than or equal to 18 years and less than 30 years (=18 years, <30 years).

• Phase 1B: Age greater than or equal to 4 years and less than 18 years (=4 years, <18 years)

• Subjects must be able to sign their own consent for Phase 1A of the study.

• Diagnosis of dilated cardiomyopathy (DCM) defined as

• Any Congenital Cardiac Malformation with systemic ventricular systolic dysfunction; Idiopathic Cardiomyopathy; Familial/Inherited and/or Genetic Cardiomyopathy; History of Myocarditis; Acquired (Chemotherapy, Iatrogenic, Infection, Rheumatic, Nutritional); Ischemic (e.g. Kawasaki Disease, post-operative); Left ventricular noncompaction; Coronary Artery Disease

• Left ventricular ejection fraction less than or equal to 45% documented by two-dimensional echocardiogram or cardiac MRI within the prior six months.

• Left ventricular dilation as defined by echocardiography left ventricular and end-diastolic dimension Z score > +2.0

• Biventricular physiology with systemic left ventricle

• Must receive guideline directed heart failure as defined by the American Heart Association, American College of Cardiology, and Heart Failure Society of America 118

• Have been unresponsive or poorly responsive to at least 3 months of maximum guideline directed treatments.

Exclusion Criteria

• Listed for heart transplantation (as UNOS status 1A) or hospitalized while waiting for transplant (while on inotropes or with ventricular assist device)

• Cardiovascular surgery of percutaneous intervention to palliate or correct congenital cardiovascular malformations within 3 months of the screening visit. Patients anticipated to undergo corrective heart surgery during the 12 months after entry into Part 1A/1B.

• Previous heart transplant recipient

• Unoperated primary obstructive or severe regurgitant valve (aortic, pulmonary, or tricuspid) disease, or significant systemic ventricular outflow obstruction or aortic arch obstruction.

• Severe mitral valve disease

• Restrictive or hypertrophic cardiomyopathy

• Cardiogenic shock

• Currently on extracorporeal membrane oxygenation support

• Ventricular assist device support

• Lethal, uncontrollable arrhythmia defined as an arrhythmia resulting in hemodynamic instability requiring need for defibrillation, continuous intravenous anti-arrhythmic medication or mechanical circulatory support

• Patients with persistent atrial fibrillation requiring specific pharmacotherapy

• Amyloidosis

• Ischemic dilated cardiomyopathy

• Clinical history of malignant neoplasm within 5 years (with the exception of curatively treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma)

• Serious neurologic disorder including loss of vision, stroke, or paralysis

• High-grade pulmonary embolism requiring interventional catheter procedure or pulmonary hypertension requiring use of pulmonary vasodilators including phosphodiesterase inhibitor or nitric oxide

• High-grade renal failure [eGFR<45] mL/min/1.73 m2 - serum potassium >5.3 mmol/L

• Multiple organ failure

• Non-cardiac condition that limits life span for <1 year

• Uncontrolled diabetes (HbA1c >9%) at screening

• Active infection (including endocarditis) requiring pharmacotherapy

• Sepsis

• Active hemorrhagic disease (e.g., gastrointestinal bleeding, injury)

• History of cardiac transplantation

• Immune system-altering medications, or immunosuppressive therapy at the time of enrolment or within the prior 12 weeks

• Dystrophin-associated cardiomyopathy confirmed by standard cardiomyopathy panel testing

• Confirmed myocarditis at time of screening

• Elevated LFTs greater than 2 times upper limit of normal at time of consent

• Elevated WBC greater than upper limit of normal as defined by local lab at time of consent

• Presence of HLA antibodies specific for therapeutic study product

• History of noncompliance, alcohol abuse, recreational drug use, or incarceration within the last year

• Currently pregnant or breastfeeding

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Dilated Cardiomyopathy

Intervention

Biological:
• Allogeneic Neonatal mesenchymal stromal cells (nMSCs)
nMSCs will be administered intravenously in the predefined dose per each group. The rate of infusion will be approximately 30- 60 minutes at 0, 15 and 30 days, with escalating dose levels.

Locations

Country	Name	City	State
United States	Egleston Children's Hospital	Atlanta	Georgia
United States	Emory Children's Center	Atlanta	Georgia
United States	Emory University Hospital	Atlanta	Georgia
United States	Hughes Spalding Children's Hospital	Atlanta	Georgia
United States	Scottish Rite Children's Hospital	Atlanta	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Emory University	The Marcus Foundation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of participants with freedom from any Common Toxicity Criteria for Adverse Events (CTCAE) Grade 3 or greater	Proportion of participants with freedom from any Common Toxicity Criteria for Adverse Events (CTCAE) Grade 3 or greater AE that is probably or related to the IP throughout the duration of the study will be recorded. Results can vary from 0 to 100% and higher proportion correlates with better outcome.; TCAE Grade 3 is defined as severe or medically significant not immediately life-threatening; hospitalization or prolongation of hospitalization.; Grade 4 and 5 AEs include composite of: death, life-threatening events, initial or prolonged hospitalization, disability of permanent damage and congenital anomaly/birth defects.	End of study, around 12 months post-intervention
Primary	Maximum tolerated dose (MTD) in patients with dilated cardiomyopathy	If two patients in a dosing group have a related SAE or Dose Limiting Toxicity (DLT), then the previous dosing group will be defined as MTD.	End of study, around 12 months post-intervention
Secondary	Change of left ventricular ejection fraction (LVEF) from baseline	Change of left ventricular ejection fraction (LVEF) between baseline, 3-month, 6-month, and 12-month follow-up determined by echocardiography and cardiac MRI.	Baseline, 3-month, 6-month, and 12-month post-intervention
Secondary	Change in N-terminal pro b-type natriuretic peptide (NT-proBNP) levels from baseline	N-terminal pro b-type natriuretic peptide (NT-proBNP) levels will be collected on infusion days, and all post infusion follow up visits.	Baseline, 3-month, 6-month, and 12-month post-intervention
Secondary	Change of 6-minute walk test (6MWT) results	A 6-minute walk test (6MWT) will be completed at baseline, 3-month, 6-month, and 1-year visits to measure functional status if the participant is developmentally appropriate. Distance in meters will be measured until the participant can either walk 6 minutes, or they become too exhausted.	Baseline, 3-month, 6-month, and 12-months post-intervention
Secondary	Change in quality-of-life validated survey scores in Peds Quality of Life (QOL) survey	Change in quality-of-life validated survey scores in Peds Quality of Life (QOL) survey (=4 years - < 18 years). Total possible score ranges from 0 to 100 and higher scores indicate better QOL.	Baseline, 3-month, 6-month and 12-month post-intervention
Secondary	Change in Kansas City Cardiomyopathy Questionnaire	Change in Kansas City Cardiomyopathy Questionnaire will be recorded (=18 years - =30 years). KCCQ scores are scaled from 0 to 100 and summarized in 25-point ranges, where scores represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent.	Baseline, 3-month, 6-month and 12-month post-intervention