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Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) (PROMETHEUS)

19. august 2019 oppdatert av: Joshua M Hare

A Phase I/II, Randomized, Double-Blinded, Placebo-Controlled Study of the Safety and Efficacy of Intramyocardial Injection of Autologous Human Mesenchymal Stem Cells (MSCs) in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction (MI) Undergoing Cardiac Surgery for Coronary Artery Bypass Grafting (CABG)

Heart attacks are a leading cause of death in both men and women in the United States. When a person has a heart attack, blood is unable to reach a certain area of the heart, and if the blood supply is not re-established quickly, that area of the heart can suffer permanent damage. While recovery from a heart attack can be managed through medications and lifestyle changes, these treatments can not reverse the original damage to the heart. Current research is focusing on the development of cell-based therapies using stem cells to repair organs that have been irreversibly damaged by disease. A specific form of stem cells, called adult mesenchymal stem cells (MSCs), has shown promise for heart repair. This study will evaluate the safety and effectiveness of injecting MSCs into the heart to repair and restore heart function in people who have had a heart attack and who are having heart surgery for coronary artery bypass grafting (CABG).

Studieoversikt

Status

Avsluttet

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

Participation in this study will last 18 months. Potential participants will undergo initial screening 5 to 7 weeks prior to CABG surgery. Screening will include a physical exam, blood draw, pregnancy test, questions about medical history, current medications, and alcohol or drug use, an electrocardiogram (ECG), magnetic resonance imaging (MRI) of the heart, questionnaires, an echocardiogram and a computed tomography (CT) scan. Eligible participants will then undergo two baseline visits within 6 weeks of their scheduled surgery. Baseline Visit 1 will consist of vital sign measurements, a bone marrow aspiration to obtain MSCs and a blood draw for a biomarker test. Baseline Visit 2 will include treadmill test, 6-minute walk test, pulmonary function (FEV1) study and a 48 Hour Ambulatory ECG. After the second baseline visit, participants will be assigned randomly to receive either MSCs or placebo after surgery.

On the day of surgery, once all of the bypass grafts have been placed, a high or low dose of MSCs or placebo will be injected into a damaged area of the heart that did not receive a bypass graft. After receiving the injections, participants will remain in the hospital for up to 7 days. During this stay, participants will undergo a daily blood draw, urine test, ECG, and ambulatory ECG monitoring for the first 96 hours after surgery.

Upon being discharged, participants will return for monthly visits for 6 months and for follow-up visits 12 and 18 months after surgery. These visits will repeat most initial screening and baseline tests. There will be one additional visit 14 days after surgery, which will include questions about side effects, a physical exam, and a 48-hour ambulatory ECG.

Studietype

Intervensjonell

Registrering (Faktiske)

9

Fase

  • Fase 2
  • Fase 1

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

  • Forente stater
    • Florida
      • Miami, Florida, Forente stater, 33136
        • University of Miami Miller School of Medicine
    • Maryland
      • Baltimore, Maryland, Forente stater, 21205
        • Johns Hopkins University School of Medicine

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

21 år til 80 år (Voksen, Eldre voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

Inclusion Criteria:

  • Diagnosis of chronic ischemic heart failure caused by a heart attack
  • Scheduled to undergo cardiac surgery for CABG
  • Ejection fraction between 15% and 50%
  • Presence of an akinetic or dyskinetic region by standard imaging

Exclusion Criteria:

  • Glomerular filtration rate of less than 50 mL/min/1.73m2 at study entry
  • Contraindication to performance of an MRI scan
  • Bone marrow dysfunction, as evidenced by a 20% or more deviation from normal hematocrit, white blood cell count, or platelet values without another explanation
  • A coagulopathy condition not due to a reversible cause (i.e., Coumadin)
  • Known, serious radiographic contrast allergy
  • Known allergies to penicillin or streptomycin
  • Organ transplant recipient
  • Clinical history of malignancy within 5 years of study entry (e.g., 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 less than 1 year
  • On chronic therapy with immunosuppressant medication
  • Serum positive for HIV, hepatitis B, or hepatitis C
  • Female who is pregnant, nursing, or of child-bearing potential and not practicing effective birth control methods

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Behandling
  • Tildeling: Randomisert
  • Intervensjonsmodell: Parallell tildeling
  • Masking: Dobbelt

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: Lower dose mesenchymal stem cell (MSC) injection
Participants will receive lower dose mesenchymal stem cell injections for a total of 2 x 10^7 cells
Biologisk: Lower dose mesenchymal stem cell (MSC) injection
Participants will receive between 10 and 20 intramyocardial injections of 2 million MSCs per 0.25-0.5 cubic centimeter (cc) for a total of 2 x 10^7 cells. The injections will be administered following completion of CABG surgery.
Eksperimentell: Higher dose MSC injection
Participants will receive higher dose of mesenchymal stem cell injections for a total of 2 x 10^8 cells
Biologisk: Higher dose MSC injection
Participants will receive between 10 and 20 intramyocardial injections of 20 million MSCs per 0.25-0.5 cc for a total of 2 x 10^8 cells. The injections will be administered following completion of CABG surgery.
Placebo komparator: (3) Placebo
Participants will receive placebo injections
Genetisk: Placebo
Participants will receive between 10 and 20 placebo injections that consist of phosphate buffered saline (PBS) and 1% human serum albumin (HSA).

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Number of Patients With Serious Adverse Events
Tidsramme: 12 Months
Six-month post-CABG surgery serious adverse event (SAE) proportion of patients experiencing a composite of sustained ventricular arrhythmias, (lasting longer than 15 seconds), with hemodynamic compromise, sudden unexpected death at six months, ectopic tissue formation at 12 months by chest/abdomen/pelvis CT exam.
12 Months

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Change in Infarct Scar Size (ISS) Over 18 Month Period
Tidsramme: Baseline, 6 Months, 18 Months
Change in infarct scar size (ISS) between baseline and 6-month and 18 month visits as determined by delayed contrast-enhanced MRI.
Baseline, 6 Months, 18 Months
Left Ventricular Function (LVF) in Region of MSC Injection
Tidsramme: Assessed at Baseline and 18 Months
The Left Ventricular Function differences in the region of MSC injection were evaluated. LVF is evaluated via ECHO as the percentage of ejected blood.
Assessed at Baseline and 18 Months
Regional Left Ventricular Wall Thickening
Tidsramme: Assessed at Baseline and 18 months
Difference between baseline and 18 month regional left ventricular wall thickening as determined by MRI.
Assessed at Baseline and 18 months
Left Ventricular End Diastolic Wall Thickness
Tidsramme: Assessed at Baseline and 18 months
Difference between the baseline and 18 month left ventricular end diastolic wall thickness as determined by MRI and echocardiogram.
Assessed at Baseline and 18 months
Change in Left Ventricular End Diastolic and Systolic Volume
Tidsramme: Baseline, 6 Months, 18 Months
Change in left ventricular end diastolic and systolic volume as determined by MRI and echocardiogram.
Baseline, 6 Months, 18 Months
Change in Left Ventricular Ejection Fraction
Tidsramme: Baseline to 6 Months, Baseline to 18 Months
Change between baseline to 6-month and 18-month left ventricular ejection fraction (LVEF) as determined by MRI and echocardiogram.
Baseline to 6 Months, Baseline to 18 Months
Change in Peak Volume Oxygen
Tidsramme: Baseline, 6 Months, 18 Months
Change in Peak VO2 as determined by treadmill test (mL/mg/min) from Baseline to 6 and from baseline to 18 months
Baseline, 6 Months, 18 Months
Change in Six Minute Walk Test
Tidsramme: Baseline, 6 Months, 18 Months
Change in Six Minute Walk Test (in meters) from Baseline to 6 Months and Baseline to 18 Months
Baseline, 6 Months, 18 Months
Change in NYHA Functional Class
Tidsramme: Baseline to 6 Months, 6 months to 18 Months

Change in New York Heart Association (NYHA) Functional Classification based on patient's self reported activity level.

Worsened: documented increase in limitations of physical activity as self-described by subject Improved: documented decrease in limitations of physical activity as self-described by subject Unchanged: no documented change in limitations of physical activity as self-described by subject
Baseline to 6 Months, 6 months to 18 Months
Minnesota Living With Heart Failure Questionnaire Scores
Tidsramme: Assessed at 6 Months and 18 Months
Minnesota Living with Heart Failure (MLHF) questionnaire has a total score from 0 to 105. A higher score indicates that participants heart failure is preventing them from living their lives measured at two time points.
Assessed at 6 Months and 18 Months
Incidence of Major Adverse Cardiac Events (MACE)
Tidsramme: 18 Months
Incidence of Major Adverse Cardiac Events (MACE). A composite incidence of (1) death, (2) hospitalization for heart failure, or (3) non-fatal recurrent Ml.
18 Months
Number of Participants With Abnormal 48-Hour Ambulatory ECG Recordings
Tidsramme: Assessed at 6 Months, 12 Months, and 18 Months

Ambulatory ECG monitoring is the most widely employed technology for the evaluation of a patient with symptoms suggestive of cardiac arrhythmia or conduction abnormality.

When the patient returns for follow up the 48- Hour Ambulatory monitor provides the data to the site staff to detect any abnormal recordings based upon standard ECG protocol.
Assessed at 6 Months, 12 Months, and 18 Months
Change in Pulmonary Function
Tidsramme: Baseline, 6 Months, 12 Months, 18 Months
Change in Pulmonary Function from Baseline to 6 month, Baseline to 12 month, and Baseline to 18 month visits as measured by forced expiratory volume in 1 second (FEV1)
Baseline, 6 Months, 12 Months, 18 Months
Serial Troponin Values (ng/mL)
Tidsramme: Assessed at Baseline, 12 hours, 24 hours, 36 hours, and 48 hours post CABG
Serial Troponin Values (ng/mL) Values from Baseline to 48 Hours Post CABG
Assessed at Baseline, 12 hours, 24 hours, 36 hours, and 48 hours post CABG
Creatinine Kinase - Muscle/Brain (MB) (ng/mL)
Tidsramme: Assessed at Baseline, 12 Hours, 24 Hours, 36 Hours, and 48 hours post CABG
Creatinine Kinase MB (ng/mL) Values every 12 hours from Baseline to 48 Hours Post CABG
Assessed at Baseline, 12 Hours, 24 Hours, 36 Hours, and 48 hours post CABG
Number of Clinically Significant Laboratory Values
Tidsramme: 18 Months
Clinically significant laboratory values are first determined via standard laboratory normal values from a CAP and CLIA certified Laboratory and then assessed by investigator based on specific patient conditions and disease state.
18 Months
Rate of Treatment Emergent Adverse Events
Tidsramme: Assessed at 6 Months, 12 Months, and 18 Months
Rate of Treatment Emergent Adverse Events Post Coronary Artery Bypass Graft (CABG) at 6 Months, 12 Months, and 18 Months
Assessed at 6 Months, 12 Months, and 18 Months
Number of Abnormal Echocardiogram Readings 2 Days Post CABG.
Tidsramme: Day 2
The number of abnormal Echocardiogram readings 2 Days Post CABG will be documented based on transthoracic Echocardiographic standards. However, although Echocardiograms 2 days post CABG operation may show abnormalities which is standard in this population, this testing is instrumental because it measures End- diastolic wall thickness and Left ventricular volumes at end-diastole and end-systole.
Day 2

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Joshua M Hare

Samarbeidspartnere

National Heart, Lung, and Blood Institute (NHLBI)
The Emmes Company, LLC
Johns Hopkins University Specialized Center for Cell Based Therapy

Etterforskere

  • Hovedetterforsker: Joshua M. Hare, MD, University of Miami
  • Hovedetterforsker: Gary Gerstenblith, MD, Johns Hopkins University
  • Hovedetterforsker: John V. Conte, MD, Johns Hopkins University
  • Hovedetterforsker: Steven P. Schulman, MD, Johns Hopkins University

Publikasjoner og nyttige lenker

Den som er ansvarlig for å legge inn informasjon om studien leverer frivillig disse publikasjonene. Disse kan handle om alt relatert til studiet.

Generelle publikasjoner

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart

1. november 2007

Primær fullføring (Faktiske)

1. juni 2011

Studiet fullført (Faktiske)

1. juni 2011

Datoer for studieregistrering

Først innsendt

2. januar 2008

Først innsendt som oppfylte QC-kriteriene

3. januar 2008

Først lagt ut (Anslag)

8. januar 2008

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

10. september 2019

Siste oppdatering sendt inn som oppfylte QC-kriteriene

19. august 2019

Sist bekreftet

1. august 2019

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • 20070598
  • U54HL081028 (U.S. NIH-stipend/kontrakt)

Plan for individuelle deltakerdata (IPD)

Planlegger du å dele individuelle deltakerdata (IPD)?

NEI

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Ja

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

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