AllogeneiC Human Mesenchymal Stem Cells (hMSC) in Patients With Aging FRAilTy Via IntravenoUS Delivery (CRATUS)

A Phase I/II, Randomized, Blinded and Placebo-controlled Trial to Evaluate the Safety and Potential Efficacy of Allogeneic Human Mesenchymal Stem Cell Infusion in Patients With Aging Frailty

The purpose of this study is to look at the safety of treatment with stem cells in patients with Frailty.

Study Overview

• Status: Completed
• Conditions: Frailty
• Intervention / Treatment: Biological: Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs); Biological: Placebo; Biological: Penicillin/Streptomycin-Free Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs)

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • ISCI/University of Miami Miller School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 95 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provide written informed consent.
• Subjects age greater than or equal to 60 and less than or equal to 95 years at the time of signing the Informed Consent Form.
• Show signs of frailty apart from a concomitant condition as assessed by the Investigator with a frailty score of 4 to 7 using the Clinical Frailty Scale
• Female subjects with an Follicle-stimulating hormone (FSH) equal to or > 25.8 milli-international units (mIU) /mL (milliliter), if not currently on hormone replacement therapy.

Exclusion Criteria:

• Score of less than or equal to 24 on the Mini Mental State Examination (MMSE)
• Inability to perform any of the assessments required for endpoint analysis (report safety or tolerability concerns, perform pulmonary function tests, undergo blood draws, read and respond to questionnaires.
• Active listing (or expected future listing) for transplant of any organ.
• Clinically important abnormal screening laboratory values, including but not limited to: hemoglobin <8 g/dl, white blood cell count <3000/mm3, platelets<80,000/mm3, international normalized ratio (INR) > 1.5 not due to a reversible cause (i.e. Coumadin), aspartate transaminase, alanine transaminase, or alkaline phosphatase > 3 times upper limit of normal, total bilirubin > 1.5 mg/dl.
• Serious comorbid illness that, in the opinion of the investigator, may compromise the safety or compliance of the patient or preclude successful completion of the study. Including, but not limited to: HIV, advanced liver or renal failure, class III/IV congestive heart failure, myocardial infarction, unstable angina, or cardiac revascularization within the last six months, or severe obstructive ventilatory defect.
• Any other condition that, in the opinion of the investigator, may compromise the safety or compliance of the patient or preclude successful completion of the study.
• Be an organ transplant recipient.
• Have a 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, melanoma in situ or cervical carcinoma if recurrence occurs.
• Have a non-pulmonary condition that limits lifespan to < 1 year.
• Have a history of drug or alcohol abuse within the past 24 months.
• Be serum positive for HIV, hepatitis B Surface Antigen (BsAg) or Viremic hepatitis C.
• Be currently participating (or participated within the previous 30 days) in an investigational therapeutic or device trial.
• Be a female who is pregnant, nursing, or of childbearing potential while not practicing effective contraceptive methods. Female patients must undergo a blood or urine pregnancy test at screening and within 36 hours prior to infusion.
• Have hypersensitivity to dimethyl sulfoxide (DMSO)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Pilot phase - Group 1; Group 1 participants will receive Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs): 20 million allo-hMSCs/kg delivered via peripheral intravenous infusion. Participants in this group have the option to receive an additional 3 infusions of 100million allo-hMSCs/kg per infusion with a 12 to 18 month interval.	Biological: Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs); Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) administered by peripheral intravenous infusion
EXPERIMENTAL: Pilot Phase - Group 2; Group 2 - Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs): 100 million allo-hMSCs/kg delivered via peripheral intravenous infusion. Participants in this group have the option to receive an additional 3 infusions of 100million allo-hMSCs/kg per infusion with a 12 to 18 month interval.	Biological: Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs); Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) administered by peripheral intravenous infusion
EXPERIMENTAL: Pilot Phase - Group 3; Group 3 - Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs): 200 million allo-hMSCs/kg delivered via peripheral intravenous infusion. Participants in this group have the option to receive an additional 3 infusions of 100million allo-hMSCs/kg per infusion with a 12 to 18 month interval.	Biological: Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs); Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) administered by peripheral intravenous infusion
EXPERIMENTAL: Randomized Phase - Group A; Group A - Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs): 100 million allo-hMSCs/kg delivered via peripheral intravenous infusion.	Biological: Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs); Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) administered by peripheral intravenous infusion
EXPERIMENTAL: Randomized phase - Group B; Group B - Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs): 200 million allo-hMSCs/kg delivered via peripheral intravenous infusion.	Biological: Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs); Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) administered by peripheral intravenous infusion
EXPERIMENTAL: Randomized Phase - Group C; Group C - Placebo delivered via peripheral intravenous infusion. Participants in this group have the option to receive one additional infusion of 100million allo-hMSCs/kg with a 12 to 18 month interval.	Biological: Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs); Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) administered by peripheral intravenous infusion; Biological: Placebo; Placebo administered by peripheral intravenous infusion.
EXPERIMENTAL: Addendum B - Antibiotic free cell Group; Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs): 100 million penicillin/streptomycin-free allo-hMSCs/kg delivered via peripheral intravenous infusion. Participants in this group have the option to receive an additional 3 infusions of 100million allo-hMSCs/kg per infusion with a 12 to 18 month interval.	Biological: Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs); Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) administered by peripheral intravenous infusion; Biological: Penicillin/Streptomycin-Free Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs); Penicillin/Streptomycin-Free Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) administered by peripheral intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Any Treatment Emergent - Serious Adverse Events (TE-SAEs)	Incidence of any treatment-emergent serious adverse events (SAE), defined as the composite of: death, non-fatal pulmonary embolism, stroke, hospitalization for worsening dyspnea and clinically significant laboratory test abnormalities.; Serum chemistry: chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose, calcium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (fractionate if total >1.5 times normal), alkaline phosphatase, albumin,; Hematology (Complete blood count): hemoglobin, hematocrit, platelets, white blood cells (WBC), WBC differential	One Month post infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Frailty as Assessed by CHAMPS Questionnaire	Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire measures duration of exercise-related activities (hours/week). The Duration variable can range from 0 - 399.75 hours per week. Higher scores indicate more activity.	At baseline and 6 month follow-up visit.
Change in Slowing of Mobility as Measured by 4 Meter Gait Speed Test	4-meter gait speed test measures the time (in seconds) taken to walk a distance of 4 meters. The total score has a range of 1 point - 4 points with the higher score indicating faster walk speed.	At baseline and 6 month follow-up visit.
Change in Slowing of Mobility as Measured by SPPB	Standard Physical Performance Battery (SPPB) Assessment has total score ranging from 0-4 with the higher score indicating better balance.	At baseline and 6 month follow-up visit.
Change in Weight	Change in weight as measured in kilograms (kg).	At baseline and 6 month follow-up visit.
Change in Diminished Hand Grip Strength	Hand grip strength as assessed by a dynamometer. Grip strength is recorded (in mmHg) three times for each hand. The average reading is reported for each hand.	At baseline and 6 month follow-up visit.
Change in Exhaustion as Measured by the MFI Questionnaire	Multi-dimensional Fatigue Inventory (MFI) Questionnaire contains 20 questions with a 5-point scale. The MFI has total score ranging from 20-100 with the higher score indicating less fatigue.	At baseline and 6 month follow-up visit.
Change in Quality of Life (QoL) as Measured by the ICECAP Questionnaire	Investigating Choice Experiences for the Preferences of Older People (ICEpop) Capability measure for Older people (ICECAP) questionnaire has total score ranging from 5-20 with the higher score indicating greater quality of life.	At baseline and 6 month follow-up visit.
Change in Quality of Life (QoL) as Measured by the SF-36 Questionnaire	Short Form (SF)-36 Questionnaire has consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale. Lower scores indicate the more disability, and higher scores indicate less disability.	At baseline and 6 month follow-up visit.
Change in Quality of Life (QoL) as Measured by the EQ-5D-3L Questionnaire	EuroQoL (EQ)- 5 Dimension (5D)- 3 levels (3L) Questionnaire has total score ranging from 0-10 for the 5 dimensions. Higher scores indicate better Quality of Life.	At baseline and 6 month follow-up visit.
Change in Quality of Life (QoL) as Measured by the EQ-5D-3L Overall Health Status Scale.	EuroQoL - 5 Dimension - 3 levels (EQ-5D-3L) Overall health status question has a range of 0-100. Higher scores indicate better Quality of Life.	At baseline and 6 month follow-up visit.
Change in Sense of Smell as Measured by UPSIT	University of Pennsylvania Smell Identification Test (UPSIT) smell test booklet has a total score ranging from 0-40 with higher scores indicating better olfaction.	At baseline and 6 month follow-up visit.
Death	Any reported death from any cause.	Up to 12 months.
Change in Ejection Fraction (EF)	Change in dobutamine stress echocardiogram induced ejection fraction	At baseline and 6 month follow-up visit.
Change in Inflammatory Markers Levels	Change in inflammatory markers including C-Reactive Protein (CRP) and Fibrinogen serum samples as measured in mg/L.	At baseline and 6 month follow-up visit.
Change in Inflammatory Markers	Change in inflammatory markers including Interleukin (IL)-6 and Tumor Necrosis Factor (TNF) Alpha from serum samples as measured in pg/mL.	At baseline and 6 month follow-up visit.
Change in Inflammatory Marker D-dimer Levels	Change in inflammatory marker D-Dimer from serum samples as measured in mg/dL.	At baseline and 6 month follow-up visit.

Collaborators and Investigators

• Sponsor: Longeveron Inc.
• Collaborators: The Emmes Company, LLC

Publications and helpful links

General Publications

• Golpanian S, DiFede DL, Pujol MV, Lowery MH, Levis-Dusseau S, Goldstein BJ, Schulman IH, Longsomboon B, Wolf A, Khan A, Heldman AW, Goldschmidt-Clermont PJ, Hare JM. Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty. Oncotarget. 2016 Mar 15;7(11):11899-912. doi: 10.18632/oncotarget.7727.
• Tompkins BA, DiFede DL, Khan A, Landin AM, Schulman IH, Pujol MV, Heldman AW, Miki R, Goldschmidt-Clermont PJ, Goldstein BJ, Mushtaq M, Levis-Dusseau S, Byrnes JJ, Lowery M, Natsumeda M, Delgado C, Saltzman R, Vidro-Casiano M, Da Fonseca M, Golpanian S, Premer C, Medina A, Valasaki K, Florea V, Anderson E, El-Khorazaty J, Mendizabal A, Green G, Oliva AA, Hare JM. Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Gerontol A Biol Sci Med Sci. 2017 Oct 12;72(11):1513-1522. doi: 10.1093/gerona/glx137.
• Golpanian S, DiFede DL, Khan A, Schulman IH, Landin AM, Tompkins BA, Heldman AW, Miki R, Goldstein BJ, Mushtaq M, Levis-Dusseau S, Byrnes JJ, Lowery M, Natsumeda M, Delgado C, Saltzman R, Vidro-Casiano M, Pujol MV, Da Fonseca M, Oliva AA Jr, Green G, Premer C, Medina A, Valasaki K, Florea V, Anderson E, El-Khorazaty J, Mendizabal A, Goldschmidt-Clermont PJ, Hare JM. Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty. J Gerontol A Biol Sci Med Sci. 2017 Oct 12;72(11):1505-1512. doi: 10.1093/gerona/glx056.

Helpful Links

• Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 3, 2014
• Primary Completion (ACTUAL): October 2, 2019
• Study Completion (ACTUAL): October 2, 2020

Study Registration Dates

• First Submitted: February 14, 2014
• First Submitted That Met QC Criteria: February 14, 2014
• First Posted (ESTIMATE): February 17, 2014

Study Record Updates

• Last Update Posted (ACTUAL): July 14, 2021
• Last Update Submitted That Met QC Criteria: July 13, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Stem Cells; Cardiovascular; Frailty; Aging Frailty
• Additional Relevant MeSH Terms: Pathologic Processes; Frailty; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Streptomycin; Penicillins
• Other Study ID Numbers: 20130646

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No