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

• Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) (Biological): Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) administered by peripheral intravenous infusion
• Placebo (Biological): Placebo administered by peripheral intravenous infusion.
• Penicillin/Streptomycin-Free Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) (Biological): Penicillin/Streptomycin-Free Allogeneic Human Mesenchymal Stem Cells (allo-hMSCs) administered by peripheral intravenous infusion.

Primary outcomes

• Incidence of Any Treatment Emergent - Serious Adverse Events (TE-SAEs) [One Month post infusion]: 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

Secondary outcomes

• Change in Frailty as Assessed by CHAMPS Questionnaire [At baseline and 6 month follow-up visit.]: 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.
• Change in Slowing of Mobility as Measured by 4 Meter Gait Speed Test [At baseline and 6 month follow-up visit.]: 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.
• Change in Slowing of Mobility as Measured by SPPB [At baseline and 6 month follow-up visit.]: Standard Physical Performance Battery (SPPB) Assessment has total score ranging from 0-4 with the higher score indicating better balance.
• Change in Weight [At baseline and 6 month follow-up visit.]: Change in weight as measured in kilograms (kg).
• Change in Diminished Hand Grip Strength [At baseline and 6 month follow-up visit.]: 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.
• Change in Exhaustion as Measured by the MFI Questionnaire [At baseline and 6 month follow-up visit.]: 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.
• Change in Quality of Life (QoL) as Measured by the ICECAP Questionnaire [At baseline and 6 month follow-up visit.]: 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.
• Change in Quality of Life (QoL) as Measured by the SF-36 Questionnaire [At baseline and 6 month follow-up visit.]: 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.
• Change in Quality of Life (QoL) as Measured by the EQ-5D-3L Questionnaire [At baseline and 6 month follow-up visit.]: 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.
• Change in Quality of Life (QoL) as Measured by the EQ-5D-3L Overall Health Status Scale. [At baseline and 6 month follow-up visit.]: 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.
• Change in Sense of Smell as Measured by UPSIT [At baseline and 6 month follow-up visit.]: University of Pennsylvania Smell Identification Test (UPSIT) smell test booklet has a total score ranging from 0-40 with higher scores indicating better olfaction.
• Death [Up to 12 months.]: Any reported death from any cause.
• Change in Ejection Fraction (EF) [At baseline and 6 month follow-up visit.]: Change in dobutamine stress echocardiogram induced ejection fraction
• Change in Inflammatory Markers Levels [At baseline and 6 month follow-up visit.]: Change in inflammatory markers including C-Reactive Protein (CRP) and Fibrinogen serum samples as measured in mg/L.
• Change in Inflammatory Markers [At baseline and 6 month follow-up visit.]: Change in inflammatory markers including Interleukin (IL)-6 and Tumor Necrosis Factor (TNF) Alpha from serum samples as measured in pg/mL.
• Change in Inflammatory Marker D-dimer Levels [At baseline and 6 month follow-up visit.]: Change in inflammatory marker D-Dimer from serum samples as measured in mg/dL.

Sex: All, ages: 60 Years to 95 Years

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)

Participant flow

Outcome results

• Incidence of Any Treatment Emergent - Serious Adverse Events (TE-SAEs) (Primary), Number, Incidents: Pilot Phase - Group 1 0; Pilot Phase - Group 2 0; Pilot Phase - Group 3 0; Randomized Phase - Group A 0; Randomized Phase - Group B 1; Randomized Phase - Group C 0; Addendum B - Antibiotic Free Cell Group 0
• Change in Frailty as Assessed by CHAMPS Questionnaire (Secondary)
• Change in Slowing of Mobility as Measured by 4 Meter Gait Speed Test (Secondary)
• Change in Slowing of Mobility as Measured by SPPB (Secondary)
• Change in Weight (Secondary)
• Change in Diminished Hand Grip Strength (Secondary)
• Change in Exhaustion as Measured by the MFI Questionnaire (Secondary)
• Change in Quality of Life (QoL) as Measured by the ICECAP Questionnaire (Secondary)
• Change in Quality of Life (QoL) as Measured by the SF-36 Questionnaire (Secondary)
• Change in Quality of Life (QoL) as Measured by the EQ-5D-3L Questionnaire (Secondary)
• Change in Quality of Life (QoL) as Measured by the EQ-5D-3L Overall Health Status Scale. (Secondary)
• Change in Sense of Smell as Measured by UPSIT (Secondary)
• Death (Secondary)
• Change in Ejection Fraction (EF) (Secondary)
• Change in Inflammatory Markers Levels (Secondary)
• Change in Inflammatory Markers (Secondary)
• Change in Inflammatory Marker D-dimer Levels (Secondary)

Adverse events

Time frame: Up to 6 years

Serious adverse events by term

• 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. PMID 26933813
• 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. PMID 28977399
• 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. PMID 28444181

• Study Protocol and Statistical Analysis Plan (PDF, 2021-03-19)

• Joshua M Hare, MD, Principal investigator, ISCI / University of Miami Miller School of Medicine