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

Samuel Golpanian, Darcy L DiFede, Marietsy V Pujol, Maureen H Lowery, Silvina Levis-Dusseau, Bradley J Goldstein, Ivonne H Schulman, Bangon Longsomboon, Ariel Wolf, Aisha Khan, Alan W Heldman, Pascal J Goldschmidt-Clermont, Joshua M Hare, Samuel Golpanian, Darcy L DiFede, Marietsy V Pujol, Maureen H Lowery, Silvina Levis-Dusseau, Bradley J Goldstein, Ivonne H Schulman, Bangon Longsomboon, Ariel Wolf, Aisha Khan, Alan W Heldman, Pascal J Goldschmidt-Clermont, Joshua M Hare

Abstract

Frailty is a syndrome associated with reduced physiological reserves that increases an individual's vulnerability for developing increased morbidity and/or mortality. While most clinical trials have focused on exercise, nutrition, pharmacologic agents, or a multifactorial approach for the prevention and attenuation of frailty, none have studied the use of cell-based therapies. We hypothesize that the application of allogeneic human mesenchymal stem cells (allo-hMSCs) as a therapeutic agent for individuals with frailty is safe and efficacious. The CRATUS trial comprises an initial non-blinded phase I study, followed by a blinded, randomized phase I/II study (with an optional follow-up phase) that will address the safety and pre-specified beneficial effects in patients with the aging frailty syndrome. In the initial phase I protocol, allo-hMSCs will be administered in escalating doses via peripheral intravenous infusion (n=15) to patients allocated to three treatment groups: Group 1 (n=5, 20 million allo-hMSCs), Group 2 (n=5, 100 million allo-hMSCs), and Group 3 (n=5, 200 million allo-hMSCs). Subsequently, in the randomized phase, allo-hMSCs or matched placebo will be administered to patients (n=30) randomly allocated in a 1:1:1 ratio to one of two doses of MSCs versus placebo: Group A (n=10, 100 million allo-hMSCs), Group B (n=10, 200 million allo-hMSCs), and Group C (n=10, placebo). Primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCs administered in frail older individuals. This study will determine the safety of intravenous infusion of stem cells and compare phenotypic outcomes in patients with aging frailty.

Keywords: Gerotarget; aging; allogeneic; frailty; mesenchymal stem cells.

Conflict of interest statement

CONFLICTS OF INTEREST

Drs. Hare reports equity interest in Longeveron and Vestion.

Figures

Figure 1. Peripheral intravenous administration of allogeneic…
Figure 1. Peripheral intravenous administration of allogeneic MSCs via systemic circulation
Figure 2. Systemic inflammation
Figure 2. Systemic inflammation
A. Areas in red color depict widespread inflammation. B. MSCs migrate to regions of injury and exert their anti-inflammatory properties (green color).
Figure 3. MSC effects on organ systems
Figure 3. MSC effects on organ systems
MSCs target various tissues throughout the body to help enhance cardiac reserve (heart), improve endothelial function (blood vessels), reduce inflammation (diffusely and in joints), and increase bone density (bone) and muscle tone (skeletal muscle) through pro-regenerative effects (i.e., paracrine signaling, mitochondrial transfer, exosomes).

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