A Study to Evaluate Allogenic Bone-Marrow Mesenchymal Stromal Cell Product StromaForte in Aging Frailty Patients

Study Overview
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Brief Summary
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This phase I/IIa study in frail patients is designed to assess the safety of intravenous human allogenic bone marrow-derived mesenchymal stromal cell product StromaForte by reporting the number of adverse events assessed by Common Terminology Criteria. 12 male and female patients aged 60 to 85 years will be enrolled.

Detailed Description
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Frailty is theoretically defined as a clinically recognizable state of increased vulnerability resulting from aging-associated decline in reserve and function across multiple physiologic systems such that the ability to cope with every day or acute stressors is comprised. In the absence of a gold standard, frailty has been operationally defined by Fried et al. as meeting three out of five phenotypic criteria indicating compromised energetics: low grip strength, low energy, slowed waking speed, low physical activity, and/or unintentional weight loss. One major factor proposed to contribute to frailty and related epigenetic dysregulation is stem cell loss. In order to treat this multifactorial dysregulation, stem cell therapy is an interesting strategy, and MSCs are a particularly tempting candidate. MSCs are an immune-privileged somatic progenitor cell type that is multipotent, self-renewing, and relatively simple to harvest (bone marrow harvest), isolate, and grow. MSCs are proven to regulate the body's immune response in many diseases and exert anti-inflammatory effects. Following their discovery over 50 years ago, mesenchymal stromal cells (MSCs) have become one of the most studied cellular therapeutic products by both academia and industry due to their regenerative potential and immunomodulatory properties. The promise of MSCs as a therapeutic modality has been demonstrated in a number of preclinical studies as well as in clinical setting. Stromaforte cells which will be used in this study is developed within CELLCOLABS AB which is a parent company to Cellcolabs Clinical SPV Limited and were generated following the same protocol established over the last 20 years by scientists CELLCOLABS AB at the Karolinska Institute in Sweden. Currently completed in vivo studies on rats, rabbits and mice models showed that MSCs could attenuate sarcopenia via increasing skeletal muscle weight and myofiber cross-sectional area. The physical performance including muscle strength as well as endurance were significantly enhanced. In addition, MSCs have capability to activate resident skeletal muscle stem cells, which lead to myogenesis and differentiation of muscle tissues. The positive results provide novel insights into sarcopenia intervention, suggesting a potential role for MSC therapy in aging frailty. This study which has been designed to evaluate the safety of intravenous human allogenic bone marrow-derived mesenchymal stromal cell product StromaForte in frail patients before further clinical development.

Official Title
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An Open-Label Single-Arm Phase I/IIa Study to Evaluate the Safety of Human Allogenic Bone-Marrow-Derived Mesenchymal Stromal Cell Product StromaForte in Patients With Aging Frailty

Conditions
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Aging Frailty

Intervention / Treatment
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* Biological: StromaForte


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent and comply with all procedures required by the protocol Aged ≥ 60 and ≤ 85 years at the time of signing the informed consent form, Have a Canadian Study on Health and Aging (CSHA) Clinical Frailty Scale score of 5 mildly frail or 6 moderately frail Have a 6-minute walk distance of > 200m and < 400 m Have a serum TNF-alpha level ≥2.5 pg/ml Exclusion Criteria: Unwilling or unable to perform any of the assessments required by the protocol Have a diagnosis of any disabling neurologic disorder, including, but not limited to, Parkinson's disease, Amyotrophic Lateral Sclerosis, multiple sclerosis, cerebrovascular accident with residual deficits (e.g., muscle weakness or gait disorder), or diagnosis of dementia Have a score of 24 or lower on the Mini Mental State Examination (MMSE) Have poorly controlled blood glucose levels (HbA1c >8.0%) Have a clinical history of malignancy within 2.5 years (i.e., patients with prior malignancy must be cancer free for 2.5 years) except curatively treated basal cell carcinoma, melanoma in situ or cervical carcinoma Have any condition that limits lifespan to < 1 year according to the Principal Investigator discretion Have autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) Undergoes chronic immunosuppressant therapy such as high-dose corticosteroids or TNF-α antagonists (prednisone use at doses of < 5 mg daily is allowed) Hepatitis B virus positive Viraemic Hepatitis C virus, HIV-1/2 or syphilis positive Have a resting blood oxygen saturation of <93% (measured by pulse oximetry) Known or suspected alcohol or drug abuse within three years preceding Screening Have a known hypersensitivity to dimethyl sulfoxide (DMSO) An organ transplant recipient (other than transplantation for corneal) Actively listed (or expected future listing) for transplant of any organ (other than corneal transplant) Have any clinically important abnormal screening laboratory values, including, but not limited to: i. Haemoglobin <10.0 g/dL, ii. White blood cell <2,500/ul, or platelet count <100,000/ul iii. Liver dysfunction evidenced by enzymes (AST and ALT) > 3 times the upper limit of normal (ULN) Coagulopathy with international normalized ratio (INR) >1.3 not due to a reversible cause (e.g., warfarin and/or Factor Xa inhibitors) Uncontrolled hypertension (resting systolic blood pressure >180 mm Hg or diastolic blood pressure of > 110 mm Hg at Screening) Have unstable angina pectoris, uncontrolled or severe peripheral artery disease within the previous 3 months Have congestive heart failure defined by New York Heart Association (NYHA) Class III or IV, or an ejection fraction of <25 Have a coronary artery bypass surgery, angioplasty, or peripheral vascular disease revascularization or a myocardial infarction within previous 3 months Have severe pulmonary dysfunction: acute exacerbation of chronic obstructive lung disease stage III or IV (Gold classification), and/or PaO2 levels <60 mmHg Have a partial ileal gastric bypass, or other significant intestinal malabsorption Have advanced liver or renal disease Have cognitive or language barriers that prohibit obtaining informed consent or any study elements (or participated within the previous 30 days of consent) in an investigational Currently hospitalized or living in an assisted living facility or a long-term care facility Currently participating therapeutic or device trial Have a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the patient's participation for the full duration of the study

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: The patients will be assigned into one group receiving allogeneic bone marrow (BM)- derived Mesenchymal Stromal Cell (MSC) formulated in infusion solution (sodium chloride supplemented with human serum albumin Pre-screening visit will be conducted within 7 days of the screening visit then eligible patient will participate in the Study for approximately 6 months and will have a total of 5 on-site visits, including a screening visit, a treatment administration visit, and 3 follow-up visits.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSC arm<br>The patients will be receiving allogeneic bone marrow (BM)-derived Mesenchymal Stromal Cell (MSC) formulated in infusion solution (sodium chloride supplemented with human serum albumin) in a low intravenous infusion of 100 millions MSCs within approximately 30 min | Biological: StromaForte<br>* 100 millions allogeneic bone marrow (BM)-derived Mesenchymal Stromal Cell (MSC) formulated in sodium chloride supplemented with human serum albumin to be given via slow intravenous infusion in approximately 30 min<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | To assess the safety and tolerability after 28 days of injection by reporting the number of adverse events assessed by Common Terminology Criteria For Adverse Events (CTCAE) which is the Incidence of any treatment-emergent serious adverse events (TE-SAEs), defined as the composite of death, non-fatal pulmonary embolism, stroke, hospitalization for worsening dyspnea and clinically significant laboratory test abnormalities determined per the Investigator's judgment along with others Adverse Events and Serious Adverse events | 28 days post-infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in TNF-alpha | Change in tumor necrosis factor α TNF-α from baseline to 6 months (baseline to 28-, 84-, and 168-days post-infusion.) | From baseline to 6 months | 
| Change in C Reactive Protein (CRP) | Change in C Reactive Protein (CRP) from baseline to 6 months (baseline to 28-, 84-, and 168-days post-infusion.) | From baseline to 6 months | 
| Change in Interleukin-6 (IL-6) | Change in Interleukin-6 (IL-6) from baseline to 6 months (baseline to 28-, 84-, and 168-days post-infusion.) | From baseline to 6 months | 
| Change in Complete Blood Count (CBC) in peripheral blood with differential | Change in Complete Blood Count (CBC) in peripheral blood with differential from baseline to 6 months (baseline to 28-, 84-, and 168-days post-infusion.) | From baseline to 6 months |