Autologous Stem Cells for the Treatment of No Option Critical Limb Ischemia

Study Overview
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Brief Summary
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The trial is a phase 1b, open label, uncontrolled, non-randomized dose-escalation study of autologous bone marrow-derived MSCs. Following informed consent, patients who meet the criteria will be screened and enrolled. Up to 100 mls of bone marrow will be harvested from the participant from which MSCs will be culture expanded. In this dose escalation study, 3 participants on each cohort will be treated with a targeted dose of either 20 million hMSC; 40 million hMSC; or 80 million hMSC. The cells will be administered to the ischemic leg by 20 intramuscular injections of approximately 0.5ml per injection . Treatment groups will be completed sequentially, beginning with the lowest dose group.

Detailed Description
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This is a phase 1b, open label, uncontrolled, non-randomized dose-escalation study to examine the safety of intramuscular autologous transplantation of escalating doses of mesenchymal stem cells to patients with no option critical limb ischemia. Trial Aims and Objectives: To examine the safety of intramuscular transplantation of escalating doses of autologous bone marrow derived mesenchymal stem cells to patients with no option critical limb ischemia. Patient Population: Patients with critical limb ischemia who are not candidates for revascularization. Trial Setting:HRB Clinical Research Facility Galway and Galway University Hospitals. Trial Intervention:Intramuscular delivery of autologous bone marrow-derived mesenchymal stem cells to patients with no option critical limb ischemia. Study Design: Open label, uncontrolled, non-randomized, dose escalation study. Sample Size: 9 Method of Participant Assignment:Sequential administration of 3 escalating doses of autologous bone marrow-derived mesenchymal stem cells. Examination Points: Day 0, 7, 30, 90, 180, 365 and 730 Primary Outcome: Serious adverse events that are attributable to intervention. Secondary Outcomes :Amputation free survival, median time to amputation, TcPo2, ABI, pain scale, ulcer healing, quality of life assessments, collateral vessel formation detected by MRI at 12 months.

Official Title
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A Phase 1b, Open Label, Uncontrolled, Non-randomized Dose-escalation Study to Examine the Safety of Intramuscular Autologous Transplantation of Escalating Doses of Mesenchymal Stem Cells to Patients With no Option Critical Limb Ischemia.

Conditions
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Critical Limb Ischemia

Intervention / Treatment
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* Drug: 20 million hMSCs
* Drug: 40 million hMSCs
* Drug: 80 million hMSCs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each patient must meet all of the following inclusion criteria to be enrolled into the study Men and women between the ages of 18 and 85 Voluntary written informed consent, given before performance of any study-related procedure not part of standard medical care, and with the understanding that consent may be withdrawn at any time without prejudice to future medical care Presented with CLI with rest pain or ulceration with no option for revascularization agreed by an expert panel including an interventional radiologist and vascular surgeon; CLI defined as persistent ischemic rest pain for greater than or equal to 2 weeks and/or ulceration or gangrene of the toe or foot Estimated life expectancy > 6 months as deemed by patient's clinician and/or investigator Suitable candidate for a bone marrow aspiration, deemed by Consultant Haematologist Chronic critical limb ischaemia with rest pain (Rutherford Class 4) or mild-to-moderate tissue loss (Rutherford Class 5) who are not candidates for revascularisation Medically fit to undergo bone marrow harvest and stem cell intramuscular injection One of the following haemodynamic parameters: ankle systolic pressure < 70 mmHg or ABI <0.9 TBI <0 .6 TcPO2 <60mmHg on room air Exclusion Criteria: Patients meeting any of the following exclusion criteria are not to be enrolled in the study: Has received prior therapy with MSCs Has had previous amputation of the talus or above Has failed revascularization within 2 weeks before entry to the study Known Aortoiliac disease with > 50% stenosis Contraindication to intramuscular procedure, including active infection in the affected limb, or wet gangrene or exposed bone or tendon in lower limb with CLI, or in the opinion of the attending clinician, is unsuitable for intramuscular procedure Severe co-morbidity limiting 6 month survival of patients Abnormal liver function as defined by AST and ALT > 2.5 fold the ULN and total bilirubin > 1.5 ULN Significant cognitive impairment (Mini Mental Status Examination <22) Presence of proliferative retinopathy (in participants with diabetes mellitus only) Presence of poorly controlled diabetes mellitus with HbAIc > 10% within previous 3 months HIV or HBsAg positive Presence of acute coronary syndrome Patient has known active malignancy Pregnancy Likely inability to comply with the protocol or cooperate fully with the investigator and site personnel Patient taking other investigational drugs at the time of enrolment or within 28 days of enrolment Rutherford class 6 CLI Significant bone marrow dysfunction, based on assessment by Haematologist or an established diagnosis of myelodysplasia, or myeloproliferative disorder etc. Bleeding diathesis, coagulopathy, thrombocytopenia etc. Patients in whom delay incurred by attempts at limb salvage using MSCs will adversely affect prognosis in the opinion of the responsible attending clinician Patients with known allergy to foetal bovine serum or trypsin -

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Advanced Therapeutic Medicinal Product ( ATMP) Bone Marrow Derived Mesenchymal Stem Cells
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: low dose cohort<br>20 million hMSCs . | Drug: 20 million hMSCs<br> <br> * Other names: 20 million hMSCs intramuscularly;|
| Experimental: mid dose cohort<br>40 million hMSCs | Drug: 40 million hMSCs<br> <br> * Other names: 40 million hMSCs intramuscularly;|
| Experimental: high dose cohort<br>80 million hMSCs . | Drug: 80 million hMSCs<br> <br> * Other names: 80 million hMSCs intramuscularly;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of Serious Adverse Events that are attributable to the treatment | The number of Serious Adverse Events that are attributable to the MScs | 12 months | 
| The severity of Serious Adverse Events that are attributable to the treatment | The number of Serious Adverse Events that are attributable to the MScs | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amputation free survival | Efficacy measured by the presence or absence of the target limb | 12 months | 
| median time to amputation, | Efficacy measured by the duration from time of cell administration to time of amputation if applicable. | 12 months | 
| Change in Transcutaneous Pressure of Oxygen TcPO2 | Efficacy will be determined by improvement from baseline in mmHg | 12 months | 
| Change in Ankle Brachial Index | Ankle Brachial Index: An indicator of peripheral perfusion measured by dividing Ankle Pressure (mmHg) by brachial pressure (mmHg) (normal ABI is 1.0 ). Efficacy outcome will be measured by improvement from baseline . The higher the ABI, the better the outcome. | 12 months | 
| Collateral vessel formation | Efficacy will be determined the presence of collateral vessel formation as detected by MRI | 12 months | 
| Change in Ischemic rest pain | Efficacy will be determined by decrease in score from baseline as measured by verbal analogue scale (0 = no pain, 10 = worst pain in life) | 12 months. | 
| Change in Ulcer size | Efficacy will be determined by decrease in the surface area from baseline as measured by ImageJ software and or complete healing of the ulcer | 12 months. | 
| Change in Quality of Life | Efficacy will be measured using the EQ 5D Quality of Life assessment tool | 12 months. |