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

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.

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.

Study Overview

• Status: Completed
• Conditions: Critical Limb Ischemia
• Intervention / Treatment: Drug: 20 million hMSCs; Drug: 40 million hMSCs; Drug: 80 million hMSCs

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Ireland
  • Galway
    • Galway City, Galway, Ireland
      • Galway University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Each patient must meet all of the following inclusion criteria to be enrolled into the study

1. Men and women between the ages of 18 and 85
2. 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
3. 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
4. Estimated life expectancy > 6 months as deemed by patient's clinician and/or investigator
5. Suitable candidate for a bone marrow aspiration, deemed by Consultant Haematologist
6. 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
7. Medically fit to undergo bone marrow harvest and stem cell intramuscular injection
8. 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:

1. Has received prior therapy with MSCs
2. Has had previous amputation of the talus or above
3. Has failed revascularization within 2 weeks before entry to the study
4. Known Aortoiliac disease with > 50% stenosis
5. 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
6. Severe co-morbidity limiting 6 month survival of patients
7. Abnormal liver function as defined by AST and ALT > 2.5 fold the ULN and total bilirubin > 1.5 ULN
8. Significant cognitive impairment (Mini Mental Status Examination <22)
9. Presence of proliferative retinopathy (in participants with diabetes mellitus only)
10. Presence of poorly controlled diabetes mellitus with HbAIc > 10% within previous 3 months
11. HIV or HBsAg positive
12. Presence of acute coronary syndrome
13. Patient has known active malignancy
14. Pregnancy
15. Likely inability to comply with the protocol or cooperate fully with the investigator and site personnel
16. Patient taking other investigational drugs at the time of enrolment or within 28 days of enrolment
17. Rutherford class 6 CLI
18. Significant bone marrow dysfunction, based on assessment by Haematologist or an established diagnosis of myelodysplasia, or myeloproliferative disorder etc.
19. Bleeding diathesis, coagulopathy, thrombocytopenia etc.
20. Patients in whom delay incurred by attempts at limb salvage using MSCs will adversely affect prognosis in the opinion of the responsible attending clinician

21. Patients with known allergy to foetal bovine serum or trypsin

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: low dose cohort; 20 million hMSCs .	Drug: 20 million hMSCs; Other Names: 20 million hMSCs intramuscularly
Experimental: mid dose cohort; 40 million hMSCs	Drug: 40 million hMSCs; Other Names: 40 million hMSCs intramuscularly
Experimental: high dose cohort; 80 million hMSCs .	Drug: 80 million hMSCs; Other Names: 80 million hMSCs intramuscularly

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: National University of Ireland, Galway, Ireland
• Collaborators: University Hospital of Limerick
• Investigators: Principal Investigator: Timothy O Brien, PhD, NUIG

Publications and helpful links

General Publications

• Mohamed SA, Howard L, McInerney V, Hayat A, Krawczyk J, Naughton S, Finnerty A, Holohan M, Duffy A, Moloney T, Kavanagh E, Burke P, Liew A, Tubassam M, Walsh SR, O'Brien T. Autologous bone marrow mesenchymal stromal cell therapy for "no-option" critical limb ischemia is limited by karyotype abnormalities. Cytotherapy. 2020 Jun;22(6):313-321. doi: 10.1016/j.jcyt.2020.02.007. Epub 2020 Apr 6.
• EU Clinical Trials Register Clinical trial results 2013-003447-37 version 1 EU-CTR publication date: of 21 01 January 2021

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2015
• Primary Completion (Actual): October 31, 2019
• Study Completion (Actual): October 31, 2019

Study Registration Dates

• First Submitted: February 16, 2018
• First Submitted That Met QC Criteria: February 27, 2018
• First Posted (Actual): March 6, 2018

Study Record Updates

• Last Update Posted (Actual): March 4, 2021
• Last Update Submitted That Met QC Criteria: March 2, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia
• Other Study ID Numbers: 2013-001

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