Clinical trial NCT03455335: Autologous Stem Cells for the Treatment of No Option Critical Limb Ischemia
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Critical Limb Ischemia
Lead sponsor: National University of Ireland, Galway, Ireland
Sponsor class: OTHER
Collaborators: name: University Hospital of Limerick
First posted: 2018-03-06
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Advanced Therapeutic Medicinal Product ( ATMP) Bone Marrow Derived Mesenchymal Stem Cells
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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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Primary outcomes:
measure: The number of Serious Adverse Events that are attributable to the treatment
timeFrame: 12 months
measure: The severity of Serious Adverse Events that are attributable to the treatment
timeFrame: 12 months
Secondary outcomes:
measure: Amputation free survival
timeFrame: 12 months
measure: median time to amputation,
timeFrame: 12 months
measure: Change in Transcutaneous Pressure of Oxygen TcPO2
timeFrame: 12 months
measure: Change in Ankle Brachial Index
timeFrame: 12 months
measure: Collateral vessel formation
timeFrame: 12 months
measure: Change in Ischemic rest pain
timeFrame: 12 months.
measure: Change in Ulcer size
timeFrame: 12 months.
measure: Change in Quality of Life
timeFrame: 12 months.
Other outcomes:
Locations:
city: Galway City
country: Ireland
facility: Galway University Hospital
state: Galway
Study officials:
affiliation: NUIG
name: Timothy O Brien, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: EU Clinical Trials Register Clinical trial results 2013-003447-37 version 1 EU-CTR publication date: of 21 01 January 2021