Phase I/II Trial of Endometrial Regenerative Cells (ERC) in Patients With Critical Limb Ischemia

Allogeneic,Unrelated, Menstrual Derived, Mesenchymal Stem Cell-Like, Endometrial Cells; Administered Intramuscular

This is a 15 patient clinical trial assessing the safety and feasibility of using Endometrial Regenerative Cells (ERC) in patients with critical limb ischemia (CLI) that are not eligible for surgical or catheter-based interventions. Three doses of ERC will be examined. The hypothesis is that ERC administration will be well-tolerated and possibly induce a therapeutic benefit.

Study Overview

• Status: Unknown
• Conditions: Peripheral Vascular Diseases
• Intervention / Treatment: Biological: Administration of ERC

Detailed Description

The purpose of the trial is to determine safety of intramuscularly derived menstrual mesenchymal stem cells (otherwise known as Endometrial Regenerative Cells, or ERC) in patients with critical limb ischemia ineligible for revascularization. Safety will be defined as freedom from treatment associated adverse events. Efficacy parameters will comprise endpoints of changes in ankle-brachial index, toe-brachial index, TcPO2, ulcer healing, rest pain, quality of life, and reduction in amputation.

Patients will receive 25, 50, or 100 million menstrual derived mesenchymal stem cells (Endometrial Regenerative Cells: ERC) in ten injections of 2.5, 5, or 10 million mesenchymal stem cells suspended in a volume of 1 ml per injection. Injections will be spaced at least 2 centimeters apart from each other in the gastrocnemius muscle above the failed vascular perfusion area.

• Study Type: Interventional
• Enrollment (Anticipated): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States
      • Indiana University School of Medicine

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Non-pregnant patients with critical limb ischemia, Rutherford IV-V, manifested as rest pain or tissue loss, or with disabling claudication, manifested as exercise induced thigh or calf pain that impairs activities of daily living, who are not candidates for surgical bypass or angioplasty due to unfavorable arterial anatomy or absence of adequate autogenous vein for a below-knee bypass.
2. Patients over 18 years of age with an expected survival of more than one year after treatment.
3. Unreconstructable arterial disease will be determined by a vascular surgeon who is not participating in the study. Unreconstructable arterial disease is defined by atherocclusive lesions within the arterial tree of the extremity that due to extent or morphology are not amenable to surgical bypass or PTCA and stenting.
4. Patients with a maximum of 3 non-healing 'flat' surface or 'transdermal' ulcers Grades 1-2, no ulcer bigger than 2 centimeters (2)
5. Patients with unfavorable anatomy or who are medically unfit to undergo bypass as determined by a vascular surgeon who is not participating in the study.
6. Vascular imaging (eg angiogram or MRA) to determine vascular anatomy must be conducted within 3 months of study entry.
7. Patients with low/absent perfusion in the area at or below the gastrocnemius muscle
8. Objective evidence of severe peripheral arterial disease will include an ankle brachial index (ABI) of less than 0.55, and/or a resting toe brachial index (TBI) of less than 40.
9. Patients must be competent to give consent.
10. No history of malignant disease except for nonmelanoma skin cancer, no suspicious findings on chest x-ray, mammography (women over age 35) , Papanicolaou smear (women over age 40), a normal fecal occult blood (over age 50) and a normal prostate specific antigen (men over age 45).
11. Patients must have a prothrombin Time (PT) between 12-14 seconds, a partial thromboplastin time (PTT) of 18-28 seconds, and platelet count >100,000/microliter
12. Patients must have white blood cell count (4.1-10.9x10(3) cells/µL)
13. Normal liver function tests (AST 8 - 20 U/L, ALT 8 - 20 U/L, and total bilirubin 0.1 - 1.0 mg/dL)
14. Patients must be male or post menopausal women.

Exclusion Criteria:

1. Patients with evidence of active proliferative retinopathy.
2. Patients with poorly controlled diabetes mellitus (HbA1C > 8.5%).
3. Patients with renal insufficiency (Creatinine > 2.5) or failure.
4. Infection as evidenced by WBC count of >15,000 k/cumm and/or temperature >38C.
5. Cellulitis in the afflicted limb that in the opinion of the investigators would require the use of antibiotics or evidence of osteomyelitis corroborated by radiographic or scintigraphic examination.
6. Pregnant women (women capable of childbearing must have a negative pregnancy test)
7. Cognitively impaired adult
8. Lower extremity venous disease with pitting edema.
9. History of organ transplant.
10. Patients with ulcer exudates, dry gangrene or exposed bone.
11. Allergies to beta-lactam antibiotics, amphotericin B, or streptomycin

12. Cardiovascular conditions:

    • Exercise limiting angina (Canadian Cardiovascular Society Class > 3
    • Congestive heart failure (New York Heart Association class > 3
    • Unstable angina
    • Acute ST elevation myocardial infarction (MI) within 1month
    • Transient ischemic attack or stroke within 1 month
    • Severe valvular disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intramuscular injection of ERC	Biological: Administration of ERC; Patients will be treated with either 25 million, 50 million, or 100 million ERC by intramuscular injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety	Adverse and serious events recorded	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy	Improvements post-treatment in rest pain (VAS), toe pressure and ABI, transcutaneous oximetry and ulcer status (with picture).	12 weeks

Collaborators and Investigators

• Sponsor: Medistem Inc.
• Investigators: Principal Investigator: Michael P Murphy, MD, Indiana University

Publications and helpful links

Helpful Links

• Murphy et al. Allogeneic endometrial regenerative cells: An "Off the shelf solution" for critical limb ischemia? J Transl Med. 2008 Aug 19;6:45.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Anticipated): May 1, 2013
• Study Completion (Anticipated): July 1, 2013

Study Registration Dates

• First Submitted: March 18, 2012
• First Submitted That Met QC Criteria: March 18, 2012
• First Posted (Estimate): March 20, 2012

Study Record Updates

• Last Update Posted (Estimate): March 20, 2012
• Last Update Submitted That Met QC Criteria: March 18, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: critical limb ischemia
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Vascular Diseases; Peripheral Arterial Disease; Peripheral Vascular Diseases
• Other Study ID Numbers: MEDS-027