Safety Study of MultiGeneAngio in Patients With Chronic Critical Limb Ischemia

Phase I/IIa Safety, Two-dose Study of MultiGeneAngio in Patients With Chronic Critical Limb Ischemia

The purpose of this study is to evaluate the safety and activity of two doses of MultiGeneAngio, a cell therapy product produced from the patient's own cells, as potential treatment for patients with chronic critical limb ischemia.

Study Overview

• Status: Active, not recruiting
• Conditions: Peripheral Arterial Disease; Peripheral Vascular Disease; Critical Limb Ischemia
• Intervention / Treatment: Biological: MultiGeneAngio; Biological: MultiGeneAngio

Detailed Description

Approximately 16 million patients worldwide (1 in 20 people over the age of 50) suffer from peripheral arterial disease(PAD). PAD is characterized by narrowing or occlusion of vessels supplying blood to the lower limbs, most often due to atherosclerosis. Symptoms of PAD include claudication that may progress to critical limb ischemia manifested by rest pain, tissue loss and gangrene, which eventually may necessitate amputation.

MultiGeneAngio is a cell therapy-based product developed for treatment of patients with chronic critical limb ischemia due to narrow or blocked leg arteries. MultiGeneAngio is composed of endothelial and smooth muscle cells that are isolated from a short vein segment harvested from the patient's arm. After isolation the cells are expanded, characterized, and gene modified by transfer of angiogenic genes.

MultiGeneAngio is a clear cell suspension injected intra-arterially at the site of blockage using a standard diagnostic catheter, in order to create and expand new collateral arteries, and thereby improve blood flow to an ischemic limb.

Comprehensive pre-clinical studies, as well as clinical experience with PAD patients suffering from claudication showed that production and administration of MultiGeneAngio was feasible and safe, as no apparent drug-related adverse events have been observed. Moreover, follow-up data of peak walking times imply a beneficial trend of this efficacy end-point. Additional follow-up data will continue to be collected to help evaluate the safety and efficacy of MultiGeneAngio.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Israel
  • Ashkelon, Israel, 78278
    • Barzilai Medical Center
  • Be'er Sheva, Israel, 84101
    • Soroka Medical Center
  • Haifa, Israel, 31096
    • Rambam Medical Center
  • Jerusalem, Israel, 91031
    • Shaare Zedek Medical Center
  • Jerusalem, Israel, 91120
    • Hadassah University Hospital, Ein Kerem
  • Rehovot, Israel, 76100
    • Kaplan Medical Center
  • Tel-Hashomer, Israel, 52621
    • Chaim Sheba Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and women 50 years of age or older
• Ischemic rest pain (Rutherford category 4) and/or
• Non-healing wounds (Rutherford category 5)
• ABI of 0.5 or less, or TBI of 0.3 or less
• Ankle systolic pressure of 70 mm Hg or less, or toe systolic pressure of 50 mm Hg or less
• Poor or no option for conventional revascularization

Exclusion Criteria:

• Life expectancy of less than one year
• Presence of significant inflow disease (>50% stenosis) in the distal aorta, common or external iliac
• Advanced CLI, characterized by extensive tissue loss or gangrene (Rutherford category 6)
• Previous major amputation on the leg to be treated or planned major amputation within a month from enrollment
• Evidence of osteomyelitis
• Ischemic wounds with uncontrolled infectious symptoms
• Heart angioplasty or CABG within 3 months prior to enrollment
• Severe congestive heart failure (New York Heart Association stage IV)
• Acute cardiovascular event within 3 months prior to enrollment
• Uncontrolled blood pressure: SBP≥ 180 mmHg or DBP ≥110 mmHg
• Known Buerger's disease
• History of bleeding diathesis (e.g., hemophilia due to Factor VIII or IX deficiency)
• Renal failure defined as a serum creatinine >2.5mg/dL
• Significant hepatic disease:>3-fold elevation in ALT/AST, HBV or HCV carriers
• Severe pulmonary disease
• Active proliferative retinopathy and/or severe macular oedema
• Intra-ocular surgery within 6 months prior to enrollment
• Immunodeficient states (e.g. known HIV positivity, or organ transplant recipient) or subject receiving immunosuppressive medication
• History of malignant neoplasm (except curable non-melanoma skin malignancies) within 5 years prior to enrollment
• Pregnant or lactating women
• Previous treatment with angiogenic growth factors or stem cells
• No demonstrable venous access
• Known hypersensitivity to VEGF, Angiopoietin-1, or heparin

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MGA - Low therapeutic dose	Biological: MultiGeneAngio; Low-therapeutic dose of MultiGeneAngio in suspension administered as one treatment, intra-arterially; Biological: MultiGeneAngio; Intermediate-therapeutic dose of MultiGeneAngio in suspension administered as one treatment, intra-arterially
Experimental: MGA - Intermediate therapeutic dose	Biological: MultiGeneAngio; Low-therapeutic dose of MultiGeneAngio in suspension administered as one treatment, intra-arterially; Biological: MultiGeneAngio; Intermediate-therapeutic dose of MultiGeneAngio in suspension administered as one treatment, intra-arterially

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The safety of MultiGeneAngio will be assessed by monitoring adverse events	Up to 15 years after treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Improvement in critical limb ischemia symptoms	Up to 3 months after treatment

Collaborators and Investigators

• Sponsor: MultiGene Vascular Systems Ltd.
• Investigators: Study Director: Sam L. Teichman, MD, Independent consultant

Publications and helpful links

General Publications

• Staudacher DL, Preis M, Lewis BS, Grossman PM, Flugelman MY. Cellular and molecular therapeutic modalities for arterial obstructive syndromes. Pharmacol Ther. 2006 Jan;109(1-2):263-73. doi: 10.1016/j.pharmthera.2005.08.005. Epub 2005 Oct 21.
• Gray BH, Conte MS, Dake MD, Jaff MR, Kandarpa K, Ramee SR, Rundback J, Waksman R; American Heart Association Writing Group 7. Atherosclerotic Peripheral Vascular Disease Symposium II: lower-extremity revascularization: state of the art. Circulation. 2008 Dec 16;118(25):2864-72. doi: 10.1161/CIRCULATIONAHA.108.191177. No abstract available. Erratum In: Circulation. 2009 Jun 30;119(25):e604.
• Staudacher DL, Flugelman MY. Cell and gene therapies in cardiovascular disease with special focus on the no option patient. Curr Gene Ther. 2006 Dec;6(6):609-23. doi: 10.2174/156652306779010705.
• Gluzman Z, Koren B, Preis M, Cohen T, Tsaba A, Cosset FL, Shofti R, Lewis BS, Virmani R, Flugelman MY. Endothelial cells are activated by angiopoeitin-1 gene transfer and produce coordinated sprouting in vitro and arteriogenesis in vivo. Biochem Biophys Res Commun. 2007 Jul 27;359(2):263-8. doi: 10.1016/j.bbrc.2007.05.097. Epub 2007 May 25.
• Tongers J, Roncalli JG, Losordo DW. Therapeutic angiogenesis for critical limb ischemia: microvascular therapies coming of age. Circulation. 2008 Jul 1;118(1):9-16. doi: 10.1161/CIRCULATIONAHA.108.784371. No abstract available.
• Isner JM, Vale PR, Symes JF, Losordo DW. Assessment of risks associated with cardiovascular gene therapy in human subjects. Circ Res. 2001 Aug 31;89(5):389-400. doi: 10.1161/hh1701.096259.

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Actual): August 1, 2011
• Study Completion (Anticipated): May 1, 2026

Study Registration Dates

• First Submitted: August 9, 2009
• First Submitted That Met QC Criteria: August 10, 2009
• First Posted (Estimate): August 11, 2009

Study Record Updates

• Last Update Posted (Estimate): March 5, 2015
• Last Update Submitted That Met QC Criteria: March 4, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Angiogenesis; Endothelial cells; Cell therapy; diabetic foot; Gene therapy; amputation; Peripheral arterial disease (PAD); Peripheral vascular disease (PVD); Arteriogenesis; Smooth muscle cells; Critical limb ischemia (CLI)
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Vascular Diseases; Ischemia; Peripheral Arterial Disease; Peripheral Vascular Diseases
• Other Study ID Numbers: MGVS-MGA 002