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Safety Study of MultiGeneAngio in Patients With Chronic Critical Limb Ischemia

Primary Purpose

Peripheral Arterial Disease, Peripheral Vascular Disease, Critical Limb Ischemia

Status

Active

Phase

Phase 1

Locations

Israel

Study Type

Interventional

Intervention

MultiGeneAngio

About this trial

This is an interventional treatment trial for Peripheral Arterial Disease focused on measuring Peripheral arterial disease (PAD), Peripheral vascular disease (PVD), Critical limb ischemia (CLI), Cell therapy, Gene therapy, Endothelial cells, Smooth muscle cells, Angiogenesis, Arteriogenesis, amputation, diabetic foot

Eligibility Criteria

50 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Barzilai Medical Center
Soroka Medical Center
Rambam Medical Center
Shaare Zedek Medical Center
Hadassah University Hospital, Ein Kerem
Kaplan Medical Center
Chaim Sheba Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

MGA - Low therapeutic dose

MGA - Intermediate therapeutic dose

Arm Description

Outcomes

Primary Outcome Measures

The safety of MultiGeneAngio will be assessed by monitoring adverse events

Secondary Outcome Measures

Improvement in critical limb ischemia symptoms

Full Information

NCT ID

NCT00956332

First Posted

August 9, 2009

Last Updated

March 4, 2015

Sponsor

MultiGene Vascular Systems Ltd.

1. Study Identification

Unique Protocol Identification Number

NCT00956332

Brief Title

Safety Study of MultiGeneAngio in Patients With Chronic Critical Limb Ischemia

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2015

Overall Recruitment Status

Active, not recruiting

Study Start Date

February 2010 (undefined)

Primary Completion Date

August 2011 (Actual)

Study Completion Date

May 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

MultiGene Vascular Systems Ltd.

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Peripheral Arterial Disease, Peripheral Vascular Disease, Critical Limb Ischemia

Keywords

Peripheral arterial disease (PAD), Peripheral vascular disease (PVD), Critical limb ischemia (CLI), Cell therapy, Gene therapy, Endothelial cells, Smooth muscle cells, Angiogenesis, Arteriogenesis, amputation, diabetic foot

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

28 (Actual)

8. Arms, Groups, and Interventions

Arm Title

MGA - Low therapeutic dose

Arm Type

Experimental

Arm Title

MGA - Intermediate therapeutic dose

Arm Type

Experimental

Intervention Type

Biological

Intervention Name(s)

MultiGeneAngio

Intervention Description

Low-therapeutic dose of MultiGeneAngio in suspension administered as one treatment, intra-arterially

Intervention Type

Biological

Intervention Name(s)

MultiGeneAngio

Intervention Description

Intermediate-therapeutic dose of MultiGeneAngio in suspension administered as one treatment, intra-arterially

Primary Outcome Measure Information:

Title

The safety of MultiGeneAngio will be assessed by monitoring adverse events

Time Frame

Up to 15 years after treatment

Secondary Outcome Measure Information:

Title

Improvement in critical limb ischemia symptoms

Time Frame

Up to 3 months after treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sam L. Teichman, MD

Organizational Affiliation

Independent consultant

Official's Role

Study Director

Facility Information:

Facility Name

Barzilai Medical Center

City

Ashkelon

ZIP/Postal Code

78278

Country

Israel

Facility Name

Soroka Medical Center

City

Be'er Sheva

ZIP/Postal Code

84101

Country

Israel

Facility Name

Rambam Medical Center

City

Haifa

ZIP/Postal Code

31096

Country

Israel

Facility Name

Shaare Zedek Medical Center

City

Jerusalem

ZIP/Postal Code

91031

Country

Israel

Facility Name

Hadassah University Hospital, Ein Kerem

City

Jerusalem

ZIP/Postal Code

91120

Country

Israel

Facility Name

Kaplan Medical Center

City

Rehovot

ZIP/Postal Code

76100

Country

Israel

Facility Name

Chaim Sheba Medical Center

City

Tel-Hashomer

ZIP/Postal Code

52621

Country

Israel

12. IPD Sharing Statement

Citations:

PubMed Identifier

16243400

Citation

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.

Results Reference

background

PubMed Identifier

19106409

Citation

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.

Results Reference

background

PubMed Identifier

17168694

Citation

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.

Results Reference

background

PubMed Identifier

17544375

Citation

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.

Results Reference

background

PubMed Identifier

18591450

Citation

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.

Results Reference

background

PubMed Identifier

11532899

Citation

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.

Results Reference

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Safety Study of MultiGeneAngio in Patients With Chronic Critical Limb Ischemia

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