Safety and Efficacy Study Using Gene Therapy for Critical Limb Ischemia

Phase 2

Completed

Conditions: Critical Limb Ischemia

Interventions: Biological: Low Dose VM202
Biological: High Dose VM202
Other: Placebo

Registration Number: NCT01064440

Lead Sponsor: Helixmith Co., Ltd.

Brief Summary: The purpose of this study is to evaluate whether intramuscular injections of VM202 into the calf is safe and effective in the treatment of critical limb ischemia.

Detailed Description: In the absence of revascularization options, most patients with CLI require amputation within 6 months. Patients requiring major amputation face a diminished quality of life, an unfavorable natural history and need extensive resources for their post-amputation rehabilitation and course. The 1-year amputation-free survival rate for patients diagnosed with CLI is 45%; the mortality rate is approximately 25% and may be as high as 45% in those who have undergone amputation. Management of this end-stage disease process consumes a significant amount of healthcare resources. Clearly, new therapeutic approaches are required.

Hepatocyte growth factor (HGF) has been shown to be a potent angiogenic growth factor stimulating the growth of endothelial cells and migration of vascular smooth muscle cells. Because of its pluripotent capabilities, increasing the availability of HGF in ischemic tissues to achieve therapeutic angiogenesis has been a growing area of research.

This study will use VM202, which is a DNA plasmid that contains novel genomic cDNA hybrid human HGF coding sequence (HGF-X7) expressing two isoforms of HGF, HGF 728 and HGF 723. As there are currently no approved drugs that can reverse CLI and as most patients have exhausted surgical and endovascular intervention options, inducing angiogenesis in the affected limb with VM202 may result in an increase in tissue perfusion, which, in turn improve wound healing, reduce pain and improve limb salvage rates.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

Inclusion Criteria

Male or female, between 18 and 90 years of age;
Diagnosis of critical limb ischemia (Rutherford Class 4 or 5), including:
- A resting ankle systolic pressure (in either the dorsalis pedis or posterior tibial arteries) of ≤ 70 mmHg in the affected limb; or
- A resting toe systolic pressure of ≤ 50 mmHg in the affected limb; or
- For patients in which measurement of ankle systolic pressure is not feasible (e.g. vessel calcification and non-compressibility); TcPO2 ≤ 30 mmHg;
Poor or suboptimal candidate for bypass graft surgery or percutaneous angioplasty;
Pain at rest, and/or ischemic ulcers, and/or focal gangrene (< 3 cm2) for a minimum of 2 weeks,
Significant stenosis (≥ 75%) of one or more of the following arteries: superficial femoral, popliteal, or two or more infra-popliteal arteries as verified by angiography within 12 months prior to enrollment;
Be willing to maintain current drug therapy for peripheral arterial disease throughout the course of the study including an anti-platelet and statin treatment unless not tolerated;
Clinically stable on optimized medical regimen for >30 days
Be capable of understanding and complying with the protocol and signing the informed consent document prior to being subjected to any study related procedures;
Women who are surgically sterile or at least 1 year postmenopausal or who have been practicing adequate contraception for at least 12 weeks prior to entering the study. If the subject is of child-bearing potential, she must have a negative urine pregnancy test result prior to study enrollment and must agree to repeat pregnancy screening tests during the study. If the subject or the subject's partner(s) is of child bearing potential, the subject and the subject's partner(s) must agree to use a "double barrier" method of birth control while participating in this study.

Exclusion Criteria

Subjects who have undergone a successful revascularization procedure or sympathectomy within 12 weeks prior to study entry. A clinically unsuccessful revascularization procedure is defined as one in which:
- the target vessel re-occludes (≥50%, as verified by a second angiogram. Duplex ultrasonography can be used to determine vessel patency if the patient cannot tolerate a second angiogram), or
- the target vessel remains patent, but there is no resolution of symptoms 6 weeks after the procedure (e.g. no evidence of ulcer healing, no improvement in pressures, no reduction in resting pain);
Subjects that will require an amputation in the target leg within 4 weeks of randomization;
Subjects with evidence of active infection (e.g., cellulitis, osteomyelitis) or deep ulceration exposing bone or tendon in the extremity planned for treatment;
Heart Failure with a NYHA classification of III or IV;
Stroke (NIH scale >2) or myocardial infarction within last 3 months;
Unstable angina
Uncontrolled hypertension defined as sustained systolic blood pressure (SBP) > 200 mmHg or diastolic BP (DBP) > 110 mmHg at baseline/screening evaluation;
Ophthalmologic conditions pertinent to proliferative retinopathy or conditions that preclude standard ophthalmologic examination;
Inflammatory disorder of the blood vessels (inflammatory angiopathy, such as Buerger's disease);
Subjects with advanced liver disease including decompensated cirrhosis, jaundice, ascites or bleeding varices;
Subjects currently receiving immunosuppressive medications chemotherapy, or radiation therapy;
Positive HIV or HTLV at screening;
Active Hepatitis B or C infection as determined by Hepatitis B surface antibody (HBsAb), Hepatitis B core antibody (IgG and IgM; HBcAb), Hepatitis B surface antigen (HBsAg) and Hepatitis C antibodies (Anti-HCV), at Screening;
Specific laboratory values at Screening including: Hemoglobin < 8.0 g/dL, WBC < 3,000 cells per microliter, platelet count <75,000/mm3, AST and/or ALT > 3 times the upper limit of normal or any other clinically significant lab abnormality which in the opinion of the investigator should be exclusionary;
Patients with a recent history (< 5 years) of or new screening finding of malignant neoplasm except basal cell carcinoma or squamous cell carcinoma of the skin (if excised and no evidence of recurrence); patients with family history of colon cancer in any first degree relative are excluded unless they have undergone a colonoscopy in the last 12 months with negative findings;
Elevated PSA unless prostate cancer has been excluded;
Subjects with any co- morbid conditions likely to interfere with assessment of safety or efficacy or with an estimated life expectancy of less than 6 months
Subjects requiring > 81 mg daily of acetylsalicylic acid; If > 81 mg are taken at screening, subjects may be enrolled if willing/able to switch to another medication;
Subjects requiring regular COX-2 inhibitor drug(s) or high dose steroids (excepting inhaled steroids);
Major psychiatric disorder in past 6 months;
History of drug or alcohol abuse / dependence in the past 2 years;
Use of an investigational drug or treatment in past 12 months; concurrent participation in investigational protocol or unapproved therapeutics and
Unable or unwilling to give informed consent.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Low Dose VM202	Low Dose VM202	Patients in this group received 8mg total of VM202. Day 0: 4mg of VM202 (16 injections of 0.5ml of VM202) Day14: 4mg of VM202 (16 injections of 0.5ml of VM202) Day 28: 16 injections of 0.5ml of normal saline Day 42: 16 injections of 0.5ml of normal saline
Low Dose VM202	Placebo	Patients in this group received 8mg total of VM202. Day 0: 4mg of VM202 (16 injections of 0.5ml of VM202) Day14: 4mg of VM202 (16 injections of 0.5ml of VM202) Day 28: 16 injections of 0.5ml of normal saline Day 42: 16 injections of 0.5ml of normal saline
High Dose VM202	High Dose VM202	Patients in this treatment group received a total of 16mg VM202. Day 0: 4mg of VM202 (16 injections of 0.5ml of VM202) Day14: 4mg of VM202 (16 injections of 0.5ml of VM202) Day 28: 4mg of VM202 (16 injections of 0.5ml of VM202) Day42: 4mg of VM202 (16 injections of 0.5ml of VM202)
Placebo	Placebo	Patients in this group received a total of 8ml normal saline. Day 0: 16 injections of 0.5ml of normal saline Day 14: 16 injections of 0.5ml of normal saline Day 28: 16 injections of 0.5ml of normal saline Day 42: 16 injections of 0.5ml of normal saline

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-emergent Adverse Events Following Intramuscular Administration of 8 and 16 mg Engensis (VM202) or Placebo in Subjects With Critical Limb Ischemia.	Baseline - Days 0, 14, 28, 42, 49, 90, 180, 270 and 365	The number of participants with treatment-emergent adverse events (TEAEs), defined as adverse events occurring after the first injection of Engensis (VM202), was assessed in moderate or high-risk Critical Limb Ischemia subjects.
Change From Baseline in Visual Analog Scale (VAS) for Pain	Days 0, 90, 180, 270, and 365	The Visual Analog Scale (VAS) for Pain scoring instrument is a 10 cm line, oriented horizontally, with the left end score of "0" indicating "no pain", and the right end score of "10" representing "pain as bad as it can be"

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Tissue Oxygenation (TcPO2) for the Dorsal Surface of the Foot Following Engensis (VM202) or Placebo	Day 0 to Days 180, 270, and 365	Tissue Oxygenation (TcPO2) measurement is reported for the dorsum of the foot. The change in baseline for the TcPO2 measured in the dorsal surface of the foot results are reported for each of the 3 study groups: 8 mg, or 16 mg for the Engensis (VM202) group, or the Placebo group. Because of the indication being peripheral vascular disease, the dorsal surface of the foot was decided by the sponsor to be a good representative of the lower extremity for any of the other measured sites.
Change From Baseline in Hemodynamic Assessment for Ankle Brachial-Index (mmHg) for the Index Leg	Days 0, 28, 90, 180, 270, and 365	Change in the Resting Ankle-Brachial Index (ABI) from Baseline (Day 0) for the Index Leg to Days 180, 270, and 365. Note that by default, Day 0 has no change from baseline. Days 28 and 90 time point data was not included,as they were not relevant to assess efficacy, because of the delayed effect of Engensis, the investigational product.
Change From Baseline in Perfusion of the Occluded Target Artery by Magnetic Resonance Angiogram (MRA)	Day 0 to Days 180 and 270	The quantitative blood flow of the occluded target artery and the volumetric analysis of the newly developed artery by Magnetic Resonance Angiogram (MRA) were recorded. Note that "no change from baseline table of data" is not presented because there was only one subject with both a Baseline and Post Treatment value for Magnetic Resonance Angiogram (MRA) measurement.
Subjects With 100% Wound Healing	Days 0, 14, 28, 42, 49, 90, 180, 270, and 365	The length and width (in cm) was based on photographs and measurements of ulcers. If a ulcer was determined to be 100% healed, the area of the ulcer was set to 0
Change From Baseline in the Vascular Quality of Life Total Score	Days 0, 90, 270, and 365	The Vascular Quality of Life Total Score (VascuQol) questionnaire has 25 questions that reviewed five domains: activity level (8 items), symptoms (4 items), pain (4 items), emotional (7 items), and social (2 items). The total score is the total of the non-missing scored divided by the number of responded questions. The Vascular Quality of Life Total Score (VascuQol) scale is a 7-point scale with "1" as the worst change from baseline score, and "7" is the least change from baseline score.
Number of Subjects With Major, Lower Leg, Amputations During the Trial	Day 0 through Day 365	The number and percentage of subjects with major amputations during the trial
The Number of Deaths During the Trial	Day 0 to Day 365	The number and percentage of subjects who died during the trial
Change From Baseline in Visual Analog Scale (VAS) for Pain at 9 Months- by Sex	Days 0 (baseline), 9 months (Day 270)	The VAS scoring instrument is a 10 cm line, oriented horizontally, with the left end indicating "no pain" (score = 0 mm, better outcome) and the right end representing "pain as bad as it can be (score = 100 mm, worse outcome).
Change From Baseline in Visual Analog Scale (VAS) for Pain at 9 Months- by Renal Dysfunction Status	Days 0 (baseline), 9 months (Day 270)	The VAS scoring instrument is a 10 cm line, oriented horizontally, with the left end indicating "no pain" (score = 0 mm, better outcome) and the right end representing "pain as bad as it can be (score = 100 mm, worse outcome).
Change From Baseline in Visual Analog Scale (VAS) for Pain at 9 Months- by Diabetes Status	Days 0 (baseline), 9 months (Day 270)	The VAS scoring instrument is a 10 cm line, oriented horizontally, with the left end indicating "no pain" (score = 0 mm, better outcome) and the right end representing "pain as bad as it can be (score = 100 mm, worse outcome).

Trial Locations

Locations (16): Boston University School of Medicine
🇺🇸
Boston, Massachusetts, United States
The Methodist Hospital
🇺🇸
Houston, Texas, United States
St. Vincent Medical Group
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Indianapolis, Indiana, United States
UNC School of Medicine
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Chapel Hill, North Carolina, United States
Saint Louis University
🇺🇸
Saint Louis, Missouri, United States
Jobst Vascular
🇺🇸
Toledo, Ohio, United States
Texas Heart Institute
🇺🇸
Houston, Texas, United States
Yonsei University Health System. Severance Cardiovascular Hospital
🇰🇷
Seoul, Seodaemun-gu, Korea, Republic of
Seoul National University
🇰🇷
Seoul, Jongno-gu, Korea, Republic of
Ewha Womans University Medical Center
🇰🇷
Seoul, YangCheon-ku, Korea, Republic of
Cardiology PC
🇺🇸
Birmingham, Alabama, United States
University of Utah
🇺🇸
Salt Lake City, Utah, United States
University of Oklahoma HSC
🇺🇸
Oklahoma City, Oklahoma, United States
Northwestern Memorial Hospital
🇺🇸
Chicago, Illinois, United States
University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
Vascular and Interventional Specialist of Orange County
🇺🇸
Orange, California, United States