Safety and Efficacy Study Using Gene Therapy for Critical Limb Ischemia

Study Overview
=================
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.

Official Title
-----------------
A Phase II, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy of VM202 in Subject With Critical Limb Ischemia

Conditions
-----------------
Critical Limb Ischemia

Intervention / Treatment
-----------------
* Biological: Low Dose VM202
* Biological: High Dose VM202
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose VM202<br>Patients in this group will receive 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 | Biological: Low Dose VM202<br>* Day 0: 4mg of VM202 (16 injections of 0.5ml of VM202) Day14: 4mg of VM202 (16 injections of 0.5ml of VM202)<br>* Other names: HGF-X7;Other: Placebo<br>* 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<br>* Other names: Normal Saline;|
| Experimental: High Dose VM202<br>Patients in this treatment group will receive 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) | Biological: High Dose VM202<br>* Day 0: 4mg of VM202 (16 injections of 0.5ml of VM202) Day 14: 4mg of VM202 (16 injections of 0.5ml of VM202) Day 28: 4mg of VM202 (16 injections of 0.5ml of VM202) Day 42: 4mg of VM202 (16 injections of 0.5ml of VM202)<br>* Other names: HGF-X7;|
| Sham Comparator: Placebo<br>Patients in this group will receive 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 | Other: Placebo<br>* 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<br>* Other names: Normal Saline;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary study endpoint is to assess the safety of IM administration of VM202 in subjects with moderate or high-risk CLI |  | Baseline - 9 Months | 
| Difference in pain level between baseline and the 9 month follow-up as determined by VAS |  | Baseline and Month 9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in tissue oxygenation (TcPO2) from baseline to 9 months and 12 months following the first treatment |  | Day 0, 9 months, 12 months | 
| Change in hemodynamic measures (ABI and TBI) from baseline to Day 28, Day 90, 6 months, 9 months and 12 months following the first treatment |  | Days 0, 28, 90, 6 months, 9 months, 12 months | 
| Change in perfusion (MRA) from baseline to 9 months following the first treatment |  | Day 0, 9 months | 
| Wound healing (no ulcer: change of skin condition, one ulcer: change of ulcer size, multiple ulcer: change of ulcer number) from baseline to 9 months following the first treatment |  | Days 0, 14, 28, 42, 49, 90, 6 months, 9 months | 
| Change in VAS score from baseline to Day 14, Day 28, Day 42, Day 90, at 6 months, 9 months, and 12 months. |  | Days 0, 14, 28, 42, 90, 6 months, 9 months, 12 months | 
| Change in QOL score (VascuQol) at 90 Days, 9 months and 12 months |  | Days 0, 90, 9 months and 12 months | 
| Amputation rate at six months and twelve months following the first treatment |  | 6 months, 12 months | 
| Mortality at six and twelve months after first treatment |  | 6 months, 12 months | 
| Difference in pain level between baseline and the 9 month follow-up as determined by VAS by sex and by comorbidities (esp. diabetes or renal dysfunction) |  | Baseline, Days 14, 28, 42, 90, Months 6, 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Painful legs, Ischemic legs, Treatment for Claudication, Gene therapy