Randomized Phase IIb Trial of DVC1-0101

Study Overview
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Brief Summary
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DVC1-0101 is a gene therapy medicine to treat peripheral arterial disease (PAD) based on recombinant F-gene-deleted, non-transmissible Sendai virus (rSeV/dF) expressing human fibroblast growth factor-2 (FGF-2) gene. The primary objective of the current Phase IIb study is to investigate the clinical efficacy of DVC1-0101 (1x10^9 ciu/leg, 5x10^9 ciu/leg) in patients with IC.

Detailed Description
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DVC1-0101 is a gene therapy medicine to treat peripheral arterial disease (PAD) based on recombinant F-gene-deleted, non-transmissible Sendai virus (rSeV/dF) expressing human fibroblast growth factor-2 (FGF-2) gene. The previous Phase I/IIa study demonstrated no serious adverse event related to the administration, and suggested possible improvement of local blood flow and walking performance of PAD patients. The primary objective of the current Phase IIb study is to investigate the clinical efficacy of DVC1-0101 (1x10^9 ciu/leg, 5x10^9 ciu/leg) in patients with IC. We also aim to examine the dose-response relationship using the rate of improvement in walking function as an indicator.

Official Title
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DVC1-0101 for Intermittent Claudication Secondary to Peripheral Artery Disease: a Randomized Phase IIb Trial

Conditions
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Intermittent Claudication, Peripheral Arterial Disease

Intervention / Treatment
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* Drug: DVC1-0101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1) Meet criteria (1) to (5) below and are confirmed as such by at least 1 specialist qualified by the Japanese Society for Cardiovascular Surgery and at least 1 physician with deep experience Cardiovascular Intervention. arteriosclerosis obliterans with stable symptoms, have intermittent claudication (ACD < 260 m) and are able to walk on a treadmill resting ankle-brachial pressure index < 0.9 refuse revascularization, risk of revascularization may be greater than the benefit, or develop obliteration after revascularization angiographic findings show patency from the abdominal aorta through to the proximal side of the external iliac artery angiographic findings meet the above criterion (4), and have stenosis or obliteration under the femoropopliteal region with morphology defined as type C or D based on TASCII 2) Administering cilostazol for at least 1 month and still meet criterion 1). 3) Aged 30 and over. 4) Either sex, either inpatients or outpatients. 5) Able to give written consent for themselves. Exclusion Criteria: Have ischemic ulcer. Diagnosed with Buerger's disease. Have a current or past history of life-threatening allergies. Have been shown or are suspected to have cancer. With concurrent proliferative intraocular neovascularization. With poorly controlled diabetes mellitus. With concurrent cardiac failure. With untreated severe arrhythmia. Have or are suspected to have interstitial pneumonia. Have progressive hepatic disorders. Have moderate or severe hepatic disorders. (1) aspartate aminotransferase or alanine aminotransferase >2.5 times the upper limit (2) Prothrombin time is 14 seconds or longer (3) Serum bilirubin >2.0 times the upper limit Diagnosed with hepatic cirrhosis (classified as B or C on the Child-Pugh). Have an inflammatory disease. Treated with immunosuppressants or corticosteroids for the treatment of various inflammatory diseases or after organ transplantation. Underwent extirpative surgery of a malignant tumor in the past 5 years. Have had a cerebral hemorrhage or cerebral infarction in the past 6 months. With blood diseases. With moderate or severe renal dysfunction (CCr <40 mL/min) With alcohol or drug dependence. Pregnant/lactating female, or who wish or are suspected to be pregnant. Positive HIV antibodies. Took part in any other clinical studies or research in the past 30 days. Have allergic to the antibiotics and/or the Ribavirin. Not permitted to participate in this study by the principal investigator or sub-investigator for any other reasons.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (0 ciu/limb)<br>Placebo control | Drug: DVC1-0101<br>* The investigational product will be drawn into a disposable 1 mL syringe using a 23G needle. A total of 0.5 mL of investigational product will be injected intramuscularly into each administration site. After administration, the administration sites will be wrapped with dressings.<br>* Other names: rSeV/dF expressing human FGF-2 gene;|
| Active Comparator: DVC1-0101 low dose (1x10^9 ciu/limb)<br>Low dose cohort | Drug: DVC1-0101<br>* The investigational product will be drawn into a disposable 1 mL syringe using a 23G needle. A total of 0.5 mL of investigational product will be injected intramuscularly into each administration site. After administration, the administration sites will be wrapped with dressings.<br>* Other names: rSeV/dF expressing human FGF-2 gene;|
| Active Comparator: DVC1-0101 high dose (5x10^9 ciu/limb)<br>High dose cohort | Drug: DVC1-0101<br>* The investigational product will be drawn into a disposable 1 mL syringe using a 23G needle. A total of 0.5 mL of investigational product will be injected intramuscularly into each administration site. After administration, the administration sites will be wrapped with dressings.<br>* Other names: rSeV/dF expressing human FGF-2 gene;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Walking performance assessed by treadmill utilizing Gardner's method | Change rate from baseline in absolute claudication distance (%ACD) at 6 months Change of ACD from baseline at 6 months Change of peak walking time from baseline at 6 months Change of initial claudication distance (ICD) from baseline at 6 months Change of claudication onset time from baseline at 6 months | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NIRS measurement | Measurement of oxygen dynamics in the leg muscles by near infrared spectroscopy after a treadmill | Pre, day 14, 1, 2, 3, 4, 5, and 6 months | 
| Readministration | Proportion of subjects in whom readministration was not required | 6 months | 
| WIQ | Evaluation of QOL based on the Walking Impairment Questionnaire (WIQ) | Pre, 1, 3, and 6 months | 
| Clinical stage classifications | Time-course changes using clinical stage classifications (Fontaine classification, Rutherford classification) | Pre, day 14, 1, 2, 3, 4, 5, and 6 months | 
| ABI/TBI | Ankle-brachial pressure index/ Toe-brachial pressure index | Pre, day 14, 1, 3, and 6 months | 
| VAS | visual analogue scale (VAS) and pain at rest evaluated by the frequency of analgesic use | Pre, day 1, 2, 3, 5, 7, 14 and monthly until 6 months | 
| MACE | Incidence of cardiovascular events (to be followed up to 5 years after administration) | Monthly until 1 year after gene transfer | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recombinant Sendai virus, fibroblast growth factor-2, treadmill