Clinical trial NCT04275323: Safety and Efficacy Study Using Gene Therapy for Critical Limb Ischemia (NL003-CLI-III-1)
Official title: A Phase III, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy of NL003 in Subject With Critical Limb Ischemia(Rutherford 4)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Arterial Occlusive Disease
Ischemia
Ulcers
Peripheral Vascular Disease
Keywords: HGF
Gene
Critical Limb Ischemia
Lead sponsor: Beijing Northland Biotech. Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2020-02-19
Enrollment: 302
Sex: ALL
Minimum age (years): 20
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To evaluate the safety and efficacy of recombinant human hepatocyte growth factor (HGF) bare plasmid injection for local intramuscular injection in the treatment of patients with severe lower limb hemorrhagic disease (Rutherford grade 4)

Detailed description: Management of CLI process consumes a significant amount of healthcare resources,and the 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 NL003, 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 NL003 may result in an increase in tissue perfusion, which, in turn improve wound healing, reduce pain and improve limb salvage rates.

Eligibility criteria: Inclusion Criteria:

* 1. Age 20 and 80 (when signing informed consent), both male and female;

  2. Patients diagnosed with lower limb arterial ischemic disease based on DSA or CTA and combined with their medical history and clinical manifestations and Rutherford grade 4 (resting pain) must meet the following criteria simultaneously (if both limbs of the subject have lower limb arterial ischemic disease, the researcher shall choose one limb for the study).Resting ankle systolic pressure (dorsal foot artery or posterior tibial artery) ≤70mmHg or ABI≤0.5 or TcPO2 \< 30mmHg;In the first 3 months after randomized inclusion, DSA or CTA confirmed severe stenosis (≥70%) or occlusion of superficial femoral artery or popliteal artery or inferior knee artery.

  3. Chronic lower limb arterial ischemia combined with resting pain met the following requirements: resting pain lasted for more than 2 weeks when the informed consent was signed;

  4. Agreed to use the basic treatment drugs as required during the trial, and recorded the daily record of the subjects in a timely and complete manner. The compliance of the basic treatment drugs and the subjects' diary filling during the screening period was 70%.

  5. Agree to use appropriate contraceptive measures during the experiment;Female subjects of reproductive age, blood pregnancy test negative;

  6. Signed informed consent

Exclusion Criteria:

* 1. Patients with acute lower limb ischemia or acute exacerbation of chronic lower limb ischemia.

  2. Vascular reconstruction (bypass or intravascular therapy) or sympathetic resection or amputation was performed within 4 weeks prior to the signing of the informed consent.

  3. Due to surgical operation, the patient is still in the postoperative risk period, and the researcher judges that the patient is not suitable for the test.

  4. Main-iliac artery stenosis 70%.

  5. Patients with ischemic ulcer of lower extremity.

  6. NYHA classification of cardiac function is classified as grade (see annex 1 for specific classification criteria).

  7. Patients with unstable angina pectoris due to cerebral infarction, cerebral hemorrhage and myocardial infarction within 3 months before signing the informed consent.

  8. Refractory hypertension (taking three or more antihypertensive drugs, systolic blood pressure 180mmHg or diastolic blood pressure 110mmHg).

  9. Proliferative retinopathy and retinopathy examination is not available.

  10. Inability to accurately describe symptoms and emotions.

  11. Severe liver disease with uncompensated cirrhosis, jaundice, ascites or hemorrhagic varices.

  12. Current recipients of immunosuppressants or chemoradiotherapy.

  13. Anti-hiv antibody positive, anti-hepatitis c antibody positive and hepatitis b surface antigen positive (if the subject is HBsAg positive and HBV DNA in peripheral blood is combined, the researcher believes that the subject's chronic hepatitis b is stable and will not increase the risk of the subject, the subject can be selected).

  14. Results of laboratory examination during screening period: hemoglobin \<80g/L, white blood cell count \< 3.0109 /L, platelet \<75 109/L, upper limit of normal AST or ALT\> 3 times, upper limit of normal serum creatinine \> 2.5 times, or other laboratory examination indicators appear abnormal that researchers think may affect the evaluation of test results.

  15. Patients with poor blood glucose control after treatment (hemoglobin a1c \>10%).

  16. Previously diagnosed with malignant tumor, or any of the following test results determined by the investigator to be at risk of tumor: fecal occult blood test;Chest X-ray examination or chest CT examination;Alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and ca19-9;Male subjects, prostate specific antigen test (PSA, free PSA);Female subjects, cervical smear (Pap), mammography/b-ultrasound and ca-125 examination;The investigators determined that additional tests were necessary to eliminate the tumor risk.

  17. In the opinion of the investigators, patients with comorbidities that affect safety and efficacy evaluation, or with a predicted survival of less than 12 months.

  18. Frequent drinkers within the 12 months prior to the signing of the informed consent, i.e., those who drank more than 14 units of alcohol per week (1 unit =360 mL beer or 45 mL alcohol of 40% spirits or 150 mL wine) or substance abusers.

  19. Participate in other clinical trials within 3 months before signing the informed consent.

Primary outcomes:
measure: Complete pain relief rate
timeFrame: Day180
Secondary outcomes:
measure: The time when the pain completely goes away
timeFrame: Day180
measure: Complete pain relief rate
timeFrame: Day90
measure: Changes in site visits, pain scores after use of the study drug
timeFrame: Day14,Day28,Day60,Day90,Day120,Day180
measure: Percent of Participants with a 50% reduction in pain score from baseline
timeFrame: Day180
measure: The type and dose of analgesics varied from baseline
timeFrame: Day14,Day28,Day60,Day90,Day120,Day180
measure: Changes in Rutherford grading from baseline to Day180
timeFrame: Day14,Day28,Day60,Day90,Day120,Day180
measure: Changes in quality of life scores from baseline to Day180
timeFrame: Day14,Day28,Day60,Day90,Day120,Day180
measure: Changes in the ABI from the baseline to Day180
timeFrame: Day60,Day90,Day120,Day180
measure: Percentage of patients who underwent revascularization (open surgery or interventional therapy) had a large amputation rate and mortality
timeFrame: Day180
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Hospitai
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Chongqing
country: China
facility: The Ninth People's Hospital of Chongqing
state: Chongqing
city: Zhangzhou
country: China
facility: Zhangzhou Municipal Hospital of Fujian Province
state: Fujian
city: Changsha
country: China
facility: The Second Xiangya Hospital of Central South University
state: Hunan
city: Changsha
country: China
facility: The Third Xiangya Hospital of Central South University
state: Hunan
city: Xuzhou
country: China
facility: Xuzhou Mining Group General Hospital
state: Jiangsu
city: Chifeng
country: China
facility: Chifeng Municipal Hospital
state: Neimenggu
city: Qingdao
country: China
facility: The Affiliated Hospital of Qingdao University
state: Shandong
city: Shanghai
country: China
facility: Shanghai seventh people's hospital
state: Shanghai
city: Taiyuan
country: China
facility: Shanxi Provincial People's Hospital
state: Shanxi
city: XiAn
country: China
facility: First Affiliated Hospital of Xi 'an Jiaotong University
state: Shanxi
city: XiAn
country: China
facility: Second Affiliated Hospital of Xi 'an Jiaotong University
state: Shanxi
Study officials:
References: