Safety and Efficacy Study Using Gene Therapy for Critical Limb Ischemia (NL003-CLI-III-1)

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)

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)

Study Overview

• Status: Recruiting
• Conditions: Ischemia; Peripheral Vascular Disease; Arterial Occlusive Disease; Ulcers
• Intervention / Treatment: Genetic: NL003; Other: Normal Saline

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.

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: yue liu; Phone Number: +86-10-82890893; Email: liuyue@northland-bio.com
• Study Contact Backup: Name: yinjian sun; Phone Number: +86-10-82890893; Email: sunyinjian@northland-bio.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100032
      • Recruiting
      • Peking Union Medical College Hospital
      • Principal Investigator: Changwei Liu
    • Beijing, Beijing, China, 100005
      • Recruiting
      • Beijing Hospitai
      • Principal Investigator: Yongjun LI
  • Chongqing
    • Chongqing, Chongqing, China, 400700
      • Recruiting
      • The Ninth People's Hospital of Chongqing
      • Principal Investigator: Shigang Duan
  • Fujian
    • Zhangzhou, Fujian, China, 363000
      • Recruiting
      • Zhangzhou Municipal Hospital of Fujian Province
      • Principal Investigator: Mingzhi Cai
  • Hunan
    • Changsha, Hunan, China, 410000
      • Recruiting
      • The Third Xiangya Hospital of Central South University
      • Principal Investigator: Kai Yao
    • Changsha, Hunan, China, 410000
      • Not yet recruiting
      • The Second Xiangya Hospital of Central South University
      • Principal Investigator: Chang Shu
    • Changsha, Hunan, China, 410000
      • Recruiting
      • The Second Xiangya Hospital of Central South University
      • Principal Investigator: Chang Shu
  • Jiangsu
    • Xuzhou, Jiangsu, China, 221006
      • Recruiting
      • Xuzhou Mining Group General Hospital
      • Principal Investigator: Jian Wang
  • Neimenggu
    • Chifeng, Neimenggu, China, 024000
      • Recruiting
      • Chifeng Municipal Hospital
      • Principal Investigator: Liu Yang
  • Shandong
    • Qingdao, Shandong, China, 266003
      • Recruiting
      • The Affiliated Hospital of Qingdao University
      • Principal Investigator: Haofu Wang
  • Shanghai
    • Shanghai, Shanghai, China, 200120
      • Recruiting
      • Shanghai Seventh People's Hospital
      • Principal Investigator: Bin Zhao
  • Shanxi
    • Taiyuan, Shanxi, China, 030012
      • Recruiting
      • Shanxi Provincial People's Hospital
      • Principal Investigator: Qiang Guan
    • XiAn, Shanxi, China, 710061
      • Recruiting
      • First Affiliated Hospital of Xi 'an Jiaotong University
      • Principal Investigator: Shaoying Lu
    • XiAn, Shanxi, China, 710061
      • Not yet recruiting
      • Second Affiliated Hospital of Xi 'an Jiaotong University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: investigational produc; Patients in this treatment group will receive 8mg NL003 respective in D0、14、28	Genetic: NL003; Day 0: 8mg of NL003 (32 injections of 0.5ml of NL003) Day 14: 8mg of NL003 (32 injections of 0.5ml of NL003) Day 28: 8mg of NL003 (32 injections of 0.5ml of NL003); Other Names: HGF plasmid; pCK-HGF-X7
Placebo Comparator: Placebo; Patients in this group will receive normal saline respective in D0、14、18	Other: Normal Saline; Day 0: 16ml of Normal Saline (32 injections ) Day 14: 16ml of Normal Saline (32 injections ) Day 28: 16ml of Normal Saline (32 injections ); Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete pain relief rate	1.Day180 visit (5-7 days prior to visit, including the visit day), mean daily pain score was 0；2.A pain score of 0 must be measured without the use of analgesics.	Day180

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The time when the pain completely goes away	The time when the pain completely goes away.	Day180
Complete pain relief rate	Day90 visit (5-7 days prior to visit, including the visit day), mean daily pain score was 0.	Day90
Changes in site visits, pain scores after use of the study drug	The Numerical Rating Scale（NRS） was used to record changes in pain in subjects, who chose a number that best represented their pain in the past 24 hours, ranging from 0 (painless) to 10 (the most intense pain imaginable).The NRS scale is pain free (0), mild pain (1-3), moderate pain (4-6), and severe pain (7-10).	Day14,Day28,Day60,Day90,Day120,Day180
Percent of Participants with a 50% reduction in pain score from baseline	Percent of Participants with a 50% reduction in pain score from baseline.	Day180
The type and dose of analgesics varied from baseline	The types and dosages of analgesics varied from baseline at each site after the use of the study drug.	Day14,Day28,Day60,Day90,Day120,Day180
Changes in Rutherford grading from baseline to Day180	The severity of critical Limb ischemia was assessed by Rutherford grading at screening, D14, D28, D60, D90, and D180, respectively.Rutherford grades chronic limb ischemic disease into grades 0 to 6, of which 4, 5 and 6 are chronic severe ischemia.	Day14,Day28,Day60,Day90,Day120,Day180
Changes in quality of life scores from baseline to Day180	The WHOQOL-BREF was conducted to evaluate the subjective perception of Critical Limb Ischemia, including the subjects' perception of quality of life, health, or other aspects of life.The whoqol-bref has 26 questions. Each question is rated on a scale of 1 to 5, with 1 for poor quality of life and 5 for good quality of life.	Day14,Day28,Day60,Day90,Day120,Day180
Changes in the ABI from the baseline to Day180	Ankle-brachial index (ABI) refers to the ratio of systolic blood pressure of the anterior tibial artery (dorsal foot artery) or posterior tibial artery to the systolic blood pressure of the brachial artery.Participants were tested for ankle-brachial index (ABI).The normal value of ABI is 0.9-1.4, where <0.4 is severe ischemia,0.41-0.9 is mild to moderate ischemia, and ABI>1.4 indicates vascular wall calcification.	Day60,Day90,Day120,Day180
Percentage of patients who underwent revascularization (open surgery or interventional therapy) had a large amputation rate and mortality	Day180, percentage of patients undergoing revascularization (open surgery or interventional therapy) major amputation rate mortality.	Day180

Collaborators and Investigators

• Sponsor: Beijing Northland Biotech. Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2019
• Primary Completion (Anticipated): October 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: January 18, 2020
• First Submitted That Met QC Criteria: February 16, 2020
• First Posted (Actual): February 19, 2020

Study Record Updates

• Last Update Posted (Actual): March 31, 2022
• Last Update Submitted That Met QC Criteria: March 29, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Critical Limb Ischemia; HGF; Gene
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Arteriosclerosis; Atherosclerosis; Vascular Diseases; Ischemia; Peripheral Arterial Disease; Peripheral Vascular Diseases; Arterial Occlusive Diseases
• Other Study ID Numbers: NL003-CLI-III-1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No