Safety and Efficacy Study Using Gene Therapy for Critical Limb Ischemia (NL003-CLI-III-2)

NCT ID: NCT04274049

Last Updated: 2024-09-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 242 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-28
• Study Completion Date: 2023-12-23

Brief Summary

The purpose of this study is to evaluate whether intramuscular injections of NL003 into the calf is safe and effective in the treatment of critical limb ischemia

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.

Conditions

Arterial Occlusive Disease; Ischemia; Ulcers; Peripheral Vascular Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

investigational produc

Patients in this treatment group will receive 8mg NL003 respective in D0、14、28

Group Type: EXPERIMENTAL

NL003

Intervention Type: GENETIC

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)

Placebo

Patients in this group will receive normal saline respective in D0、14、18

Group Type: PLACEBO_COMPARATOR

Normal Saline

Intervention Type: OTHER

Day 0: 16ml of Normal Saline (32 injections ) Day 14: 16ml of Normal Saline (32 injections ) Day 28: 16ml of Normal Saline (32 injections )

Interventions

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)

Intervention Type: GENETIC

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 )

Intervention Type: OTHER

Other Intervention Names

HGF plasmid; pCK-HGF-X7; Placebo

Eligibility Criteria

Inclusion Criteria

• 1. At the age of 20 and 80 (at the time of signing the informed consent), both male and female.

2. According to DSA or CTA, patients diagnosed with lower limb arterial ischemic disease based on the medical history and clinical manifestations and with Rutherford grade 5 (with ulcer) must meet the substandardProspective.(if both limbs of the subject suffer from lower limb arterial ischemic disease, it is up to the investigator to select 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. Patients with chronic lower limb arterial ischemia complicated with ulceration also met the following requirements: when signing the informed consent, the ischemic ulcer of the artery lasted at least 2 weeks;When signing the informed consent, the area of a single ulcer is no more than 10cm2;If there are multiple ulcers in the affected limb selected at the time of signing the informed consent, the total number of ulcers shall not exceed 3.Basic ulcer care (according to standard ulcer care procedure) should be maintained during the test to avoid aggravation of infection.The ulcer did not expose bone or joint capsule.If there is gangrene, only partial toe gangrene.

4. Agreed to use the basic treatment drugs as required during the test, and kept a complete record of the subjects' diaries on time. The compliance of the basic treatment drugs and the subjects' diaries 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 the surgical operation, the patient was still in the postoperative risk period, and the researcher judged that it was not suitable for the participant.

4. Main-iliac artery stenosis ≥70%.

5. Severe limb infection (cellulitis, osteomyelitis, etc.), distal fascia or bone exposure were observed.

6. Cardiac function NYHA class belongs to Ⅳ grading standards (see appendix 1).

7. Cerebral infarction, cerebral hemorrhage, myocardial infarction or unstable angina pectoris occurred within 3 months before signing the informed consent.

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

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 < 3.0×109/L, platelet < 75×109/L, upper limit of normal AST or ALT >, upper limit of normal serum creatinine > was 3 times, or other laboratory examination indicators showed abnormalities that researchers thought might affect the evaluation of test results.

15. Poor blood glucose control after treatment (glycosylated hemoglobin > 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, ca-125;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 those 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.

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Beijing Northland Biotech. Co., Ltd.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Changwei Liu, MD

Role: PRINCIPAL_INVESTIGATOR

Peking Union Medical College Hospital

Locations

Peking Union Medical College Hospital

Beijing, Beijing Municipality, China

Second Affiliated Hospital of Chongqing Medical University

Chongqing, Chongqing Municipality, China

Zhongshan Hospital Xiamen University

Xiamen, Fujian, China

Zhangzhou Municipal Hospital of Fujian Province

Zhangzhou, Fujian, China

The First Affiliated Hospital of Zhengzhou University

Zhengzhou, Henan, China

The Second Xiangya Hospital of Central South University

Changsha, Hunan, China

The Third Xiangya Hospital of Central South University

Changsha, Hunan, China

Xuzhou Mining Group General Hospital

Xuzhou, Jiangsu, China

The First Affiliated Hospital of Zhengzhou University

Changchun, Jilin, China

Affiliated Hospital of Inner Mongolia Medical University

Baotou, Neimenggu, China

Chifeng Municipal Hospital

Chifeng, Neimenggu, China

Affiliated Hospital of Shandong University of Traditional Chinese Medicine

Jinan, Shandong, China

The Affiliated Hospital of Qingdao University

Qingdao, Shandong, China

Qingdao Hiser Hospital Affiliated of Qingdao University（Qingdao Traditional Chinese Medicine Hospital）

Qingdao, Shandong, China

Fudan University Affiliated Pudong Medical Center

Shanghai, Shanghai Municipality, China

Shanghai 9th People's Hospital Affiliated to Shanghai JiaoTong University, School of Medicine;

Shanghai, Shanghai Municipality, China

Shanxi Provincial People's Hospital

Taiyuan, Shanxi, China

First Affiliated Hospital of Xi 'an Jiaotong University

XiAn, Shanxi, China

The First Affiliated Hospital，Zhejiang University School of Medicine

Hangzhou, Zhejiang, China

The First Affiliated Hospital of Wenzhou Medical University

Wenzhou, Zhejiang, China

zhongshan Hospital Affiliated of Dalian University

Dalian, , China

Countries

China

Other Identifiers

CTR20190750

Identifier Type: OTHER

Identifier Source: secondary_id

NL003-CLI-III-2

Identifier Type: -

Identifier Source: org_study_id