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

Primary Purpose

Arterial Occlusive Disease, Ischemia, Ulcers

Status
Recruiting
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
NL003
Normal Saline
Sponsored by
Beijing Northland Biotech. Co., Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Arterial Occlusive Disease focused on measuring HGF, Gene, Critical Limb Ischemia

Eligibility Criteria

20 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Beijing HospitaiRecruiting
  • Peking Union Medical College HospitalRecruiting
  • The Ninth People's Hospital of ChongqingRecruiting
  • Zhangzhou Municipal Hospital of Fujian ProvinceRecruiting
  • The Second Xiangya Hospital of Central South UniversityRecruiting
  • The Second Xiangya Hospital of Central South University
  • The Third Xiangya Hospital of Central South UniversityRecruiting
  • Xuzhou Mining Group General HospitalRecruiting
  • Chifeng Municipal HospitalRecruiting
  • The Affiliated Hospital of Qingdao UniversityRecruiting
  • Shanghai seventh people's hospitalRecruiting
  • Shanxi Provincial People's HospitalRecruiting
  • First Affiliated Hospital of Xi 'an Jiaotong UniversityRecruiting
  • Second Affiliated Hospital of Xi 'an Jiaotong University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

investigational produc

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

The time when the pain completely goes away
The time when the pain completely goes away.
Complete pain relief rate
Day90 visit (5-7 days prior to visit, including the visit day), mean daily pain score was 0.
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).
Percent of Participants with a 50% reduction in pain score from baseline
Percent of Participants with a 50% reduction in pain score from baseline.
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.
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.
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.
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.
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.

Full Information

First Posted
January 18, 2020
Last Updated
March 29, 2022
Sponsor
Beijing Northland Biotech. Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT04275323
Brief Title
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

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 2, 2019 (Actual)
Primary Completion Date
October 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Beijing Northland Biotech. Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Arterial Occlusive Disease, Ischemia, Ulcers, Peripheral Vascular Disease
Keywords
HGF, Gene, Critical Limb Ischemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
300 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
investigational produc
Arm Type
Experimental
Arm Description
Patients in this treatment group will receive 8mg NL003 respective in D0、14、28
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients in this group will receive normal saline respective in D0、14、18
Intervention Type
Genetic
Intervention Name(s)
NL003
Other Intervention Name(s)
HGF plasmid, pCK-HGF-X7
Intervention Description
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
Other
Intervention Name(s)
Normal Saline
Other Intervention Name(s)
Placebo
Intervention Description
Day 0: 16ml of Normal Saline (32 injections ) Day 14: 16ml of Normal Saline (32 injections ) Day 28: 16ml of Normal Saline (32 injections )
Primary Outcome Measure Information:
Title
Complete pain relief rate
Description
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.
Time Frame
Day180
Secondary Outcome Measure Information:
Title
The time when the pain completely goes away
Description
The time when the pain completely goes away.
Time Frame
Day180
Title
Complete pain relief rate
Description
Day90 visit (5-7 days prior to visit, including the visit day), mean daily pain score was 0.
Time Frame
Day90
Title
Changes in site visits, pain scores after use of the study drug
Description
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).
Time Frame
Day14,Day28,Day60,Day90,Day120,Day180
Title
Percent of Participants with a 50% reduction in pain score from baseline
Description
Percent of Participants with a 50% reduction in pain score from baseline.
Time Frame
Day180
Title
The type and dose of analgesics varied from baseline
Description
The types and dosages of analgesics varied from baseline at each site after the use of the study drug.
Time Frame
Day14,Day28,Day60,Day90,Day120,Day180
Title
Changes in Rutherford grading from baseline to Day180
Description
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.
Time Frame
Day14,Day28,Day60,Day90,Day120,Day180
Title
Changes in quality of life scores from baseline to Day180
Description
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.
Time Frame
Day14,Day28,Day60,Day90,Day120,Day180
Title
Changes in the ABI from the baseline to Day180
Description
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.
Time Frame
Day60,Day90,Day120,Day180
Title
Percentage of patients who underwent revascularization (open surgery or interventional therapy) had a large amputation rate and mortality
Description
Day180, percentage of patients undergoing revascularization (open surgery or interventional therapy) major amputation rate mortality.
Time Frame
Day180

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
yue liu
Phone
+86-10-82890893
Email
liuyue@northland-bio.com
First Name & Middle Initial & Last Name or Official Title & Degree
yinjian sun
Phone
+86-10-82890893
Email
sunyinjian@northland-bio.com
Facility Information:
Facility Name
Beijing Hospitai
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100005
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yongjun LI
Facility Name
Peking Union Medical College Hospital
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100032
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
changwei liu
Facility Name
The Ninth People's Hospital of Chongqing
City
Chongqing
State/Province
Chongqing
ZIP/Postal Code
400700
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shigang Duan
Facility Name
Zhangzhou Municipal Hospital of Fujian Province
City
Zhangzhou
State/Province
Fujian
ZIP/Postal Code
363000
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mingzhi Cai
Facility Name
The Second Xiangya Hospital of Central South University
City
Changsha
State/Province
Hunan
ZIP/Postal Code
410000
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chang Shu
Facility Name
The Second Xiangya Hospital of Central South University
City
Changsha
State/Province
Hunan
ZIP/Postal Code
410000
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chang Shu
Facility Name
The Third Xiangya Hospital of Central South University
City
Changsha
State/Province
Hunan
ZIP/Postal Code
410000
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kai Yao
Facility Name
Xuzhou Mining Group General Hospital
City
Xuzhou
State/Province
Jiangsu
ZIP/Postal Code
221006
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jian Wang
Facility Name
Chifeng Municipal Hospital
City
Chifeng
State/Province
Neimenggu
ZIP/Postal Code
024000
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Liu Yang
Facility Name
The Affiliated Hospital of Qingdao University
City
Qingdao
State/Province
Shandong
ZIP/Postal Code
266003
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Haofu Wang
Facility Name
Shanghai seventh people's hospital
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200120
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bin Zhao
Facility Name
Shanxi Provincial People's Hospital
City
Taiyuan
State/Province
Shanxi
ZIP/Postal Code
030012
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Qiang Guan
Facility Name
First Affiliated Hospital of Xi 'an Jiaotong University
City
XiAn
State/Province
Shanxi
ZIP/Postal Code
710061
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shaoying Lu
Facility Name
Second Affiliated Hospital of Xi 'an Jiaotong University
City
XiAn
State/Province
Shanxi
ZIP/Postal Code
710061
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Xi Chen

12. IPD Sharing Statement

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

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