Angiogenesis and Blood Perfusion Effect of HGF Gene Therapy in PAD Patients

Sponsor

Beijing Northland Biotech. Co., Ltd. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05968118

Collaborator

(none)

Enrollment

Location

Arms

15.1

Anticipated Duration (Months)

2.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate whether PET/CT-RGD or MIBI can be used for the angiogenesis assessment of NL003 in PAD patients.

Condition or Disease	Intervention/Treatment	Phase
Peripheral Artery Disease	Drug: NL003 Drug: Placebo	Phase 3

Detailed Description

Hepatocyte growth factor (HGF) gene therapy has been shown to be a potential choice for CLI patients without surgical option. 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. Animal studies showed that NL003 inducing angiogenesis in the affected limb and result in an increase in tissue perfusion. Our previous phase II clinical trial has suggested the successful limb-salvaging capacity of NL003 in treatment of patients with CLTI.

In this study we will use 68Ga RGD PET/CT and 99mTc MIBI SPECT imaging methods to evaluate the effect of NL003 on angiogenesis and lower limb blood flow perfusion during the treatment of chronic lower limb ischemia, and evaluated the effectiveness and safety of the drug. The subjects will be randomly divided into the investigational drug group and the placebo group in a 1:1 ratio. NL003 or placebo will be injected into the muscle of the affected limb on D0, D14 and D28, 0.5mg/0.5mL/site, total 8mg, 32 sites. PET/CT will be measured on D14, D42 before drug administration, MIBI SPECT imaging will be collected on D60.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

36 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Double-Blind, Randomized, Placebo-Controlled, Single Center Study to Assess the Angiogenesis and Blood Perfusion Effect of NL003 in Patients With Critical Limb Ischemia by PETCT-RGD and MIBI

Actual Study Start Date :

Jul 29, 2022

Anticipated Primary Completion Date :

Jul 31, 2023

Anticipated Study Completion Date :

Oct 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: investigational product Patients in this treatment group will receive 8mg NL003 respective in D0、14、28	Drug: 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、28	Drug: Placebo 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 Name: Placebo Other Names: Normal Saline

Arm

Intervention/Treatment

Experimental: investigational product

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

Drug: 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、28

Drug: Placebo

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 Name: Placebo

Other Names:

Normal Saline

Outcome Measures

Primary Outcome Measures

Changes of the new blood vessels number [Day 14、Day 42]
changes in the number of new blood vessels measured by PETCT-RGD on D14 and D42, compare with that of the baseline.
Changes of local blood perfusion [Day 60]
the changes of local blood perfusion measured by MIBI on D60, compare with that of baseline.

Secondary Outcome Measures

Changes to the ABI from the baseline [Day 60]
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).
Laser Speckle Imaging changes in blood flow from the baseline [Day 60]
Laser Speckle Imaging changes in blood flow from the baseline was measured on D60.
Changes of pain score from the baseline [Day 14、Day 28、Day 42、Day 60、Day 90]
The severity of critical Limb ischemia was assessed by Rutherford grading at screening、D14、D28、D42、D60、D90
Gangrene /Ulcer changes from the baseline [Day 14、Day 28、Day 42、Day 60、Day 90]
Changes in the area of ulcer or gangrene from baseline after use of the study drug
Changes in quality of life scores from baseline [Day 60]
The quality of life score questionnaire 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

18-80 years, diagnosed with chronic lower limb ischemia;
According to DSA or CTA，severe stenosis (≥70%) or occlusion of one or more branches of superficial femoral artery, popliteal artery, anterior tibial artery, posterior tibial artery, and peroneal artery.
Patients with obvious symptoms of lower limb ischemia, including severe claudication, resting pain, ulcers, or gangrene.
Agree to use appropriate contraceptive methods during the trial; Female subjects of reproductive age, blood pregnancy test negative.
Signing the informed consent.
Can complete PETCT-RGD check and MIBI check;

Exclusion Criteria:

The foot or lower limb infection cannot be controlled, and amputation may be accepted within 3 months.
Those with cerebral infarction, cerebral hemorrhage, heart failure, unstable angina, acute myocardial infarction, and serious arrhythmia within 3 months;
Tumor patients diagnosed with malignant tumor or suspected of having malignant tumor after tumor screening;
Main iliac artery stenosis ≥ 70%;
Refractory hypertension (taking three or more antihypertensive drugs, systolic blood pressure ≥ 180mmHg or diastolic blood pressure ≥ 110mmHg);
Anti HIV antibody positive person, anti hepatitis C antibody positive person and RNA positive person, hepatitis B surface antigen positive person (if the subject is HBsAg positive, and judging by peripheral blood HBV DNA, the researcher believes that the subject is in a stable period of chronic hepatitis B, which will not increase the risk of the subject, the subject can be selected)
Patients with poor blood glucose control after treatment (HbA1c>10%);
Persons allergic to contrast medium
The investigator believes that the patient's complications affect the evaluation of safety and effectiveness, or the expected survival period is less than 12 months;
Those who regularly drink more than 14 units of alcohol (1 unit=360 mL beer or 45 mL liquor or 150 mL wine with 40% alcohol) or drug abusers within 12 months before signing the informed consent form;
Acute lower limb ischemia or acute aggravation of chronic lower limb ischemia;
Those who received vascular reconstruction of the affected limb within 4 weeks before the informed consent form and whose blood supply improved after the operation
Serious liver or kidney disease or severe anemia judged by the investigator;
Those who cannot correctly describe symptoms and emotions;
Those who participated in other clinical trials within 3 months before signing the informed consent form.