Arterial Occlusive DiseasePhase 3NCT04274049
Safety and Efficacy Study Using Gene Therapy for Critical Limb Ischemia (NL003-CLI-III-2)
A Phase 3 study testing NL003 and Normal Saline in people with Arterial Occlusive Disease and Ischemia, run by Beijing Northland Biotech. Co., Ltd. at 21 sites in China.
Trial 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 Read more about this study
- Who is it for?
- Ages 20 to 80 years
- Conditions the study is for
- Arterial Occlusive Disease, Ischemia, Ulcers
- What is being tested?
- NL003 and Normal Saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 242 participants
- Where
- 21 sitesChina
- Study dates
- 28 Aug 2019to 23 Dec 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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).
Show all 19Show fewer
- 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.
Trial locations and contacts
21 sites in 1 country.
21 sites in 1 country
China21 sites
Affiliated Hospital of Inner Mongolia Medical University
Baotou, Neimenggu
Peking Union Medical College Hospital
Beijing, Beijing Municipality, 100032
The First Affiliated Hospital of Zhengzhou University
Changchun, Jilin
The Second Xiangya Hospital of Central South University
Changsha, Hunan, 410000
The Third Xiangya Hospital of Central South University
Changsha, Hunan, 410000
Chifeng Municipal Hospital
Chifeng, Neimenggu, 024000
Second Affiliated Hospital of Chongqing Medical University
Chongqing, Chongqing Municipality
zhongshan Hospital Affiliated of Dalian University
Dalian
The First Affiliated Hospital，Zhejiang University School of Medicine
Hangzhou, Zhejiang
Affiliated Hospital of Shandong University of Traditional Chinese Medicine
Jinan, Shandong
The Affiliated Hospital of Qingdao University
Qingdao, Shandong, 266003
Qingdao Hiser Hospital Affiliated of Qingdao University（Qingdao Traditional Chinese Medicine Hospital）
Qingdao, Shandong
Fudan University Affiliated Pudong Medical Center
Shanghai, Shanghai Municipality
Shanghai 9th People's Hospital Affiliated to Shanghai JiaoTong University, School of Medicine;
Shanghai, Shanghai Municipality
Shanxi Provincial People's Hospital
Taiyuan, Shanxi, 030012
The First Affiliated Hospital of Wenzhou Medical University
Wenzhou, Zhejiang
Zhongshan Hospital Xiamen University
Xiamen, Fujian
First Affiliated Hospital of Xi 'an Jiaotong University
XiAn, Shanxi, 710061
Xuzhou Mining Group General Hospital
Xuzhou, Jiangsu, 221006
Zhangzhou Municipal Hospital of Fujian Province
Zhangzhou, Fujian, 363000
The First Affiliated Hospital of Zhengzhou University
Zhengzhou, Henan
About this study
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 5）
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
Read the 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.
- Being tested
- NL003, Normal Saline
- Keywords
- HGF, Gene, Critical Limb Ischemia
- Medical subject headings
- Arterial Occlusive Diseases, Ischemia, Ulcer, Peripheral Vascular Diseases, Chronic Limb-Threatening Ischemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NL003Genetic
Also called HGF plasmid, pCK-HGF-X7
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)
Normal SalineOther
Also called 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 )
| Study group | Role | What they receive |
|---|---|---|
| investigational produc | Experimental | Patients in this treatment group will receive 8mg NL003 respective in D0、14、28 Receives: Genetic: NL003 |
| Placebo | Placebo comparator | Patients in this group will receive normal saline respective in D0、14、18 Receives: Other: Normal Saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of ulcer complete healing
1.At D180 visit, subjects intended to observe the healing of all arterial ischemic ulcers in the limb;2.Ulcer healing criteria: skin epidermal cell regeneration without secretion.
Measured: Day180
Secondary outcomes (10)
The time when the ulcer finally heals completely
The time between the first use of the study drug and the final full healing of the ulcer.
Measured: Day14,Day28,Day60,Day90,Day120,Day180
Percentage of cases with ulcer area reduced by ≥50% from baseline
The ulcer area at the last visit was 50% less than the baseline case percentage.
Measured: Day180
Percentage of new ulcer or gangrene cases
The percentage of new ulcer or gangrene cases after use of the study drug.
Measured: Day14,Day28,Day60,Day90,Day120,Day180
Rate of complete disappearance of pain
Rate of complete disappearance of pain.
Measured: Day180
Percentage of cases with a 50% reduction in pain score from baseline
A 50% reduction in pain score from baseline at the last visit.
Measured: Day180
Changes in pain score from baseline
The severity of critical Limb ischemia was assessed by Rutherford grading at screening, D14, D28, D60, D90, and D180, respectively.
Measured: Day14,Day28,Day60,Day90,Day120,Day180
Changes in quality of life scores from baseline
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.
Measured: Day14,Day28,Day60,Day90,Day120,Day180
Changes in Rutherford grading from baseline
The severity of critical Limb ischemia was assessed by Rutherford grading at screening, D14, D28, D60, D90, and D180, respectively.
Measured: Day14,Day28,Day60,Day90,Day120,Day180
Changes to the ABI from the baseline
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).
Measured: Day60,Day90,Day120,Day180
The percentage of patients who undergo revascularization (open surgery or interventional therapy) has a high amputation rate of mortality
The percentage of patients who undergo revascularization (open surgery or interventional therapy) has a high amputation rate of mortality.
Measured: Day180
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Feb 2020
- Study start28 Aug 2019
- Primary completion23 Dec 2023
- Study completion23 Dec 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Arterial Occlusive DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 242 participants (actual)
Sponsor and investigators
- Lead sponsor
- Beijing Northland Biotech. Co., Ltd.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Changwei Liu, MD, Principal investigator, Peking Union Medical College Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04274049
- Sponsor's protocol ID
- NL003-CLI-III-2
- Other IDs
- CTR20190750
- Status last verified
- Sep 2024
- First submitted
- 18 Jan 2020
- Last updated
- 20 Sep 2024
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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 5）
- ClinicalTrials.gov ID
- NCT04274049
- Acronym / sponsor ID
- NL003-CLI-III-2
- Keywords
- HGF, Gene, Critical Limb Ischemia
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 242 participants (actual)
- Lead sponsor
- Beijing Northland Biotech. Co., Ltd.Industry (pharma, biotech, devices)
- Study start
- 28 Aug 2019 (actual)
- Primary completion
- 23 Dec 2023 (actual)
- Study completion
- 23 Dec 2023 (actual)
- First posted
- 18 Feb 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| investigational produc | Experimental | Genetic: NL003Patients in this treatment group will receive 8mg NL003 respective in D0、14、28 |
| Placebo | Placebo comparator | Other: Normal SalinePatients in this group will receive normal saline respective in D0、14、18 |
Who may qualify
- Ages
- 20 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (19 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NL003Also: HGF plasmid, pCK-HGF-X7Day 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) | Genetic | investigational produc |
| Normal SalineAlso: PlaceboDay 0: 16ml of Normal Saline (32 injections ) Day 14: 16ml of Normal Saline (32 injections ) Day 28: 16ml of Normal Saline (32 injections ) | Other | Placebo |
Primary outcome
Percentage of ulcer complete healing
Time frame: Day180
1.At D180 visit, subjects intended to observe the healing of all arterial ischemic ulcers in the limb;2.Ulcer healing criteria: skin epidermal cell regeneration without secretion.
10 secondary outcomes
The time when the ulcer finally heals completely
Time frame: Day14,Day28,Day60,Day90,Day120,Day180
Percentage of cases with ulcer area reduced by ≥50% from baseline
Time frame: Day180
Percentage of new ulcer or gangrene cases
Time frame: Day14,Day28,Day60,Day90,Day120,Day180
Rate of complete disappearance of pain
Time frame: Day180
Percentage of cases with a 50% reduction in pain score from baseline
Time frame: Day180
Changes in pain score from baseline
Time frame: Day14,Day28,Day60,Day90,Day120,Day180
Changes in quality of life scores from baseline
Time frame: Day14,Day28,Day60,Day90,Day120,Day180
Changes in Rutherford grading from baseline
Time frame: Day14,Day28,Day60,Day90,Day120,Day180
Changes to the ABI from the baseline
Time frame: Day60,Day90,Day120,Day180
The percentage of patients who undergo revascularization (open surgery or interventional therapy) has a high amputation rate of mortality
Time frame: Day180
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Sep 2024.
Related trials for Arterial Occlusive Disease
Recruiting
Efficacy and Safety of Ischemic Preconditioning Therapy Versus Optimal Medical Therapy in Reducing the Recurrence of Ischemic Events in Symptomatic Moyamoya Disease
Moya Moya Disease, Moyamoya Syndrome
Not yet recruiting
Healthy Adults Aged 18-55, Three Ukrainian Windlass Tourniquets (SICH, DNIPRO GEN 2, PULS) Compared With CAT Gen 7, and Complete Limb Arterial Occlusion Confirmed by Doppler.
Hemorrhage, Healthy Volunteers
Recruiting
Multivessel Balloon Occlusion to Investigate Obstructive Coronary Artery Disease and aNgina
Stable Angina, Multivessel Coronary Artery Disease
Not yet recruitingObservational study
The GEIR Registry: Rationale and Design of the First Nationwide Multicentre Retinal Stroke Registry in Spain
Retinal Artery Occlusion
Not yet recruitingPhase 1
A Bioequivalence and Safety Study of AJU-B718 and B718R in Healthy Adult Volunteers Under Fasting Conditions
Peripheral Arterial Disease
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Changwei Liu, MD principal investigator
Peking Union Medical College Hospital
21 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing NL003 and Normal Saline in people with Arterial Occlusive Disease and Ischemia, run by Beijing Northland Biotech. Co., Ltd. at 21 sites in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 21 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of ulcer complete healing (time frame: Day180). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Sep 2024.