Back to resultsEfficacy and Safety of Liraglutide in Type 2 Diabetes With Lower Extremity Arterial Disease
Primary Purpose
Type 2 Diabetes, Peripheral Vascular Disorder Due to Diabetes Mellitus
Status
Unknown status
Phase
Phase 4
Locations
China
Study Type
Interventional
Intervention
Liraglutide+standard-of-care treatment
standard-of-care treatment
Sponsored by
About this trial
This is an interventional treatment trial for Type 2 Diabetes focused on measuring Glucagon-like peptide-1, Claudication, Peripheral vascular disease
Eligibility Criteria
Inclusion Criteria:
- Informed consent
- type 2 diabetes (1999 WHO criteria)
- 7.5≤HbA1c ≤14%
- Age > 40 years
- lower extremity PAD with symptom
- Absence of distal arterial pulse.
- ABI less than 0.9 or the value decreased by more than 15% after treadmill test.
- Presence of stenosis or occlusion of lower extremity arteries as determined by Duplex ultrasound imaging or lower extremity CTA; or lower extremity DSA(Digital Substraction Angiography).
Exclusion Criteria:
- Type 1 diabetes
Other Concomitant illness:
1) poorly controlled hypertension: >160 mmHg systolic blood pressure and/or>100 mmHg diastolic blood pressure (with or without long-term oral antihypertensive drugs); 2) Chronic heart failure NYHA class (III-IV); 3) An acute coronary or cerebro-vascular event within the previous 6 months; 4) hematological malignancies such as acute or chronic myeloid leukemia, or any other hematological disorders that would interfere with the determination of circulating EPC levels; 5) Personal history of non-familial medullary thyroid carcinoma; 6) Immunological disorders such as lupus, psoriasis, scleroderma and rheumatoid arthritis which would interfere with the determination of circulating EPC levels; 7) Chronic haemodialysis or chronic peritoneal dialysis; 8) End stage liver disease, presence of acute or chronic liver disease or recent history of the following: ALT level ≥ 3 times the upper limit of normal, or AST level ≥ 3 times the upper limit of normal; 9) Severe gastrointestinal diseases, such as gastrointestinal ulcer, gastrointestinal bleeding, pyloric stenosis, gastric bypass surgery; 10) History of chronic pancreatitis or idiopathic acute pancreatitis; 11) Any acute condition or exacerbation of chronic condition that would in the Investigator's opinion interfere with the initial trial visit schedule and procedures; 12) Inability to walk on a tredamill without grade at a speed of at least 3.2 km/h for at least 2 minutes.
- Drugs: 1) Known or suspected hypersensitivity to trial products or related products ; 2) Use of GLP-1 receptor agonist (exenatide (BID or OW), liraglutide, or other) within 6 months prior to screening; 3).Alcohol or drugs abuse.
- 4. Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (eg diabetes ketoacidosis) within 90 days prior to screening.
- Recent (within 6 months) surgery or trauma.
- Pregnancy and lactation.
- Psychiatric disorders
- Simultaneous participation in any other clinical trial of an investigational agent.
Sites / Locations
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Liraglutide+standard-of-care treatment
standard-of-care treatment
Arm Description
Intervention: Liraglutide is added to existing standard-of-care treatment containing one or more oral anti-hyperglycemic agents or insulin or a combination of these agents with the exception of other incretin and SGLT2i therapies.
standard-of-care treatment with the exception of incretin and SGLT2i therapies. This approach expect to yield similar glycemic control in the two study groups.
Outcomes
Primary Outcome Measures
Initial and absolute claudication distance
The primary outcome measures used to assess efficacy were pain-free walking distance (distance walked to the onset of symptoms, or the initial claudication distance [ICD]) and the maximum distance walked (absolute claudication distance [ACD]) on standardized treadmill testing. Evaluation of walking performance was accomplished with standardized treadmill testing. A constant speed of 3.2 km/h (2mile/h) and a fixed incline of 12.5% were used.
Secondary Outcome Measures
Assess the effects on ABI of a six month treatment with Liraglutide compared to control group (standard-of-care treatment).
ankle-brachial index is ratio of ankle systolic pressure to arm systolic pressure: using a 10-12 cm sphygmomanometer cuff placed just above the ankle and a doppler instrument used to measure the systolic pressure of the posterior tibial and dorsalis pedis arteries of each leg. These pressures are then normalized to the higher brachial pressure of either arm to form the ankle-brachial index (ABI). The index leg is often defined as the leg with the lower ABI.
Assess the effects on endothelial function of a six month treatment with Liraglutide compared to control group (standard-of-care treatment).
Assess the effects on endothelial function of a six month treatment with Liraglutide compared to conventional treatment, assessed as the baseline corrected change in endothelial function by flow-mediated vasodilation (FMD) of the brachial artery at 6 months.
Muscle microvascular perfusion by CEU
Contrast enhanced ultrasound (CEU) performed by experienced radiologists is used for contrast ultrasonographic examination of skeletal muscle.
Assess the effects on the endothelial circulating progenitor cells concentration of a six month treatment with Liraglutide compared to control group (standard-of-care treatment).
Circulating progenitor cells (EPCs) will be quantified using flow cytometry before and after 6 month treatment GLP-1 receptor agonist or conventional therapy (control group). Briefly, after erythrocyte lysis, peripheral blood will be stained with 10µL fluorescein isothiocyanate-conjugated anti-human CD34 mAb, 10µL phycoethrin-conjugated anti-human KDR mAb, and 10µL allophycocyanin-conjugated anti-CD133 mAb.
Changes from baseline in HbA1c
Change from baseline to last assessment during the treatment period in HbA1c
Full Information
NCT ID
NCT04146155
First Posted
October 16, 2019
Last Updated
June 30, 2021
Sponsor
Second Affiliated Hospital, School of Medicine, Zhejiang University
1. Study Identification
Unique Protocol Identification Number
NCT04146155
Brief Title
Efficacy and Safety of Liraglutide in Type 2 Diabetes With Lower Extremity Arterial Disease
Official Title
Liraglutide Efficacy and Action on Type 2 Diabetes With Peripheral Atherosclerotic intErmittent Claudication (LEADPACE STUDY): a Prospective, 24-week, Multicenter, Randomized, Controlled Clinical Study
Study Type
Interventional
2. Study Status
Record Verification Date
June 2021
Overall Recruitment Status
Unknown status
Study Start Date
May 1, 2020 (Actual)
Primary Completion Date
December 31, 2021 (Anticipated)
Study Completion Date
December 31, 2021 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Second Affiliated Hospital, School of Medicine, Zhejiang University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Diabetic lower extremity arterial disease ( DLEAD ), is a common complication of type 2 diabetes. However, DLEAD remains less studied than other diabetic vascular complications; and only few randomised controlled trials (RCTs) have dealt with major lower-limb adverse events as prespecified endpoints. Studies have suggested that glucagon-like peptide-1 (GLP-1) analogues have a protective effect on the development of atherosclerosis, potentially mediated via the GLP-1 receptors expressed on endothelial cells, smooth muscle cells, and in monocytes/macrophages. The investigators aim to evaluate the improvement of lower extremity ischemia in patients with type 2 diabetes mellitus complicated with lower limb vascular lesions after liraglutide, compared with the standard-of-care treatment group.
Detailed Description
GLP-1 is an incretin hormone that mediates glucose-stimulated insulin secretion.Accumulating data from both animal and human studies confirmed a beneficial effect of GLP-1 on myocardium, endothelium and vasculature, suggesting the potential ameliorative effect of peripheral atherosclerosis. In our preliminary studies shown that liraglutide, a long-acting GLP-1R agonist (GLP1RA), stimulate endothelial proliferation and angiogenesis. The study aims to test the hypothesis that sustained activation of the GLP-1R enhances microvascular perfusion, promotes angiogenesis, leading to increased walking distance and limb perfusion in diabetes patients with peripheral arterial disease (PAD). Eligible patients will be randomized 1:1 to with or without liraglutide treatment by a 6-month follow-up. The primary endpoints are the change in initial and absolute claudication distance and assessment of limb ischemia at 6 months compared with baseline. This trial will collect important mechanistic and clinical information on the safety and efficacy of liraglutide in T2DM patients with PAD.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes, Peripheral Vascular Disorder Due to Diabetes Mellitus
Keywords
Glucagon-like peptide-1, Claudication, Peripheral vascular disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
200 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Liraglutide+standard-of-care treatment
Arm Type
Experimental
Arm Description
Intervention: Liraglutide is added to existing standard-of-care treatment containing one or more oral anti-hyperglycemic agents or insulin or a combination of these agents with the exception of other incretin and SGLT2i therapies.
Arm Title
standard-of-care treatment
Arm Type
Active Comparator
Arm Description
standard-of-care treatment with the exception of incretin and SGLT2i therapies. This approach expect to yield similar glycemic control in the two study groups.
Intervention Type
Drug
Intervention Name(s)
Liraglutide+standard-of-care treatment
Other Intervention Name(s)
Victoza
Intervention Description
Liraglutide is available if pre-filled pens (6 mg/ml) as a solution for injection (Victoza®). One ml of solution contains 6 mg of Liraglutide (human glucagon-like peptide-1 analogue produced by recombinant DNA technology in Saccharomyces cerevisiae). One pre-filled pen contains 18 mg Liraglutide in 3 ml.
Liraglutide is added to existing standard-of-care treatment containing one or more oral anti-hyperglycemic agents or insulin or a combination of these agents with the exception of other incretin and SGLT2i therapies in accordance with local clinical practice guidelines.
Intervention Type
Other
Intervention Name(s)
standard-of-care treatment
Intervention Description
Standard-of-care treatment including: metformin should be given as the first line therapy as long as it is tolerated and not contraindicated; other agents, including sulfonylureas or glucosidase inhibitor or insulin, should be added to metformin .Glycemic control will be managed by the investigators in accordance with local clinical practice guidelines by the adjustment of concomitant glucose-lowering agents or the addition of new antidiabetic medications with the exception of incretin and SGLT2i therapies. This approach expect to yield similar glycemic control in the two study groups.
Primary Outcome Measure Information:
Title
Initial and absolute claudication distance
Description
The primary outcome measures used to assess efficacy were pain-free walking distance (distance walked to the onset of symptoms, or the initial claudication distance [ICD]) and the maximum distance walked (absolute claudication distance [ACD]) on standardized treadmill testing. Evaluation of walking performance was accomplished with standardized treadmill testing. A constant speed of 3.2 km/h (2mile/h) and a fixed incline of 12.5% were used.
Time Frame
24 weeks
Secondary Outcome Measure Information:
Title
Assess the effects on ABI of a six month treatment with Liraglutide compared to control group (standard-of-care treatment).
Description
ankle-brachial index is ratio of ankle systolic pressure to arm systolic pressure: using a 10-12 cm sphygmomanometer cuff placed just above the ankle and a doppler instrument used to measure the systolic pressure of the posterior tibial and dorsalis pedis arteries of each leg. These pressures are then normalized to the higher brachial pressure of either arm to form the ankle-brachial index (ABI). The index leg is often defined as the leg with the lower ABI.
Time Frame
24 weeks
Title
Assess the effects on endothelial function of a six month treatment with Liraglutide compared to control group (standard-of-care treatment).
Description
Assess the effects on endothelial function of a six month treatment with Liraglutide compared to conventional treatment, assessed as the baseline corrected change in endothelial function by flow-mediated vasodilation (FMD) of the brachial artery at 6 months.
Time Frame
24 weeks
Title
Muscle microvascular perfusion by CEU
Description
Contrast enhanced ultrasound (CEU) performed by experienced radiologists is used for contrast ultrasonographic examination of skeletal muscle.
Time Frame
24 weeks
Title
Assess the effects on the endothelial circulating progenitor cells concentration of a six month treatment with Liraglutide compared to control group (standard-of-care treatment).
Description
Circulating progenitor cells (EPCs) will be quantified using flow cytometry before and after 6 month treatment GLP-1 receptor agonist or conventional therapy (control group). Briefly, after erythrocyte lysis, peripheral blood will be stained with 10µL fluorescein isothiocyanate-conjugated anti-human CD34 mAb, 10µL phycoethrin-conjugated anti-human KDR mAb, and 10µL allophycocyanin-conjugated anti-CD133 mAb.
Time Frame
24 weeks
Title
Changes from baseline in HbA1c
Description
Change from baseline to last assessment during the treatment period in HbA1c
Time Frame
24 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Informed consent
type 2 diabetes (1999 WHO criteria)
7.5≤HbA1c ≤14%
Age > 40 years
lower extremity PAD with symptom
Absence of distal arterial pulse.
ABI less than 0.9 or the value decreased by more than 15% after treadmill test.
Presence of stenosis or occlusion of lower extremity arteries as determined by Duplex ultrasound imaging or lower extremity CTA; or lower extremity DSA(Digital Substraction Angiography).
Exclusion Criteria:
Type 1 diabetes
Other Concomitant illness:
1) poorly controlled hypertension: >160 mmHg systolic blood pressure and/or>100 mmHg diastolic blood pressure (with or without long-term oral antihypertensive drugs); 2) Chronic heart failure NYHA class (III-IV); 3) An acute coronary or cerebro-vascular event within the previous 6 months; 4) hematological malignancies such as acute or chronic myeloid leukemia, or any other hematological disorders that would interfere with the determination of circulating EPC levels; 5) Personal history of non-familial medullary thyroid carcinoma; 6) Immunological disorders such as lupus, psoriasis, scleroderma and rheumatoid arthritis which would interfere with the determination of circulating EPC levels; 7) Chronic haemodialysis or chronic peritoneal dialysis; 8) End stage liver disease, presence of acute or chronic liver disease or recent history of the following: ALT level ≥ 3 times the upper limit of normal, or AST level ≥ 3 times the upper limit of normal; 9) Severe gastrointestinal diseases, such as gastrointestinal ulcer, gastrointestinal bleeding, pyloric stenosis, gastric bypass surgery; 10) History of chronic pancreatitis or idiopathic acute pancreatitis; 11) Any acute condition or exacerbation of chronic condition that would in the Investigator's opinion interfere with the initial trial visit schedule and procedures; 12) Inability to walk on a tredamill without grade at a speed of at least 3.2 km/h for at least 2 minutes.
Drugs: 1) Known or suspected hypersensitivity to trial products or related products ; 2) Use of GLP-1 receptor agonist (exenatide (BID or OW), liraglutide, or other) within 6 months prior to screening; 3).Alcohol or drugs abuse.
4. Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (eg diabetes ketoacidosis) within 90 days prior to screening.
Recent (within 6 months) surgery or trauma.
Pregnancy and lactation.
Psychiatric disorders
Simultaneous participation in any other clinical trial of an investigational agent.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Chao Zheng, MD, PhD
Phone
8615057585907
Email
wallbb_1022@163.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chao Zheng, MD,PhD
Organizational Affiliation
the Second Affiliated Hospital Zhejiang University Schoolof Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Youjin Pan, MD.
Organizational Affiliation
Second Affiliated Hospital of Wenzhou Medical University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Xia Li, MD,PhD
Organizational Affiliation
Central South University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Li Li, MD.
Organizational Affiliation
Ningbo Hospital of Zhejiang University
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
City
Wenzhou
State/Province
Zhejiang
ZIP/Postal Code
325000
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Youjin Pan, MD.
Phone
86057788002723
Email
526623800@qq.com
First Name & Middle Initial & Last Name & Degree
Mengte Shi, MD.
Phone
86057788002713
Email
smt198853@163.com
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
34693515
Citation
Kanie T, Mizuno A, Takaoka Y, Suzuki T, Yoneoka D, Nishikawa Y, Tam WWS, Morze J, Rynkiewicz A, Xin Y, Wu O, Providencia R, Kwong JS. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021 Oct 25;10(10):CD013650. doi: 10.1002/14651858.CD013650.pub2.
Results Reference
derived
Learn more about this trial
Efficacy and Safety of Liraglutide in Type 2 Diabetes With Lower Extremity Arterial Disease
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