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Efficacy and Safety of Liraglutide in Type 2 Diabetes With Lower Extremity Arterial Disease

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ClinicalTrials.gov Identifier: NCT04146155
Recruitment Status : Recruiting
First Posted : October 31, 2019
Last Update Posted : July 7, 2021
Sponsor:
Information provided by (Responsible Party):
Second Affiliated Hospital, School of Medicine, Zhejiang University

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.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Peripheral Vascular Disorder Due to Diabetes Mellitus Drug: Liraglutide+standard-of-care treatment Other: standard-of-care treatment Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
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
Actual Study Start Date : May 1, 2020
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Liraglutide

Arm Intervention/treatment
Experimental: Liraglutide+standard-of-care treatment
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.
Drug: Liraglutide+standard-of-care treatment

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.

Other Name: Victoza

Active Comparator: standard-of-care treatment
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.
Other: standard-of-care treatment
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 Measures :
  1. Initial and absolute claudication distance [ Time Frame: 24 weeks ]
    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 :
  1. Assess the effects on ABI of a six month treatment with Liraglutide compared to control group (standard-of-care treatment). [ Time Frame: 24 weeks ]
    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.

  2. Assess the effects on endothelial function of a six month treatment with Liraglutide compared to control group (standard-of-care treatment). [ Time Frame: 24 weeks ]
    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.

  3. Muscle microvascular perfusion by CEU [ Time Frame: 24 weeks ]
    Contrast enhanced ultrasound (CEU) performed by experienced radiologists is used for contrast ultrasonographic examination of skeletal muscle.

  4. 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). [ Time Frame: 24 weeks ]
    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.

  5. Changes from baseline in HbA1c [ Time Frame: 24 weeks ]
    Change from baseline to last assessment during the treatment period in HbA1c



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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04146155


Contacts
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Contact: Chao Zheng, MD, PhD 8615057585907 wallbb_1022@163.com

Locations
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China, Zhejiang
The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Recruiting
Wenzhou, Zhejiang, China, 325000
Contact: Youjin Pan, MD.    86057788002723    526623800@qq.com   
Contact: Mengte Shi, MD.    86057788002713    smt198853@163.com   
Sponsors and Collaborators
Second Affiliated Hospital, School of Medicine, Zhejiang University
Investigators
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Principal Investigator: Chao Zheng, MD,PhD the Second Affiliated Hospital Zhejiang University Schoolof Medicine
Principal Investigator: Youjin Pan, MD. Second Affiliated Hospital of Wenzhou Medical University
Principal Investigator: Xia Li, MD,PhD Central South University
Principal Investigator: Li Li, MD. Ningbo Hospital of Zhejiang University
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Second Affiliated Hospital, School of Medicine, Zhejiang University
ClinicalTrials.gov Identifier: NCT04146155    
Other Study ID Numbers: zhengchao
First Posted: October 31, 2019    Key Record Dates
Last Update Posted: July 7, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Second Affiliated Hospital, School of Medicine, Zhejiang University:
Glucagon-like peptide-1
Claudication
Peripheral vascular disease
Additional relevant MeSH terms:
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Vascular Diseases
Peripheral Vascular Diseases
Peripheral Arterial Disease
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Cardiovascular Diseases
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Liraglutide
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists