Tissue Kallikrein Preventing the Restenosis After Stenting of Symptomatic MCA Atherosclerotic Stenosis

The study aims to determine whether tissue kallikrein (TK) is efficacy for preventing the long-term in-stent restenosis (ISR) after stenting of symptomatic atherosclerotic stenosis of the middle cerebral artery (MCA) M1 segment

Study Overview

• Status: Unknown
• Conditions: Cerebrovascular Disease
• Intervention / Treatment: Drug: tissue kallikrein

Detailed Description

A series of studies have confirmed the kallikrein-kinin system (KKS), including kallikrein, kininogen and kinin, plays an important role in the regulation of inflammation secondary to acute and chronic ischemic brain injury. Some researchers found that hTK gene delivery can inhibit the formation of neointimal induced by the common carotid artery ligation in mice. Further study revealed hTK gene transfection in VSMC lead to increased secretion of TK and inhibition of VSMC proliferation. In addition, it was also observed that the serum TK levels were coincident with the carotid artery stenosis. The more severe the stenosis is, the higher the serum TK level is, and the serum TK decreased after carotid artery angioplasty and stent placement. These results suggest that KKS play an important regulatory role in vascular remodeling and TK may exert a beneficial influence in the process of ISR

• Study Type: Interventional
• Enrollment (Anticipated): 99
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Recruiting
      • Department of Neurology, Jinling Hospital, Nanjing University School of Medicine
      • Contact: Renliang Zhang, MD; Phone Number: + 86-25-8480386; Email: zhangrenliang@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. TIA or stroke in the MCA territory refractory to aggressive anti-platelet and regular statin therapy in 3 months
2. Symptomatic MCA M1 segment stenosis ≥ 70% confirmed with DSA
3. Successfully treated with PTAS without acute surgical complications in 12 hours after operation
4. All patients provided fully informed consent

Exclusion Criteria:

1. Using angiotensin-converting enzyme inhibitors
2. Severe cardiopulmonary dysfunction, chronic liver disease (A / G inversion, ALT increased 2-fold greater than normal), abnormal renal function (serum creatinine greater than 1.5 times normal)
3. Allergies, the history of allergy to multi-drug
4. The history of cerebral hemorrhage, brain tumors, brain trauma, cerebral embolism and other brain lesions
5. During pregnancy or breast-feeding
6. Not expected to complete follow-up

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Tissue kallikrein group; Patients in this group will be prescribed with intravenous infusion of TK (0.15 PNAU/d, dissolved in 100ml saline) for 7 days after stenting and then oral administration of pancreatic kallikrein enteric-coated tablet (240U, 3/d) to the end of study. As the foundation treatment, all the enrolled patients will receive aspirin (100 mg/d), clopidogrel (75 mg/d), and atorvastatin (20 mg/d) for the first 6 months and continue with the combination of aspirin and atorvastatin at the previous dosage.	Drug: tissue kallikrein; Human urinary kallidinogenase can transform kininogen to bradykinin (kinin) and vasodilatory factors (kallidin); Other Names: Human urinary kallidinogenase (HUK)
NO_INTERVENTION: Control group; Patients in control group will receive foundation treatment, including aspirin (100 mg/d), clopidogrel (75 mg/d), and atorvastatin (20 mg/d) for the first 6 months and continue with the combination of aspirin and atorvastatin at the previous dosage.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Target lesion failure	Patients will be evaluated at 1 month, 6 months, and 12 months after the stenting. The primary outcomes are the asymptomatic or symptomatic in-stent restenosis ≥ 50% (affirmed by digital subtraction angiography at 6 and 12 months), new stroke (ischemic and hemorrhagic) or aggravation of the previous ischemic stroke ipsilateral to the severe stenotic artery.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical endpoint	Stroke of other artery territories, myocardial infarction and vascular death will be conducted in-hospital and planned at 1 month, 6 months, and 12 months.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Laboratory data	Laboratory data including bradykinin (BK), TK, platelet inhibitory rate, cGMP, cAMP, hs-CRP, TNF-α, IL-6, LDL-Ch and HDL-Ch will be recorded	12 months

Collaborators and Investigators

• Sponsor: Jinling Hospital, China
• Investigators: Principal Investigator: Renliang Zhang, MD, Department of Neurology, Jinling Hospital, Nanjing University School of Medicine

Publications and helpful links

General Publications

• Shi R, Zhang R, Yang F, Lin M, Li M, Liu L, Yin Q, Lin H, Xiong Y, Liu W, Fan X, Dai Q, Zhou L, Lan W, Cao Q, Chen X, Xu G, Liu X. Tissue Kallikrein Prevents Restenosis After Stenting of Severe Atherosclerotic Stenosis of the Middle Cerebral Artery: A Randomized Controlled Trial. Medicine (Baltimore). 2016 Feb;95(6):e2809. doi: 10.1097/MD.0000000000002809.
• Lan W, Yang F, Liu L, Yin Q, Li M, Li Z, Sang H, Xu G, Ma M, Zhang Z, Liu Z, Liu X, Zhang R. Tissue kallikrein preventing the restenosis after stenting of symptomatic MCA atherosclerotic stenosis (KPRASS). Int J Stroke. 2014 Jun;9(4):533-5. doi: 10.1111/ijs.12229. Epub 2013 Dec 20.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (ANTICIPATED): December 1, 2013
• Study Completion (ANTICIPATED): December 1, 2013

Study Registration Dates

• First Submitted: December 14, 2011
• First Submitted That Met QC Criteria: March 16, 2012
• First Posted (ESTIMATE): March 20, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): September 12, 2013
• Last Update Submitted That Met QC Criteria: September 11, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Keywords: ischemic stroke; in-stent restenosis; tissue kallikrein;; the middle cerebral artery; atherosclerotic stenosis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathological Conditions, Anatomical; Constriction, Pathologic; Cerebrovascular Disorders; Physiological Effects of Drugs; Coagulants; Reproductive Control Agents; Fertility Agents; Fertility Agents, Male; Kallikreins
• Other Study ID Numbers: KPRASS