• Clinical Trial Summary

  • Trial Title:** CREATE Trial: Safety and Efficacy of IVL for Carotid Calcified Lesions
  • Sponsor:** Shanghai Bluesail Boyuan Medical Technology Co., Ltd.
  • Clinical Trial Leader:** Beijing Anzhen Hospital
  • Coordinating Investigator:** Prof. Huo Xiaochuan

• Study Purpose This trial assesses a new device-a single-use neurovascular intravascular shockwave catheter and therapy device-for treating calcified blockages in the carotid artery. It uses sound waves to break up calcium deposits, facilitating stent placement and blood flow restoration.

• Eligibility

  • Adults aged 18-80 with severe carotid artery narrowing (≥50% symptomatic or ≥70% asymptomatic) due to calcium buildup.
  • Patients who failed standard balloon dilation.
  • Exclusions include pregnancy, recent strokes/heart attacks, uncontrolled hypertension, or other high-risk conditions.

• Study Design

  • **Type:** Prospective, multicenter, single-arm trial.
  • **Sample Size:** 204 patients across multiple hospitals.
  • **Duration:** 1-month follow-up post-procedure.

• Procedures

  1. **Pre-treatment:** Imaging (CT angiography, ultrasound) to confirm eligibility.
  2. **Procedure:** Shockwave catheter breaks up calcium, followed by stent placement.
  3. **Follow-up:** Assessments at 7 days (or discharge) and 1 month post-procedure.

• Benefits and Risks

  • **Benefits:** Improved stent placement success, reduced risk of complications, minimally invasive with shorter recovery time.
  • **Risks:** Bleeding, infection, vessel damage, stroke, heart attack, device malfunction. Risks are closely monitored with emergency protocols.

• Patient Protections

  • Ethics committee approval and strict safety guidelines.
  • Voluntary participation with the option to withdraw anytime.
  • Free treatment and compensation for trial-related injuries.

• For Healthcare Providers

  • **Innovation:** Adapts coronary lithotripsy technology for carotid use.
  • **Evidence:** Supported by preclinical data and a pilot study (100% success rate in 5 patients).
  • **Endpoints:** Primary: Stent success (residual stenosis <30%) and 30-day major adverse events. Secondary: Device success rate, repeat procedures, long-term outcomes.

• Contact Information

For questions, contact:

**Ms. Zhang Yanjiao** Email: yanjiao.zhang@jwmsgrp.com

**Detailed Clinical Trial Description**

### **1. Background and Rationale** **Clinical Need:**

• **Carotid artery calcification** is a major contributor to ischemic stroke, accounting for 15-20% of cases. Severe calcification complicates stent placement, leading to high rates of residual stenosis and adverse events (e.g., stroke, myocardial infarction) with conventional treatments like balloon angioplasty.
• **Current Limitations:** Standard therapies often fail to adequately modify calcified plaques, necessitating high-pressure balloon dilation, which risks embolization, vessel dissection, or hemodynamic instability.

**Innovative Solution:**

• The **intravascular lithotripsy (IVL) system** delivers localized sonic pressure waves to fracture calcium deposits while sparing soft tissue, enabling safer stent deployment.

• **Evidence Base:** Supported by coronary IVL trials (e.g., DISRUPT CAD I-IV) and off-label carotid case reports demonstrating 90-100% technical success with minimal complications.

  ### **2. Study Objectives** **Primary Objectives:**

• **Efficacy:** Assess **surgical success rate** (stent placement with residual stenosis <30%).

• **Safety:** Evaluate **30-day major adverse events (MAE)** (composite of death, stroke, or myocardial infarction).

**Secondary Objectives:**

• Device success rate (successful delivery/retrieval of IVL catheter).

• Rates of target lesion revascularization, ipsilateral stroke, and MACCE (major adverse cardiac/cerebrovascular events).

  ### **3. Methodology** **Study Design:**

• **Prospective, multicenter, single-arm, objective performance criteria (OPC) trial.**

• **No control group** due to ethical concerns (standard therapy failure is an inclusion criterion).

**Intervention:**

1. **IVL Catheter:** Rapid-exchange balloon catheter with integrated electrodes generating sonic waves (80 pulses max per device).
2. **IVL Device:** Console delivering controlled energy pulses (compatible with 3.0-5.0 mm balloons).

**Procedure Steps:**

• **Pre-treatment:** Dual antiplatelet therapy (aspirin + clopidogrel) for ≥3 days.
• **IVL Delivery:**
• Balloon inflation to 6 atm, followed by 10 pulses/cycle (up to 8 cycles).
• Stent placement post-calcium modification.
• **Post-procedure:** Monitoring for MAE at 7 days and 1 month.

**Key Assessments:**

• **Imaging:** CT angiography (baseline), DSA (intraoperative), ultrasound (follow-up).

• **Clinical:** NIHSS/mRS scores, vital signs, lab tests (hematology, biochemistry).

  • **4. Participant Selection** **Inclusion Criteria:**

• Symptomatic (≥50%) or asymptomatic (≥70%) carotid stenosis with circumferential calcium >50% (CTA-confirmed).

• Failed conventional balloon pre-dilation (residual stenosis >70%).

• Modified Rankin Scale (mRS) score ≤2.

**Exclusion Criteria:**

• Vulnerable plaques, recent stroke/MI (within 2-12 weeks), or contraindications to antiplatelets.

• Severe comorbidities (e.g., NYHA Class IV heart failure, creatinine >2.5 mg/dL).

  ### **5. Risk Management** **Anticipated Risks:**

• **Procedure-related:** Vessel dissection (1-3%), embolic stroke (2-5%), access-site hematoma.

• **Device-related:** Balloon rupture, electrode malfunction (<1%).

**Mitigation Strategies:**

• **Embolic protection devices** mandatory.

• **Strict operator training** (≥5 supervised cases required).

• **Real-time monitoring** for hemodynamic instability (bradycardia/hypotension).

  ### **6. Statistical Plan** **Sample Size Justification:**

• **Efficacy endpoint:** 107 patients needed (95% expected vs. 85% OPC, α=0.025, power=90%).

• **Safety endpoint:** 204 patients (4.5% expected vs. 11% OPC).

• **Total:** 204 (accounting for 10% dropout).

**Analysis Populations:**

• **Full Analysis Set (FAS):** All treated patients (intent-to-treat).
• **Per-Protocol Set (PPS):** Excludes major protocol deviations.

**Statistical Tests:**

• Primary endpoints: **One-sided 95% CI** (success rate lower bound >85%; MAE upper bound <11%).

• Secondary endpoints: Descriptive statistics (rates, Kaplan-Meier survival analysis).

  ### **7. Ethical and Regulatory Compliance**

• **Ethics Approval:** Obtained from all site IRBs (reference: LFBY-202501).

• **Informed Consent:** Mandatory, with provisions for legally authorized representatives.

• **Data Protection:** Compliant with China's Personal Information Protection Law (PIPL).

  ### **8. Operational Oversight**

• **Monitoring:** Centralized EDC (Medidata Rave) with 100% source data verification.

• **Audits:** Independent DSMB reviews safety data biannually.

Inclusion Criteria:

1. Age 18-80 years (inclusive), gender unrestricted.

2. Extracranial carotid artery: Preoperative CT angiography (CTA) confirms symptomatic carotid stenosis ≥50% or asymptomatic carotid stenosis ≥70% with calcification (CTA measurement: calcification > 50% of circumference).

   Note: (Extracranial carotid artery: Internal carotid artery or carotid bifurcation; Symptomatic refers to having had a non-disabling ischemic stroke or TIA within 6 months.)

3. Intraoperative digital subtraction angiography (DSA) confirms carotid stenosis ≥50% (by NASCET criteria) or asymptomatic carotid stenosis ≥70% (by NASCET criteria).

4. Participants with a pre-enrollment modified Rankin Scale (mRS) score ≤2.

5. Participants planned for carotid artery stenting (CAS) who have failed conventional balloon dilation.

6. Patients or their legal guardians understand the purpose of the trial, provide informed consent, and agree to follow-up.

Exclusion Criteria:

1. Target lesion caused by non-atherosclerotic disease.
2. Participants with complete occlusion of the target lesion or contralateral carotid artery.
3. Participants with severe disability due to cerebral infarction.
4. Participants with large acute or subacute thrombi near the target lesion, or with arteriovenous malformations or aneurysms.
5. Participants with tortuous target lesion vessels that prevent stent placement.
6. Participants with symptomatic severe stenosis in other cerebral vessels.
7. Participants requiring concurrent or additional surgical interventions during the trial period.
8. Participants with tandem severe stenosis or occlusion in vessels proximal or distal to the target lesion.
9. Participants who have had a myocardial infarction or large cerebral infarction within 2 weeks prior to screening.
10. Participants who have had intracranial hemorrhage within 3 months prior to screening.
11. Participants with vulnerable or high-risk plaques (unstable, prone to rupture, and thrombosis leading to acute cardiovascular events or death) as judged by carotid ultrasound.
12. Participants with uncontrolled hypertension (systolic blood pressure persistently ≥180 mmHg or diastolic blood pressure persistently ≥110 mmHg).
13. Participants with known platelet count < 90×10^9/L, severe liver impairment (transaminases > 3 times the upper limit of normal), severe renal impairment (serum creatinine > 2.5 mg/dL [221 µmol/L]), or New York Heart Association Class IV heart failure.
14. Participants with coagulopathy (INR ≥2.0) or contraindications to heparin or antiplatelet agents.
15. Participants with active infections.
16. Participants unable to use cerebral protection devices.
17. Participants allergic to components of the investigational device or contrast agents (excluding rash).
18. Participants with life expectancy less than 1 year.
19. Pregnant or breastfeeding women.
20. Participants currently enrolled in another drug or medical device clinical trial (before reaching the primary endpoint).
21. Other situations where the investigator deems the participant unsuitable for the trial.