Prospective Trial of IVL for Calcified Carotid Lesions(CREATE Trial)

**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:**

• **IVL Catheter:** Rapid-exchange balloon catheter with integrated electrodes generating sonic waves (80 pulses max per device).
• **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

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

• Intraoperative digital subtraction angiography (DSA) confirms carotid stenosis ≥50% (by NASCET criteria) or asymptomatic carotid stenosis ≥70% (by NASCET criteria).
• Participants with a pre-enrollment modified Rankin Scale (mRS) score ≤2.
• Participants planned for carotid artery stenting (CAS) who have failed conventional balloon dilation.
• Patients or their legal guardians understand the purpose of the trial, provide informed consent, and agree to follow-up.

Exclusion criteria

• Target lesion caused by non-atherosclerotic disease.
• Participants with complete occlusion of the target lesion or contralateral carotid artery.
• Participants with severe disability due to cerebral infarction.
• Participants with large acute or subacute thrombi near the target lesion, or with arteriovenous malformations or aneurysms.
• Participants with tortuous target lesion vessels that prevent stent placement.
• Participants with symptomatic severe stenosis in other cerebral vessels.
• Participants requiring concurrent or additional surgical interventions during the trial period.
• Participants with tandem severe stenosis or occlusion in vessels proximal or distal to the target lesion.
• Participants who have had a myocardial infarction or large cerebral infarction within 2 weeks prior to screening.
• Participants who have had intracranial hemorrhage within 3 months prior to screening.
• 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.
• Participants with uncontrolled hypertension (systolic blood pressure persistently ≥180 mmHg or diastolic blood pressure persistently ≥110 mmHg).
• 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.
• Participants with coagulopathy (INR ≥2.0) or contraindications to heparin or antiplatelet agents.
• Participants with active infections.
• Participants unable to use cerebral protection devices.
• Participants allergic to components of the investigational device or contrast agents (excluding rash).
• Participants with life expectancy less than 1 year.
• Pregnant or breastfeeding women.
• Participants currently enrolled in another drug or medical device clinical trial (before reaching the primary endpoint).
• Other situations where the investigator deems the participant unsuitable for the trial.