Atherosclerosis CerebralPhase 4RESCUENCT07819643
RESCUE: PCSK9 Inhibitors for Carotid Vulnerable Plaque Remodeling
A Phase 4 study testing Intervention 1, Intervention 3 and Intervention 2 in people with Atherosclerosis Cerebral and Carotid Plaque, run by Keqiang Zhao.
Trial summary
Carotid artery stenosis is a major cause of ischemic stroke. However, many strokes occur in patients with only mild-to-moderate stenosis. Evidence shows that it is not the degree of narrowing, but the "vulnerability" of the plaque-its internal composition-that determines rupture risk. Read more about this study
- Who is it for?
- Ages 40 to 80 years
- Conditions the study is for
- Atherosclerosis Cerebral, Carotid Plaque, Vulnerable Plaque
- What is being tested?
- Intervention 1, Intervention 3 and Intervention 2
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 120 participants
- Where
- No sites listed yet
- Study dates
- 1 Jan 2027to 1 Dec 2029
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- . Carotid stenosis ≥30% detected by carotid ultrasound, not meeting criteria for surgical intervention, and confirmed presence of vulnerable plaque by HR-MRI (meeting any of the following: incomplete or thin fibrous cap <0.5 mm; lipid-rich necrotic core [LRNC] volume ≥40% of plaque volume; intraplaque hemorrhage [IPH]; or neovascularization).
- Receiving standard statin therapy (moderate intensity or higher) for ≥3 months, with LDL-C still ≥1.8 mmol/L (70 mg/dL).
- Willing to adhere to follow-up and provide signed informed consent.
Who cannot join
- Allergy or contraindication to PCSK9 inhibitors.
- Active liver disease, myopathy, or creatine kinase (CK) elevation >5 times the upper limit of normal.
- History of carotid revascularization (carotid endarterectomy [CEA] or carotid artery stenting [CAS]).
- Renal insufficiency (estimated glomerular filtration rate [eGFR] <30 ml/min).
- MRI contraindications such as metallic implants or claustrophobia.
- Life expectancy <3 years.
Trial locations and contacts
No sites are listed yet. Contact the study team or a site near you to ask about taking part.
About this study
Official title: Remodeling Evaluation and Stabilization of Carotid Vulnerable Plaques by PCSK9 Inhibitors Using HR-MRI for Early Prediction
Carotid artery stenosis is a major cause of ischemic stroke. However, many strokes occur in patients with only mild-to-moderate stenosis. Evidence shows that it is not the degree of narrowing, but the "vulnerability" of the plaque-its internal composition-that determines rupture risk.
High-risk (vulnerable) plaques have a large lipid-rich necrotic core, a thin fibrous cap, and intraplaque hemorrhage. Statins can lower cholesterol and stabilize plaques, but some patients still experience progression or recurrent events.
Read more
PCSK9 inhibitors (such as evolocumab and alirocumab) are a new class of lipid-lowering drugs that reduce LDL cholesterol more strongly than statins alone. They may also have direct effects on the artery wall, improving plaque stability. Whether they can remodel vulnerable carotid plaques and how early this can be detected remains unclear.
This study uses high-resolution magnetic resonance imaging (HR-MRI), a non-invasive technique that visualizes plaque internal structure-including the lipid core, fibrous cap, and hemorrhage-to track changes over time.
Purpose: The RESCUE study aims to determine whether adding a PCSK9 inhibitor to standard statin therapy can remodel and stabilize vulnerable carotid plaques, and to detect these changes early using HR-MRI.
Design: This is a single-center, prospective, randomized, controlled, open-label trial with blinded endpoint evaluation (PROBE design). 120 adults with carotid vulnerable plaques will be enrolled at Beijing Tsinghua Chang Gung Hospital and randomly assigned 1:1 to: (1) Experimental group (n=60): statin PLUS PCSK9 inhibitor (subcutaneous injection); (2) Control group (n=60): statin alone. Follow-up is 24 months. HR-MRI is performed at baseline, 6, 12, and 24 months. Blood samples are collected for lipid and inflammatory markers. HR-MRI analysis is performed by blinded radiologists.
Primary Outcome: Change in lipid-rich necrotic core volume by HR-MRI at 12 and 24 months.
Secondary Outcomes: Fibrous cap thickness, intraplaque hemorrhage, remodeling index, LDL-C levels, inflammatory markers, and clinical events (stroke, TIA, cardiovascular death) over 24 months.
Status: Not yet recruiting. Planned start: January 2027. Conducted at Beijing Tsinghua Chang Gung Hospital, Beijing, China.
Read the detailed description
Background and Rationale
Carotid atherosclerotic plaque vulnerability, rather than the degree of luminal stenosis, is the primary determinant of ischemic stroke risk. High-resolution magnetic resonance imaging (HR-MRI) has emerged as a powerful non-invasive tool capable of characterizing plaque components in vivo, including the lipid-rich necrotic core (LRNC), fibrous cap integrity, intraplaque hemorrhage (IPH), and neovascularization. These imaging biomarkers provide critical insights into plaque phenotype and natural history.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as a class of potent lipid-lowering agents, have demonstrated substantial efficacy in reducing low-density lipoprotein cholesterol (LDL-C) levels and improving cardiovascular outcomes. Beyond their established lipid-lowering effects, emerging evidence suggests that PCSK9 inhibitors may exert direct pleiotropic effects on plaque stabilization, including promoting fibrous cap thickening, reducing intraplaque inflammation, and facilitating lipid regression. However, the temporal dynamics of PCSK9 inhibitor-induced plaque remodeling and their quantitative relationship with LDL-C reduction remain incompletely understood, particularly in the carotid territory.
Study Hypothesis
The RESCUE study hypothesizes that, compared with standard statin monotherapy, the addition of a PCSK9 inhibitor to statin therapy will result in more favorable remodeling of carotid vulnerable plaques, characterized by a significant reduction in LRNC volume, fibrous cap thickening, regression of neovascularization, and decreased incidence of IPH, as quantitatively assessed by HR-MRI. Furthermore, we hypothesize that specific HR-MRI-derived imaging biomarkers at early time points (e.g., 3 or 6 months) can predict long-term plaque stabilization.
Study Design Overview
RESCUE is a single-center, prospective, randomized, open-label, blinded endpoint evaluation (PROBE) trial designed to test these hypotheses. A total of 120 eligible participants with carotid vulnerable plaques will be randomly assigned in a 1:1 ratio to either the experimental group (statin plus PCSK9 inhibitor) or the control group (statin monotherapy). The study employs a PROBE design to balance operational feasibility with objectivity in endpoint assessment: while treatment allocation is open-label, all HR-MRI analyses and clinical endpoint adjudications will be performed by independent, blinded readers.
Key Methodological Considerations
HR-MRI Protocol and Analysis: A standardized multi-sequence HR-MRI protocol (including T1-weighted, T2-weighted, and contrast-enhanced sequences) will be applied at baseline, 6, 12, and 24 months. Quantitative measurements of plaque components will follow predefined, reproducible criteria. Image analysis will be conducted by two experienced radiologists blinded to treatment allocation and clinical data, with inter-reader reliability assessed.
Temporal Profiling: Serial imaging at 5 time points (baseline, 3, 6, 12, and 24 months) allows for the characterization of the temporal sequence of plaque compositional changes and their correlation with serial LDL-C levels, enabling the exploration of a dose-response relationship between lipid lowering and plaque remodeling.
Early Prediction: By leveraging machine learning or multivariate statistical approaches on early-phase HR-MRI data, the study aims to identify imaging signatures that predict long-term plaque stabilization, addressing a critical unmet need in personalized management of carotid atherosclerosis.
Significance
RESCUE will provide high-level evidence on the efficacy of PCSK9 inhibitors in reshaping carotid vulnerable plaques and establish an HR-MRI-based framework for early prediction of treatment response. The findings are expected to inform future clinical guidelines and support the development of imaging-guided therapeutic strategies for stroke prevention.
- Being tested
- Intervention 1, Intervention 3, Intervention 2, Intervention 4
- Keywords
- PCSK9 inhibitor, HR-MRI, Carotid plaque, Vulnerable plaque, Plaque remodeling, Plaque stabilization, Stroke prevention
- Medical subject headings
- Intracranial Arteriosclerosis, Carotid Stenosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intervention 1Drug
Also called Repatha
Evolocumab Description: 140 mg subcutaneous injection every 2 weeks. Dose may be adjusted based on LDL-C response per clinical judgment.
Intervention 3Drug
Also called Lipitor
Atorvastatin Description: 20 mg orally once daily. Dose titrated to achieve LDL-C target per guidelines.
Intervention 2Drug
Alirocumab Description: 75 mg subcutaneous injection every 2 weeks. Dose may be adjusted based on LDL-C response per clinical judgment.
Intervention 4Drug
Rosuvastatin Description: 10 mg orally once daily. Dose titrated to achieve LDL-C target per guidelines.
| Study group | Role | What they receive |
|---|---|---|
| Experimental: Statin + PCSK9 Inhibitor | Experimental | Participants will receive standard statin therapy (either atorvastatin 20 mg or rosuvastatin 10 mg orally once daily, dose-adjusted to achieve target LDL-C) plus a PCSK9 inhibitor (either evolocumab 140 mg subcutaneously every 2 weeks or alirocumab 75 mg subcutaneously every 2 weeks, dose-adjusted per protocol). Treatment duration is 24 months. HR-MRI assessments will be performed at baseline, 3, 6, 12, and 24 months. Receives: Drug: Intervention 1; Drug: Intervention 2 |
| Active Comparator: Statin Monotherapy | Active comparator | Participants will receive standard statin monotherapy (either atorvastatin 20 mg or rosuvastatin 10 mg orally once daily, dose-adjusted to achieve target LDL-C) without PCSK9 inhibitor. Treatment duration is 24 months. HR-MRI assessments will be performed at baseline, 3, 6, 12, and 24 months. Receives: Drug: Intervention 3; Drug: Intervention 4 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in lipid-rich necrotic core (LRNC) volume
Change from baseline in the volume of the lipid-rich necrotic core (LRNC) of the carotid plaque, measured by high-resolution magnetic resonance imaging (HR-MRI) at baseline, 6, and 12 months. LRNC volume is quantified using 3D multi-contrast HR-MRI sequences (including contrast-enhanced T1-weighted imaging) with semi-automated segmentation. The percentage change from baseline will also be reported.
Measured: Baseline, 6 months, and 12 months
Change in fibrous cap thickness
Change from baseline in the thickness of the fibrous cap of the carotid plaque, measured by high-resolution magnetic resonance imaging (HR-MRI) at baseline, 6, and 12 months. Fibrous cap thickness is quantified at the thinnest point of the plaque using 3D multi-contrast HR-MRI sequences with semi-automated segmentation and same-plaque longitudinal co-registration. The percentage change from baseline will also be reported.
Measured: Baseline, 6 months, and 12 months
Change in intraplaque hemorrhage
Change in intraplaque hemorrhage (volume or signal characteristics) of the carotid plaque, as measured by high-resolution magnetic resonance imaging (HR-MRI) at 6 months, and 12 months
Measured: Baseline, 6 months, and 12 months
Secondary outcomes (3)
Change from baseline in low-density lipoprotein cholesterol (LDL-C) levels
Change from baseline in low-density lipoprotein cholesterol (LDL-C) levels, measured from fasting venous blood samples at baseline, 6, and 12 months. LDL-C is quantified using standard enzymatic assays (or homogeneous direct method). The percentage change from baseline and the proportion of participants achieving target LDL-C (<1.4 mmol/L or per protocol) will also be reported.
Measured: Baseline, 6 months, and 12 months
Serum concentrations of inflammatory markers (hs-CRP, IL-6) at baseline, 6, and 12 months
Serum concentrations of high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) measured at baseline, 6 months, and 12 months. Change from baseline will also be calculated.
Measured: Baseline, 6 months, and 12 months
Number of participants with clinical events (ischemic stroke, transient ischemic attack [TIA], or cardiovascular death)
Number of participants experiencing a composite endpoint of ischemic stroke, transient ischemic attack (TIA), or cardiovascular death during the follow-up period, assessed at 6, 12, and 24 months.
Measured: 6 months, and 12 、24months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Sep 2026
- Study start1 Jan 2027 (estimated)
- Primary completion1 Jan 2029 (estimated)
- Study completion1 Dec 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Atherosclerosis CerebralStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The RESCUE study employs a prospective, randomized, open-label, blinded endpoint evaluation (PROBE) design with parallel assignment. Eligible participants are randomly allocated in a 1:1 ratio to either the experimental group (statin plus PCSK9 inhibitor) or the control group (statin monotherapy). Both groups are followed in parallel for 24 months with serial HR-MRI assessments at baseline, 3, 6, 12, and 24 months. Although treatment allocation is open-label, all imaging analyses and clinical endpoint adjudications are performed by independent readers blinded to group assignment, ensuring objective evaluation of plaque remodeling outcomes.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 120 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Keqiang Zhao
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Keqiang Zhao, Beijing Tsinghua Chang Gung Hospital
- Investigators
- keqiang Zhao, MD, PhD, Principal investigator, Beijing Tsinghua Chang Gung Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07819643
- Sponsor's protocol ID
- BTCH-RESCUE-202609
- Other IDs
- 2027G101
- Acronym
- RESCUE
- Status last verified
- Sep 2026
- First submitted
- 6 Sep 2026
- Last updated
- 15 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: No plan to share individual participant data at this time. Data sharing arrangements will be determined upon study completion, subject to ethics approval, informed consent provisions, and data privacy regulations.
Publications
Kini AS, Vengrenyuk Y, Liu J, Yasumura K, Revaiah PC, Mandava A, Shah H, Sweeny JM, Khera S, Kapur V, Melarcode-Krishnamoorthy P, Hooda A, Minatoguchi S, Baruah N, Pineda DA, Chen V, Ellis E, Hahn A, Krishnan P, Baber U, Moreno PR, Mehran R, Sebra R, Boerwinkle E, Zhou X, Narula J, Sharma SK. Intracoronary Imaging and Transcriptomic Characteristics Before and After Maximum Lipid-Lowering Therapy: YELLOW-III Study of Evolocumab and Maximum Statin Therapy in Chronic Coronary Disease. JACC Cardiovasc Imaging. 2026 Apr;19(4):516-534. doi: 10.1016/j.jcmg.2025.12.013. Epub 2026 Feb 27.
PubMed 41758107Huang J, Liu C, Jiao S, Chen Y, Xu L, Gong T, Zhu C, Song Y. Application of high-resolution MRI in evaluating statin efficacy on symptomatic intracranial atherosclerosis. Eur Radiol. 2025 Jan;35(1):441-452. doi: 10.1007/s00330-024-10968-1. Epub 2024 Jul 19.
PubMed 39030372Di Giovanni G, Fujino M, Kataoka Y, Butters J, Hucko T, Puri R, Nissen SE, Nelson AJ, Psaltis PJ, Nicholls SJ. Impact of evolocumab on plaque phenotypic changes in patients with acute coronary syndrome and elevated lipoprotein(a) levels: a HUYGENS secondary analysis. Eur J Prev Cardiol. 2025 Apr 8:zwaf211. doi: 10.1093/eurjpc/zwaf211. Online ahead of print.
PubMed 40424182Addeo L, Guarini P, Campana P, Argenziano L, Nardi S, Tedeschi C, Scatteia A, Silvestre M, Rapacciuolo A, Esposito G, Giordano S, Dalla Vecchia LA, Donatelli F. Patient with Vulnerable Coronary Plaque and Treatment with Evolocumab: A Clinical Case. J Clin Med. 2025 Feb 14;14(4):1257. doi: 10.3390/jcm14041257.
PubMed 40004789Papafaklis MI, Koros R, Tsigkas G, Karanasos A, Moulias A, Davlouros P. Reversal of Atherosclerotic Plaque Growth and Vulnerability: Effects of Lipid-Modifying and Anti-Inflammatory Therapeutic Agents. Biomedicines. 2024 Oct 23;12(11):2435. doi: 10.3390/biomedicines12112435.
PubMed 39595002Marfella R, Prattichizzo F, Sardu C, Paolisso P, D'Onofrio N, Scisciola L, La Grotta R, Frige C, Ferraraccio F, Panarese I, Fanelli M, Modugno P, Calafiore AM, Melchionna M, Sasso FC, Furbatto F, D'Andrea D, Siniscalchi M, Mauro C, Cesaro A, Calabro P, Santulli G, Balestrieri ML, Barbato E, Ceriello A, Paolisso G. Evidence of an anti-inflammatory effect of PCSK9 inhibitors within the human atherosclerotic plaque. Atherosclerosis. 2023 Aug;378:117180. doi: 10.1016/j.atherosclerosis.2023.06.971. Epub 2023 Jun 29.
PubMed 37422356Cui E, Kersche G, Grubic N, Hetu MF, Pang SC, Sillesen H, Johri AM. Effect of pharmacologic anti-atherosclerotic therapy on carotid intraplaque neovascularization: A systematic review. J Clin Lipidol. 2023 May-Jun;17(3):315-326. doi: 10.1016/j.jacl.2023.04.009. Epub 2023 Apr 26.
PubMed 37173161Ota H, Omori H, Kawasaki M, Hirakawa A, Matsuo H. Clinical impact of PCSK9 inhibitor on stabilization and regression of lipid-rich coronary plaques: a near-infrared spectroscopy study. Eur Heart J Cardiovasc Imaging. 2022 Jan 24;23(2):217-228. doi: 10.1093/ehjci/jeab034.
PubMed 33637979Lepor NE, Sun J, Canton G, Contreras L, Hippe DS, Isquith DA, Balu N, Kedan I, Simonini AA, Yuan C, Hatsukami TS, Zhao XQ. Regression in carotid plaque lipid content and neovasculature with PCSK9 inhibition: A time course study. Atherosclerosis. 2021 Jun;327:31-38. doi: 10.1016/j.atherosclerosis.2021.05.008. Epub 2021 May 19.
PubMed 34038761Porambo ME, DeMarco JK. MR imaging of vulnerable carotid plaque. Cardiovasc Diagn Ther. 2020 Aug;10(4):1019-1031. doi: 10.21037/cdt.2020.03.12.
PubMed 32968658
Study at a glance
From the registry record, last updated by the sponsor on 15 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Remodeling Evaluation and Stabilization of Carotid Vulnerable Plaques by PCSK9 Inhibitors Using HR-MRI for Early Prediction
- ClinicalTrials.gov ID
- NCT07819643
- Acronym / sponsor ID
- RESCUE / BTCH-RESCUE-202609
- Keywords
- PCSK9 inhibitor, HR-MRI, Carotid plaque, Vulnerable plaque, Plaque remodeling, Plaque stabilization, Stroke prevention
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 120 participants (estimated)
- Lead sponsor
- Keqiang ZhaoUniversity, hospital or other
- Study start
- 1 Jan 2027 (estimated)
- Primary completion
- 1 Jan 2029 (estimated)
- Study completion
- 1 Dec 2029 (estimated)
- First posted
- 15 Sep 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Carotid artery stenosis is a major cause of ischemic stroke. However, many strokes occur in patients with only mild-to-moderate stenosis. Evidence shows that it is not the degree of narrowing, but the "vulnerability" of the plaque-its internal composition-that determines rupture risk.
High-risk (vulnerable) plaques have a large lipid-rich necrotic core, a thin fibrous cap, and intraplaque hemorrhage. Statins can lower cholesterol and stabilize plaques, but some patients still experience progression or recurrent events.
PCSK9 inhibitors (such as evolocumab and alirocumab) are a new class of lipid-lowering drugs that reduce LDL cholesterol more strongly than statins alone. They may also have direct effects on the artery wall, improving plaque stability. Whether they can remodel vulnerable carotid plaques and how early this can be detected remains unclear.
This study uses high-resolution magnetic resonance imaging (HR-MRI), a non-invasive technique that visualizes plaque internal structure-including the lipid core, fibrous cap, and hemorrhage-to track changes over time.
Purpose: The RESCUE study aims to determine whether adding a PCSK9 inhibitor to standard statin therapy can remodel and stabilize vulnerable carotid plaques, and to detect these changes early using HR-MRI.
Design: This is a single-center, prospective, randomized, controlled, open-label trial with blinded endpoint evaluation (PROBE design). 120 adults with carotid vulnerable plaques will be enrolled at Beijing Tsinghua Chang Gung Hospital and randomly assigned 1:1 to: (1) Experimental group (n=60): statin PLUS PCSK9 inhibitor (subcutaneous injection); (2) Control group (n=60): statin alone. Follow-up is 24 months. HR-MRI is performed at baseline, 6, 12, and 24 months. Blood samples are collected for lipid and inflammatory markers. HR-MRI analysis is performed by blinded radiologists.
Primary Outcome: Change in lipid-rich necrotic core volume by HR-MRI at 12 and 24 months.
Secondary Outcomes: Fibrous cap thickness, intraplaque hemorrhage, remodeling index, LDL-C levels, inflammatory markers, and clinical events (stroke, TIA, cardiovascular death) over 24 months.
Status: Not yet recruiting. Planned start: January 2027. Conducted at Beijing Tsinghua Chang Gung Hospital, Beijing, China.
Detailed description
Background and Rationale
Carotid atherosclerotic plaque vulnerability, rather than the degree of luminal stenosis, is the primary determinant of ischemic stroke risk. High-resolution magnetic resonance imaging (HR-MRI) has emerged as a powerful non-invasive tool capable of characterizing plaque components in vivo, including the lipid-rich necrotic core (LRNC), fibrous cap integrity, intraplaque hemorrhage (IPH), and neovascularization. These imaging biomarkers provide critical insights into plaque phenotype and natural history.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as a class of potent lipid-lowering agents, have demonstrated substantial efficacy in reducing low-density lipoprotein cholesterol (LDL-C) levels and improving cardiovascular outcomes. Beyond their established lipid-lowering effects, emerging evidence suggests that PCSK9 inhibitors may exert direct pleiotropic effects on plaque stabilization, including promoting fibrous cap thickening, reducing intraplaque inflammation, and facilitating lipid regression. However, the temporal dynamics of PCSK9 inhibitor-induced plaque remodeling and their quantitative relationship with LDL-C reduction remain incompletely understood, particularly in the carotid territory.
Study Hypothesis
The RESCUE study hypothesizes that, compared with standard statin monotherapy, the addition of a PCSK9 inhibitor to statin therapy will result in more favorable remodeling of carotid vulnerable plaques, characterized by a significant reduction in LRNC volume, fibrous cap thickening, regression of neovascularization, and decreased incidence of IPH, as quantitatively assessed by HR-MRI. Furthermore, we hypothesize that specific HR-MRI-derived imaging biomarkers at early time points (e.g., 3 or 6 months) can predict long-term plaque stabilization.
Study Design Overview
RESCUE is a single-center, prospective, randomized, open-label, blinded endpoint evaluation (PROBE) trial designed to test these hypotheses. A total of 120 eligible participants with carotid vulnerable plaques will be randomly assigned in a 1:1 ratio to either the experimental group (statin plus PCSK9 inhibitor) or the control group (statin monotherapy). The study employs a PROBE design to balance operational feasibility with objectivity in endpoint assessment: while treatment allocation is open-label, all HR-MRI analyses and clinical endpoint adjudications will be performed by independent, blinded readers.
Key Methodological Considerations
HR-MRI Protocol and Analysis: A standardized multi-sequence HR-MRI protocol (including T1-weighted, T2-weighted, and contrast-enhanced sequences) will be applied at baseline, 6, 12, and 24 months. Quantitative measurements of plaque components will follow predefined, reproducible criteria. Image analysis will be conducted by two experienced radiologists blinded to treatment allocation and clinical data, with inter-reader reliability assessed.
Temporal Profiling: Serial imaging at 5 time points (baseline, 3, 6, 12, and 24 months) allows for the characterization of the temporal sequence of plaque compositional changes and their correlation with serial LDL-C levels, enabling the exploration of a dose-response relationship between lipid lowering and plaque remodeling.
Early Prediction: By leveraging machine learning or multivariate statistical approaches on early-phase HR-MRI data, the study aims to identify imaging signatures that predict long-term plaque stabilization, addressing a critical unmet need in personalized management of carotid atherosclerosis.
Significance
RESCUE will provide high-level evidence on the efficacy of PCSK9 inhibitors in reshaping carotid vulnerable plaques and establish an HR-MRI-based framework for early prediction of treatment response. The findings are expected to inform future clinical guidelines and support the development of imaging-guided therapeutic strategies for stroke prevention.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- The RESCUE study employs a prospective, randomized, open-label, blinded endpoint evaluation (PROBE) design with parallel assignment. Eligible participants are randomly allocated in a 1:1 ratio to either the experimental group (statin plus PCSK9 inhibitor) or the control group (statin monotherapy). Both groups are followed in parallel for 24 months with serial HR-MRI assessments at baseline, 3, 6, 12, and 24 months. Although treatment allocation is open-label, all imaging analyses and clinical endpoint adjudications are performed by independent readers blinded to group assignment, ensuring objective evaluation of plaque remodeling outcomes.
| Arm | Type | Receives |
|---|---|---|
| Experimental: Statin + PCSK9 Inhibitor | Experimental | Drug: Intervention 1, Drug: Intervention 2Participants will receive standard statin therapy (either atorvastatin 20 mg or rosuvastatin 10 mg orally once daily, dose-adjusted to achieve target LDL-C) plus a PCSK9 inhibitor (either evolocumab 140 mg subcutaneously every 2 weeks or alirocumab 75 mg subcutaneously every 2 weeks, dose-adjusted per protocol). Treatment duration is 24 months. HR-MRI assessments will be performed at baseline, 3, 6, 12, and 24 months. |
| Active Comparator: Statin Monotherapy | Active comparator | Drug: Intervention 3, Drug: Intervention 4Participants will receive standard statin monotherapy (either atorvastatin 20 mg or rosuvastatin 10 mg orally once daily, dose-adjusted to achieve target LDL-C) without PCSK9 inhibitor. Treatment duration is 24 months. HR-MRI assessments will be performed at baseline, 3, 6, 12, and 24 months. |
Who may qualify
- Ages
- 40 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- . Carotid stenosis ≥30% detected by carotid ultrasound, not meeting criteria for surgical intervention, and confirmed presence of vulnerable plaque by HR-MRI (meeting any of the following: incomplete or thin fibrous cap <0.5 mm; lipid-rich necrotic core [LRNC] volume ≥40% of plaque volume; intraplaque hemorrhage [IPH]; or neovascularization).
- Receiving standard statin therapy (moderate intensity or higher) for ≥3 months, with LDL-C still ≥1.8 mmol/L (70 mg/dL).
- Willing to adhere to follow-up and provide signed informed consent.
Key exclusion criteria (6 listed)
- Allergy or contraindication to PCSK9 inhibitors.
- Active liver disease, myopathy, or creatine kinase (CK) elevation >5 times the upper limit of normal.
- History of carotid revascularization (carotid endarterectomy [CEA] or carotid artery stenting [CAS]).
- Renal insufficiency (estimated glomerular filtration rate [eGFR] <30 ml/min).
- MRI contraindications such as metallic implants or claustrophobia.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Intervention 1Also: RepathaEvolocumab Description: 140 mg subcutaneous injection every 2 weeks. Dose may be adjusted based on LDL-C response per clinical judgment. | Drug | Experimental: Statin + PCSK9 Inhibitor |
| Intervention 3Also: LipitorAtorvastatin Description: 20 mg orally once daily. Dose titrated to achieve LDL-C target per guidelines. | Drug | Active Comparator: Statin Monotherapy |
| Intervention 2Alirocumab Description: 75 mg subcutaneous injection every 2 weeks. Dose may be adjusted based on LDL-C response per clinical judgment. | Drug | Experimental: Statin + PCSK9 Inhibitor |
| Intervention 4Rosuvastatin Description: 10 mg orally once daily. Dose titrated to achieve LDL-C target per guidelines. | Drug | Active Comparator: Statin Monotherapy |
Primary outcome
Change in lipid-rich necrotic core (LRNC) volume
Time frame: Baseline, 6 months, and 12 months
Change from baseline in the volume of the lipid-rich necrotic core (LRNC) of the carotid plaque, measured by high-resolution magnetic resonance imaging (HR-MRI) at baseline, 6, and 12 months. LRNC volume is quantified using 3D multi-contrast HR-MRI sequences (including contrast-enhanced T1-weighted imaging) with semi-automated segmentation. The percentage change from baseline will also be reported.
Change in fibrous cap thickness
Time frame: Baseline, 6 months, and 12 months
Change from baseline in the thickness of the fibrous cap of the carotid plaque, measured by high-resolution magnetic resonance imaging (HR-MRI) at baseline, 6, and 12 months. Fibrous cap thickness is quantified at the thinnest point of the plaque using 3D multi-contrast HR-MRI sequences with semi-automated segmentation and same-plaque longitudinal co-registration. The percentage change from baseline will also be reported.
Change in intraplaque hemorrhage
Time frame: Baseline, 6 months, and 12 months
Change in intraplaque hemorrhage (volume or signal characteristics) of the carotid plaque, as measured by high-resolution magnetic resonance imaging (HR-MRI) at 6 months, and 12 months
3 secondary outcomes
Change from baseline in low-density lipoprotein cholesterol (LDL-C) levels
Time frame: Baseline, 6 months, and 12 months
Serum concentrations of inflammatory markers (hs-CRP, IL-6) at baseline, 6, and 12 months
Time frame: Baseline, 6 months, and 12 months
Number of participants with clinical events (ischemic stroke, transient ischemic attack [TIA], or cardiovascular death)
Time frame: 6 months, and 12 、24months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Sep 2026.
- Background: PubMed 41758107Kini AS, Vengrenyuk Y, Liu J, Yasumura K, Revaiah PC, Mandava A, Shah H, Sweeny JM, Khera S, Kapur V, Melarcode-Krishnamoorthy P, Hooda A, Minatoguchi S, Baruah N, Pineda DA, Chen V, Ellis E, Hahn A, Krishnan P, Baber U, Moreno PR, Mehran R, Sebra R, Boerwinkle E, Zhou X, Narula J, Sharma SK. Intracoronary Imaging and Transcriptomic Characteristics Before and After Maximum Lipid-Lowering Therapy: YELLOW-III Study of Evolocumab and Maximum Statin Therapy in Chronic Coronary Disease. JACC Cardiovasc Imaging. 2026 Apr;19(4):516-534. doi: 10.1016/j.jcmg.2025.12.013. Epub 2026 Feb 27.
- Background: PubMed 39030372Huang J, Liu C, Jiao S, Chen Y, Xu L, Gong T, Zhu C, Song Y. Application of high-resolution MRI in evaluating statin efficacy on symptomatic intracranial atherosclerosis. Eur Radiol. 2025 Jan;35(1):441-452. doi: 10.1007/s00330-024-10968-1. Epub 2024 Jul 19.
- Background: PubMed 40424182Di Giovanni G, Fujino M, Kataoka Y, Butters J, Hucko T, Puri R, Nissen SE, Nelson AJ, Psaltis PJ, Nicholls SJ. Impact of evolocumab on plaque phenotypic changes in patients with acute coronary syndrome and elevated lipoprotein(a) levels: a HUYGENS secondary analysis. Eur J Prev Cardiol. 2025 Apr 8:zwaf211. doi: 10.1093/eurjpc/zwaf211. Online ahead of print.
- Background: PubMed 40004789Addeo L, Guarini P, Campana P, Argenziano L, Nardi S, Tedeschi C, Scatteia A, Silvestre M, Rapacciuolo A, Esposito G, Giordano S, Dalla Vecchia LA, Donatelli F. Patient with Vulnerable Coronary Plaque and Treatment with Evolocumab: A Clinical Case. J Clin Med. 2025 Feb 14;14(4):1257. doi: 10.3390/jcm14041257.
- Background: PubMed 39595002Papafaklis MI, Koros R, Tsigkas G, Karanasos A, Moulias A, Davlouros P. Reversal of Atherosclerotic Plaque Growth and Vulnerability: Effects of Lipid-Modifying and Anti-Inflammatory Therapeutic Agents. Biomedicines. 2024 Oct 23;12(11):2435. doi: 10.3390/biomedicines12112435.
- Background: PubMed 37422356Marfella R, Prattichizzo F, Sardu C, Paolisso P, D'Onofrio N, Scisciola L, La Grotta R, Frige C, Ferraraccio F, Panarese I, Fanelli M, Modugno P, Calafiore AM, Melchionna M, Sasso FC, Furbatto F, D'Andrea D, Siniscalchi M, Mauro C, Cesaro A, Calabro P, Santulli G, Balestrieri ML, Barbato E, Ceriello A, Paolisso G. Evidence of an anti-inflammatory effect of PCSK9 inhibitors within the human atherosclerotic plaque. Atherosclerosis. 2023 Aug;378:117180. doi: 10.1016/j.atherosclerosis.2023.06.971. Epub 2023 Jun 29.
- Background: PubMed 37173161Cui E, Kersche G, Grubic N, Hetu MF, Pang SC, Sillesen H, Johri AM. Effect of pharmacologic anti-atherosclerotic therapy on carotid intraplaque neovascularization: A systematic review. J Clin Lipidol. 2023 May-Jun;17(3):315-326. doi: 10.1016/j.jacl.2023.04.009. Epub 2023 Apr 26.
- Background: PubMed 33637979Ota H, Omori H, Kawasaki M, Hirakawa A, Matsuo H. Clinical impact of PCSK9 inhibitor on stabilization and regression of lipid-rich coronary plaques: a near-infrared spectroscopy study. Eur Heart J Cardiovasc Imaging. 2022 Jan 24;23(2):217-228. doi: 10.1093/ehjci/jeab034.
- Background: PubMed 34038761Lepor NE, Sun J, Canton G, Contreras L, Hippe DS, Isquith DA, Balu N, Kedan I, Simonini AA, Yuan C, Hatsukami TS, Zhao XQ. Regression in carotid plaque lipid content and neovasculature with PCSK9 inhibition: A time course study. Atherosclerosis. 2021 Jun;327:31-38. doi: 10.1016/j.atherosclerosis.2021.05.008. Epub 2021 May 19.
- Background: PubMed 32968658Porambo ME, DeMarco JK. MR imaging of vulnerable carotid plaque. Cardiovasc Diagn Ther. 2020 Aug;10(4):1019-1031. doi: 10.21037/cdt.2020.03.12.
- Individual participant dataSharing planned: No. No plan to share individual participant data at this time. Data sharing arrangements will be determined upon study completion, subject to ethics approval, informed consent provisions, and data privacy regulations.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
keqiang Zhao, MD, PhD principal investigator
Beijing Tsinghua Chang Gung Hospital
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Intervention 1, Intervention 3 and Intervention 2 in people with Atherosclerosis Cerebral and Carotid Plaque, run by Keqiang Zhao.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 15 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact keqiang Zhao, M.D. (0086-13810917596, zkqiang@btch.edu.cn), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in lipid-rich necrotic core (LRNC) volume (time frame: Baseline, 6 months, and 12 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07819643, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Sep 2026.