Coronary computed tomography study to assess the effect of inclisiran on atherosclerotic plaque progression in participants with a diagnosis of non-obstructive coronary artery disease without previous cardiovascular events
- Conditions
- on-obstructive coronary artery diseaseMedDRA version: 20.0Level: PTClassification code 10011078Term: Coronary artery diseaseSystem Organ Class: 10007541 - Cardiac disordersTherapeutic area: Diseases [C] - Cardiovascular Diseases [C14]
- Registration Number
- EUCTR2021-004601-47-IE
- Lead Sponsor
- ovartis Pharma AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 600
1. Written informed consent must be obtained before any assessment is
performed.
2. Male or female =18 to =80 years of age at signing of informed
consent.
3. Fasting LDL-C local lab value at the Screening Visit of either i) =100
mg/dL (2.6 mmol/L) if participant is on statin therapy but not on a
maximally tolerated statin therapy; ii) =150 mg/dL (3.9 mmol/L) if
participant is statin naive and without documented statin intolerance; or
iii) =55 mg/dL (1.4 mmol/L) if participant is on a stable (=4 weeks)
dose of maximally tolerated statin therapy or if statin intolerant. Local
laboratory values should be calculated using the Friedewald formula for
consistency across study sites if the Screening visit occurs prior to the
Baseline CCTA Visit. If the Screening and Baseline Visits occur on the same day, then the LDL-C value will be assessed on the central
laboratory sample. If the center can only perform the direct LDL-C test,
then the local lab should also obtain the total cholesterol, HDL-C, and
triglycerides results so that the LDL-C can be calculated using the
Friedewald estimation.
4.Fasting LDL-C local lab value =55 mg/dL (1.4 mmol/L) at the
assessment performed during the Statin Optimization Period 3 Visit for
participants going through the Statin Optimization Period. Local
laboratory values should be calculated using the Friedewald formula for
consistency across study sites. If the center can only perform the direct
LDL-C test, then the local lab should also obtain the total cholesterol,
HDL-C, and triglycerides results so that the LDL-C can be calculated
using the Friedewald estimation.
5. Participants having Non-Obstructive Coronary Artery (NOCAD)*
without previous cardiovascular events: NOCAD is defined as:
(1) Participants with a CT-adapted Leaman score >5 and a diameter
stenosis <50%***
OR
(2) Participants with a CT-adapted Leaman score >5 and a diameter
stenosis =50%*but with FFRCT =0.76**. Notes: *=In case of left main
CAD, diameter stenosis is =40%. **=In case of FFRCT between =0.76
and 0.80, participant eligibility will be assessed and determined by the
Imaging Core Lab based on the location of the lesion, proximality of the
lesion, delta FFRCT, and diffuseness of coronary artery disease
FFRCT and CT-adapted Leaman score will be determined by the Imaging
Core Lab.
A standard of care CCTA may serve as the study baseline CCTA scan if it
is performed within 3 months prior to the participant's Screening Visit
and meets the inclusion criteria as described above and as assessed by
the Imaging Core Lab.
6. At the Baseline Visit, participants must be on a stable (=4 weeks)
dose of maximally tolerated statin therapy. Participants not on
maximally tolerated statin therapy and who do not have documented
statin intolerance can be screened but must enter the study via a Statin
Optimization Period.
7.Fasting LDL-C lab value =55 mg/dL (1.4 mmol/L) at the Baseline Visit,
measured at the central laboratory. If the Baseline and Screening Visits
occur on the same day, then the LDL-C assessment will be assessed on
the central laboratory sample. If a participant qualifies at Screening but
the fasting central LDL-C value at the Baseline Visit does not meet
eligibility, the eligibility will be determined based on the central lab
result.
8.Fasting triglycerides value <400 mg/dL (4.52 mmol/L) based on the
local lab results at the Screening visit and on the central lab results at
the CCTA visit.
Are the trial subjects under 18? no
Number of subjects f
1. Previous myocardial infarction (MI), or prior coronary revascularization [percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)].
2. Planned revascularization (PCI or CABG).
3. Previous ischemic cerebrovascular event including:
•Prior ischemic stroke thought not to be caused by atrial fibrillation, valvular heart disease or mural thrombus.
•History of prior percutaneous or surgical carotid artery revascularization.
4. History of Peripheral Artery Disease (PAD):
•Prior documentation of a resting ankle-brachial index <0.85.
•History of prior percutaneous or surgical revascularization of an iliac, femoral, or popliteal artery.
•Prior non-traumatic amputation of a lower extremity due to peripheral artery disease.
5. Cardiac disorders, including any of the following:
•Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, atrial fibrillation) within 3 months prior to randomization that is not controlled by medication or via ablation at the time of the Screening Visit.
•Complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third-degree AV block) prior to randomization.
6. NOCA participant who was prescreened by the Investigator with visual diameter stenosis >50% but FFR <0.8.
7. Contraindication for CCTA (e.g., allergic reactions to the contrast dye) or CCTA not meeting entry standards after two attempts during the Baseline CCTA Visit as assessed by the Imaging Core Lab.
8. Pacemaker or implantable cardioverter-defibrillator (ICD) in situ.
9. Systolic Left Ventricle Ejection Fraction <30% at the Screening Visit.
10. Uncontrolled severe hypertension: mean systolic blood pressure >180 mmHg or mean diastolic blood pressure >110 mmHg prior to randomization (assessed at the Screening Visit) despite antihypertensive therapy.
11. Heart failure New York Heart Association (NYHA) class III or class IV at the Screening Visit.
12. Renal insufficiency (eGFR <30 mL/min/1.73m2) as measured by the Modification of Diet in Renal Disease (MDRD) formula at the Screening Visit and at the Statin Optimization 3 Visit.
13. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver at the Screening Visit.
Participants who enter Screening or the Statin Optimization Visit must
have AST and ALT =3x ULN to be allowed to continue in the Screening or
Statin Optimization Period.
13.Local creatine kinase (CK) values of either, unless a more stringent
threshold is mandated by a local regulatory authority (e.g., =3x ULN in
Korea according to MFDS internal guideline):
• CK values =5x ULN at the Screening Visit for participants on
maximally tolerated statin therapy or who are statin intolerant.
• CK values =5x ULN at Screening and before entering the Statin
Optimization Period and confirmed by repeat test within 7 days at
Screening or based on Investigator's judgement for participants entering
the Statin Optimization Period (who will be switched to or initiated on
the protocol-specified dose of high-intensity statin of atorvastatin =40
mg QD or rosuvastatin =20 mg QD during the Statin Optimization
Period).
14. Local CK values =5x ULN at the Statin Optimization 3 Visit unless a
more stringent threshold is mandated by a local regulatory authority
(e.g., =3x ULN in Korea according to MFDS internal guideline) and
monitored according to national guidelines and statin label during the
Statin Optimization Period.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: Inclisiran compared to placebo, on top of maximally tolerated statin therapy, in reducing the total coronary atheroma volume assessed by CCTA from baseline to month 24;Secondary Objective: - Inclisiran compared to placebo, administered on top of maximally tolerated statin therapy, in reducing the LDL-C from baseline to month 24<br>- Inclisiran compared to placebo in percentage change in low attenuation plaque volume evaluated by CCTA <br>- Inclisiran compared to placebo in percentage of participants experiencing progression, regression, or no change of total plaque atheroma volume (progression, regression, or no change will be defined in the Statistical analysis plan (SAP)<br>- Assess the safety and tolerability profile of inclisiran;Primary end point(s): Percentage change from baseline to month 24 in total coronary atheroma volume;Timepoint(s) of evaluation of this end point: From baseline to month 24.
- Secondary Outcome Measures
Name Time Method Secondary end point(s): -percentage change in LDL-C from baseline to month 24<br>-percentage change in low attenuation plaque volume evaluated by CCTA<br>-percentage of participants with progression, regression, or no change of total plaque atheroma volume<br>-Incidence, severity, and relationship to study drug of TEAEs and Serious<br>Adverse Events (SAEs);Timepoint(s) of evaluation of this end point: From baseline to month 24.