Study to understand if inclisiran is better than a placebo at lowering LDL-cholesterol,is safe and can have an impact on patient quality of life, when given along with other lipid lowering medications.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

8 Apr 2022 → 20 Mar 2025

Decision date (initial)

2024-07-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2024-511263-28-00

EudraCT number

2021-003759-40

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Therapy, Safety

To demonstrate the superiority of inclisiran on top of ongoing individually optimized LLT compared to placebo on top of ongoing individually optimized LLT on reaching a participant's individual LDL-C target as measured by the proportion of participants achieving individual LDL-C target (< 55mg/dL or < 70 mg/dL) at day 90

Secondary objectives 4

1. To demonstrate the superiority of inclisiran on top of ongoing individually optimized LLT compared to placebo on top of ongoing individually optimized LLT on: • Reducing mean LDL-C levels over the double-blind study period.
2. To demonstrate the superiority of inclisiran on top of ongoing individually optimized LLT compared to placebo on top of ongoing individually optimized LLT on: • Muscle-related adverse events.
3. To demonstrate the superiority of inclisiran on top of ongoing individually optimized LLT compared to placebo on top of ongoing individually optimized LLT on: • Annualized number of days pain is experienced using pain diary.
4. To demonstrate the superiority of inclisiran on top of ongoing individually optimized LLT compared to placebo on top of ongoing individually optimized LLT on: • Pain-related quality of life at day 360 using the Short-Form Brief Pain Inventory (SF-BPI).

Conditions and MedDRA coding

Hypercholesterolemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Male or female participants ≥18 years of age.
2. Very high risk participants with at least one of the following: • Documented Atherosclerotic cardiovascular disease (ASCVD) i Acute coronary syndrome: Unstable angina or myocardial infarction. ii Stable angina. iii Coronary revascularization. iv Unequivocally documented ASCVD upon prior imaging. v Stroke and TIA. vi Peripheral artery disease (PAD). • Diabetes mellitus (DM) with target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), or at least ≥ 3 major risk factors, or early onset of Type 1 DM of long duration (> 20 years). • A calculated SCORE2 ≥ 7.5% for age <50 years; SCORE2 ≥10% for age 50-69 years; SCORE2-OP ≥15% for age ≥70 years to estimate 10-year risk of fatal and non-fatal cardiovascular disease (CVD). • Pre-existing diagnosis of heterozygous familial hypercholesterolemia (HeFH) with ASCVD or with another major risk factor. High risk participants with at least one of the following: • Markedly elevated single risk factors, in particular total cholesterol >310 mg/dL, LDL-C > 190 mg/dL, or blood pressure ≥ 180/110 mmHg • Pre-existing diagnosis of HeFH without other major risk factors. • Diabetes Mellitus (DM) without target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), with DM duration ≥ 10 years or other additional risk factor. • Moderate chronic kidney disease (eGFR 30-59 mL/min/1.73m2). • A calculated SCORE2 2.5 to <7.5% for age < 50 years, SCORE2 5 to < 10% for age 50-69 years; SCORE2-OP 7.5 to < 15% for age ≥70 years to estimate 10-year risk of fatal and non-fatal CVD as defined by the cardiovascular risk categories in the 2019 ESC/EAS guideline (Mach et al 2020).
3. LDL-C levels: • in participants with very high cardiovascular risk: serum LDL-C ≥55 mg/dL. • in participants with high cardiovascular risk: serum LDL-C ≥70 mg/dL
4. Participant on a stable dose of a statin for ≥ 30 days at screening.
5. Participants on the individual MTD of statin for ≥ 30 days at baseline.
6. Fasting triglyceride < 400 mg/dL at screening and baseline.

Exclusion criteria 11

1. Participants on more than one other lipid-lowering drug on top of statin at screening visit.
2. Participants with a known intolerance to rosuvastatin at screening or baseline visit.
3. Previous (within 90 days of screening), current or planned treatment with a monoclonal antibody (mAb) directed towards PCSK9 (e.g. evolocumab, alirocumab) at screening or baseline visit.
4. Previous exposure to inclisiran or any other non-mAb PCSK9 targeted therapy, either as an investigational or marketed drug within 2 years prior to screening or baseline visit.
5. Previous, current or planned treatment with LDL-apheresis at screening or baseline visit.
6. Liver and CK: (a) Active liver disease defined as any current infectious, neoplastic, or metabolic pathology of the liver or (b) unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST) elevation >3x ULN, or total bilirubin elevation > 2x ULN (except for participants with Gilbert's syndrome), or (c) creatine kinase (CK) >5x ULN at screening or baseline visit.
7. Participant with severe renal impairment defined by eGFR <30 mL/min/1.73m2 as calculated by the Modification in Diet in Renal Disease (MDRD) formula at screening or baseline visit.
8. Acute coronary syndrome, ischemic stroke or TIA, coronary revascularization or peripheral arterial revascularization procedure or amputation due to atherosclerotic disease < 3 months prior to the screening or baseline visit.
9. Heart failure New York Heart Association (NYHA) class IV at screening or baseline visit
10. Pregnant or nursing (lactating) women at screening or baseline visit.
11. Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing of study treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of participants achieving individual LDL-C target (< 55 mg/dL or < 70 mg/dL) at day 90

Secondary endpoints 4

1. Relative change (percentage from baseline to mean LDL-C level) over the double-blind treatment period.
2. Proportion of participants experiencing at least one muscle-related AE as defined in the Standardized MedDRA Queries (SMQ) rhabdomyolysis / myopathy from day 1 to day 360.
3. Proportion of participants experiencing self-reported pain. Annualized number of days participants experiencing self-reported pain from baseline to day 360.
4. Change from baseline in SF-BPI pain severity score to day 360. Change from baseline in SF-BPI pain interference score to day 360. Proportion of participants with clinically relevant change in SF-BPI pain severity score from baseline to day 360. Proportion of participants with clinically relevant change in SF-BPI pain interference score from baseline to day 360.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 11

Locations

8 EU/EEA countries · 115 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 90 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications