Lowering of LDL-C with rosuvastatin or single-pill combination rosuvastatin/ezetimibe in high/very high-risk patients with hyperlipidaemia – LEASH

Overview

Sponsor-declared trial summary

Key facts

Sponsor

KRKA tovarna zdravil d.d. Novo mesto

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

10 Nov 2024 → 8 Jan 2026

Decision date (initial)

2024-06-05

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the efficacy and safety of treatment with high-intensity rosuvastatin or SPC rosuvastatin/ezetimibe, based on low-density lipoprotein cholesterol (LDL-C) treatment goal* achievement in patients at high or very high cardiovascular disease (CVD) risk after 12 weeks of treatment.
__________________
*Patients at very high cardiovascular (CVD) risk: LDL-C reduction of ≥50 % from baseline AND LDL-C <1.4 mmol/L (<55 mg/dL); patients at high CVD risk: LDL-C reduction of ≥50 % from baseline AND LDL-C <1.8mmol/L (<70 mg/dL).

Secondary objectives 1

1. To assess the pace of lowering of lipid parameters and proportion of patients achieving lipid goals, with focus on LDL-C treatment goal* after 4, 8 or 12 weeks of treatment with high-intensity rosuvastatin or SPC rosuvastatin/ezetimibe in high and very high-risk CVD patients. *Patients at very high cardiovascular (CVD) risk: LDL-C reduction of ≥50 % from baseline AND LDL-C <1.4 mmol/L (<55 mg/dL); patients at high CVD risk: LDL-C reduction of ≥50 % from baseline AND LDL-C <1.8mmol/L (<70 mg/dL).

Conditions and MedDRA coding

Hyperlipidaemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Patients at high or very high CVD risk# with elevated LDL-C levels: • LDL-C ≥1.8 mmol/L (70 mg/dL) if at high CVD risk OR • LDL-C ≥1.4 mmol/L (55 mg/dL) if at very high CVD risk _______________________ # Apparently healthy patients at high or very high CVD risk (according to SCORE2) OR patients with type II DM at high or very high CVD risk (if without previous ASCVD, CVD risk is assessed according to SCORE2-Diabetes) OR patients with ASCVD.
2. Patients that are treatment-naїve* to all lipid-lowering therapy**. ________________________ *Patients who never received any lipid-lowering therapy** OR were not receiving any lipid-lowering therapy for at least 4 weeks before Visit 1. **Lipid-lowering therapy: therapy with statins, ezetimibe, fibrates, bile acid sequestrants, bempedoic acid, nicotinic acid and derivatives, PCSK9 inhibitors, any other study lipid-lowering drug or intake of Red Yeast Rice (RYR) containing supplements.
3. Female or male patients aged ≥18$ and <70 years. ________________________ $Patients in the category of apparently healthy patients and patients with type II DM without ASCVD, must be ≥40 years old.
4. Patients who have been provided with information about the trial, are capable of understanding the information (according to investigator’s judgement) and have voluntarily signed informed consent.
5. Patients who have signed the consent for collection, analysis and processing of personal data, that will be collected during this clinical trial for the purpose of statistical analysis and final report of this clinical trial.
6. Patients with the ability to adhere to and are compliant with the trial protocol according to investigator’s judgement (e.g. without pathological clinical states and any other life-threatening illness that could affect patient’s compliance or have any impact on patient’s survival rate based on the investigator’s judgement).

Exclusion criteria 18

1. Patients with known or suspected statin intolerance (according to patient’s medical history and investigator’s judgement), hypersensitivity or history of adverse reactions to the active substances rosuvastatin (or any other HMG-CoA reductase inhibitors) or ezetimibe (or any other lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol) or to any of the excipients (e.g. rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption).
2. Pregnancy, lactation and women of childbearing potential not using appropriate contraceptive measures (according to the Recommendations related to contraception and pregnancy testing in clinical trials).
3. Patients currently participating in another clinical trial.
4. Any acute disease (e.g. severe respiratory failure, severe infection, exacerbation or uncontrolled phase of a chronic disease, major trauma, surgery, COVID-19 or post-COVID-19/long COVID-19 syndromes diagnosed, etc.) within 30 days prior to screening visit.
5. Any of the following laboratory findings: • moderate or severe renal impairment – eGFR (estimated glomerular filtration rate) <60 mL/min, • suspected or documented moderate or severe liver dysfunction, • active liver disease, including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation (AST or ALT) exceeding 3x the upper limit of normal (ULN), • significantly elevated levels of creatine kinase at the baseline (> 5xULN).
6. Patients with diagnosed or suspected familial hypercholesterolaemia (FH).
7. Patients with Chronic Kidney Disease (CKD).
8. Patients with type II DM with diagnosed or suspected severe target organ damage (TOD).
9. Patients with type II DM at moderate or low CVD risk (according to SCORE2-Diabetes algorithm).
10. Patients of Asian ancestry.
11. Diagnosed or suspected secondary dyslipidaemia/ hypercholesterolaemia (e.g. due to hypothyroidism).
12. Patients with previously diagnosed specific type of genetic polymorphism that can lead to increased rosuvastatin exposure.
13. Patients with diagnosed or suspected myopathy based on muscle symptoms and investigator’s judgement, a history of (statin-induced) myopathy, rhabdomyolysis or pre-disposing factors for myopathy/ rhabdomyolysis or patients with personal or family history of hereditary muscular disorders.
14. Concomitant therapy with contraindicated active ingredients, such as drug combination of sofosbuvir/velpatasvir/voxilaprevir, cyclosporine, systemic formulation of fusidic acid within last 7 days and other medicinal products which may substantially increase or decrease rosuvastatin or ezetimibe plasma concentrations.
15. Patients who have received LDL-C plasmapheresis treatment within 2 months prior to the screening visit (Visit 1), or have plans to receive it during the study.
16. Surgical procedures planned to occur during trial (patients may be rescreened following completion of and recovery from the surgical procedure).
17. Apparently healthy patients*, aged <40 years and with SBP ≥180 mmHg. _______________________ *Patients without established ASCVD and/or diabetes mellitus and/or CKD and/or familial hypercholesterolaemia, aged ≥ 40 years and with SBP < 180 mm Hg.
18. Patients with type II DM without ASCVD, <40 years old.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of patients achieving the LDL-C treatment goal* after 12 weeks of treatment (from baseline to Visit 5) in ARM 1 and ARM 2 separately. ______________________ *Patients at very high cardiovascular (CVD) risk: LDL-C reduction of ≥50 % from baseline AND LDL-C <1.4 mmol/L (<55 mg/dL); patients at high CVD risk: LDL-C reduction of ≥50 % from baseline AND LDL-C <1.8mmol/L (<70 mg/dL).

Secondary endpoints 7

1. Proportion of patients achieving LDL-C treatment goal*, after 4 and 8 weeks of treatment (from baseline to Visit 3 and to Visit 4) in ARM 1 and ARM 2 separately. ______________________ *Patients at very high cardiovascular (CVD) risk: LDL-C reduction of ≥50 % from baseline AND LDL-C <1.4 mmol/L (<55 mg/dL); patients at high CVD risk: LDL-C reduction of ≥50 % from baseline AND LDL-C <1.8mmol/L (<70 mg/dL).
2. Proportion of patients achieving LDL-C reduction ≥50 % from baseline, after 4, 8 or 12 weeks of treatment (from baseline to Visit 3, to Visit 4 and to Visit 5) in ARM 1 and ARM 2 separately.
3. Proportion of patients achieving LDL-C target values** after 4, 8 and 12 weeks of treatment (at Visit 3, Visit 4 and Visit 5, respectively) in ARM 1 and ARM 2 separately. _______________________ **LDL-C target value for patients at very high cardiovascular (CVD) risk: LDL-C <1.4mmol/L (<55 mg/dL); LDL-C target value patients at high CVD risk: <1.8mmol/L (<70 mg/dL).
4. Proportion of patients achieving target& non-HDL-C, after 4, 8 and 12 weeks of treatment (at Visit 3, Visit 4 and Visit 5) in ARM 1 and ARM 2 separately. _______________________ &Non-HDL-C target for patients at very high CVD risk: <2.2mmol/L (<85 mg/dL); non-HDL-C target for patients at high CVD risk: <2.6mmol/L (<100 mg/dL).
5. Mean absolute and relative changes in TC, LDL-C, non-HDL-C, HDL-C, and TG, after 4, 8 and 12 weeks of treatment (from baseline to Visit 3, to Visit 4 and to Visit 5) in ARM 1 and ARM 2 separately.
6. Proportion of compliant# patients after 4, 8 and 12 weeks (at Visit 3, Visit 4 and Visit 5, respectively) of treatment in ARM 1 and ARM 2 separately. ________________________ #Patients are considered compliant to treatment, if ≥80 % of their prescribed doses were administered. One dose omission is defined as omission of 1 tablet of rosuvastatin or SPC rosuvastatin/ezetimibe per day in ARM 1 OR omission of 1 tablet of rosuvastatin or SPC rosuvastatin/ezetimibe per day in ARM 2.
7. Proportion of patients achieving LDL-C treatment goal* after 4, 8 and 12 weeks of treatment in ARM1 in comparison with ARM2. ______________________ *Patients at very high cardiovascular (CVD) risk: LDL-C reduction of ≥50 % from baseline AND LDL-C <1.4 mmol/L (<55 mg/dL); patients at high CVD risk: LDL-C reduction of ≥50 % from baseline AND LDL-C <1.8mmol/L (<70 mg/dL).

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

KRKA tovarna zdravil d.d. Novo mesto

Sponsor organisation

KRKA tovarna zdravil d.d. Novo mesto

Address

Smarjeska Cesta 6

City

Novo Mesto

Postcode

8000

Country

Slovenia

Scientific contact point

Organisation

KRKA tovarna zdravil d.d. Novo mesto

Contact name

Breda Barbič-Žagar

Public contact point

Organisation

KRKA tovarna zdravil d.d. Novo mesto

Contact name

Breda Barbič-Žagar

Locations

5 EU/EEA countries · 18 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

Documents 27 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