Clinical trial NCT05192941: Study of Efficacy, Safety, Tolerability and Quality of Life of Inclisiran (KJX839) vs Placebo, on Top of Ongoing Individually Optimized Lipid-lowering Therapy, in Participants With Hypercholesterolemia
Official title: Efficacy, Safety, Tolerability and Quality of Life of Ongoing Individually Optimized Lipid-lowering Therapy With or Without Inclisiran (KJX839) - a Randomized, Placebo-controlled, Double-blind Multicenter Phase IV Study in Participants With Hypercholesterolemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypercholesterolemia
Keywords: Inclisiran
rosuvastatin
PCSK9
dyslipidemia
angina pectoris
peripheral artery disease
cardiovascular disease
LDL-C
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2022-01-14
Enrollment: 1776
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind investigational treatment inclisiran/placebo: subcutaneous injections of inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) or placebo, in 1.5 mL solution.

Open label study treatment rosuvastatin: all participants will receive rosuvastatin, starting at the lowest indicated dose and titrating up until they reach their individual LDL-C target or MTD (Maximum tolerated dose) of statin, whichever occurs first.
Primary purpose: TREATMENT

Brief summary: Study of efficacy, safety, tolerability and quality of life of inclisiran (KJX839) vs placebo, on top of ongoing individually optimized lipid-lowering therapy, in participants with hypercholesterolemia

Detailed description: The purpose of this study is to demonstrate the superiority of inclisiran compared to placebo, both on top of ongoing individually optimized lipid-lowering therapy (LLT), on reaching a participant's LDL-C target (\< 55 mg/dL or \< 70 mg/dL, depending on the cardiovascular risk category), according to the 2019 ESC/EAS guidelines for the management of dyslipidemias as well as on patient-relevant safety, tolerability outcomes and quality of life.

Eligibility criteria: Key Inclusion Criteria:

Participants eligible for inclusion in this study must meet all of the following criteria:

1. Written informed consent must be obtained before any assessment is performed.
2. Male or female participants ≥18 years of age.
3. Participants categorized as very high or high CV risk, as defined below:

   •Very high risk participants with at least one of the following: A. Documented Atherosclerotic Cardiovascular Disease (ASCVD) i) Acute Coronary Syndrome: Unstable angina or myocardial infarction ii) Stable angina iii) Unequivocally documented ASCVD upon prior imaging v) Stroke and Transient Ischaemic Attack (TIA) vi) Peripheral Artery Disease (PAD) B. 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) C. 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 CVD D. Pre-existing diagnosis of heterozygous familial hypercholesterolemia (HeFH) with ASCVD or with another major risk factor.

   OR

   •High risk participants with at least one of the following: A. Markedly elevated single risk factors, in particular total cholesterol \> 310 mg/dL, LDL-C \> 190 mg/dL, or blood pressure ≥ 180/110 mmHg B. Pre-existing diagnosis of HeFH without other major risk factors C. DM without target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), with DM duration ≥ 10 years or other additional risk factor D. Moderate chronic kidney disease (eGFR 30-59 mL/min/1.73m2) E. A calculated SCORE2 2.5 to \<7.5% for age under 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)
4. LDL-C levels:

   1. in participants with very high cardiovascular risk: serum LDL-C ≥55 mg/dL
   2. in participants with high cardiovascular risk: serum LDL-C ≥70 mg/dL
5. Participant on a stable dose of a statin for ≥ 30 days.
6. Up to approximately 20% of total participants can be on a stable dose (for ≥ 30 days prior to screening) of another LLT on top of statin such as a cholesterol absorbing inhibitor or a bile acid sequestrant, or alternatively, an adenosine triphosphate citrate lyase (ACL) inhibitor, as indicated.
7. Fasting triglyceride \< 400 mg/dL.

   At Baseline:
8. Fasting triglyceride \< 400 mg/dL.
9. Before randomization, despite being treated with the individual MTD of a statin for ≥ 30 days and, if applicable, with another LLT on top of statin (stable for ≥ 30 days),

   1. in participants with very high cardiovascular risk: serum LDL-C ≥ 55mg/dL.
   2. in participants with high cardiovascular risk: serum LDL-C ≥ 70mg/dL.

Key Exclusion Criteria: Participants meeting any of the following criteria are not eligible for inclusion in this study.

1. Severe concomitant non-CV disease that is expected to reduce life expectancy to less than 2 years at screening or baseline visit.
2. Participants on more than one other lipid-lowering drug on top of statin at screening visit.
3. Pre-existing diagnosis of homozygous familial hypercholesterolemia at screening or baseline visit.
4. Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome at screening or baseline visit.
5. 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.
6. 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.
7. Previous, current or planned treatment with LDL-apheresis at screening or baseline visit.
8. Participants with known intolerance to rosuvastatin at screening or baseline visit.
9. History of hypersensitivity to any of the study treatments, inclisiran or rosuvastatin, or its excipients or to drugs of similar chemical classes at screening or baseline visit.
10. Participants taking gemfibrozil at screening or baseline visit.
11. 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.
12. 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.
13. 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.
14. Planned or expected cardiac, cerebrovascular or peripheral artery surgery or coronary revascularization within the study duration.
15. Heart failure New York Heart Association (NYHA) class IV at screening or baseline visit.
16. History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or systemic therapy (excluding systemic adjuvant therapies given to prevent cancer recurrence eg: hormonotherapy for prostate or breast cancer) during the 3 years prior to screening or baseline visit.
17. Participant with myopathy at screening or baseline visit.
18. Participant receiving concomitant ciclosporin at screening or baseline visit.
19. Participants that are predisposed to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures).
20. Participants with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose-malabsorption.
21. Unwillingness or inability (e.g. physical or cognitive) to comply with study procedures (including study visits, fasting blood draws and compliance with study treatment regimens), and medication administration (injections) and schedule. Participant should be able and willing to read, understand and answer questionnaires.
22. Any surgical or medical condition, which in the opinion of the investigator, may place the participant at higher risk from his/her participation in the study, or is likely to prevent the participant from complying with the requirements of the study or completing the study at screening or baseline visit.
23. Use of other investigational drugs within 5 half-lives, 30 days or until the expected pharmacodynamic effect has returned to baseline (e.g. biologics), whichever is longer or longer if required by local regulation, prior to screening visit.
24. Pregnant or nursing (lactating) women at screening or baseline visit.
25. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment, which includes rosuvastatin, and for 5 days (= 5 times the terminal half-life of rosuvastatin) after stopping medication. Highly effective contraception methods include:

    * Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
    * Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant.
    * Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1%), for example hormone vaginal ring or transdermal hormone contraception.

In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms). Women are considered not of child bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessments and she is considered not of child bearing potential.

If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the local ICF.

Primary outcomes:
measure: Proportion of participants achieving individual LDL-C target (<55 mg/dL or <70 mg/dL)
timeFrame: Day 90
Secondary outcomes:
measure: Relative percentage change from baseline to mean LDL-C level over the double-blind treatment period
timeFrame: Baseline to Day 360
measure: Proportion of participants experiencing at least one Muscle-related adverse event (AE) as defined in the Standardized MedDRA Queries (SMQ)
timeFrame: Baseline to Day 360
measure: Proportion of participants experiencing self-reported pain
timeFrame: Baseline to Day 360
measure: Change from baseline in Short-Form Brief Pain Inventory (SF-BPI) pain severity score to Day 360
timeFrame: Baseline to Day 360
measure: Change from baseline in Short-Form Brief Pain Inventory (SF-BPI) pain interference score at Day 360
timeFrame: Baseline to day 360
measure: Proportion of participants with clinically relevant change in Short-Form Brief Pain Inventory (SF-BPI) pain severity score from baseline to day 360.
timeFrame: Baseline to Day 360
measure: Proportion of participants with clinically relevant change in Short-Form Brief Pain Inventory (SF-BPI) pain interference score from baseline to day 360
timeFrame: Baseline to Day 360
Other outcomes:
Locations:
city: Burgas
country: Bulgaria
facility: Novartis Investigative Site
city: Gabrovo
country: Bulgaria
facility: Novartis Investigative Site
city: Pleven
country: Bulgaria
facility: Novartis Investigative Site
city: Plovdiv
country: Bulgaria
facility: Novartis Investigative Site
city: Ruse
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facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Stara Zagora
country: Bulgaria
facility: Novartis Investigative Site
city: Varna
country: Bulgaria
facility: Novartis Investigative Site
city: Veliko Tarnovo
country: Bulgaria
facility: Novartis Investigative Site
city: Pardubice
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Trutnov
country: Czechia
facility: Novartis Investigative Site
state: CZE
city: Prerov
country: Czechia
facility: Novartis Investigative Site
state: Olomoucky Kraj
city: Chlumec nad Cidlinou
country: Czechia
facility: Novartis Investigative Site
city: Hlucin
country: Czechia
facility: Novartis Investigative Site
city: Hodonin
country: Czechia
facility: Novartis Investigative Site
city: Melnik
country: Czechia
facility: Novartis Investigative Site
city: Olomouc
country: Czechia
facility: Novartis Investigative Site
city: Olomouc
country: Czechia
facility: Novartis Investigative Site
city: Slany
country: Czechia
facility: Novartis Investigative Site
city: Parnu
country: Estonia
facility: Novartis Investigative Site
city: Tallinn
country: Estonia
facility: Novartis Investigative Site
city: Tallinn
country: Estonia
facility: Novartis Investigative Site
city: Tartu
country: Estonia
facility: Novartis Investigative Site
city: Amiens
country: France
facility: Novartis Investigative Site
city: Chambery cedex
country: France
facility: Novartis Investigative Site
city: Le Chesnay
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city: Le Kremlin Bicetre
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city: Lille
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facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Nantes Cedex 1
country: France
facility: Novartis Investigative Site
city: Paris
country: France
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city: Valenciennes
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facility: Novartis Investigative Site
city: Mannheim
country: Germany
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state: Baden Wuerttemberg
city: Regensburg
country: Germany
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state: Bavaria
city: Lichtenfels
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Frankfurt am Main
country: Germany
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state: Hessen
city: Frankfurt Am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Frankfurt Am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Langen
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Winsen
country: Germany
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state: Lower Saxony
city: Goettingen
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Hannover
country: Germany
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state: Niedersachsen
city: Hannover
country: Germany
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state: Niedersachsen
city: Koeln
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facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Loehne
country: Germany
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state: Nordrhein-Westfalen
city: Kaiserslautern
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facility: Novartis Investigative Site
state: Rheinland-Pfalz
city: Bad Gottleuba
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Dresden
country: Germany
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state: Sachsen
city: Leipzig
country: Germany
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state: Sachsen
city: Schleswig
country: Germany
facility: Novartis Investigative Site
state: Schleswig-Holstein
city: Bad Homburg
country: Germany
facility: Novartis Investigative Site
city: Bad Krozingen
country: Germany
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city: Bad Oeynhausen
country: Germany
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city: Berlin
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city: Berlin
country: Germany
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city: Berlin
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city: Berlin
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city: Berlin
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city: Berlin
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city: Bochum
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city: Bremen
country: Germany
facility: Novartis Investigative Site
city: Coburg
country: Germany
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city: Dessau-Rosslau
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Duisburg
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city: Erfurt
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city: Erfurt
country: Germany
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city: Essen
country: Germany
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city: Essen
country: Germany
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city: Essen
country: Germany
facility: Novartis Investigative Site
city: Fulda
country: Germany
facility: Novartis Investigative Site
city: Gelnhausen
country: Germany
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city: Gladbeck
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
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city: Hamburg
country: Germany
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city: Hassloch
country: Germany
facility: Novartis Investigative Site
city: Hennigsdorf
country: Germany
facility: Novartis Investigative Site
city: Hoyerswerda
country: Germany
facility: Novartis Investigative Site
city: Kassel
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
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city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Lueneburg
country: Germany
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city: Magdeburg
country: Germany
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city: Magdeburg
country: Germany
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city: Mainz
country: Germany
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city: Mannheim
country: Germany
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city: Markkleeberg
country: Germany
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city: Muehldorf
country: Germany
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city: Muenchen
country: Germany
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city: Muenster
country: Germany
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city: Nuremberg
country: Germany
facility: Novartis Investigative Site
city: Papenburg
country: Germany
facility: Novartis Investigative Site
city: Pirna
country: Germany
facility: Novartis Investigative Site
city: Potsdam
country: Germany
facility: Novartis Investigative Site
city: Reinfeld
country: Germany
facility: Novartis Investigative Site
city: Rostock
country: Germany
facility: Novartis Investigative Site
city: Ruedersdorf
country: Germany
facility: Novartis Investigative Site
city: Singen
country: Germany
facility: Novartis Investigative Site
city: St. Ingbert Oberwuerzbach
country: Germany
facility: Novartis Investigative Site
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
city: Wallerfing
country: Germany
facility: Novartis Investigative Site
city: Warendorf
country: Germany
facility: Novartis Investigative Site
city: Wuppertal
country: Germany
facility: Novartis Investigative Site
city: Daugavpils
country: Latvia
facility: Novartis Investigative Site
city: Ogre
country: Latvia
facility: Novartis Investigative Site
city: Riga
country: Latvia
facility: Novartis Investigative Site
city: Riga
country: Latvia
facility: Novartis Investigative Site
city: Riga
country: Latvia
facility: Novartis Investigative Site
city: Riga
country: Latvia
facility: Novartis Investigative Site
city: Tarnow
country: Poland
facility: Novartis Investigative Site
state: Malopolskie
city: Krakow
country: Poland
facility: Novartis Investigative Site
state: Maloposkie
city: Szczecin
country: Poland
facility: Novartis Investigative Site
state: Zachodniopomorskie
city: Gdynia
country: Poland
facility: Novartis Investigative Site
city: Katowice
country: Poland
facility: Novartis Investigative Site
city: Krakow
country: Poland
facility: Novartis Investigative Site
city: Krosno
country: Poland
facility: Novartis Investigative Site
city: Rzeszow
country: Poland
facility: Novartis Investigative Site
city: Skierniewice
country: Poland
facility: Novartis Investigative Site
city: Cordoba
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sanlucar de Barrameda
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Oviedo
country: Spain
facility: Novartis Investigative Site
state: Asturias
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: San Sebastian de los Reyes
country: Spain
facility: Novartis Investigative Site
state: Madrid
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: