Hypercholesterolemia
Conditions
Keywords
Inclisiran, rosuvastatin, PCSK9, dyslipidemia, angina pectoris, peripheral artery disease, cardiovascular disease, LDL-C
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
This was a double-blind, placebo-controlled multicenter study in adult participants with very high or high cardiovascular risk who did not meet their individual LDL-C target despite being treated with their individual maximum tolerated dose (MTD) of a statin, and if applicable, further Lipid-Lowering Therapy (LLT). The purpose of this study was to demonstrate the superiority of inclisiran compared to placebo, both on top of ongoing individually optimized 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.
Interventions
Subcutaneously injected on Day 1, Day 90, and Day 270
DRUGPlacebo
Placebo to inclisiran 300 mg subcutaneously
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Participants were randomized at the baseline visit (Day 1) to one of the following two double-blind treatment groups in a 1:1 ratio. 1. Inclisiran sodium 300 mg s.c. 2. Corresponding placebo Each participant received one injection of blinded inclisiran or placebo on Day 1, a second injection of blinded inclisiran or placebo on Day 90 and a subsequent injection of blinded inclisiran or placebo on Day 270, unless there was a need for discontinuing inclisiran/placebo in the course of the study
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 received 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Individual LDL-C Target (<55 mg/dL or <70 mg/dL) | Day 90 | Number of participants achieving individual Low-density Lipoprotein Cholesterol (LDL-C) target (\< 55 mg/dL or \< 70 mg/dL) at Day 90. The individual LDL-C target of the participants was determined according to their most recent individual cardiovascular risk category. A larger proportion of participants indicates a superior outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline to Mean LDL-C Level Over the Double-blind Treatment Period | Baseline to Day 360 | Relative (percentage) change from baseline in Low-density Lipoprotein Cholesterol (LDL-C) level averaged over the double-blind treatment period |
| Number of Participants Experiencing at Least One Muscle-related Adverse Event From Day 1 to Day 360 | Day 1 to Day 360 | The number of participants who experienced at least one muscle-related adverse event, defined as Standardized MedDRA Queries (SMQ) rhabdomyolysis / myopathy from Day 1 to Day 360. All muscle-related adverse events occurring between first dose of double-blind treatment and earliest date out of visit Day 360, death date and last contact date are considered. |
| Number of Participants Experiencing Self-reported Pain | Day 1 to Day 360 | Self-reported pain is reported at its worst in the last 24 h on a numeric rating scale from 0 (no pain) to 10 (pain as bad as you can imagine). Days with a score of 0 are considered as days without pain. The percentage of days with pain for each participant is calculated as number of days with pain divided by the total number of days where diary was completed, multiplied by 100. Diary data between the first dose of double-blind treatment up to the minimum of last contact date and Day 360 visit are considered. |
| Annualized Number of Days With Pain | Day 1 to Day 360 | Annualized rate refers to the estimated number of days with pain per year. Self-reported pain is reported at its worst in the last 24 h on a numeric rating scale from 0 (no pain) to 10 (pain as bad as you can imagine). Days with a score of 0 are considered as days without pain. |
| Average Absolute Change From Baseline in Short-Form Brief Pain Inventory (SF-BPI) Pain Severity Score Over the Double-blind Treatment Period | Baseline to Day 360 | The Short-Form Brief Pain Inventory (SF-BPI) is a self-administered standardized fifteen items questionnaire that assesses how pain interferes with or influences a participant's life. The query period covers the past 24 hours and takes 5 minutes for the participant to complete. The pain severity score was derived for each visit between screening and EOT/EOS (Day 360) as the average over the 4 items in the pain severity domain (questionnaire items number 3, 4, 5, 6). The derived pain severity score ranged between 0 (no pain) and 10 (pain as bad as you can imagine), with larger values indicating a higher level of pain severity (worse outcome). If there was missing data for a participant and the available data was more than 50% for the corresponding domain (3 of 4 \[pain severity\] ), the missing items were imputed using the mean score of the non-missing item scores. |
| Average Absolute Change From Baseline in Short-Form Brief Pain Inventory (SF-BPI) Pain Interference Score Over the Double-blind Treatment Period | Baseline to Day 360 | The Short-Form Brief Pain Inventory (SF-BPI) is a self-administered standardized fifteen items questionnaire that assesses how pain interferes with or influences a participant's life. The query period covers the past 24 hours and takes 5 minutes for the participant to complete. The pain interference score was derived for each visit between screening and EOT/EOS (Day 360) as the average over the 7 items in the pain interference domain (questionnaire items number 9A through 9G). The derived pain interference score ranged between 0 (does not interfere) and 10 (completely interferes), with larger values indicating a higher level of pain interference (worse outcome). If there was missing data for a participant and the available data was more than 50% for the corresponding domain (4 of 7 \[pain interference\] ), the missing items were imputed using the mean score of the non-missing item scores. |
| Number of Participants With Clinically Relevant Change in Short-Form Brief Pain Inventory (SF-BPI) Pain Severity Score From Baseline to Day 360. | Baseline to Day 360 | The Short-Form Brief Pain Inventory (SF-BPI) is a self-administered standardized fifteen items questionnaire that assesses how pain interferes with or influences a participant's life. The query period covers the past 24 hours and takes 5 minutes for the participant to complete. The pain severity score was derived for each visit between screening and EOT/EOS (Day 360) as the average over the 4 items in the pain severity domain (questionnaire items number 3, 4, 5, 6). The derived pain severity score ranged between 0 (no pain) and 10 (pain as bad as you can imagine), with larger values indicating a higher level of pain severity (worse outcome). A clinically relevant change is defined by a reduction from baseline in SF-BPI pain severity score by at least 2 points. If there was missing data for a participant and the available data was more than 50% for the corresponding domain (3 of 4 \[pain severity\] ), the missing items were imputed using the mean score of the non-missing item scores. |
| Number of Participants With Clinically Relevant Change in Short-Form Brief Pain Inventory (SF-BPI) Pain Interference Score From Baseline to Day 360 | Baseline to Day 360 | The SF-BPI is a self-administered standardized fifteen items questionnaire that assesses how pain interferes with or influences a participant's life. The query period covers the past 24 hours and takes 5 minutes for the participant to complete. The pain interference score was derived for each visit between screening and EOT/EOS (Day 360) as the average over the 7 items in the pain interference domain (questionnaire items number 9A through 9G). The derived pain interference score ranged between 0 (does not interfere) and 10 (completely interferes), with larger values indicating a higher level of pain interference (worse outcome). A clinically relevant change is defined by a reduction from baseline in SF-BPI pain interference score by at least 2 points. If there was missing data for a participant and the available data was more than 50% for the corresponding domain (4 of 7 \[pain interference\] ), the missing items were imputed using the mean score of the non-missing item scores. |
Countries
Bulgaria, Czechia, Estonia, France, Germany, Latvia, Poland, Spain
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Pre-assignment details
This study had a screening period of approximately 14 days for all participants. Participants must have been on a stable dose of statin for ≥ 30 days prior to the screening visit.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 429 Participants |
| Age, Categorical Between 18 and 65 years | 443 Participants |
| Age, Continuous | 63.7 years STANDARD_DEVIATION 9.84 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 17 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants |
| Race/Ethnicity, Customized White | 870 Participants |
| Sex: Female, Male Female | 262 Participants |
| Sex: Female, Male Male | 1235 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 900 | 5 / 870 | 11 / 1,770 |
| other Total, other adverse events | 416 / 900 | 462 / 870 | 878 / 1,770 |
| serious Total, serious adverse events | 148 / 900 | 148 / 870 | 296 / 1,770 |
Outcome results
None listed