LDL-C Optimization Using Inclisiran in Patients in Which Drug-Drug Interactions Limit LDL Lowering

NCT06865885 | Recruiting Phase 4 DMC FDA Drug

• 2 other identifiers: 810920315668-00001
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Drug-drug interactions often limit statin optimization in a population of patients prescribed cytochrome P3A4 inhibitors, which include immunosuppressive agents, protease inhibitors, and antifungals. These patients frequently have autoimmune conditions or rheumatologic disorders that require complex drug regimens and are often on low-dose statin therapy or no statin at all, resulting in suboptimal LDL levels despite increased cardiovascular (CV) risk. There is an unmet clinical need to improve LDL levels in this vulnerable patient population, which faces increased CV risk due to underlying conditions that also contribute to polypharmacy and multiple drug-drug interactions. This study is a randomized, open-label trial evaluating subcutaneous inclisiran plus standard of care for LDL-C lowering in high-risk primary prevention patients with multiple comorbidities (e.g., Type II diabetes, liver disease, chronic kidney disease, autoimmune disease, solid-organ transplant) who are taking five or more medications in which drug-drug interactions prevent optimization of statin therapy.

Conditions

Drug Interactions; Primary Prevention; Cardiometabolic Syndrome; LDL-Cholersterol Lowering

Keywords

Statin intolerance; drug drug interaction; inclisiran; LDL-Cholesterol; polypharmacy; multiple comorbidities

Outcome Measures

Primary Outcomes (1)

• Change of LDL-Cholesterol

  Percent Change in LDL-C from baseline to month 12 of treatment with inclisiran as add on to background lipid-lowering therapy that includes maximally tolerated statin.

  12 months

Secondary Outcomes (1)

• Change in Atherogenic Lipid Burden

  12 months

Other Outcomes (2)

• Patient-Reported Experience

  12 months

• Incidence of Adverse Events

  12 months

Study Arms (2)

Standard of Care, no intervention

NO INTERVENTION

Patients will continue the standard of care for lipid lowering as deemed appropriate by their medical team, no changes to lipid lowering therapy are permited during the study.

Inclisiran Arm

ACTIVE COMPARATOR

Patients in the intervention arm will be treated with a subcutaneous injection of inclisiran 284mg for three doses (baseline visit, 3 months, then 9 month visit) as add-on therapy to the standard of care for lipid lowering as determined by their medical team.

Drug: Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL

Interventions

Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL DRUG

The intervention arm will receive subcutaneous injection of inclisiran 284mg at the baseline visit, 3 months and 9 month visit.

Inclisiran Arm

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated informed consent form.
• Stated willingness to comply with all study procedures and availability for the duration of the study, including potential randomization to injections.
• Age \>18 and \<85 years and able to provide self-consent.
• Taking five or more prescription drugs at the time of enrollment, of any type.
• Meets at least one of the following criteria:
• Elevated 10-year ASCVD risk score ≥7.5% (based on the ACC/AHA ASCVD Risk Estimator Plus tool).
• Evidence of subclinical atherosclerosis including:
• Calcification in any vascular bed, including coronary arteries and aorta. Calcification of cardiac valves. Breast calcification. Carotid plaque that is not hemodynamically significant.
• o Type II diabetes on a stable medical regimen with HbA1c \<8.5%. Per American Diabetes Association guidelines, patients with Type II diabetes aged 40-75 years should be on a moderate-intensity statin.
• Patients with documented partial or complete statin intolerance are eligible for enrollment.
• On maximally tolerated statin therapy (which can be no statin for patients with documented intolerance) and have suboptimal LDL levels:
• For patients with Type II diabetes: LDL \>70 mg/dL or non-HDL \>120 mg/dL.
• For other patients: LDL \>90 mg/dL or non-HDL \>120 mg/dL.
• Willing to adhere to the randomized study regimen, including subcutaneous injection of inclisiran.
• Agreement to adhere to lifestyle considerations (see Section 5.3) throughout the study duration.

You may not qualify if:

• Prior or current use of inclisiran.
• Known hypersensitivity or allergy to inclisiran or its components.
• Active liver disease or unexplained persistent elevations in liver enzymes (ALT or AST \>3x upper limit of normal).
• History of rhabdomyolysis or severe muscle-related statin intolerance.
• Uncontrolled diabetes (HbA1c \>8.5%).
• Active malignancy requiring systemic therapy.
• Recent major cardiovascular event (myocardial infarction, stroke, or hospitalization for unstable angina) within the past 3 months.
• History of organ transplant other than solid-organ transplant.
• Pregnancy or breastfeeding.
• Any condition that, in the opinion of the investigator, would make participation unsafe or interfere with study procedures.

Sponsors & Collaborators

• University of California, San Diego: lead
• Novartis: collaborator

Study Sites (1)

UC San Diego Altman Clinical and Translational Research Institute

La Jolla, California, 92037, United States

RECRUITING

Related Publications (11)

• Wright RS, Ray KK, Raal FJ, Kallend DG, Jaros M, Koenig W, Leiter LA, Landmesser U, Schwartz GG, Friedman A, Wijngaard PLJ, Garcia Conde L, Kastelein JJP; ORION Phase III Investigators. Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis. J Am Coll Cardiol. 2021 Mar 9;77(9):1182-1193. doi: 10.1016/j.jacc.2020.12.058.

  PMID: 33663735 BACKGROUND

• Budoff MJ, Kinninger A, Gransar H, Achenbach S, Al-Mallah M, Bax JJ, Berman DS, Cademartiri F, Callister TQ, Chang HJ, Chow BJW, Cury RC, Feuchtner G, Hadamitzky M, Hausleiter J, Kaufmann PA, Leipsic J, Lin FY, Kim YJ, Marques H, Pontone G, Rubinshtein R, Shaw LJ, Villines TC, Min JK; CONFIRM Investigators. When Does a Calcium Score Equate to Secondary Prevention?: Insights From the Multinational CONFIRM Registry. JACC Cardiovasc Imaging. 2023 Sep;16(9):1181-1189. doi: 10.1016/j.jcmg.2023.03.008. Epub 2023 May 24.

  PMID: 37227328 BACKGROUND

• American Diabetes Association Professional Practice Committee. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care. 2024 Jan 1;47(Suppl 1):S179-S218. doi: 10.2337/dc24-S010.

  PMID: 38078592 BACKGROUND

• Iribarren C, Chandra M, Lee C, Sanchez G, Sam DL, Azamian FF, Cho HM, Ding H, Wong ND, Molloi S. Breast Arterial Calcification: a Novel Cardiovascular Risk Enhancer Among Postmenopausal Women. Circ Cardiovasc Imaging. 2022 Mar;15(3):e013526. doi: 10.1161/CIRCIMAGING.121.013526. Epub 2022 Mar 15.

  PMID: 35290077 BACKGROUND

• Fox CS, Vasan RS, Parise H, Levy D, O'Donnell CJ, D'Agostino RB, Benjamin EJ; Framingham Heart Study. Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study. Circulation. 2003 Mar 25;107(11):1492-6. doi: 10.1161/01.cir.0000058168.26163.bc.

  PMID: 12654605 BACKGROUND

• Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med. 1999 Jul 15;341(3):142-7. doi: 10.1056/NEJM199907153410302.

  PMID: 10403851 BACKGROUND

• Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, Kastelein JJP; ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-1519. doi: 10.1056/NEJMoa1912387. Epub 2020 Mar 18.

  PMID: 32187462 BACKGROUND

• Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, Wijngaard PLJ, Curcio D, Jaros MJ, Leiter LA, Kastelein JJP; ORION-9 Investigators. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020 Apr 16;382(16):1520-1530. doi: 10.1056/NEJMoa1913805. Epub 2020 Mar 18.

  PMID: 32197277 BACKGROUND

• Wiggins BS, Saseen JJ, Page RL 2nd, Reed BN, Sneed K, Kostis JB, Lanfear D, Virani S, Morris PB; American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology; Council on Hypertension; Council on Quality of Care and Outcomes Research; and Council on Functional Genomics and Translational Biology. Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2016 Nov 22;134(21):e468-e495. doi: 10.1161/CIR.0000000000000456. Epub 2016 Oct 17. No abstract available.

  PMID: 27754879 BACKGROUND

• Hughes JE, Waldron C, Bennett KE, Cahir C. Prevalence of Drug-Drug Interactions in Older Community-Dwelling Individuals: A Systematic Review and Meta-analysis. Drugs Aging. 2023 Feb;40(2):117-134. doi: 10.1007/s40266-022-01001-5. Epub 2023 Jan 24.

  PMID: 36692678 BACKGROUND

• Moran CA, Collins LF, Beydoun N, Mehta PK, Fatade Y, Isiadinso I, Lewis TT, Weber B, Goldstein J, Ofotokun I, Quyyumi A, Choi MY, Titanji K, Lahiri CD. Cardiovascular Implications of Immune Disorders in Women. Circ Res. 2022 Feb 18;130(4):593-610. doi: 10.1161/CIRCRESAHA.121.319877. Epub 2022 Feb 17.

  PMID: 35175848 BACKGROUND

MeSH Terms

Conditions

Metabolic Syndrome

Interventions

ALN-PCS

Condition Hierarchy (Ancestors)

Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Michael Wilkinson, MD

  University of California, San Diego

  STUDY DIRECTOR

• Eric D Adler, MD

  University of California, San Diego

  STUDY CHAIR

• Pam Taub, MD

  University of California, San Diego

  PRINCIPAL INVESTIGATOR

• Antoinette Birs, MD

  University of California, San Diego

  STUDY DIRECTOR

Central Study Contacts

Pam Taub, MD

CONTACT

858-657-8530; ptaub@health.ucsd.edu

Antoinette S Birs, MD

CONTACT

5612817745; abirs@health.ucsd.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine, Directior of Preventative Cardiology

Model Details: Patients will be randomized 1:1 to the inclisiran arm (n=50) or will continue with standard of care (n=50). The study will consist of 5 study visits (screening, baseline, 3 mo., 9 mo., and 12 mo.). Patients in the inclisiran arm will be treated with subcutaneous injection of inclisiran 284mg (baseline, 3 months, then 9 month visit) as add-on therapy to SOC lipid-lowering therapies. LDL-C (primary endpoint) along with other biomarkers will be measured at screening, baseline, 3 mo., 9 mo., and 12 months.

Study Record Dates

• First Submitted: March 4, 2025
• First Posted: March 10, 2025
• Study Start: April 3, 2025
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: April 11, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)