Patient case: 24-year-old female with familial hypercholesterolemia; genetic feature: PCSK9

Clinical trial: An Extension Trial of Inclisiran Compared to Evolocumab in Participants With Cardiovascular Disease and High Cholesterol

Summary: ORION-3 is a Phase II, open-label, non-randomized, active comparator extension trial to assess the efficacy, safety, and tolerability of long-term dosing of inclisiran and evolocumab given as subcutaneous injections in participants with high cardiovascular risk and elevated low-density lipoprotein cholesterol (LDL-C).

Detailed description: ORION-3, an extension of study MDCO-PCS-15-01 (ORION-1) [NCT02597127], is a Phase II, placebo-controlled, double-blind, randomized trial to evaluate the efficacy, safety, and tolerability of inclisiran (ALN-PCSSC) injection(s). All participants who completed ORION-1 (at least up to and including Day 210) and meet the study criteria will be enrolled into this study.
  ORION-3 is a long-term extension trial with an active comparator (evolocumab) in participants with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents (diabetes, familial hypercholesterolemia) and elevated LDL-C, despite maximum tolerated dose of LDL-C lowering therapies.

Eligibility: Inclusion Criteria:
  1. Completion of Study MDCO-PCS-15-01 and no contraindication to receiving inclisiran or evolocumab.
  2. Willing and able to give written and informed consent before initiation of any study related procedures and willing to comply with all required study procedures.
  3. Willing to self-inject.
  Exclusion Criteria:
  1. Any uncontrolled or serious disease, or any medical or surgical condition that may either interfere with participation in the clinical study and/or put the participant at significant risk (according to investigator's [or delegate's] judgment).
  2. An underlying known disease or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate), might interfere with interpretation of the clinical study results.
  3. Serious comorbid disease in which the life expectancy of the participant is shorter than the duration of the trial (for example, acute systemic infection, cancer, or other serious illnesses).
  4. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver; unexplained alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation greater than 2 times upper limit of normal (ULN); or total bilirubin elevation greater than 1.5 times ULN at study entry visit.
  5. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least two methods of contraception (for example, oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device) for the entire duration of the study. Exemptions from this criterion are
  -  Women >2 years postmenopausal (defined as 1 year or longer since their last menstrual period) AND more than 55 years of age
  -  Postmenopausal women (as defined above) and less than 55 years old with a negative pregnancy test within 24 hours of enrollment
  -  Women who are surgically sterilized at least 3 months prior to enrollment
  6. Males who are unwilling to use an acceptable method of birth control during the entire study period (that is, condom with spermicide).
  7. Treatment with investigational medicinal products other than inclisiran or devices within 30 days or five half˗lives, whichever is longer.
  8. Planned use of investigational medicinal products other than inclisiran or devices during the course of the study.
  9. Participants with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients
  10. Previous or current treatment (within 90 days of study entry) with monoclonal antibodies directed towards PCSK9.
  11. Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to:
  -  Inappropriate for this study, including participants who are unable to communicate or to cooperate with the investigator.
  -  Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including participants whose cooperation is doubtful due to drug abuse or alcohol dependency).
  -  Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (for example, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study).
  -  Involved with, or a relative of, someone directly involved in the conduct of the study.
  -  Any known cognitive impairment (for example, Alzheimer's Disease).

Relevance to patient case: not relevant