A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH)
Condition: Homozygous Familial Hypercholesterolemia
MeSH terms: Hyperlipoproteinemia Type II; Homozygous Familial Hypercholesterolemia; Hypercholesterolemia
Intervention: Inclisiran Sodium for injection; Placebo; Placebos
Intervention description: Inclisiran is a synthetic, chemically modified small interfering ribonucleic acid (siRNA) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) messenger ribonucleic acid (mRNA) with a covalently attached triantennary N-acetylgalactosamine (GalNAc) ligand.; Sterile normal saline (0.9% sodium chloride in water for injection); Sterile normal saline (0.9% sodium chloride in water for injection)
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking description: Double-blind
Enrollment: 56.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: HoFH

Summary:

      This study was a Phase III,A two-part (double-blind placebo-controlled/open-label)
      multicenter study to evaluate safety, tolerability, and efficacy of inclisiran in subjects
      with homozygous familial hypercholesterolemia (HoFH).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Diagnosis of HoFH by genetic confirmation or a clinical diagnosis based on a history
             of an untreated LDL-C concentration >500 mg/dL (13 mmol/L) together with either
             xanthoma before 10 years of age or evidence of heterozygous familial
             hypercholesterolemia in both parents

          2. Stable on a low-fat diet.

          3. Subjects on statins should be receiving a maximally tolerated dose. Maximum tolerated
             dose is defined as the maximum dose of statin that can be taken on a regular basis
             without intolerable adverse events.

          4. Subjects not receiving statins must have documented evidence of intolerance to at
             least two different statins.

          5. Subjects on lipid-lower therapies (such as statin and/or ezetimibe) should be on a
             stable dose for ≥30 days before screening with no planned medication or dose change
             during study participation.

          6. Fasting central laboratory LDL-C concentration ≥130 mg/dL (3.4 mmol/L).

          7. Triglyceride concentration <400 mg/dL (4.5 mmol/L)

          8. No current or planned renal dialysis or renal transplantation

          9. Subjects on a documented regimen of LDL or plasma apheresis will be allowed to
             continue the apheresis during the study, if needed.

         10. Subjects must be willing and able to give written informed consent before initiation
             of any study-related procedures. The subject should be willing to comply with all
             required study procedures.

         11. Willing to follow all study procedures including adherence to dietary guidelines,
             study visits, fasting blood draws, and compliance with study treatment regimens.

        Exclusion Criteria:

          1. Use of Mipomersen or Lomitapide therapy within 5 months of screening

          2. Treatment (within 90 days of screening) with monoclonal antibodies directed towards
             PCSK9

          3. New York Heart Association (NYHA) class IV heart failure or last known left
             ventricular ejection fraction <25%

          4. Major adverse cardiovascular event within 3 months prior to randomization

          5. Planned cardiac surgery or revascularization

          6. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood
             pressure >110 mmHg prior to randomization despite anti-hypertensive therapy

          7. Active liver disease defined as any known current infectious, neoplastic, or metabolic
             pathology of the liver or unexplained alanine aminotransferase (ALT), aspartate
             aminotransferase (AST), elevation >3x ULN, or total bilirubin >2x upper limit of
             normal (ULN) at screening confirmed by a repeat measurement at least 1 week apart

          8. Severe concomitant noncardiovascular disease that carries the risk of reducing life
             expectancy to less than the duration of the trial

          9. History of malignancy that required surgery (excluding local and wide-local excision),
             radiation therapy and/or commencement of systemic therapy as treatment during the 3
             years prior to randomization

         10. Females who are pregnant or nursing, or who are of childbearing potential and
             unwilling to use at least one acceptable effective method of contraception (eg, oral
             contraceptives, barrier methods, approved contraceptive implant, long- term injectable
             contraception, intrauterine device) for the entire duration of the study. Exemptions
             from this criterion:

               1. Women >2 years postmenopausal (defined as 1 year or longer since their last
                  menstrual period) AND more than 55 years of age

               2. Postmenopausal women (as defined above) and less than 55 years of age with a
                  negative pregnancy test within 24 hours of enrolment

               3. Women who are surgically sterilized at least 3 months prior to enrolment

         11. Known history of alcohol and/or drug abuse within 5 years

         12. Any condition that according to the investigator could interfere with the conduct of
             the study, such as but not limited to:

               1. Subjects who are unable to communicate or to cooperate with the investigator.

               2. Unable to understand the protocol requirements, instructions and study-related
                  restrictions, the nature, scope, and possible consequences of the study
                  (including subjects whose cooperation is doubtful due to drug abuse or alcohol
                  dependency)

               3. Unlikely to comply with the protocol requirements, instructions, and
                  study-related restrictions (eg, uncooperative attitude, inability to return for
                  follow-up visits, and improbability of completing the study)

               4. Have any medical or surgical condition, which in the opinion of the investigator
                  would put the subject at increased risk from participating in the study

               5. Persons directly involved in the conduct of the study

         13. 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 subject at
             significant risk (according to investigator's [or delegate] judgment) if he/she
             participates in the clinical study

         14. Any underlying known disease, or surgical, physical, or medical condition that, in the
             opinion of the Investigator, might interfere with the interpretation of clinical study
             results

         15. Treatment with other investigational medicinal products or devices within 30 days or 5
             half-lives of the screening visit, whichever is longer

         16. Previous participation in the study

         17. Hypersensitivity to any of the ingredients of Inclisiran

        The above information is not intended to contain all considerations relevant to a
        participant's potential participation in a clinical trial.