Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Homozygous Familial Hypercholesterolemia

Phase 3

Completed

Conditions: Familial Hypercholesterolemia - Homozygous

Interventions: Drug: Inclisiran
Drug: Placebo

Registration Number: NCT04659863

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This was a pivotal phase III study designed to evaluate safety, tolerability, and efficacy of inclisiran in adolescents with homozygous familial hypercholesterolemia (HoFH) and elevated low density lipoprotein cholesterol (LDL-C).

Detailed Description: This was a two-part (double-blind, inclisiran versus placebo \[Year 1\] followed by open-label inclisiran \[Year 2\]) multicenter study in adolescents (aged 12 to \< 18 years) with HoFH and elevated LDL-C (\> 130 mg/dL; 3.4 mmol/L) on stable, individualized, optimal standard of care (SoC) background lipid-lowering therapy (including maximally tolerated statin treatment, at the Investigator's discretion) to evaluate the safety, tolerability, and efficacy of inclisiran in this pediatric patient population.

Following an approximately 4-week screening/run-in period, the study had 2 sequential parts as follows:

Part 1/Year 1: 12 months double-blind, parallel group period, in which participants were randomized in a 2:1 ratio to receive either inclisiran sodium 300 mg subcutaneous (s.c.) or placebo. The primary endpoint was assessed at Day 330.

Part 2/Year 2: 12 months single arm, open-label follow-up period, with all participants receiving inclisiran sodium 300 mg s.c.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 13

Inclusion Criteria

Homozygous Familial Hypercholesterolemia (HoFH) diagnosed by genetic confirmation
Fasting LDL-C >130 mg/dL (3.4 mmol/L) at screening
On maximally tolerated dose of statin (investigator's discretion) with or without other lipid-lowering therapy; stable for ≥ 30 days before screening
Male or female participants >=12 to <18 years of age at screening

Exclusion Criteria

Documented evidence of a null (negative) mutation in both LDLR alleles
Heterozygous familial hypercholesterolemia (HeFH)
Active liver disease
Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome
Previous treatment with monoclonal antibodies directed towards PCSK9 (within 90 days of screening)
Treatment with mipomersen or lomitapide (within 5 months of screening)
Recent and/or planned use of other investigational medicinal products or devices

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1 - Inclisiran	Inclisiran	Inclisiran sodium 300 mg subcutaneous (sc) injection (given at Days 1, 90 and 270)
Part 1 - Placebo	Placebo	Placebo sc injection (given at Day 1, 90 and 270)
Part 2 - Inclisiran (Total)	Inclisiran	Inclisiran sodium 300 mg sc injection (given at Days 450 and 630). In addition, participants assigned to placebo in Part 1 received inclisiran sodium 300 mg sc injection on Day 360, while participants assigned to inclisiran in Part 1 received placebo sc injection on Day 360.

Primary Outcome Measures

Name	Time	Method
Percentage Change in LDL-C From Baseline to Day 330 (Part 1/Year 1)	Baseline and Day 330	Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to Day 330 (Year 1)

Secondary Outcome Measures

Name	Time	Method
Percent Change in Apo A1 From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in apolipoprotein A1 (Apo A1) from baseline to each assessment time up to Day 720.
Absolut Change in PCSK9 From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline to each assessment time up to Day 720.
Percent Change in LDL-C From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in LDL-C from baseline to each assessment time up to Day 720.
Absolute Change in Triglycerides From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in triglycerides from baseline to each assessment time up to Day 720.
Percent Change in VLDL-C From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in very low density lipoprotein cholesterol (VLDL-C) from baseline to each assessment time up to Day 720.
Absolute Change in Apo A1 From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in apolipoprotein A1 (Apo A1) from baseline to each assessment time up to Day 720.
Percent Change in PCSK9 From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline to each assessment time up to Day 720.
Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 330 (Part 1/Year 1)	Baseline, after Day 90 up to Day 330	Time-adjusted percent change in LDL-C (after Day 90 and up to Day 330), calculated as the average of percent changes from baseline to Days 150, 270 and 330
Absolute Change in LDL-C From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in LDL-C from baseline to each assessment time up to Day 720.
Percent Change in Apo B From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in apolipoprotein B (Apo B) from baseline to each assessment time up to Day 720.
Absolute Change in Apo B From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in apolipoprotein B (Apo B) from baseline to each assessment time up to Day 720.
Percent Change in Lp(a) From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in lipoprotein (a) \[Lp(a)\] from baseline to each assessment time up to Day 720.
Absolute Change in Lp(a) From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in lipoprotein (a) \[Lp(a)\] from baseline to each assessment time up to Day 720.
Percent Change in Non-HDL-C From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in non-high density lipoprotein cholesterol (non-HDL-C) from baseline to each assessment time up to Day 720.
Absolute Change in Non-HDL-C From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in non-high density lipoprotein cholesterol (non-HDL-C) from baseline to each assessment time up to Day 720.
Percent Change in Total Cholesterol From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in total cholesterol from baseline to each assessment time up to Day 720.
Absolute Change in Total Cholesterol From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in total cholesterol from baseline to each assessment time up to Day 720.
Percent Change in Triglycerides From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in triglycerides from baseline to each assessment time up to Day 720.
Percent Change in HDL-C From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in high density lipoprotein cholesterol (HDL-C) from baseline to each assessment time up to Day 720.
Absolute Change in HDL-C From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in high density lipoprotein cholesterol (HDL-C) from baseline to each assessment time up to Day 720.
Absolut Change in VLDL-C From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in very low density lipoprotein cholesterol (VLDL-C) from baseline to each assessment time up to Day 720.

Trial Locations

Locations (6): Excel Medical Clinical Trials LLC
🇺🇸
Boca Raton, Florida, United States
Novartis Investigative Site
🇹🇷
Izmir, Turkey
University General Hospital of Ioannina
🇬🇷
Ioannina, GR, Greece
Metropolitan Hospital
🇬🇷
Athens, Greece
Hotel Dieu de France Hospital
🇱🇧
Ashrafieh, Lebanon
American University of Beirut Medical Center
🇱🇧
Beirut, Lebanon
Excel Medical Clinical Trials LLC
🇺🇸Boca Raton, Florida, United States