Clinical trial NCT03397121: Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)
Official title: Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of Inclisiran Sodium Given as Subcutaneous Injections in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH) and Elevated Low-Density Lipoprotein Cholesterol (LDL-C).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heterozygous Familial Hypercholesterolemia
Elevated Cholesterol
Keywords: HeFH
LDL-C
Inclisiran
Lead sponsor: The Medicines Company
Sponsor class: INDUSTRY
First posted: 2018-01-11
Enrollment: 482
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase III, placebo-controlled, double-blind, randomized study in participants with HeFH and elevated LDL-C to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) injection(s) of inclisiran. The study will be multicenter and international.


Eligibility criteria: Inclusion Criteria:

Participants may be included if they meet all of the following inclusion criteria prior to randomization:

1. Male or female participants ≥18 years of age.
2. History of HeFH with a diagnosis of HeFH by genetic testing; and/or a documented history of untreated LDL-C of \>190 mg/dL, and a family history of familial hypercholesterolemia, elevated cholesterol or early heart disease that may indicate familial hypercholesterolemia.
3. Serum LDL-C ≥2.6 millimoles (mmol)/liter (L) (≥100 mg/dL) at screening.
4. Fasting triglyceride \<4.52 mmol/L (\<400 mg/dL) at screening.
5. Participants on statins should be receiving a maximally tolerated dose.
6. Participants not receiving statins must have documented evidence of intolerance to all doses of at least 2 different statins.
7. Participants on lipid-lowering therapies (such as a 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.

Exclusion Criteria:

Participants will be excluded from the study if any of the following exclusion criteria apply immediately prior to randomization:

1. New York Heart Association (NYHA) class IV heart failure.
2. Uncontrolled cardiac arrhythmia
3. Uncontrolled severe hypertension
4. Active liver disease
5. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least 2 methods of highly effective contraception (failure rate less than 1% per year) (combined oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, or 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 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 randomization.
   3. 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 (condom with spermicide).
7. Treatment with other investigational products or devices within 30 days or 5 half-lives of the screening visit, whichever is longer.
8. Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Primary outcomes:
measure: Percent Change in LDL-C From Baseline To Day 510
timeFrame: Baseline, Day 510
measure: Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540
timeFrame: Baseline, Day 90
Secondary outcomes:
measure: Absolute Change in LDL-C From Baseline to Day 510
timeFrame: Baseline, Day 510
measure: Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540
timeFrame: Baseline, Day 90
measure: Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510
timeFrame: Baseline, Day 510
measure: Percentage Change in Total Cholesterol From Baseline to Day 510
timeFrame: Baseline, Day 510
measure: Percent Change in Apolipoprotein B (Apo-B) From Baseline To Day 510
timeFrame: Baseline, Day 510
measure: Percent Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510
timeFrame: Baseline, Day 510
Other outcomes:
Locations:
city: Mission Viejo
country: United States
facility: Site 90001-005
state: California
city: Newport Beach
country: United States
facility: Site 90001-001
state: California
city: Stanford
country: United States
facility: Site 90001-015
state: California
city: Boca Raton
country: United States
facility: Site 90001-047
state: Florida
city: Boston
country: United States
facility: Site 90001-004
state: Massachusetts
city: Saint Paul
country: United States
facility: Site 90001-056
state: Minnesota
city: Butte
country: United States
facility: Site 90001-012
state: Montana
city: Las Vegas
country: United States
facility: Site 90001-112
state: Nevada
city: Summit
country: United States
facility: Site 90001-014
state: New Jersey
city: Cincinnati
country: United States
facility: Site 90001-002
state: Ohio
city: Chicoutimi
country: Canada
facility: Site 90011-005
state: Quebec
city: Montréal
country: Canada
facility: Site 90011-001
state: Quebec
city: Quebec City
country: Canada
facility: Site 90011-002
state: Quebec
city: Prague
country: Czechia
facility: Site 90420-001
city: Prague
country: Czechia
facility: Site 90420-006
city: Trutnov
country: Czechia
facility: Site 90420-005
city: Aalborg
country: Denmark
facility: Site 90045-001
city: Esbjerg
country: Denmark
facility: Site 90045-004
city: Herning
country: Denmark
facility: Site 90045-003
city: Hvidovre
country: Denmark
facility: Site 90045-006
city: Roskilde
country: Denmark
facility: Site 90045-002
city: Viborg
country: Denmark
facility: Site 90045-005
city: Amersfoort
country: Netherlands
facility: Site 90031-001
city: Amsterdam
country: Netherlands
facility: Site 90031-003
city: Hoorn
country: Netherlands
facility: Site 90031-009
city: Tilburg
country: Netherlands
facility: Site 90031-006
city: Utrecht
country: Netherlands
facility: Site 90031-005
city: Cape Town
country: South Africa
facility: Site 90027-004
state: Western Cape
city: Bloemfontein
country: South Africa
facility: Site 90027-003
city: Cape Town
country: South Africa
facility: Site 90027-005
city: Cape Town
country: South Africa
facility: Site 90027-001
city: Cape Town
country: South Africa
facility: Site 90027-008
city: Johannesburg
country: South Africa
facility: Site 90027-010
city: Pretoria
country: South Africa
facility: Site 90027-007
city: Pretoria
country: South Africa
facility: Site 90027-006
city: Witbank
country: South Africa
facility: Site 90027-009
city: A Coruña
country: Spain
facility: Site 90034-003
city: Barcelona
country: Spain
facility: Site 90034-005
city: Córdoba
country: Spain
facility: Site 90034-004
city: L'Hospitalet De Llobregat
country: Spain
facility: Site 90034-006
city: Reus
country: Spain
facility: Site 90034-001
city: Zaragoza
country: Spain
facility: Site 90034-002
city: Göteborg
country: Sweden
facility: Site 90046-002
city: Stockholm
country: Sweden
facility: Site 90046-001
city: Stockholm
country: Sweden
facility: Site 90046-003
Study officials:
affiliation: University of Witwatersrand, South Africa
name: Frederick J. Raal, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.