Clinical trial NCT04774003: Study of Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Inclisiran in Chinese Participants With Elevated Serum LDL-C
Official title: A Placebo-controlled, Participant, Investigator and Sponsor Blinded, Randomized Study to Evaluate the Pharmacokinetics and Pharmacodynamics of Inclisiran Treatment Given as Single Subcutaneous Injection in Chinese Participants With Elevated Low-density Lipoprotein Cholesterol (LDL-C) Despite Treatment With LDL-C Lowering Therapies (ORION-14)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hyperlipidemia
Keywords: Inclisiran
KJX839
LDL-C
Pharmacokinetics and pharmacodynamics
Chinese participants with elevated serum LDL-C
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-02-26
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a placebo-controlled study of inclisiran sodium given as a single subcutaneous injection of either 100 mg and 300 mg.
Primary purpose: TREATMENT

Brief summary: Study to evaluate the pharmacokinetics and pharmacodynamics of inclisiran treatment given as single subcutaneous injection in Chinese participants with elevated low-density lipoprotein cholesterol (LDL-C) despite treatment with LDL-C lowering therapies

Detailed description: The purpose of the study is to characterize pharmacokinetics, pharmacodynamics, safety and tolerability of inclisiran in Chinese participants with elevated serum LDL-C to support inclisiran registration in China.Inclisiran is a long acting RNA therapeutic agent that inhibits the synthesis of PCSK9, leading to reduced circulating LDL-C levels. Three pivotal Phase III studies have been conducted primarily in non-Asian participants to support New Drug Application/Marketing Authorization Application approval of inclisiran globally. This study design is based on the hypothesis that the global inclisiran clinical data primarily obtained in Caucasian participants could be appropriately extrapolated to Chinese participants.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent must be obtained before any assessment is performed.
2. Male or female participants ≥ 18 years of age at screening
3. Participants should meet fasting serum LDL-C ≥ 100 mg/dL (≥ 2.6 mmol/L) at screening
4. Participants should meet fasting triglyceride \< 400 mg/dL (\< 4.52 mmol/L) at screening
5. Participants should be receiving a maximally tolerated dose of statin#.
6. For all participants, all the lipid-lowering therapy/ies (such as but not limited to statins and/or ezetimibe) should have remained stable (stable dose and no medication change) for ≥ 30 days before screening with no planned medication or dose change during study participation. #Maximum tolerated dose was defined as the maximum dose of statin that could be taken on a regular basis without intolerable AEs.
7. Participants not receiving statin must have a documented evidence of intolerance to all doses of at least 2 different statins (or the corresponding local definition of complete intolerance to statins)

Exclusion Criteria:

1. Participants diagnosed with any of following: homozygous familial hypercholesterolemia, New York Heart Association class III \& IV heart failure, Type 2 diabetes, severe hypertension, active liver disease, HIV infection or any uncontrolled or serious disease;
2. History of drug abuse or unhealthy alcohol use, malignancy of any organ system, or or allergy to the investigational compound/compound class;
3. Major adverse cardiovascular event within 3 months prior to randomization;
4. Calculated glomerular filtration rate ≤30 mL/min by estimated glomerular filtration rate (eGFR) using standardized clinical methodology;
5. Use of other investigational drugs or planned use of other investigational products or devices;
6. Women of child-bearing potential unless they are using basic methods of contraception during dosing of investigational drug (total abstinence, sterilization, barrier methods, hormonal contraception, intrauterine device);
7. Treatment with monoclonal antibodies inhibiting PCSK9 within 90 days prior to screening.

Other protocol-defined inclusion/exclusion criteria may apply

Primary outcomes:
measure: PK parameters (Cmax) maximum peak observed plasma inclisiran concentration in treated participants
timeFrame: 0-48 hours post-dose
measure: PK parameters (Tmax) time to reach maximum peak plasma inclisiran concentration in treated participants
timeFrame: 0-48 hours post-dose
measure: PK parameters (T1/2) the elimination half-life associated with the terminal slope of a semi-logarithmic concentration-time curve in inclisiran treated participants
timeFrame: 0-48 hours post-dose
measure: PK parameters (AUC) area under the plasma concentration-time curve in inclisiran treated participants
timeFrame: 0-48 hours post-dose
measure: Percentage change in Proprotein convertase subtilisin kexin 9 (PCSK9) from baseline overtime
timeFrame: Baseline to Days 5, 8, 15, 30, 60 and 90
measure: Percentage change in Low density lipoprotein cholesterol (LDL-C) from baseline overtime
timeFrame: Baseline to Days 5, 8, 15, 30, 60 and 90
Secondary outcomes:
measure: Percent change from baseline to Days 30, 60 and 90 in PD parameter Proprotein convertase subtilisin kexin 9 (PCSK9)
timeFrame: Baseline to Days 30, 60 and 90
measure: Percent change from baseline to Days 30, 60 and 90 in PD parameter Low density lipoprotein cholesterol (LDL-C)
timeFrame: Baseline to Days 30, 60 and 90
measure: Rate of formation of anti-drug antibodies to Inclisiran
timeFrame: Baseline, Days 30 and 90
Other outcomes:
Locations:
city: Changsha
country: China
facility: Novartis Investigative Site
state: Hunan
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Beijing
country: China
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: