Study of Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Inclisiran in Chinese Participants With Elevated Serum LDL-C (ORION-14)

• ClinicalTrials.gov Identifier: NCT04774003
• Recruitment Status: Completed
• First Posted: February 26, 2021
• Last Update Posted: December 6, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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

Condition or disease	Intervention/treatment	Phase
Hyperlipidemia	Drug: 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran); Drug: Placebo; Drug: 300 mg inclisiran sodium (equivalent to 284 mg inclisiran)	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: This is a participant, investigator and sponsor blinded, randomized study
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: February 26, 2021
• Actual Primary Completion Date: October 18, 2021
• Actual Study Completion Date: October 18, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: 300 mg inclisiran sodium (equivalent to 284 mg inclisiran); 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) x 1 dose (n=15) at Day 1	Drug: 300 mg inclisiran sodium (equivalent to 284 mg inclisiran); 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) in 1.5 mL solution. Subcutaneous administration at Day 1; Other Name: KJX839
Experimental: 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran); 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran) x 1 dose (n=15) at Day 1	Drug: 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran); 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran) in 0.5 mL solution. Subcutaneous administration at Day 1; Other Name: KJX839
Placebo Comparator: Placebo; Placebo x 1 dose (n=10) at Day 1	Drug: Placebo; Inclisiran sodium 0mg (equivalent to inclisiran 0 mg) in 1.5 mL solution. Subcutaneous administration at Day 1

Outcome Measures

Primary Outcome Measures :

1. PK parameters (Cmax) maximum peak observed plasma inclisiran concentration in treated participants [ Time Frame: 0-48 hours post-dose ]
   Pharmacokinetics parameters of inclisiran
2. PK parameters (Tmax) time to reach maximum peak plasma inclisiran concentration in treated participants [ Time Frame: 0-48 hours post-dose ]
   Pharmacokinetics parameters of inclisiran
3. PK parameters (T1/2) the elimination half-life associated with the terminal slope of a semi-logarithmic concentration-time curve in inclisiran treated participants [ Time Frame: 0-48 hours post-dose ]
   Pharmacokinetics parameters of inclisiran
4. PK parameters (AUC) area under the plasma concentration-time curve in inclisiran treated participants [ Time Frame: 0-48 hours post-dose ]
   Pharmacokinetics parameters of inclisiran
5. Percentage change in Proprotein convertase subtilisin kexin 9 (PCSK9) from baseline overtime [ Time Frame: Baseline to Days 5, 8, 15, 30, 60 and 90 ]
   Pharmacodynamics effects of inclisiran
6. Percentage change in Low density lipoprotein cholesterol (LDL-C) from baseline overtime [ Time Frame: Baseline to Days 5, 8, 15, 30, 60 and 90 ]
   Pharmacodynamics effects of inclisiran

Secondary Outcome Measures :

1. Percent change from baseline to Days 30, 60 and 90 in PD parameter Proprotein convertase subtilisin kexin 9 (PCSK9) [ Time Frame: Baseline to Days 30, 60 and 90 ]
   Pharmacodynamics differences between inclisiran and placebo
2. Percent change from baseline to Days 30, 60 and 90 in PD parameter Low density lipoprotein cholesterol (LDL-C) [ Time Frame: Baseline to Days 30, 60 and 90 ]
   Pharmacodynamics differences between inclisiran and placebo
3. Rate of formation of anti-drug antibodies to Inclisiran [ Time Frame: Baseline, Days 30 and 90 ]
   Immunogenicity of inclisiran

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

China, Hunan

Novartis Investigative Site

Changsha, Hunan, China, 410003

China, Sichuan

Novartis Investigative Site

Chengdu, Sichuan, China, 610041

China

Novartis Investigative Site

Beijing, China, 100029

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04774003
• Other Study ID Numbers: CKJX839A12105
• First Posted: February 26, 2021
• Last Update Posted: December 6, 2021
• Last Verified: December 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Inclisiran; KJX839; LDL-C; Pharmacokinetics and pharmacodynamics; Chinese participants with elevated serum LDL-C

Additional relevant MeSH terms:

Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases