A Study of Inclisiran in Participants With Renal Impairment Compared to Participants With Normal Renal Function (ORION-7)


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Verified May 2017 by The Medicines Company

Sponsor:

Information provided by (Responsible Party):

The Medicines Company

ClinicalTrials.gov Identifier:

NCT03159416

First received: May 16, 2017

Last updated: May 16, 2017

Last verified: May 2017

This study is a Phase I, single-dose, open-label trial to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a single dose of inclisiran subcutaneous (SC) injection in participants with mild, moderate, and severe renal impairment compared to participants with normal renal function.

Renal Impairment Drug: Inclisiran Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Masking Description:

Open-Label

Primary Purpose: Treatment

Official Title: A Single-Dose, Open-Label, Parallel-Group Study to Assess the Pharmacokinetics of Inclisiran in Subjects With Renal Impairment Compared to Subjects With Normal Renal Function (ORION-7)

Primary Outcome Measures:

  • Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) Of Inclisiran [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose and Day 4, Day 7, Day 14, and Day 30 post-dose ]

    Measurement of effect of renal impairment on PK of inclisiran by assessment of Cmax. Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.

  • Pharmacokinetics: Tmax And t1/2 Of Inclisiran [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose and Day 4, Day 7, Day 14, and Day 30 post dose ]

    Measurement of effect of renal impairment on PK of inclisiran by assessment of time to reach maximum plasma concentration (Tmax) and time for inclisiran to reach half of its initial value (t1/2). Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.

  • Pharmacokinetics: AUC0-24, AUC0-48, And AUC0-inf Of Inclisiran [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose and Day 4, Day 7, Day 14, and Day 30 post dose ]

    Measurement of effect of renal impairment on PK of inclisiran by assessment of area under the curve of the plasma concentration (AUC) from time 0 to 24 hours (AUC0-24), from time 0 to 48 hours (AUC0-48), and from time 0 extrapolated to infinity (AUC0-inf). Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.

  • Pharmacokinetics: Apparent Total Clearance (CL/F) Following SC Administration Of Inclisiran [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose and Day 4, Day 7, Day 14, and Day 30 post dose ]

    Measurement of effect of renal impairment on PK of inclisiran by assessment of CL/F. Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.

  • Pharmacokinetics: Vd/F During The Terminal Elimination Phase Following SC Administration Of Inclisiran [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose and Day 4, Day 7, Day 14, and Day 30 post dose ]

    Measurement of effect of renal impairment on PK of inclisiran by assessment of apparent volume of distribution (Vd/F) of inclisiran during the terminal elimination phase. Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.

  • Pharmacokinetics: Amount Excreted Unchanged In Urine (Ae) Of Inclisiran Over 48 Hours Post-Dose [ Time Frame: 0 up to 6 hours, 6 up to 12 hours, 12 up to 24 hours, and 24 up to 48 hour post-dose intervals ]

    Measurement of effect of renal impairment on PK of inclisiran by assessment of Ae of inclisiran. Pooled urine samples will be used for the analysis.

  • Pharmacokinetics: Fraction Excreted (Fe) Of Inclisiran [ Time Frame: 0 up to 6 hours, 6 up to 12 hours, 12 up to 24 hours, and 24 up to 48 hour post-dose intervals ]

    Measurement of effect of renal impairment on PK of inclisiran by assessment of the urinary recovery rate over a specific collection interval (Fe), calculated as 100*Ae/Dose. Pooled urine samples will be used for the analysis.

  • Pharmacokinetics: Renal Clearance (CLr) Of Inclisiran [ Time Frame: 0 up to 6 hours, 6 up to 12 hours, 12 up to 24 hours, and 24 up to 48 hour post-dose intervals ]

    Measurement of effect of renal impairment on PK of inclisiran by assessment of CLr, calculated as Ae/AUC0-48 plasma. CLr will be calculated if possible (for example, if the percent of unchanged drug excreted in urine exceeds 20%). Pooled urine samples will be used for the analysis.

Secondary Outcome Measures:

  • Change From Baseline In Lipids And Lipoproteins At Day 60 [ Time Frame: Baseline, Day 60 ]

    Pharmacodynamic effects of inclisiran on lipids and lipoproteins (total cholesterol, triglycerides, and high-density lipoprotein cholesterol, calculated and measured by beta-quant low-density lipoprotein cholesterol [LDL-C]) will be measured as a percentage of change from baseline. Lipids and lipoproteins will be measured at baseline, 4, 48, 96 (Day 4), and 168 (Day 7) hours, and Day 30 and Day 60.

  • Change From Baseline In PCSK9 At Day 60 [ Time Frame: Baseline, Day 60 ]

    Pharmacodynamic effects of inclisiran on PCSK9 will be measured as a percentage of change from baseline. PCSK9 protein levels will be measured at baseline, 4, 48, 96 (Day 4), and 168 (Day 7) hours, and Day 30 and Day 60.

Estimated Enrollment: 24
Anticipated Study Start Date: June 2017
Estimated Study Completion Date: August 2018
Estimated Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)
Experimental: Inclisiran (normal renal function)

Participants will receive a single dose of 300 milligram (mg) inclisiran administered by SC injection on Day 1. Normal renal function is defined as estimated creatinine clearance (CrCl) of ≥90 milliliter (mL)/minute (min).

Drug: Inclisiran

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.

Other Name: ALN-PCSSC

Experimental: Inclisiran (mild renal impairment)

Participants will receive a single dose of 300 mg inclisiran administered by SC injection on Day 1. Mild renal impairment is defined as CrCl ranging from 60 to 89 mL/min.

Drug: Inclisiran

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.

Other Name: ALN-PCSSC

Experimental: Inclisiran (moderate renal impairment)

Participants will receive a single dose of 300 mg inclisiran administered by SC injection on Day 1. Moderate renal impairment is defined as CrCl ranging from 30 to 59 mL/min.

Drug: Inclisiran

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.

Other Name: ALN-PCSSC

Experimental: Inclisiran (severe renal impairment)

Participants will receive a single dose of 300 mg inclisiran administered by SC injection on Day 1. Severe renal impairment is defined as CrCl ranging from 15 to 29 mL/min.

Drug: Inclisiran

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.

Other Name: ALN-PCSSC

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Male and female participants 18 to 80 years of age
  • Participants should be qualified for inclusion based upon estimated CrCl ranges for normal renal function group and mild, moderate, and severe renal impairment groups

Exclusion Criteria:

  • Participants with acute renal disease and/or history of renal transplant
  • Urinary incontinence without catheterization
  • Participants requiring hemodialysis
  • Participants with LDL-C <60 mg/deciliter (dL) (or less than 1.55 millimoles/liter [mmol/L])
  • Participants with Amyloid Kidney (if known by pathology)
  • Participants with any significant hepatic, cardiac, or pulmonary disease or participants who are clinically nephritic

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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03159416

Auckland Clinical Studies Limited
Auckland, New Zealand
Christchurch Clinical Studies Trust
Christchurch, New Zealand

The Medicines Company

Principal Investigator: Richard Robson, PhD Christchurch Clinical Studies Trust

Responsible Party: The Medicines Company
ClinicalTrials.gov Identifier: NCT03159416     History of Changes
Other Study ID Numbers: MDCO-PCS-16-03
Study First Received: May 16, 2017
Last Updated: May 16, 2017
Individual Participant Data  
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Renal Insufficiency
Kidney Diseases
Urologic Diseases

ClinicalTrials.gov processed this record on May 18, 2017