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

NCT03159416 | Completed Phase 1 FDA Drug

• 1 other identifier: MDCO-PCS-16-03
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Renal Impairment

Outcome Measures

Primary Outcomes (8)

• Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) Of Inclisiran

  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.

  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

• Pharmacokinetics: Tmax And t1/2 Of Inclisiran

  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.

  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

• Pharmacokinetics: AUC0-24, AUC0-48, And AUC0-inf Of Inclisiran

  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.

  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

• Pharmacokinetics: Apparent Total Clearance (CL/F) Following SC Administration Of Inclisiran

  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.

  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

• Pharmacokinetics: Vd/F During The Terminal Elimination Phase Following SC Administration Of Inclisiran

  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.

  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

• Pharmacokinetics: Amount Excreted Unchanged In Urine (Ae) Of Inclisiran Over 48 Hours Post-Dose

  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.

  0 up to 6 hours, 6 up to 12 hours, 12 up to 24 hours, and 24 up to 48 hour post-dose intervals

• Pharmacokinetics: Fraction Excreted (Fe) Of Inclisiran

  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.

  0 up to 6 hours, 6 up to 12 hours, 12 up to 24 hours, and 24 up to 48 hour post-dose intervals

• Pharmacokinetics: Renal Clearance (CLr) Of Inclisiran

  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.

  0 up to 6 hours, 6 up to 12 hours, 12 up to 24 hours, and 24 up to 48 hour post-dose intervals

Secondary Outcomes (2)

• Change From Baseline In Lipids And Lipoproteins At Day 60

  Baseline, Day 60

• Change From Baseline In PCSK9 At Day 60

  Baseline, Day 60

Study Arms (4)

Inclisiran (normal renal function)

EXPERIMENTAL

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 (mild renal impairment)

EXPERIMENTAL

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 (moderate renal impairment)

EXPERIMENTAL

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 (severe renal impairment)

EXPERIMENTAL

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

Interventions

Inclisiran DRUG

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.

Also known as: ALN-PCSSC

Inclisiran (mild renal impairment); Inclisiran (moderate renal impairment); Inclisiran (normal renal function); Inclisiran (severe renal impairment)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female participants 18 to 80 years of age

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Medicines Company: lead

Study Sites (2)

Auckland Clinical Studies Limited

Auckland, New Zealand

Location

Christchurch Clinical Studies Trust

Christchurch, New Zealand

Location

Related Publications (1)

• Wright RS, Collins MG, Stoekenbroek RM, Robson R, Wijngaard PLJ, Landmesser U, Leiter LA, Kastelein JJP, Ray KK, Kallend D. Effects of Renal Impairment on the Pharmacokinetics, Efficacy, and Safety of Inclisiran: An Analysis of the ORION-7 and ORION-1 Studies. Mayo Clin Proc. 2020 Jan;95(1):77-89. doi: 10.1016/j.mayocp.2019.08.021. Epub 2019 Oct 17.

  PMID: 31630870 DERIVED

MeSH Terms

Conditions

Renal Insufficiency

Interventions

ALN-PCS

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Study Officials

• Richard Robson, PhD

  Christchurch Clinical Studies Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: Open-Label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2017
• First Posted: May 18, 2017
• Study Start: June 22, 2017
• Primary Completion: March 24, 2018
• Study Completion: March 24, 2018
• Last Updated: November 9, 2018

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will not share

Locations

NZ (2)