Renal Impairment
Conditions
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.
Interventions
DRUGInclisiran
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.
Sponsors
The Medicines Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-Label
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Renal Clearance (CLr) Of Inclisiran | 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. |
| Pharmacokinetics: Amount Excreted Unchanged In Urine (Ae) Of Inclisiran Over 48 Hours Post-Dose | 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 | 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: Maximum Observed Plasma Concentration (Cmax) Of Inclisiran | 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 | 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 | 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In PCSK9 At Day 60 | 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. |
| Change From Baseline In Lipids And Lipoproteins At Day 60 | 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. |
Countries
New Zealand
Outcome results
None listed