A Study of CSL112 in Healthy Adults and in Adults With Moderate Renal Impairment

A Double-blind, Randomized, Placebo-controlled, Pharmacokinetic, Safety and Tolerability Study of CSL112 in Adult Subjects With Moderate Renal Impairment and in Healthy Adult Subjects With Normal Renal Function

This is a phase 1 multicenter, randomized, double-blind, placebo-controlled, ascending dose study to investigate the pharmacokinetics (PK), safety, and tolerability of CSL112 in adult subjects with moderate renal impairment and in healthy adult subjects with normal renal function.

Study Overview

• Status: Completed
• Conditions: Acute Myocardial Infarction
• Intervention / Treatment: Biological: CSL112; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Study Site - 17101
  • Munich, Germany, D-81241
    • Study Site - 17102
• United Kingdom
  • London, United Kingdom, SE1 1YR
    • Study Site - 24101
  • Manchester, United Kingdom, M13 9WL
    • Study Site - 24102

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men or women aged 18 to 85 years (inclusive) of age, with body weight 50 kg or more.
• Subjects with renal impairment (RI) must have stable chronic moderate RI (estimated glomerular filtration rate [eGFR] ≥ 30 and < 60 mL/min/1.73 m2)
• Healthy subjects must have normal renal function (eGFR ≥ 90 mL/min/1.73 m2)

Exclusion Criteria:

• Evidence of a clinically significant medical condition, disorder or disease
• Evidence of hepatobiliary disease
• Any clinically relevant abnormal laboratory test result
• Known history of allergies, hypersensitivity or deficiencies to CSL112 or any of its components
• Other severe comorbid condition, concurrent medication, or other issue that renders the subject unsuitable for participation in the study, including: history of cancer, low platelet count, bleeding disorder or coagulopathy, significantly altered electrocardiogram waveform, unstable glycemia control in subjects with diabetes, acute renal failure, recent donation or loss of blood
• Evidence or history of alcohol or substance abuse

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low; A low dose of either CSL112 or placebo is to be administered as a single intravenous (IV) infusion. The placebo will be administered at the same frequency, volume and duration as the CSL112 infusion.	Biological: CSL112; CSL112 is a novel formulation of apolipoprotein A-I (apoA-I) purified from human plasma and reconstituted to form high-density lipoprotein (HDL) particles.; Other: Placebo; 0.9% weight/volume sodium chloride solution (ie, normal saline)
Experimental: High; A high dose of either CSL112 or placebo is to be administered as a single intravenous (IV) infusion. The placebo will be administered at the same frequency, volume and duration as the CSL112 infusion.	Biological: CSL112; CSL112 is a novel formulation of apolipoprotein A-I (apoA-I) purified from human plasma and reconstituted to form high-density lipoprotein (HDL) particles.; Other: Placebo; 0.9% weight/volume sodium chloride solution (ie, normal saline)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma apolipoprotein A-I (apoA-I) and phosphatidylcholine (PC) area under the curve (AUC)	Baseline corrected plasma apoA-I and PC AUC0-infinity	Before and at up to 10 time points (during up to 7 days) after infusion
Plasma apoA-I and PC AUC0-last and AUC 0-t	AUC from time point zero to the last quantifiable time point before the analyte first returns to baseline (AUC0-last) and/or a partial AUC from baseline to time point t (AUC0-t) with and without baseline correction	Before and at up to 10 time points (during up to 7 days) after infusion
Plasma apoA-I and PC Cmax		Before and at up to 10 time points (during up to 7 days) after infusion
Plasma apoA-I and PC Tmax		Before and at up to 10 time points (during up to 7 days) after infusion
Plasma apoA-I and PC Volume of distribution during terminal phase		Before and at up to 10 time points (during up to 7 days) after infusion
Plasma apoA-I and PC clearance		Before and at up to 10 time points (during up to 7 days) after infusion
Plasma apoA-I and PC t1/2		Before and at up to 10 time points (during up to 7 days) after infusion
Urinary excretion of apoA-I (Ae0-t)	Amount excreted (Ae) of apoA-I over a collection interval 0-t.	Before and up to 48 hours after infusion
Urinary excretion of apoA-I (%fe0-t)	Percent fraction excreted (%fe) of apoA-I in urine over time interval 0-t, calculated as Ae0-t/Dose x 100.	Before and up to 48 hours after infusion
Renal clearance of apoA-I	Renal clearance of apoA-I, calculated as Ae0-48/AUC0-48	Before and up to 48 hours after infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary excretion of sucrose(Ae0-t)	Amount of sucrose excreted over a collection interval 0-t.	Before and up to 48 hours after infusion
Urinary excretion of sucrose (%fe0-t)	Percent fraction excreted sucrose in urine over time interval 0-t, calculated as Ae0-t/Dose x 100.	Before and up to 48 hours after infusion
Urinary excretion of sucrose (clearance)	Renal clearance of sucrose, calculated as Ae0-48/AUC0-48	Before and up to 48 hours after infusion
Adverse drug reaction (ADR) or suspected ADR frequency (%)	The overall percentage of participants with adverse reactions or suspected adverse reactions: That begin during or within 1 hour of an infusion; or; That may be causally related to the administration of the investigational product; or; For which the Investigator's causality assessment is missing or indeterminate; or; For which the incidence in an active treatment arm exceeds the exposure-adjusted incidence rate in the placebo arm by 30% or more, provided the difference in incidence rates is 1% or more.	Up to approximately 127 days
Clinically significant changes in routine safety assessments	The number of participants with clinically significant changes in any of the following assessments: clinical laboratory tests, physical examinations, body weight, electrocardiograms, vital signs, immunogenicity testing, serology, nucleic acid testing or proteinuria findings.	Up to approximately 97 days
Clinically important change in drug-induced liver injury	A clinically important change in drug-induced liver injury is defined as a change (from baseline) in alanine aminotransferase (ALT) greater than 3 times the upper limit of normal (ULN) or a change in total bilirubin greater than 2 times ULN, that is confirmed upon repeat measurement.	From baseline (before infusion) up to Day 16.
Clinically important change in renal status	A clinically important change in renal status is defined as a serum creatinine (Cr) increase to ≥ 1.5 x the baseline value that is confirmed upon repeat measurement, or the need for renal replacement therapy.	From baseline (before infusion) up to Day 16.
Plasma sucrose AUC	Baseline corrected plasma sucrose AUC0-infinity	Before and at up to 7 time points (during up to 2 days) after infusion
Plasma sucrose AUC0-last and AUC 0-t	AUC from time point zero to the last quantifiable time point before the analyte first returns to baseline (AUC0-last) and/or a partial AUC from baseline to time point y (AUC0-t) with and without baseline correction	Before and at up to 7 time points (during up to 2 days) after infusion
Plasma sucrose Cmax		Before and at up to 7 time points (during up to 2 days) after infusion
Plasma sucrose Tmax		Before and at up to 7 time points (during up to 2 days) after infusion
Plasma sucrose Volume of distribution during terminal phase		Before and at up to 7 time points (during up to 2 days) after infusion
Plasma sucrose Clearance		Before and at up to 7 time points (during up to 2 days) after infusion
Plasma sucrose t1/2		Before and at up to 7 time points (during up to 2 days) after infusion
Adverse drug reaction (ADR) or suspected ADR frequency	The overall number of participants with adverse reactions or suspected adverse reactions: That begin during or within 1 hour of an infusion; or; That may be causally related to the administration of the investigational product; or; For which the Investigator's causality assessment is missing or indeterminate; or; For which the incidence in an active treatment arm exceeds the exposure-adjusted incidence rate in the placebo arm by 30% or more, provided the difference in incidence rates is 1% or more.	Up to approximately 127 days
Number of subjects with AEs		After the start of infusion up to approximately 127 days

Collaborators and Investigators

• Sponsor: CSL Behring
• Investigators: Study Director: Denise D'Andrea, M.D., CSL Behring

Publications and helpful links

General Publications

• Zheng B, Duffy D, Tricoci P, Kastrissios H, Pfister M, Wright SD, Gille A, Tortorici MA. Pharmacometric analyses to characterize the effect of CSL112 on apolipoprotein A-I and cholesterol efflux capacity in acute myocardial infarction patients. Br J Clin Pharmacol. 2021 Jun;87(6):2558-2571. doi: 10.1111/bcp.14666. Epub 2020 Dec 23.
• Tortorici MA, Duffy D, Evans R, Feaster J, Gille A, Mant TGK, Wright SD, D'Andrea D. Pharmacokinetics and Safety of CSL112 (Apolipoprotein A-I [Human]) in Adults With Moderate Renal Impairment and Normal Renal Function. Clin Pharmacol Drug Dev. 2019 Jul;8(5):628-636. doi: 10.1002/cpdd.618. Epub 2018 Sep 21.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: April 20, 2015
• First Submitted That Met QC Criteria: April 24, 2015
• First Posted (Estimate): April 27, 2015

Study Record Updates

• Last Update Posted (Actual): September 19, 2017
• Last Update Submitted That Met QC Criteria: September 18, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction
• Other Study ID Numbers: CSL112_1001; 2014-005520-10 (EudraCT Number)