A Study of CSL112 in Adults With Moderate Renal Impairment and Acute Myocardial Infarction

A Phase 2, Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group, Study to Investigate the Safety and Tolerability of Multiple Dose Administration of CSL112 in Subjects With Moderate Renal Impairment and Acute Myocardial Infarction

This study is a phase 2, multicenter, double-blind, randomized, placebo controlled, parallel-group study to investigate the renal safety and tolerability of multiple dose intravenous (IV) administration of CSL112 compared with placebo in subjects with moderate renal impairment (RI) and acute myocardial infarction (AMI).

Study Overview

• Status: Completed
• Conditions: Acute Myocardial Infarction; Moderate Renal Impairment
• Intervention / Treatment: Other: Placebo; Biological: CSL_112

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10967
    • Study Site 17009
  • Berlin, Germany, 10249
    • Study Site 17005
  • Berlin, Germany, 13353
    • Study Site 17003
  • Hamburg, Germany, 20246
    • Study Site 17006
  • Baden Wuerttemberg
    • Freiburg, Baden Wuerttemberg, Germany, 79106
      • Study Site 17001
  • Hessen
    • Frankfurt, Hessen, Germany, 65929
      • Study Site 17014
• Hungary
  • Budapest, Hungary, 1122
    • Study Site 18001
  • Budapest, Hungary, 1134
    • Study Site 18005
  • Nyiregyhaza, Hungary, 4400
    • Study Site 18007
  • Pecs, Hungary, 7624
    • Study Site 18003
  • Szeged, Hungary, 6720
    • Study Site 18009
• Israel
  • Haifa, Israel, 3109601
    • Study Site 19005
  • Nahariya, Israel, 22100
    • Study Site 19002
  • Safed, Israel, 13100
    • Study Site 19008
• Netherlands
  • Alkmaar, Netherlands, 1815 JD
    • Study Site 21001
  • Amsterdam, Netherlands, 1091 AC
    • Study Site 21006
  • Amsterfoort, Netherlands, 3818 TZ
    • Study Site 21017
  • Nijmegen, Netherlands, 6525 EC
    • Study Site 21008
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35211
      • Study Site 16101
    • Huntsville, Alabama, United States, 35801
      • Study Site 16078
  • California
    • Concord, California, United States, 94520
      • Study Site 16168
  • Colorado
    • Littleton, Colorado, United States, 80120
      • Study Site 16130
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Study Site 16135
  • Florida
    • Jacksonville, Florida, United States, 32209
      • Study Site 16003
  • Idaho
    • Boise, Idaho, United States, 83712
      • Study Site 16112
  • Louisiana
    • Alexandria, Louisiana, United States, 71301
      • Study Site 16208
  • Michigan
    • Petoskey, Michigan, United States, 49770
      • Study Site 16061
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Study Site 16056
    • High Point, North Carolina, United States, 27762
      • Study Site 16014
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Study Site 16018
  • Texas
    • Wichita Falls, Texas, United States, 76301
      • Study Site 16241

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Men or women, at least 18 years of age, with evidence of moderate renal impairment (an eGFR ≥ 30 and <60 mL/min/1.73 m2) and myocardial necrosis in a clinical setting consistent with a type I (spontaneous) acute myocardial infarction (AMI).

Exclusion Criteria:

• Symptoms, biomarker elevation or electrocardiogram (ECG) changes other than those of the index event that are consistent with a diagnosis of AMI but are likely not due to primary myocardial ischemia
• Ongoing hemodynamic instability
• Planned coronary artery bypass surgery
• Evidence of hepatobiliary disease
• History of acute kidney injury (AKI) after previous exposure to an intravenous contrast agent.
• History of nephrotic range proteinuria.
• Known history of allergy to soy beans or peanuts, immunoglobulin A (IgA) deficiency, antibodies to IgA , or hypersensitivity 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CSL_112; CSL112 will be administered intravenously, once weekly for 4 consecutive weeks (4 infusions in total).	Biological: CSL_112; CSL112 is a novel formulation of apolipoprotein A-I (apoA-I) purified from human plasma and reconstituted to form high-density lipoprotein (HDL) particles.
Placebo Comparator: Placebo; Placebo will be administered at the same frequency, volume and duration as the CSL112 infusion.	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
Percent of Participants With at Least One Occurrence of Treatment-emergent Renal Serious Adverse Events (SAEs) (SAF)	A renal SAE is defined as any SAE with a MedDRA preferred term included in the Acute Renal Failure narrow Standard MedDRA Query or a preferred term of renal tubular necrosis, renal cortical necrosis, renal necrosis, or renal papillary necrosis.	Up to 9 weeks
Percent of Participants With Treatment-emergent Acute Kidney Injury (AKI )	Acute kidney injury is defined as an absolute increase in serum creatinine from baseline ≥ 0.3 mg/dL during the Active Treatment Period that is sustained upon repeat measurement by the central laboratory no earlier than 24 hours after the elevated value. If no repeat value is obtained, a single serum creatinine value that is increased from baseline ≥ 0.3 mg/dL (26.5 μmol/L) during the Active Treatment Period would also fulfil the definition of AKI.	Up to 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs)		Up to 9 weeks
Percentage of Participants With TEAEs		Up to 9 weeks
Total Number of TEAEs		Up to 9 weeks
Number of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR	Adverse drug reactions or suspected adverse drug reactions are defined as: All TEAEs, including local tolerability events, that begin during or within 1 hour after the end of an infusion; or; Those TEAEs that the investigator or sponsor indicate may be causally related to product administration; or; All TEAEs for which the Investigator's causality assessment is missing or indeterminate; or; All TEAEs 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 9 weeks
Percentage of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR	Adverse drug reactions or suspected adverse drug reactions are defined as: All TEAEs, including local tolerability events, that begin during or within 1 hour after the end of an infusion; or; Those TEAEs that the investigator or sponsor indicate may be causally related to product administration; or; All TEAEs for which the Investigator's causality assessment is missing or indeterminate; or; All TEAEs 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 9 weeks
Number of Participants With Change in Renal Status	Number of participants with changes in renal status defined as: Absolute increases from baseline in serum creatinine as follows:i. ≤ baseline value ii. > 0 to < 0.3 mg/dL iii. ≥ 0.3 to ≤ 0.5 mg/dL iv. > 0.5 mg/dL; Increases in serum creatinine that are sustained for ≥ 24 hours upon repeat measurement that are greater than or equal to 1.5 x, 2 x, or 3.0 x the baseline value, or serum creatinine ≥ 4.0 mg/dL; Initiation of renal replacement therapy; Decrease in eGFR ≥ 25% from baseline starting during the active treatment period and that is sustained at the final study visit	Baseline and up to 4 weeks
Percentage of Participants With Change in Renal Status	Percentage of participants with changes in renal status defined as: Absolute increases from baseline in serum creatinine as follows:i. ≤ baseline value ii. > 0 to < 0.3 mg/dL iii. ≥ 0.3 to ≤ 0.5 mg/dL iv. > 0.5 mg/dL; Increases in serum creatinine that are sustained for ≥ 24 hours upon repeat measurement that are greater than or equal to 1.5 x, 2 x, or 3.0 x the baseline value, or serum creatinine ≥ 4.0 mg/dL; Initiation of renal replacement therapy; Decrease in eGFR ≥ 25% from baseline starting during the active treatment period and that is sustained at the final study visit	Baseline and up to 4 weeks
Number of Participants With Change in Hepatic Status	Number of participants with a change from baseline in hepatic status and that is sustained for ≥ 24 hours upon repeat measurement, defined as: Alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN); ALT > 5 x ULN; ALT > 10 x ULN; Serum total bilirubin > 1.5 x ULN; Serum total bilirubin > 2 x ULN; Possible Hy's law cases, as defined in the FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009).	Baseline and up to 4 weeks
Percentage of Participants With Change in Hepatic Status	Percentage of participants with a change from baseline in hepatic status and that is sustained for ≥ 24 hours upon repeat measurement, defined as: Alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN); ALT > 5 x ULN; ALT > 10 x ULN; Serum total bilirubin > 1.5 x ULN; Serum total bilirubin > 2 x ULN; Possible Hy's law cases, as defined in the FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009).	Baseline and up to 4 weeks
Number of Participants With Treatment-emergent Bleeding Events	Bleeding events are as defined by the Bleeding Academic Research Consortium (BARC) criteria (Mehran et al., 2011).	Up to 9 weeks
Percentage of Participants With Treatment-emergent Bleeding Events	Bleeding events are as defined by the Bleeding Academic Research Consortium (BARC) criteria (Mehran et al., 2011).	Up to 9 weeks
Percentage of Participants With Binding Antibodies Specific to Apolipoprotein A-I (Apo-A1) and CSL112		Up to 9 weeks
Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 1 for apoA-I and PC		Immediately after end of infusion
Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 4 for apoA-I and PC		Immediately after end of infusion
Plasma apoA-I and Phosphatidylcholine (PC) Accumulation Ratio After Infusion 4	The plasma apoA-I and PC accumulation ratio will be determined for CSL112-treated subjects.	Immediately after end of infusion

Collaborators and Investigators

• Sponsor: CSL Behring
• Investigators: Study Director: Danielle Duffy, MD, 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.
• Gibson CM, Kerneis M, Yee MK, Daaboul Y, Korjian S, Mehr AP, Tricoci P, Alexander JH, Kastelein JJP, Mehran R, Bode C, Lewis BS, Mehta R, Duffy D, Feaster J, Halabi M, Angiolillo DJ, Duerschmied D, Ophuis TO, Merkely B. The CSL112-2001 trial: Safety and tolerability of multiple doses of CSL112 (apolipoprotein A-I [human]), an intravenous formulation of plasma-derived apolipoprotein A-I, among subjects with moderate renal impairment after acute myocardial infarction. Am Heart J. 2019 Feb;208:81-90. doi: 10.1016/j.ahj.2018.11.008. Epub 2018 Nov 22.

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: March 30, 2016
• First Submitted That Met QC Criteria: April 13, 2016
• First Posted (Estimate): April 18, 2016

Study Record Updates

• Last Update Posted (Actual): June 11, 2020
• Last Update Submitted That Met QC Criteria: May 26, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Kidney Diseases; Urologic Diseases; Myocardial Infarction; Infarction; Renal Insufficiency
• Other Study ID Numbers: CSL112_2001; 2015-003017-26 (EudraCT Number)