Recombinant Human C1 Esterase Inhibitor in the Prevention of Contrast-induced Nephropathy in High-risk Subjects (PROTECT)

Recombinant Human C1 Esterase Inhibitor (Conestat Alfa) in the Prevention of Contrast-induced Nephropathy in High-risk Subjects (PROTECT): a Randomized, Placebo-controlled, Double-blind Single-center Trial

Iodinated contrast media have been causally linked to acute kidney injury known as contrast-induced nephropathy (CIN), which is the consequence of CM-induced local renal ischemia and direct toxic effects. Conestat alfa (recombinant human C1 esterase inhibitor) has been shown to decrease renal ischemic damage in experimental models of renal ischemia.

The Recombinant Human C1 Esterase Inhibitor in the Prevention of Contrast-induced Nephropathy in High-risk Subjects (PROTECT) Study is a randomized, placebo-controlled, double-blind single-center trial that will assess the effect of prophylactic administration of Conestat alfa on the degree of acute kidney injury subjects undergoing elective coronary angiography. Patient with an estimated glomerular filtration rate <=50 ml/min/1.73 m2 and at least one additional risk factor for CIN will be enrolled and randomly assigned to 1) Conestat alfa at 50 U/kg given as intravenous injection immediately before and 4 hours after coronary angiography or 2) placebo (sodium chloride). All patients will receive standard intravenous hydration with isotonic saline. Surrogate markers of kidney injury will be assessed over a 48 hours time period. Patients will be followed for cardiovascular and renal events over 12 weeks.

The primary outcome measure is peak change in urinary Neutrophil gelatinase-associated lipocalin within 48 hours after elective coronary angiography.

Study Overview

• Status: Completed
• Conditions: Acute Kidney Injury
• Intervention / Treatment: Drug: Conestat alfa; Drug: Sodium chloride 0.9%

Detailed Description

Iodinated contrast media (CM) are an essential component of contemporary imaging and interventional studies. Although CM are generally well tolerated, they have been causally linked to acute kidney injury known as contrast-induced nephropathy (CIN), the third leading cause of acute kidney injury in hospitalized patients. Preexisting renal impairment, diabetes mellitus, advanced age, congestive heart failure, or large volumes and repeated use of CM have been identified as risk factors for CIN. CIN is the consequence of CM-induced local renal ischemia in combination with direct toxic effects to renal tubular cells. Subsequent inflammation may cause further tissue damage in the reperfusion period. Apart from intravenous hydration preventive strategies for CIN are lacking.

The complement system consists of several circulating proteins that are implicated in the first-line defence against pathogens and in the removal of dying cells. Following renal ischemia activation of the lectin pathway of complement in particular has been associated with local tissue damage in the kidney. Conestat alfa is a recombinant human C1 esterase inhibitor, which inhibits activation of the complement system and is licensed in Europe and USA for the treatment of a hereditary condition (hereditary angioedema). Conestat alfa markedly reduced tissue damage in experimental models of renal ischemia and reperfusion injury, but has not been investigated in human ischemia.

The Recombinant Human C1 Esterase Inhibitor in the Prevention of Contrast-induced Nephropathy in High-risk Subjects (PROTECT) Study is a randomized, placebo-controlled, double-blind single-center trial that will assess the effect of prophylactic administration of Conestat alfa on the degree of acute kidney injury subjects undergoing elective coronary angiography. Patient with an estimated glomerular filtration rate <=50 ml/min/1.73 m2 and at least one additional risk factor for CIN will be enrolled and randomly assigned to 1) Conestat alfa at 50 U/kg given as intravenous injection immediately before and 4 hours after coronary angiography or 2) placebo (sodium chloride). All patients will receive standard intravenous hydration with isotonic saline. Surrogate markers of kidney injury including serum creatinine and cystatin C and urinary Neutrophil gelatinase-associated lipocalin and TIMP2 * Insulin-like growth factor-binding protein 7 (IGFBP7) will be assessed over a 48 hours time period. In addition, increases in troponin T, a marker of cardiac damage, will be assessed. Patients will be followed for thromboembolic, anaphylactic and a composite endpoint of cardiovascular and renal events over a 12 week period.

The primary outcome measure is peak change in urinary Neutrophil gelatinase-associated lipocalin within 48 hours after elective coronary angiography.

Total hydration and contrast media volume will be recorded. Serum C1 esterase inhibitor levels immediately before and 10 minutes after administration of Conestat alfa or placebo will be assessed.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • BS
    • Basel, BS, Switzerland, 4031
      • University Hospital Basel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Estimated glomerular filtration rate (eGFR) of <50 ml/min/1.73m2
• At least one of the following risk factors: diabetes mellitus, age at least 75 years, anemia (baseline hematocrit value less or equal 39% for men and less or equal 36% for women), congestive heart failure class III or IV by New York Heart Association classification, history of pulmonary edema.

Exclusion Criteria:

• Contraindications to the class of drugs under study (C1 esterase inhibitors), e.g. known hypersensitivity or allergy to class of drugs or the investigational product
• History of allergy to rabbits
• Current treatment with N-acetylcysteine, sodium bicarbonate, fenoldopam, mannitol (not applicable to mannitol serving as excipient in other medical drugs), dopamine or theophylline
• Women who are pregnant or breast feeding
• Multiple myeloma
• Acute decompensated heart failure (requiring hospital admission and treatment with supplemental oxygen, diuretics and/or vasodilator therapy) within two weeks prior to the date of coronary angiography
• Acute myocardial infarction (ST elevation or non-ST elevation myocardial infarction) within two weeks prior to the date of coronary angiography
• Dialysis
• Exposure to iodinated contrast media within seven days prior to the date of coronary angiography.
• Participation in another study with investigational drug within the 30 days preceding and during the present study
• Previous enrolment into the current study
• Enrolment of the investigators and their family members

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Conestat alfa; Intravenous injection of Conestat alfa, for patients less than 84kg at a dose of 50 U/kg, and for patients of 84kg body weight or greater at a dose of 4200 U (2 vials, each diluted in 14ml sterile water).	Drug: Conestat alfa; Two intravenous injections (over 5 minutes) of Conestat alfa immediately pre-procedure (elective coronary angiography) and 4 hours later; for patients less than 84kg at a dose of 50 U/kg, and for patients of 84kg body weight or greater at a dose of 4200 U.; Other Names: recombinant human C1 esterase inhibitor
Placebo Comparator: Sodium chloride 0.9%; Intravenous injection of sodium chloride 0.9%.	Drug: Sodium chloride 0.9%; Two intravenous injections of sodium chloride 0.9% (maximum 28 ml, matching the respective amount of the Conestat alfa arm) immediately pre-procedure (elective coronary angiography) and 4 hours later.; Other Names: isotonic (normal) saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak change from baseline of urinary Neutrophil gelatinase-associated lipocalin	measured at baseline, 4, 24 and 48 hours	within 48 hours after contrast exposure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of contrast-induced nephropathy	contrast-induced nephropathy is defined as serum creatinine increase of at least 25% or 44micromol/L within 48 hours after coronary angiography	within 48 hours after contrast exposure
Cystatin C increase of at least 10%	measured at baseline and 24 hours	within 24 hours after contrast exposure
increase in troponin T	measured at baseline, 4 and 24 hours	within 24 hours after contrast exposure
Peak change from baseline of urinary TIMP2 * IGFBP7	measured at baseline, 4, 24 and 48 hours	within 48 hours after contrast exposure

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite cardiovascular and renal outcome	defined as death, unstable angina/acute coronary syndrome, hospitalization for heart or renal failure, or hemodialysis	within 12-weeks after first intervention
Thromboembolic events	defined as symptomatic deep vein thrombosis or pulmonary embolism	within 12-weeks after first intervention
Anaphylactic reaction	defined as acute onset of an illness involving the skin and/or mucosa and either respiratory compromise or reduced blood pressure/evidence of end-organ malperfusion	within 24 hours after first intervention
C1 inhibitor serum concentration		Baseline and 10 minutes

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Pharming Technologies B.V.; Clinical Trial Unit, University Hospital Basel, Switzerland
• Investigators: Principal Investigator: Michael Osthoff, M.D., University Hospital Basel, Department of Infectious Diseases

Publications and helpful links

General Publications

• Panagiotou A, Trendelenburg M, Heijnen IAFM, Moser S, Bonati LH, Breidthardt T, Fahrni G, Kaiser C, Jeger R, Osthoff M. A Randomized Trial of Recombinant Human C1-Esterase-Inhibitor in the Prevention of Contrast-Induced Kidney Injury. JACC Cardiovasc Interv. 2020 Apr 13;13(7):833-842. doi: 10.1016/j.jcin.2019.11.021. Epub 2020 Mar 11.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): May 1, 2018
• Study Completion (Actual): July 1, 2018

Study Registration Dates

• First Submitted: August 12, 2016
• First Submitted That Met QC Criteria: August 15, 2016
• First Posted (Estimate): August 16, 2016

Study Record Updates

• Last Update Posted (Actual): August 8, 2018
• Last Update Submitted That Met QC Criteria: August 7, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: acute kidney injury; inflammation; coronary angiography; contrast media; Conestat alfa; recombinant C1 esterase inhibitor
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Acute Kidney Injury; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins; Complement C1s
• Other Study ID Numbers: BASEC 2016-01112

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided