Recombinant Human C1 Esterase Inhibitor (Conestat Alfa) in the Prevention of Acute Ischemic Cerebral and Renal Events After Transcatheter Aortic Valve Implantation (PAIR-TAVI)

Recombinant Human C1 Esterase Inhibitor (Conestat Alfa) in the Prevention of Acute Ischemic Cerebral and Renal Events After Transcatheter Aortic Valve Implantation: a Multi-center, Randomized, Double-blind, Placebo-controlled Investigational Study (PAIR-TAVI).

The aim of this trial is to assess the safety and efficacy of conestat alfa (Ruconest®, Pharming Technologies B.V.) on renal and cerebral ischemic events in patients undergoing TAVI for severe symptomatic aortic stenosis (AS) compared to placebo.

Study Overview

• Status: Recruiting
• Conditions: Acute Renal Injury; Acute Ischemic Stroke
• Intervention / Treatment: Drug: Conestat alfa (Ruconest®); Drug: NaCl 0.9%)

Detailed Description

Severe aortic stenosis (AS) is a frequent valvular heart disease in the elderly with a prevalence of 4 to 10% and a mean survival of only 0.5 to 5 years if left untreated. Transcatheter aortic valve implantation (TAVI) has evolved as standard of care for high-, intermediate and potentially even low surgical risk candidates due to a lower perioperative risk compared to surgical aortic valve replacement (SAVR). Despite its relative safety compared to SAVR, embolic events originating from the calcified valve and leading to ischemic stroke and acute renal injury are major complications following TAVI in the acute and subacute period, and are associated with increased morbidity including cognitive decline and mortality. While cerebral embolic protection devices (CEPD) such as the Sentinel® CEPD (Boston Scientific) were designed to reduce the burden of cerebral embolic events, their impact on clinical events has yet to be determined, and other prophylactic options are currently not available. Ischemia/reperfusion injury (IRI) is a key pathophysiological mechanism involved in cerebral and renal embolic events after TAVI resulting in activation of endothelial cells, the contact activation and the complement system and attraction of neutrophils to the site of injury. In this regard, recombinant human C1 esterase inhibitor (rhC1INH, conestat alfa), a potent inhibitor of the complement and the contact system has been shown to reduce the size of cerebral ischemic damage and of renal injury in experimental IRI models, and has successfully been investigated in a pilot study of acute kidney injury following the administration of contrast media. The aim of the current trial is to assess the safety and efficacy of conestat alfa (Ruconest®, Pharming Technologies B.V.) on renal and cerebral ischemic events in patients undergoing TAVI for severe symptomatic AS compared to placebo.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael Osthoff, Prof. Dr. med.; Phone Number: +41 61 328 54 20; Email: michael.osthoff@usb.ch
• Study Contact Backup: Name: Stephan Moser, Dr. med.; Phone Number: +41 61 265 25 25; Email: stephan.moser@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • Recruiting
    • University Hospital Basel, Division of Internal Medicine
    • Contact: Michael Osthoff, Prof Dr. med.; Phone Number: +41 61 328 54 20; Email: michael.osthoff@usb.ch
    • Contact: Stephan Moser, Dr.med.; Phone Number: +41 61 265 25 25; Email: stephan.moser@usb.ch
    • Principal Investigator: Michael Osthoff, Prof Dr. med.
  • Zürich, Switzerland, 8063
    • Recruiting
    • Stadtspital Triemli Zürich, Division of Cardiology
    • Principal Investigator: Raban Jeger, Prof. Dr. med.
    • Contact: Raban Jeger, Prof. Dr. med.; Phone Number: +41 44 416 34 11; Email: raban.jeger@stadtspital.ch

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Informed consent as documented by signature
• Severe AS and scheduled for transfemoral TAVI

Exclusion Criteria:

• Contraindications to the class of drugs under study (C1INH), e.g., known hypersensitivity or allergy to class of drugs or the investigational product
• History of allergy to rabbits (as rhC1INH is derived from the breast milk of transgenic rabbits)
• Women who are pregnant or breast feeding
• Hemodynamic instability requiring emergency TAVI
• Valve-in-valve procedure
• Other access route than transfemoral
• Non-cardiac co-morbidity with expected survival <6 months
• Ischemic or hemorrhagic stroke within 30 days before TAVI
• Dialysis or estimated glomerular filtration rate (eGFR) <20 ml/min/1.73m2
• Contraindication for MRI such as a permanent non-MRI compatible pacemaker or severe claustrophobia
• Liver cirrhosis (any Child-Pugh score)
• Incapacity or inability to provide informed consent
• Participation in another study with investigational drug or medical device within the 30 days preceding and during the present study
• Previous enrolment into the current study
• Any uncontrolled or significant concurrent illness that would put the patient at a greater risk or limit compliance with the study requirements at the discretion of the investigator

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
Active Comparator: Conestat alfa (Ruconest®) intervention group; The intervention group will receive conestat alfa (Ruconest®) as a 10-minute slow intravenous injection (up to 56 ml) once during the TAVI procedure followed by a second administration (up to 28 ml) again three hours later. The first administration will include a dosage of 100 U/kg (maximum 8400 U) conestat alfa. The dosing of the second administration will be 50 U/kg (maximum 4200 U).	Drug: Conestat alfa (Ruconest®); In the current study, participants will receive two intravenous injections of conestat alfa (immediately during the TAVI procedure and again 3h later) at a dose of 100 U/kg (first dose) and of 50 U/kg (subsequent dose), for patients less than 84 kg; two intravenous injections (immediately during the TAVI procedure and again 4h later) of conestat at a dose of 8400 U (4 vials, first dose) and of 4200 U (2 vials, subsequent dose) for patients of 84 kg body weight or greater. The chosen regimen including repeated administration should increase and maintain serum C1INH levels above twice the serum concentration for six to eight hours in the majority of patients. The timeframe of therapeutic concentrations will cover the period of the TAVI procedure itself and the immediate postprocedural period during which reperfusion and additional ischemic events related to global hypoperfusion may occur.
Placebo Comparator: saline injection placebo group; Subjects randomized into the placebo group will receive an intravenous normal saline injection with corresponding volume over 10 minutes during the TAVI procedure and three hours later after the first administration.	Drug: NaCl 0.9%); Normal saline (NaCl 0.9%) will serve as placebo treatment. The respective amount of saline (according to patient weight matching the volume of conestat alfa that would have been used for this patient) will be withdrawn in an opaque syringe for slow IV injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total volume of new cerebral ischemic lesions as evaluated by magnetic resonance imaging (MRI)	Total volume of new cerebral ischemic lesions as evaluated by magnetic resonance imaging (MRI)	on day 4 (+/-1 day) after transfemoral TAVI

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum new lesion volume as measured by MRI (i.e. volume of the largest new lesion)	Maximum new lesion volume as measured by MRI (i.e. volume of the largest new lesion)	on day 4 (+/-1 day) after transfemoral TAVI
Number of new cerebral ischemic lesions as measured by MRI	Number of new cerebral ischemic lesions as measured by MRI	on day 4 (+/-1 day) after transfemoral TAVI
Number (incidence) of clinically manifest ischemic stroke	Number (incidence) of clinically manifest ischemic stroke	within 48 hours after TAVI
Change in secondary brain atrophy at 3-months follow-up	Secondary brain atrophy at 3-months follow-up related to the gradual cellular loss as measured by high resolution 3D T1-weighted MR images (defined as the difference between the brain volumes)	at baseline and at 3-months follow-up
Change in secondary infarct growth at 3-months follow-up (defined as the difference between the infarct volumes)	Change in secondary infarct growth at 3-months follow-up (defined as the difference between the infarct volumes)	at day 4 and at 3-months
Total brain damage (defined as the sum of secondary brain atrophy and final infarct volume)	Total brain damage (defined as the sum of secondary brain atrophy and final infarct volume)	at 3 months
Change in National Institutes of Health Stroke Scale Score (NIHSS)	The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.	at baseline and at 3-months follow-up
Change in modified Rankin scale	Change in modified Rankin scale; scale runs from 0-6, running from perfect health (0) without symptoms to death (6)	at baseline and at 3-months follow-up
Change in trail making test	Change in trail making test; scoring is based on time taken to complete the test (e.g. 35 seconds yielding a score of 35) with lower scores being better.	at baseline and at 3-months follow-up
Change in Montreal Cognitive Assessment test (MOCA)	Montreal Cognitive Assessment test scores range between 0 and 30. A score of 26 or over is considered to be normal	at baseline and at 3-months follow-up
Incidence of acute kidney injury (AKI) defined according to the Kidney Disease: Improving Global Outcomes criteria (any stage)	Incidence of AKI defined according to the Kidney Disease: Improving Global Outcomes criteria (any stage)	within 3 days after TAVI
Peak increase of urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL)	Peak increase of urinary NGAL (surrogate marker of acute renal injury)	within 48 hours after TAVI
Incidence of significant increase in serum cystatin C (>10%)	Incidence of significant increase in serum cystatin C (>10%)	within 48 hours after TAVI

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Persistent renal impairment after 3 months (defined as increase in serum creatinine of at least 50% from baseline at 3 months)	Persistent renal impairment after 3 months (defined as serum creatinine increase of at least 50% from baseline at 3 months)	at 3-months follow-up
Change in concentration of C1-Esterase-Inhibitor (C1INH)	Change in concentration of C1INH	during the first 24 hours after TAVI
Change in troponin T to assess myocardial injury following TAVI	Change in troponin T to assess myocardial injury following TAVI	within 72 hours after TAVI
Change in urinary biomarkers of renal injury (Kidney Injury Molecule-1 (KIM-1) and osteopontin)	Change in urinary biomarkers of renal injury (Kidney Injury Molecule-1 (KIM-1) and osteopontin)	within 48 hours after TAVI
Change in serum neurofilament light chain (marker of neuroaxonal damage)	Change in serum neurofilament light chain (marker of neuroaxonal damage)	within 3 months after TAVI
Number of adverse events	Number of adverse events	within 3 months after TAVI
Number of serious adverse events	Number of serious adverse events	within 3 months after TAVI
Number of major cardiovascular and renal events (cardiovascular death, non-fatal myocardial infarction, heart failure hospitalization, stroke, dialysis)	Number of major cardiovascular and renal events (cardiovascular death, non-fatal myocardial infarction, heart failure hospitalization, stroke, dialysis)	within 3 months after TAVI
Number of complications of transfemoral TAVI	Number of complications of transfemoral TAVI such as conduction disturbance (including permanent pacemaker implantation) or aortic regurgitation according to the Valve Academic Research Consortium (VARC)-3 criteria, or bleeding according to the Bleeding Academic Research Consortium (BARC)-criteria)	within 3 months after TAVI

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Swiss National Science Foundation; Pharming Technologies B.V.
• Investigators: Principal Investigator: Raban Jeger, Prof. Dr. med., Stadtspital Triemli Zürich, Division of Cardiology; Principal Investigator: Michael Osthoff, Prof. Dr. med., University Hospital Basel, Division of Internal Medicine

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2022
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: November 17, 2021
• First Submitted That Met QC Criteria: November 22, 2021
• First Posted (Actual): December 6, 2021

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 19, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Valvular heart disease; Transcatheter aortic valve implantation (TAVI); cerebral embolic events; complement system; Severe aortic stenosis (AS); renal embolic events; Ischemia/reperfusion injury (IRI); recombinant human C1 esterase inhibitor (rhC1INH, conestat alfa); contact activation system
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Kidney Diseases; Urologic Diseases; Renal Insufficiency; Stroke; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Ischemic Stroke; Ischemia; Acute Kidney Injury; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Complement C1 Inhibitor Protein
• Other Study ID Numbers: 2021-02025; me19Osthoff

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No