Clinical trial NCT05145283: Recombinant Human C1 Esterase Inhibitor (Conestat Alfa) in the Prevention of Acute Ischemic Cerebral and Renal Events After Transcatheter Aortic Valve Implantation
Official title: 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).
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Ischemic Stroke
Acute Renal Injury
Keywords: Severe aortic stenosis (AS)
Valvular heart disease
Transcatheter aortic valve implantation (TAVI)
cerebral embolic events
renal embolic events
Ischemia/reperfusion injury (IRI)
recombinant human C1 esterase inhibitor (rhC1INH, conestat alfa)
complement system
contact activation system
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
name: Pharming Technologies B.V.
First posted: 2021-12-06
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized in two parallel groups to receive either conestat alfa or placebo.
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Total volume of new cerebral ischemic lesions as evaluated by magnetic resonance imaging (MRI)
timeFrame: on day 4 (+/-1 day) after transfemoral TAVI
Secondary outcomes:
measure: Maximum new lesion volume as measured by MRI (i.e. volume of the largest new lesion)
timeFrame: on day 4 (+/-1 day) after transfemoral TAVI
measure: Number of new cerebral ischemic lesions as measured by MRI
timeFrame: on day 4 (+/-1 day) after transfemoral TAVI
measure: Number (incidence) of clinically manifest ischemic stroke
timeFrame: within 48 hours after TAVI
measure: Change in secondary brain atrophy at 3-months follow-up
timeFrame: at baseline and at 3-months follow-up
measure: Change in secondary infarct growth at 3-months follow-up (defined as the difference between the infarct volumes)
timeFrame: at day 4 and at 3-months
measure: Total brain damage (defined as the sum of secondary brain atrophy and final infarct volume)
timeFrame: at 3 months
measure: Change in National Institutes of Health Stroke Scale Score (NIHSS)
timeFrame: at baseline and at 3-months follow-up
measure: Change in modified Rankin scale
timeFrame: at baseline and at 3-months follow-up
measure: Change in trail making test
timeFrame: at baseline and at 3-months follow-up
measure: Change in Montreal Cognitive Assessment test (MOCA)
timeFrame: at baseline and at 3-months follow-up
measure: Incidence of acute kidney injury (AKI) defined according to the Kidney Disease: Improving Global Outcomes criteria (any stage)
timeFrame: within 3 days after TAVI
measure: Peak increase of urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL)
timeFrame: within 48 hours after TAVI
measure: Incidence of significant increase in serum cystatin C (>10%)
timeFrame: within 48 hours after TAVI
Other outcomes:
measure: Persistent renal impairment after 3 months (defined as increase in serum creatinine of at least 50% from baseline at 3 months)
timeFrame: at 3-months follow-up
measure: Change in concentration of C1-Esterase-Inhibitor (C1INH)
timeFrame: during the first 24 hours after TAVI
measure: Change in troponin T to assess myocardial injury following TAVI
timeFrame: within 72 hours after TAVI
measure: Change in urinary biomarkers of renal injury (Kidney Injury Molecule-1 (KIM-1) and osteopontin)
timeFrame: within 48 hours after TAVI
measure: Change in serum neurofilament light chain (marker of neuroaxonal damage)
timeFrame: within 3 months after TAVI
measure: Number of adverse events
timeFrame: within 3 months after TAVI
measure: Number of serious adverse events
timeFrame: within 3 months after TAVI
measure: Number of major cardiovascular and renal events (cardiovascular death, non-fatal myocardial infarction, heart failure hospitalization, stroke, dialysis)
timeFrame: within 3 months after TAVI
measure: Number of complications of transfemoral TAVI
timeFrame: within 3 months after TAVI
Locations:
city: Basel
country: Switzerland
facility: University Hospital Basel, Division of Internal Medicine
city: Zürich
country: Switzerland
facility: Stadtspital Triemli Zürich, Division of Cardiology
Study officials:
affiliation: University Hospital Basel, Division of Internal Medicine
name: Michael Osthoff, Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Stadtspital Triemli Zürich, Division of Cardiology
name: Raban Jeger, Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: