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

Study Overview
=================
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.

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).

Conditions
-----------------
Acute Ischemic Stroke, Acute Renal Injury

Intervention / Treatment
-----------------
* Drug: Conestat alfa (Ruconest®)
* Drug: NaCl 0.9%)


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized in two parallel groups to receive either conestat alfa or placebo.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Conestat alfa (Ruconest®) intervention group<br>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®)<br>* 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.<br>|
| Placebo Comparator: saline injection placebo group<br>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%)<br>* 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.<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ischemia/reperfusion injury (IRI), Severe aortic stenosis (AS), Valvular heart disease, Transcatheter aortic valve implantation (TAVI), cerebral embolic events, renal embolic events, recombinant human C1 esterase inhibitor (rhC1INH, conestat alfa), complement system, contact activation system