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

Primary Purpose

Acute Ischemic Stroke, Acute Renal Injury

Status
Recruiting
Phase
Phase 2
Locations
Switzerland
Study Type
Interventional
Intervention
Conestat alfa (Ruconest®)
NaCl 0.9%)
Sponsored by
University Hospital, Basel, Switzerland
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Acute Ischemic Stroke focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University Hospital Basel, Division of Internal MedicineRecruiting
  • Stadtspital Triemli Zürich, Division of CardiologyRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Conestat alfa (Ruconest®) intervention group

saline injection placebo group

Arm Description

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).

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.

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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)
Number of new cerebral ischemic lesions as measured by MRI
Number of new cerebral ischemic lesions as measured by MRI
Number (incidence) of clinically manifest ischemic stroke
Number (incidence) of clinically manifest ischemic stroke
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)
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)
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)
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.
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)
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.
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
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)
Peak increase of urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL)
Peak increase of urinary NGAL (surrogate marker of acute renal injury)
Incidence of significant increase in serum cystatin C (>10%)
Incidence of significant increase in serum cystatin C (>10%)

Full Information

First Posted
November 17, 2021
Last Updated
February 1, 2023
Sponsor
University Hospital, Basel, Switzerland
Collaborators
Swiss National Science Foundation, Pharming Technologies B.V.
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1. Study Identification

Unique Protocol Identification Number
NCT05145283
Brief Title
Recombinant Human C1 Esterase Inhibitor (Conestat Alfa) in the Prevention of Acute Ischemic Cerebral and Renal Events After Transcatheter Aortic Valve Implantation
Acronym
PAIR-TAVI
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

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 16, 2022 (Actual)
Primary Completion Date
March 2025 (Anticipated)
Study Completion Date
March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Basel, Switzerland
Collaborators
Swiss National Science Foundation, Pharming Technologies B.V.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Patients will be randomized in two parallel groups to receive either conestat alfa or placebo.
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
250 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Conestat alfa (Ruconest®) intervention group
Arm Type
Active Comparator
Arm Description
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).
Arm Title
saline injection placebo group
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Conestat alfa (Ruconest®)
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
NaCl 0.9%)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Total volume of new cerebral ischemic lesions as evaluated by magnetic resonance imaging (MRI)
Description
Total volume of new cerebral ischemic lesions as evaluated by magnetic resonance imaging (MRI)
Time Frame
on day 4 (+/-1 day) after transfemoral TAVI
Secondary Outcome Measure Information:
Title
Maximum new lesion volume as measured by MRI (i.e. volume of the largest new lesion)
Description
Maximum new lesion volume as measured by MRI (i.e. volume of the largest new lesion)
Time Frame
on day 4 (+/-1 day) after transfemoral TAVI
Title
Number of new cerebral ischemic lesions as measured by MRI
Description
Number of new cerebral ischemic lesions as measured by MRI
Time Frame
on day 4 (+/-1 day) after transfemoral TAVI
Title
Number (incidence) of clinically manifest ischemic stroke
Description
Number (incidence) of clinically manifest ischemic stroke
Time Frame
within 48 hours after TAVI
Title
Change in secondary brain atrophy at 3-months follow-up
Description
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)
Time Frame
at baseline and at 3-months follow-up
Title
Change in secondary infarct growth at 3-months follow-up (defined as the difference between the infarct volumes)
Description
Change in secondary infarct growth at 3-months follow-up (defined as the difference between the infarct volumes)
Time Frame
at day 4 and at 3-months
Title
Total brain damage (defined as the sum of secondary brain atrophy and final infarct volume)
Description
Total brain damage (defined as the sum of secondary brain atrophy and final infarct volume)
Time Frame
at 3 months
Title
Change in National Institutes of Health Stroke Scale Score (NIHSS)
Description
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.
Time Frame
at baseline and at 3-months follow-up
Title
Change in modified Rankin scale
Description
Change in modified Rankin scale; scale runs from 0-6, running from perfect health (0) without symptoms to death (6)
Time Frame
at baseline and at 3-months follow-up
Title
Change in trail making test
Description
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.
Time Frame
at baseline and at 3-months follow-up
Title
Change in Montreal Cognitive Assessment test (MOCA)
Description
Montreal Cognitive Assessment test scores range between 0 and 30. A score of 26 or over is considered to be normal
Time Frame
at baseline and at 3-months follow-up
Title
Incidence of acute kidney injury (AKI) defined according to the Kidney Disease: Improving Global Outcomes criteria (any stage)
Description
Incidence of AKI defined according to the Kidney Disease: Improving Global Outcomes criteria (any stage)
Time Frame
within 3 days after TAVI
Title
Peak increase of urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL)
Description
Peak increase of urinary NGAL (surrogate marker of acute renal injury)
Time Frame
within 48 hours after TAVI
Title
Incidence of significant increase in serum cystatin C (>10%)
Description
Incidence of significant increase in serum cystatin C (>10%)
Time Frame
within 48 hours after TAVI
Other Pre-specified Outcome Measures:
Title
Persistent renal impairment after 3 months (defined as increase in serum creatinine of at least 50% from baseline at 3 months)
Description
Persistent renal impairment after 3 months (defined as serum creatinine increase of at least 50% from baseline at 3 months)
Time Frame
at 3-months follow-up
Title
Change in concentration of C1-Esterase-Inhibitor (C1INH)
Description
Change in concentration of C1INH
Time Frame
during the first 24 hours after TAVI
Title
Change in troponin T to assess myocardial injury following TAVI
Description
Change in troponin T to assess myocardial injury following TAVI
Time Frame
within 72 hours after TAVI
Title
Change in urinary biomarkers of renal injury (Kidney Injury Molecule-1 (KIM-1) and osteopontin)
Description
Change in urinary biomarkers of renal injury (Kidney Injury Molecule-1 (KIM-1) and osteopontin)
Time Frame
within 48 hours after TAVI
Title
Change in serum neurofilament light chain (marker of neuroaxonal damage)
Description
Change in serum neurofilament light chain (marker of neuroaxonal damage)
Time Frame
within 3 months after TAVI
Title
Number of adverse events
Description
Number of adverse events
Time Frame
within 3 months after TAVI
Title
Number of serious adverse events
Description
Number of serious adverse events
Time Frame
within 3 months after TAVI
Title
Number of major cardiovascular and renal events (cardiovascular death, non-fatal myocardial infarction, heart failure hospitalization, stroke, dialysis)
Description
Number of major cardiovascular and renal events (cardiovascular death, non-fatal myocardial infarction, heart failure hospitalization, stroke, dialysis)
Time Frame
within 3 months after TAVI
Title
Number of complications of transfemoral TAVI
Description
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)
Time Frame
within 3 months after TAVI

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michael Osthoff, Prof. Dr. med.
Phone
+41 61 328 54 20
Email
michael.osthoff@usb.ch
First Name & Middle Initial & Last Name or Official Title & Degree
Stephan Moser, Dr. med.
Phone
+41 61 265 25 25
Email
stephan.moser@usb.ch
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Osthoff, Prof. Dr. med.
Organizational Affiliation
University Hospital Basel, Division of Internal Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Raban Jeger, Prof. Dr. med.
Organizational Affiliation
Stadtspital Triemli Zürich, Division of Cardiology
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Basel, Division of Internal Medicine
City
Basel
ZIP/Postal Code
4031
Country
Switzerland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael Osthoff, Prof Dr. med.
Phone
+41 61 328 54 20
Email
michael.osthoff@usb.ch
First Name & Middle Initial & Last Name & Degree
Stephan Moser, Dr.med.
Phone
+41 61 265 25 25
Email
stephan.moser@usb.ch
First Name & Middle Initial & Last Name & Degree
Michael Osthoff, Prof Dr. med.
Facility Name
Stadtspital Triemli Zürich, Division of Cardiology
City
Zürich
ZIP/Postal Code
8063
Country
Switzerland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Raban Jeger, Prof. Dr. med.
Phone
+41 44 416 34 11
Email
raban.jeger@stadtspital.ch
First Name & Middle Initial & Last Name & Degree
Raban Jeger, Prof. Dr. med.

12. IPD Sharing Statement

Learn more about this trial

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

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