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| Name | Class |
|---|---|
| Swiss National Science Foundation | OTHER |
| Pharming Technologies B.V. | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Conestat alfa (Ruconest®) intervention group | Active Comparator | 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). |
|
| saline injection placebo group | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Conestat alfa (Ruconest®) | Drug | 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. |
| 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 |
| 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 |
| 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) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael Osthoff, Prof. Dr. med. | University Hospital Basel, Division of Internal Medicine | Principal Investigator |
| Raban Jeger, Prof. Dr. med. | Stadtspital Triemli Zürich, Division of Cardiology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Basel, Division of Internal Medicine | Basel | 4031 | Switzerland | |||
| Stadtspital Triemli Zürich, Division of Cardiology |
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Patients will be randomized in two parallel groups to receive either conestat alfa or placebo.
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| NaCl 0.9%) | Drug | 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. |
|
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 |
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 |
| Zurich |
| 8063 |
| Switzerland |
| ID | Term |
|---|---|
| D000083242 | Ischemic Stroke |
| D058186 | Acute Kidney Injury |
| D001024 | Aortic Valve Stenosis |
| D006349 | Heart Valve Diseases |
| D015427 | Reperfusion Injury |
| ID | Term |
|---|---|
| D020521 | Stroke |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D000082862 | Aortic Valve Disease |
| D006331 | Heart Diseases |
| D014694 | Ventricular Outflow Obstruction |
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C571093 | conestat alfa |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
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