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

NCT05145283 | Completed Phase 2

• 1 other identifier: 2021-02025; me19Osthoff
• Study Type: interventional
• Target: 141
• Locations: 1 country
• Sites: 2

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.

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• 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

  on day 4 (+/-1 day) after transfemoral TAVI

• Number (incidence) of clinically manifest ischemic stroke

  within 48 hours after TAVI

• Change in secondary brain atrophy at 3-months follow-up

  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)

  at day 4 and at 3-months

Other Outcomes (9)

• Persistent renal impairment after 3 months (defined as increase in serum creatinine of at least 50% from baseline at 3 months)

  at 3-months follow-up

• Change in concentration of C1-Esterase-Inhibitor (C1INH)

  during the first 24 hours after TAVI

• Change in troponin T to assess myocardial injury following TAVI

  within 72 hours after TAVI

Study Arms (2)

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).

Drug: Conestat alfa (Ruconest®)

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.

Drug: NaCl 0.9%)

Interventions

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.

Conestat alfa (Ruconest®) intervention group

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.

saline injection placebo group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Basel, Switzerland: lead
• Swiss National Science Foundation: collaborator
• Pharming Technologies B.V.: collaborator

Study Sites (2)

University Hospital Basel, Division of Internal Medicine

Basel, 4031, Switzerland

Location

Stadtspital Triemli Zürich, Division of Cardiology

Zurich, 8063, Switzerland

Location

MeSH Terms

Conditions

Ischemic Stroke; Acute Kidney Injury; Aortic Valve Stenosis; Heart Valve Diseases; Reperfusion Injury

Interventions

conestat alfa; Sodium Chloride

Condition Hierarchy (Ancestors)

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Aortic Valve Disease; Heart Diseases; Ventricular Outflow Obstruction; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• 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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be randomized in two parallel groups to receive either conestat alfa or placebo.

Study Record Dates

• First Submitted: November 17, 2021
• First Posted: December 6, 2021
• Study Start: March 16, 2022
• Primary Completion: January 5, 2026
• Study Completion: January 5, 2026
• Last Updated: April 22, 2026

Record last verified: 2026-04

Locations

CH (2)