Cyclosporine In Takotsubo Syndrome

Official title

Cyclosporine In Takotsubo Syndrome (CIT) Trial

Overview

The goal of this clinical trial is to investigate the impact of repetitive acute Cyclosporine A (CsA) bolus therapy in patients suffering from TTS with an elevated risk of impaired outcome. The main question it aims to answer is whether CsA reduces myocardial injury (primary outcome). Participants will receive CsA or placebo at baseline and every 12h in the first 24h after study inclusion. Researchers will compare CsA and the placebo group to see if a) myocardial injury is reduced, and b) ejection fraction is improved compared to baseline, as well as several other secondary endpoints over a one year follow-up.

Detailed description

Takotsubo syndrome (TTS) has been suggested to be caused by catecholamine excess with myocardial inflammation-enhanced cardiac injury. Substantial morbidity and mortality have repeatedly been reported, even though reduced ejection fraction frequently recovers spontaneously. So far there is no evidence-based treatment available. In a clinically relevant mouse model of catecholamine-driven TTS, cyclosporine A (CsA) bolus therapy markedly improves outcome, likely mediated via suppression of calcineurin-driven inflammation. The investigators have thus designed a pilot multicentre randomized controlled trial (RCT) to investigate the impact of repetitive CsA bolus therapy vs. placebo in acute TTS patients with an increased risk of intrahospital complications and a 32% estimated 5-year mortality. As primary outcome myocardial damage will be compared between groups via high-sensitive Troponin T plasma area under the curve (AUC). Recovery of cardiac function, the extent of myocardial oedema at 72h, length of hospital-stay, 30-day-, and 1-year composite clinical outcome as well as psychosocial and quality of life self-assessment will be secondary endpoints. The results of this trial may reveal CsA as a first pathophysiology-driven treatment option of TTS and enable a phase III follow-up trial with outcome parameters as primary endpoint.

Interventions

• Drug Cyclosporine A
  2.5mg/kg body weight Cyclosporine A as an intravenous bolus
• Drug Placebo
  The same amount of 0.9% sodium chloride (NaCl0.9%) will be applied in an indistinguishable package as an intravenous bolus

Primary outcome measures

• Myocardial damage [Time frame: baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30]

Secondary outcome measures (12)

• Change in Ejection fraction from baseline [Time frame: baseline, hour 24, hour 48, hour 72, day 30]
• Fold-change in Troponin plasma concentration [Time frame: baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30]
• Fold-change in creatine kinase plasma concentration [Time frame: baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30]
• Fold-change in NTproBNP plasma concentration [Time frame: baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30]
• Fold-change in interleukin-6 plasma concentration [Time frame: baseline, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30]
• Fold-change in procalcitonin plasma concentration [Time frame: baseline, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30]
• Myocardial edema [Time frame: hour 72]
• Myocardial inflammation [Time frame: hour 72]
• Rate of cardiovascular events at day 30 [Time frame: day 30]
• Rate of cardiovascular events at 1 year [Time frame: 1 year]
• Rate of novel disease onset [Time frame: day 30 and at 1 year]
• Symptom burden at day 30 [Time frame: day 30]

Eligibility criteria

Inclusion criteria

• Patients aged over 18
• Enrollment and first IMP administration within 24 hours after cardiac catheterization
• Regional Wall Motion Abnormality (WMA) consistent with TTS in angiography or echocardiography
• InterTAK prognostic score- or a GEIST Score ≥ 9 -
• Written informed consent

Exclusion criteria

• Acute coronary syndrome (ACS) with significant coronary stenosis potentially associated with wall motion abnormalities (WMA) or percutaneous coronary intervention (PCI)
• Infection (defined as concomitant infection with a positive blood culture at the time of study inclusion)
• History of hypersensitivity to cyclosporine
• History of hypersensitivity to egg, peanut or soybean proteins
• History of chronic renal insufficiency (either creatinin clearance <30 ml/min/1.73m² or current medical care for severe renal insufficiency)
• History of liver insufficiency
• Uncontrolled hypertension at the time of screening for study inclusion (systolic blood pressure >180mmHg and/or diastolic blood pressure >110mmHg)
• Current medication with any compound containing Hypericum perforatum (St. John's worth) or Stiripentol or Aliskiren or Bosentan or Rosuvastatine (Rosuvastatine >5mg within 24h intake<48h before IMP administration)
• Female patients currently pregnant or women of childbearing age without negative pregnancy test or without effective contraception
• Any disorder associated with immunological dysfunction ≤6 months prior to presentation (autoimmune disease, known positive serology for HIV or hepatitis)
• Immunosuppressive, chemotherapeutical, or antibody treatment
• Participation in other clinical trials except for non interventional trials

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Germany · 24 centers

• Kerckhoff Heart Center, Bad Nauheim / Gießen University — Bad Nauheim
• Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin — Berlin
• Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum — Berlin
• Heart Centre - University Hospital Bonn — Bonn
• Department of Cardiology, University Hospital Köln — Cologne
• Department of Cardiology, University Hospital Dresden — Dresden
• Cardiovascular Centre - University Hospital Düsseldorf — Düsseldorf
• Department of Cardiology - University Hospital Essen — Essen
• … and 16 more centers

Publications

• Bruns B, Elsous N, Burghaus I, Steyrer K, Joos M, Kramer T, Scheffel M, Blankenberg S, Eitel I, Massberg S, Thiele H, Meder B, Backs J, Frey N. Rationale and design of the cyclosporine in Takotsubo syndrome (CIT) trial. Am Heart J. 2025 Nov;289:147-157. doi: 10.1016/j.ahj.2025.04.020. Epub 2025 Apr 21. PMID 40268179

Identifiers

NCT: NCT05946772 · DZHK29 · DZHK29

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗