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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
204
2.5mg/kg body weight Cyclosporine A as an intravenous bolus
The same amount of 0.9% sodium chloride (NaCl0.9%) will be applied in an indistinguishable package as an intravenous bolus
Kerckhoff Heart Center, Bad Nauheim / Gießen University
Bad Nauheim, Germany
NOT_YET_RECRUITINGDepartment of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin
Berlin, Germany
RECRUITINGDepartment of Cardiology, Charité - Universitätsmedizin Berlin
Berlin, Germany
NOT_YET_RECRUITINGHeart Centre - University Hospital Bonn
Bonn, Germany
NOT_YET_RECRUITINGDepartment of Cardiology, University Hospital Köln
Cologne, Germany
NOT_YET_RECRUITINGDepartment of Cardiology, University Hospital Dresden
Dresden, Germany
NOT_YET_RECRUITINGCardiovascular Centre - University Hospital Düsseldorf
Düsseldorf, Germany
NOT_YET_RECRUITINGDepartment of Cardiology - University Hospital Essen
Essen, Germany
NOT_YET_RECRUITINGUniversity Medical Center Göttingen
Göttingen, Germany
NOT_YET_RECRUITINGUniversity Medical Center Hamburg-Eppendorf
Hamburg, Germany
NOT_YET_RECRUITING...and 11 more locations
Myocardial damage
High-sensitive Troponin T AUC over several time points between CsA and Placebo.
Time frame: baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30
Change in Ejection fraction from baseline
Multiple timepoints will be compared to baseline between CsA and Placebo.
Time frame: baseline, hour 24, hour 48, hour 72, day 30
Fold-change in Troponin plasma concentration
The change of high-sensitive Troponin T will be compared to baseline between CsA and Placebo for multiple time points.
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
The change of creatine kinase will be compared to baseline between CsA and Placebo for multiple time points.
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
The change of NTproBNP will be compared to baseline between CsA and Placebo for multiple time points.
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
The change of interleukin-6 will be compared to baseline between CsA and Placebo for multiple time points.
Time frame: baseline, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30
Fold-change in procalcitonin plasma concentration
The change of procalcitonin will be compared to baseline between CsA and Placebo for multiple time points.
Time frame: baseline, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30
Myocardial edema
Cardiac MRI will be used to assess the T2 signal intensity ratio for comparison between CsA and Placebo at 72h.
Time frame: hour 72
Myocardial inflammation
Cardiac MRI will be used to assess the early gadolinium enhancement ratio for comparison between CsA and Placebo at 72h.
Time frame: hour 72
Rate of cardiovascular events at day 30
At day 30 a composite cardiovascular outcome measure includes overall mortality, stroke, myocardial infarction, heart failure hospitalization, recurrent TTS, cardiac arrest, ventricular fibrillation, ventricular tachycardia, novel atrial fibrillation, and thromboembolism. The measure is considered positive if one of the above occurs. The amount of patients with positive and negative events is then compared between the CsA and placebo arm.
Time frame: day 30
Rate of cardiovascular events at 1 year
At 1 year a composite cardiovascular outcome measure includes overall mortality, stroke, myocardial infarction, heart failure hospitalization, recurrent TTS, cardiac arrest, ventricular fibrillation, ventricular tachycardia, novel atrial fibrillation, and thromboembolism. The measure is considered positive if one of the above occurs. The amount of patients with positive and negative events is then compared between the CsA and placebo arm.
Time frame: 1 year
Rate of novel disease onset
At 30 days and 1-year novel clinical diagnoses during follow-up including cancer or neurological diseases will be assessed.
Time frame: day 30 and at 1 year
Symptom burden at day 30
Patient-reported outcome will be quantified by the Kansas City Cardiomyopathy Questionnaire after 30d and 1 year (scale 0-100 points: 0-24 points: very poor; 25-49 points: poor; 50-74 points: fair; 75-100: good).
Time frame: day 30
Symptom burden at 1 year
Patient-reported outcome will be quantified by the Kansas City Cardiomyopathy Questionnaire at 1 year (scale 0-100 points: 0-24 points: very poor; 25-49 points: poor; 50-74 points: fair; 75-100: good).
Time frame: 1 year
Depression score at day 30
Patient-reported psychosocial assessment will be quantified by the well validated German patient health questionnaire 9 (PHQ-9) scale (range 0-27 points, higher points indicate worse depressive symptoms).
Time frame: day 30
Depression score at year 1
Patient-reported psychosocial assessment will be quantified by the well validated German patient health questionnaire 9 (PHQ-9) scale (range 0-27 points, higher points indicate worse depressive symptoms).
Time frame: 1 year
Anxiety score at day 30
Patient-reported psychosocial assessment will be quantified by the well validated German generalized anxiety disorder 7 (GAD-7) questionnaire (range 0-21 points, higher points indicate worse anxiety).
Time frame: day 30
Anxiety score at year 1
Patient-reported psychosocial assessment will be quantified by the well validated German generalized anxiety disorder 7 (GAD-7) questionnaire (range 0-21 points, higher points indicate worse anxiety).
Time frame: year 1
PTSD score at 30 days
Patient-reported psychosocial assessment will be quantified by the well validated German primary care posttraumatic stress disorder questionnaire 5 (PC-PTSD-5) (0-5 points, higher points indicate more symptoms of posttraumatic stress disorder).
Time frame: day 30
PTSD score at 1 year
Patient-reported psychosocial assessment will be quantified by the well validated German primary care posttraumatic stress disorder questionnaire 5 (PC-PTSD-5) (0-5 points, higher points indicate more symptoms of posttraumatic stress disorder).
Time frame: year 1
Length of intermediate care or intensive care unit stay
Length of intermediate care or intensive care unit stay will be compared between groups
Time frame: day 30
Length of hospital stay
Length of hospital stay will be compared between groups
Time frame: day 30
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.