Cyclosporine In Takotsubo Syndrome

Study Overview
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Brief Summary
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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
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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.

Official Title
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Cyclosporine In Takotsubo Syndrome (CIT) Trial

Conditions
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Takotsubo Cardiomyopathy

Intervention / Treatment
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* Drug: Cyclosporine A
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (age ≥ 18 years) Symptom onset < 24h With a high probability of TTS: InterTAK Diagnostic Score > 39 and Regional wall motion abnormality (WMA) consistent with TTS; no coronary intervention (PCI), or reperfused myocardial ischemia according to MRI With a high probability of impaired outcome: InterTAK Prognostic Score >15 or GEIST Score > 19 Exclusion Criteria: Suspected infection Cardiac arrest, ventricular fibrillation, invasive ventilatory support Known hypersensitivity to CsA, egg, peanut, or soya-bean proteins Renal insufficiency (creatinin clearance < 30 ml/min/1.73m²) Liver insufficiency Uncontrolled hypertension (>180/110 mmHg) Hypericum perforatum, Stiripentol, Aliskiren, Bosentan, or Rosuvastatin treatment Pregnancy or women of childbearing age without contraception Any disorder associated with immunological dysfunction < 6 months prior to presentation Immunosuppressive therapy Participation in another clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind multicentre RCT
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>A concealed 0.9% sodium chloride (NaCl) preparation will be applied intravenously at baseline, 12h, and 24h. | Drug: Placebo<br>* The same amount of 0.9% sodium chloride (NaCl0.9%) will be applied in an indistinguishable package as an intravenous bolus<br>|
| Experimental: CsA<br>Cyclosporine A will be applied intravenously at baseline, 12h, and 24h. | Drug: Cyclosporine A<br>* 2.5mg/kg body weight Cyclosporine A as an intravenous bolus<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial damage | High-sensitive Troponin T AUC over several time points between CsA and Placebo. | baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Ejection fraction from baseline | Multiple timepoints will be compared to baseline between CsA and Placebo. | 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. | 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. | 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. | 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. | 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. | 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. | hour 72 | 
| Myocardial inflammation | Cardiac MRI will be used to assess the early gadolinium enhancement ratio for comparison between CsA and Placebo at 72h. | 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. | 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. | 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. | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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 | day 30 | 
| Length of hospital stay | Length of hospital stay will be compared between groups | day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Takotsubo syndrome, Troponin, Cyclosporine, Inflammation, Acute heart failure