Cyclosporine In Takotsubo Syndrome

Phase 2

Recruiting

• Conditions: Takotsubo Cardiomyopathy
• Interventions: Drug: Placebo; Drug: Cyclosporine A

• Registration Number: NCT05946772
• Lead Sponsor: University Hospital Heidelberg

Brief Summary

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.

Study Timeline

• Study First Submitted: 2023-06-19
• Study First Submitted QC: 2023-07-07
• Study First Posted: 2023-07-14
• Study Start: 2025-02-01
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-04
• Last Update Posted: 2025-04-08
• Primary Completion: 2027-02
• Study Completion: 2028-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 204

Inclusion Criteria

1. Adult patients (age ≥ 18 years)

2. Symptom onset < 24h

3. With a high probability of TTS:

   1. InterTAK Diagnostic Score > 39 and
   2. Regional wall motion abnormality (WMA) consistent with TTS; no coronary intervention (PCI), or reperfused myocardial ischemia according to MRI

4. With a high probability of impaired outcome:

   1. InterTAK Prognostic Score >15 or
   2. GEIST Score > 19

Exclusion Criteria

1. Suspected infection
2. Cardiac arrest, ventricular fibrillation, invasive ventilatory support
3. Known hypersensitivity to CsA, egg, peanut, or soya-bean proteins
4. Renal insufficiency (creatinin clearance < 30 ml/min/1.73m²)
5. Liver insufficiency
6. Uncontrolled hypertension (>180/110 mmHg)
7. Hypericum perforatum, Stiripentol, Aliskiren, Bosentan, or Rosuvastatin treatment
8. Pregnancy or women of childbearing age without contraception
9. Any disorder associated with immunological dysfunction < 6 months prior to presentation
10. Immunosuppressive therapy
11. Participation in another clinical trial

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	A concealed 0.9% sodium chloride (NaCl) preparation will be applied intravenously at baseline, 12h, and 24h.
CsA	Cyclosporine A	Cyclosporine A will be applied intravenously at baseline, 12h, and 24h.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Change in Ejection fraction from baseline	baseline, hour 24, hour 48, hour 72, day 30	Multiple timepoints will be compared to baseline between CsA and Placebo.
Fold-change in Troponin plasma concentration	baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30	The change of high-sensitive Troponin T will be compared to baseline between CsA and Placebo for multiple time points.
Fold-change in creatine kinase plasma concentration	baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30	The change of creatine kinase will be compared to baseline between CsA and Placebo for multiple time points.
Fold-change in NTproBNP plasma concentration	baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30	The change of NTproBNP will be compared to baseline between CsA and Placebo for multiple time points.
Fold-change in interleukin-6 plasma concentration	baseline, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30	The change of interleukin-6 will be compared to baseline between CsA and Placebo for multiple time points.
Fold-change in procalcitonin plasma concentration	baseline, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30	The change of procalcitonin will be compared to baseline between CsA and Placebo for multiple time points.
Myocardial edema	hour 72	Cardiac MRI will be used to assess the T2 signal intensity ratio for comparison between CsA and Placebo at 72h.
Myocardial inflammation	hour 72	Cardiac MRI will be used to assess the early gadolinium enhancement ratio for comparison between CsA and Placebo at 72h.
Rate of cardiovascular events at day 30	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.
Rate of cardiovascular events at 1 year	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.
Rate of novel disease onset	day 30 and at 1 year	At 30 days and 1-year novel clinical diagnoses during follow-up including cancer or neurological diseases will be assessed.
Symptom burden at day 30	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).
Symptom burden at 1 year	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).
Depression score at day 30	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).
Depression score at year 1	1 year	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).
Anxiety score at day 30	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).
Anxiety score at year 1	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).
PTSD score at 30 days	day 30	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).
PTSD score at 1 year	year 1	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).
Length of intermediate care or intensive care unit stay	day 30	Length of intermediate care or intensive care unit stay will be compared between groups
Length of hospital stay	day 30	Length of hospital stay will be compared between groups

Trial Locations

Locations (21)

Leipzig Heart Center; 🇩🇪 Leipzig, Germany

Kerckhoff Heart Center, Bad Nauheim / Gießen University; 🇩🇪 Bad Nauheim, Germany

Heart Centre - University Hospital Bonn; 🇩🇪 Bonn, Germany

University Medical Center Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

Department of Cardiology, University Hospital Hannover; 🇩🇪 Hannover, Germany

Department of Cardiology, Heidelberg University Hospital; 🇩🇪 Heidelberg, Germany

University Medical Center Schleswig-Holstein/Campus Kiel; 🇩🇪 Kiel, Germany

Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin; 🇩🇪 Berlin, Germany

Department of Cardiology, University Hospital Ulm; 🇩🇪 Ulm, Germany

Department of Cardiology, Charité - Universitätsmedizin Berlin; 🇩🇪 Berlin, Germany

Department of Cardiology, University Hospital Dresden; 🇩🇪 Dresden, Germany

Cardiovascular Centre - University Hospital Düsseldorf; 🇩🇪 Düsseldorf, Germany

Department of Cardiology - University Hospital Essen; 🇩🇪 Essen, Germany

University Medical Center Göttingen; 🇩🇪 Göttingen, Germany

Department of Cardiology, University Hospital Köln; 🇩🇪 Köln, Germany

University Medical Center Schleswig-Holstein/Campus Lübeck; 🇩🇪 Lübeck, Germany

Department of Cardiology, University Hospital Magdeburg; 🇩🇪 Magdeburg, Germany

Department of Cardiology, University Hospital Mainz; 🇩🇪 Mainz, Germany

Department of Cardiology, University Hospital Mannheim; 🇩🇪 Mannheim, Germany

Department of Cardiology, Hospital of the Ludwig-Maximilians-University Munich; 🇩🇪 München, Germany

University Hospital rechts der Isar, Technical University of Munich; 🇩🇪 München, Germany