Cyclosporine In Takotsubo Syndrome

Takotsubo Cardiomyopathy Clinical Trial

— CIT  

Official title:

Cyclosporine In Takotsubo Syndrome (CIT) Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05946772
• Other study ID #: DZHK29
• Secondary ID: DZHK29
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: October 2024
• Est. completion date: October 2027

Study information

• Verified date: May 2024
• Source: University Hospital Heidelberg
• Contact: Bastian Bruns, MD
• Phone: +496221-56-36266
• Email: bastian.bruns[@]med.uni-heidelberg.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 204
• Est. completion date: October 2027
• Est. primary completion date: October 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cardiomyopathies
• Takotsubo Cardiomyopathy

Intervention

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

Locations

Country	Name	City	State
Germany	Kerckhoff Heart Center, Bad Nauheim / Gießen University	Bad Nauheim
Germany	Department of Cardiology, Charité - Universitätsmedizin Berlin	Berlin
Germany	Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin	Berlin
Germany	Heart and Diabetes Centre - University Hospital Bochum	Bochum
Germany	Heart Centre - University Hospital Bonn	Bonn
Germany	Department of Cardiology, University Hospital Dresden	Dresden
Germany	Cardiovascular Centre - University Hospital Düsseldorf	Düsseldorf
Germany	Department of Cardiology, Erlangen-Nürnberg University	Erlangen
Germany	Department of Cardiology - University Hospital Essen	Essen
Germany	Department of Cardiology - University Hospital Freiburg	Freiburg
Germany	University Medical Center Göttingen	Göttingen
Germany	Department of Cardiology, University Hospital Greifswald	Greifswald
Germany	University Medical Center Hamburg-Eppendorf	Hamburg
Germany	Department of Cardiology, University Hospital Hannover	Hannover
Germany	Department of Cardiology, Heidelberg University Hospital	Heidelberg
Germany	Department of Cardiology, University Hospital of Saarland	Homburg
Germany	Department of Cardiology, University Hospital Jena	Jena
Germany	University Medical Center Schleswig-Holstein/Campus Kiel	Kiel
Germany	Department of Cardiology, University Hospital Köln	Köln
Germany	Leipzig Heart Center	Leipzig
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	Department of Cardiology, University Hospital Oldenburg	Oldenburg
Germany	Department of Cardiology - University Hospital Rostock	Rostock
Germany	Department of Cardiology, University Hospital Tübingen	Tübingen
Germany	Department of Cardiology, University Hospital Ulm	Ulm
Germany	Department of Cardiology, University Hospital Würzburg	Würzburg

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital Heidelberg	Coordinating Centre for Clinical Studies (KKS) Heidelberg, German Centre of Cardiovascular Research (DZHK)

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Myocardial edema	Cardiac MRI will be used to assess the T2 signal intensity ratio for comparison between CsA and Placebo at 72h.	hour 72
Secondary	Myocardial inflammation	Cardiac MRI will be used to assess the early gadolinium enhancement ratio for comparison between CsA and Placebo at 72h.	hour 72
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Length of hospital stay	Length of hospital stay will be compared between groups	day 30