Cyclosporine In Takotsubo Syndrome (CIT)

Cyclosporine In Takotsubo Syndrome (CIT) Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Takotsubo Cardiomyopathy
• Intervention / Treatment: Drug: Placebo; Drug: Cyclosporine A

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 Type: Interventional
• Enrollment (Estimated): 204
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bastian Bruns, MD; Phone Number: +496221-56-36266; Email: bastian.bruns@med.uni-heidelberg.de

Study Locations

• Germany
  • Bad Nauheim, Germany
    • Kerckhoff Heart Center, Bad Nauheim / Gießen University
  • Berlin, Germany
    • Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin
  • Berlin, Germany
    • Department of Cardiology, Charité - Universitätsmedizin Berlin
  • Bochum, Germany
    • Heart and Diabetes Centre - University Hospital Bochum
  • Bonn, Germany
    • Heart Centre - University Hospital Bonn
    • Principal Investigator: Georg Nickenig, MD
  • Dresden, Germany
    • Department of Cardiology, University Hospital Dresden
  • Düsseldorf, Germany
    • Cardiovascular Centre - University Hospital Düsseldorf
  • Erlangen, Germany
    • Department of Cardiology, Erlangen-Nürnberg University
  • Essen, Germany
    • Department of Cardiology - University Hospital Essen
  • Freiburg, Germany
    • Department of Cardiology - University Hospital Freiburg
  • Greifswald, Germany
    • Department of Cardiology, University Hospital Greifswald
  • Göttingen, Germany
    • University Medical Center Göttingen
  • Hamburg, Germany
    • University Medical Center Hamburg-Eppendorf
  • Hannover, Germany
    • Department of Cardiology, University Hospital Hannover
  • Heidelberg, Germany, 69120
    • Department of Cardiology, Heidelberg University Hospital
    • Contact: Bastian Bruns, MD
    • Principal Investigator: Norbert Frey, MD
    • Sub-Investigator: Bastian Bruns, MD
  • Homburg, Germany
    • Department of Cardiology, University Hospital of Saarland
  • Jena, Germany
    • Department of Cardiology, University Hospital Jena
  • Kiel, Germany
    • University Medical Center Schleswig-Holstein/Campus Kiel
  • Köln, Germany
    • Department of Cardiology, University Hospital Köln
  • Leipzig, Germany
    • Leipzig Heart Center
  • Lübeck, Germany
    • University Medical Center Schleswig-Holstein/Campus Lübeck
  • Magdeburg, Germany
    • Department of Cardiology, University Hospital Magdeburg
  • Mainz, Germany
    • Department of Cardiology, University Hospital Mainz
  • Mannheim, Germany
    • Department of Cardiology, University Hospital Mannheim
  • München, Germany
    • Department of Cardiology, Hospital of the Ludwig-Maximilians-University Munich
  • München, Germany
    • University Hospital rechts der Isar, Technical University of Munich
  • Oldenburg, Germany
    • Department of Cardiology, University Hospital Oldenburg
  • Rostock, Germany
    • Department of Cardiology - University Hospital Rostock
  • Tübingen, Germany
    • Department of Cardiology, University Hospital Tübingen
  • Ulm, Germany
    • Department of Cardiology, University Hospital Ulm
  • Würzburg, Germany
    • Department of Cardiology, University Hospital Würzburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Heidelberg
• Collaborators: German Centre of Cardiovascular Research (DZHK); Coordinating Centre for Clinical Studies (KKS) Heidelberg
• Investigators: Principal Investigator: Norbert Frey, MD, University Hospital Heidelberg; Principal Investigator: Bastian Bruns, MD, University Hospital Heidelberg

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2024
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: June 19, 2023
• First Submitted That Met QC Criteria: July 7, 2023
• First Posted (Actual): July 14, 2023

Study Record Updates

• Last Update Posted (Actual): May 9, 2024
• Last Update Submitted That Met QC Criteria: May 8, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Inflammation; Acute heart failure; Cyclosporine; Troponin; Takotsubo syndrome
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Ventricular Dysfunction, Left; Ventricular Dysfunction; Cardiomyopathies; Takotsubo Cardiomyopathy; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Cyclosporine; Cyclosporins
• Other Study ID Numbers: DZHK29 (Other Grant/Funding Number: German Centre of Cardiovascular Research (DZHK))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No