Back to resultsCyclosporine In Takotsubo Syndrome (CIT)
Primary Purpose
Takotsubo Cardiomyopathy
Status
Not yet recruiting
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Cyclosporine A
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Takotsubo Cardiomyopathy focused on measuring Takotsubo syndrome, Troponin, Cyclosporine, Inflammation, Acute heart failure
Eligibility Criteria
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
Sites / Locations
- Kerckhoff Heart Center, Bad Nauheim / Gießen University
- Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin
- Department of Cardiology, Charité - Universitätsmedizin Berlin
- Heart and Diabetes Centre - University Hospital Bochum
- Heart Centre - University Hospital Bonn
- Department of Cardiology, University Hospital Dresden
- Cardiovascular Centre - University Hospital Düsseldorf
- Department of Cardiology, Erlangen-Nürnberg University
- Department of Cardiology - University Hospital Essen
- Department of Cardiology - University Hospital Freiburg
- Department of Cardiology, University Hospital Greifswald
- University Medical Center Göttingen
- University Medical Center Hamburg-Eppendorf
- Department of Cardiology, University Hospital Hannover
- Department of Cardiology, Heidelberg University Hospital
- Department of Cardiology, University Hospital of Saarland
- Department of Cardiology, University Hospital Jena
- University Medical Center Schleswig-Holstein/Campus Kiel
- Department of Cardiology, University Hospital Köln
- Leipzig Heart Center
- University Medical Center Schleswig-Holstein/Campus Lübeck
- Department of Cardiology, University Hospital Magdeburg
- Department of Cardiology, University Hospital Mainz
- Department of Cardiology, University Hospital Mannheim
- Department of Cardiology, Hospital of the Ludwig-Maximilians-University Munich
- University Hospital rechts der Isar, Technical University of Munich
- Department of Cardiology, University Hospital Oldenburg
- Department of Cardiology - University Hospital Rostock
- Department of Cardiology, University Hospital Tübingen
- Department of Cardiology, University Hospital Ulm
- Department of Cardiology, University Hospital Würzburg
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Experimental
Arm Label
Placebo
CsA
Arm Description
A concealed 0.9% sodium chloride (NaCl) preparation will be applied intravenously at baseline, 12h, and 24h.
Cyclosporine A will be applied intravenously at baseline, 12h, and 24h.
Outcomes
Primary Outcome Measures
Myocardial damage
High-sensitive Troponin T AUC over several time points between CsA and Placebo.
Secondary Outcome Measures
Change in Ejection fraction from baseline
Multiple timepoints will be compared to baseline between CsA and Placebo.
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.
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.
Fold-change in NTproBNP plasma concentration
The change of NTproBNP will be compared to baseline between CsA and Placebo for multiple time points.
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.
Fold-change in procalcitonin plasma concentration
The change of procalcitonin will be compared to baseline between CsA and Placebo for multiple time points.
Myocardial edema
Cardiac MRI will be used to assess the T2 signal intensity ratio for comparison between CsA and Placebo at 72h.
Myocardial inflammation
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
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
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
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
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
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
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
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
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
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
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
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
Length of intermediate care or intensive care unit stay will be compared between groups
Length of hospital stay
Length of hospital stay will be compared between groups
Full Information
NCT ID
NCT05946772
First Posted
June 19, 2023
Last Updated
July 7, 2023
Sponsor
University Hospital Heidelberg
Collaborators
German Centre of Cardiovascular Research (DZHK), Coordinating Centre for Clinical Studies (KKS) Heidelberg
1. Study Identification
Unique Protocol Identification Number
NCT05946772
Brief Title
Cyclosporine In Takotsubo Syndrome
Acronym
CIT
Official Title
Cyclosporine In Takotsubo Syndrome (CIT) Trial
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
February 2024 (Anticipated)
Primary Completion Date
March 2026 (Anticipated)
Study Completion Date
March 2027 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital Heidelberg
Collaborators
German Centre of Cardiovascular Research (DZHK), Coordinating Centre for Clinical Studies (KKS) Heidelberg
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Takotsubo Cardiomyopathy
Keywords
Takotsubo syndrome, Troponin, Cyclosporine, Inflammation, Acute heart failure
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Double-blind multicentre RCT
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Participants, investigators, care providers, and outcomes assessors are masked from study arm affiliation.
Allocation
Randomized
Enrollment
204 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
A concealed 0.9% sodium chloride (NaCl) preparation will be applied intravenously at baseline, 12h, and 24h.
Arm Title
CsA
Arm Type
Experimental
Arm Description
Cyclosporine A will be applied intravenously at baseline, 12h, and 24h.
Intervention Type
Drug
Intervention Name(s)
Cyclosporine A
Intervention Description
2.5mg/kg body weight Cyclosporine A as an intravenous bolus
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
The same amount of 0.9% sodium chloride (NaCl0.9%) will be applied in an indistinguishable package as an intravenous bolus
Primary Outcome Measure Information:
Title
Myocardial damage
Description
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
Secondary Outcome Measure Information:
Title
Change in Ejection fraction from baseline
Description
Multiple timepoints will be compared to baseline between CsA and Placebo.
Time Frame
baseline, hour 24, hour 48, hour 72, day 30
Title
Fold-change in Troponin plasma concentration
Description
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
Title
Fold-change in creatine kinase plasma concentration
Description
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
Title
Fold-change in NTproBNP plasma concentration
Description
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
Title
Fold-change in interleukin-6 plasma concentration
Description
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
Title
Fold-change in procalcitonin plasma concentration
Description
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
Title
Myocardial edema
Description
Cardiac MRI will be used to assess the T2 signal intensity ratio for comparison between CsA and Placebo at 72h.
Time Frame
hour 72
Title
Myocardial inflammation
Description
Cardiac MRI will be used to assess the early gadolinium enhancement ratio for comparison between CsA and Placebo at 72h.
Time Frame
hour 72
Title
Rate of cardiovascular events at day 30
Description
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
Title
Rate of cardiovascular events at 1 year
Description
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
Title
Rate of novel disease onset
Description
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
Title
Symptom burden at day 30
Description
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
Title
Symptom burden at 1 year
Description
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
Title
Depression score at day 30
Description
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
Title
Depression score at year 1
Description
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
Title
Anxiety score at day 30
Description
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
Title
Anxiety score at year 1
Description
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
Title
PTSD score at 30 days
Description
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
Title
PTSD score at 1 year
Description
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
Title
Length of intermediate care or intensive care unit stay
Description
Length of intermediate care or intensive care unit stay will be compared between groups
Time Frame
day 30
Title
Length of hospital stay
Description
Length of hospital stay will be compared between groups
Time Frame
day 30
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bastian Bruns, MD
Phone
+496221-56-36266
Email
bastian.bruns@med.uni-heidelberg.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Norbert Frey, MD
Organizational Affiliation
University Hospital Heidelberg
Official's Role
Principal Investigator
Facility Information:
Facility Name
Kerckhoff Heart Center, Bad Nauheim / Gießen University
City
Bad Nauheim
Country
Germany
Facility Name
Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin
City
Berlin
Country
Germany
Facility Name
Department of Cardiology, Charité - Universitätsmedizin Berlin
City
Berlin
Country
Germany
Facility Name
Heart and Diabetes Centre - University Hospital Bochum
City
Bochum
Country
Germany
Facility Name
Heart Centre - University Hospital Bonn
City
Bonn
Country
Germany
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Georg Nickenig, MD
Facility Name
Department of Cardiology, University Hospital Dresden
City
Dresden
Country
Germany
Facility Name
Cardiovascular Centre - University Hospital Düsseldorf
City
Düsseldorf
Country
Germany
Facility Name
Department of Cardiology, Erlangen-Nürnberg University
City
Erlangen
Country
Germany
Facility Name
Department of Cardiology - University Hospital Essen
City
Essen
Country
Germany
Facility Name
Department of Cardiology - University Hospital Freiburg
City
Freiburg
Country
Germany
Facility Name
Department of Cardiology, University Hospital Greifswald
City
Greifswald
Country
Germany
Facility Name
University Medical Center Göttingen
City
Göttingen
Country
Germany
Facility Name
University Medical Center Hamburg-Eppendorf
City
Hamburg
Country
Germany
Facility Name
Department of Cardiology, University Hospital Hannover
City
Hannover
Country
Germany
Facility Name
Department of Cardiology, Heidelberg University Hospital
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bastian Bruns, MD
First Name & Middle Initial & Last Name & Degree
Norbert Frey, MD
Facility Name
Department of Cardiology, University Hospital of Saarland
City
Homburg
Country
Germany
Facility Name
Department of Cardiology, University Hospital Jena
City
Jena
Country
Germany
Facility Name
University Medical Center Schleswig-Holstein/Campus Kiel
City
Kiel
Country
Germany
Facility Name
Department of Cardiology, University Hospital Köln
City
Köln
Country
Germany
Facility Name
Leipzig Heart Center
City
Leipzig
Country
Germany
Facility Name
University Medical Center Schleswig-Holstein/Campus Lübeck
City
Lübeck
Country
Germany
Facility Name
Department of Cardiology, University Hospital Magdeburg
City
Magdeburg
Country
Germany
Facility Name
Department of Cardiology, University Hospital Mainz
City
Mainz
Country
Germany
Facility Name
Department of Cardiology, University Hospital Mannheim
City
Mannheim
Country
Germany
Facility Name
Department of Cardiology, Hospital of the Ludwig-Maximilians-University Munich
City
München
Country
Germany
Facility Name
University Hospital rechts der Isar, Technical University of Munich
City
München
Country
Germany
Facility Name
Department of Cardiology, University Hospital Oldenburg
City
Oldenburg
Country
Germany
Facility Name
Department of Cardiology - University Hospital Rostock
City
Rostock
Country
Germany
Facility Name
Department of Cardiology, University Hospital Tübingen
City
Tübingen
Country
Germany
Facility Name
Department of Cardiology, University Hospital Ulm
City
Ulm
Country
Germany
Facility Name
Department of Cardiology, University Hospital Würzburg
City
Würzburg
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
No
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Cyclosporine In Takotsubo Syndrome
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