Clinical trial NCT05946772: Cyclosporine In Takotsubo Syndrome
Official title: Cyclosporine In Takotsubo Syndrome (CIT) Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Takotsubo Cardiomyopathy
Keywords: Takotsubo syndrome
Troponin
Cyclosporine
Inflammation
Acute heart failure
Lead sponsor: University Hospital Heidelberg
Sponsor class: OTHER
Collaborators: name: German Centre of Cardiovascular Research (DZHK)
name: Coordinating Centre for Clinical Studies (KKS) Heidelberg
First posted: 2023-07-14
Enrollment: 204
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind multicentre RCT
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Myocardial damage
timeFrame: baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30
Secondary outcomes:
measure: Change in Ejection fraction from baseline
timeFrame: baseline, hour 24, hour 48, hour 72, day 30
measure: Fold-change in Troponin plasma concentration
timeFrame: baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30
measure: Fold-change in creatine kinase plasma concentration
timeFrame: baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30
measure: Fold-change in NTproBNP plasma concentration
timeFrame: baseline, hour 3, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30
measure: Fold-change in interleukin-6 plasma concentration
timeFrame: baseline, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30
measure: Fold-change in procalcitonin plasma concentration
timeFrame: baseline, hour 12, hour 24, hour 36, hour 48, hour 60, hour 72, day 30
measure: Myocardial edema
timeFrame: hour 72
measure: Myocardial inflammation
timeFrame: hour 72
measure: Rate of cardiovascular events at day 30
timeFrame: day 30
measure: Rate of cardiovascular events at 1 year
timeFrame: 1 year
measure: Rate of novel disease onset
timeFrame: day 30 and at 1 year
measure: Symptom burden at day 30
timeFrame: day 30
measure: Symptom burden at 1 year
timeFrame: 1 year
measure: Depression score at day 30
timeFrame: day 30
measure: Depression score at year 1
timeFrame: 1 year
measure: Anxiety score at day 30
timeFrame: day 30
measure: Anxiety score at year 1
timeFrame: year 1
measure: PTSD score at 30 days
timeFrame: day 30
measure: PTSD score at 1 year
timeFrame: year 1
measure: Length of intermediate care or intensive care unit stay
timeFrame: day 30
measure: Length of hospital stay
timeFrame: day 30
Other outcomes:
Locations:
city: Bad Nauheim
country: Germany
facility: Kerckhoff Heart Center, Bad Nauheim / Gießen University
city: Berlin
country: Germany
facility: Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Department of Cardiology, Charité - Universitätsmedizin Berlin
city: Bonn
country: Germany
facility: Heart Centre - University Hospital Bonn
city: Dresden
country: Germany
facility: Department of Cardiology, University Hospital Dresden
city: Düsseldorf
country: Germany
facility: Cardiovascular Centre - University Hospital Düsseldorf
city: Essen
country: Germany
facility: Department of Cardiology - University Hospital Essen
city: Göttingen
country: Germany
facility: University Medical Center Göttingen
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Department of Cardiology, University Hospital Hannover
city: Heidelberg
country: Germany
facility: Department of Cardiology, Heidelberg University Hospital
city: Kiel
country: Germany
facility: University Medical Center Schleswig-Holstein/Campus Kiel
city: Köln
country: Germany
facility: Department of Cardiology, University Hospital Köln
city: Leipzig
country: Germany
facility: Leipzig Heart Center
city: Lübeck
country: Germany
facility: University Medical Center Schleswig-Holstein/Campus Lübeck
city: Magdeburg
country: Germany
facility: Department of Cardiology, University Hospital Magdeburg
city: Mainz
country: Germany
facility: Department of Cardiology, University Hospital Mainz
city: Mannheim
country: Germany
facility: Department of Cardiology, University Hospital Mannheim
city: München
country: Germany
facility: Department of Cardiology, Hospital of the Ludwig-Maximilians-University Munich
city: München
country: Germany
facility: University Hospital rechts der Isar, Technical University of Munich
city: Ulm
country: Germany
facility: Department of Cardiology, University Hospital Ulm
Study officials:
affiliation: University Hospital Heidelberg
name: Norbert Frey, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Heidelberg
name: Bastian Bruns, MD
role: PRINCIPAL_INVESTIGATOR
References: