Efficacy of Cyclosporine A Versus Placebo in Reducing Myocardial Damage in Takotsubo Syndrome: A Phase II Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this phase II, multicenter, randomized, double-blind, placebo-controlled study is to evaluate the efficacy of **Cyclosporine A** (CsA) in reducing myocardial damage in patients with Takotsubo syndrome (TTS). The primary endpoint is the high-sensitive Troponin T (TnT) area under the curve (AUC) over 72 hours, which is a reliable measure of myocardial injury. This is clinically relevant as initial troponin levels are predictive of patient outcomes, and a centrally measured TnT AUC offers greater reliability compared to single TnT values from different laboratories.

Secondary objectives include: - Change in TnT/NTproBNP levels and left ventricular ejection fraction (LVEF) at various time points compared to baseline. - Assessment of myocardial edema/inflammation using cardiac MRI and the Lake Louise criteria. - Evaluation of the length of stay in intermediate care/intensive care units and overall hospital stay. - Analysis of a composite cardiovascular outcome at 30 days and 1 year, including mortality, stroke, myocardial infarction, heart failure, and other cardiovascular events. - Psychosocial and quality of life assessments between groups at 1 month versus 12 months.

The clinical trial involves a study population comprising both **male** and **female** participants aged over 18 years. The total number of participants is not provided by the sponsor. The trial population includes individuals who have undergone cardiac catheterization and exhibit Regional Wall Motion Abnormality consistent with Takotsubo Syndrome (TTS) as observed in angiography or echocardiography. Participants are required to have an InterTAK prognostic score of 16 or higher, or a GEIST Score of 20 or higher, and an InterTAK Diagnostic Score of 40 or higher. Written informed consent is mandatory for inclusion. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, although specific details are not disclosed. The selection criteria ensure that participants are enrolled and receive the first investigational medicinal product administration within 24 hours post-cardiac catheterization.

The clinical trial is a **phase II**, multicenter, 1:1 **randomized**, **double-blind**, **placebo-controlled**, parallel-group study designed to evaluate the efficacy of bolus application of **Cyclosporine A** (CsA) or placebo in patients with Takotsubo syndrome. The primary objective is to assess whether treatment with CsA, in addition to standard care, reduces myocardial damage, as measured by the area under the curve (AUC) of centrally measured high-sensitive Troponin T (TnT) over 72 hours. The trial is expected to commence recruitment on September 1, 2024, and conclude by August 31, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18, enrollment within 24 hours post-cardiac catheterization, and specific diagnostic scores. Following randomization, participants will receive either CsA or placebo via **intravenous bolus use**. The study includes multiple follow-up visits at specified intervals (3h, 12h, 24h, 36h, 48h, 60h, 72h) to monitor TnT levels and other secondary endpoints, such as changes in NTproBNP, LVEF, and myocardial edema/inflammation. The end-of-study visit will assess the composite cardiovascular outcome at 30 days and one year, including mortality, stroke, myocardial infarction, and other cardiovascular events.

Participant involvement is expected to last for the duration of the trial, with the maximum treatment period being one day. Conditions that may lead to early termination from the study include withdrawal of consent or any adverse events that compromise participant safety. The trial's design ensures rigorous monitoring and data collection to achieve its primary and secondary objectives, contributing valuable insights into the management of Takotsubo syndrome.

The clinical trial involves the administration of **Sandimmun®**, a pharmaceutical product containing the active substance **ciclosporin**. This medication is provided as a **solution for infusion** and is manufactured by Novartis Pharma GmbH. The pharmaceutical form is a concentrate for the preparation of an infusion solution, with a concentration of 50 mg/ml. The administration route is via **intravenous bolus use**. The dosing regimen specifies a maximum daily dose of 5 mg/kg and a maximum total dose of 2.5 mg/kg, with a treatment period limited to one day. The primary objective of the trial is to evaluate the efficacy of ciclosporin in reducing myocardial damage in patients with Takotsubo syndrome, as measured by high-sensitive Troponin T AUC over a 72-hour period.

In addition to the experimental treatment, the study utilizes **sodium chloride** as a non-experimental treatment. Sodium chloride is used as a **solution for infusion** and serves as a pharmaceutical aid and diluent for the infusion of compatible drug additives. It is administered via **intravenous bolus use**. The sodium chloride solution does not have a specified maximum daily or total dose, as it functions primarily as a placebo in the trial. The use of sodium chloride allows for a double-blind, placebo-controlled study design, ensuring that the effects of ciclosporin can be accurately assessed against a control group receiving standard care without the active drug.

The efficacy of the clinical trial will be assessed by evaluating the reduction of myocardial damage in patients with Takotsubo syndrome treated with **Cyclosporine A** (CsA) compared to placebo. The primary efficacy endpoint is the area under the curve (AUC) of centrally measured high-sensitive cardiac Troponin T (TnT) over a 72-hour period. Measurements will be taken at baseline, 3 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, and 72 hours. This endpoint was selected due to its higher sensitivity and reliability in quantifying myocardial injury compared to single TnT values from different laboratories.

Secondary efficacy endpoints include changes in TnT and NT-proBNP levels at specified timepoints (T3, T12, T24, T36, T48, T60, T72, and M1) and changes in left ventricular ejection fraction (LVEF) at T24, T48, T72, and M1 compared to baseline. Additional assessments will include myocardial edema and inflammation evaluated through cardiac MRI using the T2 signal intensity and early gadolinium enhancement ratio according to the Lake Louise criteria at T48-72. Other secondary endpoints involve the length of stay in intermediate care/intensive care units, overall hospital stay, and a composite cardiovascular outcome at 30 days and 1 year, which includes mortality, stroke, myocardial infarction, heart failure, hospitalization, recurrent Takotsubo syndrome, cardiac arrest, ventricular fibrillation, ventricular tachycardia, atrial fibrillation, thromboembolism, left ventricular thrombus, atrioventricular block, ventricular rupture, and new onset atrial fibrillation. Psychosocial and quality of life assessments will also be conducted between groups at M1 versus M12.