A phase II, multicenter, 1:1 randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy of bolus application of Cyclosporine A (CsA) or Placebo in patients with Takotsubo syndrome. (Cyclosporine In Takotsubo syndrome (CIT))

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Heidelberg AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

31 Jan 2025 → ongoing

Decision date (initial)

2024-08-30

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)

External identifiers

EU CT number

2024-511037-35-00

ClinicalTrials.gov

NCT05946772

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective of this translational early clinical trial is to investigate whether TTS patients treated with cyclosporine A (CsA) compared to placebo in addition to standard of care reveal reduced myocardial damage. In order to accurately determine myocardial damage centrally measured high-sensitive Troponin T (TnT) AUC has been chosen as the primary endpoint, and after careful consideration of other options. Initial troponin levels have been shown to predict outcome in patients1, 38. However, assay heterogeneity between institutions has kept this parameter from e. g. entering the Mayo Clinic Risk Score. A centrally measured TnT AUC is more reliable regarding quantification of myocardial injury when compared to single TnT values from different laboratories39-41. Besides yielding a larger effect size in our in vivo studies, TnT as a primary endpoint features higher sensitivity compared e.g. to imaging-based EF measurements.
Therefore, the primary endpoint of this study is the high-sensitive troponin T AUC over 72h (baseline, 3h, 12h, 24h, 36h, 48h, 60h, 72h) between placebo vs. CsA.

Secondary objectives 5

1. Key secondary endpoint(s): Change in TnT/NTproBNP at T3/12/24/36/48/60/72/M1 and change in LVEF at T48/72/M1 (vs. baseline)
2. Myocardial edema/inflammation at T48-72 (cMRI, T2 SI and increased EGE ratio (lake louise criteria))
3. Length of stay on IMC/ICU and length of hospital stay
4. Composite cardiovascular outcome at 30d and 1year: mortality from any cause, stroke, myocardial infarction, heart failure, hospitalization, recurrent TTS, cardiac arrest / ventricular fibrillation, ventricular tachycardia, novel atrial fibrillation, thromboembolism, LV-Thrombus, AV-Block, ventricular rupture and new onset atrial fibrillation
5. Psychosocial and quality of life assessments between groups at M1 vs. M12

Conditions and MedDRA coding

Cyclosporine A is a well known medication and is used to prevent rejection after solid organ transplantation and in the treatment of inflammatory disorders such as myocarditis.

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Patients aged over 18
2. Enrollment and first IMP administration within 24 hours after cardiac catheterization
3. Regional Wall Motion Abnormality (WMA) consistent with TTS in angiography or echocardiography
4. InterTAK prognostic score ≥ 9 or GEIST Score ≥ 9
5. Written informed consent

Exclusion criteria 13

1. Acute coronary syndrome (ACS) with significant coronary stenosis potentially associated with wall motion abnormalities (WMA) or percutaneous coronary intervention (PCI)
2. Female patients currently pregnant or women of childbearing age without negative pregnancy test or without effective contraception
3. Any disorder associated with immunological dysfunction ≤6 months prior to presentation (autoimmune disease, known positive serology for HIV or hepatitis)
4. Immunosuppressive, chemotherapeutical, or antibody treatment
5. Participation in other clinical trials except for non-interventional trials
6. Neither male nor female at birth
7. Infection (defined as concomitant infection with a positive blood culture at the time of study inclusion)
8. History of hypersensitivity to cyclosporine
9. History of hypersensitivity to egg, peanut or soybean proteins
10. History of chronic renal insufficiency (either creatinin clearance <30 ml/min/1.73m² or current medical care for severe renal insufficiency)
11. History of liver insufficiency
12. Uncontrolled hypertension at the time of screening for study inclusion (systolic blood pressure >180mmHg and/or diastolic blood pressure >110mmHg)
13. Current medication with any compound containing Hypericum perforatum (St. John’s worth) or Stiripentol or Aliskiren or Bosentan or Rosuvastatine (Rosuvastatine > 5mg within 24h before IMP administration)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary efficacy endpoint: Reduction of myocardial damage quantified by AUC of centrally measured highsensitive cardiac Troponin T (TnT) over 72 h.

Secondary endpoints 5

1. Change in TnT/NTproBNP at T3/12/24/36/48/60/72/M1 and change in LVEF at T48/72/M1 (vs. baseline)
2. Myocardial edema/inflammation at T48-72 (cMRI, T2 SIand EGE ratio (lake louise criteria))
3. Length of stay on IMC/ICU and length of hospital stay
4. Composite cardiovascular outcome at 30d and 1year: mortality from any cause, stroke, myocardial infarction, heart failure, hospitalization, recurrent TTS, cardiac arrest / ventricular fibrillation, ventricular tachycardia, novel atrial fibrillation, thromboembolism, LV-Thrombus, AV-Block, ventricular rupture and new onset atrial fibrillation
5. Psychosocial and quality of life assessments between groups at M1 vs. M12

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Heidelberg AöR

Sponsor organisation

Universitaetsklinikum Heidelberg AöR

Address

Im Neuenheimer Feld 672, Neuenheim Neuenheim

City

Heidelberg

Postcode

69120

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

Prof. Dr. Norbert Frey

Public contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

Prof. Dr. Norbert Frey

Third parties 1

Locations

1 EU/EEA country · 24 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications