Optimized pharmacologic treatment for broken heart (takotsubo) syndrome

2022-501874-21-00 Protocol BROKEN-SWEDEHEART Therapeutic use (Phase IV) Ongoing, recruiting

Start 15 Dec 2020 · Status Ongoing, recruiting · 3 EU/EEA countries · 18 sites · Protocol BROKEN-SWEDEHEART

Overview

Sponsor-declared trial summary

Phase Therapeutic use (Phase IV)
Status Ongoing, recruiting
Participants planned 1,600
Countries 3
Sites 18

Takotsubo syndrome

The objective of the study is to investigate whether treatment with: (i) adenosine and the adenosine reuptake inhibitor dipyridamole improves clinical outcomes in patients with Takotsubo Syndrome compared to standard of care (according to current recommendations from ESC taskforce for Takotsubo Syndrome (Randomization …

Key facts

Sponsor
Vastra Gotalandsregionen
Participant type
Patients
Age range
18-64 years, 65+ years
Gender
Male and Female
Therapeutic area
Diseases [C] - Cardiovascular Diseases [C14]
Trial duration
15 Dec 2020 → ongoing
Decision date (initial)
2023-09-13
Transition trial
Yes
Low-intervention
No
Rare-disease indication
No
Vulnerable population
No

External identifiers

EU CT number
2022-501874-21-00
EudraCT number
2020-002708-38

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The objective of the study is to investigate whether treatment with: (i) adenosine and the adenosine reuptake inhibitor dipyridamole improves clinical outcomes in patients with Takotsubo Syndrome compared to standard of care (according to current recommendations from ESC taskforce for Takotsubo Syndrome (Randomization 1)

To test whether treatment with apixaban reduces the risk of thromboembolic events compared to no treatment with antithrombotic drugs (Randomization 2)

Conditions and MedDRA coding

Takotsubo syndrome

Study design 1 period

#TitleAllocationBlindingRoles blindedArms
1 BROKEN: Study period
Multinational, multicentre, randomized, open, registry-based clinical trial (R-RCT), with 2x2 factorial design. The trial consists of 2 separate parallel studies and the patient is randomised to intervention or control group for both studies at the same time (if eligible) and the study procedures are independent of what randomised group the patient is belonging to. In the intervention arm, patients in randomization 1 will be treated with adenosine and dipyridamole, and patients in the control arm will receive treatment for TS according to recommendations from the ESC task force for TS. For randomization 2, the intervention arm patients will be treated with either apixaban or no anticoagulant whereas the control arm will either receive apixaban or no anticoagulant therapy. Patients may be randomized in only one of the two trials if they fulfil eligibility criteria for only one of the two trials. A follow-up will be performed at day 30 +7 by visit or phone call, depending on clinical routine.
 Randomised Controlled None Study 1: Control: Study 1: Control (care recommended by the ESC-taskforce for Takotsubo syndrome)
Study 1: Adenosine and Dipyridamole: Study 1: Patients randomized to Adenosine and Dipyridamole
Study 2: Control + No anticoagulant therapy: Study 2: Patients included in study 1 control group who are also eligable for study 2 can be randomized to no anticoagulant therapy
Study 2: Control + Apixaban: Study 2: Patients included in study 1 control group who are also eligable for study 2 can be randomized to Apixaban
Study 2: Adenosine and Dipyridamole + No anticoagulant therapy: Study 2: Patients included in study 1 arm adenosine and dipyridamole can be randomized to no anticoagulant therapy
Study 2: Adenosine and Dipyridamole + Apixaban: Study 2: Patients included in study 1 arm adenosine and dipyridamole can be randomized to Apixaban

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

  1. 1. Age equal or above 18 years
  2. 2. A clinical diagnosis of Takotsubo Syndrome, including an ejection fraction (EF) <50% at baseline
  3. 3. Written informed consent obtained

Exclusion criteria 15

  1. Previous randomization in the study
  2. Systolic blood pressure lower than 80 mm Hg at screening
  3. Estimated glomerular filtration rate lower than 30 mL/min/1.73 m2
  4. Current dialysis
  5. Pregnancy or of childbearing potential who is not steralized or is not using a medically accepted form of contraception
  6. Not suitable in the opinion of the investigator due to severe or terminal comorbidity with poor prognosis, or characteristics that may interfere with adherence to the study-protocol
  7. Specific exclusion criteria for randomization 2 as following: 1.Any contra-indication for anticoagulant treatment. 2.Current indication for treatment with, anticoagulant or dual antiplatelet therapy 3.Declined participation in study 2.
  8. Specific exclusion criteria for randomization 1 as following: 1 Any contra-indication for treatment with adenosine or dipyridamole (including AV-block II and III, sick-sinus syndrome in subjects who don´t have a functioning pacemaker, unstable angina, ongoing treatment with dipyridamole) 2. Severe asthma (defined as asthma requiring medium or high-dose inhaled corticosteroids combined with other long-acting medications) and severe Chronic Obstructive Pulmonary Disease (COPD), (defined as FEV-1 ˂ 50 %) 3. Ongoing treatment with dipyridamole. 4 Declined participation in study 1.
  9. Any concomitant condition resulting in a life expectancy of less than one month
  10. Previously diagnosed left ventrilular ejaction fraction lower than 50%
  11. Known cardiomyopathy (except previous Takotsubo Syndrome)
  12. Known hemodynamically significant valve disease (moderate or severe aortic/mitral regurgitation or stenosis)
  13. Heart transplant or left ventricular assist device recipient
  14. Most recent (within the most recent 3 moths) haemoglobin lower than 100 g/L
  15. Any concomitant condition resulting in a life expectancy of less than one month

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

  1. Randomization 1: First co-primary endpoint - Wall motion score index at 48-96 hors
  2. Randomization 1: Second co-primary endpoint- The occurrence of the composite of death, cardiac arrest,or the need for cardiac mechanicalassist device up until day 30,or ejaction fraction less than 50% at 48-96 hours or rehospitalization for heart failure up until day 30
  3. Randomization 2:The occurrence of any thromboembolic event(defined as ischemic stroke, peripheral arterial embolization or myocardial infarction) or death up until day 30,or the presence of a cardiac thrombus at 48-96 hours as assessed by echocardiography

Secondary endpoints 15

  1. The hierarchical occurrence of time to death, time to cardiac assist device, time to cardiac arrest (all time to the first occurance up until day 30), and ejaction fraction less than 50% at 48-96 hours (binary)
  2. Ejaction fraction at 48-96 hours (continuous)
  3. Any sustained ventricular tachycardia or fibrillation within 48-96 hours (binary)
  4. Any high-grade atrioventricular block or sinus arrest within 48-96 hours (binary)
  5. Need for cardiac assist device up until day 30 (binary)
  6. Death up until day 30 (binary)
  7. Stroke up until day 30 (binary)
  8. Rehospitalization for Takotsubo Syndrome at 6 months and 1-10 years
  9. All cause mortality at 6 months and 1-10 years
  10. Worsening heart failure in hospital up until day 30
  11. Specific for randomization 2: cardiac thrombus at 48 - 96 hrs
  12. Specific for randomization 2: thrombolysis in Myocardial Infarction (TIMI) bleeding criteria minor or major up until 30 days (binary)
  13. Specific for randomization 2: ejection fraction (EF) < 50% at 48 - 96 hrs (binary)
  14. Specific for randomization 2: Bleeding Academic Research Consortium (BARC) grade 2-5 up until 30 days (binary)
  15. Specific for randomization 2: any blood transfusion (binary)

Investigational products

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

Test 3

Eliquis 5 mg film-coated tablets

PRD1722225 · Product

Active substance
Apixaban
Pharmaceutical form
FILM-COATED TABLET
Route of administration
ORAL USE
Max daily dose
10 mg milligram(s)
Max total dose
10 mg milligram(s)
Max treatment duration
30 Day(s)
Authorisation status
Authorised
ATC code
B01AF02 — -
Marketing authorisation
EU/1/11/691/014
MA holder
BRISTOL-MYERS SQUIBB/PFIZER EEIG
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Dipyridamol Alternova 200 mg depotkapslar, hårda

PRD872720 · Product

Active substance
Dipyridamole
Pharmaceutical form
PROLONGED-RELEASE CAPSULE, HARD
Route of administration
ORAL USE
Max daily dose
400 mg milligram(s)
Max total dose
400 mg milligram(s)
Max treatment duration
30 Day(s)
Authorisation status
Authorised
ATC code
B01AC07 — DIPYRIDAMOLE
Marketing authorisation
47980
MA holder
ALTERNOVA A/S
MA country
Sweden
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Adenosin Life Medical 5 mg/ml, Injektions-/infusionsvätska, lösning.

PRD757904 · Product

Active substance
Adenosine
Pharmaceutical form
SOLUTION FOR INJECTION/INFUSION
Route of administration
INFUSION
Max daily dose
70 µg/Kg microgram(s)/kilogram
Max total dose
70 µg/Kg microgram(s)/kilogram
Max treatment duration
1 Day(s)
Authorisation status
Authorised
ATC code
C01EB10 — ADENOSINE
Marketing authorisation
19361
MA holder
EVOLAN PHARMA AB
MA country
Sweden
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vastra Gotalandsregionen

4 Total trials 4 Recruiting
Academic / Non-commercial
Sponsor organisation
Vastra Gotalandsregionen
Address
Regionens Hus
City
Vänersborg
Postcode
462 80
Country
Sweden

Scientific contact point

Organisation
Vastra Gotalandsregionen
Contact name
Elmir Omerovic

Public contact point

Organisation
Vastra Gotalandsregionen
Contact name
Elmir Omerovic

Third parties 1

OrganisationCity, countryDuties
Frederiksberg Hospital
ORG-100028217
 Frederiksberg, Denmark On site monitoring

Locations

3 EU/EEA countries · 18 investigational sites

By country

CountryMS statusPlanned subjectsSites
Denmark Ongoing, recruiting 300 2
Norway Ongoing, recruiting 300 2
Sweden Ongoing, recruiting 1,000 14
Rest of world — 0 —

Investigational sites

Denmark

2 sites · Ongoing, recruiting
Aarhus Universitetshospital
Department of Cardiology, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N
Rigshospitalet
Department of Cardiology, Blegdamsvej 9, 2100, Copenhagen Oe

Norway

2 sites · Ongoing, recruiting
Oslo University Hospital HF
Department of Cardiology, Sognsvannsveien 20, 0372, Oslo
St. Olavs Hospital HF
Department of Cardiology, Prinsesse Kristinas G. 3, 7030, Trondheim

Sweden

14 sites · Ongoing, recruiting
Region Skane - Skanes Universitetssjukhus
Kardiologi, Entregatan 7, Lunds Allhelgonafors, Lund
Region Oestergoetland
Kardiologi, S S:t Lars, S:t Larsgatan 49 B, Linkoping
Uppsala University Hospital
Kardiologi, Dag Hammarskjolds Vag 20, Uppsala Domkyrkofors., Uppsala
Sahlgrenska University Hospital-Vastra Gotalandsregionen
Kardiologen, Bla Straket 5, 413 46, Goteborg
Norrlands University Hospital
Kardiologi, Daniel Naezéns Väg, 907 37, Umeå
Region Skane Helsingborg Hospital
Kardiologi, Charlotte Yhlens Gata 10, Helsingborgs Maria, Helsingborg
Region Dalarna
Kardiologi, Vasagatan 27, Falu Kristine, Falun
Karolinska University Hospital
Kardiologi, Halsovagen, Flemingsberg, Huddinge
Danderyds Sjukhus AB
Kardiologi, Morbygardsvagen 88, 182 88, Danderyd
Region Orebro lan
Kardiologi, Sodra Grev Rosengatan, 701 85, Orebro
Skaraborg Hospital-Vastra Gotalandsregionen
Kardiologi, Lovangsvagen 1, 541 42, Skovde
Region Joenkoepings Laen
Medicin kliniken, Lanssjukhuset Ryhov, Sjukhusgatan, Jonkoping
NU Hospital Group-Vastra Gotalandsregionen
Kardiologi avdelning, Larketorpsvagen, 461 85, Trollhattan
Region Jaemtland Haerjedalen
Medicin kliniken, Kyrkgatan 12, 831 50, Ostersund

Country notifications

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

Country Trial startTrial end Recruitment startRecruitment end Early termination
Denmark 2023-12-07 2024-05-28
Norway 2023-12-12 2024-02-05
Sweden 2020-12-15 2021-04-07

Results and documents

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

Documents 2 files

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

TypeTitleVersion
Recruitment arrangements (for publication) K1_Recruitment arrangement_2022-501874-21-00_Unsigned 1.0
Subject information and informed consent form (for publication) K2_Participant information and ICF NO_2022-501874-21-00_Clean 1.3

Application history

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

#TypeCodeSubmittedReference MSConclusionDecision date
1 INITIAL IN 2022-11-01 Sweden Acceptable
2022-11-16
 2022-11-18
2 SUBSTANTIAL MODIFICATION SM-1 2023-04-03 Sweden Acceptable
2023-05-31
 2023-05-31
3 SUBSEQUENT ADDITION OF MSC APP-3 2023-06-22 2023-09-13
4 SUBSEQUENT ADDITION OF MSC APP-4 2023-06-22 2023-09-06
5 SUBSTANTIAL MODIFICATION SM-3 2023-11-14 Sweden Acceptable 2023-12-20
6 NON SUBSTANTIAL MODIFICATION NSM-1 2023-12-27 Acceptable 2023-12-27
7 SUBSTANTIAL MODIFICATION SM-4 2024-04-15 Sweden Acceptable 2024-05-27
8 NON SUBSTANTIAL MODIFICATION NSM-2 2024-07-31 Sweden Acceptable 2024-07-31
9 NON SUBSTANTIAL MODIFICATION NSM-3 2024-10-25 Acceptable 2024-10-25
10 SUBSTANTIAL MODIFICATION SM-5 2025-01-03 Acceptable 2025-01-22
11 NON SUBSTANTIAL MODIFICATION NSM-4 2025-05-16 Acceptable 2025-05-16

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