Overview
Sponsor-declared trial summary
Phase
Therapeutic use (Phase IV)
Status
Ongoing, recruitment ended
Participants planned
350
Countries
1
Sites
2
Patients who have undergone successful transcatheter bioprosthetic aortic valve implantation (TAVI)
The objective of NOTION-4 is to investigate the incidence and temporal dynamics of subclinical leaflet thickening (HALT) by cardiac CT in transcatheter bioprosthetic aortic valves in patients randomised to different anti-thrombotic strategies.
Key facts
- Sponsor
- Rigshospitalet
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Cardiovascular Diseases [C14]
- Trial duration
- 12 May 2021 → ongoing
- Decision date (initial)
- 2024-11-11
- Transition trial
- Yes
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- No
External identifiers
- EU CT number
- 2024-518547-38-00
- EudraCT number
- 2020-003361-19
- ClinicalTrials.gov
- NCT06449469
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Efficacy, Prophylaxis, Safety, Therapy
The objective of NOTION-4 is to investigate the incidence and temporal dynamics of subclinical leaflet thickening (HALT) by cardiac CT in transcatheter bioprosthetic aortic valves in patients randomised to different anti-thrombotic strategies.
Secondary objectives 1
- Additionally, this study aims to examine a possible association between HALT and thromboembolic events.
Conditions and MedDRA coding
Patients who have undergone successful transcatheter bioprosthetic aortic valve implantation (TAVI)
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.0 | LLT | 10077017 | TAVI | 10042613 |
| 20.0 | SOC | 10042613 | Surgical and medical procedures | 25 |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 3
- Patients who underwent successful TAVI according to Valve Academic Research Consortium (VARC)-2 criteria
- Residing in Denmark
- Provide written informed consent
Exclusion criteria 7
- Atrial fibrillation or any other indication for lifelong OAC therapy
- Patient deemed not suitable for DOAC treatment because of previous life-threatening or major bleeding, e.g., intracranial haemorrhage or major gastrointestinal bleeding
- Patients with severe renal insufficiency (eGFR <30 mL/min/1.73 m2)
- Patient with absolute indication for anti-thrombotic therapy, e.g., recent PCI
- Iodine contrast allergy or other condition that prohibits CT imaging
- Age <18 years
- Women of childbearing potential, pregnant or nursing
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- The number of patients with at least one prosthetic valve leaflet with HALT as assessed by cardiac CT at one year after TAVI.
Secondary endpoints 13
- The combined clinical endpoint of all-cause mortality, thromboembolic event, and life-threatening or major bleeding at 1 year, 3 years and 5 years after randomization
- The number of patients with at least one prosthetic valve leaflet with HALT as assessed by cardiac CT at 3 months, 1, 3 and 5 years after TAVI
- Number of prosthetic leaflets with HALT at CT-scan at 3 months, 1 year, 3 and 5 years.
- The clinical endpoint of ischemic stroke verified by cerebrovascular imaging after the TAVI-procedure in patients with vs. without HALT.
- Any type of stroke – including ischemic and hemorrhagic stroke
- All-cause mortality
- Cardiovascular mortality as defined in current VARC definition
- Major bleeding or life-threatening bleeding
- Need for re-intervention (valve-in-valve TAVI, paravalvular leak closure, SAVR)
- Aortic bioprosthetic dysfunction (according to EAPCI/ESC/EACTS definitions)
- Rate of bioprosthetic valve failure (according to EAPCI/ESC/EACTS definitions)
- NYHA classification
- Quality of life scores
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 7
SUB12730MIG · Substance
- Active substance
- Acetylsalicylic Acid
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 75 mg milligram(s)
- Max total dose
- 75 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB32701 · Substance
- Active substance
- Edoxaban
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 60 mg milligram(s)
- Max total dose
- 60 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB25425 · Substance
- Active substance
- Apixaban
- Pharmaceutical form
- TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 10 mg milligram(s)
- Max total dose
- 10 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB20521 · Substance
- Active substance
- Dabigatran Etexilate
- Pharmaceutical form
- HARD CAPSULES
- Route of administration
- ORAL USE
- Max daily dose
- 300 mg milligram(s)
- Max total dose
- 300 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB13395MIG · Substance
- Active substance
- Clopidogrel
- Pharmaceutical form
- TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 75 mg milligram(s)
- Max total dose
- 75 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB05128MIG · Substance
- Active substance
- Warfarin Sodium
- Pharmaceutical form
- TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 10 mg milligram(s)
- Max total dose
- 10 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB29263 · Substance
- Active substance
- Rivaroxaban
- Pharmaceutical form
- TABLETS
- Route of administration
- ORAL USE
- Max daily dose
- 20 mg milligram(s)
- Max total dose
- 20 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Comparator 7
SUB25425 · Substance
- Active substance
- Apixaban
- Pharmaceutical form
- TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 10 mg milligram(s)
- Max total dose
- 10 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB12730MIG · Substance
- Active substance
- Acetylsalicylic Acid
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 75 mg milligram(s)
- Max total dose
- 75 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB20521 · Substance
- Active substance
- Dabigatran Etexilate
- Pharmaceutical form
- CAPSULE
- Route of administration
- ORAL USE
- Max daily dose
- 300 mg milligram(s)
- Max total dose
- 300 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB29263 · Substance
- Active substance
- Rivaroxaban
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 20 mg milligram(s)
- Max total dose
- 20 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB05128MIG · Substance
- Active substance
- Warfarin Sodium
- Pharmaceutical form
- TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 10 mg milligram(s)
- Max total dose
- 10 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB32701 · Substance
- Active substance
- Edoxaban
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 60 mg milligram(s)
- Max total dose
- 60 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB13395MIG · Substance
- Active substance
- Clopidogrel
- Pharmaceutical form
- TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 75 mg milligram(s)
- Max total dose
- 75 mg milligram(s)
- Max treatment duration
- 60 Month(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Rigshospitalet
- Sponsor organisation
- Rigshospitalet
- Address
- Blegdamsvej 9
- City
- Copenhagen Oe
- Postcode
- 2100
- Country
- Denmark
Scientific contact point
- Organisation
- Rigshospitalet
- Contact name
- Ole de backer
Public contact point
- Organisation
- Rigshospitalet
- Contact name
- Ole de backer
Third parties 2
| Organisation | City, country | Duties |
|---|---|---|
| Frederiksberg Hospital ORG-100028217
|
Frederiksberg, Denmark | On site monitoring |
| Aarhus Universitet ORG-100028380
|
Aarhus N, Denmark | On site monitoring |
Locations
1 EU/EEA country · 2 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Denmark | Ongoing, recruitment ended | 350 | 2 |
| Rest of world | — | 0 | — |
Investigational sites
Aarhus Universitet
Cardiology, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N
Rigshospitalet
Cardiology, Blegdamsvej 9, 2100, Copenhagen Oe
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Denmark | 2021-05-12 | 2021-05-12 | 2025-03-21 |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 29 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol 2024-518547-38-00 TC | 10 |
| Protocol (for publication) | D1_Protokol 2024-518547-38-00 | 10 |
| Protocol (for publication) | D4_Patient facing documents Medicine diary | 1 |
| Protocol (for publication) | D4_Patient facing documents MMSE | 1 |
| Protocol (for publication) | D4_Patient facing documents QoL | 1 |
| Recruitment arrangements (for publication) | K1_Recruitment arrangements | 1 |
| Subject information and informed consent form (for publication) | L1 SIS TC | 10 |
| Subject information and informed consent form (for publication) | L1_ICF | 4 |
| Subject information and informed consent form (for publication) | L1_ICF TC | 4 |
| Subject information and informed consent form (for publication) | L1_SIS | 10 |
| Subject information and informed consent form (for publication) | L1_SIS Skejby | 3 |
| Subject information and informed consent form (for publication) | L1_SIS Skejby TC | 3 |
| Subject information and informed consent form (for publication) | L2_Other subject information material Participant rights leaflet | 1 |
| Subject information and informed consent form (for publication) | L2_Other subject information material_Letter to AF patients | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Acetylsalicylic acid | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Acetylsalicylic acid | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Apixaban | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Apixaban | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Clopidogrel | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Clopidogrel | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Dabigatran Etexilat | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Dabigatran Etexilat | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Edoxaban | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Edoxaban | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Marevan | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Marevan | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Rivaroxaban | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SMPC Rivaroxaban | 1 |
| Synopsis of the protocol (for publication) | D1_Protocol synosis 2024-518547-38-00 | 5 |
Application history
2 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-11-01 | Denmark | Acceptable 2024-11-08
|
2024-11-11 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2024-12-06 | Denmark | Acceptable with conditions 2025-01-29
|
2025-02-04 |