Overview
Sponsor-declared trial summary
Phase
Therapeutic use (Phase IV)
Status
Ongoing, recruiting
Participants planned
1,041
Countries
1
Sites
6
Acute heart failure with pulmonary congestion
The main objective of this trial is to determine the superior strategy regarding emergency treatment (starting within 3 hours after hospital-admission) of pulmonary edema. The strategies are: 1. Loop-diuretics (Furosemide), 2. Vasodilation (nitrates), 3. A combination of both furosemide and nitrates. Patient-outcome w…
Key facts
- Sponsor
- Bispebjerg Hospital
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Cardiovascular Diseases [C14]
- Trial duration
- 14 Sep 2023 → ongoing
- Decision date (initial)
- 2022-06-28
- Transition trial
- No
- Low-intervention
- Yes
- Rare-disease indication
- No
- Vulnerable population
- Yes
- Funding sources
- Novo Nordisk Foundation · Aase og Ejnar Danielsens Fond · Brødrene Hartmann Fond · Alfred Benzons Foundation
External identifiers
- EU CT number
- 2022-500035-36-01
- ClinicalTrials.gov
- NCT05276219
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Efficacy
The main objective of this trial is to determine the superior strategy regarding emergency treatment (starting within 3 hours after hospital-admission) of pulmonary edema. The strategies are: 1. Loop-diuretics (Furosemide), 2. Vasodilation (nitrates), 3. A combination of both furosemide and nitrates. Patient-outcome will be evaluated through the primary endpoint as described elsewhere.
Secondary objectives 1
- To increase clinical knowledge of acute heart failure in the hyperacute setting
Conditions and MedDRA coding
Acute heart failure with pulmonary congestion
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.0 | LLT | 10000803 | Acute heart failure | 10007541 |
| 21.1 | LLT | 10066733 | Acute pulmonary congestion | 10038738 |
Study design 1 period
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | Emergency treatment Immediately after diagnosis, the standard of care-treatment can be initiated. Loop-diuretics and nitrates should be withheld. The attending physician at the site will assess the patient’s eligibility for inclusion in the trial. Inclusion/randomization procedures will be as follows: (1) the patient is screened for inclusion. If all inclusion and no exclusion criteria are found, (2) a sealed cardboard box, which is be pre-randomized by the pharmacy with study medicine will be available for the treating clinician. (3) On the sealed trial-box, a QR code will link to a REDCap screening-survey in which the trial patient identifier and CPR number and Kit ID are linked. All further registration during the admission will identify the patient by the sealed kit ID. (4) The sealed cardboard box is opened, and the intervention will commence.
|
Randomised Controlled | Double | [{"id":164116,"code":1,"name":"Subject"},{"id":164117,"code":5,"name":"Carer"},{"id":164113,"code":3,"name":"Monitor"},{"id":164115,"code":2,"name":"Investigator"},{"id":164114,"code":4,"name":"Analyst"}] | Loop-diuretics: Boluses of 40 mg iv furosemide given as soon as possible and repeated up to 10 times by the discretion of the treating physician. Vasodilation: Boluses of 3 mg iv isosorbide dinitrate given as soon as possible and repeated up to 10 times by the discretion of the treating physician. Loop-diuretics and vasodilation: Boluses of both 3 mg iv isosorbide dinitrate + 40 mg iv furosemide given as soon as possible and repeated up to 10 times by the discretion of the treating physician. |
Regulatory references
- Plan to share IPD
- No
| EU CT number | Title | Sponsor |
|---|---|---|
| 2022-500035-36-00 | VASODILATATION OR LOOP-DIURETICS FOR INITIAL TREATMENT OF PULMONARY CONGESTION DUE TO ACUTE HEART FAILURE – A RANDOMIZED PLACEBO-CONTROLLED TRIAL | Bispebjerg Hospital |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 5
- Age ≥ 18 years
- Acute (within minutes to days) onset or worsening of subjective dyspnea
- Systolic blood pressure ≥100 mmHg
- Oxygen saturation <94% or need of oxygen
- Clinical signs or suspicion of congestion (peripheral edema, rales, and/or clinical suspicion of congestion)
Exclusion criteria 4
- More than 50 mg IV furosemide within the last three hours before randomization including prehospital treatment.
- More than 3 hours from hospital-admission to randomization.
- Ongoing ventricular taky- or brady-arrythmias or supraventricular arrhythmias with HR > 180 or < 40 bpm.
- Suspected severe infection or sepsis.
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Days alive and outside hospital until day 30
Secondary endpoints 6
- Intensification of therapy defineds as at least one of: mechanical ventilation, renal replacement therapy, vasopressors, inotropes, or mechanical heart failure treatment.
- Clinical benefit at 30 days, consisting of a composite of 1. All-cause death, 2. Intubation with mechanical ventilation, and 3. rehospitalization, , assessed using a ’win-ratio’ approach.
- NT-proBNP at day 1-3
- Early Warning Score measured 6-24 hours after start of intervention
- Adverse events
- Patient-reported dyspnea assessment after 212--24 hours (7-point Likert scales in a standardized position: marked improvement from admission = 3, moderate improvement = 2, slight improvement = 1, no change = 0, slight worsening = -1, moderate worsening = -2, marked worsening = - 3
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 2
Furosemide 10 mg/ml Solution for Injection or Infusion
PRD1952561 · Product
- Active substance
- Furosemide
- Pharmaceutical form
- SOLUTION FOR INJECTION/INFUSION
- Route of administration
- INJECTION
- Max daily dose
- 400 mg milligram(s)
- Max total dose
- 400 mg milligram(s)
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- C03CA01 — FUROSEMIDE
- Marketing authorisation
- PL 20075/0339
- MA holder
- ACCORD HEALTHCARE LIMITED
- MA country
- United Kingdom
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
PRD10716171 · Product
- Active substance
- Isosorbide Dinitrate
- Pharmaceutical form
- SOLUTION FOR INJECTION/INFUSION
- Route of administration
- INJECTABLE SOLUTION
- Max daily dose
- 30 mg milligram(s)
- Max total dose
- 30 mg/g milligram(s)/gram
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Not Authorised
- MA holder
- REGION HOVEDSTADENS APOTEK
- Paediatric formulation
- No
- Orphan designation
- No
Placebo 2
Isotonisk saltvand fremstillet af sygehusapoteket
N/A · Product
- Other product name
- N/A
- Pharmaceutical form
- N/A
- Route of administration
- INJECTION
- Max daily dose
- 40 l litre(s)
- Max total dose
- 40 ml millilitre(s)
- Max treatment duration
- 1 Day(s)
- ATC code
- N/A — N/A
- Marketing authorisation
- N/A
- MA holder
- N/A
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Isotonisk saltvand fremstillet af sygehusapoteket
N/A · Product
- Other product name
- N/A
- Pharmaceutical form
- N/A
- ATC code
- N/A — N/A
- Marketing authorisation
- N/A
- MA holder
- N/A
- MA country
- Iceland
- Paediatric formulation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Bispebjerg Hospital
- Sponsor organisation
- Bispebjerg Hospital
- Address
- Borgmester Ib Juuls Vej 31
- City
- Herlev
- Postcode
- 2730
- Country
- Denmark
Scientific contact point
- Organisation
- Bispebjerg Hospital
- Contact name
- jens Jakob Thune
Public contact point
- Organisation
- Bispebjerg Hospital
- Contact name
- jens Jakob Thune
Locations
1 EU/EEA country · 6 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Denmark | Ongoing, recruiting | 1,041 | 6 |
| Rest of world | — | 0 | — |
Investigational sites
Slagelse Hospital
Emergency Deparment, Ingemannsvej 18, 4200, Slagelse
Hvidovre University Hospital
Cardiology, Kettegaard Alle 30, 2650, Hvidovre
Roskilde Hospital
Cardiology, Kogevej 7, 4000, Roskilde
Bispebjerg Hospital
Cardiology, Bispebjerg Bakke 23, 2400, Copenhagen Nv
Herlev Hospital
Department of cardiology, Borgmester Ib Juuls Vej 31, 2730, Herlev
Hillerod Hospital
Cardiology, Dyrehavevej 29, 3400, Hilleroed
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 | 2023-09-14 | 2023-09-14 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Serious breaches 1 · Art. 52 CTR
Serious breach SB-31757
- Sponsor became aware
- 2024-06-27
- Date of breach
- 2024-05-31
- Submission date
- 2024-06-27
- Member states concerned
- Denmark
- Categories
- Protocol
- Areas impacted
- Regulatory
- Benefit-risk balance changed
- No
- Description
- Missing sponsor signature for Serious Adverse Events
For the period from March 12, 2024 onwards, sponsor had not signed reported Serious Adverse Events. This was first mentioned in the GCP report from the monitoring visit at Bispebjerg on May 31, 2024. The number of Serious Adverse Events not signed for this period were 9 (nine). There were no Serious Adverse Reaction or Sudden Unexpected Serious Adverse Reactions that were unsigned in the period.
The reason for this was a human error because the sponsor had not set up his monitoring system to view more than 100 records at a time and so did not see the Serious Adverse Events for patient records above 100. This has now been changed so the sponsor can see ALL records and all Serious Adverse Events have now been signed. Going forward all Serious Adverse Events will be signed according to the protocol.
For the period from the 27. of april until 19. of june there was a delay in signing the consents from the informing part to legal guardian.
At all times consent from the legal guardian have been obtained through direct conversation or phone call imidieatly. Furthermore, written consent was also obtained imideatly. However, the person informing the legal guardian has not signed the concents in the period of 27. of april until 19. of june.
In the protocol it is stated that signature will be obtained as soon as possible thereafter, and since only the legal guardian have signed and not the informing person, this does not satisfy the term "as soon as possible". - Sponsor actions
- Actions taken by the sponsor:
The system has now been changed so the sponsor can see ALL Serious Adverse Events, which have now been signed. Going forward all Serious Adverse Events will be signed according to the protocol.
Regarding the delay in signatures on informed consent from the informing person, relevant signatures have now been put in place. Futhermore, investigators at the relevant sites have made procedures to ensure signatures in place en due time.
| Organisation | City | Country | Type |
|---|---|---|---|
| Hillerod Hospital | Hilleroed | Denmark | Clinical investigator |
| Bispebjerg Hospital | Herlev | Denmark | Sponsor (non commercial) |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 20 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | EQ5D5L | 1 |
| Protocol (for publication) | Protocol clean | 4.1 |
| Protocol (for publication) | Protocol tracked_changes | 4.1 |
| Recruitment arrangements (for publication) | Recruitment arrangement clean | 4 |
| Recruitment arrangements (for publication) | Recruitment Arrangements tracked changes | 4 |
| Subject information and informed consent form (for publication) | Brev vedrrende godtgrelse 200625 | 3 |
| Subject information and informed consent form (for publication) | Brev vedrrende godtgrelse 200625_tracked | 3 |
| Subject information and informed consent form (for publication) | Deltagerinformation forsgsvrge tracked changes | 4.2 |
| Subject information and informed consent form (for publication) | Deltagerinformation forsgsvrge_clean | 4.2 |
| Subject information and informed consent form (for publication) | Deltagerinformation parrende tracked changes | 4.2 |
| Subject information and informed consent form (for publication) | Deltagerinformation parrende_clean | 4.2 |
| Subject information and informed consent form (for publication) | Deltagerinformation parrende_ved_dd ver 4 260325 | 4.2 |
| Subject information and informed consent form (for publication) | Deltagerinformation parrende_ved_dd_clean | 4.2 |
| Subject information and informed consent form (for publication) | Deltagerinformation patient_clean | 4.2 |
| Subject information and informed consent form (for publication) | Deltagerinformation patient_substudie | 1 |
| Subject information and informed consent form (for publication) | Deltagerinformation patient_tracked changes | 4.2 |
| Summary of Product Characteristics (SmPC) (for publication) | brochure | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | Furosemide Solution for Injection Summary of Product Characteristics SmPC | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | SmPC Isoket | 1 |
| Synopsis of the protocol (for publication) | Trial synopsis | 3.5 |
Application history
7 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2022-04-08 | Denmark | Acceptable 2022-06-17
|
2022-06-28 |
| 2 | SUBSTANTIAL MODIFICATION | SM-2 | 2023-04-16 | Denmark | Not acceptable 2023-06-14
|
2023-06-15 |
| 3 | SUBSTANTIAL MODIFICATION | SM-3 | 2023-06-23 | Denmark | Acceptable 2023-07-26
|
2023-07-26 |
| 4 | SUBSTANTIAL MODIFICATION | SM-5 | 2023-09-09 | Denmark | Acceptable 2023-09-19
|
2023-09-19 |
| 5 | SUBSTANTIAL MODIFICATION | SM-6 | 2024-01-20 | Denmark | Acceptable 2024-03-20
|
2024-03-25 |
| 6 | SUBSTANTIAL MODIFICATION | SM-7 | 2025-04-24 | Denmark | Acceptable 2025-06-17
|
2025-06-23 |
| 7 | SUBSTANTIAL MODIFICATION | SM-8 | 2025-12-01 | Denmark | Acceptable 2026-01-27
|
2026-01-28 |