Overview
Sponsor-declared trial summary
Phase
Therapeutic confirmatory (Phase III)
Status
Ongoing, recruiting
Participants planned
50
Countries
1
Sites
1
Arrhythmic mitral valve prolapse
The main objective is to evaluate the effect and safety of adding flecainide to standard beta blocker therapy to reduce burden of ventricular arrhythmias in patients with arrhythmic mitral valve prolapse.
Key facts
- Sponsor
- Oslo University Hospital Hf
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Cardiovascular Diseases [C14]
- Trial duration
- 4 Jan 2023 → ongoing
- Decision date (initial)
- 2022-09-27
- Transition trial
- No
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- No
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Efficacy, Safety
The main objective is to evaluate the effect and safety of adding flecainide to standard beta blocker therapy to reduce burden of ventricular arrhythmias in patients with arrhythmic mitral valve prolapse.
Conditions and MedDRA coding
Arrhythmic mitral valve prolapse
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.0 | PT | 10027730 | Mitral valve prolapse | 100000004849 |
Study design 1 period
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | Main Study FLECAPRO is designed as a prospective randomized open-label blinded-endpoint crossover trial. Participants will receive equal time-periods of 12 months with the study intervention (flecainide + metoprolol) and with control (metoprolol) in a 1:1 randomized order. Randomization will be performed after inclusion and at the time of implantable loop recorder implantation. Participants will have a run-in period of 1 month at the beginning of the two treatment periods, which includes a washout period of 1 week. The total duration of participation in FLECAPRO is 26 months (2 periods of 1 month run-in/washout and 12 months of fixed dose).
For assessing the primary endpoint and safety, every patient will have continuous heart rhythm monitoring using an implantable loop recorder. The device will be implanted prior to randomization and initiation of study intervention. Patients with a prior cardiac device (pacemaker or implantable cardioverter-defibrillator) will also receive an implantable loop recorder. Additionally, at screening and after 1, 3 and 12 months of both treatment periods, we will perform 24-hour ambulatory Holter monitoring, which is a portable device for continuous recording the heart rhythm during 24 hours. This will detect ventricular tachycardias below the programmed detection zone of the implantable loop recorder and quantify premature ventricular complexes.
|
Randomised Controlled | Single | [{"id":106027,"code":4,"name":"Analyst"}] | Metoprolol Alone: Participants will receive a dosage of Metoprolol taking into consideration prior beta blocker use and concomitant medications. Within the run-in period, the dosage will be increase to the maximum tolerable dose. Whether metoprolol sustained release will be dosed QD or BID, will be up to the investigator and patient preference. The maximum daily dose of metoprolol will not exceed 200 mg. Flecainide and metoprolol: Participants will receive Flecainide 50 mg BID, with a dosage target of 100 mg BID. The maximum daily dose of flecainide will not exceed 300 mg. Participants will receive a dosage of Metoprolol taking into consideration prior beta blocker use and concomitant medications. The maximum daily dose of metoprolol will not exceed 200 mg. Within the run-in period, the dosage of both Flecainide and Metoprolol will be increased to the maximum tolerable dose. The Study Team can change the immediate-release formulation of Flecainide to controlled-release at the same daily dose of flecainide (see section 4.3). Whether metoprolol sustained release will be dosed QD or BID, will be up to the investigator and patient preference. |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 6
- Participants must be 18 years of age or older at the time of signing the informed consent.
- Participants must have mitral valve prolapse evident by echocardiography or cardiac magnetic resonance imaging, defined as more than or equal to 2 mm atrial displacement of any part of the mitral leaflets.
- Participants must have ventricular arrhythmias, defined as at least one of the following: a) Premature ventricular complex burden ≥3% per 24-hours by Holter monitoring b) Premature ventricular complex burden ≥1% per 24-hours if multifocal or occurring in bi-/trigemini and/or couplets by Holter monitoring c) Sustained or non-sustained ventricular tachycardia d) Aborted cardiac arrest
- Participants must have a clinical indication for antiarrhythmic therapy due to ventricular arrhythmias.
- Participants must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF).
- Participants must accede to mandatory use of a contraceptive method for the duration of the trial and until 3 days after discontinuation of study medication.
Exclusion criteria 17
- Strict contraindication for flecaininde or metoprolol.
- Heart failure (signs or symptoms, elevated NT-proBNP) according to ICD10
- Abnormal liver or kidney function (AST/ALT three times upper normal, eGFR<60)
- Prior myocardial infarction or ischemic heart diease
- Ion channelopathy, including Brugada syndrome and long QT syndrome, according to ICD10 and ECG
- Genetic cardiomyopathy (hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, dilated cardiomyopathy, including genotype positive phenotype negative individuals)
- Atrial flutter or permanent atrial fibrillation according to ICD10 an ECG
- Sinus node dysfunction according to ICD10 and ECG
- Ongoing electrolyte disorders
- More than moderate vavular disease according to international guidelines
- Pre-excitation syndrome
- Any degree of AV-block, except due to enchanced vagal tone (e.g. Wencheback-block at night in young athletes or 1st degree AV-block that disappears during exercise)
- Bundle branch block (QRS duration >120 ms) or intraventricular conduction defect with QRS >120 ms.
- Prior flecainide therapy
- Concomitant use of the following medications: a) CYP2D6 inhibitors/inducers. b) Class I, III or IV antiarrhythmic drugs. c) Clozapine, quinidine, cimetidine bupropion. d) Monoaminoxydase (MAO) inhibitors.
- Pregnancy
- Not willing to use a mandatory contraceptive method for the duration of the trial
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Number of ventricular tachyarrhythmias, composite of: a) Ventricular tachycardia b) Ventricular fibrillation.
Secondary endpoints 3
- Burden of premature ventricular complexes (by 24-hour Holter monitoring)
- Health-related quality of life (number of patients with ≥5 points increase in SF-36 overall summary score)
- Number of severe ventricular tachycardias, composite of: a) Non-sustained ventricular tachycardia with syncope b) Sustained ventricular tachycardia c) Ventricular fibrillation
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 2
SCP15543769 · ATC
- Active substance
- Flecainide
- Route of administration
- ORAL
- Max daily dose
- 300 mg milligram(s)
- Max total dose
- 119000 mg milligram(s)
- Max treatment duration
- 13 Month(s)
- Authorisation status
- Authorised
- ATC code
- C01BC04 — FLECAINIDE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP195143 · ATC
- Active substance
- Metoprolol
- Route of administration
- ORAL
- Max daily dose
- 200 mg milligram(s)
- Max total dose
- 80000 mg milligram(s)
- Max treatment duration
- 13 Month(s)
- Authorisation status
- Authorised
- ATC code
- C07AB02 — METOPROLOL
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Comparator 1
SCP195143 · ATC
- Active substance
- Metoprolol
- Route of administration
- ORAL
- Max daily dose
- 200 mg milligram(s)
- Max total dose
- 80000 mg milligram(s)
- Max treatment duration
- 13 Month(s)
- Authorisation status
- Authorised
- ATC code
- C07AB02 — METOPROLOL
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Oslo University Hospital Hf
- Sponsor organisation
- Oslo University Hospital Hf
- Address
- Taarnbygget, Kirkeveien 166 Kirkeveien 166
- City
- Oslo
- Postcode
- 0450
- Country
- Norway
Scientific contact point
- Organisation
- Oslo University Hospital Hf
- Contact name
- Eivind Westrum Aabel
Public contact point
- Organisation
- Oslo University Hospital Hf
- Contact name
- Eivind Westrum Aabel
Locations
1 EU/EEA country · 1 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Norway | Ongoing, recruiting | 50 | 1 |
| Rest of world | — | 0 | — |
Investigational sites
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 |
|---|---|---|---|---|---|
| Norway | 2023-01-04 | 2023-01-04 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Serious breaches 2 · Art. 52 CTR
Serious breach SB-11417
- Sponsor became aware
- 2024-01-10
- Date of breach
- 2024-01-08
- Submission date
- 2024-01-16
- Member states concerned
- Norway
- Categories
- Protocol
- Areas impacted
- Subject safety
- Benefit-risk balance changed
- No
- Description
- The participant underwent elective hip surgery and was prescribed analgesics (codeine and oxycodone), which are prohibited concomitant medications in the trial. The participant administrated a total of three doses of codeine 25mg (two doses on 08.01.24, and one dose on 09.01.24), and one dose of 5mg of Oksykodone on 08.01.24. The combination of the prohibited concomitant medications and the trial medication is safe in a clinical setting, and did not impact the robustness of the results, but theoretically could impact the safety of the participant.
- Sponsor actions
- The participant stopped the concomitant medications, and the trial personnel gave the participant an opportunity for an additional trial visit to ensure the participant's safety. Going forward, the trial personnel will inform participants about concomitant medications and the importance of telling other physicians about their participation in this trial.
| Organisation | City | Country | Type |
|---|---|---|---|
| Oslo University Hospital Hf | Oslo | Norway | Clinical facility BE/BA |
Serious breach SB-9596
- Sponsor became aware
- 2023-12-07
- Date of breach
- 2023-03-31
- Submission date
- 2023-12-12
- Member states concerned
- Norway
- Categories
- Protocol
- Areas impacted
- Data reliability or robustness
- Benefit-risk balance changed
- No
- Description
- At the randomization visit of one trial participant, the investigator imputed incorrectly one of the eight minimization criteria (probabilistic minimization with 80% balanced allocation, 1:1 to sequence of study treatment), possibly affecting the allocation to the sequence of treatment. However, due to the crossover design, patient safety and allocation to treatment vs control are not affected (but only the sequence of treatments).
- Sponsor actions
- No immediate action was taken related to the trial participant. The principal investigator informed the investigators about the error and the importance of correct imputation of data. The error was discussed in the steering committee and due to not affecting the rights of patients, the protocol deviation was not initially considered a serious breach. However, after a later discussion, the protocol deviation was upgraded to a serious breach. All actions taken were done immediately after the error occurred, and the late definition did not impact the actions taken due to the error. We have improved the training of new investigators to prevent the reoccurrence of similar breaches.
| Organisation | City | Country | Type |
|---|---|---|---|
| Oslo University Hospital Hf | Oslo | Norway | Sponsor (non commercial), Clinical investigator |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 7 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | FLECAPRO protocol | 2.3 |
| Protocol (for publication) | FLECAPRO protocol with track changes | 2.3 |
| Summary of Product Characteristics (SmPC) (for publication) | SmPC Flecainide - Norsk | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | SmPC Flecainide Depot - Norsk | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | SmPC Metoprolol - Norsk | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | SmPC Metoprolol - Norsk | 1 |
| Synopsis of the protocol (for publication) | Protokollsammendrag NORSK | 2.2 |
Application history
5 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2022-06-07 | Norway | Acceptable 2022-09-26
|
2022-09-27 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2022-10-11 | Norway | Acceptable 2022-10-26
|
2022-10-26 |
| 3 | SUBSTANTIAL MODIFICATION | SM-2 | 2022-11-17 | Norway | Acceptable 2022-12-07
|
2022-12-09 |
| 4 | SUBSTANTIAL MODIFICATION | SM-4 | 2024-04-03 | Norway | Acceptable 2024-04-26
|
2024-04-26 |
| 5 | SUBSTANTIAL MODIFICATION | SM-6 | 2025-01-23 | Norway | Acceptable 2025-02-18
|
2025-02-19 |