Efficacy and Safety Study of F373280

• Sponsor: Pierre Fabre Medicament (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01831856
• Collaborator: (none)
• Enrollment: 135
• Locations: 20
• Arms: 2
• Actual Duration (Months): 50.7
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy of F373280 on the maintenance of normal cardiac rhythm after direct electric cardioversion in patients with persistent atrial fibrillation and cardiac failure.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Drug: 1g of F373280; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 135 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety Study of F373280 for Maintenance of Sinus Rhythm After Electrical Cardioversion in Patients With Persistent Atrial Fibrillation and Chronic Heart Failure. International, Multicentric, Randomised, Double-blind, Placebo Controlled Study.
• Actual Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: Apr 3, 2017
• Actual Study Completion Date: Jun 21, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: F373280	Drug: 1g of F373280; Oral administration, one capsule each evening with dinner.
Placebo Comparator: Placebo	Drug: Placebo; Oral administration, one capsule each evening with dinner.

Outcome Measures

Primary Outcome Measures

1. Time to First Atrial Fibrillation (AF) Recurrence or Atrial Flutter Emergence Defined by the Time to First Episode of AF or Atrial Flutter Lasting for at Least 10 Minutes During the 20-week Follow-up After Visit 3 (Electrical Cardioversion (ECV) Visit). [from electrical cardioversion (Visit 3) to last follow-up visit (W24)]

   Time to first Atrial Fibrillation (AF) recurrence defined by the first episode of Atrial Fibrillation lasting for at least 10 minutes. AF recurrences or atrial flutter emergences: 7-day continuous electrocardiogram (ECG; 5-leads/2 or 3 channels) ambulatory recording (Holter ECG) between Visit 3 (Electrical Cardioversion Visit) and Visit 4 (Week 5). Then, the follow-up was documented using the Transtelephonic ECG monitor (TTEM): one transmission every two days from Week 9 to Week 24. For randomised patients with spontaneous cardioversion before Electrical Cardioversion, the recurrence of AF or the emergence of atrial flutter was assessed after Visit 3 (from Week 5). Moreover, during this TTEM period, if the patient experienced any AF or atrial flutter symptoms, it was recorded and documented using the TTEM.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men or women aged more than 18 years (inclusive)

• Patients with current episode of persistent Atrial Fibrillation (AF) between 7 days and 6 months duration for whom electrical cardioversion is warranted

• Previous history of first documented episode of persistent AF.

• Previous history of ischemic or non ischemic heart failure

• New York Heart Association (NYHA) class I or II chronic heart failure at selection and at inclusion

• Left ventricular systolic dysfunction defined at selection and at inclusion by a reduced left ventricular ejection fraction (LVEF) ≥ 30% and ≤ 45% or for patients with a LVEF > 45%:

• an increased left ventricular end-diastolic size (diameter ≥ 60 mm and/or > 32 mm/m² and/or volume > 97 ml/m²)

• and/or an increased left ventricular end-systolic size (diameter > 45 mm and/or > 25 mm/m² and/or volume > 43 ml/m²)

• and/or a reduced left ventricular outflow tract velocity time integral < 15 cm

• On appropriate, stable medical treatments for heart failure, including a diuretic and/or angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or mineralocorticoid receptor (MR) antagonists, and/or betablockers

• Left atrial area ≤ 40 cm² at selection and at inclusion

• Patients treated or having to be treated by vitamin K antagonist

• For female patient of child-bearing potential:

• In all the countries except Italy:

• Use of an effective method of contraception (hormonal contraception or intra-uterine device) assessed by the investigator, for at least 2 months before the selection in the study, and agreement to go on using it during the whole duration of the study and up to 1 month after the last dose of the study treatment

• Documented as surgically sterilized

• In Italy only:

• Absolute abstention from sexual intercourse during the whole duration of the study and for a month after the end of the study or

• Use of double barrier contraception method (use of effective medical contraception method) from at least 2 months before the start of the study to the entire duration of the study and for a month after the end of the study or

• Documented as surgically sterilized.

• For female patient of child-bearing potential: negative urine pregnancy test at inclusion

• For male with a child-bearing potential partner (In Italy only):

• Absolute abstention from sexual intercourse during the whole duration of the study and for 3 months after the end of the study or

• Use of double barrier contraception method (use of condom for male and effective contraception method for the partner) from the entire duration of the study to 3 months after the end of the study.

Ethical / legal considerations:

• Having signed his/her written informed consent,

• Affiliated to a social security system, or is beneficiary (if applicable in the national regulation)

Exclusion Criteria:

• No previous history of first documented episode of persistent AF

• More than two successful cardioversions (electrical or pharmacological) in the last 6 months

• Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to IV)

• NYHA class III or IV heart failure at selection or at inclusion

• Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of treatment for thyroid disease

• Myocardial infarction or unstable angina or presence of unstable ischemic coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise stress test, nuclear or MR perfusion evaluation methods) within 6 months before selection

• Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration rate < 30 ml/min) at selection

• Bradycardia (HR ≤ 50 bpm)

• Hyperkalemia or hypokalemia (according to the standards of local laboratories) at selection

• Cardiac surgery within 3 months before selection or planned during the study duration

Criteria related to treatments:

• Previously ineffective pharmacological or electrical cardioversion

• Concomitant treatment with ranolazine or any antiarrhythmic drug (within 7 days prior to selection), except amiodarone, dronedarone and stable dose of digoxin, betablockers, calcium-blockers

• Concomitant treatment with oral amiodarone or dronedarone from selection

• Concomitant treatment with intravenous amiodarone from selection

• Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT implantation within the last 6 months

• Treatment with any Polyunsaturated Fatty Acid (PUFA) within the last 3 months

• Dietary supplement with ω 3 or ω 6 according to investigator's judgement

• Having undergone any form of ablation therapy for AF

• Patient treated with oral anticoagulant treatment other than vitamin K antagonist: new oral anticoagulants (dabigatran, rivaroxaban, apixaban), or treated with irreversible antiplatelet agents P2Y12 inhibitors such as ticlopidine, clopidogrel or prasugrel

Other criteria:

• Patient liable not to comply with protocol instructions and/or with treatment, in the investigator's opinion

• Patient having taken part in a clinical trial in the preceding 2 months or taking part in a trial at the time of selection

• Patient linguistically or mentally unable to understand the nature, objectives and possible consequences of the trial, or refusing to patient himself/herself to its constraints

• Patient family member or work associate (secretary, nurse, technician,..) of the Investigator

• Patient having forfeited his / her freedom by administrative or legal award or being under guardianship

• Breastfeeding female patient

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Karlovy Vary		Czechia
2		Praha 2		Czechia	128 08
3		Praha 5 - Motol		Czechia
4		Budapest		Hungary	1023
5		Budapest		Hungary	1032
6		Budapest		Hungary	1096
7		Budapest		Hungary	1122
8		Augusta		Italy
9		Brescia		Italy
10		Foggia		Italy
11		Terni		Italy
12		Verona		Italy
13		Grodzisk Mazowiecki		Poland
14		Radom		Poland
15		Sandomierz		Poland
16		Warszawa		Poland	03-242
17		Barcelona		Spain
18		Madrid		Spain
19		Santiago de Compostela		Spain
20		Tarragona		Spain

Sponsors and Collaborators

• Pierre Fabre Medicament

Investigators

• Study Director: Karim Keddad, MD, PierreFabre Medicamment

Study Documents (Full-Text)

• Study Protocol - Nov 9, 2012
• Statistical Analysis Plan - Jun 15, 2017

More Information

Publications

None provided.

• Responsible Party: Pierre Fabre Medicament
• ClinicalTrials.gov Identifier: NCT01831856
• Other Study ID Numbers: F373280 CA 2 01; 2012-003487-48
• First Posted: Apr 15, 2013
• Last Update Posted: Jul 2, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Pierre Fabre Medicament: Cardiovascular diseases; Chronic Heart Failure
• Additional relevant MeSH terms: Atrial Fibrillation

Study Results

Participant Flow

Recruitment Details	It was planned to randomise a total of 152 patients. Due to low recruitment, the study recruitment was interrupted prematurely. Instead of 152 patients, 157 patients were screened and a total of 135 were finally randomised. 1 patient received no dose of the study treatment and was also not included in the analyses.
Pre-assignment Detail	Patients were randomised after 1 to 4-week run-in period without study treatment.

Arm/Group Title	F373280	Placebo
Arm/Group Description	1g of F373280: Oral administration, one capsule each evening with dinner.	Placebo: Oral administration, one capsule each evening with dinner.
Period Title: Overall Study
STARTED	67	67
COMPLETED	33	30
NOT COMPLETED	34	37

Baseline Characteristics

Arm/Group Title	F373280	Placebo	Total
Arm/Group Description	68 patients were randomised in the F373280 arm but one patient did not receive any dose of study treatment. 67 patients were also included in the analyses. 1g of F373280: Oral administration, one capsule each evening with dinner.	67 patients were randomised in the placebo arm. Placebo: Oral administration, one capsule each evening with dinner.	Total of all reporting groups
Overall Participants	67	67	134
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	29 43.3%	33 49.3%	62 46.3%
>=65 years	38 56.7%	34 50.7%	72 53.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.5 (9.7)	65.9 (10.8)	66.7 (10.3)
Sex: Female, Male (Count of Participants)
Female	15 22.4%	16 23.9%	31 23.1%
Male	52 77.6%	51 76.1%	103 76.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	67 100%	67 100%	134 100%
Region of Enrollment (participants) [Number]
Hungary	13 19.4%	13 19.4%	26 19.4%
Czechia	18 26.9%	15 22.4%	33 24.6%
Poland	2 3%	2 3%	4 3%
Italy	19 28.4%	20 29.9%	39 29.1%
Spain	15 22.4%	17 25.4%	32 23.9%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.4 (4.7)	29.1 (4.9)	28.8 (4.8)
Body surface area (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.98 (0.19)	2.02 (0.19)	2.0 (0.19)

Outcome Measures

1. Primary Outcome

Title	Time to First Atrial Fibrillation (AF) Recurrence or Atrial Flutter Emergence Defined by the Time to First Episode of AF or Atrial Flutter Lasting for at Least 10 Minutes During the 20-week Follow-up After Visit 3 (Electrical Cardioversion (ECV) Visit).
Description	Time to first Atrial Fibrillation (AF) recurrence defined by the first episode of Atrial Fibrillation lasting for at least 10 minutes. AF recurrences or atrial flutter emergences: 7-day continuous electrocardiogram (ECG; 5-leads/2 or 3 channels) ambulatory recording (Holter ECG) between Visit 3 (Electrical Cardioversion Visit) and Visit 4 (Week 5). Then, the follow-up was documented using the Transtelephonic ECG monitor (TTEM): one transmission every two days from Week 9 to Week 24. For randomised patients with spontaneous cardioversion before Electrical Cardioversion, the recurrence of AF or the emergence of atrial flutter was assessed after Visit 3 (from Week 5). Moreover, during this TTEM period, if the patient experienced any AF or atrial flutter symptoms, it was recorded and documented using the TTEM.
Time Frame	from electrical cardioversion (Visit 3) to last follow-up visit (W24)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set is composed of all randomised patients having received at least one dose of the study treatment and with a successful cardioversion observed at Visit 3; a successful cardioversion was defined as either spontaneous cardioversion before Visit 3 or successful Electrical Cardioversion performed at Visit 3.

Arm/Group Title	F373280	Placebo
Arm/Group Description	68 patients were randomised in the F373280 arm but one patient did not receive any dose of study treatment. 67 patients were also included in the analyses. 1g of F373280: Oral administration, one capsule each evening with dinner.	67 patients were randomised in the placebo arm. Placebo: Oral administration, one capsule each evening with dinner.
Measure Participants	52	49
Median (95% Confidence Interval) [days]	11.0	16.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	F373280, Placebo
	Comments	The primary criterion, time to first Atrial Fibrillation (AF) recurrence or atrial flutter emergence, was described using survival curves according to the Kaplan-Meier method, reporting the first and third quartiles (Q1, Q3), median, and 95% confidence interval. The time to first AF recurrence or atrial flutter emergence was compared between treatment groups using the Log rank test. Hazard ratios and 95% confidence intervals were estimated with the Cox regression model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5749
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were recorded from the visit 2 to the last visit (Visit 9 Week 24).
Arm/Group Title	F373280		Placebo
Arm/Group Description	68 patients were randomised in the F373280 arm but one patient did not receive any dose of study treatment. 67 patients were also included in the analyses. 1g of F373280: Oral administration, one capsule each evening with dinner.		67 patients were randomised in the placebo arm. Placebo: Oral administration, one capsule each evening with dinner.
All Cause Mortality
	F373280		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/67 (1.5%)		0/67 (0%)
Serious Adverse Events
	F373280		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/67 (7.5%)		1/67 (1.5%)
Cardiac disorders
Ventricular tachycardia	0/67 (0%)	0	1/67 (1.5%)	1
Cardiac failure	1/67 (1.5%)	1	0/67 (0%)	0
Atrial fibrillation	1/67 (1.5%)	1	0/67 (0%)	0
Pulmonary oedema	1/67 (1.5%)	1	0/67 (0%)	0
Sick sinus syndrome	1/67 (1.5%)	1	0/67 (0%)	0
Gastrointestinal disorders
Gastric ulcer perforation	1/67 (1.5%)	1	0/67 (0%)	0
Infections and infestations
Peritonitis	1/67 (1.5%)	1	0/67 (0%)	0
Nervous system disorders
Cerebrovascular accident	1/67 (1.5%)	1	0/67 (0%)	0
Other (Not Including Serious) Adverse Events
	F373280		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/67 (61.2%)		38/67 (56.7%)
Cardiac disorders
Cardiac failure	1/67 (1.5%)	1	4/67 (6%)	4
Cardiac failure congestive	1/67 (1.5%)	1	0/67 (0%)	0
Intracardiac thrombus	1/67 (1.5%)	1	5/67 (7.5%)	5
Mitral valve incompetence	1/67 (1.5%)	1	0/67 (0%)	0
Oedema peripheral	1/67 (1.5%)	1	1/67 (1.5%)	1
Sinus bradycardia	1/67 (1.5%)	1	0/67 (0%)	0
Tachyarrhythmia	0/67 (0%)	0	1/67 (1.5%)	1
Ventricular extrasystoles	0/67 (0%)	0	1/67 (1.5%)	1
Eye disorders
Glaucoma	1/67 (1.5%)	1	0/67 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	0/67 (0%)	0	1/67 (1.5%)	1
Abdominal distension	0/67 (0%)	0	1/67 (1.5%)	1
Abdominal pain upper	0/67 (0%)	0	1/67 (1.5%)	2
Diarrhoea	2/67 (3%)	2	1/67 (1.5%)	1
Gingival bleeding	1/67 (1.5%)	1	0/67 (0%)	0
Hypoaesthesia oral	0/67 (0%)	0	1/67 (1.5%)	1
Rectal haemorrhage	1/67 (1.5%)	1	0/67 (0%)	0
Toothache	0/67 (0%)	0	1/67 (1.5%)	1
General disorders
Asthenia	2/67 (3%)	2	0/67 (0%)	0
Fatigue	0/67 (0%)	0	1/67 (1.5%)	1
Non-cardiac chest pain	0/67 (0%)	0	1/67 (1.5%)	1
Infections and infestations
Gastrointestinal infection	1/67 (1.5%)	1	0/67 (0%)	0
Nasopharyngitis	1/67 (1.5%)	1	1/67 (1.5%)	1
Pharyngitis	0/67 (0%)	0	1/67 (1.5%)	1
Upper respiratory tract infection	0/67 (0%)	0	1/67 (1.5%)	1
Injury, poisoning and procedural complications
Accidental overdose	0/67 (0%)	0	1/67 (1.5%)	1
Limb injury	0/67 (0%)	0	1/67 (1.5%)	1
Overdose	2/67 (3%)	2	1/67 (1.5%)	1
Investigations
Blood creatinine increased	1/67 (1.5%)	1	0/67 (0%)	0
Blood triglycerides increased	0/67 (0%)	0	1/67 (1.5%)	1
International normalised ratio decreased	1/67 (1.5%)	1	0/67 (0%)	0
International normalised ratio increased	0/67 (0%)	0	1/67 (1.5%)	1
Metabolism and nutrition disorders
Hypertriglyceridaemia	1/67 (1.5%)	1	0/67 (0%)	0
Hyperuricaemia	0/67 (0%)	0	1/67 (1.5%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/67 (0%)	0	1/67 (1.5%)	1
Myalgia	1/67 (1.5%)	1	1/67 (1.5%)	1
Nervous system disorders
Dizziness	1/67 (1.5%)	1	0/67 (0%)	0
Headache	1/67 (1.5%)	2	0/67 (0%)	0
Insomnia	1/67 (1.5%)	1	0/67 (0%)	0
Partial seizures	1/67 (1.5%)	1	0/67 (0%)	0
Sciatica	0/67 (0%)	0	2/67 (3%)	2
Tremor	0/67 (0%)	0	1/67 (1.5%)	1
Reproductive system and breast disorders
Erectile dysfunction	1/67 (1.5%)	1	0/67 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/67 (0%)	0	2/67 (3%)	2
Vascular disorders
Orthostatic hypotension	24/67 (35.8%)	33	20/67 (29.9%)	24
Hypertension	1/67 (1.5%)	1	0/67 (0%)	0
Hypotension	1/67 (1.5%)	1	0/67 (0%)	0
Orthostatic hypertension	0/67 (0%)	0	1/67 (1.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.