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Clinical Trial Results:
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical cardioversion in patients with persistent atrial fibrillation and chronic heart failure.

Summary
EudraCT number	2012-003487-48
Trial protocol	ES HU CZ IT FR
Global end of trial date	03 Apr 2017

Results information
Results version number	v1(current)
This version publication date	11 Apr 2018
First version publication date	11 Apr 2018
Other versions
Summary report(s)	Synopsis

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

F373280CA201

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Institut de Recherche Pierre Fabre

Sponsor organisation address

3 Avenue Hubert Curien, Toulouse, France, 31035

Public contact

CTI Desk, Clinical Trial Information Desk Pierre Fabre Medicament, contact_essais_cliniques@pierre-fabre.com

Scientific contact

Karim KEDDAD, INSTITUT DE RECHERCHE PIERRE FABRE - Centre de R&D Pierre Fabre, 0033 (0)5 34 50 61 69, karim.keddad@pierre-fabre.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

03 Jul 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

03 Apr 2017

Global end of trial reached?

Yes

Global end of trial date

03 Apr 2017

Was the trial ended prematurely?

Yes

Main objective of the trial

Primary: Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical cardioversion in patients with persistent atrial fibrillation and chronic heart failure

Protection of trial subjects

The study was conducted in compliance with GCP, the current version of the Declaration of Helsinki, and all relevant SOPs in application within Pierre Fabre R&D.

Background therapy

F373280 (a mono ester of pantothenic alcohol and DHA) is a novel pro-drug of DHA (molecular formula: C31H49NO5) that exerts antiarrhythmic properties by interacting with electrical and structural remodelling of the atria. According to data obtained in anaesthetised pigs, rats and canine models and the animal studies described in the Investigator’s brochure (IB – F373280, 2013), the non clinical pharmacokinetic profile of F373280 is not associated with specific concerns regarding the proposed clinical phase IIa study. After single administration of different test doses (0.5 g, 1 g, 2 g, 4 g, 8 g and 16 g) of F373280 to six independent cohorts of 8 subjects (6 of whom received F373280 and 2 received placebo), no difference between F373280 and placebo was reported regarding vital signs (heart rate [HR], systolic blood pressure [SBP] and diastolic blood pressure [DBP]), biological parameters (platelets and fibrinogen) and coagulation parameters (bleeding time, prothrombin time/international normalised ratio [INR], activated partial thromboplastin time [aPTT], thrombin clotting time [TCT]). No serious adverse events (SAEs) occurred during the study. After single oral administration (0.5 g to 16 g) of F373280 in 36 young healthy male subjects (six per dose level) no circulating F373280 plasma levels were detected, confirming that F373280 is a prodrug.

Evidence for comparator

This is a placebo-controlled study in 2 parallel groups.

Actual start date of recruitment

20 May 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 4

Country: Number of subjects enrolled

Spain: 32

Country: Number of subjects enrolled

Czech Republic: 33

Country: Number of subjects enrolled

Hungary: 27

Country: Number of subjects enrolled

Italy: 39

Worldwide total number of subjects

135

EEA total number of subjects

135

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

157 patients have been screened and signed an informed consent form. After a 1 to 4 week run-in period without study treatment, 135 patients have been randomized to receive either 1g/day of F373280 or placebo per os, for 24 weeks. 1 patient did not receive the study treatment.

Screening details

Were included in the study, patients with persistent AF between 7 days and 6 months duration for whom electrical cardioversion is warranted and with history of first documented persistent AF, ischemic or non ischemic heart failure and NYHA class I or II chronic heart failure at selection and at inclusion.

Number of subjects started

135

Number of subjects completed

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Assessor

Are arms mutually exclusive

Yes

F373280

Arm description

Arm type

Experimental

Investigational medicinal product name

F373280

Investigational medicinal product code

F373280

Other name

Panthenyl Ester of DHA

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

One capsule dosed at 1g each evening with dinner.

Placebo

Arm description

Arm type

Experimental

Investigational medicinal product name

F373280

Investigational medicinal product code

F373280

Other name

Panthenyl Ester of DHA

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral, one capsule of 1g each evening with dinner

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral, one capsule each evening with dinner

Number of subjects in period 1	F373280	Placebo
Started	68	67
Completed	34	30
Not completed	34	37
Efficacy concerns	13	11
Safety Concerns	5	8
Other reason	16	18

Baseline characteristics

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Reporting group title

F373280

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	F373280	Placebo	Total
Number of subjects	68	67	135
Age categorical
Units: Subjects
Age continuous
Units: years
median (full range (min-max))	67.0 (37 to 85)	67.0 (26 to 84)	-
Gender categorical
Units: Subjects
Female	16	16	32
Male	52	51	103

Subject analysis set title

Safety set

Subject analysis set type

Safety analysis

Subject analysis set description

• Safety Set, composed of all randomised patients who received at least one dose of the study treatment;

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Full Analysis Set (FAS), composed of all randomised patients having received at least one dose of the study treatment and with a successful cardioversion observed at Visit 3

Subject analysis set title

Per Protocol set

Subject analysis set type

Per protocol

Subject analysis set description

PP set consisted of all FAS patients without any major protocol deviation or other bias for primery criteria analysis

Subject analysis sets values	Safety set	Full Analysis Set (FAS)	Per Protocol set
Number of subjects	134	101	95
Age categorical
Units: Subjects
Age continuous
Units: years
median (full range (min-max))	67.0 (26 to 85)	65 (26 to 85)	65.0 (26 to 85)
Gender categorical
Units: Subjects
Female	31	23	23
Male	103	78	72

End points

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Reporting group title

F373280

Reporting group description

Reporting group title

Placebo

Reporting group description

Subject analysis set title

Safety set

Subject analysis set type

Safety analysis

Subject analysis set description

• Safety Set, composed of all randomised patients who received at least one dose of the study treatment;

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Full Analysis Set (FAS), composed of all randomised patients having received at least one dose of the study treatment and with a successful cardioversion observed at Visit 3

Subject analysis set title

Per Protocol set

Subject analysis set type

Per protocol

Subject analysis set description

PP set consisted of all FAS patients without any major protocol deviation or other bias for primery criteria analysis

Primary: Patients with Recurrence of AF or AF emergence (FAS)

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End point title

Patients with Recurrence of AF or AF emergence (FAS) ^[1]

End point description

End point type

Primary

End point timeframe

24 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to premature termination of the study only descriptive statistical analysis were performed and this being an abbreviated report, no statistical analysis is detailed.

End point values	F373280	Placebo
Number of subjects analysed	52	49
Units: Number of patients	36	31

Attachments

Untitled (Filename: F373280 Time to 1st recurrence AF or Atrial flutter - survival curves PP.pdf)

No statistical analyses for this end point

Primary: Time to First Recurrence of AF or AF emergence (FAS)

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End point title

Time to First Recurrence of AF or AF emergence (FAS) ^[2]

End point description

End point type

Primary

End point timeframe

24 weeks

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to premature termination of the study only descriptive statistical analysis were performed and this being an abbreviated report, no statistical analysis is detailed.

End point values	F373280	Placebo
Number of subjects analysed	52	49
Units: Days
median (confidence interval 95%)	11.0 (6.0 to 45.0)	16.0 (6.0 to 141.0)

Attachments

Time to 1st recurrence of AF/Atrial flutter emerge

No statistical analyses for this end point

Primary: Patients with Recurrence of AF or AF emergence (PP)

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End point title

Patients with Recurrence of AF or AF emergence (PP) ^[3]

End point description

End point type

Primary

End point timeframe

24 weeks

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to premature termination of the study only descriptive statistical analysis were performed and this being an abbreviated report, no statistical analysis is detailed.

End point values	F373280	Placebo
Number of subjects analysed	49	46
Units: Number (%) of patients	34	30

No statistical analyses for this end point

Primary: Time to First Recurrence of AF or AF emergence (PP)

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End point title

Time to First Recurrence of AF or AF emergence (PP) ^[4]

End point description

End point type

Primary

End point timeframe

24 weeks

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to premature termination of the study only descriptive statistical analysis were performed and this being an abbreviated report, no statistical analysis is detailed.

End point values	F373280	Placebo
Number of subjects analysed	49	46
Units: Days
median (confidence interval 95%)	13.0 (6.0 to 45.0)	15.5 (6.0 to 141.0)

Attachments

Time to 1st recurrence of AF/Atrial flutter emerge

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

24 weeks

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

F373280

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	F373280	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 67 (7.46%)	1 / 67 (1.49%)
number of deaths (all causes)	1	0
number of deaths resulting from adverse events
Cardiac disorders
Ventricular tachycardia
subjects affected / exposed	0 / 67 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 67 (1.49%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 67 (1.49%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sick sinus syndrome
subjects affected / exposed	1 / 67 (1.49%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 67 (1.49%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastric ulcer perforation
subjects affected / exposed	1 / 67 (1.49%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary Edema
subjects affected / exposed	1 / 67 (1.49%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Infections and infestations
Peritonitis
subjects affected / exposed	1 / 67 (1.49%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	F373280	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	43 / 67 (64.18%)	43 / 67 (64.18%)
Injury, poisoning and procedural complications
Overdose
subjects affected / exposed	2 / 67 (2.99%)	1 / 67 (1.49%)
occurrences all number	2	1
Vascular disorders
Orthostatic hypotension
subjects affected / exposed	24 / 67 (35.82%)	20 / 67 (29.85%)
occurrences all number	33	24
Cardiac disorders
Intracardiac thrombus
subjects affected / exposed	1 / 67 (1.49%)	5 / 67 (7.46%)
occurrences all number	1	5
Cardiac failure
subjects affected / exposed	1 / 67 (1.49%)	4 / 67 (5.97%)
occurrences all number	1	4
Nervous system disorders
Sciatica
subjects affected / exposed	0 / 67 (0.00%)	2 / 67 (2.99%)
occurrences all number	0	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 67 (2.99%)	0 / 67 (0.00%)
occurrences all number	2	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 67 (2.99%)	1 / 67 (1.49%)
occurrences all number	2	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 67 (0.00%)	2 / 67 (2.99%)
occurrences all number	0	2

More information

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Were there any global substantial amendments to the protocol? Yes

01 Mar 2013

Protocol: contraception method, GP letter (Italy)

23 Oct 2013

Adjustment of criteria to improve the feasibility of the study, change of SAEs report recipient

22 Oct 2014

Planned end of study postponed to April 2016; • Clarifications regarding the management of VKA treatment; • Precision regarding the primary efficacy criterion; • Deletion of Visit 5 and Visit 8; • Changes in TTEM transmission frequency; • Previous history of a first documented persistent AF without limitation in time instead of no longer than 3 years; • Patients must have a systolic heart failure defined by a reduced ventricular ejection fraction and/or defined also through other echocardiographic parameters mentioned in the ESC guidelines for the diagnosis and treatment of acute and chronic heart failure (2012); • Non-inclusion criteria of the protocol adapted; • Informed consent form updated following the modifications done to version 8 of the protocol

28 Sep 2016

• Planned study period: January 2013 – April 2017; • Number of patients: maximum135; • IDMC to review safety data twice during the study (after randomisation of the first 30 patients and after termination of study participation of the first 80 patients)

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Early termination: small number of patients

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Clinical trials

Clinical Trial Results:
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical cardioversion in patients with persistent atrial fibrillation and chronic heart failure.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Patients with Recurrence of AF or AF emergence (FAS)

Primary: Patients with Recurrence of AF or AF emergence (FAS)

Primary: Time to First Recurrence of AF or AF emergence (FAS)

Primary: Time to First Recurrence of AF or AF emergence (FAS)

Primary: Patients with Recurrence of AF or AF emergence (PP)

Primary: Patients with Recurrence of AF or AF emergence (PP)

Primary: Time to First Recurrence of AF or AF emergence (PP)

Primary: Time to First Recurrence of AF or AF emergence (PP)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical cardioversion in patients with persistent atrial fibrillation and chronic heart failure.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Patients with Recurrence of AF or AF emergence (FAS)

Primary: Patients with Recurrence of AF or AF emergence (FAS)

Primary: Time to First Recurrence of AF or AF emergence (FAS)

Primary: Time to First Recurrence of AF or AF emergence (FAS)

Primary: Patients with Recurrence of AF or AF emergence (PP)

Primary: Patients with Recurrence of AF or AF emergence (PP)

Primary: Time to First Recurrence of AF or AF emergence (PP)

Primary: Time to First Recurrence of AF or AF emergence (PP)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical cardioversion in patients with persistent atrial fibrillation and chronic heart failure.