RAFFAELLO: Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion

• Sponsor: Menarini Group (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01534962
• Collaborator: (none)
• Enrollment: 241
• Locations: 4
• Arms: 4
• Duration (Months): 26
• Patients Per Site: 60.3
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

Dose-ranging Phase II study testing the efficacy and safety of 3 doses of Ranolazine (low, intermediate and high, given BID) versus placebo in maintaining sinus rhythm after successful electrical cardioversion in patients with persistent atrial fibrillation (AFib).

After successful cardioversion and subsequent randomisation, patients report trans-telephonic EGCs on a daily basis to a central core ECG facility.

Maximum treatment duration is 112 days (16 weeks).

Condition or Disease	Intervention/Treatment	Phase
Persistent Atrial Fibrillation	Drug: Ranolazine; Drug: Ranolazine; Drug: Ranolazine; Drug: Placebo	Phase 2

Detailed Description

Patients with persistent AFib are screened for eligibility and undergo direct current cardioversion (DCC). If DCC is successful (defined as persistence of sinus rhythm 2 h post-DCC) patients meeting all the inclusion criteria and none of the exclusion criteria are randomly assigned to the treatment arms (Ranolazine low, intermediate, high dose or placebo, given BID).

Transtelephonic ECG devices (TT-ECG) are used for recording of AFib recurrence to be read by a Central ECG Core Laboratory. Any symptoms indicative of AFib have to be recorded by the patient in a diary.

Study Visits are held for screening (Visit 1), at DCC and randomisation (Visit 2), one week post DCC (Visit 3), after 8 weeks of treatment (Visit 4), and at end of treatment (Visit 5). A safety follow-up telephone call is held 2 weeks after end of treatment.

12-Lead ECGs are performed at every visit.

Safety evaluations include regular safety laboratory blood and urine tests, 12-lead ECGs and the continuous recording of adverse events.

A double-dummy technique is used to ensure double-blind conditions.

Study Design

• Study Type: Interventional
• Actual Enrollment: 241 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomised, Double-blind, Double-dummy, Placebo-controlled, Dose-ranging Phase II Study Assessing Ranolazine in the Maintenance of Sinus Rhythm After Electrical Cardioversion in Patients With Non-permanent Atrial Fibrillation.
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ranolazine low dose Ranolazine, low dose, oral, BID	Drug: Ranolazine; Oral administration, BID; for a maximum of 112 days.; Other Names: Ranexa (R)
Experimental: Ranolazine intermediate dose Ranolazine, intermediate dose, oral, BID	Drug: Ranolazine; Oral administration, BID; for a maximum of 112 days.; Other Names: Ranexa (R)
Experimental: Ranolazin high dose Ranolazine, high dose, oral, BID	Drug: Ranolazine; Oral administration, BID; for a maximum of 112 days.; Other Names: Ranexa (R)
Placebo Comparator: Placebo Placebo (sugar pill), oral, BID.	Drug: Placebo; Oral administration, BID; for a maximum of 112 days.; Other Names: Sugar pill

Outcome Measures

Primary Outcome Measures

1. Time From Randomization to First Documented AF Recurrence. [16 weeks (112 days)]

   Time to first AF recurrence reported by patient-reported TT-ECG or 12-Lead ECG at the study site, whichever occurred first. Patients discontinuing the study without AF were censored at the time of the last available ECG.

Secondary Outcome Measures

1. Number of Patients With Documented AF Recurrences [16 weeks (112 days)]

2. Time From Randomization to First Documented and Confirmed AF Recurrence [16 weeks (112 days)]

   A confirmed AF recurrence was defined as a documented AF recurrence which was confirmed by a consecutive ECG performed at least 1 hour after first AF documentation.

3. Number of Patients With Documented and Confirmed AF Recurrences [16 weeks (112 days)]

4. Time From Randomization to First Documented AF Recurrence in Patients With Sinus Rhythm 48 Hours After Cardioversion [16 weeks (112 days)]

   Excluding patients with early relapses (within 48 hours) while the study drug, started after cardioversion, had not yet reached steady-state.

5. Number of Patients in Sinus Rhythm 48 Hours After Cardioversion With Documented AF Recurrence [16 weeks (112 days)]

   Documented AF recurrences in those patients who did not experience early relapses (within 48 hours after cardioversion)

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female patients 18 years and older

• Patients with persistent AF suitable for electrical direct current cardioversion (DCC)

• A female of childbearing potential may be enrolled providing she has a negative pregnancy test at baseline and is routinely using an effective method of birth control resulting in a low failure rate until end of study

• Able to give written informed consent before any study related procedure

• Able to attend all the visits scheduled in the study

Exclusion Criteria:

• Patients with first diagnosed AF or patients with paroxysmal AF

• Patients with long-standing persistent AF or permanent AF

• Patients having known concurrent temporary secondary causes of AF such as alcohol intoxication, pulmonary embolism, hyperthyroidism, pneumonia, hypoxemia, acute pericarditis or myocarditis

• Patients having undergone atrial catheter ablation for AF

• Patients carrying a pacemaker

• Patients with electrolytes imbalances that may cause cardiac arrhythmias, e.g. potassium < 3.5 mmol/L or > 5.5 mmol/L

• Patients with any contra-indications to Ranexa according to the drug-specific product characteristics

• Patients taking class I or Class III antiarrhythmic agents within 3 days of planned randomisation

• Patients taking beta-blockers unless used on stable doses for at least 2 weeks prior to the planned randomisation. Single doses of Intravenous beta-blockers are allowed up to 10 hours from the planned randomisation

• Patients taking Dronedarone or oral Amiodarone within 2 weeks and 3 months of planned randomisation, respectively

• Patients with a history of ECG abnormalities that in the opinion of the Investigator render the subject unsuitable for the trial, including history of congenital or a family history of long QT syndrome and a QTc interval ≥500 msec at Screening

• Patients with congestive heart failure NYHA grade III and IV;

• Patients with any serious intercurrent illness (including psychiatric and neurological disorders) which, in the opinion of the Investigator, is incompatible with the protocol.

• Patients taking Metformin at a total daily dose greater than 1000 mg.

• Patients taking Simvastatin at a total daily dose greater than 20 mg.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universitätsmedizin Göttingen (UMG), Kardiologie und Pneumologie	Goettingen	Lower Saxony	Germany	37075
2	FONDAZIONE IRCCS, Dip. Cardiotoracovascolare (U.C.C.)	Pavia	Lombardy	Italy	27100
3	Hospital Clínic i Provincial de Barcelona, Servicio de Cardiología-Sección de Arritmias	Barcelona	Catalonia	Spain	08036
4	St. George's University of London	London	Greater London	United Kingdom	SW17 0RE

Sponsors and Collaborators

• Menarini Group

Investigators

• Study Chair: Alan J Camm, Professor, Head of Clinical Cardiology; St. Gerorge's University of London, United Kingdom

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Menarini Group
• ClinicalTrials.gov Identifier: NCT01534962
• Other Study ID Numbers: RAF-01; 2011-002789-18
• First Posted: Feb 17, 2012
• Last Update Posted: Aug 19, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by Menarini Group: Atrial Fibrillation; Ranolazine; Arrhythmias, Cardiac; Antiarrhythmic Agents; Cardiac Electroversion; Ranexa
• Additional relevant MeSH terms: Atrial Fibrillation; Ranolazine

Study Results

Participant Flow

Pre-assignment Detail	A total of 310 patients were screened and underwent cardioversion (CV). Of these, 241 were still in sinus rhythm 2 hours post-CV and, thus, were eligible for randomization. Patients who experienced an atrial fibrillation (AF) recurrence could continue the study if no medical intervention was needed and otherwise had to discontinue the study.

Arm/Group Title	Ranolazine Low Dose	Ranolazine Intermediate Dose	Ranolazin High Dose	Placebo
Arm/Group Description	Ranolazine, low dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, intermediate dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, high dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Placebo (sugar pill), oral, BID. Placebo: Oral administration, BID; for a maximum of 112 days.
Period Title: Overall Study
STARTED	67	60	58	56
COMPLETED	30	34	34	24
NOT COMPLETED	37	26	24	32

Baseline Characteristics

Arm/Group Title	Ranolazine Low Dose	Ranolazine Intermediate Dose	Ranolazin High Dose	Placebo	Total
Arm/Group Description	Ranolazine, low dose, oral, BID	Ranolazine, intermediate dose, oral, BID	Ranolazine, high dose, oral, BID	Placebo, oral, BID.	Total of all reporting groups
Overall Participants	65	60	58	55	238
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.9 (11.8)	65.5 (8.5)	63.6 (11.3)	65.2 (9.5)	65.3 (10.4)
Sex: Female, Male (Count of Participants)
Female	19 29.2%	9 15%	12 20.7%	14 25.5%	54 22.7%
Male	46 70.8%	51 85%	46 79.3%	41 74.5%	184 77.3%
Time since AF diagnosis (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	10.5 (24.0)	7.2 (12.9)	15.5 (28.2)	6.9 (13.5)	10.0 (20.7)

Outcome Measures

1. Primary Outcome

Title	Time From Randomization to First Documented AF Recurrence.
Description	Time to first AF recurrence reported by patient-reported TT-ECG or 12-Lead ECG at the study site, whichever occurred first. Patients discontinuing the study without AF were censored at the time of the last available ECG.
Time Frame	16 weeks (112 days)

Outcome Measure Data

Analysis Population Description

Intention-to-treat-approach that analyzed all randomised patients who took at least one dose of study medication (N=238, i.e. excluding 3 randomized patients).

Arm/Group Title	Ranolazine Low Dose	Ranolazine Intermediate Dose	Ranolazin High Dose	Placebo
Arm/Group Description	Ranolazine, low dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, intermediate dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, high dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Placebo (sugar pill), oral, BID. Placebo: Oral administration, BID; for a maximum of 112 days.
Measure Participants	65	60	58	55
Median (95% Confidence Interval) [Days]	51.0	NA	117.0	58.0

2. Secondary Outcome

Title	Number of Patients With Documented AF Recurrences
Time Frame	16 weeks (112 days)

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (N=238)

Arm/Group Title	Ranolazine Low Dose	Ranolazine Intermediate Dose	Ranolazin High Dose	Placebo
Arm/Group Description	Ranolazine, low dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, intermediate dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, high dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Placebo (sugar pill), oral, BID. Placebo: Oral administration, BID; for a maximum of 112 days.
Measure Participants	65	60	58	55
Number [participants]	37 56.9%	25 41.7%	23 39.7%	31 56.4%

3. Secondary Outcome

Title	Time From Randomization to First Documented and Confirmed AF Recurrence
Description	A confirmed AF recurrence was defined as a documented AF recurrence which was confirmed by a consecutive ECG performed at least 1 hour after first AF documentation.
Time Frame	16 weeks (112 days)

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (N=238)

Arm/Group Title	Ranolazine Low Dose	Ranolazine Intermediate Dose	Ranolazin High Dose	Placebo
Arm/Group Description	Ranolazine, low dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, intermediate dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, high dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Placebo (sugar pill), oral, BID. Placebo: Oral administration, BID; for a maximum of 112 days.
Measure Participants	65	60	58	55
Median (95% Confidence Interval) [Days]	73.0	NA	NA	NA

4. Secondary Outcome

Title	Number of Patients With Documented and Confirmed AF Recurrences
Time Frame	16 weeks (112 days)

Outcome Measure Data

Analysis Population Description

Intention-to-Treat

Arm/Group Title	Ranolazine Low Dose	Ranolazine Intermediate Dose	Ranolazin High Dose	Placebo
Arm/Group Description	Ranolazine, low dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, intermediate dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, high dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Placebo (sugar pill), oral, BID. Placebo: Oral administration, BID; for a maximum of 112 days.
Measure Participants	65	60	58	55
Number [participants]	31 47.7%	19 31.7%	16 27.6%	24 43.6%

5. Secondary Outcome

Title	Time From Randomization to First Documented AF Recurrence in Patients With Sinus Rhythm 48 Hours After Cardioversion
Description	Excluding patients with early relapses (within 48 hours) while the study drug, started after cardioversion, had not yet reached steady-state.
Time Frame	16 weeks (112 days)

Outcome Measure Data

Analysis Population Description

Modified Intention-to-Treat Population (N=217) excluding 21 patients with AF relapse within 48 hours post cardioversion

Arm/Group Title	Ranolazine Low Dose	Ranolazine Intermediate Dose	Ranolazin High Dose	Placebo
Arm/Group Description	Ranolazine, low dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, intermediate dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, high dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Placebo (sugar pill), oral, BID. Placebo: Oral administration, BID; for a maximum of 112 days.
Measure Participants	60	54	54	49
Median (95% Confidence Interval) [Days]	56.0	NA	117.0	78.0

6. Secondary Outcome

Title	Number of Patients in Sinus Rhythm 48 Hours After Cardioversion With Documented AF Recurrence
Description	Documented AF recurrences in those patients who did not experience early relapses (within 48 hours after cardioversion)
Time Frame	16 weeks (112 days)

Outcome Measure Data

Analysis Population Description

Modified Intention-to-Treat Population (N=217) excluding 21 patients with AF relapse within 48 hours post cardioversion

Arm/Group Title	Ranolazine Low Dose	Ranolazine Intermediate Dose	Ranolazin High Dose	Placebo
Arm/Group Description	Ranolazine, low dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, intermediate dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Ranolazine, high dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.	Placebo (sugar pill), oral, BID. Placebo: Oral administration, BID; for a maximum of 112 days.
Measure Participants	60	54	54	49
Number [participants]	32 49.2%	19 31.7%	21 36.2%	27 49.1%

Adverse Events

Time Frame	16 weeks (112 days)
Arm/Group Title	Ranolazine Low Dose		Ranolazine Intermediate Dose		Ranolazin High Dose		Placebo
Arm/Group Description	Ranolazine, low dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.		Ranolazine, intermediate dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.		Ranolazine, high dose, oral, BID Ranolazine: Oral administration, BID; for a maximum of 112 days.		Placebo (sugar pill), oral, BID. Placebo: Oral administration, BID; for a maximum of 112 days.
All Cause Mortality
	Ranolazine Low Dose		Ranolazine Intermediate Dose		Ranolazin High Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ranolazine Low Dose		Ranolazine Intermediate Dose		Ranolazin High Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/65 (3.1%)		3/60 (5%)		3/58 (5.2%)		4/55 (7.3%)
Blood and lymphatic system disorders
Anaemia	0/65 (0%)	0	0/60 (0%)	0	1/58 (1.7%)	1	0/55 (0%)	0
Cardiac disorders
Acute Coronary Syndrome	0/65 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/55 (0%)	0
Angina Pectoris	0/65 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	1/55 (1.8%)	1
Angina unstable	0/65 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/55 (0%)	0
Atrial Fibrillation	0/65 (0%)	0	0/60 (0%)	0	0/58 (0%)	0	1/55 (1.8%)	1
Atrial Flutter	0/65 (0%)	0	0/60 (0%)	0	1/58 (1.7%)	1	0/55 (0%)	0
Coronary Artery Disease	0/65 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/55 (0%)	0
Sick Sinus Syndrome	0/65 (0%)	0	0/60 (0%)	0	0/58 (0%)	0	1/55 (1.8%)	1
Ventricular Tachycardia	0/65 (0%)	0	0/60 (0%)	0	0/58 (0%)	0	1/55 (1.8%)	1
Gastrointestinal disorders
Pancreatitis	1/65 (1.5%)	1	0/60 (0%)	0	0/58 (0%)	0	0/55 (0%)	0
General disorders
Sudden Death	0/65 (0%)	0	0/60 (0%)	0	0/58 (0%)	0	1/55 (1.8%)	1
Hepatobiliary disorders
Hepatitis	1/65 (1.5%)	1	0/60 (0%)	0	0/58 (0%)	0	0/55 (0%)	0
Nervous system disorders
Syncope	0/65 (0%)	0	0/60 (0%)	0	1/58 (1.7%)	1	0/55 (0%)	0
Psychiatric disorders
Psychotic Disorder	0/65 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/55 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/65 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/55 (0%)	0
Epistaxis	0/65 (0%)	0	0/60 (0%)	0	1/58 (1.7%)	1	0/55 (0%)	0
Vascular disorders
Hypertension	1/65 (1.5%)	1	0/60 (0%)	0	0/58 (0%)	0	1/55 (1.8%)	1
Orthostatic Hypotension	0/65 (0%)	0	0/60 (0%)	0	1/58 (1.7%)	1	0/55 (0%)	0
Other (Not Including Serious) Adverse Events
	Ranolazine Low Dose		Ranolazine Intermediate Dose		Ranolazin High Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/65 (78.5%)		46/60 (76.7%)		42/58 (72.4%)		41/55 (74.5%)
Cardiac disorders
Atrial Fibrillation	29/65 (44.6%)	31	24/60 (40%)	33	23/58 (39.7%)	27	27/55 (49.1%)	28
Atrial Flutter	2/65 (3.1%)	2	0/60 (0%)	0	3/58 (5.2%)	3	2/55 (3.6%)	2
Palpitations	9/65 (13.8%)	11	11/60 (18.3%)	18	11/58 (19%)	19	6/55 (10.9%)	7
Tachycardia	1/65 (1.5%)	1	1/60 (1.7%)	1	3/58 (5.2%)	4	1/55 (1.8%)	1
Ear and labyrinth disorders
Vertigo	1/65 (1.5%)	2	1/60 (1.7%)	2	4/58 (6.9%)	7	2/55 (3.6%)	3
Gastrointestinal disorders
Constipation	1/65 (1.5%)	1	2/60 (3.3%)	2	3/58 (5.2%)	3	1/55 (1.8%)	1
Nausea	5/65 (7.7%)	7	1/60 (1.7%)	1	4/58 (6.9%)	7	0/55 (0%)	0
General disorders
Asthenia	4/65 (6.2%)	4	1/60 (1.7%)	2	5/58 (8.6%)	5	2/55 (3.6%)	2
Chest Pain	8/65 (12.3%)	9	7/60 (11.7%)	16	4/58 (6.9%)	4	6/55 (10.9%)	6
Fatigue	11/65 (16.9%)	13	10/60 (16.7%)	14	9/58 (15.5%)	10	5/55 (9.1%)	5
Investigations
Blood Creatinine increased	2/65 (3.1%)	2	3/60 (5%)	3	0/58 (0%)	0	1/55 (1.8%)	1
Nervous system disorders
Dizziness	6/65 (9.2%)	7	2/60 (3.3%)	4	14/58 (24.1%)	20	7/55 (12.7%)	8
Headache	2/65 (3.1%)	2	2/60 (3.3%)	2	5/58 (8.6%)	5	2/55 (3.6%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnoea	5/65 (7.7%)	6	7/60 (11.7%)	11	5/58 (8.6%)	5	6/55 (10.9%)	6

Limitations/Caveats

Most of the Kaplan-Meier estimates could not be calculated due to the lower than expected number of observed events and the high variability of data.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.