Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion (RAFFAELLO)

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.

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).

Study Overview

• Status: Completed
• Conditions: Persistent Atrial Fibrillation
• Intervention / Treatment: Drug: Ranolazine; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 241
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time From Randomization to First Documented AF Recurrence.	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.	16 weeks (112 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Documented AF Recurrences		16 weeks (112 days)
Time From Randomization to First Documented and Confirmed AF Recurrence	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.	16 weeks (112 days)
Number of Patients With Documented and Confirmed AF Recurrences		16 weeks (112 days)
Time From Randomization to First Documented AF Recurrence in Patients With Sinus Rhythm 48 Hours After Cardioversion	Excluding patients with early relapses (within 48 hours) while the study drug, started after cardioversion, had not yet reached steady-state.	16 weeks (112 days)
Number of Patients in Sinus Rhythm 48 Hours After Cardioversion With Documented AF Recurrence	Documented AF recurrences in those patients who did not experience early relapses (within 48 hours after cardioversion)	16 weeks (112 days)

Collaborators and Investigators

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

Publications and helpful links

General Publications

• De Ferrari GM, Maier LS, Mont L, Schwartz PJ, Simonis G, Leschke M, Gronda E, Boriani G, Darius H, Guillamon Toran L, Savelieva I, Dusi V, Marchionni N, Quintana Rendon M, Schumacher K, Tonini G, Melani L, Giannelli S, Alberto Maggi C, Camm AJ; RAFFAELLO Investigators (see Online Supplementary Appendix for List of Participating Centers and Investigators). Ranolazine in the treatment of atrial fibrillation: Results of the dose-ranging RAFFAELLO (Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion) study. Heart Rhythm. 2015 May;12(5):872-8. doi: 10.1016/j.hrthm.2015.01.021. Epub 2015 Jan 17.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: February 10, 2012
• First Submitted That Met QC Criteria: February 16, 2012
• First Posted (Estimate): February 17, 2012

Study Record Updates

• Last Update Posted (Estimate): August 19, 2014
• Last Update Submitted That Met QC Criteria: July 29, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: Atrial Fibrillation; Ranolazine; Arrhythmias, Cardiac; Ranexa; Antiarrhythmic Agents; Cardiac Electroversion
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Sodium Channel Blockers; Ranolazine
• Other Study ID Numbers: RAF-01; 2011-002789-18 (EudraCT Number)