Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion

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.

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01534962

Acronym

RAFFAELLO

Enrollment

241

Registered

2012-02-17

Start date

2012-01-31

Completion date

2014-03-31

Last updated

2014-08-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Persistent Atrial Fibrillation

Keywords

Atrial Fibrillation, Ranolazine, Arrhythmias, Cardiac, Antiarrhythmic Agents, Cardiac Electroversion, Ranexa

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).

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.

Interventions

DRUGRanolazine

Oral administration, BID; for a maximum of 112 days.

DRUGPlacebo

Oral administration, BID; for a maximum of 112 days.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
Number of Patients With Documented AF Recurrences	16 weeks (112 days)	—
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.
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	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.
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)

Countries

Germany, Italy, Spain, United Kingdom

Participant flow

Pre-assignment details

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.

Participants by arm

Arm	Count
Ranolazine Low Dose Ranolazine, low dose, oral, BID	65
Ranolazine Intermediate Dose Ranolazine, intermediate dose, oral, BID	60
Ranolazin High Dose Ranolazine, high dose, oral, BID	58
Placebo Placebo, oral, BID.	55
Total	238

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Discontinued at AF recurrence	35	26	24	31
Overall Study	Randomized but did not start treatment	2	0	0	1

Baseline characteristics

Characteristic	Ranolazine Low Dose	Ranolazine Intermediate Dose	Ranolazin High Dose	Placebo	Total
Age, Continuous	66.9 years STANDARD_DEVIATION 11.8	65.5 years STANDARD_DEVIATION 8.5	63.6 years STANDARD_DEVIATION 11.3	65.2 years STANDARD_DEVIATION 9.5	65.3 years STANDARD_DEVIATION 10.4
Sex: Female, Male Female	19 Participants	9 Participants	12 Participants	14 Participants	54 Participants
Sex: Female, Male Male	46 Participants	51 Participants	46 Participants	41 Participants	184 Participants
Time since AF diagnosis	10.5 months STANDARD_DEVIATION 24	7.2 months STANDARD_DEVIATION 12.9	15.5 months STANDARD_DEVIATION 28.2	6.9 months STANDARD_DEVIATION 13.5	10.0 months STANDARD_DEVIATION 20.7

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	51 / 65	46 / 60	42 / 58	41 / 55
serious Total, serious adverse events	2 / 65	3 / 60	3 / 58	4 / 55

Outcome results

Primary

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.