Study No.: LOV Title: Rationale: Phase: IIB Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary-

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: LOV Title: A Randomized, Double-blind, -Controlled, Parallel-group Trial to Assess the Efficacy and Safety of LOVAZA for the Prevention of Recurrent, Symptomatic Atrial Fibrillation Rationale: Recent studies have provided data supporting the hypothesis that consumption of fish oil is associated with reduced rates of atrial and ventricular arrhythmias and sudden death. While the mechanisms underlying this association have not been fully elucidated, the strongest evidence favors antiarrhythmic effects of the long-chain n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are abundant in certain fish oils. LOVAZA (omega-3-acid ethyl esters; hereafter referred to as ) is the only prescription omega-3 marketed in the United States. Phase: IIB Study Period: 20 December, January, 2010 Study Design: randomized, double-blind, placebo controlled, parallel group Centres: 110 centers in the United States, of which 96 randomized at least one subject. Indication: recurrent symptomatic atrial fibrillation Treatment: Dosing for this study was 8 grams per day of or matching placebo for the first 7 days, and 4 g per day thereafter through Week 24. Eligible subjects were equally randomized (1:1) into one of two treatment groups: P- OM3 (1 g capsule) or matching placebo (1 g vegetable oil). Objectives: Primary- to assess the effect of on time to the first symptomatic recurrence of atrial fibrillation (AF) in subjects with paroxysmal AF. Time was measured as event-free days from the first dose of study drug to the first symptomatic recurrence of AF. The occurrence of symptomatic atrial flutter during the course of this clinical trial was treated as an occurrence of symptomatic AF for the primary endpoint. Primary Outcome/Efficacy Variable: primary efficacy endpoint was the number of event-free days from the first dose of study drug to the first recurrence of symptomatic AF/flutter as documented by the transtelephonic monitoring (TTM) device or other electrocardiogram (ECG) in subjects with paroxysmal AF. The occurrence of symptomatic atrial flutter was treated as an occurrence of symptomatic AF for the primary endpoint. Secondary Outcome/Efficacy Variable(s): time to first symptomatic recurrence of AF in the persistent AF stratum and in both AF strata (persistent and paroxysmal) combined. Additional secondary endpoints assessed the effects of on the following variables in the paroxysmal AF stratum, the persistent AF stratum, and both AF strata combined: event-free days after the first dose of study drug to onset of documented symptomatic AF (exclusive of atrial flutter); event-free days after the first dose of study drug to onset of any documented AF/flutter event, symptomatic or asymptomatic; event-free days after the first dose of study drug to onset of any documented AF event, symptomatic or asymptomatic; event-free days after completion of Day 7 to the first occurrence of symptomatic AF/flutter; event-free days after completion of Day 7 to the first occurrence of symptomatic AF; annualized number of rescue episodes during the double-blind treatment period after the first dose of study drug where rescue was defined as any pharmacological/electrical/surgical intervention for the termination/prevention of AF/flutter with a maximum of one rescue episode counted per day; annualized number of rescue episodes during the double-blind treatment period after the first dose of study drug where rescue was defined as any pharmacological/electrical/surgical intervention for the termination/prevention of AF with a maximum of one rescue episode counted per day; annualized cumulative frequency of symptomatic AF/flutter recurrences during the double-blind treatment period; and annualized cumulative frequency of symptomatic AF recurrences during the double-blind treatment period. Statistical Methods: For the primary efficacy variable (number of event-free days from the first dose of study drug to the first recurrence of symptomatic atrial AF/flutter), the modified Intent-to-Treat (MITT) Population (comprised of all randomized subjects who provided at least one post-randomization TTM ECG data transfer or equivalent) was used. The two treatment groups were compared using a Cox proportional hazards (PH) model to estimate the hazard ratios (HR), Wald chi-square p-values, and 95% confidence intervals (CI). Subjects were censored after initiation of chronic therapy with any anti-arrhythmic drug (AAD). Subjects who were event-free at the time of completing the trial or at early termination were censored at the last available visit date or transmission date, whichever occurred later. The Cox PH model included adjustments for treatment group, region, statin use, and time-dependent covariate for ACE-I or ARB use. Sensitivity analyses of the primary endpoint was performed using a Cox PH model with ACE-I/ARB use as a fixed covariate instead of using ACE-I/ARB as a time dependent covariate; subjects who took AAD therapy were assigned an event rather than being censored; and analysis of the primary endpoint for the paroxysmal and persistent AF strata was performed using the original classification at randomization. The time to event secondary efficacy 1

2 endpoints were analyzed as described for the primary endpoint. However, instead of using the time dependent ACE- I/ARB use in the model, a fixed effect of the ACE-I/ARB (yes, no) was used. For the continuous secondary efficacy endpoints, i.e.,annualized number of rescue episodes and annualized cumulative frequency of AF, descriptive statistics were presented by treatment group. The normality assumption of the secondary continuous efficacy variables was assessed using residual plots and Shapiro-Wilk test for normality. Non-parametric methods were used for treatment comparisons if the normality assumptions were violated. Between treatment group differences were assessed using Analysis of Covariance (ANCOVA) model or nonparametric ANCOVA model adjusting for treatment group, region, use of ACE-I or ARB (yes, no), and AAD therapy (yes, no). For nonparametric analyses, medians were presented in lieu of means. It was discovered that the rescue CRF was inadvertently not designed to identify rescue episodes for AF versus atrial flutter, therefore no descriptive statistics or analyses were performed on this secondary efficacy endpoint for rescue episodes of AF alone. Adverse events, laboratory values, and vital signs were summarized. Study Population: Male and female subjects 18 years of age or older with documented electrocardiographic evidence of symptomatic paroxysmal AF or persistent AF, not currently receiving anti-arrhythmic therapy, and without significant structural heart disease were eligible to enter the study. Paroxysmal AF was defined as AF that had never been treated with pharmacologic/electrical therapy to terminate an episode. Persistent AF was defined as AF that had been terminated at least once with pharmacologic/electrical cardioversion. A documented episode of symptomatic paroxysmal or persistent AF was defined as AF documented by an ECG or TTM tracing associated with symptoms consistent with AF in the subject s medical record. 2

3 Number of Subjects Atrial Fibrillation Strata a Combined Paroxysmal AF Persistent AF Treatment Total Total Total Planned Randomized b, N Completed, n (%) 291 (88) 293 (88) 584 (88) 246 (89) 233 (88) 479 (88) 45 (82) 60 (91) 105 (87) Total Number of Subjects Withdrawn, n (%) 40 (12) 39 (12) 79 (12) 30 (11) 33 (12) 63 (12) 10 (18) 6 (9) 16 (13) Withdrawn due to Adverse Event 16 (5) 11 (3) c 27 (4) 14 (5) 9 (3) 23 (4) 2 (4) 2 (3) 4 (3) Withdrew consent 6 (2) 12 (4) 18 (3) 5 (2) 10 (4) 15 (3) 1 (2) 2 (3) 3 (2) Noncompliance with protocol 8 (2) 3 (<1) 11 (2) 5 (2) 3 (1) 8 (1) 3 (5) 0 3 (2) Other 10 (3) 13 (4) 23 (4) 6 (2) 11 (4) 17 (3) 4 (8) 2 (3) 6 (5) a. A total of 47 subjects had their AF strata reclassified post-randomization: 39 from paroxysmal to persistent and 8 from persistent to paroxysmal AF. These reclassifications occurred when the monitors reviewed source documents for these subjects post-randomization. b. Excludes 2 Subjects who were screening failures randomized in error. c. One subject was reported as withdrew consent in the study disposition table but was also reported as withdrawn due to an AE of anxiety. Atrial Fibrillation Strata Combined Paroxysmal AF Persistent AF Treatment Total Total Total Demographics N (randomized) Females : Males 157 : : : : : : : : : 88 Mean Age, years (SD) 61.2 (12.26) 59.8 (13.38) 60.5 (12.84) 61.9 (11.57) 60.0 (13.56) 61.0 (12.61) 57.6 (14.85) 58.7 (12.65) 58.2 (13.65) White/Caucasian, n (%) 298 (90) 309 (93) 607 (92) 253 (92) 246 (92) 499 (92) 45 (82) 63 (95) 108 (89) Primary Efficacy Results (MITT Population) Paroxysmal AF Time to event from first dose of study drug to onset of documented symptomatic AF/Flutter in subjects with paroxysmal AF. Number of events, n (%) 129 (48) 135 (52) Censored, n (%) 140 (52) 123 (48) Hazard ratio estimate a (95% CI) p value 1.15 (0.90, 1.46) a. Note: Hazard ratio <1 indicates a lower risk with compared with placebo Secondary Outcome variables (MITT Population) Persistent AF Combined Strata 3

4 Time to event from first dose of study drug to onset of documented symptomatic AF/flutter in subjects with persistent AF and in both AF subgroups combined. Number of events, n (%) 18 (33) 32 (50) 147 (46) 167 (52) Hazard ratio estimate (95% CI) 1.64 (0.92, 2.92) 1.22 (0.98, 1.52) Event free days after the first dose of study drug to onset of documented symptomatic AF (exclusive of atrial flutter) Number of events, n (%) 126 (47) 133 (52) 18 (33) 30 (47) 144 (45) 163 (51) Censored, n (%) 143 (53) 125 (48) 36 (67) 34 (53) 179 (55) 159 (49) Hazard ratio estimate (95% CI) 1.17 (0.91, 1.49) 1.50 (0.83, 2.69) 1.22 (0.98, 1.53) Event free days after the first dose of study drug to onset of documented symptomatic or asymptomatic AF/Flutter Number of events, n (%) 149 (55) 153 (59) 27 (50) 40 (63) 176 (54) 193 (60) Censored, n (%) 120 (45) 105 (41) 27 (50) 24 (38) 147 (46) 129 (40) Hazard ratio estimate (95% CI) 1.12 (0.89, 1.40) 1.29 (0.79, 2.11) 1.16 (0.94, 1.42) Event free days after the first dose of study drug to onset of documented symptomatic or asymptomatic AF Number of events, n (%) 146 (54) 151 (59) 27 (50) 38 (59) 173 (54) 189 (59) Censored, n (%) 123 (46) 107 (41) 27 (50) 26 (41) 150 (46) 133 (41) Hazard ratio estimate (95% CI) 1.14 (0.90, 1.43) 1.19 (0.73, 1.95) 1.16 (0.94, 1.42) Event free days after completion of Day 7 to the occurrence of symptomatic AF/Flutter N Number of events, n (%) 88 (39) 87 (42) 15 (31) 27 (47) 103 (38) 114 (44) Censored, n (%) 136 (61) 118 (58) 34 (69) 30 (53) 170 (62) 148 (56) Hazard ratio estimate (95% CI) 1.09 (0.81, 1.47) 1.68 (0.89, 3.15) 1.20 (0.92, 1.56) 4

5 Event free days after completion of Day 7 to the occurrence of symptomatic AF N Number of events, n (%) 86 (38) 86 (42) 15 (31) 25 (44) 101 (37) 111 (42) Censored, n (%) 139 (62) 120 (58) 34 (69) 32 (56) 173 (63) 152 (58) Hazard ratio estimate (95% CI) 1.12 (0.83, 1.51) 1.51 (0.79, 2.86) 1.20 (0.92, 1.57) Annualized number of AF/Flutter rescue episodes during the treatment period N Endpoint median Difference in medians (95% CI) (-0.09, 2.08) (-0.08, 2.02) (-0.06, 1.49) 5

6 Annualized cumulative frequency of symptomatic AF/Flutter recurrences during the treatment period N Endpoint median Difference in medians (95% CI) (-0.18, 2.21) (-0.14, 3.14) (-0.10, 2.10) Annualized cumulative frequency of symptomatic AF recurrences during the treatment period N Endpoint median Difference in medians (95% CI) (-0.19, 2.17) (-0.09, 4.31) (-0.08, 2.11) 6

7 A treatment emergent adverse event (AE) was defined as an event of new onset or one that worsened during the on-treatment period (i.e., onset on or after the start date of study medication but not later than one day after the last date of study medication). An on-therapy serious adverse event (SAE) was defined as an SAE with onset on or after the start date of study medication and up to 30 days after the last dose of medication. Most Frequent Adverse Events On- Therapy 10 Most Frequent Events in Each Group N=331 N=332 Subjects with any AE(s), n (%) 199 (60) 203 (61) Nausea 13 (4) 16 (5) Edema peripheral 5 (2) 14 (4) Dizziness 11 (3) 13 (4) Urinary tract infection 12 (4) 12 (4) Diarrhea 10 (3) 11 (3) Sinusitis 12 (4) 10 (3) Nasopharyngitis 8 (2) 10 (3) Fatigue 9 (3) 10 (3) Dyspnea 7 (2) 10 (3) Upper respiratory tract infection 9 (3) 9 (3) Constipation 9 (3) 8 (2) Headache 9 (3) 8 (2) Cough 4 (1) 8 (2) Insomnia 9 (3) 8 (2) Hypertension 7 (2) 7 (2) Dyspepsia 5 (2) 6 (2) Eructation 2 (<1) 6 (2) Hematuria 10 (3) 1 (<1) Arthralgia 9 (3) 2 (<1) Back pain 8 (2) 5 (2) Pain in extremity 8 (2) 5 (2) Bronchitis 7 (2) 5 (2) Blood creatinine phosphokinase increased 7 (2) 2 (2) Blood cholesterol increased 6 (2) 5 (2) Asthenia 6 (2) 3 (<1) Anxiety 6 (2) 5 (2) Flatulence 6 (2) 2 (<1) Abdominal pain upper 5 (2) 1 (<1) Myalgia 5 (2) 1 (<1) Hypotension 5 (2) 4 (1) Rash 5 (2) 4 (1) Abdominal distension 4 (1) 3 (<1) Liver function test abnormal 4 (1) 2 (<1) Non-cardiac chest pain 4 (1) 3 (<1) Chest discomfort 4 (1) 2 (<1) Angina pectoris 4 (1) 3 (<1) Supraventricular tachycardia 4 (1) 2 (<1) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] N=331 N=332 Subjects with any non-fatal SAE, n (%) 20 (6) 25 (8) Bradycardia 1 (<1) 2 (<1) Cardiac failure congestive 1 (<1) 1 (<1) Coronary artery disease 0 2 (<1) 7

8 Sick sinus syndrome 1 (<1) 1 (<1) Angina pectoris 1 (<1) 0 Angina unstable 0 1 (<1) Aortic valve disease 0 1 (<1) Atrial fibrillation 1 (<1) 0 Cardiac arrest 0 1 (<1) Cardiac discomfort 0 1 (<1) Coronary artery occlusion 0 1 (<1) Myocardial infarction 1 (<1) 0 Abdominal pain upper 1 (<1) 0 Colitis ulcerative 1 (<1) 0 Colonic polyp 0 1 (<1) Enterovesical fistula 0 1 <1) Pancreatitis 0 1 (<1) Retroperitoneal hematoma 0 1 (<1) Presyncope 2 (<1) 0 Carotid artery stenosis 0 1 (<1) Cerebrovascular accident 0 1 <1) Syncope 1 (<1) [1] 0 Transient ischemic attack 1 (<1) 0 Hematuria 2 (<1) 0 Renal failure acute 1 (<1) 1 (<1) Nephrolithiasis 0 1 (<1) Urinary retention 0 1 (<1) Pneumonia 0 2 (<1) Appendicitis 0 1 (<1) Septic shock 1 (<1) 0 Urinary tract infection 0 1 <1) Dyspnea 2 (<1) 1 (<1) COPD 0 1 (<1) Pleural Effusion 0 1 (<1) Pleuritic pain 1 (<1) 0 Back pain 1 (<1) 0 Musculoskeletal chest pain 0 1 (<1) Osteoarthritis 0 1 (<1) Arterial thrombosis limb 0 1 (<1) Hypotension 1 (<1) 0 Vasculitis 1 (<1) [1] 0 Anemia 0 1 (<1) Idiopathic thrombocytopenic purpura 0 1 (<1) Chest pain 0 1 (<1) Non-cardiac chest pain 1 (<1) 0 False positive tuberculosis test 0 1 (<1) International normalized ratio increased 0 1 (<1) Breast cancer 1 (<1) 0 Gastrointestinal cancer metastatic 1 (<1) 0 Cholecystitis acute 1 (<1) 0 Overdose 0 1 (<1) Major depression 0 1 (<1) Polycystic ovaries 1 (<1) 0 Subjects with fatal SAEs* n (%) [n considered by the investigator to be related to study medication] N=331 N=332 Subject with any fatal SAE, n (%) 1 (<1) 1 (<1) Cardiac failure congestive 1 (<1) 0 8

9 Arteriosclerosis 0 1 (<1) *A third death was reported to have occurred approximately 113 days after completion of dosing in the group. The death was reported to be a suicide; however this was not confirmed and no documentation from the study site is available. This event was considered unrelated to study drug by the investigator. Conclusion: The results of the study demonstrated no benefit of over placebo for the prevention of recurrent symptomatic atrial fibrillation. The safety profile of was comparable with placebo in this study. LOVAZA is a registered trademark of the GlaxoSmithKline group of companies. 9