Acta Neurol Scand 2015: 132: 355–363 DOI: 10.1111/ane.12414

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA

Lacosamide cardiac safety: clinical trials in patients with partial-onset seizures Rudd GD, Haverkamp W, Mason JW, Wenger T, Jay G, Hebert D, Doty P, Horstmann R. Lacosamide cardiac safety: clinical trials in patients with partial-onset seizures. Acta Neurol Scand 2015: 132: 355–363. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objective – To evaluate the cardiac safety of adjunctive lacosamide in a large pool of adults with partial-onset seizures (POS). Methods – Post-randomization changes from baseline for electrocardiographic (ECG) measurements, diagnostic findings, and relevant adverse events (AEs) were compared for pooled data from three randomized, placebo-controlled trials of adjunctive lacosamide for the treatment of POS. Results – Lacosamide did not prolong the QTc interval or affect heart rate as determined by an analysis of data from patients randomized to lacosamide 200, 400, or 600 mg/day (n = 944) compared with placebo (n = 364). After 12-week maintenance treatment, mean changes from baseline for QRS duration were similar between the placebo and lacosamide 200 and 400 mg/day groups (0.0, 0.2, and 0.4 ms), but slightly increased for lacosamide 600 mg/day (2.3 ms). A small, dose-related mean increase in PR interval was observed (0.3, 1.4, 4.4, and 6.6 ms for the placebo and lacosamide 200, 400, and 600 mg/day groups, respectively). First-degree atrioventricular (AV) block was reported as a non-serious AE in 0.0%, 0.7%, 0.2%, and 0.5% of patients in the same respective groups. Second- or higher degree AV block was not observed. There was no evidence of a PR-interval-related pharmacodynamic interaction of lacosamide with either carbamazepine or lamotrigine. Conclusions – Evaluation of the pooled cardiac safety data from patients with POS showed that adjunctive lacosamide at the maximum recommended dose (400 mg/day) was not clearly associated with any cardiac effect other than a small, dose-related increase in PR interval that had no evident symptomatic consequence.

Introduction

Many drug classes, including antiepileptic drugs (AEDs), are known to cause conduction and rhythm abnormalities (1, 2). While the risk for non-cardiovascular drugs to induce fatal arrhythmias is low, the potential consequences necessitate a rigorous evaluation of all new drugs (3). Lacosamide is a newer AED with demonstrated efficacy and a favorable tolerability profile for the adjunctive treatment of partial-onset seizures (POS) in adults with epilepsy (4–8). Lacosamide is the first AED to selectively enhance slow inactivation of the voltage-gated sodium (Nav)

G. D. Rudd, W. Haverkamp1, J. W. Mason2, T. Wenger3, G. Jay4, D. Hebert5, P. Doty5, R. Horstmann6 1 Department of Cardiology, Campus Virchow Clinic, Charite0 -University Medicine Berlin, Berlin, Germany; 2 Cardiology Division, Department of Medicine, University of Utah, Salt Lake City, UT USA; 3Wenger Consulting, Durham, NC USA; 4RAPID Pharmaceuticals, Rockville, MD USA; 5UCB Pharma, Raleigh, NC USA; 6 Consulting Early Development, Bonn, Germany

Key words: cardiac safety; electrocardiographic intervals; lacosamide; partial seizures; PR interval G. D. Rudd, PharmD, 4002 Kildrummy Dr, Durham, NC 27705-6314, USA Tel.: +1 919 452 2238 Fax: +1 919 767 2521 e-mail: [email protected] Accepted for publication April 6, 2015

channel, without any effects on fast inactivation (9, 10). AEDs that act on neuronal Nav channels – including carbamazepine, phenytoin, and lamotrigine – may also act on cardiac sodium channels (11, 12). Prolongation of PR interval has been reported for such drugs (13, 14). Preclinical safety studies of intravenous lacosamide revealed effects on atrioventricular and intraventricular conduction times (15) prompting incorporation of frequent electrocardiograms (ECGs) into the lacosamide clinical development program to fully characterize its cardiac safety profile. Herein, we report data pooled from the three similarly designed, multicenter, randomized, 355

Rudd et al. double-blind, placebo-controlled clinical trials of lacosamide in patients with POS: SP667 (4), SP754 (5), and SP755 (6). Methods Trial design

The pooled trials included an 8-week baseline period followed by randomization to lacosamide 200, 400, 600 mg/day or placebo and a 12-week maintenance phase. Lacosamide was initiated at 50 mg BID and titrated to the randomized dose in 100 mg/day weekly increments. ECG-related exclusion criteria were confirmed clinically significant ECG abnormality (including prolonged QTc); resting heart rate (HR) 120, and >140 ms. The frequency of TE QRS duration >100 ms was 29.5%, 34.4%, 39.7%, and 29.0%, and >120 ms was 1.4%, 0.0%, 2.6%, and 3.5% for the placebo and lacosamide 200, 400, and 600 mg/day groups. Two placebo patients (0.6%) and one 400 mg/day patient (0.2%) had a TE QRS duration >140 ms. The lacosamide patient had a prolonged baseline QRS value of 132 ms, right bundle branch block (BBB) before and during treatment, and QRS values of 143 and 141 ms during successive visits in the maintenance phase. No AE related to these QRS values was reported and the patient continued treatment in an open-label extension trial. ECG findings – An increased frequency of TE intraventricular (IV) block was observed in patients randomized to lacosamide 400 mg/day (3.5%) and 600 mg/day (7.9%) versus placebo (2.4%; Table 4). Complete right BBB was infrequent in all treatment groups; complete left BBB was not reported. Adverse events – Across datasets, non-serious TEAEs of right BBB were noted in 0.5%, 0.0%, 0.6%, and 1.0% of patients treated with placebo and lacosamide 200, 400, and 600 mg/ day. One placebo-treated patient had a TEAE with a reported term of non-specific IV conduction delay; one patient treated with lacosamide 400 mg/day had a TEAE reported as IV block. Additionally, there was one TEAE of QRS complex prolonged (reported as elevated QRS complex = 111 ms) and one TEAE of QRS complex abnormal (reported as low QRS voltage) in the lacosamide 600 mg/day group. None

357

Rudd et al. Table 3 Summary of changes from baseline in electrocardiographic intervals and heart rate Lacosamide group Placebo (n = 364) n QTcF, ms Baselinea Change from BL, Minc Maxc QRS duration, ms Baselinea Change from BL, Minc Maxc Heart rate, bpm Baselinea Change from BL, Minc Maxc PR interval, ms Baselinea Change from BL, Minc Maxc

End of MPb

361 323 354

End of MPb

361 323 354

End of MPb

361 323 354

End of MPb

360 322 353

Mean (SD)

200 mg/day (n = 270) n

397.6 2.0 14.1 10.7

(18.07) (13.17) (12.79) (11.55)

267 219

93.0 0.0 7.6 6.8

(10.50) (7.71) (7.36) (6.50)

267 219

67.9 1.6 4.9 9.3

(9.78) (8.53) (6.75) (8.14)

160.6 0.3 13.2 11.2

(22.09) (13.51) (11.38) (12.18)

265

265 267 219 265 267 219 265

Mean (SD)

397.4 2.3 12.3 11.4

(17.16) (13.84) (11.84) (12.53)

93.1 0.2 7.63 5.9

(10.12) (8.81) (7.33) (6.85)

67.8 2.3 4.8 10.4

(9.48) (9.51) (6.90) (8.59)

158.5 1.4 11.2 12.7

(20.86) (13.52) (12.22) (11.11)

400 mg/day (n = 471) n 465 363 464 465 363 464 465 363 464 465 362 464

Mean (SD)

397.4 2.4 14.4 10.5

(18.50) (15.21) (14.51) (13.73)

93.4 0.4 7.4 7.3

(10.36) (8.61) (8.33) (6.95)

68.6 1.6 4.3 9.3

(10.02) (8.85) (7.29) (8.57)

158.8 4.4 8.6 14.3

(21.93) (13.62) (12.0) (13.53)

600 mg/day (n = 203) n 203 126 202 203 126 202 203 126 202 203 126 202

Mean (SD)

399.8 1.2 13.5 9.4

(18.48) (13.72) (12.29) (12.16)

92.5 2.3 5.7 7.2

(11.15) (8.61) (7.23) (6.40)

69.4 1.1 4.7 9.7

(10.21) (7.94) (6.40) (8.27)

155.9 6.6 8.0 15.7

(19.24) (13.02) (11.12) (11.80)

BL, baseline; bpm, beats per minute; MP, maintenance phase. Baseline was the average of all predose measurements at baseline (just prior to randomization) during the double-blind trial. b End of MP = End of 12-week maintenance phase. c Change from baseline; min (max) of all reported values (including unscheduled visits) during the treatment phase. Max calculated by subtracting the baseline value from the maximum absolute value observed at any time during the treatment phase (titration + maintenance) for each patient to calculate a mean maximum change from baseline value for each group. The corresponding mean minimum change value for each group was calculated using the same approach. a

of these TEAEs were serious or resulted in discontinuation.

completed the trial and transitioned into an open-label extension trial.

PR Interval – Change from baseline  A small, dose-related increase in mean PR interval was observed (0.3, 1.4, 4.4, and 6.6 ms for the placebo and lacosamide 200, 400, and 600 mg/day groups, respectively; Table 3). Placebo-subtracted mean maximum change from baseline values were 1.5, 3.1, and 4.5 ms, respectively.

ECG findings – In the SP754/SP755 pool, there was little difference between the placebo and lacosamide groups for TE first-degree AV block (Table 4). In SP667, the frequency was higher for the lacosamide groups but not dose related. Second-degree or higher AV block was not reported.

Outlier analysis – At baseline, 3.4%, 0.7%, and 0.1% of patients had PR-interval values >200, >220, and >250 ms; 14.0%, 7.0%, and 0.0% of patients aged 61–71 years (n = 43) exceeded these values. There was a higher frequency of TE PR interval >200 ms in each lacosamide group compared to placebo, although this did not appear to be dose related (Table 5). Four patients had a TE PR-interval value >250 ms. Details for one patient are provided in the adverse event section below. The other three patients were aged 63–68 years with prolonged PR intervals at baseline (223–241 ms). No AE related to PR interval was reported; all

358

Adverse events – Non-serious TEAEs of firstdegree AV block were reported in 0.0%, 0.7%, 0.2%, and 0.5% of patients in the placebo and lacosamide 200, 400, and 600 mg/day groups. There was also a single TEAE of PR prolongation in a 61-year-old with a history of sick sinus syndrome and an implanted pacemaker. The baseline PR interval (213 ms) for this patient was reported as a serious AE. The patient had recorded PR-interval values of 192 ms during titration (200 mg/day); 294 ms (400 mg/day); 208 ms when tapered from 400 to 200 mg/day; and 205 ms 7 days following discontinuation of lacosamide for the AE of PR-interval prolongation. The AE did not resolve until 121 days following discontinuation; the patient’s pacemaker

Clinical cardiac safety of lacosamide Table 4 Summary of interval- and heart rate-based treatment-emergent diagnostic electrocardiographic (ECG) findingsa

Table 5 Summary of patients with treatment-emergent PR-interval outlier values Lacosamide group

Lacosamide group Placebo (n = 364) N

n (%)

200 mg/day (n = 270)

400 mg/day (n = 471)

600 mg/day (n = 203)

N

N

N

n (%)

n (%)

n (%)

b

Prolonged QT SP667 97 0 (0.0) 107 0 (0.0) SP754/ 260 2 (0.8) 161 0 (0.0) SP755 Non-specific intraventricular conduction delay SP667 96 2 (2.1) 107 0 (0.0) Intraventricular blockc SP754/ 250 6 (2.4) 159 3 (1.9) SP755 Incomplete RBBB SP667 92 3 (3.3) 103 2 (1.9) SP754/ 251 2 (0.8) 159 0 (0.0) SP755 Complete RBBB SP667 97 1 (1.0) 107 0 (0.0) SP754/ 257 0 (0.0) 159 0 (0.0) SP755 Bradycardia (HR < 60 bpm) SP667 71 15 (21.1) 72 11 (15.3) SP754/ 176 29 (16.5) 110 15 (13.6) SP755 Marked bradycardiad SP667 93 1 (1.1) 101 5 (5.0) SP754/ 260 2 (0.8) 160 0 (0.0) SP755 Sinus tachycardia (HR > 100 bpm) SP667 96 2 (2.1) 107 5 (4.7) SP754/ 256 4 (1.6) 159 3 (1.9) SP755 First-degree AV blocke SP667 94 3 (3.2) 106 5 (4.7) SP754/ 252 6 (2.4) 159 2 (1.3) SP755

Placebo (n = 364) N

n (%)

200 mg/day (n = 270)

400 mg/day (n = 471)

600 mg/day (n = 203)

N

n (%)

N

nb (%)

N

n (%)

260 264 264

29 (11.2) 2 (0.8) 0 (0.0)

446 459 464

40 (9.0) 10 (2.2) 3 (0.6)

198 201 202

14 (7.1) 1 (0.5) 1 (0.5)

a

PR-interval outlier cutpoint >200 ms 336 15 (4.5) >220 ms 351 10 (2.8) >250 ms 353 0 (0.0)

108 362

1 (0.9) 0 (0.0)

106 96

0 (0.0) 0 (0.0)

108

3 (2.8)

106

0 (0.0)

339

12 (3.5)

89

7 (7.9)

106 349

4 (3.8) 9 (2.6)

104 85

1 (1.0) 4 (4.7)

N = number of patients who did not have a PR-interval value greater than cutpoint at baseline. n = number of patients who had one or more PR-interval value greater than the cutpoint anytime during treatment phase but not at baseline. a Patients in the 200 ms interval include those counted in the >220 and >250 ms intervals; likewise, patients counted in the >220 ms interval include those in the >250 ms interval.

107 360

0 (0.0) 2 (0.6)

106 95

2 (1.9) 1 (1.1)

was reported to have been adjusted following discontinuation from the trial.

83 241

16 (19.3) 32 (13.3)

69 70

10 (14.9) 7 (10.0)

104 360

0 (0.0) 3 (0.8)

103 95

2 (1.9) 0 (0.0)

104 359

2 (1.9) 11 (3.1)

106 93

1 (0.9) 4 (4.3)

103 355

5 (4.9) 8 (2.3)

103 95

5 (4.9) 1 (1.1)

AV, atrioventricular; bpm, beats per minute; HR, heart rate; RBBB, right bundle branch block. ECGs were acquired using a common make and model of ECG recorder (SP667, Marquette MAC-1200; SP754/755, MTX-2). The central ECG reader used for trial SP667 was BioMedical Systems Inc., St. Louis, MO; for trials SP754 and SP755, the central ECG reader was Covance Cardiac Safety Services, Reno, NV. Each ECG was transmitted to the central ECG laboratory facility for a cardiologist overread under blinded conditions. N = the number of patients who did not have the specific ECG finding present on screening ECG or any one of the three baseline ECGs; n = number of subjects who had the finding at least once during the treatment phase. a Treatment-emergent ECG finding was one that occurred at least once during the treatment phase, but was not previously observed to be present on the screening visit ECG or any one of the three ECGs collected at baseline. b QT ≥ 460 ms if 50 years (Covance Labs). c QRS > 120 ms for age 110 ms for age >36 for Covance Labs (SP754/SP755). d Heart rate threshold for marked bradycardia was based on the internal standard at each central ECG reader [220 ms for BioMedical Systems (SP667)].

Pharmacodynamic assessment – A large number of patients were taking a PR-interval-prolonging drug – carbamazepine and/or lamotrigine – when lacosamide or placebo was added to their AED regimen. The potential for a PR-interval-related pharmacodynamic interaction of lacosamide with either carbamazepine or lamotrigine was evaluated. In the lacosamide 400 mg/day group, there was little difference in PR-interval change from baseline to the end of the maintenance phase between patients taking carbamazepine (mean = 4.9 ms, 95% CI [2.3, 7.5]; n = 110) and those not taking carbamazepine (mean = 4.0 ms, 95% CI [2.4, 5.6]; n = 279), and those taking lamotrigine (mean = 2.5 ms, 95% CI [0.0, 4.9]; n = 117), compared with those not taking lamotrigine (mean = 5.1 ms, 95% CI [3.4, 6.7]; n = 272). Similar findings were observed in corresponding analyses for the other lacosamide groups. Pharmacokinetic-pharmacodynamic assessment – The results of a regression analysis of PR-interval change from baseline on corresponding lacosamide plasma concentration are shown in Fig. 1. Solution of the regression equation, using the average lacosamide plasma concentration at steady state for a 400 mg/day dose (~8.3 lg/ml), predicted an average PR-interval increase of ~4.5 ms. Other TEAEs relevant to cardiac safety

TEAEs that were potentially related to AV block included palpitations and syncope or loss of

359

Rudd et al.

Figure 1. Change from baseline in PR interval and lacosamide plasma concentration. Individual patient data points and the associated regression (solid line) for all lacosamide-treated patients (number of observations = 7012). Regression equation: PR-interval change = 0.607892499 + 0.6200861546 * LCM plasma concentration. Pearson correlation coefficient = 0.2062. For reference and comparison, the spread of the placebo data points for change in PR interval is shown at zero lacosamide concentration (gray), and the vertical dotted line at 11 lg/ml represents the mean maximum plasma concentration at steady state for lacosamide 400 mg/day (21).

consciousness. An ECG was not taken at the time of these events; however, there were no instances of prolonged PR interval on ECGs acquired prior to the event. Four non-serious TEAEs of palpitations were reported (0.4%, 0.4%, and 0.5% of patients in the lacosamide 200, 400, and 600 mg/ day groups), and each patient continued treatment. Syncope or loss of consciousness was reported in one patient each in the placebo and lacosamide 200 and 400 mg/day groups. A 48 kg (BMI = 19.3 kg/m2) female taking oxcarbazepine (1800 mg/day) and levetiracetam (1750 mg/day) had serious AEs of fluctuating intoxication symptoms (reported term) and loss of consciousness while also having intermittent dizziness and lightheadedness. These events occurred during the last week of the titration phase while the patient was taking lacosamide 400 mg/day and discontinued due to fluctuating intoxication. Loss of consciousness (not serious) was reported again in the taper phase while patient was taking placebo, 1 day following the end of the lacosamide 200 mg/day taper dose. Both loss of consciousness events resolved on the day of onset. A second patient who completed maintenance phase dosing with lacosamide 200 mg/day had an AE of syncope on the first day of transition to an open-label extension trial. This event was not serious, did not result in discontinuation, and resolved on the same day. Other TEAEs included chest pain or discomfort, reported in 1.6%, 2.2%, 1.5%, and 2.0% of patients randomized to placebo or lacosamide 360

200, 400, or 600 mg/day, respectively. Three patients who were randomized to lacosamide discontinued due to chest pain; however, two of these patients were taking placebo during titration at the time of the event. Extrasystoles or ventricular extrasystoles were reported as TEAEs for two patients each in the placebo and lacosamide 400 mg/day groups. Although these events were not serious, both lacosamide patients were discontinued due to this TEAE. Additional TEAEs that were not serious and did not result in discontinuation were angina pectoris (one patient in the lacosamide 200 mg/day group and two patients in the lacosamide 400 mg/day group [reported terms: heart pain and cardialgia]), and ECG T-wave abnormality and abnormal heart sounds (one patient each in the lacosamide 600 mg/day group).

Discussion

An overall evaluation of the controlled clinical trial data from the large pool of generally healthy patients with POS showed that lacosamide did not prolong the QTc interval or have an effect on HR. After 12-week maintenance treatment, there was little or no change in QRS duration from baseline for the placebo and the maximum recommended lacosamide dose (400 mg/day), but a slight increase in QRS duration (+2.3 ms) was observed in the lacosamide 600 mg/day group. AEs related to QRS duration were infrequent and did not result in patient discontinuation. The mean change from baseline in PR interval after 12-week maintenance treatment was +4.4 ms for the maximum recommended lacosamide dose (400 mg/day). The small increase in PR interval associated with adjunctive lacosamide in patients with POS was similar to increases observed with other AEDs that predominantly act on sodium channel fast inactivation (e.g., carbamazepine, lamotrigine, and eslicarbazepine) (13, 14, 18, 19) and those with other mechanisms of action (e.g., pregabalin) (20). A subset analysis revealed that the magnitude of the PR-interval increase associated with lacosamide was similar in the presence or absence of carbamazepine or lamotrigine, thus offering little evidence of pharmacodynamic interaction with regard to PR interval. ECG results in the POS pooled analysis were quantitatively and qualitatively consistent with a controlled thorough QT (TQT) study of lacosamide safety in healthy volunteers (21). These observations may be related to similarities in the study populations as both were relatively young and generally in good health. The placebo-subtracted

Clinical cardiac safety of lacosamide mean increase of +2.3 ms for QRS duration observed at the end of maintenance in the lacosamide 600 mg/day group was greater than the placebo-subtracted change in QRS duration observed at tmax for the 400 and 800 mg/day lacosamide groups in the TQT study (+0.2 and 0.7 ms, respectively) (21). Together, the POS and TQT findings suggest the absence of a dose-related or clinically relevant effect of lacosamide on QRS duration at recommended doses (21). For the maximum recommended lacosamide dose (400 mg/day), the placebo-subtracted mean increase in PR interval was +4.7 ms for the POS group at the end of maintenance and +7.3 ms at tmax in the TQT trial (21). The small difference in the magnitude of the PR-interval increase for the POS pool and the TQT result is likely due to the timing of ECG acquisitions. The relatively flat relationship between lacosamide plasma concentration and change from baseline PR interval observed in both POS patients (Fig. 1) and healthy volunteers (21) suggests a wide margin of safety for lacosamide with regard to PR interval in patients who are in good health. In first-degree AV block, conduction is most often delayed within the AV node; however, all atrial impulses reach the ventricles. First-degree AV block is an ECG finding that is not commonly associated with symptoms. TE first-degree AV block in the lacosamide groups was not dose related (range: 1.1–4.9%), and incidence was similar to or greater than that reported for the placebo groups in SP754/755 and SP667 (2.4% and 3.2%, respectively). In second-degree AV block, not all atrial impulses are conducted to the ventricles. This type of block may be accompanied by symptoms such as slow or irregular pulse, lightheadedness, and fainting, particularly during exercise. There were no reports of second-degree or higher AV block in this pooled analysis of POS patients or in healthy volunteers taking lacosamide doses up to 800 mg/day (21). Few patients with POS recruited into the controlled lacosamide trials were elderly or had significant underlying cardiovascular disease. However, over 80% of the pooled patients with POS were also taking at least one concomitant sodium channel-blocking AED. To more completely evaluate the safety associated with lacosamide in potentially higher risk groups, patients with a prolonged PR interval or bradycardia (HR 45 or 50 to

Lacosamide cardiac safety: clinical trials in patients with partial-onset seizures.

To evaluate the cardiac safety of adjunctive lacosamide in a large pool of adults with partial-onset seizures (POS)...
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