Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder

European Neuropsychopharmacology (]]]]) ], ]]]–]]]

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Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder$ Joseph R. Calabresea, Andrei Pikalovb,c, Caroline Streicherb,c, Josephine Cucchiarob,c, Yongcai Maob,c, Antony Loebelb,c,n a

University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, United States Sunovion Pharmaceuticals Inc., Marlborough, MA, United States c Sunovion Pharmaceuticals Inc., Fort Lee, NJ, United States b

Received 15 November 2016; received in revised form 7 June 2017; accepted 20 June 2017

KEYWORDS

Abstract

Bipolar disorder; Recurrence; Atypical antipsychotic; Lurasidone

Lurasidone (DS-RAn) has demonstrated efficacy in the acute treatment of bipolar depression, both as monotherapy, and as combination therapy with lithium or valproate. To evaluate the recurrence prevention efficacy of lurasidone for the maintenance treatment of bipolar I disorder, patients received up to 20 weeks of open-label lurasidone (20–80 mg/d) combined with lithium or valproate during an initial stabilization phase. A total of 496 patients met stabilization criteria and were randomized to 28 weeks of double-blind treatment with lurasidone (20–80 mg/d) or placebo, in combination with lithium or valproate. Based on a Cox proportional hazard model, treatment with lurasidone reduced the probability of recurrence of any mood episode by 29% (primary endpoint), however, the reduction did not achieve statistical significance. Probability of recurrence on lurasidone was significantly lower in patients with an index episode of depression (HR, 0.57; P =0.039), in patients with any index episode who were not rapid-cycling (HR, 0.69; P =0.046), and when recurrence was based on MADRS, YMRS, or CGI-BP-S severity criteria (HR, 0.53; P= 0.025; sensitivity analysis). Long-term treatment with lurasidone combined with lithium or valproate was found to be safe and welltolerated, with minimal effects on weight or metabolic parameters. & 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1.

Introduction

☆

Clinicaltrials.gov: NCT01358357 Sponsored by Sunovion Pharmaceuticals Inc. n Corresponding author at: Sunovion Pharmaceuticals Inc., One Bridge Plaza North, Suite 510, Fort Lee, NJ 07024, United States.

Bipolar disorder is a chronic illness with a high rate of recurrence that is frequently associated with reduced quality of life and impairment in functioning (Judd et al.,

http://dx.doi.org/10.1016/j.euroneuro.2017.06.013 0924-977X/& 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013

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J.R. Calabrese et al.

2005; IsHak et al., 2012; Gitlin et al., 1995). Even with treatment, 40–60% of individuals have been found to experience a relapse within a 2-year period, with depressive episodes predominant over manic episodes (Perlis et al., 2006; Tohen et al., 2003). In addition, inter-episode periods are complicated by residual manic or depressive symptoms in at least one-third of all follow-up days (Perlis et al., 2006; Tohen et al., 2003; Judd et al., 2002; Joffe et al., 2004). Treatment guidelines recommend maintenance therapy to prevent recurrence, or reduce the frequency, of acute episodes. Currently, monotherapy with lithium, olanzapine, quetiapine, and aripiprazole are recommended as first-line treatments for prevention of both manic and depressive episodes, while lamotrigine is recommended primarily for prevention of depressive episodes associated with bipolar disorder, and risperidone long-acting injection (LAI) are recommended primarily for prevention of mania (National Collaborative Centre, 2014; Grunze et al., 2013; Goodwin et al., 2016; Ostacher et al., 2016). Since episode recurrence is frequent during monotherapy, guidelines typically recommend combination therapy (Perlis et al., 2006; Tohen et al., 2003; National Collaborative Centre, 2014; Grunze et al., 2013; Goodwin et al., 2016; Ostacher et al., 2016), however, few controlled trials have been reported that evaluate the maintenance efficacy of combination therapy in preventing episode recurrence in bipolar patients presenting with either mania or depression. Use of quetiapine combined with lithium or valproate has demonstrated maintenance efficacy in preventing recurrence of both depression and mania in bipolar disorder patients regardless of the polarity of the most recent episode (Suppes et al., 2009; Vieta et al., 2008). There is also evidence that adjunctive therapy with risperidone LAI, aripiprazole, and ziprasidone may have benefit, but primarily in patients with a recent manic episode, and/or in the prevention of mania (Quiroz et al., 2010; Macfadden et al., 2009; Vieta et al., 2008a; Marcus et al., 2011; Bowden et al., 2010). Given the relative lack of evidence-based combination therapies available, it is clear that additional treatment options would benefit patients. Lurasidone (DS-RAn) has demonstrated efficacy in the acute treatment of bipolar depression, both as monotherapy, and as combination therapy with lithium and valproate (Loebel et al., 2014a, 2014b). In a 6-month extension study, treatment with lurasidone was associated with sustained improvement in depressive symptoms (Ketter et al., 2016). The current study involved a 28-week, double-blind, placebo-controlled, randomized withdrawal design to test whether treatment with lurasidone in combination with either lithium or valproate was effective in preventing recurrence of mood episodes in patients with a diagnosis of bipolar I disorder who had demonstrated a stable response to acute combination therapy with lurasidone and lithium or valproate.

2.

Experimental procedures

This was a multi-regional, randomized, double-blind, placebocontrolled study evaluating the efficacy of lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder.

2.1.

Patient population

Patients who met DSM-IV-TR criteria (APA, 2000) for bipolar I disorder were enrolled if they had Z 1 manic, mixed manic, or depressed episode in the past 2 years (with or without rapid cycling or psychotic features), and a current Young Mania Rating Scale (YMRS; Young et al., 2011) or Montgomery-Åsberg Rating Scale (MADRS; Montgomery and Åsberg, 1979) total score Z14 (if treated with lithium or valproate at the time of the screen visit), or Z 18 (if not on lithium or valproate). Patients treated with lithium or valproate with YMRS and/or MADRS scores Z 14 were judged to be partial responders, and therefore the addition of lurasidone was considered to be warranted. Reasons for exclusion included substance dependence or abuse, clinically significant acute and/or unstable medical condition, concomitant use of a potent cytochrome P450 3A4 inhibitor or inducer, history of non-response to Z 3 adequate trials of antidepressants, antipsychotics or mood stabilizers, or currently an imminent suicide risk (as judged by the investigator).

2.2.

Study design

Patients first completed 12–20 weeks of open-label treatment with lurasidone plus lithium or valproate. For patients not currently being treated with lithium or valproate, mood stabilizer treatment was initiated as described below. Patients who met clinical stability criteria after at least 12 weeks of open-label treatment were then randomized (in a 1:1 ratio) to 28 weeks of double-blind treatment with lurasidone or placebo, in combination with lithium or valproate. The study was conducted at 26 sites in the United States (n=468 patients), 10 sites in South America (n=76 patients), 48 sites in Europe (n=391 patients), and 10 sites in Asia (n=25 patients) between September 2011 and October 2014. The study was approved by an Institutional Review Board at each investigational site and was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and with the ethical principles of the Declaration of Helsinki. An independent data and safety monitoring board reviewed and monitored patient data throughout the study.

2.3.

Clinical stability criteria

Qualified patients were randomized to the 28-week double-blind phase if they achieved clinical stability during open-label treatment with lurasidone, defined as MADRS and YMRS total scores r12 for Z 12 weeks. Clinical worsening at up to two visits was permitted (YMRS Z 13 and/or MADRS Z 14), except during the last 4 weeks prior to randomization.

2.4.

Study medication

Patients who met entry criteria began open-label treatment with lurasidone 20 mg/d on days 1–3, 40 mg/d on days 4–7, and received flexible dosing thereafter in the range of 20–80 mg/d, with dose adjustments permitted in 20 mg increments/decrements per week. Following the 12–20-week open-label phase, patients who met clinical stability criteria were randomly assigned (in a 1:1 ratio) to receive either lurasidone 20–80 mg/day (flexibly dosed) or matching placebo in a double-blind manner; randomization was stratified based on which mood stabilizer was being used. Doses of lithium and valproate were adjusted throughout the study, as needed, to maintain serum trough concentrations of 0.4–1.2 mEq/ L and 50–125 μg/mL, respectively. All country-approved formulations of lithium or valproate (including extended-release and controlled-release formulations) were permitted, with the exception of lithium orotate and magnesium valproate. For patients not

Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013

Maintenance lurasidone for bipolar disorder treated with either lithium or valproate at study entry, investigators determined which mood stabilizer was clinically indicated, and initiated combination therapy on the evening after Visit 2. Mood stabilizer treatment was titrated to therapeutic levels based on country-approved prescribing recommendations. Treatment with benztropine (up to 6 mg/d) was permitted as needed for movement disorders; use of alternative medication was permitted if benztropine treatment was not effective or was poorly tolerated. Treatment with propranolol (up to 120 mg/d) was permitted as needed for akathisia. Concomitant use of lorazepam (up to 2 mg/d) was permitted for intolerable anxiety/agitation. Temazepam (r30 mg/d), eszopiclone (r3 mg/d), zaleplon (r20 mg/d), zolpidem ( r10 mg/d), and zolpidem CR (r12.5 mg/d) were permitted as need for insomnia, but not within 8 h of the scheduled efficacy assessments.

2.5.

Efficacy outcomes

The primary efficacy outcome was time to recurrence (during the double-blind phase) of any mood episode, which was defined as the presence of any of the following: met DSM-IV-TR criteria (APA, 2000) for manic, mixed manic, hypomanic, or depressive episode; required treatment for a manic, mixed manic, hypomanic, or depressive episode; required psychiatric hospitalization for any bipolar mood episode; had a YMRS or MADRS total score Z18 or CGI-BP-S score Z 4 at two consecutive assessments no more than 10 days apart; or discontinued from the study due to a mood episode (as determined by the Investigator). During the double-blind phase, efficacy assessments occurred at weekly intervals for the first 2 weeks, then every 2 weeks until study endpoint. An assessment was scheduled after one week if the YMRS or MADRS total score was Z18 or the CGI-BP-S score was Z 4. Secondary efficacy outcomes included: time to recurrence of a manic, mixed manic, hypomanic, or depressive episode; time to allcause study discontinuation; time to recurrence defined as a YMRS or MADRS total score Z18 or a CGI-BP-S score Z 4 at 2 consecutive assessments no more than 10 days apart; and change from doubleblind baseline to each post-baseline assessment time-point in the MADRS total score, YMRS score, CGI-BP-S (Guy, 1976) depression and mania scores, the 16-item Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR16; Rush et al., 2003) scale, Sheehan Disability Scale (SDS; Sheehan, 1983) total, and the Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q; Endicott et al., 1993).

2.6.

model, with treatment as a fixed effect and stratified by pooled country. A pre-planned sensitivity analysis was performed using symptom severity as the time to event criteria (YMRS or MADRS total score Z18 or CGI-BP-S score Z4 at two consecutive assessments). Kaplan–Meier (KM) survival curves for time to recurrence were plotted by treatment for the primary and secondary recurrence outcomes, and a log-rank test, with treatment as a fixed effect, was performed. Time to an event was censored at the time of study completion, or early termination, for patients who had not experienced a protocol-defined recurrence event. Post hoc Cox model and KM analyses were also performed to examine the effect of lurasidone modal dose (the most frequent dose utilized across both study phases) on time to recurrence of mood episodes for patients with depressive or manic index episodes. For each efficacy measure (MADRS, YMRS, CGI-BP-S, QIDS-SR16, SDS, Q-LES-Q), change from double-blind baseline to each postbaseline visit were evaluated using a mixed-effect model for repeated measures (MMRM) analysis with treatment, visit (as a categorical variable), pooled country, mood stabilizer, baseline score, and a treatment-by-visit interaction term included in the model. An unstructured covariance matrix was used to account for within-subject correlation and a Kenward–Rogers approximation was used to estimate the denominator degrees of freedom. Between-group effect sizes were calculated as the absolute value of the difference from placebo in least squares (LS) mean change from baseline divided by the model estimate of the pooled standard deviation (SD). Number needed to treat (NNT) was calculated by taking the reciprocal of the difference between the recurrence rates for lurasidone and placebo. The polarity index was calculated by dividing NNT for prevention of recurrence of a depressive episode by the NNT for prevention of recurrence of a manic/hypomanic/mixed manic episode (Popovich et al., 2012). All statistical tests were 2-sided and used a Type I error level of alpha (α) = 0.05. All confidence intervals (CIs) were 2-sided with 95% coverage. Statistical Analysis System (SASs), version 9.2 or higher, was used for all analyses. The study was exploratory in terms of secondary endpoints, with no adjustments made for multiple endpoints. Descriptive statistics were used to summarize changes from baseline in vital signs, weight, BMI, and ECG results, and in scores on the SAS, BARS, and AIMS. Based based on assumed recurrence event rates of 24% and 39% (Suppes et al., 2009; Bowden et al., 2010), for lurasidone and placebo, respectively, it was estimated that 120 recurrence events were needed to yield 90% power to detect a 15% difference between lurasidone and placebo at a 2-sided alpha level of 0.05.

Safety outcomes

Safety and tolerability assessments included the occurrence and severity of adverse events at each assessment visit; the SimpsonAngus Rating Scale (SAS; Simpson and Angus, 1970), the Abnormal Involuntary Movement Scale (AIMS; Guy, 1976), and the Barnes Akathisia Rating Scale (BARS; Barnes, 1989) to evaluate movement disorders; and vital signs, weight, body mass index (BMI), laboratory tests, 12-lead ECG, and physical examination. Suicidal ideation and behavior were assessed using the Columbia–Suicide Severity Rating Scale (C-SSRS; Posner et al., 2011).

2.7.

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Statistical analyses

The primary efficacy analysis sample consisted of the intent-totreat (ITT) population, which was defined as all patients who were randomized and received at least one dose of study medication in the double-blind phase. For the primary and secondary recurrence outcomes, hazard ratio estimates (with 95% confidence intervals [CI]) were obtained based on a stratified Cox proportional hazards

3.

Results

Of the 965 patients who entered the open-label stabilization phase, 496 (51.4%) met stabilization criteria and were randomized to combination therapy with lurasidone (N = 246) versus placebo (N= 250) and lithium or valproate (ITT population; Figure 1). Withdrawal of consent (24.2%) and insufficient response (23.2%) were the two most common reasons for study discontinuation during the stabilization phase. Patient demographic and clinical characteristics are summarized in Table 1 at baseline of the open-label stabilization phase, and at baseline of the double-blind phase (all randomized patients). There were a few baseline differences between the non-randomized and randomized patients, most notably, non-randomized (vs. randomized) patients reported a younger age at initial diagnosis of

Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013

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J.R. Calabrese et al.

Figure 1 Patient disposition.

bipolar disorder (24.7 vs. 28.7 years), a higher proportion with recent rapid-cycling ( Z4 episodes in the past year: 30.0% vs. 13.3%), a shorter duration of their current episode (17.2 vs. 30.9 weeks), higher mean MADRS total scores (24.5 vs. 18.2), and higher mean YMRS scores (13.5 vs. 12.4). Among randomized patients at double-blind baseline, demographic and clinical characteristics were generally similar for the lurasidone and placebo groups (Table 1). Among randomized patients, 37.1% were being treated with an adequate dose of lithium or valproate at the initial screening visit (retrospective group), while mood stabilizer was initiated and/or dose-adjusted during the open-label phase in 62.9% of randomized patients (prospective group). The mean (SD) duration of the open-label stabilization phase was 92.8 (12.9) days. The proportion of randomized patients receiving combination therapy with one of several formulations of valproate or lithium was 57.7% vs. 42.3%, respectively, in the lurasidone group, and 56.4% vs. 43.6%, respectively, in the placebo group. The mean daily dose of lurasidone was 52.3 mg during the open-label stabilization phase, and 54.4 mg during the double-blind phase. The modal daily dose of lurasidone in the double-blind phase was 20 mg, 40 mg, 60 mg, and 80 mg in 8.1%, 35.8%, 30.5%, and 25.6% of patients, respectively. The mean daily doses of lurasidone during the open-label and double-blind phases of the study were 54.5 mg and 53.9 mg, respectively, in patients with an index episode of depression, and 53.8 mg and 54.8 mg, respectively, in patients with an index episode of mania/hypomania/mixed mania. Lithium concentrations were similar in the lurasidone and placebo groups at double-blind baseline (0.69 mEq/L and 0.69 mEq/L, respectively) and at LOCF-endpoint (0.68 mEq/L vs. 0.69 mEq/L, respectively). Valproate concentrations were

similar in the lurasidone and placebo groups at double-blind baseline (71.1 mg/mL vs. 72.3 mg/mL, respectively) and at LOCF-endpoint (67.5 mg/mL vs. 68.9 mg/mL, respectively).

3.1.

Time to recurrence of any mood episode

Treatment with lurasidone was associated with a nonsignificantly longer time to recurrence of any mood episode compared to therapy with placebo (primary a priori outcome). At week 28 the hazard ratio for time to recurrence of any mood episode was 0.71 (95% CI= 0.49–1.04; Cox model P= 0.078; Figure 2), representing a risk reduction of 29%. The probability of recurrence of any mood episode was lower in the lurasidone group compared with placebo at Week 26 (18.5% vs. 26.1%; Kaplan–Meier estimate up to Day 182). The probability of recurrence for lurasidone vs. placebo at Week 28 was 20.9% vs. 51.5% (log-rank test P = 0.055; Kaplan–Meier estimate up to Day 233). For patients in the non-rapid cycling group (N= 430), the hazard ratio for time to recurrence of any mood episode was 0.69 (95% CI= 0.46–1.04; Cox model P= n.s.; log-rank test P = 0.046), representing a risk reduction of 31%. In a pre-planned sensitivity analysis, treatment with lurasidone was significantly more effective than placebo in increasing time to recurrence based on symptom severity criteria (MADRS Z18 or YMRS Z18 or CGI-BP-S Z4), with a hazard ratio of 0.53 (95% CI=0.31–0.92; Cox model P=0.025; log-rank test P=0.016; Figure 3), representing a risk reduction of 47%.

3.2. Time to recurrence of a depressive or manic episode Treatment with lurasidone was non-significantly more effective than placebo in increasing time to recurrence of a

Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013

Maintenance lurasidone for bipolar disorder

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Table 1 Demographic and clinical characteristics of bipolar I disorder patients at open-label stabilization phase baseline, and double-blind baseline (Intent-to-Treat population). Open-label Stabilization Phase Double-blind Randomized Treatment Phase (Randomized Patients) Characteristic

Male Race White Black/African-American Asian Other Prior lifetime mood episodes: Z10 Number of prior hospitalizations for bipolar disorder: Z 2 Recent history of rapid cyclinga Current (index) episode Depressive Manic Mixed manic Hypomanic

Lurasidone (+ Lithium/ Valproate) (N = 496)

Lurasidone (+ Lithium/ Valproate) (N = 246)

Placebo (+ Lithium/ Valproate) (N = 250)

N 217

% 43.8

N 110

% 44.7

N 107

% 42.8

429 44 13 10 228

86.5 8.9 2.6 2.0 46.3

213 23 6 4 117

86.6 9.3 2.4 1.6 48.1

216 21 7 6 111

86.4 8.4 2.8 2.4 44.6

262

52.8

125

50.8

137

54.8

66

13.3

33

13.4

33

13.2

263 118 84 31

53.0 23.8 16.9 6.3

144 56 31 15

58.5 22.8 12.6 6.1

119 62 53 16

47.6 24.8 21.2 6.4

Open-label Stabilization (Randomized Patients) Characteristic

Lurasidone (+ Lithium/ Valproate) (N = 496)

Lurasidone (+ Lithium/ Valproate) (N= 246)

Placebo (+ Lithium/ Valproate) (N = 250)

Mean

SD

Mean

SD

Mean

SD

12.4 11.8

45.7 29.2

12.4 12.0

43.2 28.2

12.2 11.6

158.2

34.5

178.0

27.5

136.1

9.5 0.7 1.4 1.5 9.4

4.0 1.7 1.5 1.3 2.2

3.4 0.7 0.7 0.5 2.6

4.1 1.7 1.5 1.3 2.2

3.7 0.7 0.6 0.5 2.7

Age, years 44.4 Age at onset of diagnosis, 28.7 years Duration of current epi- 30.9 sode, weeks Baseline Scores MADRS CGI-BP-S overall CGI-BP-S, depression CGI-BP-S, mania YMRS

Phase Double-blind Randomized Treatment Phase

18.2 4.1 3.2 2.5 12.4

Z4 episodes in past 12 months; MADRS = Montgomery-Åsberg Depression Rating Scale; CGI-BP-S = Clinical Global Impression Bipolar Version - Severity of Illness depression score; HAM-A = Hamilton Rating Scale for Anxiety; YMRS = Young Mania Rating Scale; QIDS-SR16: 16-item Quick Inventory of Depressive Symptomatology - Self Report; Q-LES-Q-SF: Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form; SDS = Sheehan Disability Scale. a

depressive episode, with a hazard ratio of 0.81 (95% CI =0.49–1.34; Cox model P=ns; log-rank test P =ns), representing a risk reduction of 19%. Treatment with lurasidone was also non-significantly more effective than placebo in increasing time to recurrence of mania, hypomania or a mixed mania episode, with a hazard ratio of 0.57 (95% CI =0.28–1.16; Cox model P=ns), a risk reduction of 43%.

Kaplan–Meier estimates for the probability of recurrence of a depressive episode at week 28 were 13.2% in the lurasidone group and 43.1% in the placebo group. In contrast, Kaplan–Meier estimates were low for the probability of recurrence of a manic/hypomanic/mixed manic episode, 5.7% in the lurasidone group and 10.4% in the placebo group. Based on the efficacy of lurasidone in preventing depressive

Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013

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Figure 2 Kaplan–Meier curve: time to recurrence of any mood episode (primary efficacy analysis, total sample).

Figure 3 Kaplan–Meier curve: time to recurrence based on MADRS Z18 or YMRS Z 18 or CGI-BP-S Z4 criteria (sensitivity analysis, total sample).

episode recurrence (NNT=4) relative to its efficacy in preventing episodes of mania/hypomania/mixed mania (NNT=22), the polarity index of lurasidone for the maintenance treatment of bipolar disorder in this study was 0.18.

3.3. Time to recurrence of a mood episode by index episode A series of pre-planned analyses were performed evaluating time to recurrence by the index episode.

3.3.1. Index episode: depression For patients with an index episode of depression (n = 263), treatment with lurasidone was more effective than placebo in increasing time to recurrence of any mood episode, with a hazard ratio of 0.57 (95% CI= 0.34–0.97; Cox model P = 0.039; log-rank test P= 0.068; Figure 4), representing a risk reduction of 43%. In patients with an index episode of depression, treatment with lurasidone was associated with a hazard ratio for time to recurrence of a depressive episode of 0.68 (95% CI= 0.36–1.29; Cox model P = n.s.; log-rank test P= n.s.), representing a risk reduction of 32%; and a hazard ratio for time to recurrence of a manic,

Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013

Maintenance lurasidone for bipolar disorder

Figure 4

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Kaplan–Meier curve: time to recurrence of any mood episode for patients with an index episode of depression.

hypomanic or mixed manic episode of 0.32 (95% CI= 0.09– 1.11; Cox model P= ns; log-rank test P= ns), representing a risk reduction of 68%.

3.3.2. Index episode: mania, hypomania, mixed mania For patients with an index episode of mania, hypomania, or mixed mania (n = 233), the hazard ratio for time to recurrence of any mood episode was 0.82 (95% CI = 0.47– 1.45; Cox model P = ns; log-rank test P = ns), representing a risk reduction of 18%. In patients with an index episode of mania, hypomania, or mixed mania, treatment with lurasidone was associated with a hazard ratio for time to recurrence of a depressive episode of 0.83 (95% CI = 0.35– 2.00; Cox model P = ns; log-rank test P = ns), representing a risk reduction of 17%; and a hazard ratio for time to recurrence of a manic, hypomanic or mixed manic episode of 0.72 (95% CI = 0.29–1.78; Cox model P = ns; log-rank test P = ns), representing a risk reduction of 28%.

3.4. Time to recurrence of any mood episode based on use of lithium or valproate In a pre-planned analysis by mood stabilizer treatment, when lithium was the adjunctive treatment with lurasidone (N = 213), the hazard ratio for time to recurrence of any mood episode was 0.74 (95% CI = 0.42–1.28; Cox model P=ns; log-rank P=ns), representing a risk reduction of 26%. When valproate was the adjunctive treatment with lurasidone (N = 283), the hazard ratio for time to recurrence of any mood episode was 0.71 (95% CI = 0.42–1.18; Cox model P=ns; log-rank test P=ns), representing a risk reduction of 29%.

3.5. Time to recurrence of any mood episode by ascertainment method (retrospective vs. prospective) Time-to-recurrence of any mood disorder was also analyzed by ascertainment method: retrospective (treated on adequate doses of mood stabilizer at study entry) vs. prospective (treated prospectively with a mood stabilizer to achieve a therapeutic dose). In the retrospective group (N = 184), the hazard ratio for time to recurrence of any mood episode was 0.82 (95% CI= 0.43–1.55; Cox model P= ns; log-rank test P =ns), representing a risk reduction of 18%. In the prospective group (N =312), the hazard ratio for time to recurrence of any mood episode was 0.65 (95% CI= 0.40–1.05; Cox model P= 0.079; log-rank test P= 0.106), representing a risk reduction of 35%.

3.6.

Time to all-cause discontinuation

Treatment with lurasidone was significantly more effective than placebo in increasing time to all-cause discontinuation, with a hazard ratio of 0.72 (95% CI = 0.54–0.98; Cox model P= 0.034; log-rank test P =0.019), representing a risk reduction of 28%.

3.7. Time to recurrence of any mood episode: effect of lurasidone dose A post-hoc analysis was performed to examine the effect of treatment with a lower modal dose of lurasidone (20–40 mg/ d; n = 113) compared to a higher modal dose of lurasidone (60–80 mg/d; n= 133). For lurasidone modal doses of 20– 40 mg/d, the hazard ratio for time to recurrence of any mood episode was 0.68 (95% CI= 0.41–1.12; Cox model

Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013

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Table 2 Safety and tolerability parameters (safety population; open-label stabilization phase, and randomized, doubleblind phase). A. Adverse Events (incidence Z5%) Open-label Stabilization Phase

Randomized Double-blind Phase

Lurasidone (+ Lithium/ Valproate) (N=962)c

Lurasidone (+ Lithium/ Valproate) (N = 246)

Placebo (+ Lithium/ Valproate) (N =250)

Adverse event

N

%

Adverse event

N

%

N

%

One or more event Nausea Somnolencea Headache Akathisia Insomnia Parkinsonismb Vomiting Diarrhea

635 111 106 88 80 77 65 59 53

66.0 11.5 11.0 9.1 8.3 8.0 6.8 6.1 5.5

One or more event Weight increased Headache Parkinsonismb Nasopharyngitis Insomnia

153 24 21 20 15 9

62.2 9.8 8.5 8.1 6.1 3.7

151 13 18 14 12 16

60.4 5.2 7.2 5.6 4.8 6.4

B. Median Change in Laboratory Parameters From Open-label Stabilization Phase Baseline to Double-blind Endpoint (OC and LOCF) Lurasidone (+ Lithium/Valproate)

Placebo ( + Lithium/Valproate)

OC

OC

N Total cholesterol, mg/ dL LDL cholesterol, mg/dL HDL cholesterol, mg/dL Triglycerides, mg/dL Glucose, mg/dL HbA1c, % Insulin, mU/L HOMA-IR Prolactin, ng/mL Prolactin, Males Prolactin, Females

LOCF Median Change

N

Median Change

N

LOCF Median Change

N

Median Change

164

1.0

238

0.0

144

3.0

244

4.0

161 164 164 164 162 160 153 164 71 93

0.0 1.0 +5.0 1.0 0.0 0.1 0.02 0.5 0.04 0.6

236 236 238 238 236 237 226 236 103 133

0.0 1.0 +4.0 0.0 0.0 0.03 0.02 0.4 0.04 0.6

136 144 144 143 144 146 134 146 67 79

+0.5 1.0 +1.0 0.0 +0.1 0.3 0.02 0.7 0.4 1.3

237 244 244 244 243 243 230 244 105 139

0.0 1.0 7.0 0.0 0.0 0.1 0.01 1.0 0.7 2.4

OC: observed case analysis; LOCF: last observation carried forward analysis; both confirmed and non-confirmed fasting values are presented for metabolic parameters. HbA1c = glycosylated hemoglobin; LDL = low-density lipoprotein; HOMA-IR = homeostatic model assessment – IR a Somnolence: hypersomnia, sedation, somnolence. b Parkinsonism = drooling, extrapyramidal disorder, muscle rigidity, parkinsonism, psychomotor retardation, and tremor. c Randomized and non-randomized patients, combined.

P= ns; log-rank test Po0.05), representing a risk reduction of 32%. For lurasidone modal doses of 60–80 mg/d (n = 133), the hazard ratio for time to recurrence of any mood episode was 0.75 (95% CI= 0.48–1.17; Cox model P = ns; log-rank test P=ns), representing a risk reduction of 25%. The hazard ratio for time to recurrence of a depressive episode was 0.93 for the lower modal dose group, and 0.71 for the higher modal dose groups. The hazard ratio for time to recurrence of a manic, hypomanic, or mixed manic episode was 0.31 for

the lower modal dose group, and 0.80 for the higher modal dose groups.

3.8.

Time to recurrence: US vs. non-US regions

Time-to-recurrence of any mood disorder was also analyzed for patients treated in the US versus non-US regions. In the non-US group (N=347), the hazard ratio for time to recurrence of any

Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013

Maintenance lurasidone for bipolar disorder mood episode was 0.65 (95% CI=0.41–1.04; Cox model P=ns; log-rank test P=ns), representing a risk reduction of 35%. In the US group (N=149), the hazard ratio for time to recurrence of any mood episode was 0.85 (95% CI=0.46–1.61; Cox model P=ns; log-rank test P=ns), representing a risk reduction of 15%.

3.9. Depression and anxiety symptom severity outcomes Among randomized patients, notable improvement was observed in the open-label phase from Baseline to LOCFendpoint in the mean MADRS total score (18.2 to 4.0), the CGI-BP-S overall score (4.0 to 1.7), the YMRS total score (9.4 to 3.6), and the QIDS-SR16 (8.9 to 2.8). During double-blind treatment, LS mean changes from double-blind Baseline to Week 28 (or last visit) for the lurasidone and placebo groups, respectively, were as follows: MADRS total score ( + 1.5 vs + 1.8; P =ns); CGI-BP-S overall score ( + 0.15 vs + 0.19; P= ns); CGI-BP-S depression score (+ 0.14 vs + 0.22; P= ns); CGI-BP-S mania score (+ 0.02 vs + 0.12; P = ns); YMRS total score ( + 0.8 vs + 1.7; P= ns); and QIDS-SR16 score (+ 0.2 vs + 0.0; P= ns).

9 1.6% in the lurasidone and placebo groups, respectively, reported an EPS-related event; 6.5% in the lurasidone group and 3.6% in the placebo group received anticholinergic medication; the proportion treated with anxiolytics was 14.6% and 18.4%, respectively; and the proportion treated with sedatives and hypnotics was 10.2% and 10.0%, respectively. During the open-label phase, a mean weight increase of + 1.1 kg was reported prior to randomization; 9.9% of patients experienced a Z 7% increase in weight, and 3.7% experienced a Z7% decrease in weight. In the double-blind phase, mean weight gain was + 0.2 kg (+ 0.1 kg/m2 BMI; Z7% increase: 8.2%; Z7% decrease: 5.8%) in the lurasidone group and + 0.0 kg (+ 0.0 kg/m2 BMI; Z 7% increase: 4.0%; Z7% decrease: 5.2%) in the placebo group. There were no clinically meaningful lurasidone vs. placebo differences in change from open-label baseline to double-blind endpoint in laboratory measures of lipids, glycemic indices, or prolactin (Table 2-B). No patients in either the lurasidone or placebo groups had a QTcF interval Z450 ms, or an increase in QTcF Z60 ms at any time-point during either the open-label or double-blind phase.

4. 3.10.

Discussion

Safety and tolerability

Table 2-A summarizes the frequency of adverse events during the open-label stabilization and double-blind randomized withdrawal phases of treatment. The majority of patients reported experiencing at least one event in both the open-label (66.0%) and double-blind phases (lurasidone group, 62.2%; placebo group, 60.4%). During the open-label phase, 7.3% of patients rated an adverse event as “severe”, and 6.1% discontinued from the study due to an adverse event; during the double-blind phase, 5.3% and 4.0% of patients in the lurasidone and placebo groups, respectively, rated an event as “severe”, and 3.3% and 2.0% discontinued due to an adverse event (Figure 1). During the open-label phase, 41 patients (4.3%) experienced one or more serious adverse events (SAEs). In the double-blind phase, 13 patients in the lurasidone group (5.3%) and 11 patients in the placebo group (4.4%) reported experiencing one or more SAEs. There were no deaths in the study. Based on the C-SSRS, treatment-emergent suicidal ideation in the double-blind phase was reported in 11 patients (4.5%) in the lurasidone group and 16 patients (6.4%) in the placebo group; there were no completed suicides during any phase of the study. One patient in the lurasidone group reported active suicidal ideation with a specific plan and intent (score of “5” on the C-SSRS); the ideation resolved and the patient continued in the study. Extrapyramidal symptom-related events (EPS) were reported by 2.6% of patients in the open-label phase. Minimal changes were observed in movement disorder assessments (BARS, SARS and AIMS). 3.8% of patients received anticholinergic medication, 20.3% received an anxiolytic, and 14.6% received a sedative/hypnotic. Among patients in the double-blind phase, the proportion with worsening scores on the BARS, SARS and AIMS was low and was similar for the lurasidone and placebo groups. 2.0% and

This was a double-blind, placebo-controlled, randomized withdrawal study of lurasidone in combination with lithium or valproate in patients with bipolar disorder. The study consisted of an open-label stabilization phase (up to 20 weeks) followed by a 28-week, double-blind period with patients randomized to continue lurasidone, or switch to placebo (both in combination with lithium or valproate). Treatment with lurasidone reduced the probability of recurrence to any mood episode (the primary endpoint) by 29%, however, the reduction did not achieve statistical significance (P = 0.078). Two a priori secondary analyses were significant, time to recurrence of any mood episode for the subgroup that excluded rapid-cycling patients, and a sensitivity analysis of time to recurrence based on pre-specified depressive or manic symptom severity criteria (2 consecutive assessments with YMRS or MADRS Z 18, or a CGI-BP-S score Z 4). We also evaluated risk of all-cause study discontinuation as an indicator of overall effectiveness, finding a statistically significant 28% reduction in favor of lurasidone over placebo. A number of factors may have contributed to the failure to achieve significance on the primary time to recurrence endpoint. In the current study, utilization of a relatively short (6-month) randomized withdrawal period was associated with a low episode recurrence rate in the placebo group (26.1%). In contrast, previous recurrence prevention studies have typically utilized double-blind treatment periods of 12–24 months in duration, resulting in notably higher recurrence rates in the placebo group (Tohen et al., 2004; Vieta et al., 2008; Suppes et al., 2009; Marcus et al., 2011; Weisler et al., 2011). The power calculation for the current 6-month trial was based on two published recurrence prevention trials (Suppes et al., 2009; Bowden et al., 2010) that yielded episode recurrence rate estimates at 6 months of 24% and 39% for study drug and placebo, respectively. However, the observed recurrence rate of

Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013

10 any mood episode at 6 months in the current study was notably lower for placebo (26.1%) than the estimated 39% rate in the power calculation. Given the low recurrence rate in the placebo group, it is likely that sample sizes utilized were too low, even though the recurrence rate in the lurasidone group (20.9%) was similar to the interim 6month recurrence rates of 18.5% and 20.3% in previous positive maintenance trials of adjunctive atypical antipsychotic therapy in bipolar disorder (Suppes et al., 2009; Vieta et al., 2008). The recurrence rate of any manic episode was particularly low for both lurasidone and placebo (5.7% and 10.7%) in the current study suggesting that there was insufficient power to demonstrate significance for recurrence of mania, therefore weakening the power of the overall study result. An additional factor that may have contributed to the low recurrence rate in the placebo group, and the inability of the current study to detect a significant difference in time to recurrence for lurasidone versus placebo, was the low level of depressive and manic symptoms at randomization baseline (mean MADRS = 3.8; mean YMRS =2.5). Absence of prominent residual depressive and manic symptoms is associated with a delayed time to recurrence of manic and depressive episodes (Perlis et al., 2006). As a consequence, a 6-month double-blind treatment period may not have allowed sufficient time for a mood episode to recur in patients who had achieved substantial improvement in bipolar mood symptoms during open-label stabilization treatment with lurasidone adjunctive with a mood stabilizer. Dose of lurasidone may also have been a factor that contributed to the overall study results. The dose range of lurasidone utilized in the current study was 20–80 mg/d, the approved range at the time the study was initiated (Lurasidone USPI, 2014). Based on a population doseresponse analysis, there is evidence that lurasidone exhibits a linear dose-response in the acute treatment of bipolar depression, with greater efficacy in the 80–120 mg/d dosing range (Chapel et al., 2016). Furthermore, available research suggests that treatment of acute mania benefits from use of higher doses of atypical antipsychotics than are used for the treatment of acute bipolar depression (Vieta et al., 2010). More controlled research is needed to determine whether higher maintenance doses of atypical antipsychotic agents (including lurasidone), are required for effective prophylaxis of mania. Polarity of the index episode was also examined as a possible contributor to treatment outcome. Treatment with lurasidone was significantly effective in preventing the recurrence of any mood episode in patients with an index episode of depression, but not in patients with an index episode of mania (risk reduction, 43% vs. 18%). Lurasidone is approved for the acute treatment of bipolar depression, both as monotherapy and adjunctive therapy in the US and Canada (Latuda USPI; Health Canada product monograph). The current findings suggest that lurasidone is also effective for the longer-term maintenance treatment of patients presenting with bipolar depression. Of note, in patients in the current study with an index episode of depression,

J.R. Calabrese et al. treatment with lurasidone was associated with a 68% risk reduction recurrence of mania, suggesting a potentially clinically meaningful prophylactic effect. Results from the current maintenance study found a somewhat greater reduction in risk of recurrence (35% vs. 18%) among patients started on a mood stabilizer (prospectively) during the open-label stabilization phase of the current study compared with patients on long-term mood stabilizer therapy (retrospective). This may be due, in part, to the longer stabilization phase (12–20 weeks) prior to randomization to lurasidone or placebo which might attenuate any acute placebo effect. Among previously reported maintenance trials that examined the efficacy of adjunctive therapy with an atypical antipsychotic, only two studies of quetiapine (Suppes et al., 2009; Vieta et al., 2008) have included bipolar patients with index episodes of both mania and depression. Both quetiapine trials reported significant reduction in time to recurrence of any mood event compared with placebo. In contrast, maintenance adjunctive therapy trials with olanzapine (Tohen et al., 2004,, 2006,, 2010), ziprasidone (Bowden et al., 2010), aripiprazole (Marcus et al., 2011), and risperidone LAI (Macfadden et al., 2009) did not include patients with bipolar depression. Systematic reviews suggest that depression accounts for the preponderance of episode recurrences (Vázquez et al., 2015) and related disability over the longitudinal course of bipolar disorder (Judd et al., 2002), more studies are needed that evaluate the efficacy of maintenance therapy in patients presenting with bipolar depression episodes. The results of the current study suggest that lurasidone may be a useful treatment option to help address this need. In the current study, combination treatment with lurasidone and lithium or valproate was generally well-tolerated. Two adverse events occurred in the pre-randomization phase with a frequency Z 10% (nausea and somnolence). In a comparison of the lurasidone and placebo groups, NNH values for all adverse events occurring in the double-blind phase were 420, suggesting that lurasidone was welltolerated during maintenance therapy. Consistent with this, the frequency of discontinuation on lurasidone in the double-blind phase, both overall and due to adverse events was low (xx% and 3.3%, respectively), and was similar to placebo. The adverse event profile was consistent with previous studies of lurasidone (Citrome et al., 2012). The results of this study further confirm the relatively low potential for weight gain and dyslipidemia with lurasidone. Over the open-label phase (up to 24 weeks), modest increases were observed in body weight (mean, o1 kg). There was no difference between lurasidone and placebo at endpoint in body weight or BMI during the double-blind phase of treatment. Additionally, a similar proportion of patients in the lurasidone and placebo groups had a clinically significant (Z 7%) endpoint increase in weight (6.6% and 4.8%, respectively). Consistent with results from previous long-term studies in both schizophrenia and bipolar disorder (Ketter et al., 2016; Citrome et al., 2012; Citrome et al., 2013; Loebel et al., 2013a, 2013b) there were no clinically meaningful, treatment-emergent differences

Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013

Maintenance lurasidone for bipolar disorder

11

between lurasidone and placebo in total cholesterol, HDL, LDL, triglycerides, glucose, or HbA1c. Consistent with the results of a comprehensive review of prolactin effects among pharmacologic treatments of bipolar disorder (Pacchiarotti et al., 2015), minimal changes in prolactin levels were observed during combined therapy with lurasidone and lithium or valproate.

Partners, Lilly, Lundbeck, Otsuka, Scientia, Takeda, and Teva. He has received research support from NIH. Drs. Pikalov, Cucchiaro, Mao, and Loebel, and Ms. Streicher, are employees of Sunovion Pharmaceuticals Inc. Editorial support was provided by Edward Schweizer, MD, of Paladin Consulting Group, and was funded by Sunovion Pharmaceuticals Inc.

4.1.

Acknowledgement

Limitations

In addition to the limitations noted above (e.g., relatively short duration of maintenance treatment, use of relatively lower doses of lurasidone), the generalizability of current study results is limited by use of standardized entry criteria that only permitted inclusion of patients with minimal psychiatric and substance abuse comorbidity.

4.2.

Conclusions

In this double-blind study of patients with bipolar I disorder who had been stabilized on lurasidone in combination with lithium or valproate for up to 20 weeks, continued treatment with lurasidone was associated with a non-significant reduction in the probability of recurrence of any mood episode compared with placebo. Treatment with lurasidone was found to significantly reduce the probability of any mood episode recurrence in patients presenting with an index episode of depression. Long-term treatment with lurasidone combined with lithium or valproate was found to be safe and well-tolerated, with minimal effects on weight or metabolic parameters.

Role of Funding Source This study was funded by Sunovion Pharmaceuticals Inc. Sunovion contributed to data collection and data analysis. All authors jointly made the decision to submit the manuscript.

Contributors Drs. Loebel, Pikalov, Cucchiaro, and Calabrese contributed to the design of the study and the drafting of the protocol. Dr. Mao contributed to the statistical analysis of the data, and all authors contributed to the interpretation of the results. All authors contributed to the development and revision of the manuscript, and approved the final draft.

Conflict of interest Dr. Calabrese has received lecture honoraria through speaking engagements from AstraZeneca, Benecke, CME Outfitters, Dainippon Sumitomo Pharma, Elan, Forest, Health & Wellness Partners, Lundbeck, Medwiz, Otsuka, ProMedica, Spirant Communication Private Limitex, Sunovion, Takeda, Teva, and Wenckebach Institute, American Foundation Suicide Prevention, University of Florida, and Western Psychiatric Institute. He has acted as a consultant to Biomedical Development Corporation, Convergent Health Solutions, Dainippon Sumitomo Pharma, Elan, Forest, Health & Wellness

We thank the patients who participated in this treatment study, as well as the Investigators who participated.

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Please cite this article as: Calabrese, J.R., et al., Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.06.013