Journal of Psychiatric Research 53 (2014) 14e22

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A 6-week randomized, double-blind, placebo-controlled, comparator referenced trial of vabicaserin in acute schizophrenia Joan H.Q. Shen a, Yonggang Zhao b, Sharon Rosenzweig-Lipson c, Danielle Popp d, Janet B.W. Williams d, e, *, Earl Giller d, Michael J. Detke f, g, John M. Kane h, i a

Hengrui Medicine Co., Ltd, Shanghai, China Skyview Research, Pennsylvania, USA IVS Pharma Consulting, USA d MedAvante Inc, Hamilton, NJ, USA e College of Physicians and Surgeons, Columbia University, USA f Detke Biopharma Consulting LLC, Carmel, IN, USA g Indiana University School of Medicine, USA h The Zucker Hillside Hospital, Glen Oaks, NY, USA i The Albert Einstein College of Medicine, Bronx, NY, USA b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 8 February 2013 Received in revised form 28 January 2014 Accepted 13 February 2014

Vabicaserin, a potent 5-HT2C receptor agonist, decreases nucleus accumbens extracellular dopamine levels in rats, without affecting striatal dopamine, indicating mesolimbic selectivity. This is the first study of efficacy, safety and tolerability of vabicaserin in adults with acute schizophrenia. Three hundred fourteen hospitalized subjects were randomized to: Vabicaserin 200 or 400 mg/day, olanzapine 15 mg/ day or placebo. Central raters assessed the PANSS and CGI-S. Site raters performed the BPRS and CGI-I. Central rated PANSS Positive (PANSS-PPS) was the primary endpoint. Two hundred eighty-nine subjects were included in the mITT efficacy analysis. Vabicaserin was well tolerated with no major safety concerns. Olanzapine, but not vabicaserin, caused weight gain. Vabicaserin 200 mg/day and olanzapine demonstrated significant improvement at week 6 vs. placebo on PANSS-PSS. A non-significant decrease vs. placebo was observed for 400 mg/day. Both vabicaserin groups demonstrated significant improvement over baseline on PANSS Negative while placebo worsened. Vabicaserin 200 mg/day and olanzapine demonstrated significantly greater improvement over placebo on PANSS Total whereas 400 mg/day showed a trend toward improvement. There was no significant improvement vs. placebo for either vabicaserin group on site-rated BPRS. Vabicaserin 200 mg/day and olanzapine demonstrated significant improvement vs. placebo on CGI-I and CGI-S but not 400 mg/day vabicaserin. Vabicaserin demonstrated efficacy on primary and secondary endpoints at 200 mg/day, but not at 400 mg/day which showed a trend for efficacy. The 200 mg/day vabicaserin group achieved proof of concept using central ratings. Both vabicaserin doses were well tolerated with no significant safety signals and no weight gain. Trial Registration: clinicaltrials.gov. Identifier: NCT00265551. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Clinical trial Schizophrenia Vabicaserin Olanzapine Placebo Central rater

1. Introduction Vabicaserin hydrochloride is a novel 5-HT2C agonist; this class of compounds has therapeutic potential in a wide range of psychiatric disorders, as evidenced through a number of pre-clinical

* Corresponding author. SVP, Global Science, MedAvante, Inc., 100 American Metro Blvd. #106, Hamilton, NJ 08619, USA. Tel.: þ1 609 528 9472; fax: þ1 609 528 9401. E-mail address: [email protected] (J.B.W. Williams). http://dx.doi.org/10.1016/j.jpsychires.2014.02.012 0022-3956/Ó 2014 Elsevier Ltd. All rights reserved.

animal models (Siuciak et al., 2007; Wang et al., 2008). Unlike most agents currently developed for the treatment of schizophrenia, vabicaserin does not involve directly targeting dopamine receptors and has in vitro functional selectivity for 5-HT2C without impacting 5-HT2A or 5-HT2B receptors (Dunlop et al., 2011). Vabicaserin is effective in multiple animal models of antipsychotic activity including attenuation of apomorphine-induced climbing, decreased conditioned avoidance responding, reversal of PCP and amphetamine-induced hyperactivity, and is effective in prepulse inhibition (Marquis et al., 2006; Rosenzweig-Lipson et al., 2012).

J.H.Q. Shen et al. / Journal of Psychiatric Research 53 (2014) 14e22

Acute and chronic administration of vabicaserin decreases nucleus accumbens dopamine without affecting striatal dopamine, which is indicative of mesolimbic selectivity (Marquis et al., 2006; Rosenzweig-Lipson et al., 2012). This profile is consistent with potential efficacy in the treatment of psychotic symptoms of schizophrenia. Chronic administration of vabicaserin significantly decreases the number of spontaneously active mesocorticolimbic dopamine neurons without affecting nigrostriatal dopamine neurons, consistent with the effects of atypical antipsychotics (Rosenzweig-Lipson et al., 2012). Unlike atypical antipsychotics, acute administration of vabicaserin is also selective for mesocorticolimbic dopamine neurons, suggesting that this compound could have a rapid onset of action. Vabicaserin also increases medial prefrontal cortex glutamate and acetylcholine which is suggested to be associated with improvements in cognitive function (Rosenzweig-Lipson et al., 2007). Results from completed pre-clinical studies suggest that 5-HT2C agonists could be effective in improving mood disorders and cognitive impairments associated with schizophrenia, without producing extrapyramidal side effects or weight gain (RosenzweigLipson et al., 2012). Therefore, vabicaserin offers the possibility of a new antipsychotic medication with broader efficacy (e.g., cognitive symptoms) as well as improved safety and tolerability (Rosenzweig-Lipson et al., 2012; Shen et al., 2011a,b). This study aims to 1) examine the efficacy of vabicaserin hydrochloride in adult subjects with acute schizophrenia, and 2) compare two different methodological approaches (blinded independent central raters and traditional site raters) for the assessment of symptom severity in CNS clinical trials. This was the first randomized controlled trial to use central raters in a study of treatments for schizophrenia (Shen et al., 2008). 2. Methods 2.1. Subjects Adult subjects (n ¼ 289) with acute exacerbation of schizophrenia participated in a six-week randomized, double-blind, placebo-controlled, comparator-referenced, multicenter parallelgroup trial. Subjects included 209 men and 80 women ranging in age from 20 to 63 years (M ¼ 40.2, SD ¼ 10.3) at 32 sites located in the United States (n ¼ 28) and India (n ¼ 4). Subjects were predominately African American (64.4%; n ¼ 186), Caucasian (30.1%; n ¼ 87) or Asian (3.5%; n ¼ 10). Subjects’ mean height and weight at baseline were 173.8 cm and 90 kg. The study was conducted from December 2005 to April 2007. All subjects were hospitalized for acute schizophrenia (mean duration of current episode ¼ 108.0 days; SD ¼ 425.7). Subjects remained hospitalized for a minimum of 4 weeks during the double-blind phase of the study. Subjects were discharged from the hospital either after the day 28 assessment or scheduled evaluation thereafter, based on the investigator’s judgment and subject responses to the Readiness Discharge Questionnaire (Dunlop et al., 2011). 2.2. Inclusion/exclusion criteria In order to be included in the study, all subjects were required to have a PANSS total score  70 and 120, a PANSS Positive Symptoms Subscale score  20, and scores of 4 on at least two of the following PANSS items: delusions, conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content. Further, subjects must have had CGI-S scores  4 at both screening and baseline. Subjects were excluded for having a current Axis I primary psychiatric diagnosis other than schizophrenia, being considered a

15

significant suicide risk by the investigator or having a CDSS score of 3 on the suicide item. Subjects were also excluded for a current diagnosis or history of substance dependence. Further, subjects were not enrolled if they had used olanzapine within the past 30 days or had a known history of resistance to antipsychotic treatment. 2.3. Procedure The diagnosis of schizophrenia was made by site investigators using the Structured Clinical Interview for DSM-IV-TR (SCID; First et al., 2002). After a one-week washout period, subjects were assigned to 1 of 4 treatment arms: 200 mg/day vabicaserin (n ¼ 82), 400 mg/day vabicaserin (n ¼ 77), olanzapine 15 mg/day (active comparator; n ¼ 77), or placebo (n ¼ 77). Randomization was performed by the Legacy Wyeth T&RS Randomization System using blocked randomization (block size ¼ 4). The Legacy Wyeth Computerized Randomization/Enrollment (CORE) system was used to implement the random allocation sequence. The randomization statistician generated the random sequence, sites enrolled patients, and the Legacy Wyeth CORE system was used to assign participants to interventions. Subjects received morning and evening treatment at the same time each day, either with or without food depending on individual tolerability. The following adjunctive medications were permitted during the study for the control of agitation, insomnia or extrapyramidal symptoms: lorazepam, clorazepate dipotassium, benztropine, biperiden, trihexyphenidyl HCl, zaleplon, and zolpidem. Treatment with any other anxiolytics, antiparkinsonian agents, or sedative-hypnotics was prohibited. Additional prohibited treatments included: antidepressants, MAOIs, analgesics (opioid), anticonvulsants, electroconvulsive therapy, psychostimulants or sympathomimetics, psychotropic drugs or substances, psychotherapy, lithium, barbiturates, drugs known to influence dopamine or serotonin neurotransmission, and drugs known to prolong the QT/QTc interval. Independent central raters who were blinded to study design, inclusion criteria, and visit number administered the Structured Clinical Interview for the PANSS (SCI-PANSS; Kay et al., 1987) and the Clinical Global Impressions-Severity scale (CGI-S; Guy, 1976) remotely via live, videoconferencing at screening. A member of the site staff, who did not perform any efficacy assessments at that visit, remained in the room with the subject during the remote assessment. Interviews were conducted at baseline and each of the six weekly post-baseline visits (see Shen et al., 2008 for information on central raters’ education and experience). Several studies have demonstrated high reliability between face-to-face and videoconference administration of psychiatric scales in subjects with schizophrenia (e.g., Yoshino et al., 2001; Zarate et al., 1997). Central raters were provided information on the subject’s behavior from an informant who had observed the subject over the week prior to the interview. Typically, there was a different central rater at each visit. Central rater symptom severity assessments determined subject eligibility. After central raters completed their assessments, site raters performed the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962) and the CGI-I the same day. Site raters, blinded to treatment but unblinded to inclusion criteria, study design, and visit number (as is typical in double-blind studies) performed the BPRS to avoid subject fatigue associated with undergoing two consecutive PANSS interviews. To allow for comparisons between site and central raters, a BPRS total score was derived from the central raters’ PANSS assessment. The PANSS includes all items of the BPRS along with an additional 12 items designed to assess broader psychopathology (Furukawa et al., 2011). Derived BPRS

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scores were computed by summing the relevant 18 items from the PANSS: positive symptoms items 2 through 7, negative symptoms items 1 and 2, and items 1 through 10 of the general subscale. Derived BPRS scores can range from 18 to 126. Safety was assessed by physical examination, weight, and fasting laboratory assessments including liver function and lipid tests. Adverse events were recorded as spontaneously reported by subjects. The protocol for the current study was reviewed and approved by multiple institutional review boards including Western Institutional Review Board. Written informed consent was obtained from all study subjects before enrollment. Further, study data were reviewed regularly for significant trends or findings by an independent Data and Safety Monitoring Board (Shen et al., 2008).

statistic, controlling for pooled center for comparison between each of the vabicaserin groups and the placebo group. For the CMH tests, integer scores were used. All analyses were conducted on the a priori defined mITT population using LOCF data. Logistic regression was performed for the responder analyses with treatment and pooled center as factors.

2.4. Efficacy analyses

3. Results

The primary efficacy measure was the central rated Positive Symptoms Subscale of the PANSS. Secondary efficacy measures were central rated PANSS Total and Negative Symptoms Subscale scores, response rate defined as 20% decrease from baseline on PANSS Total score, derived BPRS and CGI-S, as well as site-rated BPRS and CGI-I. All analyses use the a priori determined Last Observation Carried Forward (LOCF) imputation method and were performed on the modified Intent-to-Treat (mITT) population which was defined a priori to include all randomly assigned subjects who completed at least one post-baseline severity assessment. If up to 20% of the individual item scores were missing on the PANSS or BPRS, missing scores were replaced with the mean of the remaining items before computing total or subscale scores. If greater than 20% were missing the total score remained missing. Prospectively defined Analyses of Covariance (ANCOVA) with treatment and pooled center as factors and baseline scores as covariates were conducted on the primary efficacy measure (PANSS Positive Subscale) and the following secondary efficacy measures: PANSS Negative Subscale, PANSS Total Score, CGI-S and BPRS Score. Pairwise comparisons (t-tests) were performed between each vabicaserin group and placebo at each of the six weekly postbaseline visits. Separate comparisons between olanzapine and placebo were performed. CGI-I scores were analyzed with the generalized CochraneManteleHaenszel (CMH) mean score

There were no statistically significant differences between treatment groups on baseline demographics or characteristics (all p’s > 0.05; Table 1). The rates of discontinuation in this study were high (>50% on all four groups) with the placebo group the highest (70.1%), followed by 400 mg/day vabicaserin treatment (64.9%), 200 mg/day vabicaserin treatment (59.8%) and 15 mg/day olanzapine (51.9%).

2.5. Safety analyses Mean changes from baseline on physical characteristics and laboratory values within and across treatment groups were analyzed using paired t-tests (unadjusted for multiple comparisons).

3.1. Primary efficacy measure Central Rated PANSS Positive Symptoms Subscale (CR-PSS). Table 2 presents results of the LOCF ANCOVA for CR-PSS. Change from baseline in CR-PSS for 200 mg/day vabicaserin was statistically significantly greater than placebo at all post-baseline visits (all p’s < 0.030; Fig. 1). Change from baseline to week 6 was 4.22 (SE ¼ 0.76; p ¼ 0.030). The effect size (ES) for baseline to week 6 change in the 200 mg/day vabicaserin group was 0.36. Decreases in CR-PSS score from baseline were observed at every time point for the 400 mg/day dose of vabicaserin but were not significantly different from placebo (all p’s > 0.361; week 6 ES ¼ 0.09). The change from baseline in mean CR-PSS score for olanzapine was statistically significantly greater than placebo at every time point (all p’s < 0.009). Change from baseline to week 6 for olanzapine was 4.97 (SE ¼ 0.78; week 6 ES ¼ 0.50).

Table 1 Demographic and baseline characteristics (mITT population). Characteristic

p-Value

Treatment group Placebo (n ¼ 71)

Age: M (SD)

0.475

Sex: N (%) Male Female

0.425

Race: N (%) American Indian or Alaskan Native Asian Black or African American Hispanic Hispanic origin Mix Other White Mexican

0.513

Height (cm): M (SD) Weight (kg): M (SD) Duration of current episode (days): M (SD)

0.173 0.312 0.900

Vabicaserin 200 mg/day (n ¼ 77)

Vabicaserin 400 mg/day (n ¼ 70)

Olanzapine 15 mg/day (n ¼ 71)

Total (n ¼ 289)

39.6 (10.4)

39.3 (10.2)

41.8 (10.2)

40.1 (10.5)

40.2 (10.3)

52 (73.3) 19 (26.8)

58 (75.3) 19 (24.7)

53 (75.7) 17 (24.3)

46 (64.8) 25 (35.2)

209 (72.3) 80 (27.7)

0 3 48 0 1 1 0 17 1

0 2 48 0 0 0 0 27 0

0 1 43 1 0 0 1 24 0

1 4 47 0 0 0 0 19 0

1 10 186 1 1 1 1 87 1

(0) (4.3) (67.6) (0) (1.4) (1.4) (0) (23.9) (1.4)

173.3 (9.5) 86.0 (21.3) 95.9 (325.9)

(0) (2.6) (62.3) (0) (0) (0) (0) (35.1) (0)

175.5 (9.4) 89.4 (21.8) 135.0 (652.0)

(0) (1.4) (61.4) (1.4) (0) (0) (1.4) (34.3) (0)

174.2 (9.2) 92.8 (24.8) 84.2 (126.3)

(1.4) (5.6) (66.2) (0) (0) (0) (0) (26.8) (0)

172.1 (10.1) 92.1 (27.3) 114.4 (398.4)

(0.35) (3.5) (64.4) (0.35) (0.35) (0.35) (0.35) (30.1) (0.35)

173.8 (9.6) 90.0 (23.9) 108.0 (425.7)

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Table 2 Central and site rated secondary efficacy measures (ANCOVA). Placebo

Vabicaserin 200 mg/day

Vabicaserin 400 mg/day

Olanzapine 15 mg

25.74 (4.08) 1.86 (0.79)

25.97 (4.00) 4.22 (0.76) 0.03

26.56 (4.04) 2.13 (0.80) 0.80

26.48 (4.47) 4.97 (0.78) 0.01

PANSS total score Baseline mean (SD) Mean D baseline to week 6 (SE) p-Value vs. placebo

94.72 (10.21) 2.7 (2.44)

94.45 (12.07) 11.3 (2.35) 0.011

95.14 (10.30) 8.6 (2.47) 0.085

94.52 (11.67) 14.7 (2.40) 0.111). Change from baseline for the olanzapine group was significant at all six post-baseline visits (all p’s < 0.013). 3.2.2. Site rated BPRS (SR-BPRS). There were no statistically significant differences in change from baseline vs. placebo for either vabicaserin group at any time point (all p’s > 0.253; Fig. 2D). Effect sizes at week 6 were 0.03 and 0.14 for the 200 mg/day and 400 mg/day vabicaserin groups, respectively. Change from baseline for olanzapine was statistically significantly greater than placebo at every time point (all p’s < 0.011; ES ¼ 0.43).

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Fig. 2. Adjusted mean change from baseline: secondary efficacy measures.

CGI-I (SR-CGI-I). CGI-I scores for the 200 mg/day vabicaserin group were significantly lower (i.e., improved) than for those in the placebo group at week 5 (p ¼ 0.023) and week 6 (p ¼ 0.025). CGI-I scores for the 400 mg/day vabicaserin group were not statistically significantly different from placebo at any time point. CGI-I scores were significantly lower for the olanzapine group than for those in the placebo group at every time point (all p’s < 0.005). 3.3. Safety evaluation The safety population consists of all randomly assigned subjects who took at least one dose of study medication. 3.3.1. Deaths No deaths occurred during the study. 3.3.2. Adverse events (AEs) Adverse events (AEs) were reported during the study by 90.2% subjects in the 200 mg/day vabicaserin group (n ¼ 74), 88.3% of the 400 mg/day vabicaserin group (n ¼ 68), 89.6% of the olanzapine group (n ¼ 69) and 90.9% of subjects in the placebo group (n ¼ 70). The most common treatment emergent adverse events (TEAEs) reported in the vabicaserin doses were dyspepsia and headache. Dyspepsia (13.4% 200 mg/day; 16.9% 400 mg/day) and diarrhea (8.5% 200 mg/day; 5.2% 400 mg/day) were the only TEAEs that were reported for both vabicaserin doses at a rate that was at least 5% and 2 times greater than the rate in placebo (dyspepsia: 5.2%; diarrhea: 2.6%). Table 3 presents all TEAEs occurring in greater than 5% of subjects in any treatment group. Except for diarrhea, stomach discomfort, toothache and musculoskeletal pain, all of these TEAEs were observed in similar rates in the placebo group.

Subjects in the olanzapine group had similar frequencies of dyspepsia and headache as the subjects in the vabicaserin groups and more frequently reported increased weight, sedation, somnolence, dry mouth, dizziness, increased appetite, chest pain, toothache, diarrhea and fatigue than the vabicaserin and placebo groups. In all of the treatment groups, the majority of TEAEs were mild or moderate in severity. None of the dyspepsia events were reported as severe. Most events of diarrhea were mild or moderate in intensity; 1 of 82 (1.2%) subjects in the 200 mg/day group had severe diarrhea. A total of 20 (6.4%) subjects reported at least 1 severe TEAE including 7.3% (n ¼ 6) in the 200 mg/day vabicaserin group, 9.1% (n ¼ 7) in the 400 mg/day vabicaserin group, 5.2% (n ¼ 4) in the olanzapine group and 3.9% (n ¼ 3) of subjects in the placebo group. For the vabicaserin groups, most of the severe TEAEs were reported at low frequencies (1 or 2 subjects for each TEAE) and were similar in frequency to the olanzapine and placebo groups. Most of the events resolved with concomitant treatment. 3.3.3. Serious adverse events (SAEs) SAEs were reported in 6 subjects who received vabicaserin 200 mg/day, 7 who received vabicaserin 400 mg/day, 7 who received placebo, and 4 who received olanzapine. Table 4 presents SAEs by treatment group. The majority of SAEs in vabicaserintreated subjects were considered not related to the use of study medication, and most of the events resolved. Three subjects treated with vabicaserin had SAEs that were considered related to test article by the investigator. Two of them withdrew from the study because of treatment-related SAEs. 3.3.4. Physical characteristics and laboratory values There were no statistically significant changes from baseline to week 6 for either vabicaserin group on weight, waist circumference,

J.H.Q. Shen et al. / Journal of Psychiatric Research 53 (2014) 14e22

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Table 3 Incidence of treatment emergent adverse events occurring in 5% of any treatment group: N (%). System organ class

Placebo (n ¼ 77)

200 mg/day Vabicaserin (n ¼ 82)

400 mg/day Vabicaserin (n ¼ 77)

15 mg/day Olanzapine (n ¼ 77)

Total (n ¼ 313)

Any adverse event

64 (83.1)

63 (76.8)

59 (76.6)

64 (83.1)

250 (79.9)

6 7 3 11 8 3 4 1

8 4 2 13 6 4 4 4

3 7 8 11 4 2 6 2

Gastrointestinal disorders Constipation Diarrhea Dry mouth Dyspepsia Nausea Stomach discomfort Toothache Vomiting

5 2 2 4 4 2 2 5

General disorders Chest pain Fatigue

1 (1.3) 1 (1.3

0 (0) 3 (3.7)

2 (2.6) 1 (1.3)

4 (5.2) 4 (5.2)

7 (2.2) 9 (2.9)

Investigations Weight increased

2 (2.6)

1 (1.2)

2 (2.6)

10 (13.0)

15 (4.8)

Metabolism and nutrition disorders Increased appetite 2 (2.6)

2 (2.4)

1 (1.3)

5 (6.5)

10 (3.2)

Musculoskeletal and connective tissue disorders Muscle spasms 4 (5.2) Musculoskeletal pain 1 (1.3) Pain in extremity 3 (3.9)

1 (1.2) 0 (0) 1 (1.2)

4 (5.2) 5 (6.5) 5 (6.5)

1 (1.3) 1 (1.3) 5 (6.5)

10 (3.2) 7 (2.2) 14 (4.5)

Nervous system disorders Dizziness Headache Sedation Somnolence

1 10 7 4

(6.5) (2.6) (2.6) (5.2) (5.2) (2.6 (2.6) (6.5)

(1.3) (13.0) (9.1) (5.2)

1 18 5 1

(7.3) (8.5) (3.7) (13.4) (9.8) (3.7) (4.9) (1.2)

(1.2) (20.7) (6.1) (1.2)

3 14 5 2

(10.4) (5.2) (2.6) (16.9) (7.8) (5.2) (5.2) (5.4)

(3.9) (18.2) (6.5) (2.6)

7 15 15 8

(3.9) (9.1) (10.4) (14.3) (5.2) (2.6) (7.8) (2.6)

(9.1) (19.5) (19.5) (10.4)

22 20 15 39 22 11 16 12

12 56 32 15

(7.0) (6.4) (4.8) (12.5) (7.0) (3.5) (5.1) (3.8)

(3.8) (17.9) (10.2) (4.8)

Psychiatric disorders Agitation Insomnia Psychotic disorder

6 (7.8) 5 (6.5) 6 (7.8)

5 (6.1) 4 (4.9) 2 (2.4)

4 (5.2) 4 (5.2) 5 (6.6)

1 (1.3) 3 (3.9) 3 (3.9)

16 (5.1) 16 (5.1) 16 (5.1)

Respiratory disorders Cough

4 (5.2)

3 (3.7)

5 (6.5)

1 (1.3)

13 (4.2)

hip circumference, fasting glucose, liver function or any lipid test except for fasting high-density lipoprotein (HDL) which decreased significantly in all groups (p’s < 0.05, Table 5). Further, neither vabicaserin group was statistically significantly different from placebo on baseline to week 6 changes for any physical characteristic or laboratory values. Subjects taking olanzapine had statistically significant increases in weight, waist and hip circumference (all p’s < 0.01). These subjects had statistically significantly greater weight gain and increased waist circumference than placebo and either vabicaserin group (all p’s < 0.001) and greater increases in hip circumference than placebo and the 200 mg vabicaserin group. Further, subjects in the olanzapine group had the greatest incidence of weight gain 7% of their bodyweight (29.4%; 20 out of 68 subjects tested in safety population), followed by the placebo group (10.8%; 7/65), 400 mg/ day vabicaserin (4.6%; 3/65) and 200 mg/day vabicaserin (6.0%; 4/ 67). In addition, subjects taking olanzapine had statistically significant increases from baseline to week 6 on glucose, SGOT/AST, SGTP/ SLT, fasting triglycerides, fasting total cholesterol and fasting lowdensity lipoprotein (LDL) as well as a statistically significant decrease in HDL (all p’s < 0.05). Increases from baseline in glucose, SGOT/AST, SGPT/ALT, fasting triglycerides and fasting total cholesterol were statistically significantly greater in the olanzapine group

than for placebo and each of the vabicaserin groups (all p’s < 0.05). The decrease in HDL on olanzapine was statistically significantly greater than for placebo and each of the vabicaserin groups (all p’s < 0.05). Finally, mean GGT and bilirubin levels did not significantly change from baseline to week 6 either within or across any of the groups. Incidence of laboratory values of potential clinical importance (PCI) for glucose, SGOT/AST, SGPT/ALT, GGT, fasting total cholesterol and fasting triglyceride are presented in Table 6. The only significant between-group difference in PCI laboratory results concerned SGPT/ALT increases (p ¼ 0.022); subjects in the olanzapine group (17.3%) and placebo group (10.5%) more frequently experienced increases in SGPT/ALT than subjects in the 200 mg/day (3.8%) and 400 mg/day (5.4%) vabicaserin groups. 4. Discussion In the first randomized, double-blind, placebo-controlled, comparator-referenced, multicenter, parallel-group study of vabicaserin for the treatment of schizophrenia, statistically significant efficacy was observed for the 200 mg/day vabicaserin group as compared to placebo at every time point on the primary efficacy variable (CR-PSS) when assessed by blinded independent central

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Table 4 Incidence of serious adverse events: N (%). System organ class

Placebo (n ¼ 77)

200 mg/day Vabicaserin (n ¼ 82)

400 mg/day Vabicaserin (n ¼ 77)

15 mg/day Olanzapine (n ¼ 77)

Total (n ¼ 313)

Any serious adverse event

7 (9.1)

6 (8.5)

7 (9.1)

4 (5.2)

24 (7.7)

Cardiac disorders Supraventricular tachycardia

e

e

1 (1.3)

e

1 (0.3)

Gastrointestinal disorders Esophagitis Gastrointestinal hemorrhage

e e

e e

1 (1.3) 1 (1.3)

e e

1 (0.3) 1 (0.3)

General disorders Chest pain

e

e

1 (1.3)

e

1 (0.3)

Infections and infestations Subcutaneous abscess

1 (1.3)

e

e

e

1 (0.3)

Injury, poisoning, and procedural complications Overdose e

1 (1.2)

e

e

1 (0.3)

Metabolism and nutrition disorders Diabetes mellitus

e

e

1 (1.3)

1 (0.3)

Nervous system disorders Sedation

e

1 (1.2)

e

e

1 (0.3)

Psychiatric disorders Agitation Confusional state Homicidal ideation Psychotic disorder Schizophrenia Suicidal ideation

1 (1.3) e e 4 (5.2) e e

e 1 (1.2) 1 (1.2) 1 (1.2) 1 (1.2) 1 (1.2)

e e 1 (1.3) 3 (3.9) 1 (1.3) e

e e e 1 (1.3) e 1 (1.3)

1 1 2 9 2 2

Renal and urinary disorders Renal failure

e

e

1 (1.3)

e

1 (0.3)

Respiratory disorders Asthma

1 (1.3)

e

e

1 (1.3)

2 (0.6)

Social circumstances Substance abuse

1 (1.3)

e

e

e

1 (0.3)

Vascular disorders Hypertension

e

1 (1.2)

e

e

1 (0.3)

raters. There was also statistically significant efficacy at week 6 compared to placebo for change from baseline on the CR-Total, CRNSS score and CR-CGI-S score. Efficacy was observed for the 400 mg/day dose on the CR-NSS starting at week 3 and every week thereafter, with a moderate effect size of 0.41 for baseline to week 6 change. Further, results for the 400 mg/day dose were trending toward separation on the central rated PANSS total (p ¼ 0.085). The 200 mg/day vabicaserin group achieved proof of concept in treating adults with acute schizophrenia using central ratings. Since vabicaserin is an agonist, it is very possible that higher doses would be less effective than an intermediate dose, since over-stimulation of the receptor may lead to negative consequences. Antagonists, on the other hand, usually do not show this type of inverted-U-shaped doseeresponse curve, because complete blockade of a receptor (as compared to typical blockade of perhaps 50e90% required for efficacy) may not lead to any negative consequences. Vabicaserin was well tolerated and no major safety concerns were identified. In contrast to the central rated results, there was no signal at either dose of vabicaserin at any time point on the BPRS in ratings by site raters, although a signal was detected for olanzapine, as well as a signal on the CGI-I for vabicaserin and olanzapine. It should be

(0.3) (0.3) (0.6) (2.9) (0.6) (0.6)

noted that subject eligibility based on severity was determined solely by central rater scores at screening and baseline. Therefore, differences in efficacy measurement between site and central raters are not the result of subject selection but are due to differences in post-baseline symptom severity measurement. While the comparison between methodologies has limitations (e.g., scales differed by methodology), standardized effect sizes can be used to compare the magnitude of difference in baseline to endpoint change between the two methodologies. For example, for the 200 mg/day vabicaserin group central raters observed effect sizes of 0.36 (CR-PSS), 0.46 (CR-NSS), and 0.38 (CR-Total). For the BPRS, site raters observed an effect size of 0.03 for the 200 mg/day group while central raters observed an effect size of 0.23 on the derived BPRS. In addition to the use of multiple scales, there are several limitations to the methodological interpretations of the current study. First, there may have been an order effect in that central raters always performed their assessments first. It is possible that subjects were fatigued and reported fewer symptoms to site raters overall. Second, although subject eligibility based on symptom severity was determined by central rater assessments, diagnosis was

J.H.Q. Shen et al. / Journal of Psychiatric Research 53 (2014) 14e22

21

Table 5 Physical characters and laboratory tests: mean change from baseline to week 6 within and across groups: mean (SD). Placebo (n ¼ 77) Physical characteristics Weight (kg) Waist (cm) Hip (cm)

200 mg/day Vabicaserin (n ¼ 82)

400 mg/day Vabicaserin (n ¼ 77)

15 mg/day Olanzapine (n ¼ 77)

1.30 (4.58) 0.55 (6.61) 0.61 (4.02)

1.25 (3.78) 0.37 (6.04) 1.18 (4.96)

0.39 (4.01) 0.64 (8.31) 1.53 (5.40)

5.34 (5.09)***; xxx; yyy; 4.94 (6.80)***; x; yy; zz 4.47 (8.43)**; xxx; y

Blood chemistry Fasting glucose (mmol/L)

0.03 (0.64)

0.03 (0.54)

0.16 (0.75)

0.59 (1.31)*;

Liver function SGOT/AST (mU/mL) SGPT/ALT (mU/mL) GGT (mU/mL)

1.6 (8.2) 1.5 (22.8) 3.0 (25.9)

0.8 (8.5) 0.4 (10.1) 3.9 (15.5)

2.5 (7.2) 1.9 (12.6) 4.9 (20.4)

4.6 (12.7)*; 8.5 (20.9)*; 5.7 (22.9)

Lipids Fasting triglyceride (mmol/L) Fasting total cholesterol (mmol/L) Fasting LDL cholesterol (mmol/L) Fasting HDL cholesterol (mmol/L) Bilirubin (mmol/L)

0.1437 0.093 0.291 0.248 0.74

(0.7973) (0.974) (0.890) (0.364)** (5.99)

0.0307 0.021 0.133 0.079 0.32

0.2503 0.036 0.157 0.081 0.31

(0.7318) (0.664) (0.539) (0.180)** (2.40)

(0.9421) (0.709) (0.519) (0.176)* (2.98)

0.2986 0.463 0.408 0.093 0.45

zzz

x; y; zz

xxx; yy; zz xx; yy; zz

(0.8499)*; xxx; yy; (1.037)*; x; y; z (0.904)* (0.271)*; x;y; zz (2.05)

zzz

Note: within treatment: *p < 0.05; **p < 0.01; ***p < 0.001. Across treatment: Vs. Placebo: xp < 0.05; xxp < 0.01; xxxp < 0.001. Vs. Vabicaserin 200 mg/day: yp < 0.05; yyp < 0.01; yyyp < 0.001. Vs. Vabicaserin 400 mg/day: zp < 0.05; zzp < 0.01; zzzp < 0.001.

determined by site raters. Third, there was considerable subject drop-out over the course of the study (62.62%). Retention rates were likely negatively affected by the number of subjects who were discharged prior to the end of the study making follow-up difficult. Fourth, it is possible that the central rated results represent a Type I error or false positive. However, the results were replicated across several efficacy measures including the PANSS total and subscale scores, and CGI-S. The pattern of results was also replicated in the statistically significant site-rated CGI-I results. In addition, effect sizes for many of the efficacy measures were quite robust. Alternatively, it is possible that the site rater results represent a Type II error or false negative. Although olanzapine was statistically significantly different from placebo on the site-rated BPRS it is possible this was the result of functional unblinding which can occur when a drug is associated with adverse events that may unblind raters as to treatment allocation. In this study, subjects on olanzapine reported increased appetite, sedation and fatigue more frequently than subjects in the vabicaserin or placebo group. It is possible that these reports, coupled with statistical weight gain in

the olanzapine group, may have unblinded site raters. It should be noted that functional unblinding would be less likely with central raters as employed here, for two reasons. First, central raters did not assess AEs, and second, there was typically a different central rater at each visit and therefore it was unlikely that they would observe an effect such as weight gain over time. Finally, it is possible that olanzapine produced a stronger efficacy signal which may be evident in the larger effect sizes for olanzapine across outcome measures. We recognized that one of the limitations of this study was the high drop-out rate, which might have confounded the interpretation of efficacy when LOCF was used for missing data imputation. On the other hand, the fact that the highest drop-out rate occurred in the placebo group could be additional support for the treatment benefit of vabicaserin and olanzapine. Regardless, it is important to better control the drop-out rate, especially those from “subject request” in future studies for more accurate data computation and interpretations. A follow-up study of the efficacy of vabicaserin in acute schizophrenia using site raters for both subject inclusion and the primary efficacy outcome was stopped for

Table 6 Number (%) of subjects with laboratory test results of potential clinical importance on-therapy/number tested-safety population. Criteria: SI units

Overall p-valuea

Placebo

200 mg/day Vabicaserin

400 mg/day Vabicaserin

15 mg/day Olanzapine

>0.83 mmol/L above ULN (fasting) or >5.0 mmol/L above ULN (nonfasting) >0.83 mmol/L below LLN (fasting) or >0.56 mmol/L below LLN (nonfasting)

0.224

6/76 (7.9)

6/79 (7.6)

11/74 (14.9)

12/75 (16.0)

0.612

0/76 (0.0)

1/79 (1.3)

1/74 (1.4)

2/75 (2.7)

Liver function SGOT/AST (mU/mL) SGPT/ALT (mU/mL) GGT (mU/mL)

>2  ULN >2  ULN >3  ULN

0.435 0.022* 0.699

3/76 (3.9) 7/76 (10.5) 3/76 (3.9)

3/78 (3.8) 3/79 (3.8) 1/79 (1.3)

1/74 (1.4) 4/74 (5.4) 3/75 (4.0)

5/75 (6.7) 13/75 (17.3) 2/75 (2.7)

Lipids Fasting triglyceride (mmol/L) Fasting total cholesterol (mmol/L)

>3.39 mmol/L >7.77 mmol/L

0.249 0.485

7/76 (9.2) 4/76 (5.3)

8/79 (10.1) 1/79 (1.3)

7/75 (9.3) 2/75 (2.7)

14/75 (18.7) 3/75 (4.0)

Blood chemistry Glucose (mmol/L)

a

Overall p-value: Fisher’s Exact Test (2-tail); *p < 0.05; **p < 0.01; ***p < 0.001; ULN ¼ upper limit of normal; LLN ¼ lower limit of normal.

22

J.H.Q. Shen et al. / Journal of Psychiatric Research 53 (2014) 14e22

futility (Shen et al., 2011a,b). The active comparator, risperidone, did not separate from placebo at any time point limiting its usefulness for interpreting Type I or Type II errors in the current study. Overall, these results provide support for the efficacy, safety and tolerability of vabicaserin in the treatment of adults with acute schizophrenia, and for the use of blinded independent central raters to increase signal detection in CNS clinical trials. Contributors Dr. Shen contributed to the conception and design of the study, the acquisition and interpretation of data, and revised and approved the final version of the manuscript. Dr. Zhao contributed to the conception and design of the study, the analysis and interpretation of data, and revised and approved the final version of the manuscript. Dr. Rosenzweig-Lipson contributed to the conception and design of the study, the acquisition and interpretation of data, and revised and approved the final version of the manuscript. Dr. Popp contributed to the analysis and interpretation of data, drafted the initial manuscript, revised the manuscript in accordance with reviewers’ comments, and revised and approved the final version of the manuscript. Dr. Williams contributed to the acquisition and interpretation of data, and revised and approved the final version of the manuscript. Dr. Giller contributed to the interpretation of data, and revised and approved the final version of the manuscript. Dr. Detke contributed to the interpretation of data, and revised and approved the final version of the manuscript. Dr. Kane contributed to the conception and design of the study, acquisition and interpretation of data, and revised and approved the final version of the manuscript. Role of funding source This study was supported by legacy Wyeth, now part of Pfizer, Inc. Conflict of interest Dr. Shen reports being an employee of Hengrui Medicine Company and a former Wyeth/Pfizer employee. Dr. Zhao reports being a former Wyeth/Pfizer employee and owner of Pfizer stocks. Dr. Rosenzweig-Lipson reports being a former Wyeth/Pfizer employee and disclosed consulting fees from AgeneBio, Shire, Confluence, Vivia, and Abbott. Dr. Popp reports being a former employee of MedAvante, Inc. Dr. Williams disclosed royalties from licensing of rating scales and reports being a MedAvante, Inc. employee with stock options. Dr. Giller reports being a consultant at MedAvante, Inc. Dr. Detke reports being a former employee and major stockholder of MedAvante, a current employee of Detke Biopharma Consulting LLC, and disclosed the provision of expert testimony for Eli Lilly and fees for consultation and participation on advisory boards for MedAvante, NIH, Roche, Sonkei, Rhine Pharmaceuticals, Columbia NW Pharmaceuticals, Embera Neurotherapeutics, Alkermes, Cerecor, Edgemont, Naurex, Neurometrix, Omeros, and Tal. Lastly, Dr. Kane has received honorarium for consulting, participation in advisory boards or lecturing from

Alkermes, Amgen, Astra Zeneca, BMS, Boehringer, Eli Lilly, Esai, Forest Labs, Intracellular Therapeutics, Janssen, Jazz, Johnson & Johnson, Lilly, Lundbeck, Merck, Myriad, Novartis, Organon, Otsuka, Pfizer, Pierre Fabre, Proteus, Rules Based Medicine, Shire, Sunovion, Targacept, and is a shareholder of MedAvante. Acknowledgments We would like to thank all of the patients who participated in this study and their families/caregivers, investigators, study coordinators and operational staff. This study was supported by legacy Wyeth, now part of Pfizer Inc. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.jpsychires.2014.02.012. References Dunlop J, Watts SW, Barrett JE, Coupet J, Harrison B, Mazandarani H, et al. Characterization of vabicaserin (SCA-136), a selective 5-hydroxytryptamine 2C receptor agonist. J Pharmacol Exp Ther 2011;337:673e80. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition. (SCID-I/P). New York: Biometrics Research, New York State Psychiatric Institute; 2002. Furukawa TA, Akechi T, Wagenpfeil S, Leucht S. Relative indices of treatment effect may be constant across definitions of response in schizophrenia trials. Schizophr Res 2011;126:212e9. Guy W. Clinical global impressions. In: ECDEU assessment manual for psychopharmacology. Rockville: National Institute of Mental Health; 1976. pp. 218e22. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261e76. Marquis KL, Dunlop J, Ramamoorhy S, Beyer CE, Lin Q, Brennan J, et al. SCA-136, a novel 5-HT2C receptor agonist possessing atypical antipsychotic-like effects in preclinical models. Soc Neurosci 2006;934. Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep 1962;10:799e 812. Rosenzweig-Lipson S, Beyer C, Hughes Z, Lin Q, Zhang M-Y, Grauer S, et al. Vabicaserin: effects of a novel 5-HT2C agonist on prefrontal cortical neurotransmission, cognition and sensorimotor gating. J Eur Coll Neuropsychopharmacol 2007;17(Suppl. 4):S484. Rosenzweig-Lipson S, Comery TA, Marquis KL, Gross J, Dunlop J. 5-HT(2C) agonists as therapeutics for the treatment of schizophrenia. Handb Exp Pharmacol 2012;213:147e65. Shen J, Kobak KA, Zhao Y, Alexander MM, Kane JM. Use of remote centralized raters via live 2-way video in a multicenter clinical trial for schizophrenia. J Clin Psychopharmacol 2008;28:691e3. Shen J, Preskorn S, Dragalin V, Slomkowski M, Padmanabhan SK, Fardipour P, et al. How adaptive trial designs can increase efficiency in psychiatric drug development: a case study. Innov Clin Neurosci 2011a;8(7):26e34. Shen J, Zhao Y, Rosenzweig-Lipson S, Popp D, Williams JBW, Giller E, et al. A 6-week randomized, double-blind, placebo-controlled, comparator referenced, multicenter trial of vabicaserin in subjects with acute exacerbation of schizophrenia. Neuropsychopharmacology 2011b;36:S60. Siuciak JA, Chapin DS, McCarthy SA, Guanowsky V, Brown J, Chiang P, et al. CP809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity. Neuropharmacology 2007;52:279e90. Wang R, Xu Y, Wu HL, Li YB, Li YH, Guo JB, et al. The antidepressant effects of curcumin in the forced swimming test involve 5-HT1 and 5-HT2 receptors. Eur J Pharmacol 2008;578:43e50. Yoshino A, Shigemura J, Kobayashi Y, Nomura S, Shishikura K, Den R, et al. Telepsychiatry: assessment of televideo psychiatric review reliability with presentand next-generation internet infrastructures. Acta Psychiatr Scand 2001;104: 223e6. Zarate Jr CA, Weinstock L, Cukor P, Moranito C, Leahy L, Burns C, et al. Applicability of telemedicine for assessing patients with schizophrenia: acceptance and reliability. J Clin Psychiatry 1997;58:22e5.