A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of Vilazodone in Adolescents with Major Depressive Disorder

This was a 10-week, double-blind, randomized, placebo-controlled, parallel-group, fixed-dose study of vilazodone 15 mg/day or 30 mg/day in adolescent patients with MDD (NCT01878292). The study comprised a 1-week screening period, followed by an 8-week double-blind treatment period, and a 1-week double-blind down-taper period.

Male and female patients aged 12–17 years with a diagnosis of MDD for a minimum of 6 weeks were included in the study; diagnosis was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) [16] criteria. To ensure an accurate MDD diagnosis, the Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime (K-SADS-PL) interview [17], administered by a trained clinician to interview pediatric patients and caregivers, was used to confirm MDD diagnosis. Clinical inclusion criteria required a Children’s Depression Rating Scale–Revised (CDRS-R) [18] total score ≥ 40 and a Clinical Global Impressions–Severity (CGI-S) [19] score ≥ 4. Patients were required to have a caregiver who was responsible for safety monitoring and could provide information about the patient’s condition, oversee administration of study drug, and accompany the patient to all study visits. Psychotherapy or behavior therapy were allowed if either was initiated at least 3 months prior to screening and there was no plan to change such therapies during the study.

Key exclusion criteria included a principal DSM-IV-TR Axis I diagnosis other than MDD in the past 3 months or prior diagnosis of mental retardation or other cognitive disorders; comorbid diagnoses of learning disorders, attention deficit disorder with or without hyperactivity, communication disorders, separation anxiety disorder, dysthymic disorder, oppositional defiant disorder, and anxiety disorders were allowed. Patients with nonresponse to adequate treatment (i.e., at least 8 weeks’ duration) with two or more SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs) or the need for concomitant psychotropic medication were excluded. History of drug or alcohol abuse or dependence within the past year was also exclusionary. Patients were additionally excluded for significant suicide risk judged by the investigator based on the psychiatric interview or information collected from the Columbia-Suicide Severity Rating Scale (C-SSRS) [20], or suicide attempt within the past year. Any unstable medical condition or any condition that could interfere with study conduct, confound interpretation of study results, or endanger patient well-being was an additional reason for exclusion.

Computerized randomization codes were generated; blinding of patients, investigators, and study site personnel was implemented and maintained by interactive voice/web response systems. Breaking the blind for any reason resulted in discontinuation from the study. Based on modeling and simulation of adult pharmacokinetic (PK) data from vilazodone studies (a dose range of 2.5–80 mg/day) considering the vilazodone tablet strengths available (5 mg, 10 mg, and 20 mg), dosing schemes of 15 mg/day and 30 mg/day were selected for this study. Each approach was expected to lead to similar up-titration and steady-state exposures as those observed with 20 mg and 40 mg, respectively, in adult patients. Study medication was dispensed as vilazodone 5-, 10-, and 20-mg tablets and matching placebo tablets, identical in appearance and packaging. Eligible patients were randomized (1:1:1) to placebo or fixed-dose vilazodone 15 mg/day or 30 mg/day. Patients randomized to vilazodone received 5 mg/day for days 1–3 and 10 mg/day for days 4–7. Patients in the vilazodone 15-mg/day group were titrated up to 15 mg/day starting at week 2; patients in the vilazodone 30-mg/day group were titrated up to 20 mg/day starting at week 2 and to 30 mg/day starting at week 3. During the 1-week double-blind down-taper period, patients receiving vilazodone 15 mg/day were titrated down to 5 mg/day for 7 days; patients receiving vilazodone 30 mg/day were titrated down to 15 mg/day for 4 days, then 5 mg/day for 3 days (see the electronic supplementary material, Supplemental Figure 1). Patients randomized to placebo continued taking placebo tablets during the 7-day down-taper period.

The prespecified primary efficacy parameter was change from baseline to week 8 in CDRS-R total score [assessed at screening (week −1), baseline (week 0), and the end of double-blind study weeks 1, 2, 3, 4, 6, and 8]. The prespecified secondary efficacy parameter was change from baseline to week 8 in CGI-S score, assessed at the same study weeks as the primary efficacy parameter. Additional prespecified efficacy parameters were assessed at each post-baseline visit (weeks 1, 2, 3, 4, 6, and 8): CGI–Improvement (CGI-I) [19] score, CDRS-R response (≥ 40% reduction from baseline in CDRS-R total score), and CDRS-R remission (total score ≤ 28). A post hoc analysis was conducted to determine CGI-I response [score of 1 (very much improved) or 2 (much improved)]. Safety was assessed by adverse event (AE) reports, clinical laboratory tests, vital sign measurement, physical examinations, electrocardiogram (ECG) findings, and C-SSRS assessments. PK samples were collected at weeks 3, 6, and 8 (visits 5, 7, and 8).

Based on a mixed-effect model for repeated measures (MMRM) adjusted for multiple comparisons using the matched parallel gatekeeping procedure, a sample size of 495 patients (165 per treatment group) was planned to provide 85% power to detect an effect size of 0.36 at a two-sided significance level of 0.5%. The simulation assumed a correlation of 0.7 between the repeated measures, and a dropout rate of 17%, based on historical studies in pediatric patients with MDD. Based on a prespecified interim analysis of blinded sample size re-estimation, the sample size was later increased from 495 to 525 patients (175 per group) to maintain the desired 85% power.

Safety analyses were conducted in the safety population, defined as all patients in the randomized population who took at least one dose of double-blind study drug. Efficacy analyses were based on the intent-to-treat (ITT) population (all patients in the safety population who had a baseline and one or more post-baseline CDRS-R total score assessment).

The primary efficacy analysis, change from baseline to week 8 in CDRS-R total score, was performed using MMRM with treatment group, study center, visit, and treatment group-by-visit interaction as the fixed effects and the baseline value and baseline value-by-visit interaction as the covariates. An unstructured covariance matrix was used to model the covariance of within-patient scores. The Kenward-Roger approximation [21] was used to estimate denominator degrees of freedom. The analysis was based on all post-baseline scores using the observed cases (OC) approach without imputation of missing values.

The secondary efficacy parameter, change from baseline in CGI-S score at week 8, was analyzed using an MMRM approach that was similar to the one used for the primary efficacy parameter. To control the overall type I error rate for multiple comparisons across the primary and the secondary efficacy parameters, the matched parallel gatekeeping procedure [22] was implemented; statistically significant changes from baseline in CGI-S score could therefore only be claimed if differences in the primary outcome were statistically significant in favor of vilazodone. CGI-I score was analyzed using an MMRM approach with the baseline CGI-S score as a covariate. CDRS-R response and remission rates were analyzed using a generalized linear mixed model with random intercept and fixed terms of treatment group, visit, treatment-by-visit interaction, and baseline score. CGI-I response was analyzed post hoc using a last observation carried forward approach. All statistical tests for efficacy analyses were two-sided hypothesis tests performed at the 5% level of significance; confidence intervals (CIs) were two-sided 95% CIs, unless stated otherwise. All safety parameters were analyzed descriptively.

A total of 529 patients were randomized to placebo, vilazodone 15 mg/day, or vilazodone 30 mg/day (Figure 1). Of the 526 patients in the safety population, 452 (85.9%) completed double-blind treatment (placebo = 83.0%; vilazodone 15 mg = 85.1%; vilazodone 30 mg = 89.4%). The most common reasons for premature discontinuation in the overall study population were withdrawal of consent (4.6%) and AEs (4.0%); discontinuation due to AEs was higher in patients treated with vilazodone (15 mg/day = 5.1%; 30 mg/day = 4.4%) than in patients treated with placebo (2.3%).

Baseline characteristics were similar across treatment groups (Table 1). Mean patient age was approximately 15 years, with a higher percentage of female patients than male patients in each treatment group. Baseline CDRS-R total scores and CGI-S scores indicated similar levels of disease severity across treatment groups, with a CDRS-R total score of ≥ 40 being indicative of depression in adolescents [23].

Mean CDRS-R total scores decreased from baseline to week 8 in all treatment groups, indicating improvement in depressive symptoms; however, the least squares mean difference (LSMD) was not statistically significant for either vilazodone group versus the placebo group (Figure 2, Table 2). After adjustment for multiple comparisons, there was no significant difference between either vilazodone group and placebo in change from baseline to week 8 in CGI-S score (Table 2). There were also no other significant differences in any additional outcome.