close

Clinical Trials

Date: 2018-09-21

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the Ninth Biennial Conference of the International Society for Affective Disorders (ISAD) and the Houston Mood Disorders Conference

Company: J&J company (USA - NJ)

Product: esketamine

Action mechanism:

  • NMDA receptor antagonist. Esketamine for intranasal administration is an investigational compound being studied by Janssen as part of a global development program. Esketamine is a non-competitive and subtype non-selective activity-dependent N-methyl-D-aspartate (NMDA) receptor antagonist, which has a novel mechanism of action, meaning it works differently than currently available therapies for depression. The program in treatment-resistant depression is currently in Phase 3, with six ongoing clinical trials.

Disease: treatment-resistant depression

Therapeutic area: CNS diseases - Mental diseases

Country:

Trial details:

  • The study was an international, Phase 3, double-blind, active-controlled, multi-center study of 346 adults with treatment-resistant depression. Its purpose was to evaluate the efficacy and safety of fixed doses of esketamine plus an oral antidepressant. The primary objective was to evaluate the efficacy of switching adult patients with treatment-resistant depression from a prior antidepressant treatment (to which they had not responded) to a fixed dose of esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant plus placebo, in improving depressive symptoms. Improvement in symptoms was assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from day one (pre-randomization) to the end of the four-week double-blind induction phase. (NCT02417064)
  • In both Phase 3 studies, esketamine or placebo was provided in disposable nasal spray devices containing 200 ?l of solution (i.e., two sprays), and administered under the supervision of a health care professional. A bittering agent was added to placebo to simulate the taste of esketamine, to help mask the treatment assignment. The study in adults with treatment-resistant depression was a Phase 3, double-blind, active-control, flexibly dosed, multi-center study using blinded raters, conducted at 39 sites in Czech Republic , Germany , Poland , Spain and the United States from August 2015 to November 2017 . The study enrolled adults with moderate-to-severe, non-psychotic, recurrent or persistent depression, and history of non-response to ?2 antidepressants in the current episode of depression, with one of them assessed prospectively. Non-responders were randomized (1:1) to flexibly-dosed esketamine nasal spray (56 or 84 mg twice weekly) plus a newly initiated oral antidepressant (N=114) or placebo nasal spray plus a newly initiated oral antidepressant (N=109). The primary efficacy endpoint - change from baseline to day 28 in MADRS total score - was assessed among patients who received ?1 dose of (nasal spray and oral) study medication by mixed-effects model using repeated measures using a one-sided significance level of 0.025. (5.69).
  • The study in elderly patients with treatment-resistant depression was a Phase 3, double-blind, multicenter, active-controlled study. Patients ? 65 years of age were randomized 1:1 to either esketamine nasal spray plus a new oral antidepressant (N=72) or placebo nasal spray plus a new oral antidepressant (N=66). The primary endpoint was the change in the MADRS total score from day 1 (baseline) to day 28. Statistical analysis employed mixed-effects model repeated measures (MMRM), with a weighted combination test to account for an interim analysis for sample size re-estimation, using a one-sided significance level of 0.025.

Latest news:

  • • On September 21, 2018, the Janssen Pharmaceutical companies of Johnson & Johnson announced results from a Phase 3 clinical study of esketamine nasal spray in patients with treatment-resistant depression. Janssen researchers presented these results at the Ninth Biennial Conference of the International Society for Affective Disorders (ISAD) and the Houston Mood Disorders Conference, taking place September 20-22, 2018 in Houston.
  • This clinical trial was a randomized, double-blind study of two fixed doses of esketamine, 56 mg and 84 mg. The study did not demonstrate statistical significance for the primary endpoint, change in a depression severity rating scale score from baseline to four weeks, for esketamine 84 mg plus oral antidepressant compared to oral antidepressant plus placebo. Therefore, based on the prespecified analysis plan, the esketamine 56 mg plus oral antidepressant group could not be formally evaluated in this study.
  • Importantly, results of analyses of the primary endpoint and key secondary endpoints numerically favored both esketamine plus oral antidepressant treatment groups over the oral antidepressant plus placebo group.
  • Primary Efficacy Endpoint: Results of the study were based on a mixed-effects model for repeated measures (MMRM) analysis of change in MADRS total score from baseline to day 28. The results numerically favored both esketamine plus an oral antidepressant groups over the oral antidepressant plus placebo group. The median unbiased estimate of the difference (95% confidence interval) between esketamine 84 mg plus oral antidepressant and the oral antidepressant plus placebo treatment groups was -3.2 (-6.88, 0.45), and that of esketamine 56 mg plus oral antidepressant and the oral antidepressant plus placebo treatment groups was -4.1 (-7.67, -0.49).
  • Using a weighted combination test, the difference between the esketamine 84 mg plus oral antidepressant group and oral antidepressant plus placebo group was not statistically significant (two-sided p=0.088). Therefore, in accordance with the predefined testing sequence, esketamine 56 mg plus oral antidepressant treatment group could not be formally evaluated.
  • Secondary Efficacy Endpoints: The key secondary endpoints included onset of clinical response by day two, and change from baseline to day 28 in total scores from the Sheehan Disability Scale (SDS), a subject-reported outcome measure widely used and accepted for assessment of functional impairment and associated disability, and Patient Health Questionnaire-9 (PHQ-9), a self-report scale assessing depressive symptoms. These endpoints could not be formally evaluated due to the predefined testing sequence, however the proportion of subjects with onset of clinical response by day two maintained to four weeks was numerically higher, and the change in SDS and PHQ-9 total scores at day 28 numerically favored, both esketamine plus oral antidepressant groups compared to the oral antidepressant plus placebo group.
  • As observed in the other Phase 3, short-term studies of esketamine, overall response rates (?50% improvement from baseline) and remission rates (MADRS total score ?12) at day 28 were higher for both esketamine plus oral antidepressant groups compared with the oral antidepressant plus placebo group. Response rate at day 28 was 53.1% and 54.1% in patients treated with esketamine 84 mg plus oral antidepressant and 56 mg plus oral antidepressant, respectively, compared to 38.9% for oral antidepressant plus placebo. Remission rate at day 28 was 38.8% and 36.0% in patients treated with esketamine 84 mg plus oral antidepressant and 56 mg plus oral antidepressant, respectively, compared to 30.6% with placebo plus oral antidepressant.
  • Safety Results: Safety results were consistent with previously reported findings from completed Phase 2 and 3 studies of esketamine. There were no clinically meaningful differences in safety between the esketamine 56 mg plus oral antidepressant and esketamine 84 mg plus oral antidepressant groups, and no new or dose-related safety concerns were identified.
  • Most adverse events were mild or moderate in severity, and were typically observed on nasal spray dosing days, and generally resolved the same day. The most common treatment-emergent adverse events (TEAEs) (reported by ?10% of study patients) in the esketamine 84 mg plus oral antidepressant group during the double-blind induction phase were nausea, dissociation, dizziness, headache, vertigo, somnolence (sleepiness), dysgeusia (taste disturbance), hypoesthesia (diminished sense of touch or sensation), vomiting, and hypoesthesia oral; and in the esketamine 56 mg plus oral antidepressant group were dizziness, nausea, dissociation, somnolence, vertigo, headache, paresthesia (tingling sensation), dysgeusia, hypoesthesia oral, hypoesthesia, and fatigue. A slightly higher incidence of severe events of dissociation and nausea was observed in the esketamine 84 mg plus oral antidepressant treatment group as compared to the esketamine 56 mg plus oral antidepressant treatment group.
  • • On May 5, 2018,  the Janssen Pharmaceutical Companies of Johnson & Johnson announced the results from two Phase 3 clinical studies of esketamine nasal spray in patients with treatment-resistant depression. These studies will be presented at the American Psychiatric Association Annual Meeting, taking place May 5-9 in New York .
  • Data from a study in adults with treatment-resistant depression showed that flexibly dosed esketamine nasal spray plus a newly initiated oral antidepressant demonstrated a statistically significant, clinically meaningful rapid reduction of depressive symptoms as compared to placebo nasal spray plus a newly initiated oral antidepressant. The study defined treatment-resistant as patients who had not responded to two or more currently available antidepressants of adequate dose and duration in the current episode of depression.
  • Data from a second study, in elderly patients aged 65 and older with treatment-resistant depression, which is the first study of its kind, showed treatment with flexibly dosed esketamine plus a newly initiated oral antidepressant demonstrated clinically meaningful effects compared to placebo nasal spray plus a newly initiated oral antidepressant. However, the study narrowly missed statistical significance for its primary efficacy endpoint.
  • Results of the Study in Adults with Treatment-Resistant Depression:  In the Phase 3 study of adults with treatment-resistant depression, patients were randomized to flexibly dosed esketamine nasal spray (56 mg or 84 mg) added to a newly initiated oral antidepressant or placebo nasal spray added to a newly initiated oral antidepressant.
  • Primary Efficacy Endpoint: The primary efficacy endpoint, change from baseline in the Montgomery -Åsberg Depression Rating Scale (MADRS) total score, demonstrated the statistically significant clinical improvement in patients' depressive symptoms for esketamine nasal spray plus an oral antidepressant at day 28 (Least Squares Mean Difference Standard Error from placebo nasal spray plus a newly initiated oral antidepressant: -4.0 [1.69], 95% Confidence Interval [CI]: -7.31, -0.64; one-sided p=0.010).
  • Secondary and Other Efficacy Endpoints: The first key secondary endpoint (onset of clinical response by 24 hours post-dose that is maintained through day 28) numerically favored esketamine nasal spray plus an oral antidepressant vs. placebo nasal spray plus an oral antidepressant, but did not meet statistical significance (1-sided p=0.161). The other two key secondary endpoints (Sheehan Disability Scale [SDS], a subject-reported outcome measure widely used and accepted for assessment of functional impairment and associated disability, and Patient Health Questionnaire-9 [PHQ-9], a self-report scale assessing depressive symptoms) could not be formally evaluated since onset of clinical response was not statistically significant. Among other endpoints, response rate was notable with 69.3% responding in the esketamine group vs. 52% in the placebo group at 28 days (response ? 50% improvement in MADRS from baseline). Remission rate (MADRS total score ?12) at day 28 was 52.5% and 31.0% for the esketamine and placebo groups, respectively.
  • The most common treatment-emergent adverse events ( > 10%) reported in the esketamine group were metallic taste, nausea, vertigo, dizziness, headache, drowsiness, dissociation, blurred vision, paraesthesia (tingling sensation) and anxiety. The most common treatment-emergent adverse events ( > 10%) reported in the placebo group were metallic taste and headache.
  • Results of the Study in Elderly Patients with Treatment-Resistant Depression: Janssen conducted a separate Phase 3 study in elderly patients with treatment-resistant depression. Elderly populations with major depressive disorder are historically hard to treat and often have co-morbidities and long-standing depression. To improve tolerability, patients were given a lower starting dose (28 mg) of esketamine nasal spray (flexibly dosed at 28 mg, 56 mg or 84 mg) plus a newly initiated oral antidepressant or placebo nasal spray plus a newly initiated oral antidepressant.
  • Primary Efficacy Endpoint: Although statistical significance for the primary endpoint for the overall patient population studied was narrowly missed, results favored the esketamine nasal spray plus a newly initiated oral antidepressant group (median unbiased estimate of the difference from placebo nasal spray plus a newly initiated oral antidepressant: -3.6, 95% CI: -7.20, 0.07; one-sided p=0.029). To put this into context, an analysis of placebo-controlled data from three prior studies conducted by Duru and Fantino determined that a minimum change in MADRS of 1.9 was clinically meaningful.2 In addition, the average difference is between 2-3 points for currently approved antidepressants vs. placebo.
  • Safety results were consistent with previous studies of esketamine in younger adult populations. The most common treatment-emergent adverse events ( > 10%) reported in the esketamine group were dizziness, nausea, headache, fatigue, increased blood pressure, vertigo and dissociation. There were no treatment-emergent adverse events reported in > 10% of patients in the placebo group.
  • Esketamine nasal spray has an acceptable safety and tolerability profile, based on the adverse event data from both Phase 3 studies. Adverse events and associated symptoms were seen predominately on the day of dosing and were generally transient and resolved on the day of dosing.

Is general: Yes