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TRD Efficacy & Safety | SPRAVATO® (esketamine) HCP

TRD Efficacy & Safety

Over 30,000 patients in the US have received treatment with SPRAVATO®. Learn more about the recent data and results from the short-term and long-term studies below.1

Data as of November 2022. Source: IQVIA projected data and Janssen data on file.

TRD=treatment-resistant depression in adults (for patients with MDD who have had an inadequate response to 2 or more oral ADs).

Person in light blue shirt in orange circle Actor portrayal.
Demonstrated rapid and superior improvement in depressive symptoms at Week 4 compared to placebo + oral AD2,3

TRD Study 1 (Short-term)

Time course of treatment response chart with results of SPRAVATO® + oral AD versus placebo nasal spray + oral AD
  • Most of the treatment difference between SPRAVATO® and placebo was observed at 24 hours
  • Between 24 hours and Day 28, both SPRAVATO® and placebo groups continued to improve, and the difference between these 2 groups generally remained the same

AD=antidepressant.

LS=least squares.

MADRS=Montgomery-Åsberg Depression Rating Scale.

Click here to see short-term safety data

TRD Study 1 (Short-term) study design2,3

Evaluated in a randomized, placebo-controlled, double-blind, short-term (4-week) study in adults with TRD; all patients in the trial received a new oral AD. Primary endpoint was change from baseline in the MADRS total score at 4 weeks.2,3

Demonstrated superior improvement in depression symptoms at Week 4 for adults with TRD2,3

TRD Study 1 short-term study design overview of SPRAVATO® + new oral AD and placebo nasal spray + new oral AD

Other Secondary Descriptive Endpoints

  • Response at Week 4
  • Remission at Week 4

Flexible Dosing

  • Patients (aged 18-64 years) were randomized to receive twice-weekly doses of SPRAVATO® (flexible dose; 56 mg or 84 mg) plus a newly initiated oral AD or intranasal placebo plus newly initiated oral AD
  • Dosages could be titrated to 84 mg or maintained on 56 mg, and were adjusted on Day 4, 8, 11, or 15
  • Dosages remained stable after Day 15

Oral Antidepressant

  • A newly initiated open-label oral AD (SSRIs: escitalopram, sertraline; SNRIs: duloxetine, venlafaxine extended-release) was initiated on Day 1
  • The selection of the newly initiated oral AD was determined by the investigator based on patient’s prior history

Demographics and Baseline Characteristics

  • Median age 47 years; 62% female; 93% Caucasian; 5% Black

SSRI=selective serotonin reuptake inhibitor.

SNRI=serotonin and norepinephrine reuptake inhibitor.

Key secondary efficacy results3,4

  • 7.9% of patients receiving SPRAVATO® + oral AD achieved response by Day 2 and maintained response by Day 28 vs 4.6% with placebo + oral AD

    The difference was not statistically significant

  • Mean total SDS score change with SPRAVATO® + oral AD was -13.6 vs -9.4 with placebo + oral AD by Day 28
  • Mean total PHQ-9 score change with SPRAVATO® + oral AD was -13.0 vs -10.2 with placebo + oral AD by Day 28

*Response was defined as ≥ 50% improvement in MADRS total score by Day 2 that continued through to the end of the double-blind treatment phase, with 1 excursion allowed.

Given the lack of statistical significance on the first secondary endpoint, analyses of the other 2 key secondary endpoints could not be formally evaluated.

The 3 key secondary endpoints were analyzed sequentially and were considered significant at the 2-sided, 0.05 level only if the individual and previous endpoints in the hierarchy, including the primary endpoint, were significant.

AD=antidepressant.

MADRS=Montgomery-Åsberg Depression Rating Scale.

PHQ-9=Patient Health Questionnaire-9 (used specifically for depression).

SDS=Sheehan Disability Scale.

Secondary descriptive endpoints:

  • At Week 4, 52.5% of patients receiving SPRAVATO® + oral AD achieved remission vs 31.0% with placebo + oral AD

TRD Study 1 (Short-term)

Two bar graphs comparison of secondary descriptive endpoints between response rates at week 4 versus remission rates at week 4
  • Response was defined as an improvement of at least 50% from baseline in total MADRS score
  • Remission was defined as a MADRS total score of ≤12
  • All subjects taking SPRAVATO® started on 56 mg on Day 1. Dose adjustment was made on prespecified days based on clinical judgment
Short-term Studies:
TRD Safety and Tolerability of SPRAVATO®

SPRAVATO® plus oral antidepressant offers your patients a consistent safety profile with a minimal risk for sexual dysfunction compared to placebo + oral antidepressant2,5

  • Sexual dysfunction was not observed in SPRAVATO® trials at a rate greater than 2%

TRD=treatment-resistant depression in adults (for patients with MDD who have had an inadequate response to 2 or more oral ADs).

Adverse events chart of SPRAVATO® + oral AD versus placebo + oral AD
  • Most TEAEs (93.7%) occurred and resolved on the same day of dosing6
    • In a 4-week study, the majority of dissociation (98.3%), blood pressure increase (86.4%), and sedation (83.3%) occurred and resolved on the same day of dosing6

*The following terms were combined:

Dissociation includes: delusional perception; depersonalization/derealization disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; feeling of body temperature change; hallucination; hallucination, auditory; hallucination, visual; hyperacusis; illusion; ocular discomfort; oral dysesthesia; paresthesia; paresthesia oral; pharyngeal paresthesia; photophobia; time perception altered; tinnitus; vision blurred; visual impairment

Dizziness includes: dizziness; dizziness exertional; dizziness postural; procedural dizziness

Sedation includes: altered state of consciousness; hypersomnia; sedation; somnolence

Vertigo includes: vertigo; vertigo positional

Hypoesthesia includes: hypoesthesia; hypoesthesia oral, hypoesthesia teeth, pharyngeal hypoesthesia

Anxiety includes: agitation; anticipatory anxiety; anxiety; fear; feeling jittery; irritability; nervousness; panic attack; tension

Lethargy includes: fatigue; lethargy

Blood pressure increased includes: blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension

Headache includes: headache; sinus headache

Dysgeusia includes: dysgeusia; hypogeusia

Nasal discomfort includes: nasal crusting; nasal discomfort; nasal dryness; nasal pruritus

Dysarthria includes: dysarthria; slow speech; speech disorder

Tachycardia includes: extrasystoles; heart rate increased; tachycardia

AD=antidepressant.

TEAEs=treatment-emergent adverse effects.

Click here to see long-term efficacy data

You can have the confidence that SPRAVATO® demonstrated low discontinuation rates:

4-week and 4-year TRD study percentages of discontinued treatment

Across all Phase 3 studies, adverse reactions leading to SPRAVATO® discontinuation in more than 2 patients included anxiety (1.2%), depression (0.9%), blood pressure increased (0.6%), dizziness (0.6%), suicidal ideation (0.5%), dissociation (0.4%), nausea (0.4%), vomiting (0.4%), headache (0.3%), muscular weakness (0.3%), vertigo (0.2%), hypertension (0.2%), panic attack (0.2%), and sedation (0.2%).2

For additional information, please see full Prescribing Information, including Boxed WARNINGS.

*Two short-term TRD studies in adults <65 years.

An ongoing study of which the proportion of patients with greater duration of exposure (ie, ≥36 months) is expected to increase with time and does not currently reflect discontinuations related to adverse reactions.

OP/M=optimization/maintenance.

SPRAVATO® is administered at certified treatment centers.

Safety Considerations2
Click to expand each SPRAVATO® safety consideration below
Contraindication red icon

Contraindications

Cloud with 'zz' red icon

Sedation

Clock red icon

Dissociation

Schedule 3 controlled substance red icon

Abuse and Misuse

REMS red icon

REMS

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Suicidal Thoughts and Behaviors in Young Adults

Blood pressure red icon

Blood Pressure

Cognition red icon

Cognitive Impairment

No driving red icon

Impaired Ability to Drive and Operate Heavy Machinery

Ulcerative or interstitial cystitis red icon

Ulcerative or Interstitial Cystitis

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Use in Specific Populations

Drug interactions red icon

Drug Interactions

References:

  1. Data on File. RF-247473. Janssen Pharmaceuticals, Inc.

  2. SPRAVATO® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. July 2020.

  3. Popova V, Daly E, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438. doi:10.1176/appi.ajp.2019.19020172

  4. Popova V, Daly E, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6)(Suppl.). https://ajp.psychiatryonline.org/doi/suppl/10.1176/appi.ajp.2019.19020172/suppl_file/appi.ajp.2019.19020172.ds001.pdf

  5. Data on File. RF-210003. Janssen Pharmaceuticals, Inc.

  6. Data on File. RF-240359. Janssen Pharmaceuticals, Inc.

  7. Zaki N, Fu DJ, Daly E, et al. Long-term safety of esketamine nasal spray in adults with treatment-resistant depression: a subgroup analysis of the ongoing SUSTAIN-3 study. Poster presented at: Neuroscience Education Institute (NEI) Congress; November 4-7, 2021; Colorado Springs, CO.

No new safety signals were observed in the 4-year analysis of the ongoing SUSTAIN-3 trial2,3

During the combined Induction (IND) and Optimization/Maintenance (OP/M) phases, 93.5% of patients experienced ≥1 TEAEs2

IND Phase=56 mg or 84 mg—twice weekly.

OP/M Phase=56 mg or 84 mg—flexibly dosed.*

*Based on CGI-S and tolerability.

Nasal spray and calendar in orange circle

Most TEAEs (96.7%) occurred and resolved on same day of dosing2

Less than or equal to two hours orange icon

The majority of dissociation (93.2%), blood pressure increase (86.1%), and sedation (87.4%) resolved in less than 2 hours3

Percentages of TRD long-term study results TEAEs table

Additional 4-year safety results2

  • Three patients (0.7%) in the IND phase (N=436) and 139 patients (14.3%) in the OP/M phase (N=971) experienced ≥1 serious AE
  • Three deaths occurred: 1 in the IND phase and 2 in the OP/M phase (COVID-19, accidental polytrauma, suicide); none were related to SPRAVATO®
  • A total of 60 (6.0%) patients experienced 1 or more TEAEs potentially related to suicidality (suicidal ideation, n=44; suicide attempt, n=11; suicidal behavior, n=3; complete suicide, n=1; depression suicidal, n=1)
TRD 4-year MADRS Results & PHQ-9 Scores

TRD=treatment-resistant depression in adults (for patients with MDD who have had an inadequate response to 2 or more oral ADs).

In an ongoing, long-term, open-label safety study, MADRS scores were consistent through interim analysis at 4 years2,4

Mean MADRS Total Scores (LOCF) during the induction and optimization/maintenance phases over 4 years

4-year safety trial was composed of 2 phases: a 4-week IND phase and a variable OP/M phase.2,4

  • Of the 1006 patients studied in this cohort, 68.9% were treated with SPRAVATO® for at least 30 months
    • Patients eligible for this subgroup were 18-64 years of age and received SPRAVATO® 56 mg or 84 mg twice weekly during IND phase and flexible dosing during OP/M phase; all patients should have taken a permitted oral AD for the duration of the study
  • N-size: ≥1 year (n=817), ≥2 years (n=738), ≥3 years (n=481), and ≥4 years (n=6) of SPRAVATO® exposure. Because SUSTAIN-3 is an ongoing study, proportions of patients with ≥3 years and ≥4 years of exposure are expected to increase with time and do not currently reflect discontinuations related to SPRAVATO® tolerability

BL=baseline.

LOCF=last observation carried forward.

MADRS=Montgomery-Åsberg Depression Rating Scale.

PHQ-9=Patient Health Questionnaire-9 (used specifically for depression).

In an open-label, long-term safety study, SPRAVATO®-treated patients showed consistent PHQ-9 scores over 4 years4

Mean PHQ-9 Total Scores during the induction and optimization/maintenance phases over 4 years

Mean change from baseline in the PHQ-9 total scores (LOCF) showed an improvement over the 4-week IND phase.

This improvement appeared to be maintained with flexibly dosed SPRAVATO® over the OP/M phase.

  • N-size: ≥1 year (n=817), ≥2 years (n=738), ≥3 years (n=481), and ≥4 years (n=6) of SPRAVATO® exposure. Because SUSTAIN-3 is an ongoing study, proportions of patients with ≥3 years and ≥4 years of exposure are expected to increase with time and do not currently reflect discontinuations related to SPRAVATO® tolerability

BL=baseline.

LOCF=last observation carried forward.

PHQ-9=Patient Health Questionnaire-9 (used specifically for depression).

TRD long-term safety extension study2

The following data is drawn from an ongoing, Phase 3, open-label, long-term safety extension study in adults with treatment-resistant depression (TRD).

Limitations:

  • Results from an open-label, long-term safety study with no comparator group. Efficacy data not assessed for statistical significance
  • Generalizability of study findings may be limited by patients who chose to continue from the parent study and by exclusion of participants with significant comorbidities (psychiatric or medical, or substance dependence); decrease in sample size later in the trial may have implications for representativeness/generalizability of findings

Study Design2

A subgroup analysis was conducted on a cohort of 1006 patients who met criteria consistent with the on-label population.

  • Patients eligible for this subgroup analysis were 18-64 years of age and received SPRAVATO® 56 mg or 84 mg twice weekly during induction (IND) phase and flexible dosing during optimization/maintenance (OP/M) phase; all patients should have taken a permitted oral AD for the duration of the study
TRD long-term safety extension study comparison of IND Phase and OP/M Phase

Primary Endpoint: Number of participants with treatment-emergent adverse effects (TEAEs)

IND Phase=56 mg or 84 mg - twice weekly.

OP/M Phase=56 mg or 84 mg - flexibly dosed.*

*Based on CGI-S and tolerability.
CGI-S=Clinical Global Impressions-Severity scale.

AD=antidepressant.

Maintenance-of-effect study

In a separate long-term maintenance-of-effect trial, patients in stable remission were less likely to relapse* when they continued SPRAVATO® vs those who discontinued and were switched to placebo5,6
TRD Study 2 (long-term) of SPRAVATO® + oral AD versus placebo + oral AD over 80 weeks
  • Stable remission was defined as a MADRS total score of ≤12 in at least 3 of the last 4 weeks of the optimization phase

*Relapse was defined as a MADRS total score of ≥22 for 2 consecutive weeks and/or hospitalization for worsening depression, or any other clinically relevant event determined per clinical judgment to be suggestive of a relapse of depressive illness.

AD=antidepressant.

MADRS=Montgomery-Åsberg Depression Rating Scale.

TRD Study 2 (Long-term) study design5,6

Evaluated in a long-term, randomized, double-blind, parallel-group, variable duration study in adults who were known remitters and responders. Primary endpoint was time to relapse in patients in stable remission.5,6

Significantly delayed time to relapse in a long-term maintenance trial in adults with TRD with stable remission5,6

TRD Study 2 (Long-term) study design overview of SPRAVATO® + oral AD and placebo nasal spray + oral AD

Enrollment

  • 437 patients (aged 18-64 years) were directly enrolled
    • Patients who were directly enrolled received SPRAVATO® (56 mg or 84 mg twice/week) plus a new oral AD in a 4-week open-label induction phase before entering a 12-week optimization phase
  • 268 patients (aged 18-64 years) were transferred from short-term studies

Demographics and Baseline Characteristics

  • Median age 48 years (range 19-64 years); 66% female; 90% Caucasian, 4% Black

SPRAVATO® is administered at certified treatment centers.

References:

  1. Data on File. RF-247473. Janssen Pharmaceuticals, Inc.

  2. Zaki N, Fu DJ, Daly E, et al. Long-term safety of esketamine nasal spray in adults with treatment-resistant depression: a subgroup analysis of the ongoing SUSTAIN-3 study. Poster presented at: Neuroscience Education Institute (NEI) Congress; November 4-7, 2021; Colorado Springs, CO.

  3. Data on File. RF-201855. Janssen Pharmaceuticals, Inc.

  4. Zaki N, Fu DJ, Daly E, et al. Long-term efficacy of esketamine nasal spray in adults with treatment-resistant depression: a subgroup analysis of the ongoing SUSTAIN-3 study. Poster presented at: Neuroscience Education Institute (NEI) Congress; November 4-7, 2021; Colorado Springs, CO.

  5. SPRAVATO® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. July 2020.

  6. Daly E, Trivedi M, Janik A, et al. Efficacy of esketamine nasal spray plus an oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903. doi:10.1001/jamapsychiatry.2019.1189