) in adult patients 18 to <65 yearsold with treatment-resistant depression (TRD). Patients in Study 1 met DSM-5 criteria for majordepressive disorder (MDD) and in the current depressive episode, had not responded adequatelyto at least two different antidepressants of adequate dose and duration. After discontinuing priorantidepressant treatments, patients in Study 1 were randomized to receive twice weekly doses ofintranasal SPRAVATO (flexible dose; 56 mg or 84 mg) or intranasal placebo. All patients also
received open-label concomitant treatment with a newly initiated daily oral antidepressant (AD)(duloxetine, escitalopram, sertraline, or extended-release venlafaxine as determined by theinvestigator based on patient’s prior treatment history). SPRAVATO could be titrated up to84 mg starting with the second dose based on investigator discretion.
The demographic and baseline disease characteristics of patients in Study 1 were similar for theSPRAVATO and placebo nasal spray groups. Patients had a median age of 47 years (range 19 to64 years) and were 62% female, 93% Caucasian, and 5% Black. The newly initiated oral ADwas an SSRI in 32% of patients and an SNRI in 68% of patients.
In Study 1, the primary efficacy measure was change from baseline in the Montgomery-AsbergDepression Rating Scale (MADRS) total score at the end of the 4-week double-blind inductionphase. The MADRS is a ten-item, clinician-rated scale used to assess severity of depressivesymptoms. Scores on the MADRS range from 0 to 60, with higher scores indicating more severedepression. SPRAVATO plus a newly initiated oral AD demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus a newly initiated oral AD(see Table 8).
Table 8: Primary Efficacy Results for Change from Baseline in MADRS Total Score at Week 4 inPatients with TRD in Study 1 (MMRM)
Treatment Group
Number
of
Patients
Mean
Baseline
Score (SD)
LS Mean (SE)
Change from
Baseline to end
of Week 4
LS Mean
Difference
(95% CI)*
SPRAVATO (56 mg or 84 mg) + Oral AD† 114 37.0 (5.7) -19.8 (1.3) -4.0
(-7.3; -0.6)
Placebo nasal spray + Oral AD 109 37.3 (5.7) -15.8 (1.3) -
MMRM=mixed model for repeated measures; SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=confidence interval;AD=antidepressant
* Difference (SPRAVATO + Oral AD minus Placebo nasal spray + Oral AD) in least-squares mean change from baseline
† SPRAVATO + Oral AD was statistically significantly superior to placebo nasal spray + oral AD
Time Course of Treatment Response
Figure 4 shows the time course of response for the primary efficacy measure (MADRS) in
Study 1. Most of SPRAVATO’s treatment difference compared to placebo was observed at 24hours. Between 24 hours and Day 28, both the SPRAVATO and placebo groups continued toimprove; the difference between the groups generally remained but did not appear to increase
over time through Day 28. At Day 28, 67% of the patients randomized to SPRAVATO werereceiving 84 mg twice weekly.
Figure 4: Least Squares Mean Change from Baseline in MADRS Total Score Over Time in Patients with
TRD in Study 1* (Full Analysis Set) – MMRM Analysis
* Note: In this flexible-dose study, dosing was individualized based on efficacy and tolerability. Few subjects (<10%) had reduction in
SPRAVATO dosage from 84 mg to 56 mg twice weekly.
14.2 Treatment-Resistant Depression – Long-term StudyStudy 2 ( |
