SUMMARY

• A short-term trial of flexibly-dosed SPRAVATO in adults with treatment-resistant depression (TRD) aged <65 years found that most of the treatment difference, based on the Montgomery-Åsberg Depression Rating Scale (MADRS), for SPRAVATO + newly initiated antidepressant (AD) (SPRAVATO+AD) vs newly initiated AD + placebo (PBO) (AD+PBO) was observed at 24 hours. Between 24 hours and day 28, both the SPRAVATO+AD and AD+PBO groups continued to improve; the difference between the groups generally remained but did not appear to increase over time through day 28.¹ A similar trend was found in another short-term, fixed-dose study.²
• A study conducted in patients with major depressive disorder and active suicidal ideation with intent found a statistically significant decrease in the MADRS score at 24 hours postdose in patients treated with 84 mg SPRAVATO + standard of care (SOC) vs patients treated with PBO+SOC. This treatment effect was first observed at 4 hours postdose; however, the primary endpoint was measured at 24 hours. A similar trend occurred in a second identically designed study.^3,4
  • SOC treatment included initial hospitalization and newly initiated/optimized oral AD therapy. The SOC AD treatment was either AD monotherapy or AD + augmentation therapy (i.e., a second AD, an atypical antipsychotic, or a mood stabilizer).^3,4

BACKGROUND

Montgomery-Åsberg Depression Rating Scale (MADRS)

The MADRS is a 10 item, clinician-administered scale designed to measure overall severity of depressive symptoms in patients with MDD. Each item is scored 0-6 with a total possible MADRS score of 0-60. A higher score indicates a higher severity of depressive symptoms. Items included in the MADRS are apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts.⁵

CLINICAL DATA

Phase 3 Short-Term Flexible Dose SPRAVATO in Adults with Treatment-Resistant Depression (TRD)

Popova et al (2019) (TRANSFORM-2)¹ conducted a 4-week, randomized, double-blind (DB), multinational study to compare the efficacy and safety of flexibly-dosed SPRAVATO+AD vs AD+PBO in adult patients (18-64 years) with TRD.

Patients were directly observed as they self-administered either SPRAVATO (56 to 84 mg) or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff. A new daily oral open-label AD (duloxetine, sertraline, escitalopram, or venlafaxine XR) was administered for the duration of the DB phase following a fixed titration schedule.

A key secondary endpoint was the proportion of patients showing onset of clinical response (≥50% improvement from baseline in MADRS total score) by day 2 (or 24 hours postdose) that was maintained for the duration of the DB phase. Patients were allowed one excursion on days 8, 15, or 22 provided the MADRS score was ≥25% improved from baseline. Patients with missed assessments or who discontinued early were not considered to have onset of clinical response. The proportion of patients with an onset of sustained clinical response by day 2 was numerically larger in the SPRAVATO+AD group (n=114) vs the AD+PBO group (n=109) (7.9% vs 4.6%, respectively), though the difference was not statistically significant. A graphical representation of the MADRS is seen in Figure: Least-Squares Mean Change in MADRS Total Score Over Time in Double-Blind Phase [TRANSFORM-2].

Phase 3 Study of 84 mg SPRAVATO in Adults with Major Depressive Disorder and Active Suicidal Ideation with Intent

Fu et al (2020) (ASPIRE-I)³ conducted 4-week DB, randomized, PBO-controlled study to compare 84 mg SPRAVATO+SOC vs PBO+SOC in adult (18-64 years) patients with MDD and active suicidal ideation with intent.

Patients self-administered nasal SPRAVATO or PBO under supervision twice weekly for 4 weeks. Patients were also given SOC treatment defined as initial hospitalization and initiation/optimization of AD treatment. The AD of SOC treatment consisted of either AD monotherapy or AD + augmentation therapy (i.e., an atypical antipsychotic, or a mood stabilizer. A single reduction in the SPRAVATO dose from 84 mg to 56 mg was permitted for intolerance and was continued through the end of the DB phase.

The primary endpoint was the change in MADRS total score from baseline to 24 hours post-dose. As depicted below in Figure: Least-Squares Mean Change in MADRS Total Score in Double-Blind Phase [ASPIRE-I], there was statistically significant improvement in the change from baseline of mean MADRS total score at 24 hours in patients treated with SPRAVATO+SOC vs PBO+SOC. The least-squares mean difference was -3.8 (95% CI: -6.56 to -1.09; P = 0.006). The treatment effect of SPRAVATO, as measured by a reduction in MADRS total score, was observed starting at 4 hours after the first dose.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 07 March 2024.