Patient Characteristics

Figure 1. Figure 1. Screening, Randomization, and Follow-up.

Table 1. Table 1. Characteristics of the Patients.

A total of 169 patients were screened, of whom 89 were enrolled and underwent randomization. Patients were assigned in a 1:1 ratio to receive SAGE-217 (45 patients) or placebo (44 patients) (Figure 1). Demographic characteristics were similar in the two groups except that patients in the SAGE-217 group were older than those in the placebo group (mean age, 49 years vs. 38 years), there were fewer women in the SAGE-217 group than in the placebo group (56% vs. 68%), and there were more black patients in the SAGE-217 group than in the placebo group (80% vs. 64%) (Table 1). Most patients (96% in the SAGE-217 group and 91% in the placebo group) reported previous depressive episodes. The percentage of patients who were receiving antidepressants at baseline was 27% in the SAGE-217 group and 23% in the placebo group, and the duration of this treatment before the patients entered the trial was 2 months to more than 48 months (Table S3 in the Supplementary Appendix). In the SAGE-217 group, 2 patients discontinued the trial drug because of adverse events (1 patient after day 6 and 1 patient after day 10). One patient was lost to follow-up after 9 days, and 1 patient withdrew consent after 10 days (neither of these patients had adverse events). In the placebo group, 3 patients were lost to follow-up during the follow-up period, and 2 patients withdrew from the trial (1 patient after 5 days and 1 patient after 6 days).

Efficacy

Table 2. Table 2. Primary and Secondary End Points Assessed at Day 15.

Figure 2. Figure 2. Efficacy End Points. Scores on the 17-item Hamilton Depression Rating Scale (HAM-D) range from 0 to 52, with higher scores indicating more severe depression. The primary end point was the change in HAM-D score from baseline to day 15 (Panel A). 𝙸 bars indicate ±1 SE. The percentage of patients who had a reduction from baseline in HAM-D score of more than 50% (Panel B) and the percentage of patients who had a HAM-D score of 7 or lower (Panel C) were secondary end points.

The mean HAM-D score at baseline was 25.2 in the SAGE-217 group and 25.7 in the placebo group. On day 15, the least-squares mean change from baseline in HAM-D score was −17.4±1.3 points in the SAGE-217 group and −10.3±1.3 points in the placebo group (least-squares mean difference in change, −7.0; 95% confidence interval [CI], −10.2 to −3.9; P<0.001) (Table 2). Results of the sensitivity analyses for missing data that used multiple imputation or the last-observation-carried-forward method were similar to those of the primary analysis (Table S4 in the Supplementary Appendix). At each time point from day 2 through day 28, the unadjusted 95% confidence intervals for the between-group difference in the change from baseline in HAM-D scores did not include zero, and the differences were generally in the same direction as those of the primary outcome, but the unadjusted 95% confidence intervals for days 35 and 42 included zero (Table S5 and Fig. S3A in the Supplementary Appendix). At day 15, the percentage of patients who had a reduction of more than 50% from baseline in the HAM-D score was 79% in the SAGE-217 group and 41% in the placebo group (model-based odds ratio [analyzed with the use of a generalized estimating equation model], 9.6; 95% CI unadjusted for multiplicity, 2.9 to 31.6); the percentage of patients with a HAM-D score of 7 or lower was 64% in the SAGE-217 group and 26% in the placebo group (model-based odds ratio, 5.3; unadjusted 95% CI, 2.1 to 13.3) (Figure 2B and 2C and Table 2, and Table S5 in the Supplementary Appendix). At day 28, the percentage of patients who had a reduction of more than 50% from baseline in the HAM-D score was 62% in the SAGE-217 group and 46% in the placebo group, and the percentage of patients with a HAM-D score of 7 or lower was 52% and 28%, respectively (Fig. S3B and S3C and Table S5 in the Supplementary Appendix).

During the follow-up period, 3 patients in the SAGE-217 group and 11 patients in the placebo group were given concomitant antidepressants by investigators (Table S7 in the Supplementary Appendix). Patients and investigators remained unaware of the group assignments throughout the follow-up period. Results regarding the effects of SAGE-217 and placebo in patients who received and in patients who did not receive concomitant antidepressants are provided in Table S6 in the Supplementary Appendix.

Results for secondary end points are shown in Table 2. At day 15, the least-squares mean change from baseline in the Bech-6 score was −40.7±3.3 points in the SAGE-217 group and −25.7±3.4 points in the placebo group (least-squares mean difference in change, −15.1 points; unadjusted 95% CI, −23.3 to −6.8). At day 15, the least-squares mean change from baseline in the MADRS score was −22.5±1.9 in the SAGE-217 group and −15.0±1.9 in the placebo group (least-squares mean difference in change, −7.6 points; unadjusted 95% CI, −12.3 to −2.8). At all time points, a higher percentage of patients in the SAGE-217 group than in the placebo group had a CGI-I score of 1 or 2, and the least-squares mean change from baseline in HAM-A score was greater in the SAGE-217 group than in the placebo group, but no inferences can be made because of the lack of adjustment for multiplicity in the analyses of secondary outcomes. (Additional data on secondary end points are provided in Figs. S4 through S6 and Tables S8 through S10 in the Supplementary Appendix.)

Safety

Table 3. Table 3. Adverse Events during the Treatment Period.

There were no serious adverse events and no deaths during this trial. The percentage of patients who had at least one adverse event during the treatment period was 53% in the SAGE-217 group and 45% in the placebo group (Table 3). During days 21 through 42, a total of 4 additional adverse events in the SAGE-217 group and 10 additional adverse events in the placebo group were reported (Table S11 in the Supplementary Appendix). Two patients in the SAGE-217 group discontinued the trial drug because they met a protocol criterion for discontinuation (one patient after day 6 because of nausea, dizziness, and headache, and the other patient after day 10 because of increased levels of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase [this patient had mildly elevated baseline values and was asymptomatic throughout the trial, and all values returned to baseline or near-baseline levels after discontinuation of the trial medication]).

The most common adverse events that occurred in at least 5% of patients in the SAGE-217 group were headache, dizziness, nausea, and somnolence (Table 3). Subjective sleepiness, as assessed with the use of the Stanford Sleepiness Scale, was similar in the two groups. The score on the Stanford Sleepiness Scale was assessed before and after administration of SAGE-217 or placebo at multiple time points daily; data for days 1, 7, 14, and 15 are summarized in Table S12 in the Supplementary Appendix. In the SAGE-217 group, adverse events occurred in 67% of patients who received concomitant antidepressants and in 48% of patients who received SAGE-217 as monotherapy (Table S13 in the Supplementary Appendix). Six patients in the SAGE-217 group had dose reductions (from 30 mg to 20 mg) — five as the result of adverse events (dizziness [in two patients], somnolence [in one patient], sedation [in one patient], and nausea and vomiting [in one patient]) and one because of patient-reported sleepiness as assessed by the Stanford Sleepiness Scale. No patients in the placebo group had dose reductions.