Buprenorphine/samidorphan combination for the adjunctive treatment of major depressive disorder: results of a phase III clinical trial (FORWARD-3)

Figures & data

Figure 1 Patient disposition in groups 1 and 2.

Note: FORWARD-2 is a safety extension study.
Abbreviations: ADT, antidepressant therapy; BUP, buprenorphine; HAM-D, Hamilton Rating Scale for Depression; SAM, samidorphan.

Table 1 Demographics and baseline clinical characteristics for randomized patients in the analysis population (group 1 placebo nonresponders)

	Placebo + ADT (n=148)	BUP/SAM 2 mg/2 mg + ADT (n=147)	All patients (N=295)
Age, years
Mean (SD)	48.1 (12.5)	47.4 (12.3)	47.8 (12.4)
Sex (female), n (%)	94 (63.5)	88 (59.9)	182 (61.7)
Primary race, n (%)
White	115 (77.7)	106 (72.1)	221 (74.9)
Black or African–American	33 (22.3)	33 (22.4)	66 (22.4)
American Indian or Alaska Native	0	5 (3.4)	5 (1.7)
Asian	0	2 (1.4)	2 (0.7)
Native Hawaiian or other Pacific Islander	0	1 (0.7)	1 (0.3)
Region, n (%)
US	128 (86.5)	118 (80.3)	246 (83.4)
Non-US	20 (13.5)	29 (19.7)	49 (16.6)
BMI (kg/m^2), mean (SD)	29.6 (5.9)	28.8 (5.5)	29.2 (5.7)
MADRS-10 score, mean (SD)	27.4 (6.6)	27.7 (6.4)	NA
MADRS-6 score, mean (SD)	18.4 (4.3)	18.8 (4.5)	NA
CGI-S score, mean (SD)	4.0 (0.6)	4.2 (0.7)	NA
HAM-D total score, mean (SD)	25.0 (3.3)	24.9 (3.3)	NA
Duration of current MDE (months), mean (SD)	9.0 (5.8)	8.3 (5.7)	8.6 (5.73)
Class of ADT for current MDE, n (%)
SSRI	97 (65.5)	103 (70.1)	200 (67.8)
SNRI	35 (23.6)	31 (21.1)	66 (22.4)
Bupropion	16 (10.8)	13 (8.8)	29 (9.8)
Lifetime number of MDEs, mean (SD)	4.6 (4.9)	4.8 (3.6)	4.7 (4.3)
Lifetime number of ADTs, mean (SD)	2.4 (1.7)	2.5 (1.6)	2.4 (1.7)

Notes: MADRS-10, MADRS-6, CGI-S, and HAM-D scores are for the efficacy-analysis population, defined as those who were randomized, received one or more doses of study drug, and had one or more postbaseline MADRS assessment (n=142 for BUP/SAM 2 mg/2 mg and n=146 for placebo).

Abbreviations: ADT, antidepressant therapy; BMI, body-mass index; BUP, buprenorphine; CGI-S, Clinical Global Impression – severity; HAM-D, Hamilton Rating Scale for Depression; MADRS, Montgomery–Åsberg Depression Rating Scale; MDE, major depressive episode; NA, not available; SAM, samidorphan; SNRI, serotonin–norepinephrine-reuptake inhibitor; SSRI, selective serotonin-reuptake inhibitor.

Figure 2 Change from baseline in MADRS-10 total score over time in the analysis population.

Abbreviations: ADT, antidepressant therapy; BUP, buprenorphine; LS, least squares; MADRS, Montgomery–Åsberg Depression Rating Scale; SAM, samidorphan.

Table 2 Patients with treatment-emergent AEs during the 6-week postrandomization treatment period in the analysis population

	Placebo + ADT (n=148), n (%)	BUP/SAM 2 mg/2 mg + ADT (n=147), n (%)
Any AE	51 (34.5)	63 (42.9)
Any serious AE	1 (0.7)	0
AE leading to study discontinuation	2 (1.4)	2 (1.4)
Common AEs (≥2% in any treatment group)
Nausea	1 (0.7)	13 (8.8)
Headache	5 (3.4)	6 (4.1)
Blood creatine phosphokinase increased	0	4 (2.7)
Fatigue	3 (2.0)	4 (2.7)
Upper respiratory tract infection	3 (2.0)	4 (2.7)
Vomiting	2 (1.4)	4 (2.7)
Constipation	1 (0.7)	3 (2.0)
Dry mouth	2 (1.4)	3 (2.0)
Hypertension	2 (1.4)	3 (2.0)
Muscle spasms	0	3 (2.0)
Nasopharyngitis	3 (2.0)	3 (2.0)
Diarrhea	3 (2.0)	1 (0.7)
Dizziness	3 (2.0)	1 (0.7)

Abbreviations: ADT, antidepressant therapy; AEs, adverse events; BUP, buprenorphine; SAM, samidorphan.

Figure 3 MADRS-10 score change in the FORWARD-3 vs FORWARD-4 and FORWARD-5 studies during 6-week treatment period in stage 2.

Notes: (A) BUP/SAM 2 mg/2 mg; (B) placebo.
Abbreviations: BUP, buprenorphine; LS, least squares; MADRS, Montgomery–Åsberg Depression Rating Scale; SAM, samidorphan.

Figure S1 Comparison of trial designs in FORWARD-3 (left, double-blind run-in) vs FORWARD-4 and FORWARD-5 (right, sequential parallel-comparison design).

Notes: ^aResponse defined as ≥50% reduction in MADRS total score from baseline. Analysis populations indicated by dark gray tints; analysis stages indicated by light gray tint.

Abbreviations: ADT, antidepressant therapy; BUP, buprenorphine; HAM-D, 17-item Hamilton Rating Scale for Depression; MADRS, Montgomery–Åsberg Depression Rating Scale; SAM, samidorphan.

Availability of data and material

The data collected in this study are proprietary to Alkermes, Inc. Alkermes, Inc. is committed to public sharing of data in accordance with applicable regulations and laws.