Depressive Disorder, Treatment-Resistant
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy of each individual dose of esketamine nasal spray, 56 milligram (mg) and 84 mg, compared with placebo nasal spray in improving depressive symptoms in participants with treatment resistant depression (TRD), as assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 (prerandomization) to the end of the 4 week double-blind treatment phase (Day 28).
Interventions
DRUGEsketamine 56 mg
Esketamine 56 mg will be self administered as nasal spray.
DRUGEsketamine 84 mg
Esketamine 84 mg will be self administered as nasal spray.
DRUGPlacebo
Matching placebo will be self administered as nasal spray.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must meet the Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) diagnostic criteria for single-episode MDD or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the MINI. Participants 65 years of age or older must have had the first onset of depression prior to 55 years of age * Participant must have had nonresponse (\<=25% improvement) to \>=2 oral antidepressant treatments in the current episode of depression, assessed using the MGH-ATRQ, and confirmed by documented records (example, medical/pharmacy/prescription records or a letter from a treating physician) * Participant must have an Inventory of Depressive Symptomatology-Clinician rated, 30-item (IDS-C30) total score of \>=34 * The participant's current major depressive episode, depression symptom severity, and antidepressant treatment response in the current depressive episode, must be confirmed by the State vs. Trait, Assessibility, Face Validity, Ecological Validity, Rule of Three P's (SAFER) Interview * Participant must be medically stable on the basis of physical examination, medical history, vital signs (including blood pressure), and 12-lead electrocardiogram (ECG) performed in the screening phase. If there are any abnormalities that are not specified in the inclusion and
Exclusion criteria
, the determination of their clinical significance must be determined by the investigator and recorded in the participant's source documents and initiated by the investigator * Participant must be medically stable on the basis of clinical laboratory tests performed in the screening phase. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the participant's source documents and initialed by the investigator: (a) Participants with a pre-existing history of thyroid disease/disorder who are treated with thyroid hormones must be on a stable dosage for 3 months prior to the start of the screening phase; (b) For any participant (regardless of thyroid history), if the thyroid-stimulating hormone (TSH) value is out of range, a free thyroxine (FT4) will be conducted. If the FT4 value is abnormal and considered to be clinically significant (after discussion with the medical monitor), the participant is not eligible * Participant must be comfortable with self-administration of nasal spray medication and be able to follow the nasal spray administration instructions provided
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double-blind Treatment Phase: Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Day 1 (Pre-randomization) to Day 28 | Day 1 (pre-randomization) to Day 28 (end of DB treatment phase) | The MADRS was a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consisted of 10 items, each of which was scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score was the sum of scores from individual question items, which ranged from 0 to 60, higher scores represented a more severe condition. The MADRS evaluated apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts. Negative change in MADRS total score indicated improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Double-blind Treatment Phase: Change in MADRS Total Score From Day 1 (Pre-randomization) to Day 2 (24 Hours Post First Dose on Day 1) | Day 1 (pre-randomization) to Day 2 of DB treatment phase (24 hours post first dose on Day 1) | The MADRS was a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consisted of 10 items, each of which was scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score was the sum of scores from individual question items, which ranged from 0 to 60, higher scores represented a more severe condition. The MADRS evaluated apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts. Negative change in MADRS total score indicated improvement. |
Countries
United States
Participant flow
Recruitment details
Adult participants with recurrent or single (duration greater than or equal to \[\>=\] 2 years) episode major depressive disorder (DSM-5 criteria) without psychotic features who experienced inadequate response (less than or equal to \[\<=\] 25 percent \[%\] improvement) to \>=2 oral antidepressants during the current depressive episode were randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo In the double-blind (DB) phase, participants received placebo nasal spray (matching to esketamine) twice a week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25. After completion of the DB phase (including Day 28 visit), participants opted to enter the open-label (OL) phase (treatment/observation phase). Participants who opted OL treatment phase received esketamine 56 milligrams (mg) nasal spray on Day 28 regardless of the treatment assignment in the DB phase and received subsequent doses at the same or adjusted (56 mg or 84 mg) dose level based on efficacy and tolerability with dosing frequency: twice weekly from Weeks 5 to 8 followed by once weekly from Weeks 9 to 12 and then weekly or every other week from Weeks 13 to 16 based on clinical judgment and was individualized to the least frequent dosing to maintain remission/response. During this period participants were given the option to receive standard-of-care treatment for depression. Participants who opted OL observation phase were only observed without esketamine nasal spray treatment but received standard-of-care treatment for depression. All participants underwent 1-week follow-up phase for safety assessment after their last dose of study treatment in DB or OL treatment phase. | 250 |
| Esketamine 56 mg In the DB phase, participants received esketamine 56 mg nasal spray twice a week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25. After completion of the DB phase (including Day 28 visit), participants opted to enter the OL phase (treatment/observation phase). Participants who opted OL treatment phase received esketamine 56 mg nasal spray on Day 28 regardless of the treatment assignment in the DB phase and received subsequent doses at the same or adjusted (56 mg or 84 mg) dose level based on efficacy and tolerability with dosing frequency: twice weekly from Weeks 5 to 8 followed by once weekly from Weeks 9 to 12 and then weekly or every other week from Weeks 13 to 16 based on clinical judgment and was individualized to the least frequent dosing to maintain remission/response. During this period participants were given the option to receive standard-of-care treatment for depression. Participants who opted OL observation phase were only observed without esketamine nasal spray treatment but received standard-of-care treatment for depression. All participants underwent 1-week follow-up phase for safety assessment after their last dose of study treatment in DB or OL treatment phase. | 105 |
| Esketamine 84 mg In the DB phase, participants received esketamine 84 mg nasal spray twice a week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25. After completion of the DB phase (including Day 28 visit), participants opted to enter the OL phase (treatment/observation phase). Participants who opted OL treatment phase received esketamine 56 mg nasal spray on Day 28 regardless of the treatment assignment in the DB phase and received subsequent doses at the same or adjusted (56 mg or 84 mg) dose level based on efficacy and tolerability with dosing frequency: twice weekly from Weeks 5 to 8 followed by once weekly from Weeks 9 to 12 and then weekly or every other week from Weeks 13 to 16 based on clinical judgment and was individualized to the least frequent dosing to maintain remission/response. During this period participants were given the option to receive standard-of-care treatment for depression. Participants who opted OL observation phase were only observed without esketamine nasal spray treatment but received standard-of-care treatment for depression. All participants underwent 1-week follow-up phase for safety assessment after their last dose of study treatment in DB or OL treatment phase. | 121 |
| Total | 476 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double Blind Period (Day 1 to Day 28) | Adverse Event | 2 | 1 | 5 |
| Double Blind Period (Day 1 to Day 28) | Lack of Efficacy | 2 | 0 | 2 |
| Double Blind Period (Day 1 to Day 28) | Lost to Follow-up | 0 | 1 | 0 |
| Double Blind Period (Day 1 to Day 28) | Other | 1 | 0 | 1 |
| Double Blind Period (Day 1 to Day 28) | Pregnancy | 1 | 0 | 0 |
| Double Blind Period (Day 1 to Day 28) | Protocol Violation | 1 | 0 | 1 |
| Double Blind Period (Day 1 to Day 28) | Randomized but not treated | 0 | 1 | 0 |
| Double Blind Period (Day 1 to Day 28) | Withdrawal by Subject | 5 | 2 | 5 |
| Period Title: OL Period (Week 5 to 16) | Adverse Event | 4 | 2 | 1 |
| Period Title: OL Period (Week 5 to 16) | Lack of Efficacy | 10 | 3 | 2 |
| Period Title: OL Period (Week 5 to 16) | Lost to Follow-up | 4 | 1 | 2 |
| Period Title: OL Period (Week 5 to 16) | Other | 5 | 1 | 0 |
| Period Title: OL Period (Week 5 to 16) | Protocol Violation | 2 | 0 | 0 |
| Period Title: OL Period (Week 5 to 16) | Withdrawal by Subject | 8 | 5 | 6 |
Baseline characteristics
| Characteristic | Placebo | Esketamine 56 mg | Esketamine 84 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 10 Participants | 14 Participants | 45 Participants |
| Age, Categorical Between 18 and 65 years | 229 Participants | 95 Participants | 107 Participants | 431 Participants |
| Age, Continuous | 45.4 Years STANDARD_DEVIATION 13.72 | 45.1 Years STANDARD_DEVIATION 13.92 | 45.1 Years STANDARD_DEVIATION 14.75 | 45.3 Years STANDARD_DEVIATION 14.01 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 9 Participants | 8 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 221 Participants | 95 Participants | 112 Participants | 428 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 3 Participants | 5 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants | 7 Participants | 11 Participants | 35 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 1 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 217 Participants | 91 Participants | 102 Participants | 410 Participants |
| Region of Enrollment United States | 250 Participants | 105 Participants | 121 Participants | 476 Participants |
| Sex: Female, Male Female | 147 Participants | 60 Participants | 77 Participants | 284 Participants |
| Sex: Female, Male Male | 103 Participants | 45 Participants | 44 Participants | 192 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 250 | 0 / 106 | 0 / 121 | 0 / 237 | 0 / 99 | 0 / 105 | 0 / 1 | 0 / 477 |
| other Total, other adverse events | 73 / 250 | 69 / 105 | 80 / 121 | 147 / 237 | 49 / 99 | 44 / 105 | 0 / 1 | 8 / 476 |
| serious Total, serious adverse events | 3 / 250 | 1 / 105 | 2 / 121 | 6 / 237 | 3 / 99 | 0 / 105 | 0 / 1 | 1 / 476 |
Outcome results
Primary
Double-blind Treatment Phase: Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Day 1 (Pre-randomization) to Day 28
The MADRS was a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consisted of 10 items, each of which was scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score was the sum of scores from individual question items, which ranged from 0 to 60, higher scores represented a more severe condition. The MADRS evaluated apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts. Negative change in MADRS total score indicated improvement.
Time frame: Day 1 (pre-randomization) to Day 28 (end of DB treatment phase)
Population: Full efficacy analysis set included all randomized participants who met nonresponse criteria and received at least 1 dose of DB study intervention. Here 'N' (overall number of participants analyzed) refers to the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB: Placebo | Double-blind Treatment Phase: Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Day 1 (Pre-randomization) to Day 28 | -7.0 Score on a scale | Standard Deviation 10.07 |
| DB: Esketamine 56 mg | Double-blind Treatment Phase: Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Day 1 (Pre-randomization) to Day 28 | -12.7 Score on a scale | Standard Deviation 11.82 |
| DB: Esketamine 84 mg | Double-blind Treatment Phase: Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Day 1 (Pre-randomization) to Day 28 | -13.9 Score on a scale | Standard Deviation 11.89 |
p-value: <0.00195% CI: [-7.91, -2.33]Mixed model for repeated measures
p-value: <0.00195% CI: [-9.48, -4.07]Mixed model for repeated measures
Secondary
Double-blind Treatment Phase: Change in MADRS Total Score From Day 1 (Pre-randomization) to Day 2 (24 Hours Post First Dose on Day 1)
The MADRS was a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consisted of 10 items, each of which was scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score was the sum of scores from individual question items, which ranged from 0 to 60, higher scores represented a more severe condition. The MADRS evaluated apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts. Negative change in MADRS total score indicated improvement.
Time frame: Day 1 (pre-randomization) to Day 2 of DB treatment phase (24 hours post first dose on Day 1)
Population: Full efficacy analysis set included all randomized participants who met nonresponse criteria and received at least 1 dose of DB study intervention. Here 'N' (overall number of participants analyzed) refers to the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB: Placebo | Double-blind Treatment Phase: Change in MADRS Total Score From Day 1 (Pre-randomization) to Day 2 (24 Hours Post First Dose on Day 1) | -9.7 Score on a scale | Standard Deviation 10.27 |
| DB: Esketamine 56 mg | Double-blind Treatment Phase: Change in MADRS Total Score From Day 1 (Pre-randomization) to Day 2 (24 Hours Post First Dose on Day 1) | -13.9 Score on a scale | Standard Deviation 10.15 |
| DB: Esketamine 84 mg | Double-blind Treatment Phase: Change in MADRS Total Score From Day 1 (Pre-randomization) to Day 2 (24 Hours Post First Dose on Day 1) | -13.0 Score on a scale | Standard Deviation 9.68 |
p-value: =0.00495% CI: [-6.29, -1.22]Mixed model for repeated measures
p-value: =0.00695% CI: [-5.89, -1]Mixed model for repeated measures