Major Depressive Disorder
Conditions
Brief summary
Study Comparing Discontinuation Symptoms in subjects with Major Depressive Disorder treated for 24 Weeks with Open-label 50 mg Desvenlafaxine Succinate Sustained-Release Formulation (DVS SR)
Interventions
DRUGDesvenlafaxine Succinate Sustained-Release Formulation 50 mg
DVS SR 50 mg Reference Group/Arm, oral tablet, 2 tablets/day during the first week and 1 tablet/day during weeks 2 through 4 of the double-blind treatment phase.
DRUGDesvenlafaxine Succinate Sustained-Release Formulation 25 mg
DVS SR 25 mg Taper Group/Arm, oral tablet, 2 tablets/day during the first week and 1 tablet/day during weeks 2 through 4 of the double-blind treatment phase.
DRUGPlacebo
DVS SR Placebo Abrupt Discontinuation Group/Arm, oral tablet, 2 tablets/day during the first week and 1 tablet/day during weeks 2 through 4 of the double-blind treatment phase.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Primary Diagnosis of Major Depressive Disorder * Hamilton Psychiatric Rating Scale for Depression-17-Item score of greater than or equal to 14 at baseline
Exclusion criteria
* Current psychoactive substance abuse or dependence, manic episode, or a lifetime diagnosis of bipolar or psychotic disorder * Potentially violent to others or is at significant risk for suicide * History or current evidence of gastrointestinal disease or history of surgery known to interfere with absorption or excretion * Known presence of raised intraocular pressure or history of narrow angle glaucoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Discontinuation - Emergent Signs and Symptoms (DESS) Score Over the First 2 Weeks of the Double-blind Phase | Double-blind phase: Week 1 (Study Day 175), Week 2 (Study Day 182) | Clinician-administered 43-item assessment to evaluate discontinuation-emergent symptoms resulting from withdrawal from study treatment. Total score=sum of number of new symptoms and old (but worse) symptoms (score=1) and old and unchanged symptom, absent, or old symptom but improved (score=0); total possible range 0 to 43. Higher score=more symptoms. New symptom=any symptom that appeared within 7 days before DESS administration; old symptom=any symptom that appeared 7 days before DESS administration and continued into 7-day period. DESS calculated as 2\*mean(of DESSDB Week 1, DESSDB Week 2). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Taper Adverse Events (AEs) in the Double-blind Phase | Double-blind phase: Baseline (Study Day 168) up to Week 4 (Study Day 196) | Any untoward medical occurrence in a patient who received study drug was considered an AE without regard to possibility of causal relationship. Taper-emergent AEs (TPAEs) are those events which occurred during the double-blind period but did not occur during the last 7 days of the on-therapy period or existed during the last 7 days and worsened in the double-blind period. |
| Percentage of Participants Who Were Unable to Successfully Complete Tapering of the Study Drug Because of the Number and/or Severity of Their Discontinuation Symptoms | Double-blind phase: Baseline (Study Day 168) up to Week 4 (Study Day 196) | Discontinuation symptoms may occur following abrupt cessation of serotonergic antidepressants in a minority of participants following short-term treatment of an episode of Major Depressive Disorder (MDD). The symptoms include emotional and somatic symptoms such as dizziness, nausea, and paresthesia and typically appear within 2 to 3 days of reducing the dose or stopping the antidepressant medication. Discontinuation symptoms are usually mild and resolve spontaneously within a week in the majority of patients, though a minority can have intense and prolonged symptoms. |
Participant flow
Pre-assignment details
Eligible participants entered a 24 Week Open-label treatment phase; participants who completed the Open-label phase were randomized to a 4 Week Double-blind treatment phase.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population 24 Week Open-label phase DVS SR 50 mg PO QD followed by 4 Week Double-blind phase: DVS SR 50 mg (reference group), DVS SR 25 mg (taper group), or Placebo (abrupt-discontinuation group). | 480 |
| Total | 480 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind Phase | Adverse Event | 0 | 1 | 2 | 1 |
| Double-blind Phase | Discontinuation symptom | 0 | 1 | 2 | 2 |
| Double-blind Phase | Lost to Follow-up | 0 | 2 | 2 | 2 |
| Double-blind Phase | Other | 0 | 0 | 1 | 2 |
| Double-blind Phase | Physician Decision | 0 | 0 | 1 | 0 |
| Double-blind Phase | Protocol Violation | 0 | 0 | 1 | 1 |
| Double-blind Phase | Withdrawal by Subject | 0 | 0 | 4 | 2 |
| Open-label Phase | Adverse Event | 29 | 0 | 0 | 0 |
| Open-label Phase | Lack of Efficacy | 18 | 0 | 0 | 0 |
| Open-label Phase | Lost to Follow-up | 30 | 0 | 0 | 0 |
| Open-label Phase | Not randomized to Double-blind phase | 1 | 0 | 0 | 0 |
| Open-label Phase | Other | 9 | 0 | 0 | 0 |
| Open-label Phase | Protocol Violation | 6 | 0 | 0 | 0 |
| Open-label Phase | Withdrawal by Subject | 26 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age Continuous | 46.5 years STANDARD_DEVIATION 13 |
| Sex: Female, Male Female | 330 Participants |
| Sex: Female, Male Male | 150 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 197 / 480 | 9 / 73 | 18 / 140 | 33 / 148 |
| serious Total, serious adverse events | 5 / 480 | 0 / 73 | 0 / 140 | 0 / 148 |
Outcome results
Primary
Total Discontinuation - Emergent Signs and Symptoms (DESS) Score Over the First 2 Weeks of the Double-blind Phase
Clinician-administered 43-item assessment to evaluate discontinuation-emergent symptoms resulting from withdrawal from study treatment. Total score=sum of number of new symptoms and old (but worse) symptoms (score=1) and old and unchanged symptom, absent, or old symptom but improved (score=0); total possible range 0 to 43. Higher score=more symptoms. New symptom=any symptom that appeared within 7 days before DESS administration; old symptom=any symptom that appeared 7 days before DESS administration and continued into 7-day period. DESS calculated as 2\*mean(of DESSDB Week 1, DESSDB Week 2).
Time frame: Double-blind phase: Week 1 (Study Day 175), Week 2 (Study Day 182)
Population: Full Analysis Set (FAS): all randomized participants who had at least 1 postrandomization DESS record. Mean was adjusted for baseline DESS score and study center.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DVS SR 50 mg | Total Discontinuation - Emergent Signs and Symptoms (DESS) Score Over the First 2 Weeks of the Double-blind Phase | 4.1 scores on a scale | Standard Error 0.72 |
| DVS SR 25 mg | Total Discontinuation - Emergent Signs and Symptoms (DESS) Score Over the First 2 Weeks of the Double-blind Phase | 4.8 scores on a scale | Standard Error 0.54 |
| Placebo | Total Discontinuation - Emergent Signs and Symptoms (DESS) Score Over the First 2 Weeks of the Double-blind Phase | 5.3 scores on a scale | Standard Error 0.52 |
Comparison: Difference: Placebo versus DVS SR 50 mg95% CI: [-0.51, 2.83]ANCOVA
Comparison: Difference: DVS SR 25 mg versus DVS SR 50 mg95% CI: [-1.03, 2.35]ANCOVA
Comparison: Difference: Placebo versus DVS SR 25 mg95% CI: [-0.88, 1.89]ANCOVA
Secondary
Percentage of Participants Who Were Unable to Successfully Complete Tapering of the Study Drug Because of the Number and/or Severity of Their Discontinuation Symptoms
Discontinuation symptoms may occur following abrupt cessation of serotonergic antidepressants in a minority of participants following short-term treatment of an episode of Major Depressive Disorder (MDD). The symptoms include emotional and somatic symptoms such as dizziness, nausea, and paresthesia and typically appear within 2 to 3 days of reducing the dose or stopping the antidepressant medication. Discontinuation symptoms are usually mild and resolve spontaneously within a week in the majority of patients, though a minority can have intense and prolonged symptoms.
Time frame: Double-blind phase: Baseline (Study Day 168) up to Week 4 (Study Day 196)
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DVS SR 50 mg | Percentage of Participants Who Were Unable to Successfully Complete Tapering of the Study Drug Because of the Number and/or Severity of Their Discontinuation Symptoms | 1.4 percentage of participants |
| DVS SR 25 mg | Percentage of Participants Who Were Unable to Successfully Complete Tapering of the Study Drug Because of the Number and/or Severity of Their Discontinuation Symptoms | 1.4 percentage of participants |
| Placebo | Percentage of Participants Who Were Unable to Successfully Complete Tapering of the Study Drug Because of the Number and/or Severity of Their Discontinuation Symptoms | 1.4 percentage of participants |
Secondary
Percentage of Participants With Taper Adverse Events (AEs) in the Double-blind Phase
Any untoward medical occurrence in a patient who received study drug was considered an AE without regard to possibility of causal relationship. Taper-emergent AEs (TPAEs) are those events which occurred during the double-blind period but did not occur during the last 7 days of the on-therapy period or existed during the last 7 days and worsened in the double-blind period.
Time frame: Double-blind phase: Baseline (Study Day 168) up to Week 4 (Study Day 196)
Population: Safety population (Double-blind phase): all participants who received at least 1 dose of study treatment and were randomized into the Double-blind treatment phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DVS SR 50 mg | Percentage of Participants With Taper Adverse Events (AEs) in the Double-blind Phase | 35.6 percentage of participants |
| DVS SR 25 mg | Percentage of Participants With Taper Adverse Events (AEs) in the Double-blind Phase | 38.6 percentage of participants |
| Placebo | Percentage of Participants With Taper Adverse Events (AEs) in the Double-blind Phase | 50.7 percentage of participants |