Major Depressive Disorder
Conditions
Brief summary
This study will examine SPD489 in subjects aged 18-65 with major depressive disorder (MDD) who are taking certain types of antidepressants but continue to have residual depression symptoms. The purpose of this study is to help answer the following questions: * How safe is SPD489 for the supplemental treatment of depression and what are the side effects that might be related to it? * Can SPD489 help patients with depression who are also taking an antidepressant? * How much SPD489 should be given to patients with depression who are also taking an antidepressant? * How does SPD489 compare to placebo in depressed patients who are also taking an antidepressant?
Interventions
DRUGAntidepressant + SPD489 (Lisdexamfetamine dimesylate) 10 mg
Antidepressant + SPD489 oral, 10 mg, once daily for 8 weeks
DRUGAntidepressant + SPD489 (Lisdexamfetamine dimesylate) 30 mg
Antidepressant + SPD489 oral, 30 mg, once daily for 8 weeks
DRUGAntidepressant + SPD489 (Lisdexamfetamine dimesylate) 50 mg
Antidepressant + SPD489 oral, 50 mg, once daily for 8 weeks
DRUGAntidepressant + SPD489 (Lisdexamfetamine dimesylate) 70 mg
Antidepressant + SPD489 oral, 70 mg, once daily for 8 weeks
oral, once daily for 8 weeks
Sponsors
Shire
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 65 Years
Healthy volunteers
No
Inclusion criteria
1. Subject is able to provide written, personally signed and dated informed consent to participate in the study before completing any study-related procedures. 2. Subject is between 18-65 years of age. 3. Subject has a primary diagnosis of non-psychotic MDD. 4. Subject has a MADRS total score 24 5. Subject is willing and has an understanding and ability to fully comply with study procedures and restrictions defined in this protocol. 6. Subject, who is female, must have a negative serum beta human chorionic gonadotropin (HCG) pregnancy test and a negative urine pregnancy test and agrees to comply with any applicable contraceptive requirements. 7. Subject is able to swallow a capsule.
Exclusion criteria
1. Subject whose current episode of MDD has not responded to an adequate treatment regimen. 2. Subject who has a lifetime history of treatment resistant depression, defined as having not responded to adequate treatment with 2 or more treatment regimens. 3. Subject has a current comorbid psychiatric disorder that is either controlled with medications prohibited in this study or is uncontrolled and associated with significant symptoms. 4. Subject has been hospitalized (within the last 12 months) for their current MDD episode. 5. Subject has a current or lifetime history of attention-deficit/hyperactivity disorder (ADHD). 6. Subject has a first degree relative that has been diagnosed with bipolar I disorder. 7. Subject has a recent history (within the last 6 months) of suspected substance abuse or dependence disorder. 8. Subject is considered a suicide risk, has previously made a suicide attempt within the past 3 years, or is currently demonstrating active suicidal ideation. 9. Subject has a concurrent chronic or acute illness or unstable medical condition. 10. Subject has a history of seizures (other than infantile febrile seizures), any tic disorder, or a current diagnosis and/or a known family history of Tourette's Disorder, serious neurological disease, history of significant head trauma, dementia, cerebrovascular disease, Parkinson's disease, or intracranial lesions. 11. Subject has known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant medication. 12. Subject has a history of thyroid disorder that has not been stabilized on thyroid medication or treatment within 3 months prior to the Screening Visit. 13. Subject has a known family history of sudden cardiac death or ventricular arrhythmia. 14. Subject has glaucoma. 15. Subject has any clinically significant ECG or clinical laboratory abnormalities at the Screening Visit. 16. Subject has a history of moderate to severe hypertension. 17. Current use of any other medication (including over-the-counter \[OTC\], herbal or homeopathic preparations) that has central nervous system effects. 18. Subject has the potential to need to initiate or modify frequency of psychotherapy or to continue or initiate other treatments for depression, outside of those allowed in this protocol. 19. Subject has had electroconvulsive therapy for the current depressive episode 3 months prior to the Lead-in Baseline Visit. 20. The subject has a known or suspected intolerance or hypersensitivity to the investigational product. 21. The subject has a known or suspected intolerance or hypersensitivity to any of the possible antidepressant treatments (escitalopram oxalate or venlafaxine HCL extended release. 22. Subject has a positive urine drug result. 23. Subject has a body mass index of \<18.5 or \>40. 24. Subject is female and is pregnant or nursing. 25. Subject has participated in another clinical study involving SPD489/NRP104 or has previously used commercial lisdexamfetamine dimesylate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Montgomery-Ǻsberg Depression Rating Scale (MADRS) Total Score From Augmentation Baseline (Week 8) to Week 16 (Double-blind Phase, Dose Response Evaluable Set) | Augmentation Baseline (Week 8) to Week 16 | MADRS is a validated, 10-item rating scale with each item being scored on a scale from 0-6 with a total score ranging from 0-60. Lower scores indicate a decreased severity of depression. CHange in MADRS total score in Augmentsion Baseline to Week 16. |
Secondary
| Measure | Time frame |
|---|---|
| Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | From Augmentation Baseline (Week 8) to Week 16 |
| Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | From Augmentation Baseline (Week 8) to Week 16 |
| Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16 | From Augmentation Baseline (Week 8) to Week 16 |
Countries
Argentina, Australia, Chile, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Antidepressant + Double-blind Placebo Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily double-blind placebo (matching SPD489). | 78 |
| Antidepressant + Double-blind SPD489 10mg Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily over-encapsulated SPD489 as a 10mg dose. | 77 |
| Antidepressant + Double-blind SPD489 30mg Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily over-encapsulated SPD489 as a 30mg dose. | 76 |
| Antidepressant + Double-blind SPD489 50mg Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily over-encapsulated SPD489 as a 50mg dose. | 78 |
| Antidepressant + Double-blind SPD489 70mg Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily over-encapsulated SPD489 as a 70mg dose. | 80 |
| Total | 389 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Antidepressant Lead-in Phase | Adverse Event | 40 | 0 | 0 | 0 | 0 | 0 |
| Antidepressant Lead-in Phase | Lost to Follow-up | 83 | 0 | 0 | 0 | 0 | 0 |
| Antidepressant Lead-in Phase | Met BP or Pulse Withdrawal Criteria | 10 | 0 | 0 | 0 | 0 | 0 |
| Antidepressant Lead-in Phase | Other | 119 | 0 | 0 | 0 | 0 | 0 |
| Antidepressant Lead-in Phase | Protocol Violation | 16 | 0 | 0 | 0 | 0 | 0 |
| Antidepressant Lead-in Phase | Withdrawal by Subject | 74 | 0 | 0 | 0 | 0 | 0 |
| Double-blind Phase | Adverse Event | 7 | 0 | 1 | 1 | 1 | 3 |
| Double-blind Phase | Lost to Follow-up | 31 | 1 | 2 | 0 | 3 | 3 |
| Double-blind Phase | Met BP or Pulse Withdrawal Criteria | 1 | 0 | 0 | 0 | 3 | 0 |
| Double-blind Phase | Other | 8 | 2 | 0 | 2 | 0 | 0 |
| Double-blind Phase | Protocol Violation | 2 | 0 | 1 | 2 | 0 | 1 |
| Double-blind Phase | Withdrawal by Subject | 17 | 4 | 3 | 4 | 2 | 2 |
Baseline characteristics
| Characteristic | Antidepressant + Double-blind Placebo | Antidepressant + Double-blind SPD489 10mg | Antidepressant + Double-blind SPD489 30mg | Antidepressant + Double-blind SPD489 50mg | Antidepressant + Double-blind SPD489 70mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 43.7 Years STANDARD_DEVIATION 10.48 | 39.1 Years STANDARD_DEVIATION 11.83 | 43.4 Years STANDARD_DEVIATION 12.06 | 43.8 Years STANDARD_DEVIATION 12.4 | 41.5 Years STANDARD_DEVIATION 10.81 | 42.3 Years STANDARD_DEVIATION 11.61 |
| Age, Customized 18-55 | 69 Participants | 70 Participants | 62 Participants | 60 Participants | 71 Participants | 332 Participants |
| Age, Customized 56-65 | 9 Participants | 7 Participants | 14 Participants | 18 Participants | 9 Participants | 57 Participants |
| Region of Enrollment ARGENTINA | 2 Participants | 3 Participants | 5 Participants | 3 Participants | 5 Participants | 18 Participants |
| Region of Enrollment AUSTRALIA | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Region of Enrollment CHILE | 3 Participants | 6 Participants | 12 Participants | 9 Participants | 2 Participants | 32 Participants |
| Region of Enrollment UNITED KINGDOM | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment UNITED STATES | 72 Participants | 68 Participants | 59 Participants | 64 Participants | 70 Participants | 333 Participants |
| Sex: Female, Male Female | 53 Participants | 53 Participants | 52 Participants | 53 Participants | 53 Participants | 264 Participants |
| Sex: Female, Male Male | 25 Participants | 24 Participants | 24 Participants | 25 Participants | 27 Participants | 125 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 78 | 30 / 77 | 29 / 76 | 36 / 78 | 44 / 80 |
| serious Total, serious adverse events | 0 / 78 | 0 / 77 | 0 / 76 | 0 / 78 | 1 / 80 |
Outcome results
Primary
Change in Montgomery-Ǻsberg Depression Rating Scale (MADRS) Total Score From Augmentation Baseline (Week 8) to Week 16 (Double-blind Phase, Dose Response Evaluable Set)
MADRS is a validated, 10-item rating scale with each item being scored on a scale from 0-6 with a total score ranging from 0-60. Lower scores indicate a decreased severity of depression. CHange in MADRS total score in Augmentsion Baseline to Week 16.
Time frame: Augmentation Baseline (Week 8) to Week 16
Population: Dose Response Evaluable Set (DRES): All randomized subjects who had at least 1 valid primary efficacy measurement (MADRS total score) during the Dose Maintenance Period (Weeks 11-16) while on the target dose level of investigational product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Antidepressant + Double-blind Placebo | Change in Montgomery-Ǻsberg Depression Rating Scale (MADRS) Total Score From Augmentation Baseline (Week 8) to Week 16 (Double-blind Phase, Dose Response Evaluable Set) | -5.4 units on a scale |
| Antidepressant + Double-blind SPD489 10mg | Change in Montgomery-Ǻsberg Depression Rating Scale (MADRS) Total Score From Augmentation Baseline (Week 8) to Week 16 (Double-blind Phase, Dose Response Evaluable Set) | -6.7 units on a scale |
| Antidepressant + Double-blind SPD489 30mg | Change in Montgomery-Ǻsberg Depression Rating Scale (MADRS) Total Score From Augmentation Baseline (Week 8) to Week 16 (Double-blind Phase, Dose Response Evaluable Set) | -5.3 units on a scale |
| Antidepressant + Double-blind SPD489 50mg | Change in Montgomery-Ǻsberg Depression Rating Scale (MADRS) Total Score From Augmentation Baseline (Week 8) to Week 16 (Double-blind Phase, Dose Response Evaluable Set) | -6.1 units on a scale |
| Antidepressant + Double-blind SPD489 70mg | Change in Montgomery-Ǻsberg Depression Rating Scale (MADRS) Total Score From Augmentation Baseline (Week 8) to Week 16 (Double-blind Phase, Dose Response Evaluable Set) | -6.3 units on a scale |
Comparison: Analysis of Dose-Response Using the MCP-Mod Analysis Methodp-value: 1MCP-Mod Analysis Method
Comparison: Analysis of Dose-Response Using the MCP-Mod Analysis Method.p-value: 0.942MCP-Mod Analysis
Comparison: Analysis of Dose-Response Using the MCP-Mod Analysis Method.p-value: 0.995MCP-Mod Analysis
Comparison: Analysis of Dose-Response Using the MCP-Mod Analysis Methodp-value: 0.978MCP-Mod Analysis
Secondary
Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16
Time frame: From Augmentation Baseline (Week 8) to Week 16
Population: Vital Signs Evaluable Set: All randomized subjects who had at least 1 valid vital signs measurement during the Dose Maintenance Period while on the target dose level of investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antidepressant + Double-blind Placebo | Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | -0.1 mmHg | Standard Deviation 6.69 |
| Antidepressant + Double-blind SPD489 10mg | Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | -0.9 mmHg | Standard Deviation 6.64 |
| Antidepressant + Double-blind SPD489 30mg | Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | -0.1 mmHg | Standard Deviation 7.39 |
| Antidepressant + Double-blind SPD489 50mg | Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | 2.8 mmHg | Standard Deviation 6.58 |
| Antidepressant + Double-blind SPD489 70mg | Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | 1.9 mmHg | Standard Deviation 7.45 |
p-value: 0.011MCP-Mod Analysis
p-value: 0.023MCP-Mod Analysis
p-value: 0.003Least Squares Means
p-value: 0.009MCP-Mod Analysis
p-value: 0.005MCP-Mod Analysis
Secondary
Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16
Time frame: From Augmentation Baseline (Week 8) to Week 16
Population: Vital Signs Evaluable Set: All randomized subjects who had at least 1 valid vital signs measurement during the Dose Maintenance Period while on the target dose level of investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antidepressant + Double-blind Placebo | Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16 | -0.8 bpm | Standard Deviation 9.95 |
| Antidepressant + Double-blind SPD489 10mg | Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16 | 0.8 bpm | Standard Deviation 7.32 |
| Antidepressant + Double-blind SPD489 30mg | Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16 | 5.3 bpm | Standard Deviation 8.08 |
| Antidepressant + Double-blind SPD489 50mg | Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16 | 4.0 bpm | Standard Deviation 9.8 |
| Antidepressant + Double-blind SPD489 70mg | Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16 | 6.0 bpm | Standard Deviation 11.25 |
p-value: <0.001MCP-Mod Analysis
p-value: 0.002MCP-Mod Analysis
p-value: <0.001MCP-Mod Analysis
p-value: <0.001MCP-Mod Analysis
p-value: <0.001MCP-Mod Analysis
Secondary
Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16
Time frame: From Augmentation Baseline (Week 8) to Week 16
Population: Vital Signs Evaluable Set: All randomized subjects who had at least 1 valid vital signs measurement during the Dose Maintenance Period while on the target dose level of investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antidepressant + Double-blind Placebo | Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | -0.2 mmHg | Standard Deviation 9.55 |
| Antidepressant + Double-blind SPD489 10mg | Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | 0.2 mmHg | Standard Deviation 8.58 |
| Antidepressant + Double-blind SPD489 30mg | Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | 0.5 mmHg | Standard Deviation 9.17 |
| Antidepressant + Double-blind SPD489 50mg | Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | 3.5 mmHg | Standard Deviation 7.82 |
| Antidepressant + Double-blind SPD489 70mg | Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 | 2.6 mmHg | Standard Deviation 10.55 |
p-value: 0.004MCP-Mod Analysis
p-value: 0.032MCP-Mod Analysis
p-value: 0.003MCP-Mod Analysis
p-value: 0.01MCP-Mod Analysis Method
p-value: 0.005MCP-Mod Analysis