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SPD489 in Combination With an Antidepressant in the Treatment of Adults With Major Depressive Disorder

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01435759
Recruitment Status : Completed
First Posted : September 19, 2011
Results First Posted : February 19, 2015
Last Update Posted : January 8, 2019
Sponsor:
Information provided by (Responsible Party):
Shire

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Major Depressive Disorder
Interventions Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 10 mg
Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 30 mg
Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 50 mg
Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 70 mg
Drug: Antidepressant + Placebo
Enrollment 1197
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Antidepressant + Single-blind Placebo Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
Hide Arm/Group Description Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily single-blind placebo (matching SPD489). 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). 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. 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. 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. 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.
Period Title: Antidepressant Lead-in Phase
Started 1197 [1] 0 0 0 0 0
Completed 855 0 0 0 0 0
Not Completed 342 0 0 0 0 0
Reason Not Completed
Adverse Event             40             0             0             0             0             0
Protocol Violation             16             0             0             0             0             0
Withdrawal by Subject             74             0             0             0             0             0
Lost to Follow-up             83             0             0             0             0             0
Met BP or Pulse Withdrawal Criteria             10             0             0             0             0             0
Not Specified             119             0             0             0             0             0
[1]
Of these 1197 subjects, 19 subjects were not dosed.
Period Title: Double-blind Phase
Started 463 [1] 78 78 [2] 78 [3] 78 80
Completed 397 71 71 69 69 71
Not Completed 66 7 7 9 9 9
Reason Not Completed
Adverse Event             7             0             1             1             1             3
Protocol Violation             2             0             1             2             0             1
Withdrawal by Subject             17             4             3             4             2             2
Lost to Follow-up             31             1             2             0             3             3
Met BP or Pulse Withdrawal Criteria             1             0             0             0             3             0
Not Specified             8             2             0             2             0             0
[1]
These subjects were not included in the Safety Dose Response Evaluable Set or Safety Analysis Set.
[2]
One subject was not dosed.
[3]
Two subjects were not dosed.
Arm/Group Title 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
Hide Arm/Group Description 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). 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. 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. 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 78 77 76 78 80 389
Hide Baseline Analysis Population Description
Safety Analysis Set: All subjects who took at least 1 dose of randomized investigational product and who had at least 1 post-augmentation baseline safety assessment (e.g. coming back for any visit, reporting of an adverse event [AE] or reporting the absence of AEs). Subjects who received only single-blind placebo were not included in this group.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 78 participants 77 participants 76 participants 78 participants 80 participants 389 participants
43.7  (10.48) 39.1  (11.83) 43.4  (12.06) 43.8  (12.4) 41.5  (10.81) 42.3  (11.61)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 78 participants 77 participants 76 participants 78 participants 80 participants 389 participants
18-55 69 70 62 60 71 332
56-65 9 7 14 18 9 57
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 78 participants 77 participants 76 participants 78 participants 80 participants 389 participants
Female
53
  67.9%
53
  68.8%
52
  68.4%
53
  67.9%
53
  66.3%
264
  67.9%
Male
25
  32.1%
24
  31.2%
24
  31.6%
25
  32.1%
27
  33.8%
125
  32.1%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 78 participants 77 participants 76 participants 78 participants 80 participants 389 participants
ARGENTINA 2 3 5 3 5 18
AUSTRALIA 0 0 0 2 3 5
CHILE 3 6 12 9 2 32
UNITED KINGDOM 1 0 0 0 0 1
UNITED STATES 72 68 59 64 70 333
1.Primary Outcome
Title 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)
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
Hide Arm/Group Description:
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).
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.
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.
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.
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.
Overall Number of Participants Analyzed 72 71 69 66 71
Least Squares Mean (90% Confidence Interval)
Unit of Measure: units on a scale
-5.4
(-7.2 to -3.5)
-6.7
(-8.6 to -4.9)
-5.3
(-7.1 to -3.4)
-6.1
(-8.1 to -4.1)
-6.3
(-8.2 to -4.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments Analysis of Dose-Response Using the MCP-Mod Analysis Method
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
Comments Any p-value <=0.10 indicates successful establishment of dose-response relationship.
Method MCP-Mod Analysis Method
Comments The adjusted p-value was based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value -.11
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.07
Estimation Comments The t-statistic used for this analysis, 0.10, was based on MCP-Mod Analysis from the linear contrast using optimal coefficients for the pre-specified candidate model Betamod.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments Analysis of Dose-Response Using the MCP-Mod Analysis Method.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.942
Comments Any p-value <=0.10 indicates successful establishment of dose-response relationship.
Method MCP-Mod Analysis
Comments The adjusted p-value was based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 0.43
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.06
Estimation Comments The t-statistic used for this analysis, 0.41, was based on MCP-Mod Analysis from the linear contrast using optimal coefficients for the pre-specified candidate model Emax.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments Analysis of Dose-Response Using the MCP-Mod Analysis Method.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.995
Comments Any p-value <=0.10 indicates successful establishment of dose-response relationship.
Method MCP-Mod Analysis
Comments The adjusted p-value was based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 0.21
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.06
Estimation Comments The t-statistic used for this analysis, 0.20, was based on MCP-Mod Analysis from the linear contrast using optimal coefficients for the pre-specified candidate model Linear.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments Analysis of Dose-Response Using the MCP-Mod Analysis Method
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.978
Comments Any p-value <=0.10 indicates successful establishment of dose-response relationship.
Method MCP-Mod Analysis
Comments The adjusted p-value was based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value -.32
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.07
Estimation Comments The t-statistic used for this analysis, 0.30, was based on MCP-Mod Analysis from the linear contrast using optimal coefficients for the pre-specified candidate model Logistic.
2.Secondary Outcome
Title Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16
Hide Description [Not Specified]
Time Frame From Augmentation Baseline (Week 8) to Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
Hide Arm/Group Description:
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).
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.
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.
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.
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.
Overall Number of Participants Analyzed 67 68 65 51 63
Mean (Standard Deviation)
Unit of Measure: mmHg
-0.2  (9.55) 0.2  (8.58) 0.5  (9.17) 3.5  (7.82) 2.6  (10.55)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The systolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Mean
Estimated Value 3.16
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.01
Estimation Comments The t-statistic used for this analysis, 3.14, was based on MCP-Mod Analysis for the candidate model EMax.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.032
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The systolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 2.50
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.01
Estimation Comments The t-statistic used for this analysis, 2.48, was based on MCP-Mod Analysis for the candidate model Exponential.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The systolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Mean
Estimated Value 3.28
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.01
Estimation Comments The t-statistic used for this analysis, 3.26 was based on MCP-Mod Analysis for the candidate model Linear.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.010
Comments [Not Specified]
Method MCP-Mod Analysis Method
Comments The systolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 2.91
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.01
Estimation Comments The t-statistic used for this analysis, 2.88, was based on MCP-Mod Analysis for the candidate model Logistic1.
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The systolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 3.15
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.01
Estimation Comments The t-statistic used for this analysis, 3.12, was based on MCP-Mod Analysis for the candidate model Logistic2.
3.Secondary Outcome
Title Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16
Hide Description [Not Specified]
Time Frame From Augmentation Baseline (Week 8) to Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
Hide Arm/Group Description:
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).
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.
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.
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.
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.
Overall Number of Participants Analyzed 67 68 65 51 63
Mean (Standard Deviation)
Unit of Measure: mmHg
-0.1  (6.69) -0.9  (6.64) -0.1  (7.39) 2.8  (6.58) 1.9  (7.45)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.011
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The diastolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 2.16
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.75
Estimation Comments The t-statistic used for this analysis, 2.86 was based on MCP-Mod Analysis for the candidate model Emax.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.023
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The diastolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 1.95
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.75
Estimation Comments The t-statistic used for this analysis, 2.59, was based on MCP-Mod Analysis for the candidate model Exponential.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method Least Squares Means
Comments The diastolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter MCP-Mod Analysis
Estimated Value 2.47
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.75
Estimation Comments The t-statistic used for this analysis, 3.28, was based on MCP-Mod Analysis for the candidate model Linear.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.009
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The diastolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 2.22
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.76
Estimation Comments The t-statistic used for this analysis, 2.93, was based on MCP-Mod Analysis for the candidate model Logistic1.
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The diastolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 2.37
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.76
Estimation Comments The t-statistic used for this analysis, 3.13, was based on MCP-Mod Analysis for the candidate model Logistic2.
4.Secondary Outcome
Title Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16
Hide Description [Not Specified]
Time Frame From Augmentation Baseline (Week 8) to Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
Hide Arm/Group Description:
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).
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.
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.
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.
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.
Overall Number of Participants Analyzed 67 68 65 51 63
Mean (Standard Deviation)
Unit of Measure: bpm
-0.8  (9.95) 0.8  (7.32) 5.3  (8.08) 4.0  (9.80) 6.0  (11.25)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 4.45
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.05
Estimation Comments The t-statistic used for this analysis, 4.24, was based on MCP-Mod Analysis for the candidate model Emax
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 3.52
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.05
Estimation Comments The t-statistic used for this analysis, 3.36, was based on MCP-Mod Analysis for the candidate model Expontential.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 4.30
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.05
Estimation Comments The t-statistic used for this analysis, 4.10, was based on MCP-Mod Analysis for the candidate model Linear.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 4.63
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.05
Estimation Comments The t-statistic used for this analysis, 4.39, was based on MCP-Mod Analysis for the candidate model Logistic1.
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method MCP-Mod Analysis
Comments The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation Estimation Parameter Least Squares Means
Estimated Value 4.63
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.05
Estimation Comments The t-statistic used for this analysis, 4.39 was based on MCP-Mod Analysis for the candidate model Logistic2.
Time Frame [Not Specified]
Adverse Event Reporting Description Safety Analysis Set: All subjects who took at least 1 dose of randomized investigational product and who had at least 1 post-augmentation baseline safety assessment (e.g. coming back for any visit, reporting of an AE or reporting the absence of AEs). Subjects who received only single-blind placebo were not included in this group.
 
Arm/Group Title Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
Hide Arm/Group Description 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). 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. 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. 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. 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.
All-Cause Mortality
Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/78 (0.00%)      0/77 (0.00%)      0/76 (0.00%)      0/78 (0.00%)      1/80 (1.25%)    
Hepatobiliary disorders           
Cholecystitis  0/78 (0.00%)  0 0/77 (0.00%)  0 0/76 (0.00%)  0 0/78 (0.00%)  0 1/80 (1.25%)  1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   20/78 (25.64%)      30/77 (38.96%)      29/76 (38.16%)      36/78 (46.15%)      44/80 (55.00%)    
Gastrointestinal disorders           
Diarrhoea  4/78 (5.13%)  5 2/77 (2.60%)  2 3/76 (3.95%)  3 2/78 (2.56%)  2 5/80 (6.25%)  5
Dry mouth  1/78 (1.28%)  1 2/77 (2.60%)  2 2/76 (2.63%)  2 10/78 (12.82%)  10 10/80 (12.50%)  10
Nausea  1/78 (1.28%)  1 5/77 (6.49%)  5 6/76 (7.89%)  6 1/78 (1.28%)  1 6/80 (7.50%)  7
General disorders           
Fatigue  1/78 (1.28%)  1 0/77 (0.00%)  0 2/76 (2.63%)  2 1/78 (1.28%)  1 4/80 (5.00%)  4
Infections and infestations           
Influenza  2/78 (2.56%)  3 1/77 (1.30%)  1 4/76 (5.26%)  4 4/78 (5.13%)  5 1/80 (1.25%)  1
Nasopharyngitis  0/78 (0.00%)  0 5/77 (6.49%)  5 4/76 (5.26%)  5 2/78 (2.56%)  2 7/80 (8.75%)  8
Upper respiratory tract infection  0/78 (0.00%)  0 3/77 (3.90%)  3 3/76 (3.95%)  3 4/78 (5.13%)  4 3/80 (3.75%)  3
Urinary tract infection  5/78 (6.41%)  5 1/77 (1.30%)  1 2/76 (2.63%)  2 1/78 (1.28%)  1 2/80 (2.50%)  2
Investigations           
Blood pressure increased  0/78 (0.00%)  0 1/77 (1.30%)  1 0/76 (0.00%)  0 3/78 (3.85%)  3 4/80 (5.00%)  4
Metabolism and nutrition disorders           
Decreased appetite  1/78 (1.28%)  1 4/77 (5.19%)  4 5/76 (6.58%)  6 5/78 (6.41%)  5 4/80 (5.00%)  6
Nervous system disorders           
Dizziness  2/78 (2.56%)  2 2/77 (2.60%)  2 2/76 (2.63%)  2 5/78 (6.41%)  5 1/80 (1.25%)  1
Headache  10/78 (12.82%)  12 7/77 (9.09%)  8 5/76 (6.58%)  9 3/78 (3.85%)  5 8/80 (10.00%)  9
Psychiatric disorders           
Bruxism  1/78 (1.28%)  1 0/77 (0.00%)  0 1/76 (1.32%)  1 4/78 (5.13%)  4 6/80 (7.50%)  7
Insomnia  2/78 (2.56%)  2 7/77 (9.09%)  9 2/76 (2.63%)  2 8/78 (10.26%)  10 9/80 (11.25%)  11
Skin and subcutaneous tissue disorders           
Hyperhidrosis  1/78 (1.28%)  1 4/77 (5.19%)  4 0/76 (0.00%)  0 1/78 (1.28%)  1 3/80 (3.75%)  3
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
Results Point of Contact
Name/Title: Study Physician
Organization: Shire
Phone: +1 866 842 5335
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT01435759     History of Changes
Other Study ID Numbers: SPD489-209
2011-003615-28 ( EudraCT Number )
First Submitted: September 15, 2011
First Posted: September 19, 2011
Results First Submitted: February 3, 2015
Results First Posted: February 19, 2015
Last Update Posted: January 8, 2019