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Clinical Study to Test a New Drug to Treat Major Depression (PKI113009)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00976560
First received: September 11, 2009
Last updated: May 11, 2017
Last verified: May 2017
  Purpose

In this randomized, double-blind, multi-centre, placebo controlled, exploratory, adaptive design study, the antidepressant and plasma cytokine lowering effects of the GW856553 will be investigated in adult subjects diagnosed with MDD. Subjects will receive oral doses of GW856553 or placebo for six weeks. Safety, tolerability, pharmacokinetics and pharmacodynamics, defined as biomarkers in blood and clinical symptoms, will be assessed.

The primary endpoint is the change from baseline associated with GW856553 versus placebo at Week 6 in the Bech (6-item HAMD-17) score. Interim analyses of the primary endpoint will be performed throughout the study to potentially adapt the study design by changing the randomization ratio and/ or reducing the total number of subjects to be randomized into the study. Exploratory analyses will be performed by associating changes in cytokine levels and selected clinical symptoms; PK/PD modelling will also be used to identify the most sensitive clinical and biological markers.


Condition Intervention Phase
Depressive Disorder, Major
Drug: GW856553
Other: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: A Six Week Randomized, Double-blind, Multi-center, Placebo-controlled, Exploratory, Adaptive Design Study to Explore the Antidepressant Properties of the p38 MAP Kinase Inhibitor GW856553 Compared to Placebo in Adult Subjects With Major Depressive Disorder

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Change from Randomization (Week 0) associated with GW856553 versus placebo at Week 6 in the Bech (6-item HAMD-17) score. [ Time Frame: At week 6 ]
    HAMD-17 is Hamilton Depression Rating Scale which has 17 questions. The HAMD-17 Total Score was calculated by summing the individual response scores over the 17 individual components of the interview. The highest possible score was 52, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. There were 9 five point questions and 8 three point questions. The responses to the individual questions had values of 0-2 (three points response) or 0-4 (five points response). The BECH scale was extracted from the HAMD-17 and comprises of 6 items out of which 5 are 5 point questions and 1 is 3 point question. The Bech Total Score is calculated by summing the individual response scores. Week 0 values were considered as Baseline.The change from randomization was analysed using suitable Bayesian mixed-effects model repeated measures (BMMRM) assuming missing at random (MAR).


Secondary Outcome Measures:
  • Number of participants with adverse events [ Time Frame: 6 weeks ]
    An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A Serious Adverse Event (SAE) is any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect.

  • Number of participants with suicidality as assessed by the Columbia Suicidality Severity Rating scale score [ Time Frame: 6 weeks ]
    Suicidility can be defined as participants with major depressive disorder who experienced worsening of their depression and/or the emergence of suicidal ideation and behavior. Number of partcipants who experienced suicidality has been listed here. Suicidal ideation of type 4 or 5 on the Columbia Suicide-Severity Rating Scale (C-SSRS) is categorized as suicidility here.

  • Number of participants with abnormal haematology and clinical chemistry values [ Time Frame: Upto Week 6 ]
    Samples for haematology and clinical chemistry were collected on Weeks 1, 5 and 6. The analyzed haematological parameters were Platelet Count, Red Blood Cells Count, White Blood Cells Count, Reticulocyte Count, Hemoglobin and Hematocrit. The analyzed clinical chemistry parameters were Urea, Creatinine, Glucose (fasting), Sodium, Lactate dehydrogenase (LDH), Potassium, Chloride, Calcium, Triglycerides, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Gamma-Glutamyl Transferase (GGT), Alkaline phosphatase, Creatine Kinase (CK), Total and direct bilirubin, Albumin, Total Protein and Total cholesterol. Number of participants with any abnormal haematological or clinical chemistry parametrs are summarized here.

  • Number of participants with abnormal Vital signs (blood pressure, Heart rate) [ Time Frame: Upto week 6 ]
    Vital signs including systolic and diastolic blood pressure and heart rate were taken from screening to follow-up. Number of participants with abnormal systolic blood pressure, diastolic blood pressure and heart rate values were summarized.

  • Number of participants with abnormal Electrocardiogram (ECG) findings [ Time Frame: Upto week 6 ]
    ECG was obtained at Screening, Randomization, Week 2 and Week 6. ECG was recorded using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and Corrected QT (QTc) intervals (Bazett's correction was applied to QTc measurements). Number of participants with abnormal ECG readings are summarized.

  • Changes from Randomization (Week 0)in IL-6 and TNF-alpha associated with GW856553 versus placebo at Week 1 and Week 6 in the morning plasma levels [ Time Frame: Upto week 6 ]
    Interlukin-6 (IL-6) and Tumor Necrosis Factor-Alpha (TNF-alpha) from the participants with Major Depressive Disorder (MDD) were evaluated and analyzed using suitable mixed-effects model repeated measures (MMRM). Exploratory analysis on plasma levels of IL-6 and TNF-alpha were performed. Week 0 values were considered as Baseline.The change from Baseline was calculated by subtracting the baseline values from the individual post-randomisation values.

  • Change from Randomisation Bech Total Score: Bech (6-item HAMD-17) score [ Time Frame: Upto week 6 ]
    The BECH scale was extracted from the HAMD-17 and comprised of 6 items out of which 5 were 5 point questions and 1 was 3 point question. The Bech Total Score was calculated by summing the individual response scores. Due to the small number of items, missing data was not imputed for the Bech Total Score. If any of the 6 items were missing, the total score was not calculated at that visit. The change from randomization was analysed using suitable BMMRM assuming missing at random MAR.

  • Mean HAMD-17 Total Score [ Time Frame: Upto week 6 ]
    HAMD-17 is Hamilton Depression Rating Scale which has 17 questions. The HAMD-17 Total Score was calculated by summing the individual response scores over the 17 individual components of the interview. The highest possible score was 52, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. If not more than 1 response was missing, the total score was caculated as Observed Total Score * [1 + (Sum of the Maximum Score of the missing values/Sum of the Maximum Score of the non -missing values)]. There were 9 five point questions and 8 three point questions. The responses to the individual questions can have values of 0-2 (three points response) or 0-4 (five points response).

  • Mean Inventory of Depressive Symptomatology clinician (IDS-C) total score [ Time Frame: Upto Follow up ]
    The 30 item IDS is available in two versions IDS-C and Inventory of Depressive Symptomatology self-rated (IDS-SR). To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84.If more than one response was missing then the score was calculated using the formula Observed Total Score*[1+(Sum of the Maximum Score of the missing values/Sum of the Maximum Score of the non -missing values)].

  • Mean IDS-SR total score [ Time Frame: Upto Follow up ]
    The 30 item IDS is available in two versions IDS-SR and IDS-C. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84.If more than one response was missing then the score was calculated using the formula Observed Total Score*[1+(Sum of the Maximum Score of the missing values/Sum of the Maximum Score of the non -missing values)].

  • Mean Quick Inventory of Depressive Symptomatology Self Report-16 item (QIDS-SR16) total score derived from the IDS-SR (only at Weeks 0, 2, 4 and 6) [ Time Frame: Weeks 0, 2, 4 and 6 ]
    QIDS-SR assesses symptoms severity of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criterion for major depressive disorder. It contains 16 separate items (corresponding to 16 items of the much longer IDS-SR), defining 9 DSM-IV symptom criterion domains. A total score was obtained by summing scores on each domain. The QIDS-SR total score was calculated by summing over the domain scores. The highest possible score was 27, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. Due to the small number of items, missing data was not imputed for the QIDS-SR total score.

  • Percentage of IDS-C responders (participants with a reduction in total score of ≥50% from Randomization at Week 6/study exit). [ Time Frame: Week 6 ]
    The 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. A responder is a participant who has a ≥50% reduction from randomisation in the total score for IDS-C. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as {(Total score at post randomisation visit - Total score at randomisation visit)/ Total score at randomisation visit} * 100%. Responders were those with values of ≤ -50%. The change from randomization was analysed using suitable Bayesian mixed-effects model repeated measures (BMMRM) assuming missing at random (MAR).

  • Percentage of IDS-C remitters (participants whose total score was ≤ 15 at Week 6/study exit). [ Time Frame: Week 6 ]
    The 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. IDS-C total score was calculated for each participant at each timepoint and those participants with non-missing values for IDS-C total scores were categorised as having an IDS-C for the respective endpoint of ≤ 15 or > 15. Participants whose total score was ≤ 15 were included here.

  • Percentage of IDS-SR responders (participants with a reduction in total score of ≥ 50% from Randomization at Week 6/study exit). [ Time Frame: Week 6 ]
    The 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. A responder is a participant who has a ≥50% reduction from randomisation in the total score for IDS-SR. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as {(Total score at post randomisation visit - Total score at randomisation visit)/ Total score at randomisation visit} * 100%. Responders were those with values of ≤ -50%. The change from randomization was analysed using suitable Bayesian mixed-effects model repeated measures (BMMRM) assuming missing at random (MAR).

  • Percentage of IDS-SR remitters (participants whose total score was ≤ 15 at Week 6/study exit). [ Time Frame: Week 6 ]
    he 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. IDS-SR total score was calculated for each participant at each timepoint and those participants with non-missing values for IDS-SR total scores were categorised as having an IDS-C for the respective endpoint of ≤ 15 or > 15. Participants whose total score was ≤ 15 were included here.

  • Percentage of QIDS-SR16 responders (participants with a reduction in total score of ≥ 50% from Randomization at Week 6/study exit). [ Time Frame: Week 6 ]
    QIDS-SR assesses symptoms severity of DSM-IV diagnostic criterion for major depressive disorder. It contains 16 separate items (corresponding to 16 items of the much longer IDS-SR), defining 9 DSM-IV symptom criterion domains. A total score was obtained by summing scores on each domain.The highest possible score was 27, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. Due to the small number of items, missing data was not imputed for the QIDS-SR total score. A responder is a participant who has a ≥50% reduction from randomisation in the total score for that given endpoint. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as {(Total score at post randomisation visit - Total score at randomisation visit)/ Total score at randomisation visit} * 100%. Responders were those with values of ≤ -50%.

  • Percentage of QIDS-SR16 remitters (subjects whose total score was ≤ 5 at Week 6/study exit). [ Time Frame: Week 6 ]
    QIDS-SR assesses symptoms severity of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criterion for major depressive disorder. It contains 16 separate items (corresponding to 16 items of the much longer IDS-SR), defining 9 DSM-IV symptom criterion domains. A total score was obtained by summing scores on each domain. The QIDS-SR total score was calculated by summing over the domain scores. The highest possible score was 27, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. Due to the small number of items, missing data was not imputed for the QIDS-SR total score. The QIDS total score was calculated for each subject at each timepoint and those subjects with no missing value for QIDS total score was categorised as having a QIDS total score of ≤ 5 or > 5. Participants whose total score was ≤ 5 were included here.

  • Percentage of Bech responders (participants with a reduction in total score of ≥ 50% from Randomization at Week 6/study exit). [ Time Frame: Week 6 ]
    The BECH scale was extracted from the HAMD-17 and comprised of 6 items out of which 5 were 5 point questions and 1 was 3 point question. The Bech Total Score was calculated by summing the individual response scores. Due to the small number of items, missing data was not imputed for the Bech Total Score. If any of the 6 items were missing, the total score was not calculated at that visit. A responder is a participant who has a ≥50% reduction from randomisation in the total score for that given endpoint. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as {(Total score at post randomisation visit - Total score at randomisation visit)/ Total score at randomisation visit} * 100%. Responders were those with values of ≤ -50%. The change from randomization was analysed using suitable Bayesian mixed-effects model repeated measures (BMMRM) assuming missing at random (MAR).

  • Percentage of Bech remitters (participants whose total score was ≤ 4 at Week 6/study exit). [ Time Frame: Week 6 ]
    The BECH scale was extracted from the HAMD-17 and comprised of 6 items out of which 5 were 5 point questions and 1 was 3 point question. The Bech Total Score was calculated by summing the individual response scores. Due to the small number of items, missing data was not imputed for the Bech Total Score. If any of the 6 items were missing, the total score was not calculated at that visit. The change from randomization was analysed using suitable BMMRM assuming missing at random MAR. The BECH total score was calculated for each subject at each timepoint and those subjects with no missing value for BECH total score were categorised as having a BECH total score of ≤ 4 or > 4.

  • Percentage of participants with a Clinicians Global Impression of Improvement (CGI-I) score of 1 ("very much improved") or 2 ("much improved") at Weeks 1, 2, 3, 4, 5, 6 and at follow-up. [ Time Frame: Weeks 1, 2, 3, 4, 5 and 6 ]
    The number of subjects with a CGI-I score of either 1 ("very much improved") or 2 (much improved") were grouped together for each timepoint. Subjects with no missing CGI-I scores were categorised as having a CGI-I score of ≤ 2 or > 2.

  • Changes from Randomization (Week 0) associated with GW856553 versus placebo at Weeks 1, 2, 3,4, 5, 6 and at follow-up in the CGI-S score [ Time Frame: Upto Week 6 ]
    The number of subjects with a CGI-I score of either 1 ("very much improved") or 2 (much improved") were grouped together for each timepoint. Subjects with no missing CGI-I scores were categorised as having a CGI-I score of ≤ 2 or > 2. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as {(Total score at post randomisation visit - Total score at randomisation visit)/ Total score at randomisation visit} * 100%. The change from randomization was analysed using suitable Bayesian mixed-effects model repeated measures (BMMRM) assuming missing at random (MAR).


Enrollment: 180
Actual Study Start Date: September 25, 2009
Study Completion Date: July 7, 2010
Primary Completion Date: July 7, 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dose 1
GW856553 2.5 mg BID
Drug: GW856553
Wet granulated tablets, film coated white, 9mm round, biconvex, plain faced, containing 2.5 mg of GW856553
Experimental: Dose 2
GW856553 7.5 mg BID
Drug: GW856553
Wet Granulated, film coated white, 9mm round, biconvex, plain faced tablets, containing 7.5 mg of GW856553
Placebo Comparator: Placebo
Matching Placebo BID
Other: Placebo
Film coated white, 9mm round, biconvex, plain faced tablets obtained by direct compression.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Adult subjects with primary diagnosis of moderate to severe MDD without psychotic features, for at least 4 weeks and one previous MDD episode
  • Males or Females who agree to use protocol specified contraception if of child bearing potential
  • BMI 18.5-35.0 kg/m2
  • Normal liver function tests

Key Exclusion Criteria:

  • History of liver disease or positive hepatitis B surface antigen or hepatitis C antibody in the last 3 months
  • Elevated liver function tests on >2 ocassions in the last 7 months
  • Significant medical illness, autoimmune disease or infectious disease
  • Pregnant or nursing females
  • Excessive and regular alcohol consumption
  • History of substance abuse or dependence in past 6 months or positive urine drug screen
  • Significant suicidal or homicidal risk
  • Currently receiving chronic biological or pharmacologic anti-inflammatory therapy or is not euthyroid
  • Psychoactive drugs within 1 week or 5 half lives of randomization visit
  • Treatment resistant subjects
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00976560

Locations
United States, Illinois
GSK Investigational Site
Hoffman Estates, Illinois, United States, 60169
GSK Investigational Site
Park Ridge, Illinois, United States, 60068
United States, New York
GSK Investigational Site
New York, New York, United States, 10128
United States, Ohio
GSK Investigational Site
Columbus, Ohio, United States, 43210
Bulgaria
GSK Investigational Site
Pazardzhik, Bulgaria, 4400
GSK Investigational Site
Plovdiv, Bulgaria, 4000
GSK Investigational Site
Ruse, Bulgaria
GSK Investigational Site
Sofia, Bulgaria, 1113
Estonia
GSK Investigational Site
Tartu, Estonia, 50417
Germany
GSK Investigational Site
Huettenberg, Hessen, Germany, 35625
GSK Investigational Site
Schwerin, Mecklenburg-Vorpommern, Germany, 19053
GSK Investigational Site
Achim, Niedersachsen, Germany, 28832
GSK Investigational Site
Westerstede, Niedersachsen, Germany, 26655
GSK Investigational Site
Bielefeld, Nordrhein-Westfalen, Germany, 33647
GSK Investigational Site
Dresden, Sachsen, Germany, 01097
GSK Investigational Site
Berlin, Germany, 10629
Russian Federation
GSK Investigational Site
Moscow, Russian Federation, 107076
GSK Investigational Site
Moscow, Russian Federation, 125367
GSK Investigational Site
Samara, Russian Federation, 443016
GSK Investigational Site
Smolensk, Russian Federation, 214 019
GSK Investigational Site
St-Petersburg, Russian Federation
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Study Data/Documents: Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: 113009
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 113009
For additional information about this study please refer to the GSK Clinical Study Register
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 113009
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: 113009
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 113009
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 113009
For additional information about this study please refer to the GSK Clinical Study Register
Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: 113009
For additional information about this study please refer to the GSK Clinical Study Register

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00976560     History of Changes
Other Study ID Numbers: 113009
Study First Received: September 11, 2009
Last Updated: May 11, 2017
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Keywords provided by GlaxoSmithKline:
Lack of interest and energy
Psychomotor retardation
Cytokines
Major Depressive disorder

Additional relevant MeSH terms:
Depressive Disorder
Depression
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Behavioral Symptoms

ClinicalTrials.gov processed this record on May 22, 2017