Clinical Study to Test a New Drug to Treat Major Depression

Depressive Disorder, Major Clinical Trial

— PKI113009  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00976560
• Other study ID #: 113009
• Status: Completed
• Phase: Phase 2
• First received: September 11, 2009
• Last updated: October 11, 2017
• Start date: September 25, 2009
• Est. completion date: July 7, 2010

Study information

• Verified date: October 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 128
• Est. completion date: July 7, 2010
• Est. primary completion date: July 7, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major

Intervention

Drug:
• GW856553
Wet Granulated, film coated white, 9mm round, biconvex, plain faced tablets, containing 7.5 mg of GW856553

Other:
• Placebo
Film coated white, 9mm round, biconvex, plain faced tablets obtained by direct compression.

Locations

Country	Name	City	State
Bulgaria	GSK Investigational Site	Pazardzhik
Bulgaria	GSK Investigational Site	Plovdiv
Bulgaria	GSK Investigational Site	Ruse
Bulgaria	GSK Investigational Site	Sofia
Estonia	GSK Investigational Site	Tartu
Germany	GSK Investigational Site	Achim	Niedersachsen
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Bielefeld	Nordrhein-Westfalen
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Huettenberg	Hessen
Germany	GSK Investigational Site	Schwerin	Mecklenburg-Vorpommern
Germany	GSK Investigational Site	Westerstede	Niedersachsen
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Samara
Russian Federation	GSK Investigational Site	Smolensk
Russian Federation	GSK Investigational Site	St-Petersburg
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Hoffman Estates	Illinois
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Park Ridge	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Bulgaria,  Estonia,  Germany,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Randomization (Week 0) Associated With GW856553 Versus Placebo at Week 6 in the Bech (6-item HAMD-17 [Hamilton Depression Rating Scale]) Score.	HAMD-17 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 was calculated by summing the individual response scores and ranged from 0 to 22, with higher scores indicating more severe depression. 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).	At Week 6
Secondary	Number of Participants With Adverse Events	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. The AEs row include participants with SAEs.	6 Weeks
Secondary	Number of Participants With Suicidality as Assessed by the Columbia Suicidality Severity Rating Scale Score	Suicidility was 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 were reported. On the Suicidal Ideation scale of the Columbia Suicide-Severity Rating Scale (C-SSRS) participants were scored as "non-suicidal" (00), "wish to be dead" (01), "non-specific active suicidal thoughts" (02), "active suicidal ideation with associated thoughts of methods without intent" (03), "active suicidal ideation with some intent to act on suicidal thoughts without clear plan" (04) and "active suicidal ideation with plan and intent" (05), based on the most severe score (5 being the most severe).Suicidal ideation of type 4 or 5 in the C-SSRS was categorized as suicidility here.	Upto Week 6
Secondary	Number of Participants With Abnormal Haematology and Clinical Chemistry Values	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.	Upto Week 6
Secondary	Number of Participants With Abnormal Vital Signs (Blood Pressure, Heart Rate)	Vital signs including systolic and diastolic blood pressure and heart rate were taken from day 1 upto follow-up visit. Number of participants with abnormal systolic blood pressure, diastolic blood pressure and heart rate values were summarized.	Up to follow-up Visit (Day 53)
Secondary	Number of Participants With Abnormal Electrocardiogram (ECG) Findings	ECG was obtained at 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.	Up to follow-up Visit (Day 53)
Secondary	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	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.	Upto Week 6
Secondary	Change From Randomisation Bech Total Score: Bech Score	HAMD-17 has 17 questions. 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 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 and ranged from 0 to 22, with higher scores indicating more severe depression. 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 Bayesian Mixed-Effects Models for Repeated Measures (BMMRM) assuming missing at random MAR.	Up to Follow-up visit (Day 53)
Secondary	Mean HAMD-17 Total Score	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).	Up to Follow-up visit (Day 53)
Secondary	Mean Inventory of Depressive Symptomatology Clinician (IDS-C) Total Score	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 weight loss or weight gain, appetite loss or appetite gain is scored because only one member of each pair is applicable to any given respondent. The standard total score is obtained by summing the ratings of 28 of the 30 items. Each of the 28 items is scored on a 0 to 3 scale (0 - the absence of pathology; 3 - severe pathology). The total scores range from 0 to 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)].	Up to Follow-up visit (Day 53)
Secondary	Mean IDS-SR Total Score	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 weight loss or weight gain, appetite loss or appetite gain is scored because only one member of each pair is applicable to any given respondent. The standard total score is obtained by summing the ratings of 28 of the 30 items. Each of the 28 items is scored on a 0 to 3 scale (0 - the absence of pathology; 3 - severe pathology). The total scores range from 0 to 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)].	Up to Week 6
Secondary	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)	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.	Weeks 0, 2, 4 and 6
Secondary	Percentage of IDS-C Responders (Participants With a Reduction in Total Score of =50% From Randomization at Week 6/Study Exit).	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).	Week 6
Secondary	Percentage of IDS-C Remitters (Participants Whose Total Score Was = 15 at Week 6/Study Exit).	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.	Week 6
Secondary	Percentage of IDS-SR Responders (Participants With a Reduction in Total Score of = 50% From Randomization at Week 6/Study Exit).	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 BMMRM assuming missing at random.	Week 6
Secondary	Percentage of IDS-SR Remitters (Participants Whose Total Score Was = 15 at Week 6/Study Exit).	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-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.	Week 6
Secondary	Percentage of QIDS-SR16 Responders (Participants With a Reduction in Total Score of = 50% From Randomization at Week 6/Study Exit).	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%.	Week 6
Secondary	Percentage of QIDS-SR16 Remitters (Subjects Whose Total Score Was = 5 at Week 6/Study Exit).	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.	Week 6
Secondary	Percentage of Bech Responders (Participants With a Reduction in Total Score of = 50% From Randomization at Week 6/Study Exit).	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 BMMRM assuming missing at random.	Week 6
Secondary	Percentage of Bech Remitters (Participants Whose Total Score Was = 4 at Week 6/Study Exit).	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 perticipants with no missing value for BECH total score were categorised as having a BECH total score of = 4 or > 4.	Week 6
Secondary	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 and 6.	The number of participantts with a CGI-I score of either 1 ("very much improved") or 2 (much improved") were grouped together for each timepoint. Participants with no missing CGI-I scores were categorised as having a CGI-I score of = 2 or > 2.	Weeks 1, 2, 3, 4, 5 and 6
Secondary	Assessment of Clinical Global Impression-Severity of Illness (CGI-S) up to 6 Weeks	CGI-S assesses the severity of the participant's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill). The number of participants with a CGI-I score of either 1 ("very much improved") or 2 (much improved") were grouped together for each timepoint. Participants with no missing CGI-S scores were categorised as having a CGI-S score of = 2 or > 2. The total score was calculated for each participant at each timepoint and percentage was calculated.	Upto Week 6

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