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Study to Evaluate the Efficacy, Safety and Tolerability of Bupropion Hydrochloride Extended-release Tablet, and Escitalopram Oxalate Capsule in Subjects With Major Depressive Disorder

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ClinicalTrials.gov Identifier: NCT02191397
Recruitment Status : Completed
First Posted : July 16, 2014
Last Update Posted : March 6, 2017
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:

This multi-centre study will follow a randomised, double-blind, parallel-group, active-controlled design and will evaluate the efficacy, safety and tolerability of bupropion extended-release (XL) (300 mg/day) compared with escitalopram (10-20 mg/day) in outpatients and inpatients with major depressive disorder (MDD). The total duration of the study will be 11 weeks consisting of three phases. The screening phase (phase I) will be lasting for 0-14 days, subjects will be randomised to bupropion XL or escitalopram in a 1:1 ratio for acute phase treatment phase (phase II) for 8 weeks. There are 3 dose levels during this acute treatment phase. The 3-dose level plan is designed to ensure each drug is titrated according to the prescribing information and to reach an optimal clinical dose. Finally patients will enter the taper phase (phase III) for up to 1 week to assess and reduce the possible withdrawal symptoms.

In China almost all existing antidepressants are available on the market, but bupropion XL has not yet been approved. This Phase III clinical trial will be used for the purpose of registering bupropion XL in China.


Condition or disease Intervention/treatment Phase
Depressive Disorder, Major Drug: Bupropion Drug: Bupropion Matching Placebo Drug: Escitalopram Drug: Escitalopram Matching Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 529 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multi-centre, Randomised, Double-blind, Parallel Active-controlled Study Evaluating the Efficacy, Safety and Tolerability of Bupropion Hydrochloride Extended-release (Bupropion XL 300mg Once Daily), Escitalopram Oxalate (Escitalopram, 10mg-20mg Once Daily) in Subjects With Major Depressive Disorder
Study Start Date : February 2015
Actual Primary Completion Date : October 2016
Actual Study Completion Date : October 2016


Arm Intervention/treatment
Experimental: Bupropion Treatment Arm
Subject will receive bupropion in 3 dose levels along with escitalopram matching placebo to maintain the blind in acute treatment phase. At dose level 1 (Week 0 to Week 1), Subjects will receive bupropion XL 150 milligram (mg) per day for a week. At dose level 2 (Week 1 to Week 4), bupropion XL dose will be increased to 300mg/day for further 3 weeks. At dose level 3 (Week 4 to Week 8), bupropion XL dose will be maintained at 300mg/day. Subjects intolerable to dose level 3 will be allowed to down titrate to dose level 2 at anytime, and maintain the dose until the end of acute treatment phase (Week 8, Visit 7). At the end of acute treatment phase, the dose of bupropion XL will be reduced to 150mg/day for 1 week before discontinuation.
Drug: Bupropion
Bupropion is an extended-release plain creamy white colored tablet which contains bupropion hydrochloride equivalent to 150 mg of bupropion.

Drug: Escitalopram Matching Placebo
Escitalopram oxalate matching placebo tablets will be supplied to maintain blinding

Active Comparator: Escitalopram Treatment Arm
Subject will receive escitalopram in 3 dose levels along with bupropion matching placebo to maintain the blind in acute treatment phase. At dose level 1 (Week 0 to Week 1), Subjects will receive escitalopram 10mg/day for a week. At dose level 2 (Week 1 to Week 4), escitalopram dose will be maintained at 10mg/day for further 3 weeks. At dose level 3 (Week 4 to Week 8), escitalopram dose will be increased to 20mg/day. Subjects intolerable to dose level 3 will be allowed to down titrate to dose level 2 at anytime, and maintain the dose until the end of acute treatment phase (Week 8, Visit 7). At the end of acute treatment phase, the dose of escitalopram 20mg/day, the dose will be reduced to 10 mg/day for 1 week before discontinuation, while those receiving 10mg/day will discontinuation directly.
Drug: Bupropion Matching Placebo
Bupropion hydrochloride matching placebo tablets will be supplied to maintain blinding

Drug: Escitalopram
Escitalopram is available as a Swedish orange capsule containing escitalopram oxalate equivalent to 10 mg of escitalopram.




Primary Outcome Measures :
  1. Mean change in Hamilton Depression Rating Scale - 17 (HAMD-17) total score from baseline to end of acute treatment phase (Week 8) [ Time Frame: Baseline (Week 0) and Week 8 ]
    HAMD-17 is a 17-item questionnaire used to assess the severity of depression and symptom improvement during the treatment. HAMD-17 has a total score in a range of 0 (not present) to 52 (severe).


Secondary Outcome Measures :
  1. Response rate based on HAMD-17 total scores [ Time Frame: Up to Week 8 ]
    HAMD-17 is a 17-item questionnaire used to assess the severity of depression and symptom improvement during the treatment. HAMD-17 has a total score range of 0 (not present) to 52 (severe). Response is defined as decrease in HAMD-17 total score at end-of-treatment relative to baseline by at least 50%.

  2. Remission rate based on HAMD-17 total scores [ Time Frame: Up to Week 8 ]
    Remission is defined as HAMD-17 total score at end-of-treatment <=7.

  3. Sustained response rate based on HAMD-17 total scores [ Time Frame: Up to Week 8 ]
    Sustained response is defined as response at end-of-treatment and an earlier visit and decrease in HAMD-17 total score without missing score at all visits between these two visits by at least 40%.

  4. Sustained remission rate based on HAMD-17 total scores [ Time Frame: Up to Week 8 ]
    Sustained remission is defined as remission at end-of-treatment and an earlier visit and HAMD-17 total score without missing score at all visits between these two visits <= 8.

  5. Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at weeks 1, 2, 4, 6, 8 [ Time Frame: Baseline (Week 0), Weeks 1, 2, 4, 6 and 8 ]
    MADRS is a 10-point rating scale used to assess the efficacy of antidepressant treatment. Each item is scored on a scale of 0-6, with a total score range of 0-60.

  6. Change from baseline in HAMD-17 Item 1 depressed mood item score at weeks 1, 2, 4, 6, 8 [ Time Frame: Baseline (Week 0), Weeks 1, 2, 4, 6 and 8 ]
    HAMD-17 Item 1 depressed mood item assesses feelings of sadness, hopelessness, helplessness, and worthlessness on a scale of 0 to 4

  7. Change from baseline in HAMD-17 anxiety/somatization subscale score at Weeks 1, 2, 4, 6, 8 [ Time Frame: Baseline (Week 0), Weeks 1, 2, 4, 6 and 8 ]
    Anxiety/somatization subscale score is the sum of scores of items 10, 11, 12, 13, 15 and 17.

  8. Change from baseline in HAMD-17 retardation subscale score (sum of scores of items 1, 7, 8 and 14) at Weeks 1, 2, 4, 6, 8 [ Time Frame: Baseline (Week 0), Weeks 1, 2, 4, 6 and 8 ]
    Retardation subscale score is the sum of scores of items 1, 7, 8 and 14 where Item 1 is depressed mood, 7-work and activities, 8-retardation-psychomotor and 14-genital symptoms.

  9. Change from baseline in HAMD-17 sleep disorder subscale at Weeks 1, 2, 4, 6, 8 [ Time Frame: Baseline (Week 0), Weeks 1, 2, 4, 6 and 8 ]
    Sleep disorder subscale score is the sum of scores of items 4, 5 and 6 where Item 4 is insomnia early, 5-insomina middle and 6- insomnia late

  10. Change from baseline in Clinical Global Impression-Severity of Illness Scale (CGI-S) score at Weeks 1, 2, 4, 6, 8. [ Time Frame: Baseline (Week 0), Weeks 1, 2, 4, 6 and 8 ]
    CGI-S records the severity of illness at specific time points, with a range of responses from 1 (normal) to 7 (Among the most extremely ill patients).

  11. Percentage of subjects with a CGI-I score of 1 ("very much improved") or 2 ("much improved") at Weeks 1, 2, 4, 6, 8 [ Time Frame: Baseline (Week 0), Weeks 1, 2, 4, 6 and 8 ]
    Clinical Global Impression Global Improvement (CGI-I) rating, indicate assessment of the subject's total improvement or worsening compared to the subject's condition at the Baseline Visit, whether or not the improvement or worsening is thought to be treatment related.

  12. Number of subject with Adverse events [ Time Frame: Up to Week 10 ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  13. Change from baseline in vitals sign [ Time Frame: Up to Week 10 ]
    Vital sign measurements includes systolic and diastolic blood pressure and pulse rate.

  14. Change from baseline in -lead electrocardiogram (ECG) [ Time Frame: Up to Week 10 ]
    The 12-lead ECG will be performed in accordance with the study procedures.

  15. Change from baseline in clinical laboratory test [ Time Frame: Up to Week 10 ]
    Clinical laboratory parameters include: Hematology, clinical chemistry and urinalysis parameters

  16. Change from baseline in changes in sexual functioning questionnaire (CSFQ) [ Time Frame: Up to Week 8 ]
    CSFQ is a 14-item subject-rated scale assessing changes in sexual activity and functioning; structured interview/questionnaire, designed to measure medication related changes in sexual functioning. 5 dimensions of sexual behavior: pleasure; desire/frequency; desire/interest; arousal; orgasm. Total score: obtained across all 5 dimensions, ranges from 14 to 70.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must have the ability to effectively communicate with investigator, complete study related documents, comprehend the key components of the consent form and must provide written informed consent to participate in the study prior to any study-specific assessments or procedures.
  • An in- patient or out-patient (male or female) and aged >=18 years.
  • A diagnosis of MDD, nonpsychotic, single episode or recurrent, Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) (296.2/296.3), utilizing the Mini International Neuropsychiatric Interview (MINI).
  • Established MDD diagnosis with a duration of at least 4 weeks.
  • HAMD-17 total score of >=20 and a CGI-S score of >=4 at both the Screening Visit and the Baseline Visit.
  • Subject must be in general good health and be considered clinically appropriate for therapy with bupropion or escitalopram, based upon the investigator's overall clinical evaluation.
  • Female patients of child-bearing potential only: patients must not be lactating and must test negative for pregnancy at screening and agree to use a medically accepted method of birth control during the study.
  • Liver function tests: alanine aminotransferase (ALT) <2x upper limit of normal (ULN); alkaline phosphatase and bilirubin <=1.5xULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Corrected QT (QTc) criteria: QTc <450 milliseconds (msec) or QTc <480msec for patients with bundle branch block. The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or machine or manual overread. For subject eligibility and withdrawal, QTcF will be used. For purpose of data analysis, QTcF will be used. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period.

Exclusion Criteria:

  • Has been diagnosed or received treatment for a primary Axis I disorder with the exception of MDD (including current or past diagnosis of anorexia nervosa or bulimia). Additionally, subjects diagnosed with dysthymic disorder within the past 2 years will be excluded.
  • Current DSM-IV Axis II diagnosis that suggests non-compliance with the protocol.
  • A subject who, in the assessment with the Columbia Suicide Severity Rating Scale (C-SSRS) and investigator's judgment, poses suicidal risk, or had suicide attempt or behavior within 6 months prior to the Screening Visit.
  • Current or past history of seizure disorder or brain injury (traumatic or disease related); or any condition which, in the opinion of the investigator, predisposed to seizure; subjects treated with other medications or treatment regimes that lower seizure threshold. Note: single childhood febrile seizure is not exclusionary.
  • In the Investigator's judgment, presence of clinically significant laboratory test results (including ECG, hematology, chemistry and urine), or the conditions which render patients unsuitable for the study (such as serious cardiovascular disease, uncontrolled hypertension, liver or renal insufficiency) and pose a safety concern or interfere with the accurate safety and efficacy assessments. Subjects with co-morbidities (such as diabetes, hypertension, hypothyroid, chronic respiratory diseases or other physical illness) were eligible if their condition had been stable for at least three months and they had been receiving standard therapy for the condition for at least three months.
  • Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
  • Frequent and/or severe allergic reactions with multiple medications, or history of a medically significant adverse effect (including allergic reaction) from any medications or compounds in the study.
  • Use of prohibited psychotropic drugs not allowed within seven days (14 days for monoamine oxidase inhibitors (MAOIs), 30 days for fluoxetine) prior to the Baseline Visit.
  • Subjects who have attended any studies investigating bupropion or escitalopram 6 months prior to this study, or use of bupropion or escitalopram in the last 4 weeks.
  • Participation in other clinical studies unrelated to the current illness within 30 days or participation in other clinical studies related to the current illness within 3 months.
  • Initiation of systematic psychotherapy within three months prior to the Screening Visit, or plans to initiate systematic psychotherapy during the study.
  • Received electroconvulsive therapy (ECT), modify electroconvulsive therapy (MECT), transcranial magnetic stimulation (TMS), or other physical therapy within the 6 months prior to the Screening Visit.
  • Previous failure of bupropion or escitalopram treatment with adequate courses and doses.
  • Previous or present failure of two different classes of antidepressants treatment with adequate courses (e.g. maximum labelled doses for >=4 weeks).
  • History of substance abuse (alcohol or drugs) or substance dependence within 12 months (as defined in the DSM-IV).
  • Other conditions which, in the Investigator's judgment, render patients unsuitable for the clinical study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02191397


Locations
China, Guangdong
GSK Investigational Site
Guangzhou, Guangdong, China, 510180
China, Guangxi
GSK Investigational Site
Nanning, Guangxi, China, 530021
China, Guizhou
GSK Investigational Site
Guiyang, Guizhou, China, 550004
China, Hebei
GSK Investigational Site
Baoding, Hebei, China, 071000
China, Heilongjiang
GSK Investigational Site
Harbin, Heilongjiang, China, 150070
China, Henan
GSK Investigational Site
Changsha, Henan, China, 410011
China, Hunan
GSK Investigational Site
Changsha, Hunan, China
China, Jiangsu
GSK Investigational Site
Nanjing, Jiangsu, China, 210029
China, Shaanxi
GSK Investigational Site
Xian, Shaanxi, China, 710032
China, Shanxi
GSK Investigational Site
Taiyuan, Shanxi, China
GSK Investigational Site
Xi'an, Shanxi, China
China, Yunnan
GSK Investigational Site
Kunming, Yunnan, China, 650032
China, Zhejiang
GSK Investigational Site
Hangzhou, Zhejiang, China, 310003
China
GSK Investigational Site
Beijing, China, 100083
GSK Investigational Site
Beijing, China, 100088
GSK Investigational Site
Beijing, China, 100096
GSK Investigational Site
Guangzhou, China, 510370
GSK Investigational Site
Shanghai, China, 200030
GSK Investigational Site
Shanghai, China, 200065
GSK Investigational Site
Wuhan, China
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02191397     History of Changes
Other Study ID Numbers: 114589
First Posted: July 16, 2014    Key Record Dates
Last Update Posted: March 6, 2017
Last Verified: March 2017

Keywords provided by GlaxoSmithKline:
Escitalopram
Major depressive disorder
Non-inferiority
Bupropion

Additional relevant MeSH terms:
Disease
Depressive Disorder
Depression
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Pathologic Processes
Behavioral Symptoms
Benzocaine
Dexetimide
Citalopram
Bupropion
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Antiparkinson Agents
Anti-Dyskinesia Agents
Parasympatholytics