Controlled-release Paroxetine in Major Depressive Disorder (Double-blind, Placebo-controlled Study)

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy of controlled-release (CR) formulation of paroxetine orally administered to patients with major depressive disorder (MDD) at a dose level in the range of 25 - 50 mg/day (initial dose level, 12.5 or 25 mg/day) once daily after evening meal for 8 weeks based on the decrease in HAM-D (Hamilton Depression Rating Scale) total score, to evaluate the safety based on adverse events, laboratory data and vital signs, and to describe the efficacy and safety of immediate release (IR) formulation of paroxetine.

Official Title
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A Randomized, Double-blind, Placebo Controlled Trial to Evaluate the Clinical Effects of Controlled Release Paroxetine in the Treatment of Major Depressive Disorder

Conditions
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Depressive Disorder

Intervention / Treatment
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* Drug: paroxetine IR 10mg tablet
* Drug: paroxetine IR 20mg tablet
* Drug: matched placebo to paroxetine IR 10mg or 20mg
* Drug: Paroxetine CR 12.5mg tablet
* Drug: Paroxetine CR 25mg tablet
* Drug: matched placebo to paroxetine CR 12.5mg or 25mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: <at the start of placebo run-in phase> Only the patients who meet all of the following conditions at Week -1 (at the start of placebo run-in phase) will be enrolled in this study. The hospitalization status will be no object. and Gender: No object. Target disease: Patients diagnosed as having one of the following depressive disorders based on DSM-IV-TR classification in conjunction with M.I.N.I. (The Mini International Neuropsychiatric Interview, Japanese version 5.0.0. [2003]) and showing currently a symptom of depression or depressed sate Major depressive disorder, single episode (296.2) (excluding those accompanied by comorbid psychiatric disorders) Major depressive disorder, recurrent (296.3) (excluding those accompanied by comorbid psychiatric disorders) Age: >= 20 years (at the time of obtaining consent) Consent: Patients from whom written consent to participate in this study can be obtained Gender: Female patients of childbearing potential can be enrolled. But, such patients who can be enrolled are limited to only those who are negative in the pregnancy test performed at the start of the placebo run-in phase and who agree to receive a pregnancy test at the time point defined in the study period and surely perform any of the contraceptive methods. Male subjects must abstain from (or use a condom during) sexual intercourse with a pregnant or lactating female. Male subjects must abstain from or use a condom plus spermicidal agent (foam/gel/film/cream/suppository) during sexual intercourse with a female of child-bearing potential. Patients whose HAM-D (17 items) total score is >= 20 points Patients whose duration of current episode at least 12 weeks but no longer than 24 months Patients whose score of depressed mood (HAM-D Item 1) is >= 2 points QTc<450 millisecond (msec) or <480 msec for patients with Bundle Branch Block - values based on either single ECG values or triplicate ECG averaged QTc values obtained over a brief recording period. For the purposes of these criteria, QTc B (Bazett's correction) is defined as (QT interval [msec]) /(square root of RR interval [seconds]) <at the start of treatment phase> Only the patients who meet all of the following conditions at Week -1 (at the start of the placebo run-in phase) and Week 0 (at the start of treatment phase) can be shifted to the treatment phase. Patients whose HAM-D (17 items) total score is >=20 points Patients whose score of depressed mood (HAM-D Item 1) is >=2 points Exclusion Criteria: <at the start of placebo run-in phase> The patients who are meeting any of the following conditions at Week -1 (at the start of placebo run-in phase) must not be enrolled in this study. Patients whose primary diagnosis is a disorder classified to Axis I other than major depressive disorder in DSM-IV-TR classification (dysthymic disorder, eating disorder, specific phobia (monophobia), posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder, etc.) Patients with a current DSM-IV-TR Axis II diagnosis that suggested non-responsiveness to pharmacotherapy or non- compliance with the protocol (e.g., antisocial or borderline personality disorder) Patients with a history or complication of another (non-MDD) mental disorder (schizophrenia, etc.) Patients with a history or complication of manic episodes Patients diagnosed as having an attentional deficit disorder or hyperactivity disorder Patients diagnosed as having a pervasive development disorder or mental retardation Patients diagnosed as abusing or dependent on alcohol or drug within one year before the Week -1 visit Patients who have undergone electroconvulsive therapy within one year before the Week -1 visit for the treatment of the current episode Patients who have a history of treatment with depot neuroleptics Patients with a history of serotonin syndrome or neuroleptic malignant syndrome Patients with a >= 3-point score of suicide (HAM-D Item 3) or patients whose Columbia Suicide Severity Rating Scale (C-SSRS) assessment suggests that they are or have been at significant risk for harming themselves or have actually harmed themselves, or who, in the opinion of the investigator (subinvestigator), are at significant risk for harming self or others. Patients with a history of suicide attempt, self-injurious action (excluding action with no intention of suicide) or overdosage (excluding apparently accidental overdosage) Patients who have taken another investigational product or a drug used in a post-marketing clinical study within 12 weeks before the Week -1 visit Patients with glaucoma Patients with a convulsive disorder such as epilepsy or a history of it Patients using a drug increasing an onset risk of bleeding, patients with a bleeding tendency or bleeding diathesis Patients complicated with severe renal or hepatic dysfunction Patients complicated with serious organic brain disorder Patients with a history or complication of cancer or malignant tumor Patients complicated by chronic hepatitis B or C being positive in test of hepatitis B surface antigen (HbsAg) or hepatitis C antibody Pregnant, lactating or possibly pregnant female patients, and female patients wishing to be pregnant during the study period Patients who have previously been unresponsive to paroxetine therapy (e.g. >4wks unresponsive to paroxetine for depression). Patients with a history of having discontinued treatment due to an adverse event caused by paroxetine Patients with a history of hypersensitivity to paroxetine. Patients judged ineligible to participate in this study by the investigator or subinvestigator Exclusion criteria < at the start of treatment phase> The patients who are meeting any of the following conditions at Week 0 (at the start of treatment phase) must not be allowed to the treatment phase. Patients with a 3 or more-point score of suicide (HAM-D Item 3) or with a strong suicidal tendency by C-SSRS and investigator clinical judgement. Patients whose HAM-D (17 items) total score at the Week 0 visit has changed ±25 %, or exceeding the range of ±25 % of the score at the Week -1 visit Patients whose Drug 1 (run-in placebo) compliance rate in the period from Week -1 to Week 0 has been < 80 % Patients judged ineligible as the study subjects by the investigator or subinvestigator

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: paroxetine CR group<br>controlled-release (CR) of paroxetine 12.5 to 50mg/day | Drug: matched placebo to paroxetine IR 10mg or 20mg<br>* 1 or 2 tablets once a day<br>Drug: Paroxetine CR 12.5mg tablet<br>* 1 or 2 tablets once a day<br>Drug: Paroxetine CR 25mg tablet<br>* 1 or 2 tablets once a day<br>Drug: matched placebo to paroxetine CR 12.5mg or 25mg<br>* 1 or 2 tablets once a day<br>|
| Other: paroxetine IR group<br>Immediate-release (IR) of paroxetine 10 to 40mg/day as a reference arm | Drug: paroxetine IR 10mg tablet<br>* 1 or 2 tablets once a day<br>Drug: paroxetine IR 20mg tablet<br>* 1 tablet once a day<br>Drug: matched placebo to paroxetine IR 10mg or 20mg<br>* 1 or 2 tablets once a day<br>Drug: matched placebo to paroxetine CR 12.5mg or 25mg<br>* 1 or 2 tablets once a day<br>|
| Placebo Comparator: placebo group<br>matched placebo to both paroxetine CR and paroxetine IR | Drug: matched placebo to paroxetine IR 10mg or 20mg<br>* 1 or 2 tablets once a day<br>Drug: matched placebo to paroxetine CR 12.5mg or 25mg<br>* 1 or 2 tablets once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in the Hamilton Depression Rating Scale (HAM-D; 17 Items) Total Score at Week 8 | The HAM-D measures the severity of depressive symptoms in participants with major depressive disorder (MDD). It is a checklist of 17 items that are ranked on a scale of 0-4 or 0-2. The range for the total score (which is the sum of the scores of all 17 items) is 0-52; a higher score indicates greater severity of symptoms. Mean change from baseline was calculated as the value at Week 8 minus the Baseline value. | Baseline (Week 0) and Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the HAM-D Total Score at Weeks 1, 2, 3, 4, 6, and 8 | The HAM-D measures the severity of depressive symptoms in participants with MDD. It is a checklist of 17 items that are ranked on a scale of 0-4 or 0-2. The range for the total score (which is the sum of the scores of all 17 items) is 0-52; a higher score indicates greater severity of symptoms. Mean change from baseline was calculated as the value at each time point minus the Baseline value. | Baseline (Week 0); Weeks 1, 2, 3, 4, 6, and 8 | 
| Percentage of HAM-D Responders at Weeks 4 and 8 | The HAM-D measures the severity of depressive symptoms in participants with MDD. It is a checklist of 17 items that are ranked on a scale of 0-4 or 0-2. The range for the total score (which is a sum of the scores of all 17 items) is 0-52; a higher score indicates greater severity of symptoms. Responders are defined as participants with a 50 percent or greater reduction from baseline in the HAM-D total score. | Weeks 4 and 8 | 
| Percentage of HAM-D Remitters at Weeks 4 and 8 | The HAM-D measures the severity of depressive symptoms in participants with MDD. It is a checklist of 17 items that are ranked on a scale of 0-4 or 0-2. The range for the total score (which is the sum of the scores of all 17 items) is 0-52; a higher score indicates greater severity of symptoms. Remitters are defined as participants with a HAM-D total score of 7 or less. | Weeks 4 and 8 | 
| Mean Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-SI) Scores at Weeks 1, 2, 3, 4, 6, and 8 | The 7-point CGI-SI scale assesses the clinician's impression of the participant's current illness state. Scores on the CGI-SI range from 1 = not ill at all to 7 = among the most extremely ill. Mean change from baseline was calculated as the value at each time point minus the baseline value. | Baseline (Week 0); Weeks 1, 2, 3, 4, 6, and 8 | 
| Percentage of Responders Based on the Clinical Global Impression-Global Improvement (CGI-GI) Scores at Weeks 4 and 8 | The 7-point CGI-GI assesses the participant's improvement or worsening from baseline. Scores on the CGI-GI range from 1 = very much improved to 7 = very much worse. Responders are defined as participants with a score of 1 or 2 = much improved. | Weeks 4 and 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immediate-release formulation of paroxetine (paroxetine IR), HAM-D (17 items), Controlled-release formulation of paroxetine (paroxetine CR)