A Randomized, Double-blind, Two-arm Study Comparing the Efficacy and Safety of Trazodone Contramid® OAD and Placebo in the Treatment of Unipolar Major Depressive Disorder.

Study Overview
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Brief Summary
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The purpose of this study was to demonstrate efficacy, safety and clinical benefit of Trazodone Contramid® OAD (Once A Day) in the treatment of Unipolar Major Depressive Disorder (MDD).

Detailed Description
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This two-arm, multicentre, randomized, placebo-controlled, double-blind, parallel-design study consisted of a baseline phase (screening and wash-out) and a double-blind randomized phase (randomization to Trazodone Contramid® OAD or placebo). The total study duration including wash-out of prohibited medications was approximately 11 weeks; the total duration of the randomized phase was 8 weeks (titration: 2 weeks + treatment: 6 weeks).

Official Title
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A Randomized, Double-blind, Two-arm Study Comparing the Efficacy and Safety of Trazodone Contramid® OAD and Placebo in the Treatment of Unipolar Major Depressive Disorder.

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Trazodone Hydrochloride (HCl) Extended-Release Tablets
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females. Aged 18 years or older. Fulfills Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for Unipolar Major Depressive Disorder (MDD) (Axis I) as confirmed by the Mini-International Neuropsychiatric Interview (MINI). The primary DSM-IV Axis I diagnosis should be MDD (296.22, 296.23, 296.32, 296.33); any subject meeting criteria for another, non excluded Axis I disorder, must demonstrate MDD as the primary disorder. The current episode of MDD should have lasted for a minimum of 1 month, whether the patient has been diagnosed with one single or recurrent episodes. Presence of dysphoria for most days over the past four weeks. Montgomery-Åsberg Depression Rating Scale (MADRS) total score of at least 26 at screening and baseline. Oral and written language comprehension at a level sufficient to comply with the protocol and to complete study-related materials. Sign and date a written Informed Consent Form (ICF) approved by a Research Ethic Board (REB) which has also been signed and dated by the Investigator prior to study participation. Exclusion Criteria: DSM-IV Major Depressive Disorder Specifiers: [a] With Catatonic Features; [b] With Postpartum Onset; [c] With Seasonal Pattern; Presence of any of the following DSM-IV Axis I disorders: generalized anxiety disorder, panic disorder, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, eating disorder, bipolar disorder, alcohol/substance abuse or dependence (caffeine and nicotine allowed), any psychotic disorder. Depression secondary to stroke, cancer or other severe medical illnesses. Positive urine drug screen at screening visit. History or present condition of any DSM-IV Axis II disorder. History of treatment refractory major depressive episodes defined as incomplete or no therapeutic response to two prior courses of at least one month of conventional antidepressant drug treatment in adequate dosages. Currently in psychotherapy (at least one session in the past month with a plan for continuing) with a licensed/registered/certified mental health provider, marriage counselor, or family therapist. Meet criteria for high suicide risk on the MINI suicide scale, or in the opinion of the investigator is inappropriate for the trial due to clinically significant suicidal or homicidal potential. Require hospitalization for treatment of the current episode of depression. Uncorrected hypo- or hyperthyroidism. A history of seizures other than pediatric febrile seizure. A history of cardiac arrythmias requiring therapy. A history of myocardial infarction within 1 year before screening. Clinically significant abnormal findings of Electrocardiography (ECG), laboratory parameters. Unwilling to discontinue use of any antidepressants, including herbal remedies, for a minimum of 5 drug half-lives prior to screening. Unwilling to discontinue use of prohibited medications for a minimum of 5 drug half-lives prior to screening. Treatment within the last 3 weeks with Monoamine Oxidase (MAO) inhibitors. Use of the following concomitant treatment during the study: medications causing QT prolongation (e.g. amiodarone, droperidol, erythromycin). medications causing PR prolongation (e.g. digoxin). Anti -psychotics (e.g. haloperidol). protease inhibitors such as ritonavir and indinavir. Hormonal treatment (e.g. estrogen, oral contraceptives) which has started within 3 months of study entry. Treatment with another investigational agent within the last 30 days. Known and documented allergy to trazodone or any structurally similar drugs. Previous failure of treatment with trazodone, or previous discontinuation of treatment with trazodone due to Adverse Events. Bowel disease causing malabsorption. Serious, unstable illnesses during the 3 months before screening including but not limited to: hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic or hematological disease. Pregnant or lactating, or is of childbearing potential and not willing to use an approved method of contraception. Significant liver disease, defined as active hepatitis or elevated liver enzymes >3 times the upper boundary of the normal range. Significant renal disease, defined as Blood Urea Nitrogen (BUN) and/or creatinine >3 times the upper boundary of the normal range clearance. Any other condition that, in the opinion of the investigators, would adversely affect the patient's ability to complete the study or its measures.

Ages Eligible for Study
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Minimum Age: 18 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: Trazodone Contramid Once A Day (OAD)<br> | Drug: Trazodone Hydrochloride (HCl) Extended-Release Tablets<br> <br> * Other names: Oleptro;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hamilton Depression Scale (HAMD-17) Total Score From Baseline | The Hamilton Depression Rating Scale 17 items [HAMD-17] is a 17-item scale that evaluates depressed mood, vegetative and cognitive symptoms of depression, and co-morbid anxiety symptoms. The 17 items are rated on either a 5-point (0-4) or a 3-point (0-2) scale. In general, the 5 point scale items use a rating of 0=absent; 1=doubtful to mild; 2=mild to moderate; 3=moderate to severe; 4=very severe. The 3-point scale items use a rating of 0=absent; 1=probable or mild; 2=definite. The total HAMD-17score ranges from 0 (not ill) to 52 (severely ill). | Baseline to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HAMD-17 Responders at Each Visit | Number of patients who show a response (defined as at least a 50% reduction from baseline in HAMD-17 score) at each post-baseline visit. | Weeks 1, 2, 3, 4, 6, 8 | 
| HAMD-17 Remitters at Each Visit | Number of patients who are remitters (defined as patients who achieved a HAMD-17 total score ≤7) at each post-baseline visit. | Weeks 1, 2, 3, 4, 6, 8 | 
| Change in HAMD-17 Depressed Mood Item (Item 1) Score From Baseline to Each Visit | Change from baseline in the HAMD-17, item 1: Depressed Mood item, at each post-baseline visit. The Depressed Mood item is rated on a 5-point scale ranging from rating of 0=absent; to 4=very severe. | Baseline to Weeks 1, 2, 3, 4, 6, 8 | 
| Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score From Baseline | The Montgomery-Åsberg Depression Rating Scale (MADRS) is a 10 item clinician-administered depression rating scale. The 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts) are rated on a scale ranging from 0 (low severity/difficulty) to 6 (high severity/difficulty) with anchors at 2-point intervals. The overall total score range is from 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). | Baseline to Week 8 | 
| Change From Baseline in Clinical Global Impression of Severity (CGI-S) to Each Visit | The CGI-Severity (CGI-S) consists of one question for the investigator: Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? which is rated on the following seven-point scale: 1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. | Baseline to Weeks 1, 2, 3, 4, 6, 8 | 
| Clinical Global Impression - Improvement of Illness (CGI-I) Score at Last Study Visit | The CGI-Improvement of Illness (CGI-I) consists of one question for the investigator: Compared to his condition at the start of the study, how much has this patient changed? which is rated on the following seven-point scale 1=very much improved; 2=much improved; 3=minimally improved; 4=no change from baseline; 5=minimally worse; 6= much worse; 7=very much worse. | Week 8 | 
| Patient Global Impression - Improvement of Illness (PGI-I) Score at Last Study Visit | The PGI-Improvement of Illness (PGI-I) consists of one question for the patient: Since the start of the study, my overall status with regard to depression is? which is rated on the following seven-point scale 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6= much worse; 7=very much worse. | Week 8 | 
| Clinical Global Impression - Improvement of Illness (CGI-I) Responders at Last Study Visit | Patients were responders if the CGI-I rating was Much Improved or Very Much Improved. The CGI-Improvement of Illness (CGI-I) consists of one question for the investigator: Compared to his condition at the start of the study, how much has this patient changed? which is rated on the following seven-point scale 1=very much improved; 2=much improved; 3=minimally improved; 4=no change from baseline; 5=minimally worse; 6= much worse; 7=very much worse. Results are expressed in number of patients. | Week 8 | 
| Patient Global Impression - Improvement of Illness (PGI-I) Responders at Last Study Visit | Patients were responders if the PGI-I rating was Much Improved or Very Much Improved. The PGI-Improvement of Illness (PGI-I) consists of one question for the patient: Since the start of the study, my overall status with regard to depression is? which is rated on the following seven-point scale 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6= much worse; 7=very much worse. Results are expressed in number of patients. | Week 8 | 
| Overall Quality of Sleep at Each Visit | Overall Quality of Sleep was measured on a 4-point rating scale ranging from 1 = very poor to 4 = excellent in response to the question: Since the last study visit, how would you rate the overall quality of your sleep?. | Weeks 1, 2, 3, 4, 6, 8 | 
| Trouble Falling Asleep at Each Visit | Trouble Falling Asleep was measured on a 4-point rating scale ranging from 1 = never to 4 = always in response to the question: Since the last study visit, how often did you experience trouble falling asleep?. | Weeks 1, 2, 3, 4, 6, 8 | 
| Awakening During the Night at Each Visit | Awakening during the night was measured on a 4-point rating scale ranging from 1 = never to 4 = always in response to the question: Since the last study visit did you awaken during the night?. | Weeks 1, 2, 3, 4, 6, 8 | 
| Discontinuation Due to Lack of Efficacy | Number of patients who discontinued due to lack of efficacy during the whole study period (8 weeks). | Baseline to Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Unipolar