Study to Assess Clinical Response of Duloxetine in Patients Hospitalized for Severe Depression

Study Overview
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Brief Summary
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Study to assess efficacy of Duloxetine 120 mg and Duloxetine 60 mg in patients hospitalized for severe depression after 4 weeks of treatment. To evaluate the rescue option in non-responding patients. Safety of Duloxetine will also be assessed.

Official Title
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An Eight-week, Randomized, Double-blind, Two Parallel Groups, Study to Assess Clinical Response of Duloxetine 60 mg and 120 mg Per Day in Patients Hospitalized for Severe Depression

Conditions
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Depressive Disorder, Major

Intervention / Treatment
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* Drug: Duloxetine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients of 18 years of age at the screening visit or older Meet criteria for severe Major Depressive Disorder (MDD) Montgomery-Asberg-depression rating scale (MADRS) total score ≥ 30 and the 6-item Hamilton Depression scale (HAMD-6) score ≥12 at both screening (V1) visit and baseline (V2) visits Clinical Global Impression of Severity (CGI-Severity) score ≥4 at both screening visit and baseline visit. Requirement of hospitalization (not for social or other non-medical reasons) at screening visit and at least up to Visit 4 Patient willing and able to comply with the requirement for hospitalization and with all scheduled visits, tests and procedures required by the protocol Have a level of understanding sufficient to provide informed consent and to communicate with the investigators and site personnel. Informed consent document must be signed at screening visit, in accordance with Good Clinical Practice (GCP) and local regulatory requirements, prior to any study procedure Exclusion Criteria: More than two previous episodes of major depression that did not respond to adequate doses and duration (minimum of 6 weeks) of two different antidepressant therapies Lack of response to at least two antidepressant therapies given at adequate doses for at least 6 weeks for the current depressive episode Concurrent presence of symptoms fulfilling criteria for any Axis I disorder other than anxiety disorders (with exception of the Obsessive-Compulsive Disorder (OCD)) or Major Depressive Disorder, in the investigator's judgment Any previous diagnosis of a bipolar disorder, schizophrenia or OCD Depression with catatonic features, depression with post-partum onset, or organic mental disorders The presence of an Axis II disorder MDD with psychotic features requiring neuroleptic treatment and/or interfering with patient's ability to provide informed consent, at investigator's discretion History of substance abuse or dependence within the past year, excluding nicotine and caffeine, but including alcohol or benzodiazepines Positive urine screen for drug abuse (cannabinoids, cocaine, opiates including methadone, or amphetamines) at screening Epilepsy or a history of seizure disorder or of a treatment with anticonvulsant medication for epilepsy or seizures Patients with acute liver injury (such as hepatitis) or severe cirrhosis (such as Child-Pugh Class C) Known diagnosis of congenital galactosaemia, glucose or galactose malabsorption syndrome, or lactose deficiency Patient with a known diagnosis of raised intraocular pressure, or at known risk of acute narrow-angle glaucoma Serious medical illness or clinically significant laboratory abnormalities that, in the judgment of the investigator, are likely to require intervention/exclusion of study medication during the course of the study: cardiovascular (e.g. uncontrolled hypertension, abnormal initial ECG findings according to investigator judgement), respiratory, haematological, hepatic or gastrointestinal End stage renal disease (estimated creatinine clearance ≤30 mL/min) and undergoing dialysis Abnormal thyroid-stimulating hormone (TSH) concentrations, based on the performing laboratory's reference ranges. Patients must be clinically and chemically euthyroid at the time of randomization. Patients may be taking thyroid replacement therapy provided their dose is stable and their compliance is good for at least three months before the screening visit Pregnancy (to be excluded by urine pregnancy test at screening visit) or breast-feeding Sexually active woman of childbearing potential (i.e. not 6 months post-menopausal, or not surgically sterilized) not using a medically approved method of birth control (i.e. oral contraceptives, intrauterine device, or double-barrier) for at least one month prior to the screening visit and throughout the study Participation in another clinical trial within 30 days prior to screening visit Current treatment with Duloxetine for any indication and previous treatment with Duloxetine for psychiatric indications Known hypersensitivity to Duloxetine or any of the inactive ingredients History of oversensitivity to psychotropic drugs, in the investigator's judgment Electro-convulsive Therapy (ECT) or Transcranial Magnetic Stimulation (TMS) within one year prior to screening visit and during the study Initiation or discontinuation of depression-oriented psychotherapeutic treatment (e.g. behaviour therapy, psychoanalytic therapy, cognitive therapy, etc) within 6 weeks prior to screening visit, or planned use of such treatment at any time during the study Treatment with a Monoamine Oxidase Inhibitor (MAOI) within 14 days prior to baseline visit or the potential need to use an MAOI during the study or within 5 days after discontinuation of duloxetine Treatment with Fluoxetine within 30 days prior to baseline visit Treatment with any excluded medication listed in the protocol

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Duloxetine 60 mg<br>Duloxetine 60 mg | Drug: Duloxetine<br>* Capsule<br>Drug: Placebo<br>* Capsule<br>|
| Experimental: Duloxetine 120 mg<br>Duloxetine 120 mg | Drug: Duloxetine<br>* Capsule<br>Drug: Placebo<br>* Capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Week 4 | The MADRS total score is used to measure the severity of depression. It is based on 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts) scored from 0 to 6 each. The total score is calculated as the sum over the 10 items, ranging from 0 to 60. A lower score indicates a better outcome. Missing items (≤2 items) were replaced by the mean score of the participant's treatment group per time point. Otherwise, the MADRS total score was set to missing. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | At baseline and at Week 4. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hamilton Depression 6-item Scale (HAMD-6) Total Score From Baseline to Week 1, 2, 3 and Week 4 | HAMD-6 is a 6-item rating instrument that assesses items thought to represent 'core' symptoms of depression. It was derived from standard 17-item Hamilton Depression Scale (HAMD-17) with assessment being restricted to items 1, 2, 7, 8, 10 and 13. The HAMD-6 score is calculated as the sum over the 6 items, ranging from 0 to 22, with a lower score indicating a better patient status. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | At baseline and at Week 1, 2, 3 and Week 4. | 
| Change in Hamilton Depression 6-item Scale (HAMD-6) Total Score From Baseline to Week 6 and Week 8 - by Post-week 4 Treatment Groups | HAMD-6 is a 6-item rating instrument that assesses items thought to represent 'core' symptoms of depression. It was derived from standard 17-item Hamilton Depression Scale (HAMD-17) with assessment being restricted to items 1, 2, 7, 8, 10 and 13. The HAMD-6 score is calculated as the sum over the 6 items, ranging from 0 to 22, with a lower score indicating a better patient status. Results are reported by 'post-week 4 treatment groups' (treatment regimen (60 vs. 120 mg duloxetine) and responder/non-responder status). Patients were assigned their responder status at Visit 6 and the data were retrospectively divided into these groups. | At baseline and at Week 6 and Week 8. | 
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Week 1, 2 and Week 3 | The MADRS total score is used to measure the severity of depression. It is based total score is based on 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts) ranging from 0 to 6 each. The total score is calculated as the sum over the 10 items, ranging from 0 to 60. A lower score indicates a better outcome. Missing items (≤2 items) were replaced by the mean score of the participant's treatment group per time point. Otherwise, the MADRS total score was set to missing. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | At baseline and at Week 1, 2 and Week 3. | 
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Week 6 and Week 8 - by Post-week 4 Treatment Groups | The MADRS total score is based on 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts) ranging from 0 to 6 each. The total score is calculated as the sum over the 10 items, ranging from 0 to 60. A lower score indicates a better outcome. Missing items (≤2 items) were replaced by the mean score of the participant's treatment group per time point. Otherwise, the MADRS total score was set to missing. Results are reported by 'post-week 4 treatment groups' (treatment regimen (60 vs. 120 mg duloxetine) and responder/non-responder status). Patients were assigned their responder status at Visit 6 and the data were retrospectively divided into these groups. | At baseline and at Week 6 and Week 8. | 
| Percentage of Responders at Week 1, 2, 3 and Week 4 According to Montgomery-Asberg Depression Rating Scale (MADRS) Scale | Percentage of patient 'responders', i.e. patients with at least a 50% improvement in MADRS scores from baseline. The MADRS total score is used to measure the severity of depression. It is based on 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts) ranging from 0 to 6 each. The total score is calculated as the sum over the 10 items, ranging from 0 to 60. A lower score indicates a better outcome. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | At week 1, 2, 3 and week 4. | 
| Percentage of Responders at Week 6 and Week 8 According to Montgomery-Asberg Depression Rating Scale (MADRS) Scale - by Post-week 4 Treatment Groups | Percentage of patient 'responders', i.e. patients with at least a 50% improvement in MADRS scores from baseline. The MADRS total score is used to measure the severity of depression. It is based on 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts) ranging from 0 to 6 each. The total score is calculated as the sum over the 10 items, ranging from 0 to 60. A lower score indicates a better outcome. Results are reported by 'post-week 4 treatment groups' (treatment regimen (60 vs. 120 mg duloxetine) and responder/non-responder status). Patients were assigned their responder status at Visit 6 and the data were retrospectively divided into these groups. | At week 6 and week 8. | 
| Percentage of Responders at Week 1, 2, 3 and Week 4 According to Hamilton Depression 6-item Scale (HAMD-6) | Percentage of patient 'responders', i.e. patients with at least a 50% improvement in HAMD-6 scores from baseline. HAMD-6 is a 6-item rating instrument that assesses items thought to represent 'core' symptoms of depression. It was derived from standard 17-item Hamilton Depression Scale (HAMD-17) with assessment being restricted to items 1, 2, 7, 8, 10 and 13. The HAMD-6 score is calculated as the sum over the 6 items, ranging from 0 to 22, with a lower score indicating a better patient status. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | At week 1, 2, 3 and week 4. | 
| Percentage of Responders at Week 6 and Week 8 According to Hamilton Depression 6-item Scale (HAMD-6) - by Post-week 4 Treatment Group | Percentage of patient 'responders', i.e. patients with at least a 50% improvement in HAMD-6 scores from baseline. HAMD-6 is a 6-item rating instrument that assesses items thought to represent 'core' symptoms of depression. It was derived from standard 17-item Hamilton Depression Scale (HAMD-17) with assessment being restricted to items 1, 2, 7, 8, 10 and 13. The HAMD-6 score is calculated as the sum over the 6 items, ranging from 0 to 22, with a lower score indicating a better patient status. Results are reported by 'post-week 4 treatment groups' (treatment regimen (60 vs. 120 mg duloxetine) and responder/non-responder status). Patients were assigned their responder status at Visit 6 and the data were retrospectively divided into these groups. | At week 6 and week 8. | 
| Percentage of Patients Reaching Remission at Week 8 | Remission is defined as a total Montgomery-Asberg Depression Rating Scale (MADRS) score of ≤ 12 at week 8. The MADRS total score is based on 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts) ranging from 0 to 6 each and a total MADRS score ranging from 0 to 60. Results are reported by 'post-week 4 treatment groups' (treatment regimen (60 vs. 120 mg duloxetine) and responder/non-responder status). Patients were assigned their responder status at Visit 6 and the data were retrospectively divided into these groups. | At week 8. | 
| Clinical Global Impressions Scales of Severity of Illness (CGI-SI): Number of Patients Per Score at Baseline, Week 1, 2, 3 and Week 4 | Clinical Global Impression (CGI) scales were developed as an independent, simple way for clinicians to make overall evaluations of a patient's disease status. The CGI-SI assess the severity of illness, with the following question: Considering your total clinical experience with the particular population, how mentally ill is the patient at this time?. The CGI-SI ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). A higher score indicates a worse patient status. Reported is the number of patients per score by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). At week 4 treatment groups were compared using the Cochran Mantel-Haenszel test with stratification by centre. | At baseline and at week 1, 2, 3 and week 4. | 
| Clinical Global Impressions Scales of Severity of Illness (CGI-SI): Number of Patients Per Score at Week 6 and Week 8 - by Post-week 4 Treatment Groups | The Clinical Global Impressions scales of Severity of Illness (CGI-SI) were developed as an independent, simple way for clinicians to make overall evaluations of a patient's disease status. The CGI-SI assess the severity of illness, with the following question: Considering your total clinical experience with the particular population, how mentally ill is the patient at this time?. The scale ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). A higher score indicates a worse patient status. Number of patients per score is reported. Results are reported by 'post-week 4 treatment groups' (treatment regimen (60 vs. 120 mg duloxetine) and responder/non-responder status). Patients were assigned their responder status at Visit 6 and the data were retrospectively divided into these groups. At week 8, within-group comparison versus week 4 was performed for each post-week 4 treatment group using Mc Nemar test. | At week 6 and week 8. | 
| Clinical Global Impression of Improvement (CGI-I) Scale: Number of Patients Per Score at Week 1, 2, 3 and Week 4 | The Clinical Global Impression of Improvement (CGI-I) scale was developed as an independent, simple way for clinicians to make overall evaluations of a patients disease status. The CGI-I rates the total improvement with the following question: Compared to the patients condition at admission, how much has he or she changed?. The scale ranges from 1 (very much improved) to 7 (very much worse). A higher score indicates a worse patient status. Number of patients per score is reported. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). At week 4 treatment groups were compared using the Cochran Mantel-Haenszel test with stratification by centre. | At week 1, 2, 3 and week 4. | 
| Clinical Global Impression of Improvement (CGI-I) Scale: Number of Patients Per Score at Week 6 and Week 8 - by Post-week 4 Treatment Groups | Clinical Global Impression (CGI) scale was developed as an independent, simple way for clinicians to make overall evaluations of a patients disease status. The CGI-I rates the total improvement with the following question: Compared to the patients condition as admission, how much has he or she changed?. The CGI-I score ranges from 1 (very much improved) to 7 (very much worse). A higher score indicates a worse patient outcome. Number of patients per score is reported. Results are reported by 'post-week 4 treatment groups' (treatment regimen (60 vs. 120 mg duloxetine) and responder/non-responder status). Patients were assigned their responder status at Visit 6 and the data were retrospectively divided into these groups. | At week 6 and week 8. | 
| Patient Global Impressions of Improvement (PGI-I) Score: Number of Patients Per Score at Week 1, 2, 3 and Week 4 | Patient Global Impression of Improvement scale is a patient-rated instrument that measures the improvement of the patient's symptoms, ranging from 1 (very much better) to 7 (much worse). A higher score indicates a worse outcome. Number of patients per score is reported. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). At week 4 treatment groups were compared using the Cochran Mantel-Haenszel test with stratification by centre. | At week 1, 2, 3 and week 4. | 
| Patient Global Impressions of Improvement (PGI-I) Score: Number of Patients Per Score at Week 6 and Week 8 - by Post-week 4 Treatment Groups | Patient Global Impression of Improvement scale is a patient-rated instrument that measures the improvement of the patient's symptoms, ranging from 1 (very much better) to 7 (much worse). A higher score indicates a worse outcome. Results are reported by 'post-week 4 treatment groups' (treatment regimen (60 vs. 120 mg duloxetine) and responder/non-responder status). Patients were assigned their responder status at Visit 6 and the data were retrospectively divided into these groups. | At week 6 and week 8. | 
| Change in Hamilton Scale of Anxiety (HAMA) Score From Baseline to Week 4 | HAMA scale consists of 14 items to measure the severity of anxiety symptoms. Each item ranges from 0 (not present) to 4 (very severe). The total score is calculated as the sum over all items, ranging from 0 to 56, with a higher score implying a worse outcome. Change from baseline to week 4 is reported. Reduction in the score over time is interpreted as improvement in the patient´s status. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | At baseline and at week 4. | 
| Change in Hamilton Scale of Anxiety (HAMA) Score From Baseline to Week 8 - by Post-week 4 Treatment Groups | HAMA scale consists of 14 items to measure the severity of anxiety symptoms. Each item ranges from 0 (not present) to 4 (very severe). The total score is calculated as the sum over all items, ranging from 0 to 56, with a higher score implying a worse outcome. Change from baseline to week 8 is reported. Reduction in the score over time is interpreted as improvement in the patient´s status. Results are reported by 'post-week 4 treatment groups' (treatment regimen (60 vs. 120 mg duloxetine) and responder/non-responder status). Patients were assigned their responder status at Visit 6 and the data were retrospectively divided into these groups. | At baseline and at week 8. | 
| Reason for Living (RFL) Questionaire at Baseline | The Reason for Living (RFL) questionnaire is a self-report instrument, to evaluate a variety of expectations and adaptive beliefs for living, if suicide is considered. The RFL is thought to assess 6 domains of reasons for living: 1) survival and coping beliefs, 2) responsibility to family, 3) child related concerns, 4) fear of suicide, 5) fear of social disapproval, and 6) moral objections. The RFL uses a 6-point rating scale, with the total score ranging from 1 not at all important and to 6 extremely important. A higher score indicates more reasons to live (i.e. better outcome). Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | At baseline. | 
| Change From Baseline to Week 8 in Reason for Living (RFL) Questionnaire - by Post-week 4 Treatment Groups | The Reason for Living (RFL) questionnaire is a self-report instrument, to evaluate a variety of expectations and adaptive beliefs for living, if suicide is considered. The RFL is thought to assess 6 domains of reasons for living: 1) survival and coping beliefs, 2) responsibility to family, 3) child related concerns, 4) fear of suicide, 5) fear of social disapproval, and 6) moral objections. The RFL uses a 6-point rating scale, with the total score ranging from 1 not at all important and to 6 extremely important. A higher score indicates more reasons to live (i.e. better outcome). Results are reported by 'post-week 4 treatment groups' (treatment regimen (60 vs. 120 mg duloxetine) and responder/non-responder status). Patients were assigned their responder status at Visit 6 and the data were retrospectively divided into these groups. | At baseline and at week 8. | 
| Number of Patients With Intake of Concomitant Medication for Anxiety and Sleep | Number of patients with concomitant medication for anxiety and sleep taken at different timepoints. V1: Screening V2: Baseline V3: Week 1 V4: Week2 V5: Week 3 V6: Week 4 V7: Week 6 V8: Week 8. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | 1 week prior to baseline and at baseline, week 1, 2, 3, 4, 5, 6, 7, 8 and week 10. | 
| Number of Patients With Treatment Emergent Adverse Event | Number of patients with any adverse event occuring during on-treatment phase. Results are reported for treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | From start of treatment until 3 days after end of treatment, up to 120 days. | 
| Change From Baseline in Blood Pressure to Week 4 and Week 8 | Change from baseline in systolic and diastolic blood pressure (BP) to week 4 and week 8. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | At baseline, at week 4 and week 8. | 
| Change From Baseline in Weight to Week 4 and Week 8 | Change from baseline in weight to week 4 and week 8. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | At baseline, at week 4 and week 8. | 
| Number of Patients With Potentially Clinically Significant Laboratory Findings | Number of patients with potentially clinically significant abnormalities. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | Up to week 8. | 
| Number of Patients Withdrawn Due to Adverse Events | Number of patients withdrawn due to adverse events. Results are reported by treatment regimen (60 mg duloxetine vs. 120 mg duloxetine). | From start of treatment until 3 days after end of treatment, up to 120 days. |