E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Major depressive disorder |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025453 |
E.1.2 | Term | Major depressive disorder NOS |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to test the hypothesis that duloxetine given 60 mg (30 mg for first week) once daily (QD), orally, for 8 weeks is superior to placebo QD, orally, for 8 weeks in the treatment of adult outpatients with MDD and associated painful physical symptoms. The primary objective will be evaluated from 2 perspectives: the reduction of pain severity and the improvement in depressive symptoms. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate duloxetine 60 mg QD versus placebo on the mean change from baseline to 8-week endpoint on the Sheehan Disability Scale (SDS) global functional impairment (gated) and SDS individual item scores. • To evaluate duloxetine 60 mg QD versus placebo on remission rate (defined as MADRS total score ≤12 at the 8-week endpoint [gated]). • To evaluate duloxetine 60 mg QD versus placebo on the mean change from baseline to 8-week endpoint on the BPI-SF Severity and Interference Scores. • To evaluate duloxetine 60 mg QD versus placebo on the 8-week mean endpoint of the Patient Global Impression of Improvement (PGI-I) scale. • To assess safety of duloxetine 60 mg QD versus placebo during an 8-week trial with reasons and rates for early discontinuations, treatment-emergent adverse events (TEAEs), vital signs, laboratory measurements, and suicide-related events (behavior and/or ideation) as examined by the Columbia-Suicide Severity Rating Scale (C-SSRS)
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Sample Storage Addendum F1J-US-HMGR(1): Objective: To collect and store sample(s) of whole blood for research into genetic variants in DNA associated with major depressive disorder and associated painful physical symptoms and treatment with duloxetine. DNA samples may be analyzed for genetic variants (polymorphisms and/or SNPs) of genes coding for, but not limited to, serotonin transporter (5-HTT), norephinephrine transporter (NET), noradrenergic receptors, COMT, and drug and neurotransmitter metabolism and transport. The impact of other candidate gene SNPs and other polymorphisms, such as copy number variants, on various other measures of efficacy and side effects will also be assessed. Subject participation in this substudy is optional. |
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E.3 | Principal inclusion criteria |
[1] Meet criteria for MDD as defined by DSM-IV-TR and confirmed by the Mini International Neuropsychiatric Interview (MINI). [2] Male or female outpatients ≥ 18 years old. [3] Have a MADRS total score ≥ 20. [4] At least 1 previous episode of depression in medical history. [5] Have a painful physical symptoms with a score ≥ 3 on the BPI-SF average pain question. [6] Have Clinical Global Impression of Severity (CGI-S) score ≥ 4. [7] Provided written informed consent prior to any study procedure in accordance with Good Clinical Practice (GCP) and local regulatory requirements. [8] Have a level of understanding sufficient to provide informed consent, complete protocol required self-rated assessments, and communicate intelligibly with the investigators, study coordinator, and site personnel. [9] Are judged by the investigator to be reliable and agree to keep all appointments for clinic visits, tests, and procedures required by the protocol, and able to swallow all required medication without opening or crushing. [10] Agree to not participate in any other research trial or study while enrolled in this study.
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E.4 | Principal exclusion criteria |
[1] Are investigator site personnel directly affiliated with this study and/or their immediate families. [2] Are Lilly employees. [3] Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device (other than the study drug used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. [4] Have previously completed or withdrawn from this study or any other study investigating duloxetine. (Note: Subjects who have been previously screened for a duloxetine study other than this study and who never received study drug will be eligible for this study if they meet all current entry criteria and none of the exclusion criteria). [5] Are women of child-bearing potential (not surgically sterilized and between menarche and 1 year postmenopausal) who are not using a medically accepted means of contraception when engaging in sexual intercourse during the study and 1 month following the last dose of study drug. Note: Women who are pregnant or breastfeeding may not participate in the study. [6] Have any current (within past 6 months) DSM-IV-TR primary Axis I diagnosis other than MDD, including, but not limited to, any anxiety disorder, dysthymia, or eating disorders as determined by subject history or by diagnosis using specific modules of the MINI. [7] Have a history of alcohol abuse or dependence within 1 year immediately prior to screening. [8] Have any prior history of bipolar disorder, psychosis, or schizophrenia. [9] Have an Axis II disorder that, in the judgment of the investigator, would interfere with study compliance. [10] Have a lack of response of any (lifetime of subject) episode of major depression to 2 or more adequate courses of antidepressant therapy at a clinically appropriate dose for a minimum of 4 weeks or, in the judgment of the investigator, the subject meets criteria for treatment-resistant depression. [11] Have previously received treatment of MDD or GAD with an adequate trial of duloxetine and did not respond or could not tolerate duloxetine. [12] Diagnosis with acute liver injury (for example, hepatitis) or severe cirrhosis (Child-Pugh Class C). [13] Have uncontrolled narrow-angle glaucoma. [14] Have a positive urine drug screen for any substance of abuse. [15] Have a serious medical illness or clinically significant laboratory abnormality that is not stabilized or is anticipated to require intervention, hospitalization, or use of an excluded medication during the study, in the opinion of the investigator. [16] Have a history of substance abuse or dependence within 1 year immediately prior to screening (drug categories defined in the DSM-IV-TR), excluding nicotine and caffeine. [17] Have a history of serious suicide attempt or subject judged clinically to be at serious suicidal risk in the opinion of the investigator. [18] Require continuous use of analgesics (>step 2 WHO definition) because of chronic pain (>6 months). [19] Have pain of a known origin. [20] Meets criteria for fibromyalgia as defined by the American College of Rheumatology which includes the presence of chronic widespread pain and tenderness in all 4 body quadrants (above and below waist, and on the left and right sides of the body) for ≥ 3 months and at least 11 of 18 tender point sites (Wolfe et al. 1990). [21] Experience ≥1 migraine headache per week. [22] Have had electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or vagus nerve stimulation (VNS) within 1 year prior to screening. [23] Initiating, changing, or stopping psychotherapy within 6 weeks prior to screening or initiating, changing, or stopping psychotherapy at any time during the study. [24] Initiating, changing, or stopping non-pharmacologic or alternative therapies (for example, acupuncture, biofeedback, or massage) for painful physical symptoms at any time during the study. [25] Are taking any excluded medications. [26] Treatment with a MAOI within 14 days prior to enrollment or have the potential need to use an MAOI during the study or within 5 days of discontinuation of study drug. [27] Have frequent and/or severe allergic reactions with multiple medications. Known hypersensitivity to duloxetine or any of the inactive ingredients. [28] HAve abnormal thyroid stimulating hormone (TSH) concentration (that is, outside the reference range of the performing laboratory). Note: Subjects diagnosed with hyperthyroidism or hypothyroidism who have been treated on a stable dose of thyroid supplement for at least the past 3 months prior to screening, have a medically appropriate TSH concentration, and are clinically euthyroid are allowed. [29] Have epilepsy or history of seizure disorder or received treatment with anticonvulsant medication for epilepsy or seizures.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end point for this study is the mean change from baseline in BPI-SF average pain question score and the MADRS total score over 8 weeks of treatment. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit of the last subject undergoing the trial. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |