| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Generalised Anxiety Disorder |
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| MedDRA Classification |
| 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 assess whether duloxetine hydrochloride 60 to 120 mg once daily (QD) is superior to placebo in the treatment of generalized anxiety disorder (GAD), as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), during a 10-week, double-blind, acute therapy phase. Superiority is defined as statistically greater reduction in the mean change from baseline to endpoint in anxiety symptoms as measured by the Hamilton Anxiety Rating Scale (HAMA) total score (Hamilton 1959). |
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| E.2.2 | Secondary objectives of the trial |
| Secondary gatekeeper objective: to evaluate the efficacy of duloxetine 60 to 120 mg QD compared with placebo. Non-inferiority objective: to compare the efficacy of duloxetine 60 to 120 mg QD with venlafaxine extended-release 75 to 225 mg QD in treating GAD. Additional secondary objectives:to assess the efficacy of duloxetine 60 to 120 mg QD compared with placebo; to evaluate the effects of duloxetine 60 to 120 mg QD with placebo on patients’ quality of life; to compare the frequency of titration of duloxetine 60 to 120 mg QD with venlafaxine; to compare the safety and tolerability of duloxetine 60 to 120 mg QD with placebo and venlafaxine. (Data from two studies will be combined); to evaluate and compare the effects of discontinuation of duloxetine 60 to 120 mg QD, venlafaxine, and placebo; to compare the time to onset of action of duloxetine 60 to 120 mg QD with venlafaxine (Data from two studies will be combined); to evaluate the efficacy of duloxetine 20 mg QD compared with placebo |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] Male and female outpatients at least 18 years of age presenting with generalized anxiety disorder (GAD) based on the disease diagnostic criteria (Section 4.2.1). Patients must suffer from GAD and not from an adjustment disorder or anxiety disorder not otherwise specified (NOS). Symptoms of GAD should not be situational in nature.
[2] Females of childbearing potential (not surgically sterilized and between menarche and 1 year postmenopause) who are not breastfeeding; test negative for pregnancy at the time of enrollment based on a urine pregnancy test; and agree to use a reliable method of birth control (for example, use of oral contraceptives or Norplant®; a reliable barrier method of birth control: diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam; intrauterine devices; partner with vasectomy; or abstinence) during the study and for 1 week following the last dose of study drug.
[3] Must have a Clinical Global Impressions of Severity (CGI-Severity) score >=4 at Visit 1 and Visit 2.
[4] At Visit 1, patient must have a Covi Anxiety Scale (CAS) score >=9, no item in the Raskin Depression Scale (RDS) may be >3, and the CAS must be greater than the RDS.
[5] Must have Hospital Anxiety and Depression Scale (HADS) anxiety subscale score ≥10 at Visit 1.
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| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[6] Any current and primary DSM-IV-TR Axis I diagnosis other than GAD.
· Patients diagnosed with or who have a history of major depressive disorder (MDD) within the past 6 months or
· Patients diagnosed with or who have a history of panic disorder, post-traumatic stress disorder (PTSD), or an eating disorder within the past year or
· Patients who have been diagnosed with obsessive-compulsive disorder (OCD), bipolar affective disorder, psychosis, factitious disorder, or somatoform disorders during their lifetime.
[7] The presence of an Axis II disorder or history of antisocial behavior, which, in the judgment of the investigator, would interfere with compliance with the study protocol.
[8] Benzodiazepine use 14 days prior to Visit 2.
[9] Patients judged clinically to be at serious suicidal risk, or patients who, in the opinion of the investigator, are poor medical or psychiatric risks for study completion.
[10] Have received treatment within the last 30 days with a drug (not including study drug) that has not received regulatory approval for any indication at the time of study entry.
[11] Have previously completed or withdrawn from this study or any other study investigating duloxetine or have previously been treated with duloxetine.
[12] History of alcohol or any psychoactive substance abuse or dependence (as defined in the DSM-IV-TR) within the past 6 months.
[13] Excessive use of caffeine, in the opinion of the investigator. Note: Tapering of caffeine-containing substances is permitted during the screening period as long as stabilization at a permitted level of use for 7 days has been established before Visit 2.
[14] A positive urine drug screen (UDS) for any substance of abuse at Visit 1. A retest may be performed if the UDS is positive for any excluded prescribed medications that may not have had an adequate washout. The results of the retest must be available prior to Visit 2.
[15] Serious medical illness, including any cardiovascular, hepatic, renal, respiratory, hematologic, endocrinologic, or neurologic disease; or clinically significant laboratory abnormality that is not stabilized or is anticipated to require hospitalization within 6 months, in the opinion of the clinical investigator. Clinically significant laboratory abnormalities are those that, in the judgment of the investigator, indicate a serious medical problem.
[16] Acute hepatic injury (such as hepatitis) or severe cirrhosis (Child-Pugh Class C).
[17] Abnormal thyroid-stimulating hormone (TSH) concentrations (outside the reference range of the performing laboratory). Note: Patients previously diagnosed with hyperthyroidism or hypothyroidism who have been treated on a stable dose of thyroid supplement for at least the past 3 months, have medically appropriate TSH concentrations, and are clinically euthyroid are allowed.
[18] Initiation of psychotherapy, change in intensity of psychotherapy or other non-drug therapies (such as acupuncture or hypnosis) within 6 weeks prior to enrollment or at any time during the study.
[19] Taking any excluded medication within 7 days prior to Visit 2 (also see exclusion criteria [8] and [20]).
[20] Treatment with a monoamine oxidase inhibitor (MAOI) or fluoxetine within 30 days of Visit 2 or potential need to use an MAOI during the study or within 7 days of discontinuation of study drug.
[21] Lack of response of the current episode of GAD to two or more adequate studies of antidepressants, benzodiazepines, or other anxiolytics at a clinically appropriate dose for a minimum of 4 weeks.
[22] History of severe allergies, hypersensitivity to duloxetine or venlafaxine extended-release or to any of the inactive ingredients, or other contraindication to venlafaxine extended-release; multiple adverse drug reactions; transcranial magnetic stimulation (TMS); history of seizures; or history of psychosurgery or electroconvulsive therapy (ECT) within 12 months.
[23] Women who are pregnant or breast-feeding.
[24] Are investigator site personnel directly affiliated with the study, or are immediate family of investigator site personnel directly affiliated with the study. “Immediate family” is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The Hamilton Anxiety Rating Scale (HAMA; Hamilton 1959) is a clinician-administered rating scale that is used to assess the severity of anxiety, its improvement during the course of treatment, and the timing of such improvement (Riskind et al. 1987). The scale consists of 14 items, which provide an overall measure of general anxiety, including psychic anxiety and somatic anxiety. Each item is rated on a 5-point scale of 0 (not present) to 4 (very severe). The HAMA total score is the sum of the 14 items and ranges from 0 to 56. Higher scores indicate a greater degree of symptom severity. |
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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 | Information not present in EudraCT |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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) | Yes |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 7 |
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