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 | 9.1 |
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 assess the efficacy of duloxetine compared with placebo in the acute treatment of children (aged 7 through 11 years) and adolescents (aged 12 through 17 years) who meet criteria for MDD without psychotic features, single or recurrent episode, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR [APA 2000]). The primary objective will be evaluated by assessing the mean change from baseline to endpoint (10 weeks) on the Children’s Depression Rating Scale-Revised (CDRS-R) total score between duloxetine and placebo. |
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E.2.2 | Secondary objectives of the trial |
EFFICACY • To test assay sensitivity by comparing fluoxetine with placebo • To evaluate the efficacy of treatment with duloxetine compared with placebo • To assess changes in depressive symptoms
SAFETY/TOLERABILITY • To evaluate the safety & tolerability of treatment with duloxetine compared with placebo • To assess safety and tolerability of duloxetine
PHARMACOKINETICS/PHARMACODYNAMICS • To characterise the pharmacokinetics of duloxetine at steady-state • To compare the steady-state duloxetine pharmacokinetics in the treatment of children & adolescents with MDD with historical adult duloxetine pharmacokinetics. • To investigate the relationship between duloxetine exposure & efficacy endpoints during a 10-week, double-blind, acute treatment phase in children & adolescents with MDD.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all of the following criteria: 1. Outpatient male or female aged 7 to 17 years, inclusive, at the time of signing the informed consent/assent document and diagnosed with MDD as defined by the DSM-IV-TR and supported by the MINIKID. 2. Diagnosis of moderate or greater severity of MDD as determined by CDRS-R with a total score ≥40 at Visit 1, Visit 2, and Visit 3 and a CGI-Severity rating of ≥4 at Visit 1, Visit 2, and Visit 3. 3. Female patients must test negative for pregnancy during screening. Furthermore, female patients must agree to abstain from sexual activity or to use a reliable method of birth control as determined by the investigator during the study. Examples of reliable birth control methods include the use of oral contraceptives; 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. 4. Patient’s parent/legal representative and patient, if capable, are judged to be reliable by the investigator to keep all appointments for clinical visits, tests, and procedures required by the protocol. 5. Patient’s parent/legal representative and patient, if capable, must have a degree of understanding such that they can communicate intelligently with the investigator and study coordinator. 6. Patients must be capable of swallowing study drug whole (without opening the capsule, crushing, dissolving, dividing, etc.). It is anticipated the patients will need to swallow up to 6 capsules per day. 7. Patients must have venous access sufficient to allow blood sampling and are compliant with blood draws as per the protocol |
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E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria: 8. Are the children of investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted. 9. Are the children of Lilly employees or employees of the designated Clinical Research Organisation assisting with the conduct of the study. 10. Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. 11. Have a current or previous diagnosis of bipolar disorder, psychotic depression, schizophrenia or other psychotic disorder, anorexia, bulimia, obsessive compulsive disorder, or pervasive development disorder, as judged by the investigator. In addition, patients with an Axis II disorder (eg, borderline personality disorder) will be excluded if, in the judgment of the investigator, the Axis II disorder would interfere significantly with protocol compliance. 12. Have a history of DSM-IV-TR-defined substance abuse or dependence within the past year, excluding caffeine and nicotine. 13. Have a current primary DSM-IV-TR Axis I disorder other than MDD or a current secondary DSM-IV-TR Axis I disorder that requires any pharmacologic treatment (other than those disorders listed in Exclusion Criteria 11 and 12). 14. Have 1 or more first-degree relatives (parents or siblings) with diagnosed bipolar I disorder. 15. Have a significant suicide attempt within 1 year of Visit 1 or are currently at risk of suicide in the opinion of the investigator. 16. Have a weight less than 20 kg at any Screening Phase visit. 17. Have a lack of response to 2 or more adequate treatment trials of antidepressants at a clinically appropriate dose for a minimum of 4 weeks for the same MDD episode. In addition, patients who have had a lack of response of their current depressive episode to a clinically appropriate dose of fluoxetine (ie, at least 20 mg/day for 4 weeks) will be excluded. Patients who have had a lack of response of their current depressive episode to duloxetine, as judged by the investigator, will be excluded. 18. Have initiated, stopped, or changed the type or intensity of psychotherapy within 6 weeks prior to Visit 1. Patients who require a change to psychotherapy (start, stop, or change in type, intensity, or frequency) during study Period II will be excluded. 19. Have a history of seizure disorder (other than febrile seizures). 20. Have a history of electroconvulsive therapy (ECT) within 1 year of Visit 1. 21. Have had treatment with a monoamine oxidase inhibitor (MAOI) within 14 days or fluoxetine within 30 days of Visit 3; or the potential need to use an MAOI during the study or within 5 weeks of discontinuation of study drug. 22. Have previously enrolled (ie, received study drug), completed, or withdrawn from this study or any other study investigating duloxetine or fluoxetine. 23. Have a positive urine drug screen for any substances of abuse or excluded medication. Note: If the patient has a positive urine drug screen at Visit 1 for an excluded medication that may not have had an adequate washout period, a re-test may be performed and evaluated prior to Visit 3. 24. Are taking any excluded medications (eg, stimulants or other antidepressants) that cannot be discontinued by Visit 2. 25. Have known hypersensitivity to duloxetine, fluoxetine, or their inactive ingredients; or have frequent or severe allergic reactions to multiple medications. 26. Have uncontrolled narrow-angle glaucoma. 27. Have acute liver injury (for example, hepatitis) or severe cirrhosis (Child-Pugh Class C). 28. Have a serious or unstable medical illness, psychological condition, or clinically significant laboratory or ECG result that, in the opinion of the investigator, would compromise participation in the study or be likely to lead to hospitalisation during the course of the study. A serious or unstable medical condition is one that, in the judgment of the investigator, is likely to require intervention, hospitalisation, or use of excluded medications during the course of the study. 29. Have abnormal thyroid-stimulating hormone (TSH) concentration. Note: Patients previously diagnosed with hyperthyroidism or hypothyroidism who have taken a stable dose of thyroid supplement for at least the past 3 months, have medically appropriate TSH concentrations, and are clinically euthyroid will be permitted to enrol 30. Have initiated or discontinued hormone therapy within the previous 3 months. 31. Female patients who are either pregnant, nursing or have recently given birth. 32. Need to use thioridazine during the study or within 5 weeks after discontinuation of study drug or need to use pimozide during the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of this study is to assess the efficacy of duloxetine compared with placebo in the treatment of children and adolescents who meet criteria for MDD without psychotic features, single or recurrent episode, based on the mean change from baseline to endpoint on the CDRS-R total score. The CDRS-R total score will be calculated by summing the 17 individual scores. If three or fewer CDRS-R items are missing, the average of the nonmissing values will be substituted for the missing items. If more than three assessment items are missing, the total assessment score will be set to missing. The primary efficacy analysis will be the contrast between duloxetine and placebo at the last visit in Study Period II (visit 8, week 10) from a MMRM analysis on mean change from baseline in the CDRS-R total score. The model for this analyses will include the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline CDRS-R total score, baseline CDRS-R total score-by-visit interaction, age category (pediatrics 7-11, adolescents 12-17), and age category-by-visit interaction. The ITT population will be used to perform this analysis. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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 | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 54 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |