| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 10004939 |
| E.1.2 | Term | Bipolar I disorder |
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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 |
To evaluate the efficacy of quetiapine versus placebo in increasing time from randomization to recurrence of a mood event in patients with Bipolar I Disorder. Recurrence of a mood event is defined as fulfilling at least 1 of the following: (a) initiation of an antipsychotic, antidepressant, mood stabilizer, anxiolytic other than lorazepam, or any other medication to treat a manic, depressed or mixed event, (b) hospitalization for a manic, depressed or mixed event, (c) Young Mania Rating Scale (YMRS) score more than or equal to 20 at 2 consecutive assessments or at the final assessment if the patient discontinues, or Montgomery-Asberg Depression Rating Scale (MADRS) score more than or equal to 20 at 2 consecutive assessments or at the final assessment if the patient discontinues, or (d) discontinuation from the study by the patient if, in the opinion of the investigator, the discontinuation was due to a manic, depressed or mixed event.
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of quetiapine versus placebo in increasing time from randomization to recurrence of a manic event. Recurrence of a manic event is defined as fulfilling at least 1 of the following: (a) initiation of an antipsychotic, mood stabilizer, anxiolytic other than lorazepam, or any other medication to treat a manic event or a mixed event with predominantly manic symptoms, (b) hospitalization for a manic event or a mixed event with predominantly manic symptoms, (c) YMRS score ≥20 for 2 consecutive assessments, or YMRS score ≥20 at final assessment if the patient discontinues, or (d) discontinuation from the study by the patient if, in the opinion of the investigator, the discontinuation was due to a manic event or a mixed event with predominantly manic symptoms.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For inclusion in the Open-label Treatment Phase patients must fulfill all of the following criteria:
1. Provide written informed consent before initiation of any study-related procedures
2. A diagnosis of Bipolar I Disorder, Most Recent Episode Manic (296.4x), Bipolar I Disorder, Most Recent Episode Depressed (296.5x), or Bipolar I Disorder, Most Recent Episode Mixed (296.6x), with or without psychotic features, as defined by Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV)
3. Male or female aged more than or equal to 18 years
4. At least 1 manic, depressed or mixed episode in the 2 years prior to the index episode
5. One of the following:
a. A current manic, depressed or mixed episode by DSM-IV criteria
b. A past manic, depressed or mixed episode within 26 weeks as documented by medical records, that was treated with quetiapine. Since this episode, treatment with quetiapine must not have been interrupted for more than 2 weeks continuously
6. Female patients of childbearing potential must be using a reliable method of contraception. Reliable methods of contraception include hormonal contraceptives (e.g., oral contraceptive or long-term injectable or implantable hormonal contraceptive), double-barrier methods (e.g., condom and diaphragm, condom and foam, condom and sponge), intrauterine devices, and tubal ligation
7. Able to understand and comply with the requirements of the study
For inclusion in the Randomized Treatment Phase, patients must fulfill all of the following criteria during the Open-label Treatment Phase:
1. Has been prescribed a dose of quetiapine within the range 300-800 mg/day for the last 4 weeks
2. YMRS less than or equal to 12 and MADRS less than or equal to 12 at all assessments during the last 4 weeks
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| E.4 | Principal exclusion criteria |
Exclusion criteria for entering the Open-label Treatment Phase
Any of the following is regarded as a criterion for exclusion from the study at enrollment:
1. Diagnosis of an anxiety disorder as defined by DSM-IV, which was treated with medication within the past year
2. Known intolerance or lack of response to quetiapine fumarate or to lithium, as judged by the investigator
3. Pregnancy or lactation. Female patients of childbearing potential must have a negative serum human chorionic gonadotropin (HCG) test at enrollment
4. Substance or alcohol dependence at enrollment (except dependence in full remission, and except for caffeine or nicotine dependence), as defined by DSM IV criteria
5. Opiate, amphetamine, barbiturate, cocaine, cannabis, or hallucinogen abuse by DSM-IV criteria within 4 weeks prior to enrollment
6. Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrollment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, and saquinavir
7. Use of any of the following cytochrome P450 3A4 inducers in the 14 days preceding enrollment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampin, St. John’s Wort, and glucocorticoids
8. Thyroid stimulating hormone (TSH) concentration more than 10% above the upper limit of the normal range, regardless of treatment for hypothyroidism or hyperthyroidism
9. Unstable or inadequately treated medical illness (e.g., angina pectoris and hypertension) as judged by the investigator
10. A patient with Diabetes Mellitus (DM) fulfilling one of the following criteria:
- Unstable DM defined as enrollment Glycosylated hemoglobin (HbA1c) >8.5%
- Admitted to hospital for treatment of DM or DM related illness in past 12 weeks
- Not under care of physician responsible for patient’s DM care
- Physician responsible for patient’s DM care has not indicated that patient’s DM is controlled
- Physician responsible for patient’s DM care has not approved patient’s participation in the study
- Has not been on the same dose of oral hypoglycemic drug(s) and/or diet for the 4 weeks prior to randomization. For thiazolidinediones (glitazones) this period should not be less than 8 weeks
- Taking insulin whose daily dose on one occasion in the past 4 weeks has been more than 10% above or below their mean dose in the preceding 4 weeks
Note: If a diabetic patient meets one of these criteria the patient is to be excluded even if the treating physician believes that the patient is stable and can participate in the study
11. Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment
12. Use of an experimental drug within 30 days of enrollment
13. Previously enrolled into this study, study D1447C00126 or study D1447C00127
14. Involvement in the planning and conduct of the study (applies to both AstraZeneca, Quintiles staff or staff at the investigational site)
Exclusion criteria for entering the Randomized Treatment Phase
Any of the following is regarded as a criterion for exclusion from the study:
1. Hospitalization due to a mood event (manic, depressed or mixed) during the Open-label Treatment Phase
2. Electroconvulsive therapy (ECT) during the Open-label Treatment Phase
3. Attempt to commit suicide or homicide during the Open-label Treatment Phase
4. Substance or alcohol dependence (except dependence in full remission, and except for caffeine or nicotine dependence), as defined by DSM-IV criteria
5. Opiate, amphetamine, barbiturate, cocaine, cannabis, or hallucinogen abuse by DSM-IV criteria during the last 4 weeks
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary variable measured will be time to recurrence of a mood event (manic, depressed, or mixed) from randomization confirmed by at least 1 of the following as judged by the investigator:
- initiation of an antipsychotic, antidepressant, mood stabilizer other than the assigned mood stabilizer, anxiolytic other than lorazepam, or any other medication to treat a manic, depressed or mixed event
- hospitalization for a manic, depressed or mixed event
- YMRS score more than or equal to 20 at 2 consecutive assessments or at the final assessment if the patient discontinues, or MADRS score more than or equal to 20 at 2 consecutive assessments or at the final assessment if the patient discontinues
- Discontinuation from the study by the patient if, in the opinion of the investigator, the discontinuation was due to a manic, depressed or mixed event
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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
| Information not present in EudraCT |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
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