E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bipolar I Mania (manic or mixed episode) |
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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 | 10026749 |
E.1.2 | Term | Mania |
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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 adjunctive treatment with aripiprazole compared to placebo, as measured by YMRS, in the treatment of Bipolar I Disorder Mania subjects treated with valproate or lithium and in need of further clinical improvement |
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E.2.2 | Secondary objectives of the trial |
To assess the effect of adjunctive treatment with aripiprazole compared to placebo in terms of: • Efficacy, as measured on − Clinical Global Impression - Bipolar Version (CGI-BP) Severity of Illness Score − Response rate (≥ 50% improvement in YMRS Total score) − Remission rate (YMRS ≤ 12) • Patient reported outcomes for − Longitudinal Interval Follow-up Evaluation-Rating Impaired Functioning Tool (LIFE-RIFT) score − Functional Assessment Short Test (FAST) score − Patient Global Impression Improvement (PGI-I) scale • Safety and Tolerability including: − Frequency and severity of adverse events (AE) and serious adverse events (SAE) reports − Percentage of subjects with potentially clinically relevant changes in vital signs, routine laboratory tests and ECG − Mean change from baseline in subjects’ weight and the number and percentage of subjects with ≥ 7% increase or decrease in weight from baseline and median change from baseline in BMI |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent a) Subjects must be competent to understand the nature of the study, sign the informed consent, agree to comply with prescribed dosage regimens, discontinuation of prohibited concomitant medication, report for regularly scheduled visits, able to provide reliable information for safety, efficacy and Quality of Life assessments and communicate to the investigator about adverse events and concomitant medication use; b) The informed consent process must be documented by signing the informed consent form prior to any study-related procedures including alterations in medications in preparation for study entry and subject’s assignment via Interactive Voice Response System (IVRS). 2) Target Population a) Subjects with Bipolar I Disorder Mania, manic or mixed episode, with or without psychotic features, as defined by DSM-IV-TR and confirmed by the M.I.N.I., presenting with ongoing treatment with lithium or valproate and based on the investigator’s clinical judgment could benefit from adjunctive treatment with aripiprazole. b) Subjects with therapeutic serum levels of lithium or valproate (as per local SmPC) and a YMRS Total Score of ≥ 16 at screening and baseline and, in case of decrease, a ≤ 35% decrease of YMRS score from the initial screening visit prior to randomization (YMRS to be assessed 14-28 days after blood draw confirming the therapeutic serum level of lithium or valproate). c) Subjects on lithium or valproate treatment combined with antipsychotic medication other than aripiprazole can be enrolled provided that the other antipsychotic medication is washed out at least 3 days prior to the blood draw for the therapeutic plasma levels of lithium and valproate determination. Long-acting antipsychotics must be washed out prior to entering the double-blind treatment as indicated in Section 5.5 of the protocol. Those subjects who are currently improving or stable on a lithium/valproate and antipsychotic combination treatment and who in Investigator's clinical judgment would not benefit from adjunctive treatment with aripiprazole should not be considered for the trial. 3) Age and Sex a) Men and women, ≥ 18 years of age Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product. |
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E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 4 weeks after the last dose of investigational product. Acceptable methods include oral, injectable or implantable contraceptives, intrauterine devices or barrier methods such as condoms, diaphraghms; b) WOCBP using a prohibited contraceptive method. No specific contraceptive methods are prohibited in this study. Women practicing abstinence should use a reliable method of contraception if they choose to become sexually active during the study; c) Women who are pregnant or breastfeeding; d) Women with a positive pregnancy test on enrollment or prior to investigational product administration. 2) Target Disease Exceptions a) Subjects presenting clinically with a DSM-IV-TR diagnosis of: delirium, dementia, amnestic or other cognitive disorders, or a psychotic disorder (e.g., schizophrenia or schizoaffective disorder). b) Subjects with a current Axis I (DSM-IV-TR) diagnosis of Bipolar II Disorder, Bipolar Disorder NOS, or any other primary psychiatric disorder other than Bipolar I Disorder Mania. 3) Medical History and Concurrent Diseases a) Subjects considered treatment refractory by investigator judgment for manic symptoms b) Subjects previously nonresponsive (by investigator judgment) to aripiprazole for manic symptoms. c) Subjects with a significant risk of committing suicide based on history, mental status exam, or investigator’s judgment. d) Subjects who meet DSM-IV-TR criteria for cocaine dependence or abuse only within the past 3 months prior to screening. e) Subjects with thyroid pathology (i.e., hypothyroidism or hyperthyroidism) that in the investigator’s judgment may interfere with safety and efficacy assessments. f) Subjects with a history of neuroleptic malignant syndrome from antipsychotic agents, or subjects where - according to investigator’s judgment - neuroleptic malignant syndrome can not be ruled out in the presence of an increased CPK; g) Subjects who have a history or evidence of a medical condition that would expose them to an undue risk of a significant adverse event or interfere with assessments of safety or efficacy during the course of the trial, including but not limited to hepatic, renal, respiratory, cardiovascular, endocrine (e.g., Addison’s Disease), immune, neurologic, or hematologic disease as determined by the clinical judgment of the investigator; h) Subjects with a significant history of seizure disorder (e.g., epilepsy); 4) Physical and Laboratory Test Findings a) The following laboratory test results, vital sign and ECG findings are exclusionary: ♦ QTc > 475 msec ♦ Platelets ≤ 75,000/mm³ ♦ Hemoglobin ≤ 9g/dL ♦ Neutrophils, absolute ≤ 1000/mm³ ♦ Subjects with detectable levels of cocaine in the drug screen. ♦ AST (SGOT) or ALT (SGPT) > 3x upper limit of normal ♦ Creatinine ≥ 2 mg/dL [or ≥ 177 μmol/L] ♦ Diastolic blood pressure > 105 mmHg If one or more laboratory, vital signs or ECG values are questionable, the test(s) may be repeated and these eligibility criteria re-evaluated. In addition, subjects should be excluded if they have any other abnormal laboratory test result, vital sign result or ECG finding that in the investigator’s judgment is medically significant, in that it would impact the safety of the subject or the interpretation of the study results. 5) Allergies and Adverse Drug Reactions a) Subjects who are known to be allergic, intolerant, or unresponsive to aripiprazole; 6) Prohibited Treatments and/or Therapies a) Subjects who are likely to require prohibited concomitant therapy during the study as indicated in Section 5.5.1 of the protocol; b) Recent treatment of their most recent manic or mixed acute episode with a long acting antipsychotic in which the last dose was less than one full cycle plus one week prior to randomization (haloperidol decanoate treatment within the past 5 weeks, fluphenazine decanoate treatment within the past 3 weeks or Risperdal Consta™ treatment within the past 3 weeks); c) Subjects who have participated in a clinical trial with an investigational agent within the past month or who ever participated in a clinical trial with aripiprazole; 7) Other Exclusion Criteria d) Prisoners or subjects who are involuntarily incarcerated e) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness |
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E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate the efficacy of adjunctive treatment with aripiprazole compared to placebo, as measured by the mean change from baseline to week 12 in the YMRS total score, in the treatment of Bipolar I Disorder Mania subjects treated with valproate or lithium and in need of further clinical improvement. |
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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 | No |
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 | 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 | 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 71 |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 10 |