| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Manic or Mixed Episodes Associated with Bipolar I 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 test the superiority of olanzapine compared with divalproex in improving overall manic symptomatology in patients with mild to moderate mania associated with bipolar I disorder, as measured by reductions on the Young Mania Rating Scale (YMRS) total score from baseline to the endpoint of Study Period II (3-week acute therapy phase). |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follows:
· Treatment comparisons for the reductions of the YMRS total score from baseline to the endpoint of Study Period II:
o Assess the superiority of olanzapine compared to placebo.
o Assess the superiority of divalproex compared to placebo.
o In the event that olanzapine vs. divalproex comparison is not significant, and that divalproex is superior to placebo, an assessment of non-inferiority of olanzapine compared with divalproex will be performed.
· To assess the acute efficacy of olanzapine compared with divalproex and placebo in improving clinical symptomatology during Study Period II, using several measures:
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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 or female patients (inpatient or outpatient), 18 to 65 years of age.
[2] All female patients must test negative for pregnancy and, if of childbearing potential, must be using a medically accepted means of contraception.
[3] Individuals who are reliable, have a level of understanding sufficient to perform all tests and examinations required by the protocol, understand the nature of the study, and have given informed consent.
[4] Patients must have a diagnosis of bipolar I disorder and currently meet DSM-IV-TR criteria for an acute manic or mixed episode based on clinical assessment and confirmed by structured diagnostic interview using the SCID-CV plus the Rapid Cycling item from the Bipolar Specifiers obtained from the SCID-I; allowable diagnoses include mild manic episode (296.41), moderate manic episode (296.42), mild mixed episode (296.61), or moderate mixed episode (296.62).
[5] Has YMRS total score of ³20 and £30 at both Visits 1 and 2.
[6] Has CGI-BP Mania sub-score of 3 or 4 at both Visits 1 and 2.
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| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[7] Exhibit rapid cycling behavior (ie, 4 or more episodes per year, as specified in DSM-IV-TR).
[8] Exhibit psychotic features (with mood-congruent or mood-incongruent delusions or hallucinations), as specified in DSM-IV-TR.
[9] Current episode meets criteria for hypomania associated with Bipolar II Disorder as defined in DSM-IV-TR.
[10] Have current or lifetime diagnosis of any of the following according to DSM-IV-TR criteria: schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, psychotic disorder not otherwise specified, delirium of any type, dementia of any type, amnestic disorder, any substance-induced disorder, or any psychotic disorder due to a general medical condition, unless there is substantive reason to believe patient was misdiagnosed. The Lilly clinical research physician or designee for this study must approve any scenario regarding a suspected misdiagnosis.
[11] Have received treatment with an oral antipsychotic, mood stabilizer, or other CNS medication within 24 hours prior to randomization (Visit 2), other than those allowed as specified in Section 5.7 below.
[12] Have received treatment with depot antipsychotics within one dosing interval prior to Visit 1.
[13] Have received treatment with electroconvulsive therapy (ECT) within 3 months (90 days) prior to Visit 1.
[14] Have received treatment with reversible monoamine oxidase inhibitor, guanethidine, or guanadrel within 1 week prior to Visit 1.
[15] Have received treatment with nonreversible monoamine oxidase inhibitor within 2 weeks prior to Visit 1.
[16] Have received treatment with remoxipride within 6 months (180 days) prior to Visit 1.
[17] Have received treatment with clozapine within 3 months (90 days) prior to Visit 1.
[18] Exclusion criterion [18] has been deleted.
[19] Have history of intolerance to either olanzapine or divalproex.
[20] Have history of nonresponse to an adequate treatment trial with olanzapine or divalproex.
[21] Have history of allergic reaction to olanzapine or divalproex.
[22] Have any serious, unstable illness such that death is anticipated within 1 year or intensive care unit hospitalization for the disease is anticipated within 6 months.
[23] Have acute, serious or unstable medical conditions, including (but not limited to) inadequately controlled diabetes (Hemoglobin A1c [HgbA1c] >8%), severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL), hepatic insufficiency (specifically any degree of jaundice), recent cerebrovascular accidents, uncontrolled seizure disorders, serious acute systemic infection or immunologic disease, unstable cardiovascular disorders (including ischemic heart disease), renal, gastroenterologic, respiratory, endocrinologic, neurologic, or hematologic diseases (specifically current absolute neutrophil count <1500 mm3).
[24] Have had one or more seizures without a clear and resolved etiology. However, if the patient has had one or more seizures in the past with an identifiable etiology, and that etiology has been resolved, the patient may be entered. Note: the site must contact the sponsor or its representatives prior to entering a patient who has experienced any seizure.
[25] Have a diagnosis of Parkinson’s disease or related disorders. If a patient has a past misdiagnosis of Parkinson’s disease or related disorders, the investigator will need to contact the Lilly Clinical Research Physician (CRP) or designee for this study prior to enrollment.
[26] Have uncorrected hypothyroidism or hyperthyroidism. Patients needing a thyroid hormone supplement to treat hypothyroidism must have been on a stable dose of the medication for at least 2 months prior to Visit 2.
[27] Have known uncorrected narrow-angle glaucoma.
[28] Have leukopenia or history of leukopenia without a clear and resolved etiology or known history of agranulocytosis (absolute neutrophil count <500mm3) during the patient’s lifetime.
[29] Have thrombocytopenia or history of thrombocytopenia without a clear and resolved etiology or known history of severe thrombocytopenia (platelet count <50,000mm3) during the patient’s lifetime.
[30] Have prolactin level at Visit 1 of greater than 200 ng/mL (or 200mg/L).
[31] Have been diagnosed with DSM-IV or DSM-IV-TR substance (except nicotine and caffeine) dependence within the past 30 days.
[32] Are actively suicidal (eg, any suicide attempts within the past month or any current suicidal intent including plan) in the opinion of the investigator.
[33] Have known Human Immunodeficiency Virus positive (HIV+) status.
[34] Have ALT/SGPT values ³2 times the upper limit of normal (ULN) of the performing laboratory or AST/SGOT values ³3 times the ULN or total bilirubin values ³1.5 times the ULN at Visit 1.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Young Mania Rating Scale
The YMRS will by the primary efficacy measure in protocol F1D-MC-HGKQ and will be used to test the superiority of olanzapine compared with divalproex in improving overall manic symptomatology, as measured by reductions on the YMRS total score from baseline to the endpoint of Study Period II.
The YMRS is commonly used to assess the severity of manic symptoms and consists of eleven items. Items 5, 6, 8, and 9 (irritability, speech, content, and disruptive-aggressive behavior) are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe), according to specific descriptive anchor points. The remaining items (elevated mood, increased motor activity-energy, sexual interest, sleep, language-thought disorder, appearance, and insight) are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe), also with anchor points. Items 5, 6, 8, and 9 are given twice the weight of the remaining seven items. The YMRS total score ranges from 0 to 60 and is the primary efficacy parameter.
The YMRS is validated for use in monitoring gradual improvement in symptoms from mania to remission.
A mean YMRS score of 30 is typical of patients entering studies with acute mania (Tohen et al, 1999; Tohen et al, 2000), and an upper limit of 30 would be consistent with the definition of mild to moderate mania. A lower limit of 20 is consistent with the study entry criteria.
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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) | Information not present in EudraCT |
| 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) | 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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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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