Bipolar Depression in Children and Adolescent

主要目的是針對10至17歲、處於躁鬱症鬱期的孩童和青少年，評估quetiapine XR配方於每天150至300 mg劑量治療8週後，以基期至最後評估(第57日)的修正版兒童憂鬱評量表(CDRS-R)總分差異，了解其療效是否優於安慰劑。 次要目的為： 1. 評估quetiapine XR在減輕孩童和青少年躁鬱症鬱期方面是否優於安慰劑。 2. 評估quetiapine XR在達到孩童和青少年躁鬱症鬱期的憂鬱症狀反應方面是否優於安慰劑。 3. 與安慰劑比較，評估quetiapine XR在減少快速循環和非快速循環型病患憂鬱症狀的療效。 4. 評估quetiapine XR在減少第一型或第二型躁鬱症兒童或青少年憂鬱症狀的療效上是否優於安慰劑。 5. 評估quetiapine XR在治療各類兒童或青少年憂鬱症狀的療效上是否明顯較安慰劑有效。 6. 評估每天一次quetiapine XR 150至300 mg對治療兒童或青少年憂鬱症狀的安全性和耐受性。 7. 藉由評估主要療效和安全性變數，比較quetiapine XR和安慰劑對較為年輕(10至12歲)和年齡稍大(13至17歲)族群的療效 8. 針對第一型和第二型躁鬱症受試者，收集血液檢體以進行選擇性探索性遺傳學研究，鑑定影響quetiapine XR療效、安全性和耐受性的基因

Quetiapine fumarate XR, SEROQUEL XR

Quetiapine fumarate

tablet

50

主要目的是針對10至17歲、處於躁鬱症鬱期的孩童和青少年，評估quetiapine XR配方於每天150至300 mg劑量治療8週後，以基期至最後評估(第57日)的修正版兒童憂鬱評量表(CDRS-R)總分差異，了解其療效是否優於安慰劑。

次要目的為：
1. 評估quetiapine XR在減輕孩童和青少年躁鬱症鬱期方面是否優於安慰劑。

2. 評估quetiapine XR在達到孩童和青少年躁鬱症鬱期的憂鬱症狀反應方面是否優於安慰劑。

3. 與安慰劑比較，評估quetiapine XR在減少快速循環和非快速循環型病患憂鬱症狀的療效。

4. 評估quetiapine XR在減少第一型或第二型躁鬱症兒童或青少年憂鬱症狀的療效上是否優於安慰劑。

5. 評估quetiapine XR在治療各類兒童或青少年憂鬱症狀的療效上是否明顯較安慰劑有效。

6. 評估每天一次quetiapine XR 150至300 mg對治療兒童或青少年憂鬱症狀的安全性和耐受性。

7. 藉由評估主要療效和安全性變數，比較quetiapine XR和安慰劑對較為年輕(10至12歲)和年齡稍大(13至17歲)族群的療效

8. 針對第一型和第二型躁鬱症受試者，收集血液檢體以進行選擇性探索性遺傳學研究，鑑定影響quetiapine XR療效、安全性和耐受性的基因

SUBJECT SELECTION CRITERIA
The subject population should be selected without bias.
Investigators must keep a record of subjects who entered pre-trial screening but were never
enrolled, eg, subject screening log. Each subject must meet all of the inclusion criteria and none of the exclusion criteria for this study. Under no circumstances can there be exceptions to this rule.
Inclusion criteria
For inclusion in the study, subjects must fulfill the following criteria:
1. Provision of informed consent by one or both parents or by legal guardian prior to any study procedures at enrollment.
2. Provision of written assent by the subject prior to any study procedures at enrollment.
3. Male or female subjects aged 10-17 years (inclusive) at randomization (Visit 2).
4. Documented clinical diagnosis meeting the DSM-IV-TR criteria for bipolar I or bipolar II disorder, current episode depressed (296.50-296.54 and 296.89, respectively) (Appendix E) confirmed by psychiatric and K-SADS-PL diagnostic interviews at enrollment (Visit 1). Subjects with psychotic features will be allowed in the study.
5. CDRS-R total score of 45 at enrollment (Visit 1) and randomization (Visit 2).
6. Subjects must be able to understand and comply with the requirements of the study, as judged by the investigator at time of enrollment.
7. Outpatient status at the enrollment and randomization visits and believed likely to remain an outpatient for the duration of the study.
8. The duration of the current episode of depression should be 4 weeks at enrollment (Visit 2).
9. At enrollment, subjects must meet the DSM-IV-TR criteria for primary bipolar I or bipolar II depression confirmed by the K-SADS-PL. Subjects who meet the criteria for rapid cycling are permitted. Rapid cycling is understood to occur in approximately 10-20% of adult subjects with bipolar disorder and women comprise 70-90% of individuals with a rapid-cycling pattern. The prevalence of rapid cycling in the pediatric population is thought to be higher. Subjects may also have a secondary diagnosis of ADHD. Subjects with ADHD may, if judged necessary by the investigator, continue psychostimulant treatment if the FDA-prescribed dose has been stable for 30 days preceding randomization.
10. At enrollment, the subject must have a parent or legal guardian who will accompany
the subject at each scheduled study visit, who can provide reliable information, and
can be responsible for receiving and dispensing study medication.
11. Subjects must be able to swallow the study medication tablets.
Exclusion criteria
Subjects must not enter the study if any of the following exclusion criteria are fulfilled:
1. At enrollment, diagnosis of another current DSM-IV-TR Axis I disorder with the exception of those noted in the inclusion criteria. Excluded diagnoses include Tourette’s Disorder, Obsessive-Compulsive Disorder (OCD), acute (<3 months) Post-traumatic Stress Disorder (PTSD), Panic Disorder, and Pervasive Developmental Disorders (eg, Autistic Disorder and Asperger’s Disorder).
2. Subjects are excluded whose YMRS total >16 at enrollment or randomization and/or subject meets criteria for bipolar I/II disorder, most recent episode mania/hypomania/mixed as confirmed by K-SADS-PL.
3. Subjects with a history of non-response to an adequate treatment (ie, of duration 6 weeks) with more than 2 antidepressants during their current episode at enrollment.
4. Current alcohol or other substance dependence or abuse as defined by DSM-IV-TR criteria at enrollment, except for caffeine and nicotine dependence.
5. Subjects are excluded if they use or need to use, within the 2 weeks (14 days) before randomization, drugs that strongly induce or inhibit the hepatic metabolizing cytochrome P450 (CYP) 3A4 enzymes. Subjects will also be excluded if they need to use these drugs during the study. Examples of inducers are carbamazepine, phenytoin, barbiturates, rifampin, rifabutin, glucocorticoids, thioridazine, and St. John’s Wort. Examples of inhibitors are ketoconazole (except for topical use), itraconazole, fluconazole, erythromycin, larithromycin, indinavir, nelfinavir, ritonavir, and saquinavir) (Appendix D).
6. Use of the following medications:
Antipsychotic, mood stabilizer, antidepressant, anxiolytic, hypnotic or other psychoactive drugs within 7 days before randomization.
Fluoxetine within 28 days before randomization.
A depot antipsychotic injection within two dosing intervals (for the depot) before randomization.
Lithium within 7 days before randomization and/or tapering off started at least 14 days before randomization.
Irreversible monoamine oxidase inhibitors (MAOI) within 14 days before randomization.
7. Receipt of electroconvulsive therapy (ECT) within 30 days before randomization.
8. Subjects who in the investigator’s opinion will require formalized psychotherapy during the study period, unless psychotherapy has been ongoing for a minimum of 3 months prior to randomization and is documented as such in the subject’s medical record.
9. Subjects who, in the investigator’s judgment, pose a current serious suicidal or homicidal risk, have a CDRS-R item 13 score of 3 at enrollment or randomization, or have made a suicide attempt within the past 6 months prior to enrollment.
10. Pregnancy or, if lactating, subject is nursing. Female subjects of childbearing potential must have a negative serum pregnancy test (beta human chorionic gonadotrophin ["-hCG]) at enrollment prior to randomization and be willing to use a reliable method of birth control during the study. Acceptable methods of birth control include abstinence, double-barrier method, oral contraceptive, implant, dermal contraception, long-term injectable contraceptive, intrauterine device, or tubal ligation.
11. A diagnosis of diabetes mellitus.
12. Clinically significant deviation from the reference range in clinical laboratory test
results at enrollment, as judged by the investigator and the Medical Monitor.
13. Subjects are excluded if they have conditions that could affect absorption or metabolism of study medication (eg, malabsorption syndrome, severe liver disease), as judged by the investigator and Medical Monitor at enrollment or randomization.
14. History of seizure disorder, except febrile convulsions at enrollment or randomization.
15. Evidence of a clinical disorder or clinical finding problematic to the study, as judged by the investigator at enrollment, such as renal (serum creatinine 1.5 mg/dL) or hepatic impairment (alanine transaminase [ALT] or aspartate transaminase [AST] 3x the upper limit of normal [ULN]), significant coronary artery disease, active viral hepatitis B or chronic active hepatitis C, or acquired immunodeficiency syndrome (AIDS).
16. An ANC of <1.5 x 109/L at enrollment.
17. A thyroid-stimulating hormone (TSH) concentration more than 10% above the upper limit of the normal range of the laboratory used for sample analysis whether or not the subject is being treated for hypothyroidism at enrollment.
18. After the assessment by a centrally located, experienced cardiologist interpreting the ECG obtained at enrollment using centralized telephonically transmitted ECG methods, a subject will be excluded if this ECG result is considered to be clinically significant as determined by the investigator. In some rare clinical situations, the central reading cardiologist’s interpretation will be exclusionary without the local investigator’s interpretation.
19. An ECG QTcF measurement 450 ms at enrollment.
20. Subjects with a history of non-compliance as judged by the investigator at enrollment.
21. Subjects are excluded if they have a history of episodic, idiopathic orthostatic hypotension, with our without near-syncopal or syncopal episodes, or conditions that would predispose them to episodic hypotension, such as dehydration or hypovolemia at enrollment or randomization.
22. Known history of intolerance or hypersensitivity to quetiapine or to any other components in the tablets at enrollment or randomization.
23. Contraindications at enrollment or randomization as detailed in the country-specific
prescribing information for quetiapine.
24. Participation (receiving investigational product) in another clinical study or compassionate use program within 30 days of enrollment or as required by local regulations.
25. Involvement of a first-degree relative in the planning and conduct of the study (applies to both AstraZeneca staff, their representatives and staff at the investigational site).
26. CDRS-R decreased >20% between enrollment and randomization.
27. Previous enrollment or randomization of treatment in the present study.
28. Subject is unable to swallow the study medication.
For the subject to be qualified for the optional genetic research, the subject must not:
1. Have had previous bone marrow transplant.
2. Received whole blood transfusion within 120 days prior to the date of genetic
sample collection.
If either of these two exclusion criteria is present, the subject cannot participate in the optional genetic research.