| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 |
To evaluate the efficacy of aripiprazole in combination with lithium or valproate, compared with placebo in combination with lithium or valproate, as long-term maintenance therapy for patients with Bipolar I Disorder, manic or mixed, with or without psychotic features, demonstrating maintenance of stability for a minimum of
12 weeks when treated with aripiprazole in combination with lithium or valproate, as measured by the time to relapse. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of aripiprazole in combination with lithium or valproate as long-term maintenance therapy in this same patient population. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Patients able to give informed consent, and/or consent obtained from a legally acceptable representative (as required by IRB/IEC) prior to the initiation of any protocol required procedures;
2) Patients meeting DSM-IV-TR criteria for Bipolar I Disorder, currently experiencing a
manic or mixed episode with or without psychotic features, as confirmed by the SCID; Rapid cyclers with <7 mood episodes in the last year will be included;
3) Patients with a Y-MRS total score of ≥ 16 at the Screening Visit;
4) Patients with a history of one or more manic or mixed episodes of sufficient severity to require hospitalization and/or treatment with a mood stabilizer or antipsychotic;
5) Patients who are able to understand the nature of the study and follow protocol requirements, and who can be reliably rated on assessments scales;
6) Men and women, ≥ 18 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 study. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal. Postmenopausal is defined as:
• Amenorrhea ≥ 12 consecutive months without another cause or
• For women with irregular menstrual periods and on hormone replacement therapy
(HRT), a documented serum follicle stimulating hormone (FSH) level ≥ 35 mIU/mL.
Inclusion Criteria Assessed during Phase 1:
7) Patients with an adequate washout of prohibited concomitant medications;
8) Patients with lithium or valproate serum level within therapeutic range (lithium: 0.6 -
1.0 mmol/l or valproate: 50 - 125 µg/ml);
9) Patients with a Y-MRS total score of ≥ 16, two weeks after therapeutic levels of
mood stabilizer are achieved, with no more than a 35% decrease from the initial YMRS assessment; an increased or unchanged Y-MRS score is also allowed;
Inclusion Criteria Assessed Prior to Entry into Phase 3:
10) Patients whose bipolar disorder is stable as evidenced by:
a) Y-MRS total score and MADRS total score that has been ≤ 12 for at least 12 weeks, with a maximum of one excursion (defined as a Y-MRS total score > 12 and/or a MADRS total score > 12) in the intervening interval;
b) Y-MRS and a MADRS total score of ≤ 12 at the final Phase 2 Visit.
|
|
| E.4 | Principal exclusion criteria |
1) 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 study.
2) WOCBP using a prohibited contraceptive method.
3) Women who are pregnant or breastfeeding.
4) Women with a positive pregnancy test on enrollment or prior to study drug administration.
5) Patients presenting with a current DSM-IV-TR diagnosis of delirium, dementia, amnestic or other cognitive disorders, or a psychotic disorder. Also, patients with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder;
6) Patients with a current Axis I (DSM-IV-TR) diagnosis of bipolar II disorder, rapid cyclers experiencing seven or more mood episodes (manic, depressive, or mixed) within the past year, bipolar disorder NOS, or any other primary psychiatric disorder other than Bipolar I Disorder;
7) Patients experiencing their first manic episode;
8) Patients with a current manic or mixed episode with a duration of > 2 years;
9) Patients considered treatment refractory to treatment for manic symptoms. In addition, patients with a history of unresponsiveness to clozapine must be discussed with the CRO Medical Monitor prior to initiating study medication;
10) Patients with a significant risk of committing suicide;
11) Patients who currently meet DSM-IV-TR criteria for substance abuse or substance
dependence;
12) Patients with thyroid pathology, unless condition has been stabilized with medications for at least the past three months. In addition, patients with thyroid conditions will not be allowed treatment with lithium;
13) Patients 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;
14) Patients with epilepsy or a history of seizures (except for childhood febrile seizures, post traumatic, alcohol withdrawal, etc.);
15) Patients with a CPK ≥ 550 U/L must be approved by the sponsor prior to randomization;
16) Patients with a positive drug screen for cocaine;
17) The following laboratory tests results, vitals signs, and ECG findings are
exclusionary:
a) Platelets ≤ 75,000/mm3
b) Hemoglobin ≤ 9g/dL
c) Neutrophils, Absolute ≤ 1000/ mm3
d) SGOT (AST) > 3x Upper Limit of Normal
e) SGPT (ALT) > 3x Upper Limit of Normal
f) Creatinine ≥ 2 mg/dL
g) Patients may be retested during the screening period (Phase 1) at the investigator’s discretion. Upon retest, if results do not meet the exclusion criteria listed above, the patient may continue onto Phase 2;
h) Diastolic blood pressure > 105 mmHg
i) QTc > 475 msec
In addition, patients 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 patient or the interpretation of the study results (see Protocol Appendices 3, 4, and 5);
18) Patients who are known to be allergic, intolerant, or unresponsive to previous aripiprazole treatment;
19) Hypersensitivity to antipsychotic agents;
20) Patients allergic, intolerant, hypersensitive or refractory to both lithium and valproate;
21) Patients with a history of neuroleptic malignant syndrome from antipsychotic agents;
22) Patients likely to require prohibited concomitant therapy, (see Protocol Section 6.4);
23) Patients who have participated in a clinical trial with an investigational agent within the past month or who were randomized in a clinical trial with aripiprazole;
24) Prisoners or subjects who are compulsorily detained;
Exclusion Criteria Assessed Prior to Entry into Phase 2
25) Patients on mood stabilizers other than lithium or valproate within two weeks of entry into Phase 2;
26) Patients who have received antidepressants within two weeks prior to entry into Phase 2;
27) Recent treatment of their most recent manic or mixed acute episode with a longacting antipsychotic in which the last dose was less than one full dosing interval plus three weeks prior to entering Phase 2;
28) ECT treatment during the current episode or within three months prior to entry into Phase 2;
Exclusion Criteria Assessed Prior to Entry into Phase 3
29) Patients who have not responded to combination therapy by Week 12 of Phase 2;
30) Patients who have more than one mood excursion after achieving a response to combination therapy at a point in the trial where they would not be able to maintain stability for a minimum of 12 weeks without exceeding 24 total weeks in Phase 2. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy outcome measure will be the time from randomization to relapse to any mood episode.
Secondary Outcome Measures include mean change from baseline (end of Phase 2) to endpoint (Week 52 LOCF) in the following scales:
• CGI-BP Severity of Illness Score (mania) |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| 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) | 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 | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 |
|
| 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
|
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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