| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 trial is to assess the adjunctive anti-manic efficacy of paliperidone ER relative to placebo during 6 weeks of treatment in subjects with Bipolar I Disorder who are suffering from a manic episode and who already have been taking lithium or valproate for treatment of Bipolar I Disorder. The primary efficacy measure is the change from baseline to endpoint in the Young Mania Rating Scale (YMRS) total score at study end. |
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| E.2.2 | Secondary objectives of the trial |
1. To assess the safety and tolerability of paliperidone ER.
2. To assess the impact on depressive symptoms during 6 weeks of treatment based on the total MADRS score.
3. To explore the pharmacokinetics of paliperidone in subjects with Bipolar I Disorder, and to assess possible pharmacokinetic relationships to efficacy and safety of paliperidone ER.
4. To evaluate the impact of paliperidone ER therapy on global functioning.
5. To evaluate the impact of paliperidone ER therapy on overall subject reported quality of life.
6. To allow for determination of the genes/genotypes that may be related to the response or metabolism of paliperidone ER or to Bipolar I Disorder (as necessary).
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Subjects must meet DSM-IV criteria for Bipolar I Disorder, Most Recent Episode Manic or Mixed at the time of screening. Other Axis I and II disorders except those listed in the exclusion criteria are acceptable. All diagnoses will be confirmed by the Mini International Neuropsychiatric Interview (MINI);
2. Subjects must have been taking the mood stabilizers, lithium or valproate, as part of treatment for Bipolar I Disorder for a minimum of 2 weeks prior to screening. At screening, the therapeutic drug levels of subjects on lithium and valproate should be within 0.6-1.2 mEq/L and 50-125 mcg/ml, respectively. All oral dosage forms of lithium and valproate (i.e. immediate and modified release tablets, or oral solutions) are allowed. The valproate preparations may contain valproate, valproic acid, or divalproex sodium;
3. Subjects must receive a total score of at least 20 on the Young Mania Rating Scale (YMRS) at screening and at baseline;
4. Subjects must have a history of experiencing at least one prior documented manic or mixed episode that required medical treatment within 3 years prior to screening;
5. Subjects must be between 18 (or the minimum age to provide informed consent in the jurisdiction in which the study is taking place, whichever is older) and 65 years of age inclusive;
6. Female subjects must be either postmenopausal for at least 1 year, surgically sterile, abstinent, or practicing an effective method of birth control if sexually active (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization). Female subjects must also have a negative urine pregnancy test at screening, baseline, and other time points throughout study;
7. Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. It is acceptable to have additional signatures if required by local regulations;
8. Subjects must have signed the informed consent for genetic testing indicating whether they do or do not wish to participate in the genetic component of the study (where local regulations permit). Participation in the genetic component is not required for participation in the study;
9. Subjects must be able and willing to comply with self-administration of medication, or have consistent help/support available;
10. Subjects must be able and willing to meet or perform study requirements. Note: If a subject is unable to read the question, study personnel may read documents and the subject may then mark his/her choice. Inability to complete a self-administered questionnaire due to the acute manic state at entry should not preclude a subject from participating.
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| E.4 | Principal exclusion criteria |
1. Subjects who meet DSM-IV criteria for any type of episode associated with bipolar disorder other than Bipolar I Disorder, Most Recent Episode Manic or Mixed (particularly, subjects with anxious, agitated depression, which may mimic a mixed episode);
2. Subjects who meet DSM-IV criteria for rapid cycling;
3. Subjects who meet DSM-IV criteria for Schizoaffective Disorder;
4. Subjects with a known or suspected borderline or antisocial personality disorder;
5. Subjects with a known or suspected history of substance dependence
6. Subjects believed by the investigator to be at significant risk for suicidal or violent behavior during the course of the trial;
8. Subjects with a history of neuroleptic malignant syndrome (NMS) or similar encephalopathic syndrome;
9. Subjects with a known or suspected seizure disorder, and subjects who require treatment with anticonvulsants for another indication (e.g. migraine prophylaxis);
10. Subjects with a serious, unstable medical illness
11. Subjects with active hypo- or hyperthyroidism unless stabilized
12. If the results of the serum ALT or AST tests are greater than twice the upper limit
13. Subjects with a moderate to severe degree of tardive dyskinesia
14. Subjects who are receiving antiparkinsonian drugs or beta-adrenergic blockers (for any indication other than hypertension) within 3 days of baseline;
15. Subjects who have continuously received benzodiazepines at doses equivalent to 4 mg/day of lorazepam or higher for a period of 3 months or longer prior to screening;
16. Subjects who have received clozapine within 1 month prior to screening;
17. Subjects who have received a depot neuroleptic within one treatment cycle prior to screening;
18. Subjects who have had an injection of Risperdal Consta within 5 weeks prior to screening;
19. Subjects who have received antidepressant therapy within 7 days
20. Subjects who have had electroconvulsive therapy within 6 months prior to baseline;
21. Subjects who have recently used cocaine, phencyclidine, amphetamine, methylphenidate, pemoline, an opioid (excluding codeine), hallucinogen
23. Subjects with a known or suspected history of life-threatening drug allergy, or hypersensitivity or intolerance to paliperidone, risperidone, lithium, or valproate;
24. Subjects with a history of severe pre-existing gastrointestinal narrowing
25. Female subjects who are pregnant or nursing;
26. Subjects who have previously participated in this trial;
27. Subjects with an anticipated life expectancy of 6 months or less;
28. Have received an experimental drug or used an experimental medical device within 3 months before the planned start of treatment;
29. Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| primary efficacy end point is the change in the total YMRS score from baseline to the last post-baseline assessment during 6 weeks of treatment. |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| 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.8.5 | 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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