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 objectives of this study are to demonstrate the antimanic efficacy and to assess the safety and tolerability of paliperidone ER relative to placebo during 6 weeks of treatment in subjects with Bipolar I Disorder who experience an acute manic or mixed episode (with or without psychotic features) while they are taking lithium or valproate for treatment of Bipolar I Disorder.
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E.2.2 | Secondary objectives of the trial |
To assess the effect of paliperidone ER on global functioning compared with placebo during 6 weeks of treatment. Other objectives of this study include: " To assess the onset of antimanic clinical response to paliperidone ER compared with placebo. " To assess the global improvement in severity of illness associated with the use of paliperidone ER compared with placebo. " To evaluate the impact of paliperidone ER therapy on health-related functional status, using the Short Form (SF-36), compared with placebo. " To assess the impact of paliperidone ER on depressive symptoms compared with placebo. " To assess the impact of paliperidone ER on psychotic symptoms compared with placebo using a symptom-rating scale. " To explore the pharmacokinetics of paliperidone ER in subjects with Bipolar I Disorder and assessing the relationship of pharmacokinetics to the efficacy and safety of paliperidone ER.
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1- Man or woman, 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. 2- 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. Note: It is acceptable to have additional signatures if required by local regulations. 3- In countries where health authorities have approved the pharmacogenomic testing, subjects must have signed the informed consent form for pharmacogenomic testing indicating whether they do or do not agree to participate in the genetic part of the study. NOTE: Participation in the genetic testing component is not mandatory for participation in the study 4- Meet DSM-IV criteria for Bipolar I Disorder, Most Recent Episode Manic or Mixed (with or without psychotic features) at the time of screening/washout (Days -7 to -1). Subjects with other Axis I and II disorders, except those listed in the exclusion criteria, are also acceptable. All diagnoses will be confirmed by the MINI. 5- 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 before screening. At screening, the drug levels of subjects on lithium and valproate should be within the therapeutic range (0.6-1.2 mEq/L and 50-125 µg/mL, respectively). For subjects on lithium, documentation should be available of therapeutic drug levels from the period between 2 months and 2 weeks before screening. The dosage of lithium should not have changed in the period between the therapeutic drug monitoring and screening. For subjects on valproate, the dosage of the mood stabilizer should not have been changed over a period of at least 2 weeks before screening. 6- History of at least 1 previously documented manic or mixed episode requiring medical treatment within the 3 years before the screening/washout phase. 7- Total score of at least 20 on the YMRS at screening and at baseline (Day 1). 8- Women must be postmenopausal (no spontaneous menses for at least 2 years), surgically sterile, abstinent, or, agree to practice an effective method of birth control if they are sexually active before entry and throughout the study (effective methods of birth control include prescription hormonal contraceptives, intrauterine device, double-barrier method, and male partner sterilization). 9- Able and willing to comply with self-administration of medication, or have consistent help or support available. 10- Able to meet study requirements (e.g., answer self-administered questionnaires). NOTE: If a subject is unable to read study information or answer study questions, study personnel may read the questions to the subject and the subject may then mark his or her choice.
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E.4 | Principal exclusion criteria |
1- In the opinion of the investigator, are at significant risk for suicidal or violent behavior during the course of the study. 2- Meet DSM-IV criteria for any type of episode associated with bipolar disorder other than Bipolar I Disorder, Most Recent Episode Manic or Mixed (with or without psychotic features). 3- Meet DSM-IV criteria for rapid cycling and schizoaffective disorder. 4- Known or suspected borderline or antisocial personality disorder. 5- Known or suspected history of substance dependence (excluding nicotine and caffeine) according to DSM-IV criteria, with DSM-IV duration criteria modified to at any time within the previous 3 months. 6- Serious or unstable, medical illness or have a history of cerebrovascular disease or uncontrolled or insulin dependent diabetes mellitus. Subjects with chronic illness may be included but must be stable and otherwise physically healthy. 7- Known or suspected seizure disorder or require treatment with anticonvulsants for another indication (except for valproate). 8- History of severe pre-existing gastrointestinal narrowing or inability to swallow oral study drug whole with the aid of water. 9- Results at screening or baseline for ALAT or ASAT greater than twice the upper limit of the central laboratory's reference range. If the results for any other serum chemistry, hematology, or urinalysis testing are not within the central laboratory's reference ranges, the subject can be enrolled only if, in the opinion of the investigator, the deviations are not clinically significant. 10- Have active hypo- or hyperthyroidism unless stabilized on appropriate medication for at least 3 months before the screening/washout phase. 11- History of neuroleptic malignant syndrome or similar encephalopathic syndrome. 12- Have a moderate-to-severe degree of tardive dyskinesia at screening. 13- Known or suspected history of hypersensitivity or intolerance to paliperidone, risperidone, lithium, or valproate; or suspected history of life-threatening drug allergy or hypersensitivity to any drug. 14- Have received benzodiazepines at doses equivalent to 4 mg/day of lorazepam or higher for a period of 3 months or longer immediately before the screening/washout phase. 15- Use of clozapine, aripiprazole, or fluoxetine within 1 month before the screening/washout phase. 16- Have received antidepressant therapy, other than fluoxetine, within 7 days (or 5 times the half-life of the product, whichever is longer) before study drug administration on Day 1. Antidepressant medications include known antidepressants used for other indications as well as St. John's Wort, SAM-e, and other over-the-counter (OTC) antidepressants. 17- Use of antiparkinsonian drugs or beta-adrenergic blockers (for any indication other than hypertension) within 3 days before study drug administration on Day 1. 18- Have used cocaine, phencyclidine, amphetamine, methylphenidate, pemoline, an opioid (excluding low-dose codeine), hallucinogen, or any other drug that may be associated with manic symptoms as evidenced by a positive urine drug screen. 19- Alcohol intoxication within 3 days before study drug administration on Day 1. 20- Have had an injection of RISPERDAL CONSTA within 5 weeks before the screening/washout phase, or have received another depot antipsychotic within 1 treatment cycle before the screening/washout phase. 21- Have received an experimental drug or used an experimental medical device within 3 months before the screening/washout phase. 22- Electroconvulsive therapy within 6 months before study drug administration on Day 1. 23- Women who are pregnant or nursing. 24- Have an anticipated life expectancy of 6 months or less. 25- Unable to provide their own consent. 26- Previous participation in this study.
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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 |