| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039621 |
| E.1.2 | Term | Schizoaffective disorder |
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| 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 evaluate the efficacy of flexible dose paliperidone ER (3 to 12 mg/day, in 3 mg/day increments), compared with placebo in the treatment of acutely ill subjects with schizoaffective disorder as measured by Positive and Negative Syndrome Scale (PANSS) total score. The safety and tolerability of paliperidone ER in subjects with schizoaffective disorder will also be assessed. |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives are listed below
• Assessment of the rate of response to paliperidone ER among subjects with schizoaffective disorder. Response is defined as a composite of a greater than or equal to 30% reduction from baseline in the PANSS total score and a Clinical Global Impression-Change Scale (CGI-C)
• Evaluation of the effects of paliperidone ER on mood symptoms in subjects with schizoaffective disorder, as measured by relevant PANSS factor scores (hostility/excitement and depression/anxiety)
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenomics.
Included in Protocol R076477-SCA-3002, Final version 5, Date 13-Nov-2006
This sub-study will only be carried out in countries/localities where the procedure is permitted. Participation in this study is optional and the subject must sign an additional informed consent for the procedure to take place.
Genetic variation within the population can be an important contributory factor in interindividual differences in drug distribution and response and can also serve as a marker for disease susceptibility and prognosis. A genetic association between genetic polymorphisms and clinical outcomes may help to identify population subgroups that are likely to better respond to or better tolerate the drug. A deeper understanding of such genetic variation and its impact on drug response is expected to enable the development of safer, more effective, and ultimately individualized therapies based on subject genotype. Therefore, DNA samples will be collected in this clinical study in order to help address emerging clinical issues and to develop safer, more effective drugs in the future.
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| E.3 | Principal inclusion criteria |
1. The subject must be, in the opinion of the investigator, able to understand the informed consent form approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC), as appropriate. All subjects must sign the study informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. In addition, reasonable efforts should be made to provide information about the study to a subject’s designated contact person. Note: It is acceptable to have additional signatures if required by local regulations. In addition, where permitted, if a subject has an appointed legal representative, both the representative and the subject will sign the form. Subjects who are unable to provide their own consent or who have been involuntarily committed to psychiatric hospitalization are not eligible to enroll in the study
2. Subjects may be male or female.
3. Age must be between 18 and 65 years, inclusive
4. Women must be postmenopausal for at least 1 year, 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, contraceptive injections, intrauterine devices, double-barrier method, contraceptive patch, and male partner sterilization). Female subjects must also have a negative urine pregnancy test at screening and baseline (Day 0).
5. Subjects must have lifetime and current diagnosis of schizoaffective disorder (DSM-IV 295.70), as confirmed by the SCID at screening
6. Subjects must be experiencing an acute exacerbation, with a PANSS total score greater than or equal to 60 at the time of study enrollment and at time of randomization
7. The onset of current episode (exacerbation of symptoms) must be no less than 4 days and no more than 4 weeks prior to screening
8. At screening and at randomization, subjects must have a score of 4 on at least 2 of the following PANSS items: Hostility (P7), Excitement (P4), Tension (G4), Uncooperativeness (G8), and Poor Impulse Control (G14)
9. At screening and at randomization, subject must have a score of >=16 on YMRS OR a score of greater than or equal to 16 on the HAM-D 21
10. Subjects must be hospitalized or be willing to be hospitalized at the time of screening
11. Subjects must be healthy on the basis of physical examinations, electrocardiogram (ECG), laboratory tests, medical history, and vital signs measurements
12. Subjects must be able, in the opinion of the investigator, to be compliant with self-administration of medication or have consistent help/support available.
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| E.4 | Principal exclusion criteria |
1. Women who are pregnant (as confirmed by urine pregnancy test performed at screening and baseline), planning to become pregnant, or breast-feeding
2. 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
3. Subjects with a urine drug screen that is positive for cocaine, opiates, PCP or amphetamines at screening or baseline
4. Subjects with an inability to swallow the study medication whole with the aid of water (subjects must not chew, divide, dissolve, or crush the study medication, as this may affect the release profile)
b. Psychiatric history
5. Subjects meeting the DSM-IV criteria for major depressive disorder (diagnostic categories 296.2x and 296.3x), bipolar disorder (diagnostic categories 296.0x, 296.40, 296.4x, 296.5x, 296.6x, 296.7, and 296.89), or schizophrenia (diagnostic categories 295.10, 295.20, 295.30, 295.60, and295.90),or schizophreniform disorder
(diagnostic category 295.40).
6. Subjects currently meeting criteria for any other Axis I diagnosis except substance abuse
7. Subjects meeting the DSM-IV criteria for substance dependence in the 6 months before study entry
8. Subjects with an Axis II diagnosis of Mental Retardation or Borderline Personality Disorder
9. Subjects who have attempted suicide within 12 months before study entry or are at imminent risk of suicide according to the investigator’s clinical judgment
10. First-episode subjects (no prior history of psychotic symptoms)
c. Treatment history
11. Subjects receiving therapy with antidepressants or mood stabilizers that has been initiated and/or changed in dose <4 weeks prior to screening
12. Subjects with a history of receiving electroconvulsive therapy in the 6 months before study entry
13. Subjects with a history of hypersensitivity to paliperidone or risperidone or any of their excipients
14. Subjects who have participated in a clinical investigation or received an experimental therapy within 30 days before study entry or have participated in >2 clinical studies within the last 12 months
15. Subjects receiving depot antipsychotics, including long-acting injectable risperidone and paliperidone palmitate, within 2 treatment cycles of screening visit
16. Subjects with a history of neuroleptic malignant syndrome
17. Subjects with a previous history of lack of response to antipsychotic medication. Lack of response is defined as the subject having had (at least twice) a documented medical history of no clinical response, despite adequate doses and durations of treatment, or the inability to tolerate effective doses.
18. Subjects receiving therapy with clozapine or having received therapy with clozapine within 3 months prior to randomization
19. Subjects receiving therapy with carbamazepine and monoamine oxidase inhibitors
d. Somatic history
20. Subjects with a serious neurological disease, including but not limited to Alzheimer’s disease, vascular dementia, Parkinson’s disease, unstable seizure disorder, intracranial lesions, hydrocephalus, or significant head trauma
21. Relevant history of or current presence of any significant and/or unstable cardiovascular, respiratory, neurological (including seizures or significant cerebrovascular), renal, hepatic, hematologic, endocrine (including untreated or unstable hypo/hyperthyroidism unless stabilized on an appropriate medication for at least 3 months before the screening phase), immunologic or other systemic disease that would increase the risk associated with taking study medication or would confound the interpretation of the study. Clinically significant abnormal findings should be discussed with the medical monitor prior to the subject’s entry.
22. Subjects with a medical or surgical condition that might interfere with the absorption, metabolism, or excretion of paliperidone, such as gastrectomy, colostomy, Crohn��s disease, liver disease, or renal disease
23. Subjects with any severe preexisting gastrointestinal narrowing (pathologic or iatrogenic)
24. History of any active malignancy within the previous 5 years, with the exception of basal cell carcinoma
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Measure
The PANSS has been chosen as the primary efficacy measure in this study because it assesses a number of symptom domains relevant to diagnosis and treatment of this disorder. The PANSS is a measure of the severity of 30 symptoms related to schizophrenia as rated by clinicians.19 Numerous studies have shown the PANSS to have strong psychometric properties, including good inter-rater reliability, internal consistency, and construct validity. The PANSS is frequently used as the primary endpoint in schizophrenia studies and is sensitive to global symptomatic changes, in addition to specific domains.
Schizoaffective disorder is characterized by core symptoms of schizophrenia with prominent mood symptoms, which can be manic, depressive, or mixed. Analyses of pooled data from 6 studies with olanzapine demonstrated similar PANSS factor structure in subjects with schizophrenia, those with bipolar disease, and those with schizoaffective disorder. In addition to core characteristics of psychotic disorders, PANSS evaluates a variety of symptoms, including those reflecting affective disturbances. Studies have shown correlation between PANSS scores and scores on depression or mania scales in patients with affective symptoms. Therefore, available evidence strongly suggests that PANSS provides a composite score measuring the majority of symptoms that comprise the diagnostic criterion for the schizoaffective disorder and is thus a valid efficacy measure in subjects with this disorder.
Secondary Efficacy Measures
Secondary variables will include the CGI-S and the CGI-C scores; the effect of treatment on PANSS factor scores, including hostility/excitement and depression/anxiety factor scores; and the percentage of patients responding to therapy. In order to capture both improvement in psychometrically evaluated symptoms and discernible overall clinical change, the response to therapy is defined as a composite of a greater than or equal to 30% improvement from baseline to endpoint in PANSS total score AND a CGI-C of 1 (very much improved) or 2 (much improved). In order to ensure that all potential symptoms of schizoaffective disorder are taken into account when evaluating the CGI scales, the investigators will be asked to perform ratings of severity and change for each of the relevant dimensions of symptoms (positive, negative, depressive, manic). After these are completed, the investigators will provide the overall CGI-S and CGI-C ratings based on their clinical evaluation. Although all the scores will be collected, only the overall CGI-S and CGI-C ratings will be used for statistical analysis and for evaluation of treatment response. |
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 |
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| 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
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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 | 3 |
| 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 | 3 |
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