| 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 | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009134 |
| E.1.2 | Term | Chronic schizophrenia |
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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 |
•To evaluate the efficacy of PF-02545920 in the treatment of acute exacerbation of schizophrenia during a 4-week double-blind treatment period using the Positive and Negative Syndrome Scale (PANSS) to measure change in symptoms from baseline compared to placebo.
•To evaluate the safety and tolerability of two fixed dose regimens of PF-02545920 in the treatment of acute exacerbation of schizophrenia.
•To evaluate the incidence rate of dystonia associated with two doses of PF-02545920 compared to placebo in the treatment of acute schizophrenia.
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| E.2.2 | Secondary objectives of the trial |
To assess the efficacy of PF-02545920 in the treatment of acute exacerbation of schizophrenia using the:
•Clinical Global Impression of Improvement (CGI-I) and Clinical Global Impression of Severity (CGI-S);
•PANSS Subscales: Positive, Negative, General;
•PANSS derived Marder factor scores1 (positive, negative, disorganized thought, hostility/excitement, anxiety/depression);
•PANSS derived Brief Psychiatric Rating Scale (BPRS) core psychosis items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content);
•Global Assessment of Function (GAF);
•Treatment Satisfaction Questionnaire for Medication (TSQM).
Other secondary objectives:
•Collection of de-identified molecular profiling blood samples to support qualification of exploratory biomarkers and pharmacogenomic endpoints for use in future studies of PF-02545920 and other novel neuroscience therapeutic compounds.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study. Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Males or females aged 18-65 years of age (inclusive) are eligible.
2. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
3. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
4. Body Mass Index (BMI) of approximately 18 to 40 kg/m2; and a total body weight
>50 kg (110 lbs).
5. Subjects with a diagnosis of schizophrenia must meet the following eligibility criteria in order to be considered for participation in the study. All psychiatric diagnoses specified in the inclusion/exclusion criteria are according to the DSM-IV TR criteria. The subjects are to be assessed by a qualified psychiatrist. The Mini International Neuropsychiatric Interview (M.I.N.I.) will be used to confirm diagnosis and exclude comorbid diagnoses:
• Subjects must have a total BPRS score of ≥45 at the screen visit.
• Subjects must have a score of ≥4 (moderate) on at least 2 items of the 4 BPRS core psychosis items (ie, #4 conceptual disorganization, #11 hallucinatory behavior, #12 suspiciousness, #15 unusual thought content) at screening and baseline.
• Subjects must have a total score of at least 12 on the combination of the 4 BPRS core psychosis items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) at screening and baseline.
• Subjects must have a Clinical Global Impression of Severity (CGI-S) scale score of
≥4 (moderately ill) at the screen and baseline visit.
6. Subjects must have a known change in their level of functioning associated with their current acute exacerbation of schizophrenia (eg, ER admission, change in level of supervision, worsening of symptoms) as noted/documented by the treating psychiatrist, family member or caregiver, or other clinical information source.
7. The current acute exacerbation of schizophrenia must be less than 4 weeks duration prior to the screen date. Narrative information must be recorded in the screening worksheets documenting the acuteness of current episode, history of exacerbations, and levels of response to past treatments.
8. If subjects are hospitalized for acute exacerbation of schizophrenia at the time of screening, the duration of the current hospitalization must be less than 2 weeks prior to the screen date.
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study (the list of exclusion criteria is abridged - a full list of exclusion criteria can be found within the protocol):
1. Subjects who have a greater than a 25% decrease in the BPRS core psychosis items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) total score between screening and baseline.
2. Female subjects who are pregnant or breastfeeding: Female subjects of childbearing potential may be included in the study but must be sexually abstinent or must agree to practice established effective contraception from the screening evaluation until 30 days following the last dose of the study drug. Investigators should specifically question female subjects regarding potential unprotected sexual activity in the 14 days prior to screening to assess risk for pregnancy.
3. Subjects with evidence or history of clinically significant hematological, renal, endocrine (excluding adequately controlled hypothyroidism or hyperthyroidism), pulmonary (excluding chronic bronchitis, mild emphysema or chronic obstructive pulmonary disease), gastrointestinal (including conditions that can affect drug absorption, eg, gastrectomy), oncological, dermatologic, immunologic disease, as determined by the investigator. Controlled Type 2 diabetes (glucose <180 mg/100 mL at screening with dietary or oral hypoglycemic treatment) will not be considered a significant medical illness and would not exclude a subject from the study.
4. Subject with evidence or history of significant hepatic disorder, including acute or chronic hepatitis B and acute hepatitis C, with liver function test results higher than the normal limits. Subjects with positive hepatitis C antibody and normal liver functions tests can be included in the study.
5. Subjects who are known to have AIDS or to be HIV positive.
6. Subjects with evidence or history of clinically significant cardiovascular disease, including uncontrolled hypertension (sitting or supine diastolic pressure >95 mm Hg and/or sitting or supine systolic pressure >170 mm Hg with or without treatment), bypass surgery, history of myocardial infarction or ischemic heart disease, uncompensated heart failure or recent acute myocardial infarction. Controlled essential hypertension and non clinically significant sinus bradycardia and sinus tachycardia will not be considered significant medical illnesses and would not exclude a subject from the study.
7. Subjects with a 12-lead ECG with repeated demonstration of QTcF >450 msec at screening or at baseline (Day 1) based on the machine reading.
8. Subjects with a WBC<3500/mm3 and ANC <2000/mm3, or WBC <3000/mm3 and an ANC <1500/mm3 in subjects with a documented history of benign ethnic neutropenia.
9. Subjects with a history of myeloproliferative disorder or clozapine induced agranulocytosis or granulocytopenia.
10. Subjects with screening laboratory test results that deviate from the upper or lower limits of the reference range, except for not clinically significant values, as determined by the investigator. AST or ALT must be ≤2 X upper limit of reference range, and total bilirubin must be within 1.5 X of the upper limit of reference range at screening.
11. Subjects who have a positive urine drug screen which cannot be explained by prescribed medications.
12. Subjects who are using prohibited medications (as described in Section 5.5 and Appendix 1 of the protocol) and who will not be able to discontinue these concomitant medications after the screening visit.
13. Subjects with a current DSM-IV axis I diagnosis of schizoaffective disorder, major depression, bipolar disorder, or obsessive compulsive disorder.
14. Subjects who have taken an investigational drug within 90 days prior to baseline.
15. Subjects who meet DSM-IV defined diagnostic criteria for psychoactive substance dependence (excluding nicotine dependence) within 12 months of screening or DSM-IV defined substance abuse within 3 months prior to screening.
16. Subjects who have attempted suicide within 3 months prior to Screening.
17. For subjects who answer “Yes” the C SSRS questions 4 or 5 or a SBQ-R total score ≥8, a risk assessment should be done by a qualified mental health professional (MHP: a psychiatrist or licensed PhD level clinical psychologist) to assess whether it is safe for the subject to participate in the study. In addition, subjects deemed by the investigator to be at significant risk of suicidal or violent behavior should be excluded.
18. Subjects who have received clozapine in the 6 months prior to randomization.
19. Subjects who have received depot antipsychotic medication in the 3 months prior to randomization.
20. Subjects with a history of hypersensitivity to treatment with risperidone. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy:
• PANSS Total change from baseline.
Primary Safety:
• Dystonia incidence rate.
Pharmacokinetics:
•Sparse PK sampling for population PK analysis. |
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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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | Yes |
| 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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| End of Trial in all participating countries is defined as the Last Subject Last Visit (LSLV). |
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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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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