A Positron-Emission-Tomography (PET) Study to Measure the Blockade of Dopamine Receptors (D2) in Specific Areas of the Brain in Relation to the Plasma Concentrations of Paliperidone Extended Release (ER) and Oral Risperidone in Schizophrenia Patients and Healthy Controls

Official Title: “The "Therapeutic Window" of the "Atypical" Antipsychotic Paliperidone Extended Release (ER)-A Positron Emission Tomography Study With [18F]Fallypride as the Radiotracer”

The primary objective of this study is to compare the effect of two different antipsychotic compounds which are used in the treatment of schizophrenia (paliperidone ER and risperidone) at their target sites in two specific areas of the brain in patients with schizophrenia. A specialized X-ray known as Positron Emission Tomography (PET) Imaging is used to assess the areas of the brain targeted by both compounds.

This is an open-label (all people involved know the identity of the intervention), non-randomized (patients are assigned to treatment groups), phase IV, monocentric (at one single study site) interventional study evaluating the blocking effects two different doses of paliperidone ER and oral risperidone have on the dopamine D2 receptors in the brain of subchronic patients with schizophrenia. Dopamine is a substance produced and released in the brain. Research indicates that dopamine levels are elevated in some areas of the brain in acute schizophrenia psychosis. Antipsychotic medications like risperidone and paliperidone ER are used to treat psychosis by blocking the dopamine receptors. Fallypride is a radioactive tracer (a drug that emits radioactivity) that binds to the dopamine receptors in the brain much the same as antipsychotic medications. It competes with the antipsychotic compounds at the binding sites and is used when performing a specialized x-ray known as Positron Emission Tomography (PET) Imaging. After a patient receives Fallypride, it temporally binds to specific target areas in the brain and emits a brief and harmless radioactive signal that is detected by the PET Scanner. Since paliperidone ER and risperidone compete with Fallypride at the same target sites, the signal will differ according to the binding effect of the compound. This technique provides an image showing the direct effect medication has on the human brain and allows for comparisons of the effects of different medications to be made. As this effect will fluctuate depending on the concentration of the drug in the blood, during this study, PET measurements will be correlated with the blood levels sampled. Patients will receive either paliperidone ER (6 patients with 6 mg per day, 6 patients with 9 mg per day) or oral risperidone (6 patients with 4 mg per day, 6 patients with 6 mg per day). The primary objective of this study is to compare the blocking effects each medication has on the dopamine D2 receptors at different time points (shortly after taking medication and 24 hours after taking medication) correlated with blood levels of the medication. The study consists of 3 visits on 3 consecutive days. Blood levels will be assessed for treatment groups 1 to 4 on day 2 and day 3 and for groups 5 to 8 on day 3 (according to the last intake of study medication).

PET-Scans will be assessed for every group on day 3. Group 1 to 4 consists of patients whose PET Scan will be assessed approximately 2 hours after taking medication (group 1 receives paliperidone ER 6 mg, group 2 receives paliperidone ER 9 mg, group 3 receives risperidone 4 mg, group 4 receives risperidone 6 mg). Group 5 to 8 consists of patients whose PET Scan will be assessed approximately 24 hours after taking medication (group 5 receives paliperidone ER 6 mg, group 6 receives paliperidone ER 9 mg, group 7 receives risperidone 4 mg, group 8 receives risperidone 6 mg). Adverse Events (AE's) will be assessed as reported spontaneously throughout the trial. The dose of antipsychotic medication will represent the most frequent dose used in post acute treatment of schizophrenia. A group of healthy volunteers (group 9) will serve as a control group to measure fallypride dopamine D2- receptor occupancies under normal circumstances, in patients not affected by schizophrenia.

Patients will receive the same dosage throughout the study as prescribed prior to the start of the study either paliperidone ER 6 mg tablet once daily or 9 mg tablet once daily or risperidone 4 mg tablet once daily or 6 mg daily (two 3 mg tablets).

Intervention(s) in this Clinical Trial

• Drug: Paliperidone ER
  • 9 mg tablet once a day followed by PET scan in approximately 2 hours
• Drug: Oral risperidone
  • 6 mg tablet once a day followed by PET scan in approximately 2 hours
• Other: PET Scan
  • PET Scan
• Drug: Oral risperidone
  • 4 mg tablet once a day followed by PET scan in approximately 24 hours
• Drug: Oral risperidone
  • 4 mg tablet once a day followed by PET scan in approximately 2 hours
• Drug: Paliperidone ER
  • 6 mg tablet once a day followed by PET scan in approximately 2 hours
• Drug: Paliperidone ER
  • 6 mg tablet once a day followed by PET scan in approximately 24 hours
• Drug: Oral risperidone
  • 6 mg tablet once a day followed by PET scan in approximately 24 hours
• Drug: Paliperidone ER
  • 9 mg tablet once a day followed by PET scan in approximately 24 hours

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 002
  • Paliperidone ER 9 mg tablet once a day followed by PET scan in approximately 2 hours
• Active Comparator: 003
  • Oral risperidone 4 mg tablet once a day followed by PET scan in approximately 2 hours
• Active Comparator: 004
  • Oral risperidone 6 mg tablet once a day followed by PET scan in approximately 2 hours
• Active Comparator: 005
  • Paliperidone ER 6 mg tablet once a day followed by PET scan in approximately 24 hours
• Active Comparator: 006
  • Paliperidone ER 9 mg tablet once a day followed by PET scan in approximately 24 hours
• Active Comparator: 007
  • Oral risperidone 4 mg tablet once a day followed by PET scan in approximately 24 hours
• Active Comparator: 008
  • Oral risperidone 6 mg tablet once a day followed by PET scan in approximately 24 hours
• Other: 009
  • PET Scan PET Scan
• Active Comparator: 001
  • Paliperidone ER 6 mg tablet once a day followed by PET scan in approximately 2 hours

Primary Measures

• Percentage of Paliperidone or Risperidone Dopamine D2 Receptor Occupancies
  • Time Frame: Visit 3 (on day 3)
    Safety Issue?: No

Secondary Measures

• Plasma Concentrations of Paliperidone and Risperidone
  • Time Frame: Measurement of plasma concentration at Visit 3 (day 3)
    Safety Issue?: No
• Assessment of the Ratio of Dopamine D2-receptor Occupancies in Two Different Areas of the Brain
  • Time Frame: Analysis of PET scans at Visit 3 (day 3)
    Safety Issue?: No

Inclusion Criteria:

• Patients with a diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria
• Patients with a specified severity of the disease (Clinical Global Impression Scale of Severity (CGI-S) range of > 2 < 5)
• Patients must be on antipsychotic medication with either paliperidone ER or oral risperidone in monotherapy for at least two weeks and must be at least five days on a stable dose of either paliperidone ER 6 mg or 9 mg or oral risperidone 4 mg or 6 mg once daily
• Female patients of childbearing potential must have a negative human chorionic gonadotropin urine pregnancy test (ß-HCG) at visit 1 or must be postmenopausal for at least 1 year, surgically sterile, abstinent, or, if sexually active, agree to practice an effective method of birth control before entry, throughout the study and at least one month after study end
• Healthy control volunteers must be off all standard prescription drug therapy, over the counter compounds (OTC) and recreational substances/drugs for at least one week prior to participation in the study
• Female volunteers of childbearing potential must have a negative ß -HCG pregnancy test at visit 1 or be postmenopausal for at least 1 year, surgically sterile, abstinent, or, if sexually active, agree to practice an effective method of birth control before entry, throughout the study and at least one month after the study end
• Patients and volunteers must be able to read, understand and sign the Institutional
• Review Board approved informed consent form

Exclusion Criteria:

• Patients: Any depot neuroleptic medication (long acting injectables) in the last three months
• Any antipsychotic compound, antidepressant, antiepileptic ("mood stabilizers"), lithium, anticholinergic within 2 weeks prior to study
• Any psychopharmacologically active medication (except benzodiazepines, paracetamol and zopiclone as rescue medication) taken within the trial
• Physical and psychological conditions that interfere with the study procedures, or could influence the study results, or could endanger the patient during the study
• Alcohol and/or drug abuse four weeks prior to study start (patients with alcohol or drug abuse as defined by the DSM-IV criteria can participate if free of their of abuse for at least four weeks)
• Clinically relevant laboratory abnormality
• Pregnant or breast feeding patients

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 50 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Investigator: Janssen-Cilag G.m.b.H Industry

Overall Clinical Trial Officials and Contacts

Janssen-Cilag G.m.b.H. Clinical Trial Study Director Janssen-Cilag G.m.b.H  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00934635

Study ID Number: CR015277

ClinicalTrials.gov Identifier: NCT00934635

Health Authority: Germany: Federal Institute for Drugs and Medical Devices