A 6 Month Study to Compare the Metabolic Effects of Paliperidone ER and Olanzapine in Patients With Schizophrenia

Official Title: “A Prospective Randomized Open-label 6-Month Head-To-Head Trial to Compare Metabolic Effects of Paliperidone ER and Olanzapine in Subjects With Schizophrenia”

The purpose of this 6 month study is to compare the metabolic effects of paliperidone ER and olanzapine in patients with schizophrenia, using the ratio of the concentration of lipids (triglycerides (TG)) in the blood to the concentration of good cholesterol (high density lipoproteins (HDL)) in the blood as the primary parameter. Approximately 456 adult patients will participate in this study.

This is a prospective randomized (study medication is assigned by change) open-label, parallel-group, multicenter, 6 month study to compare the metabolic effects of paliperidone ER and olanzapine in patients with schizophrenia using the ratio of the concentration of lipids (triglycerides) in the blood to the concentration of good cholesterol (high density lipoproteins (HDL)) as the primary parameter. Secondary objectives include evaluation of additional parameters related to the total of the actions of the body to keep it alive (metabolic endpoints) and demonstration of non-inferiority of paliperidone ER versus olanzapine in efficacy as measured by Positive and Negative Syndrome Scale (PANSS). Patients previously treated with any oral antipsychotic, except those treated with paliperidone ER, olanzapine or clozapine during the last 6 months, can be enrolled and will be treated with paliperidone ER (6 to 9 mg/day) or olanzapine (10 to 15 mg/day). Patients will be divided into groups according to the metabolic effects of their previous antipsychotic medication (medication that does not increase body weight vs. medication that increases body weight).

Throughout the study flexible dosing is allowed based on the investigator discretion. A study treatment period of 6 months is planned for all patients. Medication to treat symptoms like confusion, blurred vision, constipation, dry mouth, light-headedness, difficulty starting and continuing to urinate, and loss of bladder control may continue up to four weeks and should then be tapered off at the discretion of the investigator. Approximately 456 adult patients (228 in each treatment group) will participate in this study. Efficacy will be assessed with the following measures: PANSS (total score and subscale scores), Clinical Global Impression - Severity (CGI-S), Self-rated health status Survey SF-36, and Sleep and daytime drowsiness evaluation scale. The parameters related to the total of the actions of the body to keep it alive (metabolic endpoints) will be assessed with the following: ratio of blood lipids to blood good cholesterol concentrations (TG:HDL ratio) (for this primary evaluation, plasma fasting lipids and good cholesterol concentrations will be measured), fasting plasma insulin and fasting plasma glucose, plasma glucose and insulin concentrations before and after a 75 gram oral glucose tolerance test (OGTT) to asses insulin sensitivity and changes in insulin secretion, fasting good cholesterol, lipids, and glucose levels for the determination of new onset or presence of metabolic syndrome during treatment according to criteria of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP/ATPIII criteria), weight, Body-Mass-Index and waist circumference for the determination of new onset or presence of a medical condition associated with abdominal obesity, abnormalities in glucose, lipid and cholesterol metabolism, and elevated blood pressure that increases the risk of cardiovascular disease and type 2 diabetes (metabolic syndrome) during treatment according to NCEP/ATP III criteria. All patients who receive trial medication (paliperidone ER or olanzapine) at least once will be included in the analysis of the demographic and baseline characteristic data. 2 dosage levels of paliperidone ER (6 or 9mg per day) and 2 of olanzapine (10 and 15mg per day) are available to the patients. Throughout the study flexible dosing is allowed based on the investigator's discretion. Study medication is to be taken in the morning orally, with water. A study treatment period of 6 months is planned for all patients.

Intervention(s) in this Clinical Trial

• Drug: olanzapine
  • 10-15 mg (using 5-mg or 10-mg tablets) once daily flexible dosing for 6 months
• Drug: paliperidone ER
  • 6-mg or 9-mg tablet once daily flexible dosing for 6 months

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 001
  • paliperidone ER 6-mg or 9-mg tablet once daily flexible dosing for 6 months
• Active Comparator: 002
  • olanzapine 10-15 mg (using 5-mg or 10-mg tablets) once daily flexible dosing for 6 months

Primary Measures

• Change From Baseline to End Point in the Triglycerides (TG) to High Density Lipoprotein (HDL) Ratio (TG:HDL Ratio)
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No

Secondary Measures

• Change From Baseline to End Point in Triglycerides
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline to End Point in High Density Lipoprotein
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline to End Point in Total Cholesterol
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline to End Point in Low Density Lipoprotein Cholesterol (Friedwald QT)
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline to End Point in Converted Insulin
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline to End Point in Fasting Glucose
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline to End Point in Homeostatic Model Assessment of Beta-cell Function (HOMA-%B)
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline to End Point in Homeastatic Model Assessment of Insulin Resistance (HOMA-IR)
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Number of Patients Meeting the Criteria for Type 2 Diabetes Mellitus During Follow-up
  • Time Frame: 6 months
    Safety Issue?: No
• Number of Patients With Onset of Impaired Glucose Tolerance
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Number of Patients With Impaired Fasting Glucose
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline at End Point of the Insulinogenic Index
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline at End Point of Mari-Type Analysis of Glucose Sensitivity for Insulin
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline at End Point in Body Weight
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline at End Point in Body Mass Index (BMI)
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Change From Baseline at End Point in Waist Circumference
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No
• Number of Patients First Meeting the NCEP/ATP III Criteria for Metabolic Syndrome During Follow-up
  • Time Frame: 6 months
    Safety Issue?: No
• Change From Baseline to End Point in Total Positive and Negative Syndrome Scale Score (PANSS)
  • Time Frame: Baseline to End Point (up to 6 months)
    Safety Issue?: No

Inclusion Criteria:

• Patient meets the DSM-IV criteria for schizophrenia
• Patient has a PANSS total score at screening of 60 to 100, inclusive
• Patient must, in the opinion of the investigator, benefit from treatment with paliperidone ER or olanzapine
• Patients on lipid-lowering therapy must be on a stable dose for at least 4 weeks for statins, niacin, ezetimibe and resins or for at least 12 weeks for fibrates
• Female patients must be postmenopausal (for at least 1 year), surgically sterile, abstinent, or, if sexually active, be practicing and effective method of birth control (e.g. prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study
• Women of child-bearing potential must have a negative urine pregnancy test at screening
• Patient is healthy on the basis of a physical examination and vital signs at screening

Exclusion Criteria:

• Patient has previously been treated with paliperidone ER, olanzapine, or clozapine within the past 6 months or has never been treated with an antipsychotic before
• Treatment with a depot antipsychotic within the past 3 months
• Treatment with a mood stabilizer or a recently initiated antidepressant (<= 3 months)
• Patient has abnormal fasting plasma glucose (> 126 mg/dL) or fasting triglycerides (TG) levels (> 400 mg/dL) at screening
• Relevant history of any significant and/or unstable cardiovascular, respiratory, neurologic (including seizures or significant cerebrovascular), renal, hepatic, endocrine, or immunologic diseases, including recent or present clinically relevant laboratory abnormalities (as deemed by the investigator)
• History or current symptoms of tardive dyskinesia
• History of neuroleptic malignant syndrome
• Pregnant or breast-feeding female

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Janssen-Cilag International NV Industry

Overall Clinical Trial Officials and Contacts

Janssen-Cilag International NV Clinical Trial Study Director Janssen-Cilag International NV  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00645099

Study ID Number: CR013189

ClinicalTrials.gov Identifier: NCT00645099

Health Authority: Belgium: Ministry of Social Affairs, Public Health and the Environment

A Prospective Randomized Open-label 6-Month Head-To-Head Trial to Compare Metabolic Effects of Paliperidone ER and Olanzapine in Subjects With Schizophrenia