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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: olanzapine
* Drug: paliperidone ER


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 001<br>paliperidone ER 6-mg or 9-mg tablet once daily flexible dosing for 6 months | Drug: paliperidone ER<br>* 6-mg or 9-mg tablet once daily flexible dosing for 6 months<br>|
| Active Comparator: 002<br>olanzapine 10-15 mg (using 5-mg or 10-mg tablets) once daily flexible dosing for 6 months | Drug: olanzapine<br>* 10-15 mg (using 5-mg or 10-mg tablets) once daily flexible dosing for 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End Point in the Triglycerides (TG) to High Density Lipoprotein (HDL) Ratio (TG:HDL Ratio) | Plasma fasting TG and HDL concentrations were measured to determine the TG:HDL ratio. | Baseline to End Point (up to 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End Point in Triglycerides | The TG level was assessed under fasted conditions. | Baseline to End Point (up to 6 months) | 
| Change From Baseline to End Point in High Density Lipoprotein | The HDL level was assessed under fasted conditions. | Baseline to End Point (up to 6 months) | 
| Change From Baseline to End Point in Total Cholesterol | The total cholesterol level was assessed under fasted conditions. | Baseline to End Point (up to 6 months) | 
| Change From Baseline to End Point in Low Density Lipoprotein Cholesterol (Friedwald QT) | The level of low density lipoprotein cholesterol was calculated using the Friedwald QT formula. | Baseline to End Point (up to 6 months) | 
| Change From Baseline to End Point in Converted Insulin | The insulin level was assessed under fasted conditions. | Baseline to End Point (up to 6 months) | 
| Change From Baseline to End Point in Fasting Glucose |  | Baseline to End Point (up to 6 months) | 
| Change From Baseline to End Point in Homeostatic Model Assessment of Beta-cell Function (HOMA-%B) | HOMA-%B is used to assess beta-cell function. HOMA-%B is a dimensionless measure of beta-cell function (higher values present increased insulin secretion for a given glucose level). HOMA-%B is normalized so that lean, healthy individuals will have values of HOMA-%B close to 100%. | Baseline to End Point (up to 6 months) | 
| Change From Baseline to End Point in Homeastatic Model Assessment of Insulin Resistance (HOMA-IR) | HOMA-IR is used to assess insulin resistance (IR). HOMA-IR is a dimensionless measure of insulin resistance (higher values present more insulin resistance. HOMA-IR are normalized so that lean, healthy individuals will have values of HOMA-IR close to 1. | Baseline to End Point (up to 6 months) | 
| Number of Patients Meeting the Criteria for Type 2 Diabetes Mellitus During Follow-up | Fasting plasma glucose ≥126 mg/dL or 2-hour post-load plasma glucose ≥200 mg/dL during an oral glucose tolerance test (OGTT) or initiated use of glucose-lowering agents during the course of the study. | 6 months | 
| Number of Patients With Onset of Impaired Glucose Tolerance | Glucose ≥140 mg/dL, <200 mg/dL after a 75g OGTT. | Baseline to End Point (up to 6 months) | 
| Number of Patients With Impaired Fasting Glucose | Post-baseline glucose level under fasted conditions ≥100 mg/dL but <126 mg/dL. | Baseline to End Point (up to 6 months) | 
| Change From Baseline at End Point of the Insulinogenic Index | The insulinogenic index, defined as (insulin at 30 min - insulin at 0)/(glucose at 30 min [G(30)] - glucose at 0 [G(0)]) was used as a measure of early insulin secretion in response to the OGTT. Because the index is undefined when G(30)-G(0)=0, and poorly defined when G(30)-G(0)<0, the index was only calculated when G(30)>G(0). | Baseline to End Point (up to 6 months) | 
| Change From Baseline at End Point of Mari-Type Analysis of Glucose Sensitivity for Insulin | As another measure of beta-cell function, the relationship between plasma insulin and glucose concentrations during the OGTT was calculated using a simplified version of the method described by Mari et al. (Mari A, Sallas WM, He YL, Watson C, Ligueros-Saylan M, Dunning BE, Deacon CF, Holst JJ, Foley JE. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes. J Clin Endocrinol Metab. 2005; 90:4888-4894.). | Baseline to End Point (up to 6 months) | 
| Change From Baseline at End Point in Body Weight | Patients were weighed lightly clothed. The same amount of clothing had to be worn each time. | Baseline to End Point (up to 6 months) | 
| Change From Baseline at End Point in Body Mass Index (BMI) | BMI is calculated by dividing the body weight (in kg) by the square of height (in meters). | Baseline to End Point (up to 6 months) | 
| Change From Baseline at End Point in Waist Circumference | Patients had to be instructed to stand erect with abdomen relaxed, arms at sides, feet together, and weight divided equally over both legs. The tape measure was placed around the bare abdomen midway between the palpated iliac crest and the palpated lowest rib margin in the left and right mid-axillary lines. A nonstretchable tape was evenly placed around the natural waist covering the left and right natural-waist marks. The measurement scale had to face outward, and there could not be any twists in the tape. The tape had to be just touching the skin but not compressing the soft tissue. | Baseline to End Point (up to 6 months) | 
| Number of Patients First Meeting the NCEP/ATP III Criteria for Metabolic Syndrome During Follow-up | Metabolic syndrome is defined according the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP/ATPIII) of which 3 out of 5 criteria must be met: waist circumference men > 102 cm; waist circumference women > 88 cm TG ≥ 150 mg/dL HDL cholesterol men <40 mg/dL; HDL cholesterol women <50 mg/dL Blood pressure systolic ≥ 130 mmHg; Blood pressure diastolic ≥ 85 mmHg Fasting glucose ≥ 110 mg /dL | 6 months | 
| Change From Baseline to End Point in Total Positive and Negative Syndrome Scale Score (PANSS) | PANSS is an investigator-rated 30-item scale to assess the neuropsychiatric symptoms of schizophrenia. The PANSS provided a total score and scores for 3 subscales, the positive subscale (7 items), the negative subscale (7 items), and the general psychopathology subscale (16 items), each rated on a scale of 1 (absent) to 7 (extreme). | Baseline to End Point (up to 6 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paliperidone ER, Olanzapine, Schizophrenia