Effectiveness and Safety of 3 Fixed Doses (25 mg eq., 100 mg eq., and 150 mg eq.) of Paliperidone Palmitate in Patients With Schizophrenia

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose Response Study to Evaluate the Efficacy and Safety of 3 Fixed Doses (25 mg eq., 100 mg eq., and 150 mg eq.) of Paliperidone Palmitate in Subjects With Schizophrenia

The primary objectives of this study are to evaluate the efficacy and safety of 3 fixed doses of paliperidone palmitate administered i.m. after an initial loading dose of 150 mg eq. in the deltoid muscle followed by either deltoid or gluteal injections for a total of 13 weeks of treatment as compared with placebo in patients with schizophrenia.

The primary hypothesis is that, after an initial 150 mg eq. loading dose in the deltoid muscle followed by either deltoid or gluteal injections in patients with schizophrenia, paliperidone palmitate (25, 100, or 150 mg eq.) is superior to placebo as measured by the change in Positive and Negative Syndrome Scale for Schizophrenia (PANSS) total score over a 13-week period.This is a randomized, double blind, placebo-controlled, parallel group, multicenter, dose-response study of men and women who have a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia. The secondary objectives are to: Assess the benefits in personal and social functioning (key secondary endpoint) associated with the use of paliperidone palmitate compared with placebo, Assess the global improvement in severity of illness associated with the use of paliperidone palmitate compared with placebo, Assess the dose-response and exposure-response relationship of paliperidone palmitate The study includes a screening period of up to 7 days and a 13 week double-blind treatment period. The screening period includes washout of disallowed psychotropic medications. Subjects without source documentation of previous exposure to at least 2 doses of oral risperidone, or paliperidone ER, or one dose of i.m. RISPERDAL CONSTA, or paliperidone palmitate will be given 4 to 6 days of paliperidone ER 6 mg/day for tolerability testing. Patients who have source documentation of previous exposure to the above medications and are currently taking another antipsychotic regimen will continue their current treatment through Day -1. At the beginning of the double-blind treatment period, subjects will be randomly assigned in equal numbers to 1 of 4 treatment groups (an initial loading dose of 150 mg eq. of paliperidone palmitate given by deltoid injection followed by 3 fixed i.m. doses of paliperidone palmitate [25, 100, or 150 mg eq.] on Days 8, 36, and 64 or placebo given in the same manner). Note: The choice of the injection site (deltoid or gluteal) for all remaining injections after the initial loading dose will be at the discretion of the investigator. The entire study, including the screening period, will last approximately 14 weeks.Samples for pharmacokinetic (PK) evaluation will be collected at designated time points. Effectiveness and safety will be evaluated periodically throughout the study. A pharmacogenomic blood sample (10 mL) will be collected from patients who give separate written informed consent for this part of the study (where local regulations permit). This will allow for pharmacogenomic research, as necessary. Participation in pharmacogenomic research is optional. Approximately 105 to 115 mL of whole blood will be collected during the study. Patients randomly assigned to paliperidone palmitate will receive i.m. injections of paliperidone palmitate (150 mg eq. deltoid injection of paliperidone palmitate on Day 1, followed by 25, 100, or 150 mg eq. of paliperidone palmitate i.m. on Days 8, 36, and 64). Patients randomly assigned to placebo will receive a deltoid injection of placebo on Day 1 followed by placebo on Days 8, 36, and 64.

Inclusion Criteria:

• Met diagnostic criteria for schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) for at least 1 year before screening. Prior medical records, written documentation or verbal information obtained from previous psychiatric providers obtained by the investigator must be consistent with the diagnosis of schizophrenia
• A total PANSS score at screening of between 70 and 120, inclusive and at baseline of between 60 and 120, inclusive
• Body mass index (BMI)
• i.e., [weight (kg)]/[height (m)]², of >17.0 kg/m2
• Women must be postmenopausal for at least 2 years, 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, intrauterine device, double-barrier method, and male partner sterilization. Women of childbearing potential must have a negative urine pregnancy test at baseline, before receiving a dose of study drug
• Is able and willing to meet or perform study requirements (e.g., answer self-administered questionnaires). If a patient is unable to read the questions, study personnel may read documents and the patient may then mark his or her choice
• Patients in the US must be able to understand spoken English to permit adequate ratings by the blinded central rater

Exclusion Criteria:

• Primary diagnosis other than schizophrenia
• Patients who are unable to provide their own consent or who are currently involuntarily committed to psychiatric hospitalization
• DSM-IV diagnosis of active substance dependence within 3 months before the screening evaluation (nicotine and caffeine dependence are not exclusionary)
• History of treatment resistance as defined by failure to respond to 2 adequate studies of different antipsychotic medications
• an adequate study is defined as a minimum of 4 weeks at the patient's maximum tolerated dose
• Relevant history of or current presence of any significant or unstable cardiovascular, respiratory, neurological (including seizures or significant cerebrovascular), renal, hepatic, hematologic, endocrine, immunologic, morbid obesity (BMI>=40), or other systemic disease
• History of any severe preexisting gastrointestinal narrowing (pathologic or iatrogenic) or inability to swallow the oral tolerability medication whole with the aid of water for patients requiring oral tolerability testing
• Biochemistry, hematology or urinalysis test results that are not within the laboratory's normal reference range and are deemed to be clinically significant by the investigator
• History or evidence of clinically significant hepatic disease (including aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >2 times the upper limit of normal) at screening
• History of neuroleptic malignant syndrome
• Significant risk of suicidal, homicidal or violent ideation or behavior as clinically assessed by the investigator
• History of life threatening allergic reaction to any drug
• Known or suspected hypersensitivity or intolerance of risperidone, paliperidone, Intralipid (placebo) or any of their excipients (e.g., soybean oil, egg yolks, phospholipids, glycerol)
• Exposure to an experimental drug, experimental biologic, or experimental medical device within 6 months before screening or prior randomization into this study
• Enrollment in 2 or more clinical research studies in the previous year or one or more clinical research studies in the previous 6 months (non intervention, observational, and retrospective studies excluded)
• History of any active malignancy within the previous 5 years, with the exception of excised basal cell carcinomas
• A woman who is pregnant, breast-feeding, or planning to become pregnant during the study period
• Employee 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
• Treatment with any of the following disallowed therapies: an injectable antipsychotic within 1 injection cycle before screening, an injection of RISPERDAL CONSTA within 6 weeks of screening, electroconvulsive therapy within 60 days before screening, previous injection of paliperidone palmitate within the past 10 months before baseline, use of clozapine within 3 months before baseline, nonselective or irreversible monoamine oxidase inhibitor antidepressants within 30 days before screening: other antidepressants unless patient has been on a stable dose for at least 30 days before screening, mood stabilizers and beta-blockers must be washed out by the beginning of the study
• History or presence of circumstances that may increase the risk of the occurrence of serious illness or death in association with the use of drugs that affect heart rhythm