Study of Paliperidone Palmitate 3 Month and 1 Month Formulations for the Treatment of Patients With Schizophrenia

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to demonstrate that a paliperidone palmitate 3 month formulation (PP3M) is as effective as the paliperidone palmitate 1 month formulation (PP1M) in the treatment of patients with schizophrenia who have been stabilized on PP1M.

Detailed Description
-----------------
This is a randomized (the study drug is assigned by chance), double blind (neither physician nor patient knows the treatment that the patient receives), parallel group (each group of patients will be treated at the same time), multicenter non-inferiority (the effect of the new treatment is not worse than that of the comparison treatment) study. A new formulation of paliperidone palmitate with a 3-month injection interval (PP3M) is being tested for use as maintenance treatment for subjects with schizophrenia who have been first stabilized on paliperidone palmitate with a 1-month injection interval (PP1M). The study consists of 3 phases: a screening/washout/tolerability phase (up to 21 days); a 17-week open-label (all people know the identity of the intervention) stabilization phase (referred to as the Open-label Phase) and a 48-week fixed dose, randomized, double-blind controlled phase (referred to as the Double-blind Phase). After completion of the Screening Phase, all patients will receive PP1M in the Open-label Phase. During this time, flexible dosing will occur at Weeks 5 and 9. At Week 13 patients are to receive the dose of PP1M that was administered at Week 9. Patients who are clinically stable at the end of the Open-label Phase will enter the Double-blind Phase and will be randomly assigned in a 1:1 ratio to receive fixed doses of PP3M or PP1M.

Official Title
-----------------
A Randomized, Multicenter, Double-Blind, Non-inferiority Study of Paliperidone Palmitate 3 Month and 1 Month Formulations for the Treatment of Subjects With Schizophrenia

Conditions
-----------------
Schizophrenia

Intervention / Treatment
-----------------
* Drug: PP3M 175 mg eq.
* Drug: PP3M 263 mg eq.
* Drug: PP3M 350 mg eq.
* Drug: PP3M 525 mg eq.
* Drug: Placebo (20% Intralipid)
* Drug: PP1M 50 mg eq.
* Drug: PP1M 75 mg eq.
* Drug: PP1M 100 mg eq.
* Drug: PP1M 150 mg eq.


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with schizophrenia for more than 1 year and whose symptoms are worsening in the opinion of the investigator A total score in the Positive and Negative Syndrome Scale (PANSS) between 70 and 120 Signed informed consent Women must not be pregnant, breastfeeding, and if capable of pregnancy must practice an effective method of birth control Men must agree to use a double-barrier method of birth control Be medically stable on the basis of clinical laboratory tests, physical examination, medical history, vital signs, and electrocardiogram (ECG) Exclusion Criteria: A diagnosis other than schizophrenia, e.g., dissociative disorder, bipolar disorder, major depressive disorder, schizoaffective disorder, schizophreniform disorder, autistic disorder, primary substance-induced psychotic disorder, dementia-related psychosis Relevant history or current presence of any significant or unstable medical condition(s) determined to be clinically significant by the Investigator (ie, obesity, diabetes, heart disease etc) A diagnosis of substance dependence within 6 months before screening History of neuroleptic malignant syndrome (NMS) or tardive dyskinesia Clozapine use in the last 2 months when used for treatment-resistant or treatment-refractory illness Clinically significant findings in biochemistry, hematology, ECG or urinalysis results Any other disease or condition that, in the opinion of the investigator, would make participation not in the best interest of the patient or that could prevent, limit, or confound the protocol-specified assessments

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paliperidone palmitate 3-month (PP3M)<br>A formulation of paliperidone palmitate with a 3-month injection interval | Drug: PP3M 175 mg eq.<br>* Type= exact number, unit= mg eq., number= 175, form= injection, route= intramuscular use. One injection every third month for 48 weeks.<br>Drug: PP3M 263 mg eq.<br>* Type= exact number, unit= mg eq., number= 263, form= injection, route= intramuscular use. One injection every third month for 48 weeks.<br>Drug: PP3M 350 mg eq.<br>* Type= exact number, unit= mg eq., number= 350, form= injection, route= intramuscular use. One injection every third month for 48 weeks.<br>Drug: PP3M 525 mg eq.<br>* Type= exact number, unit= mg eq., number= 525, form= injection, route= intramuscular use. One injection every third month for 48 weeks.<br>Drug: Placebo (20% Intralipid)<br>* Form= injection, route= intramuscular use. One injection monthly when not receiving active medication for 48 weeks.<br>|
| Active Comparator: Paliperidone palmitate 1-month (PP1M)<br>A formulation of paliperidone palmitate with a 1-month injection interval | Drug: PP1M 50 mg eq.<br>* Type= exact number, unit= mg eq., number= 50, form= injection, route= intramuscular use. One injection every month for 48 weeks.<br>Drug: PP1M 75 mg eq.<br>* Type= exact number, unit= mg eq., number= 75, form= injection, route= intramuscular use. One injection every month for 48 weeks.<br>Drug: PP1M 100 mg eq.<br>* Type= exact number, unit= mg eq., number= 100, form= injection, route= intramuscular use. One injection every month for 48 weeks.<br>Drug: PP1M 150 mg eq.<br>* Type= exact number, unit= mg eq., number= 150, form= injection, route= intramuscular use. One injection every month for 48 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Without Relapse at Week 48 During the Double-Blind Phase | Relapse defined as: Psychiatric hospitalization;participant had an increase of 25 percent in total PANSS score from randomization for 2 consecutive assessments separated by 3-7 days if score at randomization was greater than (>) 40; had a 10 point increase in total PANSS score from randomization for 2 consecutive assessments separated by 3-7 days if score at randomization was less than or equal to (<=) 40; deliberate self-injury or exhibited violent behavior resulting in suicide, clinically significant injury;suicidal or homicidal ideation and aggressive behavior;For PANSS items-had a score of greater than or equal to (>=) 5 after randomization for 2 consecutive assessments separated by 3-7 days on any of above items if maximum score for these above PANSS items was <=3 at randomization; had a score of >=6 after randomization for 2 consecutive assessments separated by 3-7 days on any of above items if maximum score for these above PANSS items was 4 at randomization. | Up to 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Double-Blind (DB) Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 48 | The neuropsychiatric symptoms of schizophrenia were assessed by means of the 30-item Positive and Negative Syndrome Scale (PANSS). The PANSS provides a total score (sum of the scores of all 30 items) ranging from 30 to 210, higher scores indicate more severe neuropsychiatric symptoms of schizophrenia. Scores for 3 subscales, that is, for positive subscale (sum of the scores of all 7 items) and negative subscale (sum of the scores of all 7 items) ranges from 7 (absent) to 49 (extreme psychopathology), and for the general psychopathology subscale (sum of the scores of all 16 items) score ranges from 16 (absent) to 112 (extreme psychopathology). | DB Baseline (Week 17) and 48 week or DB Endpoint | 
| Change From DB Baseline in Clinical Global Impression Severity (CGI-S) Scale Score at Week 48 | The Clinical Global Impression Severity (CGI-S) rating scale is a 7 point global assessment that measures the clinician's impression of the severity of illness exhibited by a participant. A rating of 1 is equivalent to Normal, not at all ill and a rating of 7 is equivalent to Among the most extremely ill participants. Higher scores indicate worsening. | DB Baseline (Week 17) and 48 week or DB Endpoint | 
| Change From DB Baseline in Personal and Social Performance (PSP) Total Score at Week 48 | The Personal and Social Performance (PSP) scale assesses degree of a participant's dysfunction within 4 domains of behavior: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behavior. Score ranges from 1 to 100. Participants with a score of 71 to 100 have mild degree of difficulty; from 31 to 70, varying degrees of disability; less than or equal to 30, functioning so poorly as to require intensive supervision. | DB Baseline (Week 17) and 48 week or DB Endpoint | 
| Percentage of Participants Who Met the Criteria for Symptomatic Remission Based on Andreasen Criteria | Symptomatic remission criterion was defined as having a simultaneous score of mild or less on all selected PANSS items (P1, P2, P3, N1, N4, N6, G5, and G9). Symptomatic remission was defined for the last 6 months of the Double-blind Phase as meeting the remission criterion during the 6 months prior to the End of study visit during the Double-blind Phase, with one excursion allowed. | Weeks 41 to 65 | 
| Change From Baseline in Positive and Negative Syndrome Subscales Score at Week 48 | The neuropsychiatric symptoms of schizophrenia were assessed by means of the 30-item Positive and Negative Syndrome Scale (PANSS). The PANSS provides a total score (sum of the scores of all 30 items) ranging from 30 to 210, higher scores indicate more severe neuropsychiatric symptoms of schizophrenia. Scores for 3 subscales, that is, for positive subscale (sum of the scores of all 7 items) and negative subscale (sum of the scores of all 7 items) ranges from 7 (absent) to 49 (extreme psychopathology), and for the general psychopathology subscale (sum of the scores of all 16 items) score ranges from 16 (absent) to 112 (extreme psychopathology). | DB Baseline (Week 17) and 48 week or DB Endpoint | 
| Change From Baseline in Marder Factor Subscale Score at Week 48 | 5 PANSS Marder factor scores (positive symptoms [range:8 to 56], negative symptoms [range: 7 to 49], disorganized thoughts [range: 7 to 49], uncontrolled hostility/excitement [range: 4 to 28], and anxiety/depression [range: 4 to 28]) were examined to gain insight into the symptoms affected by treatment with the study drug. Negative change from baseline in subscales score for positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression indicates improvement in various symptoms of schizophrenia. | DB Baseline (Week 17) and 48 week or DB Endpoint | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Schizophrenia, R092670, Paliperidone Palmitate, Paliperidone palmitate 1 month formulation (PP1M), Paliperidone palmitate 3 month formulation (PP3M)