A Study of Paliperidone Palmitate 6-Month Formulation

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate that injection cycles consisting of a single administration of paliperidone palmitate 6-month (PP6M) are not less effective than 2 sequentially administered injections of paliperidone palmitate 3-month PP3M) (350 or 525 mg eq.) for the prevention of relapse in participants with schizophrenia previously stabilized on corresponding doses of paliperidone palmitate 1-month (PP1M) (100 or 150 mg eq.) or PP3M (350 or 525 mg eq.).

Detailed Description
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The primary hypothesis of this study is that the efficacy of PP6M is non-inferior to PP3M for preventing relapse in participants with schizophrenia who were previously stabilized on corresponding doses of PP1M or PP3M. The study consists of mainly 3 phases: a screening phase (up to 28 days), a maintenance phase (of 1 or 3 months), and a double-blind phase (of 12 months [neither the researchers nor the participants know what treatment the participant is receiving]). Additional/conditional phases include a transition phase (before maintenance phase). Study evaluations include efficacy, pharmacokinetics, pharmacodynamics, and safety. The study duration will vary from approximately 13 months to 19 months.

Official Title
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A Double-blind, Randomized, Active-controlled, Parallel-group Study of Paliperidone Palmitate 6-Month Formulation

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: PP6M
* Drug: PP3M 350 mg eq.
* Drug: PP3M 525 mg eq.
* Drug: PP1M
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must meet the diagnostic criteria for schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) for at least 6 months before screening Must be receiving treatment with paliperidone palmitate (as either the paliperidone palmitate 1-month (PP1M) or paliperidone palmitate 3-month (PP3M) formulation), or injectable risperidone, or any oral antipsychotic Must be able, in the opinion of the investigator, to discontinue any antipsychotic medication other than PP1M) or PP3M during the Screening Phase Must have a full Positive and Negative Syndrome Scale (PANSS) score of less than (<) 70 points at screening Must have a body mass index (BMI) between 17 and 40 kilogram (kg)/meter (m)^2 (inclusive) and must have a body weight of at least 47 kg at screening Must be willing to receive gluteal injections of medication during the Double-blind Phase Exclusion Criteria Must not be receiving any form of involuntary treatment, such as involuntary psychiatric hospitalization, parole-mandated treatment, or court-mandated treatment Must not have attempted suicide within 12 months before screening and must not be at imminent risk of suicide or violent behavior, as clinically assessed by the investigator at the time of screening Must not have a DSM-5 diagnosis of moderate or severe substance use disorder (except for nicotine and caffeine) within 6 months of screening; however, acute or intermittent substance use prior to screening is not exclusionary, depending upon the clinical judgment of the investigator Must not have a history of neuroleptic malignant syndrome or tardive dyskinesia Must not have a history of intolerability or severe reactions to moderate or higher doses of antipsychotic medications and must not have any other factors that would, in the judgment of the investigator, indicate that treatment with moderate or higher doses of paliperidone palmitate would be intolerable or unsafe

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PP1M: Transition Phase<br>Participants who previously have not achieved stability with moderate to higher doses of Paliperidone palmitate 1-month (PP1M) or Paliperidone palmitate 3-month (PP3M) will enter into a transition period of up to 4 months. During transition period participants will receive 1 to 5 injections of PP1M 50 to 100 milligrams equivalent (mg eq.). The participants who achieved stability (stability is defined as at least 3 months of injections with the last 2 doses being the same strength) with PP1M 100 mg eq. will precede from transition phase to maintenance phase. | Drug: PP1M<br>* Participants will receive intramuscular injection of PP1M 50 to 150 mg eq.<br>* Other names: R092670;|
| Experimental: PP1M/PP3M: Maintenance Phase<br>All the participants will receive only 1 dose of PP1M 100 or 150 mg eq. or PP3M 350 or 525 mg eq. The participants will precede from maintenance phase to double-blind phase. | Drug: PP3M 350 mg eq.<br>* Participants will receive intramuscular injection of PP3M 350 mg eq.<br>* Other names: R092670;Drug: PP3M 525 mg eq.<br>* Participants will receive intramuscular injection of PP3M 525 mg eq.<br>* Other names: R092670;Drug: PP1M<br>* Participants will receive intramuscular injection of PP1M 50 to 150 mg eq.<br>* Other names: R092670;|
| Experimental: PP6M or Placebo: Double-Blind Phase<br>Participants will receive intramuscular injection of PP6M in left gluteal muscle on Day 1 and right gluteal muscle on Day 183 with alternating placebo in right gluteal muscle on Day 92 and left gluteal muscle on Day 274. | Drug: PP6M<br>* Participants will receive intramuscular injection of PP6M.<br>* Other names: R092670;Other: Placebo<br>* Participants will receive matching placebo.<br>|
| Experimental: PP3M: Double-Blind Phase<br>Participants will receive intramuscular injections of PP3M at dose of 350 mg eq. or 525 mg eq. in left gluteal muscle on Day 1 and 274 and right gluteal muscle on Day 92 and 183. | Drug: PP3M 350 mg eq.<br>* Participants will receive intramuscular injection of PP3M 350 mg eq.<br>* Other names: R092670;Drug: PP3M 525 mg eq.<br>* Participants will receive intramuscular injection of PP3M 525 mg eq.<br>* Other names: R092670;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Relapse During the Double-Blind (DB) Phase | Time to relapse is time between participant randomization in DB Phase and first documentation of relapse event by end of Month 12 of DB phase. Relapse is defined as: a) Psychiatric hospitalization; b) Positive and Negative Syndrome Scale (PANSS) total score: Increase of 25 percentage (%), 10 point increase in PANSS for 2 analysis separated by 3-7 days if score was greater than (>) 40, less than or equal to (<=)40; c) Participants inflicted knowing self-injury/shown violent behavior leading to suicide, clinically significant injury to him/herself or other person/property; d) Participants had suicidal/homicidal ideation/violent behavior that was clinically significant as per investigator; e) PANSS items P1- delusions, P2- conceptual disorganization, P3-hallucinatory behavior, P6- suspiciousness/ persecution, P7-hostility, G8-uncooperativeness: score: greater than or equal to (>=)5, >=6 for 2 analysis separated by 3-7 days on any items if maximum score for PANSS: <=3 or 4, respectively. | Up to 12 months of DB Phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score | The neuropsychiatric symptoms of schizophrenia were assessed using the 30-item PANSS scale, which provides a total score (sum of the scores for all 30 items) and scores for 3 subscales: the 7-item positive-symptom (P) subscale, the 7-item negative-symptom (N) subscale, and the 16-item general-psychopathology symptom (G) subscale. Each item is rated on a scale from 1 (absent) to 7 (extreme). The PANSS total score ranges from 30 (absent disease)-210 (more severe neuropsychiatric symptoms of schizophrenia). | Baseline (DB) to 12 Months of DB Phase | 
| Change From Baseline in the Clinical Global Impression - Severity (CGI-S) Score | CGI-S is defined as clinician-rated scale that assesses the severity of mental illness on a scale of 0 to 7. Considering total clinical experience, a participant was assessed on severity of mental illness at the time of rating according to:1: normal, not at all ill; 2: borderline mentally ill; 3: mildly ill; 4: moderately ill; 5: markedly ill; 6: severely ill; 7: among the most extremely ill patients. A higher score implies a more severe condition. | Baseline (DB) to 12 Months of DB Phase | 
| Change From Baseline in the Personal and Social Performance (PSP) Scale Total Score | The Personal and Social Performance (PSP) scale assesses degree of a participant's dysfunction within 4 domains of behavior: 1) socially useful activities, 2) personal and social relationships, 3) self-care, and 4) disturbing and aggressive behavior. Each domain was assessed on a 6-point scale, from 1 (absent) to 6 (very severe) (1 = absent, 2 = mild, 3 = manifest, 4 = marked, 5 = severe, and 6 = very severe). PSP total score was calculated as sum of all the domain scores and ranges from 1 to 100. Participants with 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. Higher score indicates better performance. | Baseline (DB) to 12 Months of DB Phase | 
| Percentage of Participants With Symptomatic Remission Based on PANSS Score During DB Phase | Symptomatic remission was defined as achieving intensity level of mild or moderate on PANSS scale by all 8 items as the determinants for symptomatic remission: delusions, unusual thought content, hallucinatory behavior, conceptual disorganization, mannerisms/posturing, blunted affect, social withdrawal, lack of spontaneity. The PANSS is a 30-item scale to assess the neuropsychiatric symptoms of schizophrenia (psychiatric disorder with symptoms of emotional instability, detachment from reality, often with delusions and hallucinations, and withdrawal into the self). The PANSS provides 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 item scored on a scale of 1 (absent), 2 (minimal), 3 (mild), 4 (moderate), 5 (moderately severe), 6 (severe) and 7 (extreme). The total score ranges from 30 to 210 and higher score indicates greater severity. | Up to 12 months of DB Phase | 
| Change From Baseline in the Satisfaction With Participants in Social Roles (SPSR) Score | The SPSR Short Form 8a is a participant-reported outcome used to assess the satisfaction with participation in social roles. The participants were asked to rate 8 items on 5-point Likert scale, with scores ranging from 8 to 40, where higher scores represents higher satisfaction. | Baseline (DB) to 12 Months of DB Phase | 
| Change From Baseline in the Treatment Satisfaction Questionnaire for Medication (TSQM-9) Total Score | TSQM-9 consists of 9 questions to assess patients' satisfaction with medication using a range of responses from 1 (extremely dissatisfied) to (7 extremely satisfied). This patient reported outcome provides scores on three parts: effectiveness, convenience, and global satisfaction. The sum of the 9-questions were calculated and used for analysis. The total score ranges from 0 to 63, with higher scores indicating better treatment satisfaction. | Baseline (DB) to 12 Months of DB Phase | 
| Change From Baseline in the Simpson-Angus Rating Scale (SAS) Total Score | The SAS rates 10 items for general extrapyramidal symptoms (EPS) on a 5-point scale from 0 (normal) to 4 (extreme), including gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head rotation, Glabellar tap, tremor, and salivation. The SAS total score is the average score (total sum of item scores divided by the number of items) and ranges between 0 and 4. Negative change in score indicates improvement. Higher scores denote more severe condition of EPS. | Baseline (DB) to 12 Months of DB Phase | 
| Number of Participants With Symptoms of Akathisia Assessed Using Barnes Akathisia Rating Scale (BARS) Score | BARS is used to rate observable, restless movements of drug induced akathisia and subjective awareness of restlessness and any distress associated with the akathisia. BARS consists of the following 4 items: objective assessment of akathisia symptoms, subjective assessment of the participants's awareness of inner restlessness, distress restlessness, and global clinical assessment of akathisia. First three items are rated on a 4-point scale ranging from 0 (no abnormal movements or absence of inner restlessness or no distress) to 3 (severe akathisia or awareness of intense compulsion to move most of the time or severe distress). The last item, the global clinical assessment of akathisia, is rated on a 6-point scale, ranging from 0 (no evidence of akathisia) to 5 (severe akathisia). | Up to 12 Months of DB Phase | 
| Change From Baseline in the Abnormal Involuntary Movement Scale (AIMS) Total Score | AIMS is a 14-item scale. Items 1 to 8 are rated on a 5-point scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Item 9 assesses the participant's incapacitation due to abnormal movements, and item 10 assesses the participant's awareness of the abnormal movements and associated distress. Items 9 and 10 are rated on 5-point scales ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Items 11 to 14 are yes/no questions regarding the global judgement and dental status of the participant. The total score is the sum of the scores for the 14 items and the possible total score ranges from 0 to 44. A higher total score is indicative of more severe dyskinetic movements. | Baseline (DB) to 12 Months of DB Phase | 
| Number of Participants Based on Columbia Suicide Severity Rating Scale (C-SSRS) Total Score | The C-SSRS is a questionnaire used for suicide risk assessment. Affirmative or negative responses are provided to items 1 to 5 for suicidal ideation (1. Wish to be dead, 2. Non-specific active suicidal thoughts, 3. Active suicidal ideation with any methods [not plan] without intent to act, 4. Active suicidal ideation with some intent to act, without specific plan, 5. Active suicidal ideation with specific plan and intent) and items 6 to 10 for suicide behavior (6. Preparatory acts or behavior, 7. Aborted attempt, 8. Interrupted attempt, 9. Actual attempt, 10. Completed suicide). Total score ranges from 1 to 10. Higher scores indicate more severe suicidal ideation. | Baseline and endpoint (12 Months of DB Phase) | 
| Number of Participants With Treatment-emergent Abnormal Electrocardiogram (ECG) Values During DB Phase | Number of participants with treatment-emergent abnormal ECG values were reported. It includes heart rate (abnormally low refers to less than or equal to [<=] 50 beats per minute (bpm) , abnormally high refers greater than or equal to [>=] 100 bpm), pulse rate (PR) interval (abnormally high refers to >= 210 milliseconds [msec]), QRS interval (abnormally Low refers to <= 50, abnormally high refers to >= 120 msec) and QT interval (abnormally low refers to <= 200, abnormally high >= 500 msec). | Baseline (DB) to 12 Months of DB Phase | 
| Change From Baseline in the Body Mass Index (BMI) During DB Phase | Change from baseline in BMI was reported. | Baseline (DB) to 12 Months of DB Phase | 
| Change From Baseline in the Waist Circumference During DB Phase | Change from baseline in waist circumference was reported. | Baseline (DB) to 12 Months of DB Phase | 
| Change From Baseline in the Body Weight During DB Phase | Change from baseline in body weight was reported. | Baseline (DB) to 12 Months of DB Phase | 
| Change From Baseline in the Vital Signs (Pulse Rate) During DB Phase | Change from baseline vital signs (pulse rate) were reported. This included supine pulse rate, standing pulse rate and supine-standing pulse rate. | Baseline (DB) to 12 Months of DB Phase | 
| Change From Baseline in the Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) During DB Phase | Change from baseline in vital signs including SBP and DBP (supine/standing) were reported. | Baseline (DB) to 12 Months of DB Phase | 
| Change From Baseline in Positive and Syndrome Scale (PANSS) Subscales Score During DB Phase | The neuropsychiatric symptoms of schizophrenia were assessed using the 30-item PANSS scale, which provides a total score (sum of the scores for all 30 items) and 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). | Baseline (DB) to 12 Months of DB Phase | 
| Number of Participants With Treatment-emergent Clinically Significant Abnormal Laboratory Values in Chemistry During DB Phase | Number of participants with clinically significant abnormal laboratory values in chemistry included alanine aminotransferase (Unit per Litre [U/L]), albumin (Gram per Litre [g/L]), alkaline phosphatase (U/L), aspartate aminotransferase (U/L), bicarbonate (millimoles per litre [mmol/L]), bilirubin (micromoles per litre [umol/L]), calcium (mmol/L), chloride (mmol/L), cholesterol (mmol/L), creatinine (umol/L), gamma glutamyl transferase (GGT) (U/L), glucose (mmol/L), high-density lipoproteins (HDL) cholesterol (mmol/L), low density lipoproteins (LDL) cholesterol (mmol/L), lactate dehydrogenase (U/L), phosphate (mmol/L), potassium (mmol/L), protein (mmol/L), sodium (mmol/L), triglycerides (mmol/L), urate (umol/L), urea nitrogen (mmol/L) were reported. Here, ABL signifies abnormally low and ABH signifies abnormally high levels. | Up to 12 Months of DB Phase | 
| Number of Participants With Treatment-emergent Clinically Significant Abnormal Laboratory Values in Hematology During DB Phase | Number of participants with clinically significant abnormal laboratory values in hematology included hemoglobin (Hb), hematocrit (Hct), red blood cell (RBC) count, white blood cell (WBC) count with differential, platelets, hemoglobin A1c. Here, ABL signifies abnormally low and ABH signifies abnormally high levels. | Up to 12 Months of DB Phase |