Prevention of Relapse With Injectable Paliperidone Palmitate Versus Oral Antipsychotics

Schizophrenia Clinical Trial

— PROSIPAL  

Official title:

A 24-month, Prospective, Randomized, Active-Controlled, Open-Label, Rater-Blinded, Multicenter, International Study of the Prevention of Relapse Comparing Long-Acting Injectable Paliperidone Palmitate to Treatment as Usual With Oral Antipsychotic Monotherapy in Adults With Schizophrenia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01081769
• Other study ID #: CR015199
• Secondary ID: R092670SCH300520
• Status: Completed
• Phase: Phase 3
• First received: March 4, 2010
• Last updated: February 17, 2015
• Start date: February 2010
• Est. completion date: February 2013

Study information

• Verified date: February 2015
• Source: Janssen-Cilag International NV
• Contact: n/a
• Is FDA regulated: No
• Health authority: Czech Republic: State Institute for Drug ControlEgypt: Ministry of Health and PopulationEstonia: The State Agency of MedicineFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesGreece: National Organization of MedicinesHungary: National Institute of PharmacyCroatia: Ministry of Health and Social CareBulgaria: Bulgarian Drug AgencyAustria: Agency for Health and Food SafetyIsrael: Ministry of HealthItaly: Ethics CommitteeKorea: Food and Drug AdministrationLithuania: State Medicine Control Agency - Ministry of HealthPoland: Ministry of HealthRomania: National Medicines AgencyRussia: Ministry of Health of the Russian FederationSlovakia: State Institute for Drug ControlSouth Africa: Medicines Control CouncilSpain: Spanish Agency of MedicinesTaiwan: Department of HealthTurkey: Ministry of HealthUkraine: State Pharmacological Center - Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyGermany: Ethics CommissionHungary: National Institute for Quality and Organizational Development in Healthcare and MedicinesUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the efficacy (how well the drug works; primarily through the time to relapse) of long-acting injectable paliperidone palmitate compared to treatment as usual with orally administered antipsychotics in monotherapy over 24 months in the treatment of recently diagnosed (1-5 years since diagnosis) schizophrenia.

Description:

This is a randomized (study drug assigned by chance), open-label (both physician and patient know the name of the assigned drug), rater-blinded (the person who assesses the condition of the patient does not know the name of the assigned drug), active-controlled, parallel-group, multicenter, prospective international study of paliperidone palmitate versus treatment as usual with oral antipsychotic agents in monotherapy in the prevention of relapse (return of symptoms). Patients who have been recently diagnosed with schizophrenia (within 5 years) and are suffering from a schizophrenic relapse (return of symptoms of schizophrenia) will be enrolled. This study consists of a 2-week initial acute oral treatment phase, followed by a treatment phase (core phase) until relapse or up to maximally 24 months, whichever comes first. Prior to a 2-week oral treatment phase, patients will be randomly (by chance) assigned in a 1:1 ratio to receive treatment with paliperidone palmitate injection (once-monthly) or oral antipsychotic medication (daily). Patients randomized to paliperidone palmitate will first receive oral paliperidone ER once daily for 2 weeks followed by paliperidone palmitate injections at a dose of 150 mg eq. on Day 1, 100 mg eq. on Day 8 both in the deltoid muscle and 75 mg eq. on Day 38 and doses in a dose range of 25 to 150 mg eq. in either the deltoid or the gluteal muscle thereafter. Patients randomized to oral comparator arm will receive oral antipsychotics (haloperidol, paliperidone ER, risperidone, olanzapine, quetiapine or aripiprazole) as per investigator discretion and prescribed according to the label. Total treatment duration is maximally 24 months. During the 24 month treatment phase, investigators will be allowed to flexibly decrease or increase the dose of paliperidone palmitate with one dose level in the range of 25 to 150 mg eq. or the oral antipsychotic in the respective locally approved dose range, all according to the patient's clinical needs. The primary endpoint of the 24-month treatment phase will be the time to relapse. Safety will be monitored by evaluating Adverse Events (AEs), rating of extrapyramidal symptoms (symptoms like abnormal muscle movements, abnormal movements of the tongue or jaw, slow or sustained muscle contractions, muscle spasms, shaking, abnormal movements of the eyes, involuntary muscle contractions, slow movements, or restlessness), vital signs measurements (including heart rate and blood pressure), body weight and physical examination findings. A urine pregnancy test will be performed in females of childbearing potential. Adverse events (unintended, but not necessarily unexpected, results of therapy that can be unpleasant or dangerous), associated concomitant medications, and symptoms of relapse will be recorded as needed.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 769
• Est. completion date: February 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Have been meeting the diagnostic criteria for schizophrenia for 1 to 5 years before screening, and have a history of treatment with antipsychotics

• Have a history of two or more relapses requiring psychiatric hospitalization in the preceding 24 months, which may include the current acute episode

• Experiencing at screening an acute schizophrenic episode with a Positive And Negative Syndrome Scale (PANSS) total score at screening between 70 and 120, inclusive

• Be healthy on the basis of physical examination, medical history and vital signs performed at screening

• Woman must be postmenopausal (for at least 1 year) or surgically sterile or abstinent or be practicing an effective method of birth control, must agree to continue to use the same method of contraception throughout the study and must have a negative urine pregnancy test at screening

• be able to fill out questionnaires

• Men must agree to use a double barrier method of birth control and to not donate sperm during the study and for 3 months after receiving the last dose of study drug

Exclusion Criteria:

• Patients that have never been treated with antipsychotics before

• Treatment resistant patient and/or currently (i.within the last 3 months) treated with clozapine

• Substance dependence within 6 months prior to entry and current intravenous drug use or abuse

• allergies, hypersensitivity, or intolerance to risperidone or paliperidone or excipients

• treatment with a long-acting injectable antipsychotic within three injection cycles prior to screening

• newly started psychotherapy program within the two months preceding the treatment phase baseline

• evidence of clinically significant hepatic, renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances in the past 6 months (as determined by medical history, clinical laboratory or ECG results, or physical examination) that would increase the risk associated with taking study medication or would confound the interpretation of the study

• history or current symptoms of tardive dyskinesia or neuroleptic malignant syndrome

• involuntarily hospitalized patient

• pregnant or breast-feeding females

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Schizophrenia

Intervention

Drug:
• paliperidone palmitate injection
injection with 150 mg equivalent on Day 1, 100 mg equivalent on Day 8, 75 mg equivalent on Day 38 and flexible dosing with 25, 50, 75, 100 or 150 mg equivalent once monthly thereafter
• oral antipsychotics
daily treatment according to local label for maximally 24 months

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Janssen-Cilag International NV

Countries where clinical trial is conducted

Austria,  Belgium,  Bulgaria,  Croatia,  Czech Republic,  Egypt,  Estonia,  France,  Germany,  Greece,  Hungary,  Israel,  Jordan,  Korea, Republic of,  Lithuania,  Poland,  Romania,  Russian Federation,  Slovakia,  South Africa,  Spain,  Taiwan,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to First Relapse Event	Number of days from baseline (day 1 of core phase) to relapse as evaluated according the Csernansky criteria. A patient was considered to have relapsed if they met one or more of the following criteria: (1) psychiatric hospitalization; (2) an increase in the level of psychiatric care and an increase of 25 percent (%) from baseline in the Positive And Negative Syndrome Score (PANSS) total score (or an increase of 10 points if the baseline score was 40 or less); (3) deliberate self-injury; (4) suicidal or homicidal ideation that was clinically significant in the investigator's judgment; (5) violent behavior resulting in clinically significant injury to another person or property damage; (6) substantial clinical deterioration, defined as a change score of 6 ("much worse") or 7 ("very much worse") on the Clinical Global Impressions Scale (CGI-C); and/or (7) the required dose of the antipsychotic exceeds the maximum approved dose.	from baseline (Day 1 of core phase) up to maximally 24 months.	No
Primary	Number of Participants With a Relapse Event	Number of participants with a relapse event with relapses evaluated according the Csernansky criteria. A patient was considered to have relapsed if they met one or more of the following criteria: (1) psychiatric hospitalization; (2) an increase in the level of psychiatric care and an increase of 25% from baseline in the PANSS total score (or an increase of 10 points if the baseline score was 40 or less); (3) deliberate self-injury; (4) suicidal or homicidal ideation that was clinically significant in the investigator's judgment; (5) violent behavior resulting in clinically significant injury to another person or property damage; (6) substantial clinical deterioration, defined as a change score of 6 ("much worse") or 7 ("very much worse") on the Clinical Global Impressions Scale (CGI-C); and/or (7) the required dose of the antipsychotic exceeds the maximum approved dose.	from baseline (Day 1 of core phase) up to maximally 24 months	No
Secondary	Percentage of Treatment Responders	The proportion of patients achieving a treatment response, defined as a =30% decrease (i.e., improvement) in Positive and Negative Syndrome Scale (PANSS) total score from baseline to endpoint. The PANSS is a 30-item scale (Range 30-210) designed to assess various symptoms of schizophrenia including delusions, grandiosity, blunted affect, poor attention, and poor impulse control. The 30 symptoms are rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology). The PANSS total score consists of the sum of all 30 PANSS items. Higher scores indicate increased severity of schizophrenia symptoms.	from baseline (day 1 of core phase) up to maximally 24 months	No
Secondary	Change From Baseline in PANSS Total Score	Change from baseline in the PANSS: The PANSS is a 30-item scale (Range 30-210) designed to assess various symptoms of schizophrenia including delusions, grandiosity, blunted affect, poor attention, and poor impulse control. The 30 symptoms are rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology). The PANSS total score consists of the sum of all 30 PANSS items. Higher scores indicate worsening.	Baseline, day 8, month 1, 2, 3, 4, 6, 9, 12, 15, 18, 21, 24	No
Secondary	Change From Baseline in PANSS Subscale Score	Change from baseline in positive symptom, negative symptom and general psychopathology subscales of the PANSS scale. The PANSS scale is designed to assess symptoms of schizophrenia by means of the 30-items. The PANSS scale provides subscores for 3 subscales, that is, the positive symptoms subscale (7 items, range 7-49), the negative symptoms subscale (7 items, range 7-49), and the general psychopathology subscale (16 items, range 16-112). Each item of the scale is to be scored on a scale of 1 (absent) to 7 (extreme). Higher scores indicate higher severity of schizophrenia symptoms.	Baseline (day 1 of core phase), day 8, month 12, 24	No
Secondary	Change From Baseline in PANSS Marder Factor Scores	Change from baseline in schizophrenia symptoms were assessed through the following PANSS factor scores as described by Marder: (1) positive symptoms (range 8-56): sum of delusions, hallucinatory behavior, grandiosity, suspiciousness, stereotyped thinking, somatic concern, unusual thought content, lack of judgment and insight; (2) negative symptoms (range 7-49): sum of blunted affect, emotional withdrawal, poor rapport, passive social withdrawal, lack of spontaneity, motor retardation, and active social avoidance; (3) disorganized thoughts (range 7-49): sum of conceptual disorganization, difficulty in abstract thinking, mannerisms and posturing, disorientation, poor attention, disturbance of volition, and preoccupation; (4) uncontrolled hostility/excitement (range 4-28): sum of excitement, hostility, uncooperativeness and poor impulse control; (5) anxiety/depression (range 4-28): sum of anxiety, guilt feelings, tension, and depression. Higher scores indicate higher severity of symptoms	Baseline (day 1 of core phase), day 8, month 12 and 24	No
Secondary	Change From Baseline in Clinical Global Impression Severity (CGI-S) Score	The Clinical Global Impression Severity (CGI-S) rating scale is a 7 point global clinical 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 higher impression of illness severity.	Baseline (day 1 of core phase), day 8, month 1, 2, 3, 4, 6, 9, 12, 15, 18, 21, 24	No
Secondary	Clinical Global Impression-Change (CGI-C)	The Clinical Global Impression-Change (CGI-C) rating scale is used to rate the change in severity of the patient's illness compared to baseline (day 1 of core phase) on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse).	Month 24 and endpoint	No
Secondary	Changes From Baseline in Personal and Social Performance (PSP) Total Score	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, divided into 10 equal intervals to rate degree of difficulty (1, absent to 6, very severe) in each of the 4 domains. Based on 4 domains there will be 1 total score. 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.	baseline (day 1 of core phase), month 1, 3, 6, 9, 12, 15, 18, 21 and 24	No
Secondary	Change From Baseline in Short Form-36 Health Survey (SF-36)	The Short Form-36 Health Survey (SF-36) is a measure of Participant-reported health status. It is a 36-item questionnaire measuring 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Two summary scale scores are computed based on weighted combinations of the 8 subscale scores: the Physical Component Summary and the Mental Component Summary. Each summary scale score ranges from 0 (worst) to 100 (best), with higher scores reflecting better health-related functional status.	baseline (day 1 of core phase), month 6, 12 and 24	No
Secondary	Change From Baseline in EuroQol 5-Dimensional Questionnaire (EQ-5D) VAS Score	The EQ-5D VAS records the respondent's self-rated health on a vertical, visual analog scale, with 0 representing the worst imaginable health state and 100 representing the best imaginable health state. The EQ VAS is used as a quantitative measure of health outcome as judged by the individual respondent.	baseline (day 1 of core phase), month 6, 12 and 24	No
Secondary	Change From Baseline in EuroQol 5-Dimensional Questionnaire (EQ-5D) Index Score	The EuroQol-5 is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. A higher score indicates an improvement in health in the Health Status Index.	baseline (day 1 of core phase), month 6, 12 and 24	No
Secondary	Change From Baseline in Subjective Well-Being Under Neuroleptics-Short Form (SWN-S) Total Score	The SWN-S is a patient self-rated scale developed to measure the subjective well-being for the previous 7 days of a patient under neuroleptic treatment. The SWN-S consists of 20 items (each item is rated from 1=not at all to 6=very much). The total score ranges from 20 to 120 with higher score indicating greater subjective well-being.	baseline (day 1 of core phase), month 6, 12 and 24	No
Secondary	Change From Baseline in Patient's Treatment Satisfaction	Patient's satisfaction with medication was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM). The TSQM is divided into 4 subscales (effectiveness, side effects, convenience, and global satisfaction), with the value of each subscale ranging from 0 to 100. Higher scores indicate greater treatment satisfaction.	baseline (day 1 of core phase), month 12 and 24	No
Secondary	Change From Baseline in Physician's Treatment Satisfaction	Physician's treatment satisfaction was assessed using the physician's treatment satisfaction scale which is designed to rate 4 aspects of treatment (efficacy, safety, mode of administration, and overall satisfaction), each on a scale ranging from 1 (extremely satisfied) to 7 (extremely dissatisfied).	baseline (day 1 of core phase), month 12 and 24	No