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Prevention of Relapse With Injectable Paliperidone Palmitate Versus Oral Antipsychotics (PROSIPAL)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Janssen-Cilag International NV
ClinicalTrials.gov Identifier:
NCT01081769
First received: March 4, 2010
Last updated: February 17, 2015
Last verified: February 2015
  Purpose
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.

Condition Intervention Phase
Schizophrenia
Drug: paliperidone palmitate injection
Drug: oral antipsychotics
Phase 3

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

Resource links provided by NLM:


Further study details as provided by Janssen-Cilag International NV:

Primary Outcome Measures:
  • Time to First Relapse Event [ Time Frame: from baseline (Day 1 of core phase) up to maximally 24 months. ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With a Relapse Event [ Time Frame: from baseline (Day 1 of core phase) up to maximally 24 months ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Percentage of Treatment Responders [ Time Frame: from baseline (day 1 of core phase) up to maximally 24 months ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in PANSS Total Score [ Time Frame: Baseline, day 8, month 1, 2, 3, 4, 6, 9, 12, 15, 18, 21, 24 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in PANSS Subscale Score [ Time Frame: Baseline (day 1 of core phase), day 8, month 12, 24 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in PANSS Marder Factor Scores [ Time Frame: Baseline (day 1 of core phase), day 8, month 12 and 24 ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in Clinical Global Impression Severity (CGI-S) Score [ Time Frame: Baseline (day 1 of core phase), day 8, month 1, 2, 3, 4, 6, 9, 12, 15, 18, 21, 24 ] [ Designated as safety issue: No ]
    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.

  • Clinical Global Impression-Change (CGI-C) [ Time Frame: Month 24 and endpoint ] [ Designated as safety issue: No ]
    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).

  • Changes From Baseline in Personal and Social Performance (PSP) Total Score [ Time Frame: baseline (day 1 of core phase), month 1, 3, 6, 9, 12, 15, 18, 21 and 24 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Short Form-36 Health Survey (SF-36) [ Time Frame: baseline (day 1 of core phase), month 6, 12 and 24 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in EuroQol 5-Dimensional Questionnaire (EQ-5D) VAS Score [ Time Frame: baseline (day 1 of core phase), month 6, 12 and 24 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in EuroQol 5-Dimensional Questionnaire (EQ-5D) Index Score [ Time Frame: baseline (day 1 of core phase), month 6, 12 and 24 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Subjective Well-Being Under Neuroleptics-Short Form (SWN-S) Total Score [ Time Frame: baseline (day 1 of core phase), month 6, 12 and 24 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Patient's Treatment Satisfaction [ Time Frame: baseline (day 1 of core phase), month 12 and 24 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Physician's Treatment Satisfaction [ Time Frame: baseline (day 1 of core phase), month 12 and 24 ] [ Designated as safety issue: No ]
    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).


Enrollment: 769
Study Start Date: February 2010
Study Completion Date: February 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Paliperidone Palmitate
paliperidone palmitate 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
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
Active Comparator: Oral Antipsychotics
oral antipsychotics daily treatment according to local label for maximally 24 months
Drug: oral antipsychotics
daily treatment according to local label for maximally 24 months

Detailed 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.
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01081769

  Show 99 Study Locations
Sponsors and Collaborators
Janssen-Cilag International NV
Investigators
Study Director: Janssen-Cilag International NV Clinical Trial Janssen-Cilag International NV
  More Information

Responsible Party: Janssen-Cilag International NV
ClinicalTrials.gov Identifier: NCT01081769     History of Changes
Other Study ID Numbers: CR015199  R092670SCH3005  2008-002247-16 
Study First Received: March 4, 2010
Results First Received: November 17, 2014
Last Updated: February 17, 2015
Health Authority: Czech Republic: State Institute for Drug Control
Egypt: Ministry of Health and Population
Estonia: The State Agency of Medicine
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Greece: National Organization of Medicines
Hungary: National Institute of Pharmacy
Croatia: Ministry of Health and Social Care
Bulgaria: Bulgarian Drug Agency
Austria: Agency for Health and Food Safety
Israel: Ministry of Health
Italy: Ethics Committee
Korea: Food and Drug Administration
Lithuania: State Medicine Control Agency - Ministry of Health
Poland: Ministry of Health
Romania: National Medicines Agency
Russia: Ministry of Health of the Russian Federation
Slovakia: State Institute for Drug Control
South Africa: Medicines Control Council
Spain: Spanish Agency of Medicines
Taiwan: Department of Health
Turkey: Ministry of Health
Ukraine: State Pharmacological Center - Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Germany: Ethics Commission
Hungary: National Institute for Quality and Organizational Development in Healthcare and Medicines
United States: Food and Drug Administration

Keywords provided by Janssen-Cilag International NV:
Schizophrenia
paliperidone palmitate
Invega
Intramuscular injection
Oral antipsychotics
Relapse

Additional relevant MeSH terms:
Schizophrenia
Recurrence
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Disease Attributes
Pathologic Processes
Antipsychotic Agents
Paliperidone Palmitate
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin 5-HT2 Receptor Antagonists
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Dopamine D2 Receptor Antagonists
Dopamine Antagonists
Dopamine Agents

ClinicalTrials.gov processed this record on December 02, 2016