Primary ObjectivesThe primary objective is to assess the efficacy (primarily through time to relapse) of long-acting injectable (LAI) paliperidone palmitate compared to treatment as usual with orally administered antipsychotics in monotherapy over…
ID
Source
Brief title
Condition
- Schizophrenia and other psychotic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of the 24-month treatment phase will be the time to
relapse. The relapse criteria are based on criteria reported by Csernansky et
al.40, and have been employed in several previous trials. Relapse in the
current study is defined by any one of the following:
•Psychiatric hospitalization; or
•An increase in the level of psychiatric care (e.g., significant crisis
intervention needed to avert hospitalization, clinically notable increases in
the frequency or intensity of patient contact required to maintain outpatient
status) and an increase of 25% from baseline in the total score on the PANSS
(or an increase of 10 points if the base-line score was 40 or less); or
•Deliberate self-injury; or
•Suicidal or homicidal ideation that was clinically significant in the
investigator*s judgment; or
•Violent behavior resulting in clinically significant injury to another person
or property damage; or
•Substantial clinical deterioration, defined as a change score of 6 (*much
worse*) or 7 (*very much worse*) on the Clinical Global Impressions Scale; or
•The required dose of the antipsychotic exceeds the maximum approved dose.
Key efficacy evaluations will include the following:
•Rate of patients with relapse at the 24-month endpoint;
•Rate of patients with psychiatric hospitalizations;
•Psychiatric hospitalizations (total number and mean duration);
•Response rate using PANSS and changes versus baseline in total PANSS and PANSS
subscales;
•Changes from baseline in levels of personal and social functioning measured
using the PSP scale;
•Global severity of illness overall score and changes measured using the CGI-S
and CGI-C scales;
•Measures of subject's mental health (SF-36; EQ5D) and well-being (SWN);
•Subject treatment satisfaction (TSQM) and physician treatment satisfaction
(7-point categorical scale).
Secondary outcome
SAFETY EVALUATIONS
•A physical examination will be performed at screening and at endpoint;
•Vital signs and weight will be measured at screening, at all visits during the
24-month treatment phase, and upon early withdrawal;
•Height will be measured at screening;
•A urine pregnancy test (for females of childbearing potential) will be
performed at screening and at endpoint;
•Extrapyramidal symptom rating scales (AIMS, SAS, and BARS) will be assessed at
screening, and at Visits 2-4 and Visit 8-13 during the 24-month treatment phase
and at endpoint;
•(S)AE .
OTHER EVALUATIONS
•Health/social care utilization measured through HRUQ;
•Measures of alcohol and substance use (CRAUS; CRSUS);
•Measures of subject*s suicidality (ISST).
Background summary
Paliperidone palmitate (R092670) is the palmitate ester prodrug of paliperidone
(9 hydroxy risperidone, R076477), a selective, monoaminergic antagonist that
exhibits the characteristic dopamine type 2 (D2) and serotonin (5
hydroxytryptamine [5-HT]) type 2A (5HT2A) antagonism of the newer, or second
generation, antipsychotic drugs. Paliperidone is the major active metabolite of
risperidone and is a racemic mixture of the enantiomers R078543(+) and
R078544(-). Paliperidone palmitate is being developed as a long acting
intramuscular (i.m.) injectable aqueous suspension formulation for the
treatment of schizophrenia.
Study objective
Primary Objectives
The primary objective is to assess the efficacy (primarily through time to
relapse) of long-acting injectable (LAI) 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.
The relapse criteria (see Section 9.2.2.1.) are based on criteria reported by
Csernansky et al.40, and have been employed in several previous studies.
Secondary Objectives
The secondary objectives are to examine additional efficacy, safety and
tolerability of paliperidone palmitate compared with treatment as usual with a
variety of orally administered antipsychotic medications in monotherapy, until
relapse or over maximally 24 months (whichever comes first), in subjects with
recently diagnosed schizophrenia, and to compare the effect of paliperidone
palmitate to treatment as usual with orally administered antipsychotic
medications in monotherapy on clinically important domains.
Study design
This is a randomized, open-label, rater-blinded, 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. Approximately 766 subjects, of both
genders and between 18 and 65 years of age, who have a Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of
recently diagnosed (1 to 5 years since diagnosis) schizophrenia and suffering
from a schizophrenic relapse will be enrolled. The oral comparator arm consists
of 6 oral antipsychotics, i.e. oral haloperidol and the 5 atypical
antipsychotics paliperidone ER, risperidone, olanzapine, quetiapine and
aripiprazole.
The study consists of a 2-week initial acute oral treatment phase, followed by
a core treatment phase until relapse or up to maximally 24 months, whichever
comes first. Only subjects fulfilling the response criteria at the end of the 2
week initial acute oral treatment phase, will enter the subsequent 24-month
treatment phase.
Intervention
Upon meeting the response criteria, subjects will enter the 24-month treatment
phase for initiation of paliperidone palmitate or continuation of oral
antipsychotic therapy, in an open-label, rater-blinded fashion. This will be
obtained by appointing blinded raters, who are not involved in any other aspect
of the study. The blinded raters will be responsible for administering the
PANSS, the PSP, the CGI-S and the CGI-C. The investigator will be responsible
for all other assessments and the treatments. The investigator will therefore
also decide whether a dose change is required.
Subjects randomized to paliperidone palmitate will receive paliperidone
palmitate deltoid injections in alternate arms at a dose of 150 mg eq. on Day 1
and a dose of 100 mg eq. on Day 8, followed by 75 mg eq. on Day 38 in either
the deltoid or gluteal muscle, and clinically-defined doses in a dose range of
25 to 150 mg eq. in either the deltoid or the gluteal muscle thereafter.
Subjects randomized to treatment with oral medications will have this oral
antipsychotic medication continued as the randomization-defined treatment at a
dose defined by the investigator.
Subjects randomized to treatment with paliperidone palmitate will be treated
with paliperidone ER (INVEGA*). Flexible dosing will be applied within the
approved dose range of 3 to 12 mg once daily in the morning. Subjects entering
the initial acute oral treatment phase on oral antipsychotic medication and
randomized to treatment with paliperidone palmitate will have their oral
antipsychotic medication tapered off over a maximum of 7 days and replaced with
oral paliperidone ER (INVEGA). This initial acute oral treatment phase includes
tolerability testing of paliperidone. A review of the oral RISPERDAL and
RISPERDAL CONSTA safety databases has revealed some cases of allergic and
hypersensitivity reactions. Since paliperidone palmitate is a long acting
medication with a half-life of 20 to 30 days, it is important to identify those
subjects who may have either a severe tolerability problem or an allergic
reaction before injection. Only subjects who demonstrate an ability to tolerate
the drug as judged by the treating physician, will be eligible for treatment
with paliperidone palmitate. The first dose of paliperidone ER will be given on
the day of screening if the screening visit is performed in the morning of that
day, otherwise in the morning of the next day.
Subjects randomized to the oral antipsychotics arm will be treated with one of
the 6 oral antipsychotics (paliperidone ER, risperidone, olanzapine,
quetiapine, aripiprazole, or oral haloperidol) as prescribed by the
investigator as clinically indicated. Subjects entering the initial acute oral
treatment phase on oral antipsychotic medication and randomized to treatment
with oral antipsychotics will have their previous oral antipsychotic medication
tapered off over a maximum of 7 days and replaced with the newly selected oral
antipsychotic
Study burden and risks
Burden:
1. 15 visits to site during 2 years
2. Efficacy evaluation through PANSS and PSP (blinded rater)
2. Safety evaluation
3. Health and well-beeing questionnaires
Risks:
1. Adverse Events Paliperidone Palmitate or Oral Antipsychotic
2. Unknown risks
While the subject is participating in this study, the studyteam will follow-up
on his condition very closely. The subject may benifit from the health
information provided to him/her as a result of study procedures.
Roderveldlaan 1
2600 Berchem
België
Roderveldlaan 1
2600 Berchem
België
Listed location countries
Age
Inclusion criteria
• Man or woman between 18 and 65 years of age, inclusive
• The subject has a current diagnosis of schizophrenia according to DSM-IV, and has been recently diagnosed, i.e. between 1 and 5 years before screening, and was receiving antipsychotics in the past;
• The subject has a history of two or more relapses requiring psychiatric hospitalization in the preceding 24 months, which may include the current acute episode. Daytime hospitalization is acceptable in those countries where this reflects standard of care in acutely ill patients. In countries where hospitalization for relapse is not clinical standard, the requirement for hospitalization is not required;
• Subject must be experiencing at screening an acute schizophrenic episode with a PANSS total score at screening between 70 and 120, inclusive;
• The subjects may benefit from a switch of antipsychotic medication to either paliperidone palmitate or one of the oral antipsychotics used in this study;
• Otherwise healthy on the basis of physical examination, medical history and vital signs performed at screening. If there are abnormalities, they must be consistent with the underlying illness in the study population.
• Woman are not pregnant; must not get pregnant
• Subjects must be willing and able to fill out self-administered questionnaires;
• Willing/able to adhere to the prohibitions and restrictions specified in this protocol;
• The subject is cooperative and reliable, and agrees to receive regular injections and complete all aspects of the protocol;
• Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
Exclusion criteria
•The subject*s psychiatric diagnosis is due to direct pharmacological effects of a substance (e.g., a drug of abuse or medication) or a general medical condition (e.g., clinically notable hypothyroidism);
•First antipsychotic treatment ever;
•Subject cannot be treated with an atypical oral antipsychotic (except oral clozapine) or oral haloperidol in monotherapy according to the investigator;
•The subject is treatment resistant in the judgment of the investigator and/or currently (i.e., within the last 3 months) treated with clozapine;
•The subject meets the DSM-IV definition of substance dependence (except for nicotine and caffeine) within 6 months prior to entry; subjects with current substance use or abuse, with the exception of intravenous drug use, will be allowed to enroll;
•Known allergies, hypersensitivity, or intolerance to risperidone or paliperidone or its excipients
•Any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subjects from meeting or performing study requirements;
•The subject has received treatment with a long-acting injectable antipsychotic within three injection cycles prior to screening;
•The subject has begun a psychotherapy program within the two months preceding the treatment phase baseline. Psychosocial treatment is not considered psychotherapy;
•The subject received an investigational drug or used an investigational medical device within 60 days before the planned start of treatment, or has participated in more than one investigational drug trial in the past 12 months, or has planned use of other investigational drugs during the time frame of the trial, or is currently enrolled in an investigational study;
•The subject has 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;
•Subjects with a narrowing or blockage of their gastrointestinal tract;
•Inability to swallow the study medication whole with the aid of water (subjects may not chew, divide, dissolve, or crush the Paliperidone ER study medication, if applicable, as this may affect the release profile);
•Contraindications, warnings and precautions for oral antipsychotics used in this study apply according to local Summaries of Product Characteristics (SmPCs);
•History or current symptoms of tardive dyskinesia;
•History of neuroleptic malignant syndrome;
•Subject is involuntarily hospitalized;
•Subject is pregnant or breast-feeding;
•Employees 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.
•Use of disallowed therapies
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-002247-16-NL |
| CCMO | NL30911.097.09 |