Primary ObjectivesThe primary objective is to explore the tolerability, safety and treatment response (maintained/improved efficacy), based on total Positive and Negative Syndrome Scale (PANSS) score, of a transition to flexibly dosed paliperidone…
ID
Source
Brief title
Condition
- Schizophrenia and other psychotic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
STATISTICAL METHODS
A total of approximately 1,000 subjects will be included in this study.
For the group of non-acute subjects switching from oral antipsychotics (group
A) the primary objective is driven by the reason for switching of antipsychotic
medication. For subjects switching for reason lack of efficacy, the primary
objective is to investigate improved efficacy, based on total Positive and
Negative Syndrome Scale (PANSS) score. The expected percentage of subjects with
at least 20% improvement in total PANSS is 30%. When the sample size is 81, a
two-sided 95.0% confidence interval for a single proportion using the large
sample normal approximation will extend 10% from the observed proportion for an
expected proportion of 30%.
For subjects switching for other reasons, i.e., lack of tolerability or lack of
compliance or patient*s wish, the primary objective is to investigate
maintained efficacy. A difference of 5 points in change versus baseline on the
total PANSS is considered to be a minimum clinically relevant difference. With
a standard deviation of 17, a power of 90% and a (one-sided) significance level
of 0.025, 124 subjects are needed to test the hypothesis that paliperidone
palmitate is not inferior in efficacy to the previous antipsychotic treatment
(by means of Schuirmann's test).
Preferably, the above grouping on reason for switching will be evaluated within
each of the two diagnostic groups (recently diagnosed versus not recently
diagnosed), but only if the subgroup size is sufficiently large, i.e. meeting
the respective sample size criterion.
For the group of non-acute subjects switching from long acting injectable
antipsychotics (group B) the objective is to descriptively explore
tolerability, safety and treatment response of switching from each individual
LAI antipsychotic to paliperidone palmitate. Five different long acting
injectable antipsychotics will be studied, each with a target of approximately
40 subjects.
For the group of acute subjects (group C) the primary objective is to
investigate improved efficacy, based on total PANSS score. The expected
percentage of subjects with at least 30% improvement in total PANSS is 40%.
When the sample size is 93, a two-sided 95.0% confidence interval for a single
proportion using the large sample normal approximation will extend 10% from the
observed proportion for an expected proportion of 40%.
Assuming that in 4% of the subjects the primary parameter (based on the PANSS)
cannot be evaluated, the minimum (sub)group size will be 85 (group A switching
for lack of efficacy or group C) or 130 (group A - switching for other reasons,
i.e., lack of tolerability or lack of compliance or patient*s wish) or 97
(group C). To be able to explore certain additional subgroups (e.g., prior
treatment with oral risperidone, prior treatment with olanzapine, prior
treatment with other oral atypical antipsychotics, prior treatment with oral
conventional antipsychotic medication), the sample size of group A has been
increased to 600.
Recruitment of subjects into the 4 subgroups of group A and group C and the 5
subgroups in group B will be monitored regularly. Once a subgroup has reached
the intended number of subjects, investigators will be notified and asked not
to include that specific type of subjects anymore in the study.
The statistical analysis will be done by or under the supervision of
Janssen-Cilag EMEA.
All subjects who receive paliperidone palmitate at least once will be included
in the analysis of demographic and baseline characteristic data. This is the
intent-to-treat analysis set.
All subjects who receive paliperidone palmitate at least once and provide * 1
post-baseline efficacy measurement will be included in efficacy data analyses.
This is the intent-to-treat analysis set for efficacy.
All subjects who receive paliperidone palmitate at least once and provide any
post-baseline information will be included in safety data analyses. This is the
intent-to-treat analysis set for safety.
Changes from baseline (if appropriate) and observed values for
continuous/ordinal efficacy variables will be summarized descriptively at each
assessment time point and at the subject's last efficacy evaluation (endpoint).
Safety analyses include descriptive summaries of incidence of adverse event and
changes in vital signs, body weight/BMI and ESRS from baseline.
The extension phase of the trial is focused at exposure and safety and will be
analyzed descriptively.
Secondary outcome
See primary study parameters/outcome of the study.
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 (LAI)
intramuscular (i.m.) injectable aqueous suspension formulation for the
treatment of schizophrenia. Paliperidone palmitate enables the slow release of
the drug from the injection site, and thus a single dose may enable therapeutic
plasma concentrations for 1 or 3 months depending on the particle size of the
formulation.
Study objective
Primary Objectives
The primary objective is to explore the tolerability, safety and treatment
response (maintained/improved efficacy), based on total Positive and Negative
Syndrome Scale (PANSS) score, of a transition to flexibly dosed paliperidone
palmitate in subjects with schizophrenia previously unsuccessfully treated with
oral or long-acting injectable (LAI) antipsychotics. Subjects may present
either acute or non-acute symptoms of schizophrenia.
Improved efficacy (i.e., at least 20% improvement in total PANSS score at
endpoint versus baseline) will be the primary endpoint for non-acute subjects
transitioned from oral antipsychotics to paliperidone palmitate due to lack of
efficacy of the previous oral antipsychotic treatment.
Improved efficacy (i.e., at least 30% improvement in total PANSS score at
endpoint versus baseline) will be the primary endpoint for acute subjects
transitioned from oral antipsychotics to paliperidone palmitate.
Maintained efficacy will be the primary endpoint for non-acute subjects
transitioned to paliperidone palmitate due to lack of tolerability of or lack
of compliance with the previous oral antipsychotic treatment and for non-acute
subjects transitioned to paliperidone palmitate due to patient*s wish.
For the group of non-acute subjects switching from LAI antipsychotics, the
primary objective is to descriptively explore tolerability, safety and
treatment response of switching from each individual LAI antipsychotic to
paliperidone palmitate. Five different long-acting injectable antipsychotics
will be studied, each with a target of approximately 40 subjects.
Secondary Objectives
To collect data in order to develop recommendations for use of and transition
to paliperidone palmitate from previous oral and LAI antipsychotic medications.
This will be done by assessing:
• PANSS subscores and Marder factors;
• General measures of disease severity (Clinical Global Impression-Severity
Scale [CGI-S], Clinical Global Impression-Change Scale [CGI-C]);
• Personal and social functioning (Personal and Social Performance Scale
[PSP]);
• Health status (Self-reported health status questionnaire [SF-36]);
• Measure of Health Outcome (EQ-5D);
• Patient well-being (Subjective Well-Being under Neuroleptics Scale [SWN-S]);
• Hospitalizations during the 6 months before and after enrollment in the study
(e.g., number of stays, number of days,*);
• Extrapyramidal symptoms (Extrapyramidal Symptom Rating Scale [ESRS]);
• Quality of sleep and daytime drowsiness (11-point categorical rating scales);
• Patient satisfaction with medication (Treatment Satisfaction Questionnaire
for Medication [TSQM]);
• Physician treatment satisfaction (7-point categorical scale);
• Caregiver burden (Involvement Evaluation Questionnaire [IEQ]; in limited
number of countries depending on availability of the scale in local languages);
Additional Objectives
• Assessment of activity or capacity limitations and participation restrictions
in psychological and mental disorders (Mini International Classification of
Functionality, Disability and Health Rating for Activity and Participation
Disorders in Psychological Illnesses [Mini-ICF-APP]);
• Measures of alcohol and substance use (Clinician Rating Alcohol Use Scale
[CRAUS], Clinician Rating Substance Use Scale [CRSUS]);
• Medical Resource Utilization (MRU through the Healthcare Resource Use
Questionnaire [HRUQ]);
• Clear Thinking Scale [CTS] will be explored in a limited number of countries
depending on availability of the scale in local languages.
Overall safety will be assessed.
Study design
OVERVIEW OF STUDY DESIGN
This is a non-randomized, single arm, multicenter, 6-month study that is aiming
to explore the tolerability, safety and treatment response of flexibly dosed
paliperidone palmitate in approximately 1,000 subjects with schizophrenia
previously unsuccessfully treated with an oral or LAI antipsychotic medication.
Approximately 1,000 subjects of both genders and of minimally 18 years of age,
who have a Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition (DSM-IV) diagnosis of schizophrenia (acute and non-acute) will be
enrolled. Subjects can be either in- or outpatients. A transition period of
preferably a maximum of 4 weeks will be allowed for the previous oral
antipsychotic. When switching subjects from previous LAI antipsychotics,
paliperidone palmitate will be initiated in place of the next scheduled
injection. Anticholinergic medication may continue up to four weeks and should
then be tapered off at the discretion of the investigator.
Subjects transitioning from oral antipsychotics will receive a first injection
of 150 mg eq. of paliperidone palmitate at Day 1, followed by a second
injection of 100 mg eq. at Day 8, both in the deltoid muscle. Subjects
transitioning from previous LAI antipsychotics will receive their first
injection with paliperidone palmitate in place of the next scheduled injection
in the deltoid muscle. The paliperidone palmitate starting dose (Day 1) in
subjects previously unsuccessfully treated with conventional depots should be
guided both by the previous depot dose and the clinical status of the subject,
and should be within the range of 50 to 150 mg eq. The paliperidone palmitate
starting dose (Day 1) in subjects previously unsuccessfully treated with
risperidone LAI (RLAI) should be guided both by the previous RLAI dose and the
clinical status of the subject. Subjects previously on 25 mg RLAI every 2
weeks can attain similar steady state exposure to paliperidone with 50 mg eq.
paliperidone palmitate once monthly. Subjects previously on 37.5 mg RLAI every
2 weeks can attain similar steady state exposure to paliperidone with 75 mg eq.
paliperidone palmitate once monthly. Subjects previously on 50 mg RLAI every 2
weeks can attain similar steady state exposure to paliperidone with 100 mg eq.
paliperidone palmitate once monthly. In exceptional cases, depending on the
clinical situation of the subject, a starting dose of 150 mg eq. may be
allowed. Subjects transitioning from a LAI antipsychotic treatment will not
need a second injection on Day 8. Subsequent once monthly injections will then
be administered in either the deltoid or gluteal muscle during the duration of
the study. The recommended maintenance dose is 75 mg eq. monthly but flexible
dosing in the range of 50 to 150 mg eq. monthly will be allowed. Flexible
dosing will allow investigators to individually adjust the dosage of each
subject.
Subjects who successfully complete the 6-month core treatment phase and would
like to continue treatment with paliperidone palmitate may be enrolled in an
extension phase until paliperidone palmitate is available in their respective
country or until a maximum duration of 12 months (per subject) whichever comes
first. Subjects will receive without cost paliperidone palmitate.
Intervention
DOSAGE AND ADMINISTRATION
Paliperidone palmitate will be administered once-monthly after the first 2
injections that are given one week apart (Day 1 and Day 8). In subjects
transitioning from oral antipsychotics, the first dose of paliperidone
palmitate will be 150 mg eq. given at Day 1 of the 6-month core treatment phase
(Visit 2). The second dose of paliperidone palmitate will be 100 mg eq. given
at Day 8 (* 2 days) of the 6-month core treatment phase (Visit 2b). The 3rd
dose of paliperidone palmitate will be given at Day 38 of the 6-month core
treatment phase (Visit 3). Subsequent doses of paliperidone palmitate will be
given within the range of 50 to 150 mg eq. every 30 (* 7) days.
Subjects transitioning from previous LAI antipsychotics will receive their
first injection with paliperidone palmitate in place of the next scheduled
injection in the deltoid muscle. The paliperidone palmitate starting dose (Day
1) in subjects previously unsuccessfully treated with conventional depots
should be guided both by the previous depot dose and the clinical status of the
subject, and should be within the range of 50 to 150 mg eq. The paliperidone
palmitate starting dose (Day 1) in subjects previously unsuccessfully treated
with risperidone LAI (RLAI) should be guided both by the previous RLAI dose and
the clinical status of the subject. Subjects previously on 25 mg RLAI every 2
weeks can attain similar steady state exposure to paliperidone with 50 mg eq.
paliperidone palmitate once monthly. Subjects previously on 37.5 mg RLAI every
2 weeks can attain similar steady state exposure to paliperidone with 75 mg eq.
paliperidone palmitate once monthly. Subjects previously on 50 mg RLAI every 2
weeks can attain similar steady state exposure to paliperidone with 100 mg eq.
paliperidone palmitate once monthly. In exceptional cases, depending on the
clinical situation of the subject, a starting dose of 150 mg eq. may be
allowed. For subjects transitioned from previous LAI antipsychotic treatment,
the injection at Day 8 (Visit 2b) will not be required (see Switching
Guidelines below for details). Their 2nd dose of paliperidone palmitate will be
given at Day 31 of the 6-month core treatment phase (Visit 3) and will be
guided both by the previous LAI dose and the clinical status of the subject
(within the range of 50 to 150 mg eq.). Subsequent doses of paliperidone
palmitate will be given within the range of 50 to 150 mg eq. every 30 (* 7)
days.
In subjects switching from oral antipsychotics, the doses on Day 1 and Day 8
will be administered through a deltoid injection on alternating arms,
subsequent injections can be given either in the deltoid or the gluteal muscle.
In subjects switching from LAI antipsychotics, the dose on Day 1 is given in
the deltoid muscle. Subsequent once monthly injections will then be
administered in either the deltoid or gluteal muscle for the duration of the
study in both groups of subjects.
The recommended maintenance dose is 75 mg eq. monthly (every 30 * 7 days) but
flexible dosing in the range of 50 to 150 mg eq. monthly will be allowed. The
investigator may flexibly increase or decrease the dose preferably by one
dosing level according to the subjects* clinical needs. Subjects will continue
to return to the study site once monthly for injections and, if scheduled,
study evaluations.
Study burden and risks
TREATMENT PHASE
The subject will be in the study for about 6 months and will be visiting your
study doctor on day 1 (day of first injection with paliperidone palmitate;
Visit 2) and 1 week later (Visit 2b). If the subject is changing from a
long-acting inject able treatment, the visit 1 week after the first injection
with paliperidone palmitate is not required. During the rest of the study,
subject will visit the doctor monthly for 6 months (i.e., Visits 3 to 8).
During these visits, subject will receive the injection with paliperidone
palmitate. Inject able paliperidone palmitate must be administered by the study
doctor. The first injection will be given into one of the arms and the second
injection (1 week later) into the other arm. The subsequent injections will be
given once monthly either in the arms or in the buttock.
A urine sample will be collected for a pregnancy test if the subject is a woman
capable of becoming pregnant to make sure that she is not pregnant at Visit 8.
Subject should not take any over the counter medicine (including vitamins and
herbal remedies) that subject purchase without a prescription, unless the study
doctor approves its use.
After subject have completed the 6-month treatment period, subject will be
eligible to take part in an *extension phase* until paliperidone palmitate is
available in the country or for a maximum of 12 additional months, whichever
comes first. During that extension phase subject can continue receiving
treatment with paliperidone palmitate monthly. The study doctor will discuss
this with the subject. If subjects are eligible to participate and choose to
participate in the extension part of the study, subject will be expected to see
the study doctor every three months. At these visits subject will also be asked
about possible side effects he/she suffered from since the previous visit and
the doctor will measure the body weight.
To test the study drug paliperidone, some of the medicines subject now take may
have to be stopped. Stopping these medicines may cause a return of some
symptoms that were under control. For example, stopping antipsychotics may
cause insomnia (difficulty sleeping), or the appearance of abnormal muscle
movements. The study doctor may be able to give medicine to help control these
symptoms.
One of the best known side effects of Paliperidone is a group of movement
disorders known under the name of extrapyramidal disorder. Symptoms may include
abnormal muscle movements, abnormal movements of the mouth, tongue or jaw, jaw
spasms, drooling, slow or persistent muscle spasms, stiff muscles allowing the
subject jerking movements, slow, shuffling gait, muscle cramps, tremors
(shaking), abnormal eye movements, involuntary muscle contractions, prolonged
contraction of the neck muscles to face an unnatural attitude, slow movements,
or restlessness. Sometimes these reactions can be treated with another medicine
while the subject continues to use Paliperidone.
The most common side effects subject might have when he/she take paliperidone
(the study medication) are: headache and insomnia (difficulty falling or
staying asleep). These side effects are experienced at some point during
treatment by at least 1 out of every 10 patients taking the drug.
One of the most well-known side effects of paliperidone is a group of movement
problems known as extra pyramidal disorder. Symptoms may include: restlessness,
slow or sustained involuntary contraction of muscles, abnormal movements of the
eyes, mouth, tongue or jaw, repetitive, spastic or writhing movements,
sensation of stiffness or tightness of the muscles, a slow shuffling walk, and
a loss of expression on the face. Sometimes these side effects can be treated
with another medicine while you continue on paliperidone.
There may be risks with the use of paliperidone palmitate or paliperidone that
are not yet known. Sometimes, during the course of a study, we may learn new
information about the treatment or study drug that might change whether or not
you want to continue in the study. If this happens, your study doctor will
tell you about it in a timely manner.
Dr. Paul Janssenweg 150
5026 RH Tilburg
NL
Dr. Paul Janssenweg 150
5026 RH Tilburg
NL
Listed location countries
Age
Inclusion criteria
•Man or woman of minimally 18 years of age:
•Subjects who meet the DSM-IV criteria for schizophrenia;
•A) Subject is currently non-acute, i.e. on the same antipsychotic medication used for the treatment of schizophrenia given in an adequate dose and a CGI-S change < or = in the past 4 weeks before enrollment. Subject has been given an adequate dose of either an appropriate oral antipsychotic, or one of the following LAI antipsychotics: haloperidol decanoate, flupentixol decanoate, fluphenazine decanoate, zuclopenthixol or LAI risperidone, for an adequate period of time prior to enrollment, but current treatment is considered unsuccessful due to one or more of the following reasons:
- Lack of efficacy, or
- Lack of tolerability or safety, or
- Lack of compliance, or
- Patient*s wish
Lack of efficacy is defined as subjects with a baseline total PANSS score >= 70 or >= 2 items scoring >= 4 in the PANSS positive or negative subscale or >= 3 items scoring >= 4 in the PANSS general psychopathology subscale, as judged by the investigator.
Lack of tolerability is defined as the presence of clinically relevant (i.e., either clinically relevant according to the investigator and/or intolerable to the subject) side effects with the current antipsychotic medication.;OR,;B) Subjects with acute symptoms of schizophrenia, previously treated with an oral antipsychotic, having a baseline total PANSS score >= 80 and a baseline CGI-S score >= 4;
•The subjects may benefit from a switch of antipsychotic medication to paliperidone palmitate at the discretion of the investigator;
•In the opinion of the investigator, subject is otherwise healthy on the basis of a 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;
•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;
•Women must be:
-postmenopausal for at least 1 year,
-surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy),
-abstinent (at the discretion of the investigator/per local regulations), or
-if sexually active, be practicing a highly effective method of birth control (e.g. prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method [e.g. condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel], male partner sterilization) as local regulations permit,
before entry, and must agree to continue to use the same method of contraception throughout the study. Prescription hormonal contraceptives (the *pill*) should not contain less than 20 ug of estrogen and should not be used as the only method of birth control. Women using oral contraceptives should agree to use an additional birth control method.
•Women of childbearing potential must have a negative urine pregnancy test at screening;
•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;
•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
•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, i.e., subject has never been treated with antipsychotics before and antipsychotic treatment given in this study will be the first antipsychotic treatment that the subject will have ever received;
•On clozapine during the last 3 months;
•Subjects who remain at imminent risk of suicide even after clinical intervention;
•Serious unstable medical condition, including recent and present clinically relevant laboratory abnormalities;
•History or current symptoms of tardive dyskinesia;
•History of neuroleptic malignant syndrome;
•Subject received an investigational drug or used an investigational medical device within 3 months 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;
•Pregnant or breast-feeding female;
•Known allergies, hypersensitivity, or intolerance to risperidone or paliperidone or its excipients (refer to Section 14.1, Physical Description of Study Drug(s);
•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;
•Subjects who have evidence of alcohol or drug dependence (except for nicotine and caffeine) according to DSM-IV Axis 1 criteria within 6 months prior to entry. However, subjects with current substance use or abuse, with the exception of intravenous drug use, will be eligible for enrolment;
• 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.
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 | EUCTR2009-018022-30-NL |
| CCMO | NL33246.060.10 |