A Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Sublingual Asenapine in a Pediatric Population With Schizophrenia or Bipolar I Disorder (P06522 AM1)
Condition: Schizophrenia; Bipolar I Disorder
MeSH terms: Schizophrenia
Intervention: Asenapine 2.5 mg; Asenapine 5 mg; Asenapine 10 mg
Intervention description: Asenapine tablet, sublingually (SL), 2.5 mg b.i.d. on Days 1-6 and one 2.5 mg tablet, SL, on Day 7.; Asenapine tablet, SL, 5 mg b.i.d. on Days 1-6 and one 5 mg tablet, SL, on Day 7.; Asenapine tablets, SL, in a rising dose schedule to 10 mg b.i.d. (with a single 10 mg dose on final day). For Cohorts 3b, 3c and 3d, rising dose schedule begins with asenapine 5 mg b.i.d. on Day 1 and dosing occurs through Day 8. For Cohort 3a, rising dose schedule begins with asenapine 2.5 mg b.i.d. on Day 1 and dosing occurs through Day 12.
Intervention MeSH terms: Asenapine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 10 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: asenapine; pediatric schizophrenia; bipolar I disorder

Summary:

      This study is an open label, sequential-group, two site, multiple dose escalating study of
      sublingual administered asenapine in a pediatric population with schizophrenia or bipolar I
      disorder; in one study cohort (3a) participants with other conditions treatable with chronic
      antipsychotic medication can also be enrolled. Participants will receive a single sublingual
      placebo dose on Day -1, followed by multiple sublingual doses of asenapine twice daily
      (b.i.d.) for 6 days (Cohorts 1 and 2), 7 days (Cohort 3b-d), or 11 days (Cohort 3a), and a
      final once daily administration on Day 7 (Cohorts 1 and 2), Day 8 (Cohort 3b-d) or Day 12
      (Cohort 3a).
    

Eligibility criteria:

        Inclusion Criteria

        For participants in Cohorts 1, 2, 3b, 3c and 3d:

          -  Diagnosis of schizophrenia or bipolar I disorder

          -  A schizophrenic participant must have a diagnosis of current schizophrenia of paranoid
             disorganized, catatonic, or undifferentiated subtype as determined by a structured
             clinical interview at screening

          -  A bipolar I disorder participant must have a primary diagnosis of bipolar I disorder,
             current episode manic, or mixed as determined by a structured clinical interview at
             screening

        For participants in Cohort 3a:

          -  Documented history of schizophrenia, bipolar disorder, autism, conduct disorder,
             oppositional defiant disorder, or any condition for which the chronic use of
             antipsychotic medication (e.g, risperidone, olanzapine, aripiprazole, haloperidol) was
             warranted and/or administered

        All participants:

          -  Must be at least 10 and not older than 17 years of age at the day of first asenapine
             dosing (Cohort 3); for Cohort 1 and 2 subjects should be at least 10 and not older
             than 11 years of age at the day of first asenapine dosing

          -  Must be able and willing to sign an informed assent as required by local regulations
             before study participation and able to adhere to dose and visit schedules or their
             parent/authorized legal representative(s) should be able and willing to sign an
             informed consent, and should be fluent in the language of the informed consent

          -  Must have a caregiver or an identified responsible person who is considered reliable
             by the investigator and who has agreed to provide support to the subject to ensure
             compliance with trial treatment, outpatient visits, and protocol procedures

          -  Must be fluent in the language of the investigator, trial staff (including raters) and
             the informed assent

          -  Must be willing to discontinue all psychotropic medication during the treatment period
             except for those specified in the protocol

          -  Have discontinued the use of strong inhibitors or inducers of cytochrome P450 (CYP)1A2
             and/or CYP2D6 (e.g. fluvoxamine, citalopram, fluoxetine, paroxetine, omeprazole, and
             rifampicin) and beta-blockers, applying a washout period of 5 half lives or 7 days,
             whichever is longer, AND be stabilized on non-interacting alternative medication (i.e.
             medication not interacting with asenapine pharmacokinetics) for 2 weeks prior to
             baseline if their medical condition requires this

          -  Clinical laboratory tests (complete blood count [CBC], blood chemistry, and
             urinalysis) must be within normal limits or clinically acceptable to the investigator,
             after discussion with the Sponsor and following agreement of the Sponsor's medical
             monitor

          -  Screening 12 lead electrocardiogram (ECG) conduction intervals and vital signs
             recordings (oral body temperature, systolic/diastolic blood pressure and pulse rate)
             must be clinically acceptable according to the investigator, after discussion with the
             Sponsor and following agreement of the Sponsor's medical monitor

          -  If male, and non-vasectomized, must agree to use a condom with spermicide (when
             marketed in the country) or abstain from sexual intercourse, during the trial and for
             3 months after stopping the medication

        Female participants must:

        If unsterilized, have used a medically accepted method of contraception for 3 months (or
        abstained from sexual intercourse) prior to the screening period, and agree to use a
        medically accepted method of contraception during the trial (including the screening period
        prior to receiving trial medication) and for 2 months after stopping the trial medication.
        An acceptable method of contraception includes one of the following:

          -  stable oral, transdermal, injectable, or sustained-release vaginal hormonal
             contraceptive regimen without breakthrough uterine bleeding for 3 months prior to
             Screening; in addition, during study use of condom and/or spermicide (when marketed in
             the country)

          -  intrauterine device (inserted at least 2 months prior to Screening visit); in
             addition, during study use of condom and/or spermicide (when marketed in the country)

        Note: Vasectomy of the partner is not considered sufficient contraception and one of the 2
        methods listed above must be used

        Females who are not currently sexually active must also consent to use one of these
        accepted methods of contraception should they become sexually active while participating in
        the study

          -  condom (male or female) with spermicide (when marketed within the country),

          -  diaphragm or cervical cap with spermicide (when marketed within the country) and
             condom (male),

        Exclusion Criteria

        The participant will be excluded from entry if ANY of the criteria listed below are met at
        baseline

        The participant:

          -  Is pregnant, intends to become pregnant (within 3 months of ending the study), or is
             breastfeeding

          -  In the opinion of the investigator, will not be able to participate optimally in the
             study

          -  Has an uncontrolled, unstable clinically significant medical condition (e.g., renal,
             endocrine, hepatic, respiratory, cardiovascular, hematologic, immunologic,
             gastrointestinal or cerebrovascular disease, or malignancy) that may interfere with
             the interpretation of pharmacokinetic, safety and tolerability evaluations in the
             opinion of the investigator

          -  Has a history of any infectious disease within 4 weeks prior to drug administration
             that in the opinion of the investigator, affects the subject's ability to participate
             in the trial

          -  Is positive for hepatitis B surface antigen, hepatitis C antibodies or human
             immunodeficiency virus (HIV)

          -  Has a positive screen for drugs with a high potential for abuse (during the Screening
             period or clinical conduct of the trial)

          -  Has a history of psychiatric or personality disorders that in the opinion of the
             investigator and sponsor, affects the subject's ability to participate in the trial

          -  Has a history of neuroleptic malignant syndrome

          -  Has a diagnosis of mental retardation or organic brain disorder

          -  Has a primary diagnosis other than schizophrenia or bipolar I disorder, current
             episode manic or mixed, that is primarily responsible for current symptoms and
             functional impairment; this exclusion is not applicable to participants in Cohort 3a

          -  Has a diagnosis of psychotic disorder or a behavioral disturbance thought to be
             substance induced or due to substance abuse

          -  Has a current (past 6 months) substance and alcohol abuse or dependence (excluding
             nicotine and caffeine)

          -  Has a history of tardive dyskinesia or tardive dystonia

          -  If has attention-deficit/hyperactivity disorder (ADHD), has not been on a stable dose
             of stimulants (e.g. amphetamines, methylphenidate) for the last 3 months (participants
             who have not taken any stimulants in the last month will not be excluded)

          -  Has a history of alcohol or drug abuse in the past 2 years

          -  Has donated blood in the past 60 days

          -  Has previously received asenapine

          -  Is at imminent risk of self-harm or harm to others, in the investigator's opinion
             based on clinical judgment

          -  Report at Screening, suicidal ideation, or suicidal behavior in the past 6 months

          -  Is currently participating in another clinical study or have participated in a
             clinical study (e.g., laboratory or clinical evaluation) within 30 days of baseline

          -  Is part of the study staff personnel or family members of the study staff personnel

          -  Has demonstrated allergic reactions (eg, food, drug, atopic reactions or asthmatic
             episodes) which, in the opinion of the investigator and sponsor, interfere with their
             ability to participate in the trial

          -  Smokes more than 10 cigarettes or equivalent tobacco use per day

          -  Has a history of malignancy