A Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Sublingual Asenapine in a Pediatric Population With Schizophrenia or Bipolar I Disorder (P06522 AM1)

A Sequential Groups, Open Label, Rising Multiple Dose Study to Assess the Pharmacokinetics, Safety and Tolerability of Sublingual Asenapine in a Pediatric Population With Schizophrenia or Bipolar I Disorder

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).

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