Please select the eligibility criteria that correspond to the clinical trial below.
Title: A 6-Week, Randomized, Parallel, Double-Blind, Placebo-Controlled, Fixed-Dose, Multicenter Study to Evaluate the Efficacy and Safety of Lurasidone in Children and Adolescent Subjects With Irritability Associated With Autistic Disorder
Brief Summary: This is a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of 2 fixed doses of lurasidone (20 mg/day and 60 mg/day) for 6 weeks compared with placebo in pediatric and adolescent subjects with irritability associated with autistic disorder who reside in the community setting.


Options:
A: Inclusion Criteria

1. Male or female outpatients, 10-17 years of age inclusive.
2. Meet Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Diagnostic and Statistical Manual (DSM-IV) criteria will be established by a clinician with expertise with individuals with ASD. Best estimate Diagnosis will be reached using DSM-IV criteria, the Autism Diagnostic Observation Schedule (ADOS-2) and the Autism Diagnostic Interview (ADI-R).
3. Have a Clinician's Global Impression-Severity (CGI-S) score ≥ 4 (moderately ill) at Screening.
4. Verbal and performance scale Intelligence Quotient (IQ) ≥ 70 (both subtests of the Wechsler Abbreviated Scale of Intelligence (WASI-I or WASI-II ≥ 70).
5. If already receiving stable concomitant medications affecting behavior, have continuous participation for 1 month prior to Screening (with the exception of fluoxetine, where a period of 6 weeks is needed), and not electively initiate new or modify ongoing medications for the duration of the study.
6. If already receiving stable non-pharmacologic educational, behavioral, and/or dietary interventions, have continuous participation during the preceding 3 months prior to Screening, and not electively initiate new or modify ongoing interventions for the duration of the study.
7. Have normal physical examination and laboratory test results at Screening. If abnormal, the finding(s) must be deemed not clinically significant by the Treating Clinician.
8. Ability to speak and understand English sufficiently to allow for the completion of all study assessments.
9. Ability to obtain written informed consent from the participant, if developmentally appropriate. If a participant does not have the capacity to consent, ability to obtain assent (if developmentally appropriate), as well as written informed consent from their parent(s)/legal guardian.

Exclusion Criteria

1. Patients born prior to 35 weeks gestational age.
2. Patients with a primary psychiatric diagnosis other than ASD.
3. Patients with a medical history of neurological disease, including, but not limited to, epilepsy/seizure disorder (except simple febrile seizures), movement disorder, tuberous sclerosis, fragile X, and any other known genetic syndromes, or known abnormal brain MRI/structural lesion.
4. Pregnant female patients, sexually active female patients on hormonal birth control and sexually active females who do not use at least two types of non-hormonal birth control.
5. Patients with evidence or history of malignancy or any significant hematological, endocrine, cardiovascular (including any rhythm disorder), respiratory, renal, hepatic, or gastrointestinal disease.
6. Patients with one or more of the following: HIV, Hepatitis B virus, Hepatitis C virus, hemophilia (bleeding problems, recent nose and brain injuries), abnormal blood pressure (hypotension or hypertension), drug abuse, immunity disorder or severe depression.
7. Patients who are currently taking oxytocin or have taken intranasal oxytocin in the past with no response.
8. Patients with a sensitivity to oxytocin or any components of its formulation.
9. Patients unable to tolerate venipuncture procedures for blood sampling.
10. Patients in foster care for whom the province/state is defined as a legal guardian
B: Inclusion Criteria:

* Males or females ages 6 to 12 years
* Diagnosis of autistic disorder, according to DSM-IV-TR using Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule (modules 2 \& 3).
* A knowledgeable caregiver capable of providing reliable information about the patient's condition, able to attend all clinic visits with the patient
* Patients over age 12, only if they completed Study MEM-PK-21

Exclusion Criteria:

* Medical history of active epilepsy/seizure disorder except simple febrile seizures
* Participation in any other clinical investigation using an experimental drug within 30 days of the start of this study
C: Inclusion Criteria:

* Written informed consent from parent(s) or legal guardian(s) with sufficient intellectual capacity to understand the study and support subjects' adherence to the study procedures must be obtained for subjects who are not emancipated. In accordance with Institutional Review Board (IRB) requirements, the subject will complete an informed assent when developmentally appropriate, to participate in the study before conduct of any study-specific procedures.
* Male or female subjects 6 to 17 years of age, inclusive, at the time of consent.
* A reliable informant (eg, parent, legal guardian, or caregiver) who has past and current direct knowledge of the subject must accompany the subject at each visit and must oversee the administration of the study drug.
* DSM-IV-TR primary diagnosis of autistic disorder confirmation of the diagnosis by a trained clinician (eg, psychiatrist, psychologist, social workers, etc) at the time of screening, by means of the Autism Diagnostic Interview, Revised (ADI-R).
* Screening and Baseline ABC irritability subscale score ≥ 18.
* Screening and Baseline CGI-S ≥ 4.
* Within 5th to 95th percentile for gender specific Growth Charts from Centers for Disease Control (CDC).
* No clinically relevant abnormal laboratory values.
* No clinically relevant abnormal vital sign values/findings

  1. Females who participate in this study:

     * are unable to become pregnant (eg, premenarchal, surgically sterile, etc.) -OR-
     * practices true abstinence (consistent with lifestyle) and must agree to remain abstinent from signing informed consent to at least 7 days after the last dose of study drug has been taken;

-OR-

•are sexually active and willing to use a medically effective method of birth control (eg, male using condom and female using condom, diaphragm, contraceptive sponge, spermicide, contraceptive pill, or intrauterine device) from signing informed consent to at least 7 days after the last dose of study drug has been taken.

* Males must be willing to remain sexually abstinent (consistent with lifestyle) or use an effective method of birth control (eg, male using condom and female using condom, diaphragm, contraceptive sponge, spermicide, contraceptive pill, or intrauterine device) from signing informed consent to at least 7 days after the last dose of study drug has been taken.
* In the judgment of the investigator, the subject is able to swallow the size and number of study drug tablets specified per protocol (See Table 4 for study drug tablet size).
* Able to adhere to protocol-specified meal requirements during dosing.
* Have a stable living arrangement for at least 3 months prior to screening.
* Non-pharmacologic therapy (eg, behavior modification) must be stable for at least 4 weeks before screening and consistent throughout the study.

Exclusion Criteria:

* Subjects with profound intellectual disability.
* Current diagnosis of bipolar disorder, psychosis, schizophrenia or major depression, or childhood disintegrative disorder as confirmed by the MINI-Kid (as appropriate) at screening. Confirmed genetic disorders with cognitive and behavioral disturbances are also exclusionary.
* Clinically significant neurological, metabolic (including type 1 and type 2 diabetes), hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, carcinoma, and/or urological disorder that would pose a risk to the subjects if they were to participate in the study or that might confound the results of the study.

Note: Active medical conditions that are minor or well-controlled are not exclusionary if they do not affect risk to the subject or the study results. In cases in which the impact of the condition upon risk to the subject or study results is unclear, the Medical Monitor should be consulted. Any subject with a known cardiovascular disease or condition (even if controlled) must be discussed with the Medical Monitor during screening.

* Evidence of any chronic organic disease of the CNS such as tumors, inflammation, active seizure disorder, vascular disorder, potential CNS related disorders that might occur in childhood- eg, Duchenne Muscular dystrophy, myasthenia gravis, or other neurologic or serious neuromuscular disorders. In addition, subjects must not have a history of persistent neurological symptoms attributable to serious head injury. Past history of febrile seizure, drug-induced seizure, or alcohol withdrawal seizure is not exclusionary.
* If the subject has a history of seizures, the subjects must not currently be taking any antiepileptic drugs (AEDs) and be seizure-free for at least 6 months.
* Clinically significant finding(s) on physical examination determined by the investigator to pose a health concern to the subject while on study.
* A history or presence of abnormal ECG, which in the investigator's opinion is clinically significant. Screening ECGs will be centrally over-read, and eligibility will be determined based on the over-read.
* Known history or presence of clinically significant intolerance to any antipsychotic medications including but not limited to angioedema, serotonin or neuroleptic malignant syndromes, severe dystonia, or moderate to severe tardive dyskinesia.
* Clinically significant alcohol abuse/dependence or drug abuse/dependence based on Mini International Neuropsychiatric Interview for children and adolescents (MINI-Kid) criteria within the last 6 months prior to screening.
* Clinically significant orthostatic hypotension (ie, a drop in systolic blood pressure of 20 mmHg or more and/or drop in diastolic blood pressure of 10 mmHg or more within 4 minutes of standing up).
* Presence or history (within the last year) of a medical or surgical condition (eg, gastrointestinal disease) that might interfere with the absorption, metabolism, or excretion of orally administered lurasidone.
* Positive test results at screening for:

  1. Urine drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, cannabinoids, methamphetamine, and methadone). However, a positive test for amphetamines, barbiturates, opiates, benzodiazepines or methadone may not result in exclusion of subjects if the investigator determines that the positive test is as a result of prescription medicine(s).
  2. Pregnancy test (only in female subjects ≥ 11 years old).
* Lifetime history of human immunodeficiency virus (HIV) positive or acquired immune deficiency syndrome (AIDS), or history of Hepatitis B or C.
* Participated in another interventional clinical trial or receiving an investigational product within 30 days prior to study drug administration.
* Use of concomitant medications that consistently prolong the QT/QTc interval within 28 days prior to randomization.
* Received depot neuroleptics unless the last injection was at least 1 month or 1 treatment cycle prior to screening, whichever is longer.
* Subject has received treatment with antidepressants within 3 days, fluoxetine hydrochloride at any time within 21 days, an MAO inhibitor within 21 days of randomization or clozapine within 120 days of randomization. Depot neuroleptics must be discontinued at least one treatment cycle prior to randomization.
* Use of any antipsychotic medication (other than study drug), carbamazepine, oxcarbazepine or fluvoxamine, within 3 days prior to randomization.
* Females who are pregnant, lactating, or likely to become pregnant during the study.
* Donation of whole blood within 60 days prior to randomization.
* Has a prolactin concentration greater than or equal to 100 ng/mL at screening.
* Subject is considered by the investigator to be at imminent risk of suicide during the study. Subject has a history of one or more serious suicide attempts (based on the investigator's judgment) in the 12 months prior to screening. Subjects determined to be at risk of suicide or injury, as assessed by the investigator at screening, will be referred for further psychiatric evaluation.
* Clinically relevant history of drug hypersensitivity to lurasidone or any components in the formulation.
* Subject requires use of concomitant medications that are potent inducers or inhibitors of the cytochrome P450 (CYP) 3A4 enzyme system (Appendix C) from signing informed consent until follow-up.
D: Inclusion Criteria:

* DSM-IV diagnosis of Autistic Disorder (299.00)
* ABC-I Subscale score of greater than or equal to 18
* CGI-S of greater than or equal to 4
* mental age \>18 months, body weight of at least 20 kg, seizure-free for at least 6 consecutive months and if on anticonvulsants must be on a dosage that has been stable for at least 4 weeks
* Medication free for 1 week before the start of the study for all psychotropic drugs, except 4 weeks for fluoxetine and at least 8 weeks for injectable medications
* Female patients must be premenarchal or sexually abstinent or, if heterosexually active, must practice an effective method of birth control.

Exclusion Criteria:

* History of prior or current DSM-IV psychotic disorder (e.g., schizophrenia, bipolar disorder, other psychosis), Pervasive Developmental Disorder not otherwise specified (PDD NOS), Asperger's, or Rett's
* Any history of hypersensitivity to risperidone, or its excipients in formulation, or other known drug allergy
* Patients who received risperidone within 3 months before screening (except p.r.n. use)
* Patients who did not demonstrate sufficient clinical response to an adequate trial of risperidone treatment in the past (an adequate trial is defined as a period of at least 4 weeks at an adequate dose)
* Neurologic disorder (e.g., Neuroleptic Malignant Syndrome, seizure disorders that are unstable, seizure activity within the past 6 months)
* History of alcohol or substance dependence within 3 months of screening
* Female subject who is pregnant (positive beta-HCG) or breast feeding
* Patients with existing moderate or severe EPS or history of tardive dyskinesia
* Patients who have received an experimental drug or used an experimental medical device within 3 months before the planned start of treatment.

Answer: C