Please select the eligibility criteria that correspond to the clinical trial below.
Title: Biomarkers in Autism of Aripiprazole and Risperidone Treatment
Brief Summary: The Biomarkers in autism of aripiprazole and risperidone treatment (BAART) project will provide evidence-based guidance in the selection and monitoring of drug treatment of autism. BAART involves 3 academic centers across South Carolina. Although the FDA has approved use of the antipsychotic drug risperidone for irritability associated with autistic disorder, a moderate response rate in pivotal clinical trials and concerns over tolerability and weight gain can force clinicians to select alternative drug treatments for which evidence-based support is sparse.


Options:
A: Inclusion Criteria:

1. Outpatients 5-17 years of age inclusive.
2. Meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). DSM-5 criteria will be established by a clinician with expertise with individuals with ASD. Diagnosis will be supported by the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2).
3. Complex language to qualify for ADOS-2 modules 3 or 4.
4. If already receiving stable concomitant medications affecting behaviour, have stable regimens with no changes during the preceding 6 weeks prior to Screening, and will not electively initiate new or modify ongoing medications for the duration of the study.
5. If already receiving stable non-pharmacological educational and behavioural interventions, have continuous participation during the preceding 3 months prior to Screening, and will not electively initiate new or modify ongoing interventions for the duration of the study.
6. Have normal physical examination and laboratory test results at Screening. If abnormal, the finding(s) must be deemed clinically insignificant by the Investigator.
7. 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(s).

Exclusion Criteria:

1. Pregnant females; sexually active females on inadequate birth control.
2. Have a serious medical condition that, based on Investigator judgment, might interfere with the conduct of the study, confound interpretation of the study results, or endanger their own well-being. Have evidence of any significant hematological, endocrine, cardiovascular (including uncorrected symptomatic congenital heart disease), respiratory, renal, hepatic, or gastrointestinal disease, not including mild common pediatric diseases in these areas that are stable (e.g. mild asthma, constipation, etc.).
3. Have unstable epilepsy (i.e. seizures occurring within the last 6 months), or have epilepsy and not on stable doses of antiepileptic medications (i.e. dose changes within the last 3 months).
4. Have a history of drug abuse.
5. Have hypersensitivity to arbaclofen or any components of its formulation.
6. Unable to tolerate venipuncture procedures for blood sampling.
7. Actively enrolled in another intervention study.
8. Taking racemic bacblofen, vigabatrin, tiagapine, riluzole, clobazam or regular benzodiazepine use (prn and hs use is allowed).
9. Unable to take oral medications.
10. Known hypersensitivity to racemic baclofen.
11. Inability to speak and understand English sufficiently enough to allow for the completion of all study assessments (parent/legal guardian; participant).
B: Inclusion Criteria

* Aged 6 to 17 years and weight of at least 15 kg
* Meet DSM-IV criteria for of AD, established by chart review, clinical judgment and the Autism Diagnostic Interview- Revised (ADI-R) criteria
* Clinical Global Impressions Severity (CGI-S) score of \>4 (moderately ill)
* ABC Irritability subscale score of \>18
* Mental age of at least 18 months
* If female and sexually active, must agree to an acceptable method of birth control during the trial
* Medication free or adequate washout period (2-4 weeks prior to enrollment) of psychoactive drugs (anticonvulsants permitted for seizure management if dosage is stable for 4 weeks)
* Parent/guardian able to read and provide informed consent.

Exclusion Criteria

* Psychiatric disorder that is effectively managed by psychoactive medication (e.g. ADHD, MDD)
* Prior diagnosis or evidence of genetic or other disorder that may interfere with assessments (e.g. Fragile X syndrome, Fetal alcohol syndrome, history of very low birth weight) assessed by personal and family history, dysmorphology, and clinical judgment.
* Prior use of risperidone or aripiprazole for more than 2 weeks
* Seizure during the past 6 months
* History or evidence of a medical condition that would expose them to an undue risk of a significant adverse event or interfere with assessments during the trial including but not limited to hepatic, renal, respiratory, cardiovascular, endocrine, hematologic or immunologic disease as determined by the clinical judgment of the investigator
* Current suicidal or homicidal risk
* Positive urine pregnancy test at baseline
* Dependent on other substances, with the exception of nicotine or caffeine
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:

* Meets DSM-IV criteria for autistic disorder, .
* CYBOCS-PDD score of at least 10 at screening.

Exclusion Criteria:

* Diagnosis of Asperger Syndrome or Pervasive Developmental Disorder Not Otherwise Specified, Rett Syndrome, Childhood Disintegrative Disorder.
* Patients planning to commence cognitive behaviour therapy during the period of the study or those who have begun cognitive behaviour therapy within 8 weeks prior to enrolment.
* Patients who are currently taking fluoxetine or who have previously taken it are not eligible for the study.

Other protocol-defined Inclusion/Exclusion criteria may apply.

Answer: B