Please select the eligibility criteria that correspond to the clinical trial below.
Title: Ph 3 Multicenter DBRCT Parallel Group Study to Evaluate Safety & Efficacy of Evening-dosed HLD200, a Novel Delayed & Extended Release Formulation (DELEXIS) of MPH HCl, on Post-waking, Early Morning Function in Children Aged 6-12 With ADHD
Brief Summary: This Phase 3 pivotal efficacy trial will examine the effects of HLD200 (methylphenidate) in patients aged 6-12 years with ADHD in a naturalistic setting. Following a screening/washout period (Visit 1), subjects will randomized to double-blind placebo or HLD200 for a period of 3 weeks (Visits 2-5) before assessing clinical study endpoints at last study visit.


Options:
A: Inclusion Criteria:

* Must be male or non-pregnant female at least 12 years of age and less than 18 years of age.
* Must have an ADHD diagnosis, in attentive, hyperactive/impulsive or combined, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) based on clinician assessment using multiple informants and a structured interview.
* Must be unsatisfied with his or her current pharmacological therapy for treatment of ADHD or not currently receiving pharmacological therapy for ADHD. Inclusion of subjects naïve to pharmacological therapy for ADHD is permitted.
* Female subjects must be one of the following: a. surgically sterile prior to screening; b. if of childbearing potential, abstinent or willing to use a reliable method of contraception, such as oral contraceptive, two barrier methods, a barrier method plus a spermicidal agent.
* Female subjects of Child-Bearing Potential (FOCP) must be a negative serum β-hCG pregnancy test at screening.
* Must have a minimum level of intellectual functioning, as determined by an Intelligence Quotient (IQ) score of 80 or above based on the WASI or the KBIT.
* Mentally and physically competent to sign an informed assent document, in the case of the subject, and an informed consent document, in the case of the parent/guardian, indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
* Able and willing to comply with the study procedures for the entire length of the study, including a successful swallow test of an empty 85 mg capsule.
* Total score of 24 or greater on the clinician-rated ADHA-5-RS, as assessed at Visit 2

Exclusion Criteria:

* Having an allergy to methylphenidate or amphetamines or a history of serious adverse reactions to methylphenidate.
* Known to be non-responsive to methylphenidate treatment. Non-response is defined as methylphenidate use at various doses for a phase of at least four weeks at each dose with little or no clinical benefit.
* Being diagnosed with or having a history of strokes, epilepsy, migraine headaches (greater than 1 instance every two months), glaucoma, thyrotoxicosis, tachyarrhythmias or severe angina pectoris or have serious or unstable medical illness. Subjects with controlled or stable asthma or diabetes will be permitted.
* Elevated blood pressure, defined as any values above 89 diastolic or 139 systolic, as assessed at Visit 1.
* Clinically significant ECG abnormalities, as assessed at Visit 1.
* Clinically significant laboratory abnormalities, as assessed at Visit 1.
* Currently receiving guanethidine, pressor agents, MAO inhibitors, coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), phenylbutazone, tricyclic antidepressants (e.g., imipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs) or herbal remedies (unless on a stable dose for 4 weeks).
* Subject has known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary heart disease, transient ischemic attack or stroke or other serious cardiac problems that may place the subject at increased vulnerability to the sympathomimetic effects of a stimulant drug.
* Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
* Subjects who are currently considered a suicide risk by the investigator.
* Having a primary diagnosis of schizophrenia, schizoaffective disorder, primary affective disorder, schizotypal personality, major depression, bipolar disorder, generalized anxiety, borderline personality disorder, antisocial personality or another unstable psychiatric condition requiring treatment, as assessed by the structured interview conducted at Visit 1.
* Having a history or suspected physiological dependence (excluding nicotine) on narcotic analgesics or other psychoactive drugs (including barbiturates, opiates, cocaine, cannabinoids, amphetamines and benzodiazepines).
* Excessive consumption of alcohol (consumes alcohol in quantities greater than 15 drinks per week; 1 drink is defined as 360 mL/12 oz. of beer, 120 mL/4 oz. of wine, or 30 mL/1 oz. of hard liquor), or history (within previous 6 months) of alcohol abuse.
* Currently (or within 30 days before the planned start of treatment) receiving an investigational drug or using an experimental medical device.
* Homeless.
B: Inclusion Criteria. Participants for the study must meet all of the following criteria:

1. Consent: The family must provide signature of informed consent by parents or legal guardians.
2. Age at time of Screening: 7 years to 11 years, inclusive
3. Gender: includes male and female children.
4. ADHD Diagnostic Status: ADHD patients must meet DSM-IV criteria for ADHD, Inattentive or Combined subtype. Normal controls must not meet DSM-IV criteria for ADHD, any subtype. Section D.4 below describes in detail the diagnostic process for arriving at diagnosis.
5. Cognitive Functioning: IQ of greater than 80 as estimated by Vocabulary and Block Design subtests of the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV).
6. Learning Disability: All children will be administered the abbreviated WIAT including the Spelling, Reading, and Math subtests. Children must score above 80 on all three WIAT subtests.
7. School: Children must be enrolled in a school setting from which teacher ratings can be obtained.

Exclusion Criteria. Potential participants will be excluded if they meet any of the following criteria:

1. Understanding Level. The patient and parent cannot understand or follow instructions given in the study.
2. History of Psychiatric Medications: Children who have a history of taking any medication for psychological or psychiatric problems will be excluded from participation.
3. Exclusionary Psychiatric Conditions: Children whose primary diagnosis is something other than ADHD will be excluded from participation.
4. Developmental Disabilities. As a result of scores on the IQ screening, additional assessments, or the judgment of the study clinicians, patients will be excluded if they are deemed to be significantly developmentally delayed. This includes clinically significant delays in cognitive function or the presence of other Pervasive Developmental Disorders (PDD).
5. Organic Brain Injury: Children must not have a history of head trauma, neurological disorder, or any other organic disorder that could possibly affect brain function.
C: Inclusion Criteria:

1. Subjects must be male or female children (6 to 12 years at the time of consent).
2. Subjects must have a diagnosis of ADHD as defined by DSM5 criteria and confirmation using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID).
3. Subjects must have a baseline ADHD-RS-IV score at or above the 90th percentile normalized for sex and age in total score. In addition, this ADHD-RS-IV total score must be ≥26 at Baseline.
4. Subjects must have a Clinical Global Impression of Severity (CGI-S) score ≥4 and a CGI-P score \>10 at the Baseline Visit.
5. Subjects have demonstrated, in the judgment of the investigator, at least a partial clinical response to MPH.
6. Parental or legal guardian confirmation of the child's before-school functional impairment and/or difficulties performing a morning routine of at least 30 minutes minimum duration occurring between 6:00 and 9:00 am.
7. Subject body weight must be ≥20 kg.
8. Subject must be considered clinically appropriate for treatment with MPH and HLD200, including ability to swallow treatment capsules.
9. Subject must be in general good health based upon the medical history, physical, and laboratory examinations (including urine drug screen).
10. Subject and parent or legal guardian must be able to read, write, and/or understand at a level sufficient to provide informed consent (parent/legal guardian) and assent (subject) prior to study participation and to complete study-related materials. Subject and parent or legal guardian must plan to be available for the entire study period.
11. Female subjects of childbearing potential (i.e., post-menarche) are required to have a negative result on urine pregnancy testing at screening (and will be given specific instructions for avoiding pregnancy during the study).
12. A medically highly effective form of birth control must be used during the study and for 90 days thereafter for subjects of either sex of childbearing potential. Examples of medically highly effective forms of birth control are as follows:

    * No sexual activity
    * Use of acceptable methods of birth control including intra-uterine device, oral, implantable,or injectable contraceptives.

Exclusion Criteria:

1. History of, or current, medical condition or laboratory result which, in the opinion of the investigator, unfavorably alters the risk-benefit of study participation, may jeopardize subject safety, or may interfere with the satisfactory completion of the study and study-related procedures.
2. Serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other cardiac problems that may place the subject at increased vulnerability to the sympathomimetic effects of a stimulant drug.
3. History of seizure disorder (except febrile seizures prior to age 5 and with last occurrence at least 1 year prior to study participation), Tourette's disorder, or intellectual disability of minor severity or greater (DSM5 criteria).
4. History of psychosis, bipolar disorder, anorexia nervosa, bulimia, or suicide attempt. Current depression, anxiety, conduct/behavior disorder, substance use disorder, or other psychiatric condition which, in the investigator's opinion, may jeopardize subject safety or may interfere with the satisfactory completion of the study and study-related procedures.
5. Active suicidal ideation as evidenced by an ideation score of 2 or greater on the C-SSRS.
6. History of severe allergic reaction or intolerance to MPH.
7. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, or creatinine greater than 1.5x the upper limit of normal. Elevated bilirubin due only to Gilbert's syndrome is not exclusionary.
8. History of alcohol abuse or illicit drug use.
9. Use of prescription medications (except per protocol allowed medications) within 7 days of Baseline (Visit 2), except for ADHD stimulant medication (72 hours) and monoamine oxidase inhibitors (MAOIs) (14 days), and over-the-counter medications (except birth control and allowed medications) within the 3 days preceding Baseline (Visit 2). Medications not covered in allowed medications or prohibited medications must be cleared by the medical monitor prior to enrolling the subject.
10. Use of psychotropic medications including antidepressants, mood stabilizers, and antipsychotics.
11. Participation in a clinical trial with an investigational drug within the 30 days preceding study enrollment.
12. Previous treatment experience with HLD200.
13. Positive screening for illicit drug use or nicotine and/or current health conditions or use of medications that might confound the results of the study or increase risk to the subject.
14. In the opinion of the investigator, the subject may have problems complying with the protocol or the procedures of the protocol, or for which the study could pose unnecessary safety risks. This includes current health conditions or use of medications that might confound the results of the study or increase risk to the subject.
15. A sibling or step-sibling that is concurrently participating in this study who resides with and is cared for by the same parent/legal guardian as the subject.
D: Inclusion Criteria:

* Patients must meet Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) diagnostic criteria for ADHD based on Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime (K-SADS-PL) prior to randomization.
* Patients must have an Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version:Investigator-Administered and Scored (ADHD-RS-IV-PV:IR) total score at least 1.5 standard deviations above the age/gender norm prior to randomization. They must have a Clinical Global Impression-Attention Deficit Hyperactivity Disorder-Severity Scale (CGI-ADHD-S) score greater than or equal to 4 at both the patients screening visit, prior to randomization.
* Patients must have laboratory results; showing no clinically significant abnormalities.
* Patients must be of normal intelligence, as assessed by the investigator.
* Patients/parents must have been judged by the investigator to be reliable to keep appointments for clinic visits and all tests, including venous punctures and examinations required by the protocol.
* Patients of child-bearing potential agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug. Female patients of child-bearing potential must test negative for pregnancy at the time of enrollment based on a urine pregnancy test.

Exclusion Criteria:

* Patients who weigh less than 18 kg or greater than 75 kg at screening and at randomization.
* Female patients who are pregnant or who are breast-feeding. Patients who have a history of Bipolar I/ II, psychosis, or pervasive developmental disorder.
* Patients who have current motor tics or a diagnosis of Tourette's Syndrome.
* Patients with marked anxiety, tension, and agitation sufficient, to contraindicate treatment with extended-release methylphenidate.
* Patients with a history of any seizure disorder, known electroencephalographic (EEG) abnormalities in the absence of seizures.
* If the electrocardiogram (ECG) assessed at screening/prior to randomization shows an abnormality meeting one or more of the absolute exclusion criteria listed in the Pediatric ECG Alert Criteria must be excluded from the study.
* Patients who, in the opinion of the investigator, are at serious suicidal risk.
* Patients with a history of severe allergies to more than one class of medications, multiple adverse drug reactions, or known hypersensitivity to extended-release methylphenidate.
* Patients with a history of alcohol or drug abuse within the past 3 months prior to, or who are currently using alcohol, drugs of abuse, or any prescribed or over-the-counter medication in a manner that the investigator considers indicative of abuse.
* Patients who screen positive for drugs of abuse not prescribed by a physician cannot participate. Drug screen may be repeated at the discretion of the investigator, and the patient may be allowed to enter the study if the repeat screen is negative. All patients must have a negative drug screen before enrollment in the study.
* Patients who have a medical condition that would increase sympathetic nervous system activity markedly, or who are taking a medication on a daily basis that has sympathomimetic activity are excluded. Such medications can be taken on an as-needed basis.
* Patients with problems that would be exacerbated by increased norepinephrine tone, including a history of cardiovascular disease, thyroid dysfunction, glaucoma, urinary retention, or severe gastrointestinal narrowing.
* Patients who, at any time during the study, are likely to need psychotropic medications apart from the drugs under study.
* Patients who, at any time during the study, are likely to begin structured psychotherapy aimed at ADHD symptoms are excluded. Psychotherapy initiated at least 1 month prior to screening is acceptable.
* Patients who have used a monoamine oxidase inhibitor (MAOI) during the 2 weeks prior to randomization.
* Patients with current or past history of clinically significant hypertension.
* Patients who are currently enrolled in, or discontinued within the last 30 days from a clinical trial involving an off-label use of an investigational drug, or concurrently enrolled in any other type of medical research.
* Patients who have participated in a prior study of LY2216684.

Answer: C