Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Double-blind, Parallel Group, Randomized, Placebo Controlled Study of the Efficacy of Circadin® 2mg in Patients With Mild to Moderate Alzheimer Disease (AD) Treated With Acetylcholinesterase (AChE) Inhibitor
Brief Summary: The aim of this exploratory randomized, placebo controlled study is to evaluate the efficacy of Circadin® 2mg in patients with mild to moderate Alzheimer Disease (AD) treated with the acetylcholinesterase (AChE) inhibitor. The effects of add-on Circadin® 2mg vs. placebo on the decline in cognitive skills and global functioning, as well as on daytime somnolence and will be assessed.


Options:
A: Inclusion Criteria:

* Male or post-menopausal female out-patients diagnosed with Alzheimer's disease
* Patients should have mild to moderate dementia as evidenced by a Mini-Mental State Examination score of 10-24 inclusive at screening
* The patient must show a history of cognitive decline that has been gradual in onset and progressive over a period of at least six months
* There must be evidence of sustained memory deterioration in an otherwise alert patient, plus additional impairment in at least one of the following five areas: orientation, judgement and problem solving, functioning in community affairs, functioning in home and hobbies, or functioning in personal care
* The caregiver resides with the patient and is able to speak with the investigative team about the patient's activities, medication use and adverse events. In addition, the caregiver will participate in assessment interviews and complete questionnaires for themselves and the patients. The caregiver will monitor their own sleep, the patient's sleep, and complete questionnaires regarding sleep patterns and care giving activities

Exclusion Criteria:

* Neurodegenerative disorders such as Parkinson's disease, Pick's disease or Huntington's chorea, Down's syndrome, Creutzfeldt-Jacob disease
* One of the following conditions possibly resulting in cognitive impairment: acute cerebral trauma or injuries secondary to chronic trauma, hypoxic cerebral damage, e.g., post resuscitation (cardiac arrest, post anesthesia, secondary to severe self-poisoning episode, or secondary to severe hypovolemia)
* Patients with the following medical conditions: any history of epilepsy or convulsions except for febrile convulsions during childhood, clinically significant: endocrine disease, metabolic disease, psychiatric disease, cardiovascular disease, peptic ulcer disease, hepatic disease, renal disease, pulmonary disturbances or urinary outflow obstruction
* Use of any agent for the treatment of dementia (approved, experimental or over the counter agents) including patients who have previously received tacrin, donepazil, metrifonate, rivastigmine tartrate, galantamine, or memantine for treatment of Alzheimer's disease
B: Inclusion Criteria:

* Diagnosis of probable Alzheimer's disease based on either a) the National Institute on Aging - Alzheimer's Association (NIA-AA) criteria or b) the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, (DSM-5) criteria for AD.
* Have sleep complaints that meet DSM-5 criteria for a diagnosis of insomnia (e.g., difficulty initiating or maintaining sleep, and/or early morning awakenings with inability to return to sleep for at least 3 nights per week for ≥ the past 3 months prior to study start, despite adequate opportunity for sleep) based on the investigator's judgment and by the participant's sleep history, as assessed by the sleep items on the Insomnia Diagnostic Interview and Sleep History assessments.
* Be willing to stay overnight in a sleep laboratory and must be willing to stay in bed for at least 8 hours for PSG testing
* Regular bedtime is between 8 pm and 1 am and is willing to maintain it for the duration of the trial
* Be able and willing to wear an activity/sleep watch on the wrist throughout the day and night
* Based on the investigator's judgment the participant should: a) be able to speak, read, and understand the language of the trial staff and the informed consent form; b) possess the ability to respond verbally to questions, follow instructions, and complete study assessments; c) be able to adhere to dose and visit schedules.
* Have a reliable and competent trial partner (e.g., spouse, family member, or other caregiver) who:
* a) Signs their own informed consent, after the trial has been explained to them, and before Screening assessments;
* b) Is not diagnosed with dementia;
* c) Resides with the participant overnight and has a close relationship with the participant (defined as daily face-to-face contact, at least 15 waking hours a week for at least 3 months prior to Visit 1);
* d) Accompanies the participant to and from trial visits and stays overnight at the sleep laboratory for the 3 PSG visits;
* e) Assumes responsibility for trial medication procedures (e.g., witnessing and/or helping to administer trial medication, assessing compliance), for completion of the sleep e-diary each morning, and oversight of the activity/sleep watch worn throughout the trial;
* f) Answers questions regarding the trial partner's sleep quality and trial partner's distress related to the subject's behaviors.
* If female, not of childbearing potential as indicated by one of the following: has reached natural menopause, defined as:
* a) ≥45 years of age with either: ≥12 months of spontaneous amenorrhea OR ≥6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels \> 40 IU/L as determined by the central laboratory
* b) has had a hysterectomy;
* c) has had bilateral tubal ligation; or
* d) has had a bilateral oophorectomy (with or without a hysterectomy) and greater than 6 weeks have passed since the surgery
* Be willing to provide a blood sample for Apolipoprotein E (APOE) genotyping

Exclusion Criteria:

* Apnea Hypopnea Index (AHI) score \> 30 or Periodic Leg Movements with Arousal per hour of Sleep (PLMA) \> 30.
* Resides in a nursing home (or similar institutional facility); assisted-living facilities are not excluded if full-time nursing care is not required.
* Has a Modified Hachinski Ischemia Scale (MHIS) Score \> 4 at Screening (i.e., evidence of vascular dementia)
* Has a known history of recent (or past) stroke that in the investigator's opinion confounds the diagnosis of either AD or insomnia
* Has evidence of a clinically relevant neurological disorder other than the disease being studied (i.e., probable AD) at Screening, including but not limited to: vascular dementia, parkinsonism, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear palsy, neurosyphilis, dementia with Lewy bodies, other types of dementia, mental retardation, hypoxic cerebral damage, cognitive impairment due to other disorders, or history of head trauma with loss of consciousness that either led to persistent cognitive deficits or in the opinion of the investigator confounds the diagnosis of either AD or insomnia.
* Has a history of seizures or epilepsy within the last 5 years before study start
* Has a history or diagnosis of any of the following conditions, in the opinion of the investigator:
* Narcolepsy
* Cataplexy (familial or idiopathic)
* Circadian Rhythm Sleep Disorder
* Parasomnia including nightmare disorder, sleep terror disorder, sleepwalking disorder
* Rapid eye movement (REM) behavior disorder
* Significant degree of sleep-related Breathing Disorder (i.e., AHI \>30, and/or use of Continuous Positive Airway Pressure \[CPAP\] or Bilevel Positive Airway Pressure \[BIPAP\])
* Periodic Limb Movement Disorder
* Restless Legs Syndrome
* Primary Hypersomnia
* Excessive Daytime Sleepiness (EDS) characterized by uncharacteristic chronic and persistent sleepiness throughout the day
* Has a clinically significant movement disorder, such as akinesia, that would affect the activity/sleep watch differentiation of sleep and wakefulness
* In the opinion of the investigator, has difficulty sleeping primarily due to a confounding medical condition. NOTE: "Medical Conditions" may include chronic pain syndromes, chronic migraine, cardiac disease, nocturia (\> 3 times/night), asthma, gastroesophageal reflux disease (GERD), or hot flashes.
* Has evidence of a current episode of major depression based on investigator's judgment. Major depression in remission is not exclusionary.
* Has any of the following based on clinician interview and DSM-5 criteria:
* Lifetime history of bipolar disorder, a primary psychotic disorder, or posttraumatic stress disorder; or,
* A psychiatric condition requiring treatment with a prohibited medication; or,
* Other psychiatric condition that, in the investigator's opinion, would interfere with the subject's ability to participate in the study.
* Is at imminent risk of self-harm, based on clinical interview and responses on the Columbia-Suicide Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the investigator. Subjects must be excluded if they report suicidal ideation with intent, with or without a plan or method in the past 2 months or suicidal behavior in the past 6 months.
* Has a history of alcoholism or drug dependency/abuse within the last 5 years of study start
* Has a recent history (within the 6 months prior to Screening) of regular consumption (3 or more days per week) of either:
* More than 2 alcoholic beverages per day or alcohol consumption within 3 hours prior to bedtime
* More than \> 600 mg caffeine a day (e.g., 4 standard 8-ounce cups of brewed coffee, or consumes caffeine after 4pm (16:00)
* Consumes the equivalent of \>15 cigarettes a day and the investigator confirms that the participant's insomnia is in part the result of tobacco consumption (e.g., participants unable to refrain from smoking during the night, participants who interrupt sleep to smoke or use tobacco products, or participants who require a cigarette within 30 minutes of waking in the morning).
* Has a history of excessive daytime napping (defined as more than 3 hours a day for more than 3 days of the week based on trial partner estimates, on average for the past 4 weeks).
* Has a recent or ongoing, uncontrolled, clinically significant medical condition or major surgery where participation in the trial would pose a significant medical risk to the subject within 3 months of study start, such as: conditions including but not limited to diabetes, hypertension, Human Immunodeficiency Virus (HIV) or other relevant infections, thyroid or endocrine disease, Chronic Obstructive Pulmonary Disease (COPD), delirium, congestive heart failure, angina, cardiac or gastrointestinal disease, or renal disease requiring dialysis. Note: controlled co-morbid conditions (including diabetes, hypertension, heart disease, etc.) are not exclusionary if stable within 3 months of the study start. All concomitant medications, supplements, or other substances must be kept as stable as medically possible during the trial. Urinary tract infections at study start are not exclusionary if adequately treated.
* Major surgery including not limited to abdominal, thoracic, cardiac or orthopedic surgery, or any procedure requiring general anesthesia
* Has a history of hepatitis or liver disease that, in the opinion of the investigator, has been active within the 6 months prior to study start.
* Has a known allergy or hypersensitivity to suvorexant or to any of the formulation components
* Has a history of hypersensitivity or idiosyncratic reaction to more than 3 chemical classes of drugs, including prescriptions and over-the-counter medications.
* Has donated blood products or has had phlebotomy of \>300 mL within 8 weeks of study start, or intends to donate or receive blood products during participation in the study.
* History of malignancy within the 5 years prior to study start, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, localized prostate cancer, who has undergone potentially curative therapy with no evidence of recurrence for \>=3 year post-therapy, and who is deemed at low risk for recurrence by her/his treating physician.
* Is pregnant, is attempting to become pregnant, or is nursing children
* Has a Body Mass Index (BMI) \> 40 kg/m\^2
* Is currently participating or has participated in a study with an investigational compound or device within 30 days of signing informed consent
C: Inclusion Criteria:

1. Written informed consent as dictated by local legal circumstances.
2. Age range: adult patients between 50-85 years of age.
3. Gender: men and women. Women of child bearing potential or within two years of the menopause must have a negative urine pregnancy test at the Screening Visit.
4. A documented history of confirmed Alzheimer's disease
5. Dementia severity: MMSE score \> 15,
6. Stable AChE inhibitor dose for 2 months prior to Screening visit.
7. Stable medications for non-excluded concurrent medical conditions for four weeks prior to the screening visit.
8. Stable doses of B12 and/or Folic acid supplements for at least 3 months prior to enrollment and throughout the study.
9. Cranial image: no evidence of focal disease to account for dementia (established by CT, PET or MRI). If there is no such available scan (CT, PET or MRI), one must be performed prior to enrollment.
10. Health: Physically acceptable for the study with no pathology likely to occur during or immediately after the study, as confirmed by medical history and exam and ECG.
11. Clinical laboratory values must be within normal limits, or judged not clinically significant by the investigator.
12. Residence: Stable home situation with no planned move during the 28-week investigational period.
13. A family member or a regular caregiver that will be available for visits and will ensure compliance. The caregiver must speak fluent Hebrew, Russian or English.
14. Ability to ingest oral medication and participate in all scheduled evaluations.
15. Ability to spend 2 daily hours outdoors exposed to sunlight.

Exclusion Criteria:

1. Severe agitation.
2. Unstable medical condition, mental retardation.
3. moderate to severe depression as defined by DSM-IV
4. Use of benzodiazepines or other hypnotics during the study and the preceding four weeks.
5. Use of Circadin® during the two weeks prior to study enrollment.
6. Pharmacological immunosuppression.
7. Participation in a clinical trial with any investigational agent within two months prior to study enrollment.
8. Alcoholism.
9. Known or suspected hypersensitivity to exogenous melatonin or melatonin receptor agonists.
10. Patients with rare hereditary problems of galactose intolerance, the LAPP lactose deficiency or glucose mal absorption.
11. Renal Failure with creatinine \>150 micromol/l.
12. Hepatic Failure with ASAT; ALAT; GGT levels above three times the upper normal limit.
13. Clinically significant abnormal laboratory findings which have not been approved by the Safety Officer (sponsor)
14. Other serious diseases that could interfere with patient assessment.
15. Caregivers who are unwilling or unable to give informed consent or otherwise fulfill requirements of the study.
16. Untreated B12 and/or Folic acid deficiency.
D: Inclusion Criteria:

* Patient and study partner to sign informed consent before initiation of any study-related procedures.
* Clinical diagnosis of Alzheimers (AD) or mild cognitive impairment (MCI) disease.
* Single caregiver for at least 6 months prior to Screening, capable of accompanying the patient on clinic visits as needed. The caregiver must either be living with or visiting the patient at least 10 hours per week, split over multiple (at least 2) days, for the duration of the study.
* Single study partner, for at least several months prior to Screening, capable of accompanying the patient on clinic visits as needed. The study partner must either be living with or visiting the patient at least 3 days per week for the duration of the study.
* A body mass index (BMI=weight/height2) of 18 kg/m2 to 32 kg/m2.

Exclusion Criteria:

* Significant neurological disease or dementia other than AD or MCI.
* Current episode or symptoms of major depressive disorder or other major psychiatric disorder.
* History of self-reported sleep duration of less than 4 hours per night or less than 4 hours average total sleep time per night during Baseline PSG assessment.
* History or present symptoms of a sleeping disorder such as sleep apnea.
* History of cancer in the last 5 years.
* Use of anti-AD drugs (including off-label drugs and herbal medications) with the exception of donepezil, memantine, and/or rivastigmine transdermal system, as monotherapy or in combination in the following conditions: treatment with donepezil (5 mg to 10 mg daily), memantine, and/or rivastigmine transdermal system or combination regimens for at least 3 months and a stable dose(s) for the last 2 months prior to randomization is allowed.

Answer: C