Please select the eligibility criteria that correspond to the clinical trial below.
Title: Effect of γ-Secretase Inhibition on the Progression of Alzheimer's Disease: LY450139 Versus Placebo
Brief Summary: Alzheimer's disease (AD) is a fatal degenerative disease of the brain for which there is no cure. AD causes brain cells to die. AD is thought to be caused by an excess of beta-amyloid (β-amyloid), a sticky protein in the brain that forms amyloid plaques. At autopsy, AD patients are required to have these amyloid plaques in the brain in order to have a definitive diagnosis of AD. Inhibiting the enzyme gamma-secretase (γ-secretase) lowers the production of β-amyloid. Semagacestat (LY450139) is a functional γ-secretase inhibitor and was shown to lower β-amyloid in blood and spinal fluid in humans tested thus far and in blood, spinal fluid, and brain in animals tested thus far. This study used several different tests to measure the effect of semagacestat on both β-amyloid and amyloid plaques for some participants. The build-up of amyloid plaques was measured by a brain scan that takes a picture of amyloid plaques in the brain. Other tests measured the overall function of the brain and brain size in some participants. In this trial, participants who initially received placebo (inactive sugar pill) were, at a certain point in the study, switched over to active drug, semagacestat. In other words, all participants could eventually receive active drug. Participation could last approximately 2 years. Participants taking approved AD medications were permitted to participate in this study and continue taking these medications during the study. All participants who completed this study had the option to continue receiving semagacestat by participating in an open-label study.

Preliminary results from this study (H6L-MC-LFAN \[LFAN\]) and another similar study (H6L-MC-LFBC \[LFBC; NCT00762411\]) showed semagacestat did not slow disease progression and was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living. Study drug was stopped in all studies. Studies LFAN, LFBC, and open-label H6L-MC-LFBF (LFBF; NCT01035138) were amended to continue collecting safety data, including cognitive scores, for at least 7 months. The Clinical Trial Registry (CTR) will reflect results of analyses from the original LFAN protocol in addition to those from the amended LFAN protocol.


Options:
A: Inclusion criteria

* Probable Alzheimer's disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria), with Mini-Mental score of 5-28 inclusive
* A medication for agitation is appropriate, in the opinion of the study physician
* Clinically significant agitation for which either

  1. the frequency of agitation as assessed by the Neuropsychiatric Inventory (NPI) is 'Very frequently', or
  2. the frequency of agitation as assessed by the NPI is 'Frequently' AND the severity of the agitation as assessed by the NPI is 'Moderate', or 'Marked'
* Provision of informed consent for participation in the study by patient or surrogate (if necessary) and caregiver
* Availability of primary caregiver, who spends several hours a week with the patient and supervises his/her care, to accompany the patient to study visits and to participate in the study
* No change to Alzheimer's disease (AD) medications within the month preceding randomization, including starting, stopping, or dosage modifications

Exclusion criteria

* Meets criteria for Major Depressive Episode by Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV (TR)) criteria
* Presence of a brain disease that might otherwise explain the presence of dementia, such as extensive brain vascular disease, Parkinson's disease, dementia with Lewy bodies, traumatic brain injury, or multiple sclerosis
* Psychosis (delusions or hallucinations) requiring antipsychotic treatment in the opinion of the study physician
* Prolonged measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QT interval)
* Treatment with citalopram is contraindicated in the opinion of the study physician
* Failure of past treatment with citalopram for agitation after adequate trial at a minimally accepted dose (greater than or equal to 20 mg/day)
* Treatment with a medication that would prohibit the safe concurrent use of citalopram, such as Monoamine oxidases (MAO) inhibitors
* Need for psychiatric hospitalization or suicidal
* Current participation in a clinical trial or in any study that may add a significant burden or affect neuropsychological or other study outcomes
* Current treatment with antipsychotics, anticonvulsants (other than dilantin), other antidepressants (other than trazodone, less than or equal to 50 mg per day at bedtime), benzodiazepines (other than lorazepam), or psychostimulants
* Any condition that, in the opinion of the study physician, makes it medically inappropriate or risky for the patient to enroll in the trial
B: Inclusion Criteria:

* Probable AD by National Institute of Neurological Disorders and Stroke (NINDS)-Alzheimer's Disease and Related Disorder Association (ADRDA) criteria.
* Males or females.
* \> 55 and \< 90 years of age.
* Weight \> 40 kg (88.2 lbs.).
* Residing in the community at Screen and Baseline. Participants may reside in assisted living facilities, but not in long-term care nursing facilities or assisted living facilities that provide intensive support for people with dementia nor may they reside in a secure unit necessary for behavioral management.
* Mini Mental State Examination (MMSE) at Screen and Baseline 12-20 inclusive.
* Computed tomography (CT) or magnetic resonance imaging (MRI) since onset of dementia consistent with the diagnosis of probable AD. Single lacunes in non-critical areas and non-specific white matter changes that are interpreted as age-related are not grounds for exclusion. Any ambiguous scan results must be reviewed with the Project Director.
* Fluent in English or Spanish.
* Supervision available for study medication.
* Study partner to accompany subject to all visits.
* Study partner must have in-person contact with the participant \> 2 days/week.
* Able to ingest oral medication.
* Total Neuropsychiatric Inventory (NPI) score for previous 4 weeks \< 8 at Screening, and for the period between Screening and Baseline.
* NPI item score for the items assessing delusions, hallucinations, agitation/aggression all greater than or equal to 1 for 4 weeks prior to Screening (less than once/week and mild severity at most) and for the period between Screening and Baseline.
* Scores of greater than or equal to 1 for items rating delusions, hallucinations, and agitation/aggression taken from the NPI, modified to assess these features since onset of illness. This will be derived from a second interview with the modified NPI. (Agitation/psychosis during episodes of delirium are not considered exclusionary.).

Exclusion Criteria:

Exceptions to these criteria may be considered on a case-by-case basis at the discretion of the Project Director:

* Non-AD dementia.
* Females of child-bearing potential.
* Residence in a long-term care facility or equivalent at Baseline.
* Presence or previous history of agitation or psychosis requiring active psychotropic medication since the illness began.
* History of clinically significant stroke.
* Current evidence or history in past two years of: focal brain lesion, head injury with loss of consciousness or Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse.
* Sensory impairment that would prevent subject from participating in or cooperating with the protocol.
* Medical contraindications to study participation.
* Use of another investigational agent within two months prior to Screening.
* Evidence of any significant clinical disorder or laboratory finding that renders the subject unsuitable for receiving an investigational new drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, metabolic, renal, or other systemic disease or laboratory abnormality.
* Clinical contraindication to the use of valproate (e.g., known hypersensitivity or allergic reactions, severe neutropenia, severe hepatic disease, or urea cycle disorder. A urea cycle disorder should be considered in patients with history of unexplained encephalopathy following protein meals, or family history of urea cycle disorder).
* History of seizure within past 5 years prior to Screening.
* Platelet count \< 100,000/mm\^3.
* International Normalized Ratio (INR) \> 1.2 or partial thromboplastin time (PTT) \> 40 seconds.
* Active neoplastic disease. Exceptions: skin tumors other than melanoma are not excluded; patients with stable prostate cancer may be included at the discretion of the Project Director; women who have been treated for breast cancer and have no metastases and whose survival is expected to exceed 2 years may be considered for inclusion on a case-by-case basis in consultation with the Project Director; patients with purely localized bladder wall cancers may be included at the discretion of the Project Director.

Excluded Medications:

* Use of psychotropics for treatment of agitation or psychosis. Antidepressants used in stable doses for 3 months prior to Screening to treat depression or anxiety, but not agitation, will be permitted. Low dose sedatives for sleep, but not agitation, will be permitted. Cholinesterase inhibitors used in stable doses for at least 3 months prior to Screening are permitted.
* Regular use of narcotic analgesics within 3 months of Screening.
* Anti-parkinsonian medications (e.g. levodopa, selegiline, pergolide, bromocriptine, pramipexole) within 2 months of Screening.
* Use of drugs with significant central anticholinergic or antihistaminic effects (eg, benztropine, trihexyphenidyl, dicyclomine, diphenhydramine, cyproheptadine, diphenoxylate, hydroxyzine, meclizine, prochlorperazine, promethazine) within 2 months of Screening.
* Use of other investigational drug studies within two months prior to Screening.
* Use of other anticonvulsants within 5 years prior to Screening.
* Use of zidovudine at any time.
* Use of tricyclic antidepressants within 1 month prior to Screening.
* Regular use of high doses of salicylates at Screening (\> 1,300 mg/d).
* Vitamin E \> 2,100 IU/d within 1 month prior to Screening.
* Warfarin use is permitted when approved by the Project Director and INR and PTT criteria are met.
C: Inclusion Criteria:

* Meets criteria for mild to moderate Alzheimer's disease (AD) with Mini-Mental State Examination (MMSE) score of 16-26 at Visit 1
* Modified Hachinski Ischemia Scale score of less than or equal to 4
* Geriatric Depression Scale score of less than or equal to 6
* A magnetic resonance imaging (MRI) or computerized tomography (CT) scan in the last 2 years with no findings inconsistent with a diagnosis of AD
* If female, must be without menstruation for at least 12 consecutive months or have had both ovaries removed

Exclusion Criteria:

* Is not capable of swallowing whole oral medication
* Has serious or unstable illnesses
* Does not have a reliable caregiver
* Chronic alcohol or drug abuse within the past 5 years
* Has ever had active vaccination for AD
D: Inclusion Criteria:

* diagnosis of mild to moderate stage Probable Alzheimer's disease
* on a stable dose of a cholinesterase inhibitor medication for at least 30 days
* clinically elevated levels of apathy as measured by the Frontal Systems Behavior Scale

Exclusion Criteria:

* diagnosis of Major Depression
* focal brain lesion on neuroimaging
* history of significant substance abuse
* history of significant head trauma with loss if consciousness \>10 minutes

Answer: C