Clinical trial NCT01009255 (phase 2, status: completed)
Conditions: alzheimer's disease
ICD codes: G30.8, G30.9, G30.0, G30.1
Drugs: gsk239512, placebo
SMILES: CN1C(=O)C=C(N2CCC[C@@H](N)C2)N(CC2=C(C=CC=C2)C#N)C1=O
Eligibility criteria:

        A subject will be eligible for inclusion in this study only if all of the following
        criteria apply:

          -  Male or female subjects with a clinical diagnosis of probable Alzheimer's disease in
             accordance with the NINCDS-ADRDA criteria, with symptoms of AD for at least 3 months.

          -  A Haschinski ischaemia score less than or equal to 4.

          -  Has undergone MRI or CT scan in the last 12 months. (For subjects not meeting this
             criteria, as scan will be conducted as part of the screening procedures).

          -  The subject has an MMSE score at Screening of 16 to 24 inclusive.

          -  Male or female aged 50 or above, at the time of signing the informed consent.

          -  If female, the subject must be post-menopausal, i.e. 12 months of spontaneous
             amenorrhea [in questionable cases a blood sample with simultaneous follicle
             stimulating hormone (FSH) greater than 40 MlU/ml and estradiol less than 40 pg/ml
             (<140 pmol/L) is confirmatory] or surgically sterile (documented tubal ligation or
             hysterectomy). [Females on hormone replacement therapy (HRT) and whose menopausal
             status is in doubt will be required to use one of the contraception methods in Section
             8.1 if they wish to continue their HRT during the study. Otherwise, they must
             discontinue HRT to allow confirmation of post-menopausal status prior to study
             enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the
             cessation of therapy and the blood draw; this interval depends on the type and dosage
             of HRT. Following confirmation of their post-menopausal status, they can resume use of
             HRT during the study without use of a contraceptive method.]

          -  Male subjects must agree to use one of the contraception methods listed in Section
             8.1. This criterion must be followed from the time of the first dose of study
             medication until 14 days after the last dose of study medication.

          -  The subject has the ability to comply with the study procedures as judged by the
             investigator.

          -  Subject lives with (or has substantial periods of contact with) a permanent caregiver
             who is willing to attend all visits, oversee the subject's compliance with
             protocol-specified procedures and study medication, and report on subject's status. A
             permanent caregiver is one who is able to provide care to the subject for the duration
             of the study without interruption for more than 1 week at a time. If at times during
             the study the permanent caregiver is unable to look after the subject, this period of
             absence of the caregiver must be covered by another caregiver. A permanent caregiver
             need not be living in the same residence with the subject. For such a caregiver, the
             investigator has to be satisfied that the subject can contact the caregiver readily
             during the times when the caregiver is not with the subject. If in doubt about whether
             a subject's care arrangements are suitable for inclusion, the investigator should
             discuss this with the GSK Medical Monitor.

          -  The subject has provided full written informed consent prior to the performance of any
             protocol specific procedure, or if unable to provide informed consent due to cognitive
             status, full written informed consent on behalf of the subject has been provided by a
             legally acceptable representative.

          -  The caregiver has provided his / her written consent prior to the performance of any
             protocol specific procedure

          -  AST and ALT less than 2xULN; alkaline phosphatase and bilirubin, less than or equal to
             1.5xULN (isolated bilirubin greater than 1.5xULN is acceptable if bilirubin is
             fractionated and direct bilirubin less than 35%).

          -  If the subject is on any prior medications, they should satisfy the requirements in
             Section 9.

        A subject will not be eligible for inclusion in this study if any of the following criteria
        apply:

          -  In the opinion of the investigator, following review of CT/MRI scans in the past 12
             months and completion of neurological review there could be other probable causes of
             dementia which include, but are not limited to:

          -  History and/or evidence (CT or MRI scan performed since the onset of symptoms) of any
             other CNS disorder that could be interpreted as the primary cause of dementia: e.g.
             cerebrovascular disease, structural or developmental abnormality, epilepsy,
             infections, degenerative or inflammatory/demyelinating CNS conditions other than AD.

          -  Clinically significant focal findings on the neurological exam (excluding changes
             attributable to peripheral nervous system injury).

          -  Abnormal result of vitamin B12 and syphilis serology, where this is thought to be the
             cause of, or to contribute to the severity of, the subject's dementia. Subjects should
             be euthyroid based on laboratory results at the screening visit. Subjects maintained
             on thyroid medication must be euthyroid for a period of 2 months prior to the
             screening visit. If laboratory values are outside normal limits, but the investigator
             believes that the thyroid condition is stable and has no impact on cognition, such
             cases will be decided on case by case basis in discussion with the medical monitor.

          -  Diagnosis of possible, probable or definite vascular dementia in accordance with
             National Institute of Neurological Disorders and Stroke-Association Internationale
             pour la Recherche l'Enseignement en Neurosciences (NINDS-AIREN) criteria.

          -  Prior diagnosis of significant psychiatric illness such as schizophrenia or bipolar
             affective disorder with current symptoms related to the diagnoses such that in the
             opinion of the Investigator would interfere with participation in the study, or
             current depression (a score of greater than or equal to 8 on the Cornell Scale for
             Depression in Dementia), or subjects with other psychiatric features (including but
             not limited to having hallucinations) in their AD which in the opinion of the
             investigator, increase risk to safety.

          -  Subjects, who in the investigator's judgement, pose a significant suicide risk.
             Evidence of serious suicide risk may include any history of suicidal behavior in the
             last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the last 2
             months prior to screening.

          -  History or presence of significant sleep disturbance, such as severe insomnia or sleep
             disturbance associated with nocturnal wandering, nocturnal confusion / disorientation
             / agitation, which in the opinion of the investigator, may increase safety risk.

          -  History or presence of known or suspected seizures, unexplained significant loss of
             consciousness within last 6 months. Subjects who had febrile seizures in childhood may
             be included if these ceased by age 10 and they have had no other type of seizure in
             their medical history and have not been on anti-epileptic medications.

          -  History or presence of significant cardiovascular, gastro-intestinal, hepatic, or
             renal disease or other condition known to interfere with the absorption, distribution,
             metabolism, or excretion of drugs, or any other clinically relevant abnormality,
             medical or psychiatric condition, which, in the opinion of the Investigator, makes the
             subject unsuitable for inclusion in the study.

          -  History of alcohol or other substance abuse, according to the Diagnostic and
             Statistical Manual of Mental Disorders - Substance related disorders (DSM-IV) criteria
             within 3 years prior to the onset of AD symptoms, or since the onset of AD symptoms.

          -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
             result within 3 months of screening

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  Uncontrolled hypertension with systolic BP greater than or equal to 160 and/or
             diastolic greater than or equal to 95 mmHg. Subjects with controlled hypertension with
             systolic BP less than 160 mmHg and diastolic less than 95 mmHg for at least 4 weeks
             are acceptable.

          -  Systolic BP less than 100 mmHg and/or diastolic less than 60 mmHg.

          -  Subjects with a QTcB and/or QTcF of greater than 450ms or greater than 480ms if they
             have bundle branch block or other ECG abnormalities which, in the opinion of the
             investigator is clinically significant in that they may increase safety risk.

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period prior to the first dosing day in the current
             study: 30 days, 5 half-lives or twice the duration of the biological effect of the
             investigational product (whichever is longer).

          -  Exposure to more than four new chemical entities within 12 months prior to the first
             dosing day.

          -  History of sensitivity to any of the study medications, or components thereof or a
             history of drug or other allergy that, in the opinion of the investigator or GSK
             Medical Monitor, contraindicates their participation.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within a 56 day period.

          -  Pregnant females as determined by positive urine human chorionic gonadotropin (hCG)
             test at screening or prior to dosing.

          -  Treatment with cholinesterase inhibitors (including Tacrine), memantine or selegiline
             within the last 3 months prior to screening. No patients with AD who are already on
             these medications at the time of screening will be recruited, as it would be unethical
             to withdraw these medications for study participation. Only AD subjects who are not
             yet on these medications, or who have withdrawn from these medications for other
             reasons previously, may be enrolled into this study.

          -  Use of the following medications within the last 30 days or 5 half-lives of these
             medications from screening (prohibited in Section 9.2):

          -  Any other treatments approved in the countries for treatment of cognitive symptoms of
             AD.

          -  Anti-psychotic drugs (typical or atypical dopaminergic antagonists or modulators).

          -  Any CNS stimulants (e.g., modafinil).

          -  Mood stabilization drugs (e.g. lithium, valproate, cabamazepine).

          -  Barbiturates, MAO inhibitors, Gingko biloba and other herbal treatments for cognitive
             impairment.

          -  Potent P-glycoprotein inhibitors (e.g. itraconazole, ketoconazole, cyclosporin,
             loperamide, diltiazem, verapamil, spironolactone, quinidine, bepridil, quinine,
             carvedilol).

          -  Known potent inhibitors or inducers of the CYP3A4 enzyme (e.g., verapamil,
             ketoconazole, cimetidine, rifampin, modafinil).

          -  Anti-cholinergic drugs or drugs which have anti-cholinergic effects (e.g.
             amitriptyline, amantidine).

          -  Anti-histamines which are CNS penetrant.

          -  Chronic sedative medications (greater than or equal to 4 days per week for the past 4
             weeks prior to screening).

          -  Any other investigational drug.

          -  Use of other prescription or non-prescription drugs, including herbal and dietary
             supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5
             half-lives (whichever is longer) prior to the first dose of study medication, unless
             in the opinion of the Investigator and GSK Medical Monitor the medication will not
             interfere with the study procedures or compromise subject safety, or are permitted
             under Section 9).

          -  Subjects who plan to commence treatment with prohibited medications in Section 9.2.

          -  Consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days
             prior to the first dose of study medication until the follow-up visit.

          -  Subjects who have commenced or are already undertaking a cognitive rehabilitation
             programme within 1 month of screening. Subjects who have stopped their cognitive
             rehabilitation programme at least 1 month prior to screening need not be excluded if
             they satisfy other eligibility criteria.

          -  Unwillingness or inability to follow the procedures outlined in the protocol.

          -  Subject or caregiver is an immediate family member or employee of the participating
             Investigator, any of the participating site staff or GSK staff.