A Phase 2a Study to Evaluate the Effect of Rilapladib (SB-659032) in Alzheimer's Disease
Condition: Alzheimer's Disease
MeSH terms: Alzheimer Disease
Intervention: 250mg rilapladib; placebo
Intervention description: Experimental Drug; Placebo comparator
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 124.0
Sex: All
Minimum age: 50 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Alzheimer's disease

Summary:

      The study is designed to investigate the effects of rilapladib on biomarkers related to the
      Alzheimer's disease, and cognitive function.
    

Eligibility criteria:

        Inclusion Criteria:

          1. A clinical diagnosis of possible Alzheimer's disease in accordance with the National
             Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease
             and Related Disorders Association (NINCDS-ADRDA) criteria, with radiological (Magnetic
             Resonance Imaging [MRI] or Computed Tomography [CT]) evidence of significant
             cerebrovascular disease (CVD), assessed within the last 12 months

          2. Male or female between 50 and 80 years of age inclusive, at the time of signing the
             informed consent.

          3. Subject has a documented history of at least 6 months of ongoing Alzheimer's disease
             therapy (AChEIs and/or memantine) with stable dosing for at least the last 2 months
             (and with no intent to change for the duration of the study).

          4. Mini-Mental Status Examination (MMSE) score between 20 and 26 at Screening.

          5. Clinical Dementia Rating Scale (CDR) score of 0.5 or 1.0 at Screening.

          6. A female subject is eligible to participate if she is of non-childbearing potential
             defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or
             postmenopausal defined as 12 months of spontaneous amenorrhea; or of child-bearing
             potential and agrees to use acceptable contraception methods

          7. Subject has provided full written informed consent prior to the performance of any
             protocol-specified procedure; or if the subject is unable to provide informed consent
             due to cognitive status, the subject will provide assent and full written informed
             consent will be provided by a legally acceptable representative

          8. The subject has a dedicated caregiver who is willing to supervise participation in the
             study

          9. In the opinion of the investigator, the subject has the ability to comply with study
             procedures (cognitive and other testing) and is fluent in the language used for the
             administration of the cognitive tests.

        Exclusion Criteria:

          1. History and/or evidence of any other CNS disorder that could be interpreted as a cause
             of dementia: e.g. structural or developmental abnormality, epilepsy, infectious,
             degenerative or inflammatory/demyelinating CNS conditions such as, Parkinson's disease
             and frontotemporal dementia

          2. History of significant psychiatric illness such as schizophrenia or bipolar affective
             disorder that in the opinion of the Investigator would interfere with participation in
             the study; major depressive disorder (according to DSM-IV) in the past year; current
             active depression requiring initiation of treatment (or is believed to account for
             substantial degree of cognitive impairment)

          3. Evidence of the following disorders: current vitamin B12 deficiency, positive syphilis
             serology (unless neurosyphilis was ruled out) or active thyroid dysfunction
             (particularly suggestive of hypothyroidism), including abnormally high or low serum
             levels of thyroid stimulating hormone (TSH), where this is thought to be the cause of,
             or to contribute to the severity of the subject's dementia.

          4. History of alcohol or other substance abuse, according to the DSM-IV criteria, or
             recent or remote history of the same if that could be a contributing factor to
             dementia.

          5. History of intra cerebral haemorrhage due to any of the following causes: cerebral
             amyloid angiopathy, uncontrolled hypertension, cerebral arteriovenous malformation,
             coagulopathy, CNS vasculitis or any other condition that the investigator and/or
             medical monitor considers as a relevant risk factor for intracerebral haemorrhage

          6. Recent (i.e.,<6 months from Screening Visit) cardiovascular event defined as:

               1. ST-elevation MI or non-ST-elevation MI, confirmed by cardiac enzyme elevation and
                  ECG changes

               2. coronary revascularization (percutaneous coronary intervention or coronary artery
                  bypass graft )

               3. stroke of any etiology

               4. resuscitated sudden death

               5. prior carotid surgery or stenting procedure

          7. Poorly controlled hypertension despite lifestyle modifications and pharmacotherapy
             (either systolic blood pressure >160mmHg or diastolic blood pressure >110mmHg)

          8. QTcB interval >450 msec; or QTcB > 480 msec in subjects with bundle branch block based
             on ECG assessment at the Screening visit.

          9. HbA1c >12.0 at Screening, or uncontrolled diabetes in the opinion of the investigator.

         10. History of glaucoma or any other findings in the baseline eye exam that, in the
             opinion of the investigator, would exclude the subject from participation in the
             study.

         11. History of adult asthma (or reactive airway disease) manifested by bronchospasm in the
             past 6 months, or currently taking regular anti-asthmatic medication(s).

         12. Previous history of anaphylaxis, severe allergic reaction or history of
             hypersensitivity to any of the components of the formulation.

         13. Significant abnormalities on clinical chemistry, haematology or urinalysis at
             Screening, including clinically significant anaemia.

         14. History of chronic viral hepatitis (including presence of B surface antigen or
             hepatitis C antibody), or other chronic hepatic disorders.

         15. Abnormal Screening blood tests exceeding any of the limits defined below:

               1. Alanine transaminase (ALT) or aspartate transaminase (AST) >1.5 x the upper limit
                  of normal (ULN)

               2. Alkaline phosphatase (AP) and bilirubin >1.5X ULN (isolated bilirubin >1.5x ULN
                  is acceptable if bilirubin is fractionated and direct bilirubin <35%).

               3. Calculated creatinine clearance < 30 ml/min (per Cockcroft & Gault) at Screening

         16. Other clinically significant abnormality on physical (including neurological),
             laboratory or ECG examination that could be detrimental to the subject in the opinion
             of the Investigator or could compromise the integrity of the study.

         17. Planned major surgery within the study period.

         18. Use of systemic steroids or other immunosuppressants within the last 30 days prior to
             screening.

         19. Current treatment with barbiturates, MAO inhibitors, butyrophenones, phenothiazines
             and other "conventional" antipsychotic within 30 days or 5 half-lives prior to
             Screening, whichever is longer.

         20. Treatment with antidepressants, (other than MAO inhibitors), thyroid hormones,
             atypical antipsychotics (e.g. risperidone), benzodiazepines and other sedatives /
             hypnotics unless prescribed at a stable dose for at least 2 months prior to Screening.
             Note: Benzodiazepines or other sedatives/hypnotics (including antihistamines) with
             half-life less than 6 hours can be taken on a prn (as needed) basis but must not be
             taken within 5 half lives prior to cognitive testing.

         21. Current treatment with known potent inhibitors of CYP3A4 (e.g. ketoconazole, rifampin,
             modafinil).

         22. Current treatment with known potent Pgp inhibitors (itraconazole, ketoconazole,
             cyclosporin, loperamide, diltiazem, verapamil, spironolactone, quinidine, bepridil,
             quinine, carvedilol)

         23. Cognitive tasks prescribed for cognitive rehabilitation and performed under medical
             supervision in the 6 months prior to screening and/or during study

         24. Investigational medications or devices including symptomatic AD treatment during the
             60 days prior to the Screening visit, or within 5 half-lives of use of the
             investigational drug prior to the Screening Visit, whichever is longer.

         25. Participation in another investigational drug (with the exception of anti-amyloid
             monoclonal antibodies [mAbs]) or device study where subject was treated chronically
             (i.e. > 1 single dose) with a study agent intended to impact AD progression during the
             12 months prior to the Screening visit.

               1. Subjects who participated in an investigational drug study that involved chronic
                  dosing with a monoclonal antibody at any time in the past are excluded from this
                  study, unless it is known that they received placebo during the previous study.

               2. Subjects who participated in previous single-dose studies of anti-amyloid mAbs
                  will be permitted provided the subject's dose of the mAb is at least 5 half-lives
                  removed; the subjects did not experience any moderate adverse events classified
                  as possibly drug-related or any serious adverse event during that study; the
                  subject did not drop out of the previous study (i.e. completed all safety
                  assessments)

         26. Subjects, who in the investigator's judgement, pose a significant suicide risk (e.g.
             history of suicidal behaviour in the last 6 months and/or any suicidal ideation of
             type 4 or 5 on the C-SSRS in the last 2 months).

         27. Subject or caregiver is an immediate family member or employee of the participating
             Investigator, any of the participating site staff or GSK staff.

         28. Any contraindication to lumbar puncture or insertion of CSF catheter, including but
             not limited to

               1. Thrombocytopenia or other coagulation disorders (including subjects receiving
                  coumarin-derived anti-coagulants or low-molecular-weight heparin).

               2. The presence of cutaneous or soft tissue infection overlying or adjacent to the
                  site of lumbar puncture.

               3. Previous spinal surgery that could complicate access to the subarachnoid space.

               4. Suspicion of increased intracranial pressure due to a cerebral mass.