A phase 2a study to evaluate the effect of rilapladib (SB-659032)

INTERVENTION: Product Name: rilapladib Product Code: SB‐659032 Pharmaceutical Form: Tablet Current Sponsor code: SB‐659032 Other descriptive name: rilapladib Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 250‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use CONDITION: Alzheimer's Disease ; MedDRA version: 14.1 Level: LLT Classification code 10001896 Term: Alzheimer's disease System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: To examine in an exploratory manner whether rilapladib produces changes in CSF biomarkers that are consistent with effects on increased CNS Aß clearance in AD patients and whether these findings are associated with changes in CSF neurodegenerative markers and selected cognitive endpoints. Primary end point(s): • Change from baseline in CSF Aß42, Aß40 and Aß42/ Aß40 ratios at Week 24.; • Change from baseline in CSF tau and P‐tau measures at Week 24.; • Change from baseline in the CogState battery working memory/executive function composite score at Week 24. Secondary Objective: ‐ To examine the effects of rilapladib on BBB permeability (CSF albumin; quotient), peripheral Aß levels (Aß42 and Aß40) and plasma Lp‐PLA2 activity.; ‐ To further evaluate the effects of rilapladib on cognition.; ‐ To assess the safety and tolerability of rilapladib over a 24 week treatment period. Timepoint(s) of evaluation of this end point: Week 24 SECONDARY OUTCOME: Secondary end point(s): • Change from baseline in CSF albumin quotients at Week 24. ; • Change from baseline in plasma levels of Aß42, Aß40 and ratio Aß42/Aß40 at Week 24. ; • Change from baseline in plasma Lp‐PLA2 activity at Week 24. ; • Change from baseline in CogState battery overall composite score. ; • Change from baseline in CogState battery attention composite score. ; ; Safety Endpoints ; • Assessment of safety and tolerability by analysis of AE data and changes from ; baseline in vital signs, clinical laboratory values, neurological examination, EM ; of peripheral blood mononuclear cells and electrocardiograms (ECGs). ; Timepoint(s) of evaluation of this end point: Week 24 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, including at least one of the following: a. CT: Extensive periventricular and deep white matter lesions: patchy or diffuse symmetrical areas of low attenuation (intermediate density between normal white matter and cerebrospinal fluid), with ill‐defined margins extending to the centrum semiovale, and at least one lacunar infarct. And/Or b. MRI: White matter lesions: extending caps or irregular halo or diffusely confluent hyperintensities or extensive white matter changes And/Or c. Lacunar cases: Multiple lacunes (e.g. > 5) in the deep grey matter.