A Phase 2 Clinical Study to Investigate Effects of Darapladib in Subjects With Diabetic Macular Edema

• Change from baseline in Visual Acuity as measured by ETDRS BCVA [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Mean change from baseline in ETDRS Best Corrected Visual Acuity (BCVA) after 3 months of treatment
• Change from baseline in Spectral Domain Optical Coherance Tomography [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Mean change from baseline in SD-OCT after 3 months of treatment

• Changes in Retinal Anatomy [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Changes in retinal anatomy as assessed by fluorescein angiography and fundus photography and SD-OCT in the study eye
• Safety and Tolerability as assessed by change from baseline in outcome measures [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Safety and tolerability as assesed by: change from baseline in blood pressure and heart rate; assessed by change from baseline in complete ophthalmic exam and visual acuity; assessed by change from baseline in clinical laboratory tests; assessed by change from baseline in the collection of adverse events
• Changes in Pharmacodynamic LP-PLA2 enzyme inhibition [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Changes over 3 months in the study of LP-PLA2 Enzyme inhibition as data permit
• Peak plasma concentration (Cmax) of study drug [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Plasma Pharmacokinetic parameters of darapladib as data permit
• Plasma concentration versus time curve (AUC) of study drug [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Plasma Pharmacokinetic parameters of darapladib as data permit

• Changes in Retinal Anatomy [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Changes in retinal anatomy as assessed by fluorescein angiography and fundus photography and SD-OCT in the study eye
• Safety and Tolerability as assessed by change from baseline in blood pressure and heart rate [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Safety and tolerability assessed by complete ophthalmic examination, visual acuity, vital sign measures, clinical laboratory tests, clinical monitoring and adverse event reporting
• Changes in Pharmacodynamic LP-PLA2 enzyme inhibition [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Changes over 3 months in the study of LP-PLA2 Enzyme inhibition as data permit
• Safety and Tolerability as assessed by change from baseline in complete ophthalmic examination and visual acuity [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Safety and tolerability assessed by complete ophthalmic examination, visual acuity, vital sign measures, clinical laboratory tests, clinical monitoring and adverse event reporting
• Safety and Tolerability as assessed by change from baseline in clinical laboratory tests [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Safety and tolerability assessed by complete ophthalmic examination, visual acuity, vital sign measures, clinical laboratory tests, clinical monitoring and adverse event reporting
• Safety and Tolerability as assessed by change from baseline in the collection of adverse events [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Safety and tolerability assessed by complete ophthalmic examination, visual acuity, vital sign measures, clinical laboratory tests, clinical monitoring and adverse event reporting
• Peak plasma concentration (Cmax) of study drug [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Plasma Pharmacokinetic parameters of darapladib as data permit
• Plasma concentration versus time curve (AUC) of study drug [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  Plasma Pharmacokinetic parameters of darapladib as data permit

The purpose of this study is to characterize the systemic and ocular safety and tolerability, pharmacokinetics, exploratory efficacy and pharmacodynamics of 3 months of repeat administration of oral darapladib in diabetic macular edema patients with centre involvement.

This is a multi-national, multi-centre, randomised, double-masked, placebo-controlled, parallel-group study of repeat oral administration of 160 mg darapladib for 3 months in adult subjects with DME with centre involvement.

Eligible subjects will be randomised in a 2:1 ratio of active treatment to placebo, with the placebo group to allow a comparison of safety between treatment arms and to minimize the open label effect that can be observed with the visual acuity endpoint.

The primary aim of the study is to determine the effect of repeat doses of darapladib on the mean change from baseline of both best-corrected visual acuity (BCVA) and spectral domain OCT (SD-OCT) centre subfield. The study eye will be examined for changes over the life of the study. As this investigational treatment is systemic, the fellow eye may be examined in tandem to provide additional data.

• Drug: darapladib
  Experimental compound 160 mg dose
• Drug: placebo
  Placebo to match

• Experimental: darapladib
  darapladib dosed at 160 mg once daily
  Intervention: Drug: darapladib
• Placebo Comparator: placebo
  Placebo to match once daily
  Intervention: Drug: placebo

Inclusion Criteria:

• A female subject is eligible to participate if she is of: Non-childbearing potential or child-bearing potential and agrees to contraception for an appropriate period of time
• Diagnosis of diabetes mellitus (type 1 or type 2)
• Confirmation of DME in the study eye by angiography
• Confirmation of retinal thickening in the study eye by study doctor
• Best corrected visual acuity score of 78-24 letters in the study eye

Exclusion Criteria:

• Additional eye disease in the study eye that could compromise study assessments
• Intraocular surgery, or laser photocoagulation in the study eye within 3 months of dosing
• Uncontrolled intraocular pressure in the study eye despite treatment with glaucoma medication
• Uncontrolled diabetes
• Certain types of liver disease
• Severe reduction in kidney function OR removal of a kidney OR kidney transplant
• Blood pressure higher than normal despite lifestyle changes and treatment with medications
• Certain medications that may interfere with the study medication or eye assessments (these will be identified by the study doctor)
• Current severe heart failure
• Severe asthma that is poorly controlled with medication
• Previous severe allergic reaction to food, medications, drink, insect stings, etc
• If both birth parents are at least 50% Japanese, Chinese, or Korean ancestry, must have a blood sample collected for Lp-PLA2 activity. Those with Lp-PLA2 activity less than or equal to 20.0 nmol/min/mL are excluded
• Recent participation in a study of an investigational medication
• Any other reason the investigator deems the subject should not participate in the study
• Other protocol-defined inclusion/exclusion criteria may apply