The TIME-2b Study: A Study of AKB-9778 (Razuprotafib), a Novel Tie 2 Activator, in Patients With Non-Proliferative Diabetic Retinopathy (NPDR)

• AKB-9778 (Drug): Subcutaneous AKB-9778 15mg
• Placebo (Drug): Subcutaneous Placebo

Primary outcomes

• Percentage of Subjects With an Improvement in Study Eye Severity of Diabetic Retinopathy (DR) (ETDRS DR Severity Score or DRSS) of ≥ 2 Steps [Baseline to Week 48]: Change from baseline to Week 48 in Diabetic Retinopathy Severity Scale Score in Study Eye by visit in the modified intent-to-treat population. ETDRS DR severity levels 10-85; ETDRS Steps 1-12

Secondary outcomes

• Summary of Subjects With a Worsening in the Study Eye DRSS of ≥ 2 Steps at Week 48 [Baseline to Week 48]: Worsening of Diabetic Retinopathy Severity Score (DRSS) severity of ≥ 2 steps in study eyes at Week 48 (compared to placebo group) Grading will follow Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) criteria. DRSS grades ranging from 10-85 will be converted to an ordinal score ranging from 1-11. ETDRS DRSS Level 10 = No retinopathy ETDRS DRSS Level 20 = Very mild NPDR ETDRS DRSS Level 35 = Mild NPDR ETDRS DRSS Level 43 = Moderate NPDR ETDRS DRSS Level 53 = Severe NPDR ETDRS DRSS Level 61 = Mild PDR ETDRS DRSS Level 65 = Moderate PDR ETDRS DRSS Level 71-75 = High-Risk PDR ETDRS DRSS Level 81-85 = Advanced PDR
• Mean Change From Baseline in DRSS in the Study Eye at Week 48 [Week 48]: Mean change from baseline in Diabetic Retinopathy Severity Score (DRSS) in the study eye at week 48. Note: Observed values at Week 48 instead of change from baseline values at Week 48 were analyzed Grading will follow Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) criteria. DRSS grades ranging from 10-85 will be converted to an ordinal score ranging from 1-11. ETDRS DRSS Level 10 = No retinopathy ETDRS DRSS Level 20 = Very mild NPDR ETDRS DRSS Level 35 = Mild NPDR ETDRS DRSS Level 43 = Moderate NPDR ETDRS DRSS Level 53 = Severe NPDR ETDRS DRSS Level 61 = Mild PDR ETDRS DRSS Level 65 = Moderate PDR ETDRS DRSS Level 71-75 = High-Risk PDR ETDRS DRSS Level 81-85 = Advanced PDR
• Summary of Subjects With an Improvement or Worsening in the Study Eye DRSS of ≥ 3 Steps at Week 48. [Baseline to Week 48]: Summary of subjects with an improvement or worsening in the study eye Diabetic Retinopathy Severity Score (DRSS) of ≥ 3 steps at Week 48 (compared to placebo) Grading will follow Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) criteria. DRSS grades ranging from 10-85 will be converted to an ordinal score ranging from 1-11. ETDRS DRSS Level 10 = No retinopathy ETDRS DRSS Level 20 = Very mild NPDR ETDRS DRSS Level 35 = Mild NPDR ETDRS DRSS Level 43 = Moderate NPDR ETDRS DRSS Level 53 = Severe NPDR ETDRS DRSS Level 61 = Mild PDR ETDRS DRSS Level 65 = Moderate PDR ETDRS DRSS Level 71-75 = High-Risk PDR ETDRS DRSS Level 81-85 = Advanced PDR
• Subjects With Criterion Step Improvement in DRSS at Week 48/EOT (>=2 Steps Improvement in the Study Eye for Patients With Non-qualified Fellow Eye and >=3 Steps Improvement on the Person Scale for Patients With Qualified Fellow Eyes) [Treatment Period - 12 months (48 weeks)]: Subjects with Criterion Step Improvement in Diabetic Retinopathy Severity Score (DRSS) at Week 48/EOT (>=2 Steps Improvement in the Study Eye for Patients with Non-qualified Fellow Eye and >=3 Steps Improvement on the Person Scale for Patients with Qualified Fellow Eyes). Grading will follow Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) criteria. DRSS grades ranging from 10-85 will be converted to an ordinal score ranging from 1-11. ETDRS DRSS Level 10 = No retinopathy ETDRS DRSS Level 20 = Very mild NPDR ETDRS DRSS Level 35 = Mild NPDR ETDRS DRSS Level 43 = Moderate NPDR ETDRS DRSS Level 53 = Severe NPDR ETDRS DRSS Level 61 = Mild PDR ETDRS DRSS Level 65 = Moderate PDR ETDRS DRSS Level 71-75 = High-Risk PDR ETDRS DRSS Level 81-85 = Advanced PDR
• Subjects With Criterion Step Improvement in DRSS at Week 48/EOT (>=2 Steps Improvement in the Study Eye for Patients With Non-qualified Fellow Eye and >=3 Steps Improvement on the Binocular Scale for Patients With Qualified Fellow Eyes) [Treatment Period - 12 months (48 weeks)]: Subjects With Criterion Step Improvement in Diabetic Retinopathy Severity Score (DRSS) at Week 48/EOT (>=2 Steps Improvement in the Study Eye for Patients With Non-qualified Fellow Eye and >=3 Steps Improvement on the Binocular Scale for Patients With Qualified Fellow Eyes). Grading will follow Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) criteria. DRSS grades ranging from 10-85 will be converted to an ordinal score ranging from 1-11. ETDRS DRSS Level 10 = No retinopathy ETDRS DRSS Level 20 = Very mild NPDR ETDRS DRSS Level 35 = Mild NPDR ETDRS DRSS Level 43 = Moderate NPDR ETDRS DRSS Level 53 = Severe NPDR ETDRS DRSS Level 61 = Mild PDR ETDRS DRSS Level 65 = Moderate PDR ETDRS DRSS Level 71-75 = High-Risk PDR ETDRS DRSS Level 81-85 = Advanced PDR
• Summary of Patients Developing Center-involved DME or PDR or PDR-related Outcomes During Treatment Period Based on Clinical Data. [Treatment Period - 12 months (48 weeks)]: Summary of patients developing center-involved Diabetic Macular Edema (DME) or Proliferative Diabetic Retinopathy (PDR) or PDR-related outcomes during treatment period based on Clinical Data. Based on either clinical data or central image reading center evaluation.
• Summary of Subjects Developing Center-involved DME or PDR or Worsening of >=2 Steps DRSS at Week 48 Based on Central Image Reading Center Evaluation [Treatment Period - 12 months (48 weeks)]: Summary of Subjects Developing Center-involved Diabetic Macular Edema (DME) or Proliferative Diabetic Retinopathy (PDR) or Worsening of >=2 Steps Diabetic Retinopathy Severity Scale (DRSS) at Week 48 Based on Central Image Reading Center Evaluation - Study Eyes Grading will follow Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) criteria. DRSS grades ranging from 10-85 will be converted to an ordinal score ranging from 1-11. ETDRS DRSS Level 10 = No retinopathy ETDRS DRSS Level 20 = Very mild NPDR ETDRS DRSS Level 35 = Mild NPDR ETDRS DRSS Level 43 = Moderate NPDR ETDRS DRSS Level 53 = Severe NPDR ETDRS DRSS Level 61 = Mild PDR ETDRS DRSS Level 65 = Moderate PDR ETDRS DRSS Level 71-75 = High-Risk PDR ETDRS DRSS Level 81-85 = Advanced PDR

Sex: All, ages: 18 Years to 80 Years

Key Inclusion Criteria:

* Adults 18 through 80 years of age (inclusive)
* Subjects with moderate to very severe NPDR (ETDRS Level 43 - 53 inclusive)
* No evidence of central involved diabetic macular edema
* ETDRS best-corrected visual acuity letter score ≥ 70 (Snellen 20/40 or better)

Key Exclusion Criteria:

* Ocular disease other than DR that may cause substantial reduction in visual acuity, including iris neovascularization, retinal detachment, visually significant epiretinal membrane, vitreous hemorrhage or fibrosis, ocular inflammation (uveitis), other retinal inflammatory or infectious diseases
* Evidence of neovascularization on clinical examination or imaging
* Hemoglobin A1C (HbA1C) ≥ 12.0% at Screening
* Severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation

Participant flow

Outcome results

• Percentage of Subjects With an Improvement in Study Eye Severity of Diabetic Retinopathy (DR) (ETDRS DR Severity Score or DRSS) of ≥ 2 Steps (Primary), Count of units, eyes: Razuprotafib 15mg Twice Daily 0; Razuprotafib 15mg Daily 5; Placebo Twice Daily 2 (p 0.495)
• Summary of Subjects With a Worsening in the Study Eye DRSS of ≥ 2 Steps at Week 48 (Secondary), Count of units, study eyes: AKB-9778 15mg Daily 5; AKB-9778 15mg Twice Daily 6; Placebo Twice Daily 4
• Mean Change From Baseline in DRSS in the Study Eye at Week 48 (Secondary), Mean, score on a scale: AKB-9778 15mg Daily 5.0 +/- 1.15; AKB-9778 15mg Twice Daily 4.9 +/- 1.55; Placebo Twice Daily 4.8 +/- 1.35
• Summary of Subjects With an Improvement or Worsening in the Study Eye DRSS of ≥ 3 Steps at Week 48. (Secondary), Count of units, study eyes: AKB-9778 15mg Daily 3; AKB-9778 15mg Twice Daily 4; Placebo Twice Daily 3
• Subjects With Criterion Step Improvement in DRSS at Week 48/EOT (>=2 Steps Improvement in the Study Eye for Patients With Non-qualified Fellow Eye and >=3 Steps Improvement on the Person Scale for Patients With Qualified Fellow Eyes) (Secondary), Count of participants, Participants: AKB-9778 15mg Daily 0; AKB-9778 15mg Twice Daily 5; Placebo Twice Daily 1
• Subjects With Criterion Step Improvement in DRSS at Week 48/EOT (>=2 Steps Improvement in the Study Eye for Patients With Non-qualified Fellow Eye and >=3 Steps Improvement on the Binocular Scale for Patients With Qualified Fellow Eyes) (Secondary), Count of participants, Participants: AKB-9778 15mg Daily 0; AKB-9778 15mg Twice Daily 5; Placebo Twice Daily 1
• Summary of Patients Developing Center-involved DME or PDR or PDR-related Outcomes During Treatment Period Based on Clinical Data. (Secondary), Count of units, study eyes: AKB-9778 15mg Daily 12; AKB-9778 15mg Twice Daily 10; Placebo Twice Daily 10
• Summary of Subjects Developing Center-involved DME or PDR or Worsening of >=2 Steps DRSS at Week 48 Based on Central Image Reading Center Evaluation (Secondary), Count of participants, Participants: AKB-9778 15mg Daily 10; AKB-9778 15mg Twice Daily 8; Placebo Twice Daily 7

Adverse events

Time frame: Adverse events were collected from Screening through the last protocol specified visit [approximately 56 weeks (Screening period up to 4 weeks, Baseline and Treatment period for 48 weeks, and Follow-up period for 4 weeks)]

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2017-09-18)
• Statistical Analysis Plan (PDF, 2019-02-27)