OTT166 in Diabetic Retinopathy (DR)

• ClinicalTrials.gov Identifier: NCT05409235
• Recruitment Status: Active, not recruiting
• First Posted: June 8, 2022
• Last Update Posted: November 22, 2023
• Sponsor: OcuTerra Therapeutics, Inc.
• Collaborator: Parexel
• Information provided by (Responsible Party): OcuTerra Therapeutics, Inc.

Tracking Information

• First Submitted Date: June 3, 2022
• First Posted Date: June 8, 2022
• Last Update Posted Date: November 22, 2023
• Actual Study Start Date: July 29, 2022
• Estimated Primary Completion Date: December 29, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 3, 2022)

• Proportion of participants with treatment-emergent adverse events (TEAEs) [ Time Frame: Upto end of the study (Week 24) ]
  To characterize the safety of topical OTT166 in participants with DR.
• Proportion of participants who have improved by ≥ 2 steps from baseline in Diabetic Retinopathy Severity Scale (DRSS) scores [ Time Frame: At week 24 ]
  To characterize the efficacy of topical OTT166 in participants with DR. Difference between treatments in proportion of participants achieving ≥ 2 steps improvement from baseline as determined by central reading center assessment using the DRSS will be assessed. Greater DR scores confer a greater chance of converting to PDR. Higher scores are also associated with decreased vision-related quality of life measures.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 20, 2023)

• Proportion of participants developing worse than mild PDR (DRSS 65 and above) [ Time Frame: At week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of visually threatening complications (VTC). VTC is defined as the composite outcome of PDR (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or anterior segment neovascularization (ASNV) (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle).
• Proportion of participants who develop ASNV [ Time Frame: At week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of VTC. VTC is defined as the composite outcome of PDR (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or ASNV (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle).
• Time to development of PDR worse than mild (DRSS 65 and above) [ Time Frame: At week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of VTC. VTC is defined as the composite outcome of PDR (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or ASNV (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle). Time to develop PDR worse than mild (DRSS 65 and above) will be assessed.
• Proportion of participants who develop CI-DME [ Time Frame: At week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of CI-DME. CI-DME is defined as the presence of fluid in the central subfield in participants who have no fluid at baseline or CST> 325 μm.
• Time to development of CI-DME [ Time Frame: At week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of CI-DME. CI-DME is defined as the presence of fluid in the central subfield in participants who have no fluid at baseline or CST> 325 μm.
• Proportion of participants developing visually threatening complications (VTC) [ Time Frame: At Week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of VTC. VTC is defined as the composite outcome of PDR and/or ASNV and/or CI-DME.
• Time to development of PDR worse than mild (DRSS 65 and above) or CI-DME [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of CI-DME. CI-DME is defined as the presence of fluid in the central subfield in participants who have no fluid at baseline or CST> 325 μm.
• Proportion of participants with change in DRSS steps [ Time Frame: At week 24 ]
  To determine the effect of OTT166 on DRSS in participants with moderately severe to severe NPDR and mild PDR treated with topical OTT166. Change in DRSS steps is defined as DR worsening or improving by 1, 2, or ≥ 3 steps.
• Proportion of participants with mild PDR (DRSS score 61B) at baseline who regress to NPDR (DRSS score ≤ 53) [ Time Frame: At week 24 ]
  To determine the effect of OTT166 on DRSS in participants with moderately severe to severe NPDR and mild PDR treated with topical OTT166.
• Change from baseline in best corrected visual acuity (BCVA) [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on BCVA in participants with moderately severe to severe NPDR and mild PDR. BCVA will be assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) letters score. A higher score represents better functioning.
• Proportion of participants with lines gained/lost of BCVA [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on BCVA in participants with moderately severe to severe NPDR and mild PDR. Proportion of participants who gained/lost lines of BCVA (± 5, 10, and 15 ETDRS letters) will be assessed.
• Area under the curve (AUC) for change from baseline in BCVA [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on BCVA in participants with moderately severe to severe NPDR and mild PDR. BCVA will be assessed by ETDRS letters score. A higher score represents better functioning.
• Change from baseline in central subfield thickness (CST) [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on CST in participants with moderately severe to severe NPDR and mild PDR. CST will be assessed by optical coherence tomography (OCT).
• AUC for change from baseline in CST [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on CST in participants with moderately severe to severe NPDR and mild PDR. CST will be assessed by OCT.
• Proportion of participants who met the objective rescue criteria [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on the need for rescue therapy in participants with moderately severe to severe NPDR and mild PDR.
• Time to meet objective rescue therapy criteria [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on the need for rescue therapy in participants with moderately severe to severe NPDR and mild PDR. Time required to meet rescue therapy criteria will be assessed.
• Time to administration of rescue therapy [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on the need for rescue therapy in participants with moderately severe to severe NPDR and mild PDR. Time required to meet rescue therapy criteria will be assessed.

Original Secondary Outcome Measures (submitted: June 3, 2022)

• Proportion of participants developing worse than mild PDR (DRSS 65 and above) [ Time Frame: At week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of visually threatening complications (VTC). VTC is defined as the composite outcome of PDR (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or anterior segment neovascularization (ASNV) (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle) and/or center-involved diabetic macular edema (CI-DME).
• Proportion of participants who develop ASNV [ Time Frame: At week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of VTC. VTC is defined as the composite outcome of PDR (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or ASNV (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle) and/or CI-DME.
• Time to development of PDR worse than mild (DRSS 65 and above) [ Time Frame: At week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of VTC. VTC is defined as the composite outcome of PDR (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or ASNV (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle) and/or CI-DME. Time to develop PDR worse than mild (DRSS 65 and above) will be assessed.
• Proportion of participants who develop CI-DME [ Time Frame: At week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of VTC. VTC is defined as the composite outcome of PDR (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or ASNV (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle) and/or CI-DME.
• Time to development of CI-DME [ Time Frame: At week 24 ]
  To determine if topical OTT166 will prevent or delay the occurrence of VTC. VTC is defined as the composite outcome of PDR (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or ASNV (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle) and/or CI-DME. Time to develop CI-DME will be assessed.
• Proportion of participants with change in DRSS steps [ Time Frame: At week 24 ]
  To determine the effect of OTT166 on DRSS in participants with moderately severe to severe NPDR and mild PDR treated with topical OTT166. Change in DRSS steps is defined as DR worsening or improving by 1, 2, or ≥ 3 steps.
• Proportion of participants with mild PDR (DRSS score 61) at baseline who regress to NPDR (DRSS score ≤ 53) [ Time Frame: At week 24 ]
  To determine the effect of OTT166 on DRSS in participants with moderately severe to severe NPDR and mild PDR treated with topical OTT166.
• Change from baseline in DRSS step [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on DRSS in participants with moderately severe to severe NPDR and mild PDR treated with topical OTT166. Change in DRSS steps is defined as DR worsening or improving by 1, 2, or ≥ 3 steps.
• Change from baseline in best corrected visual acuity (BCVA) [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on BCVA in participants with moderately severe to severe NPDR and mild PDR. BCVA will be assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) letters score. A higher score represents better functioning.
• Proportion of participants with lines gained/lost of BCVA [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on BCVA in participants with moderately severe to severe NPDR and mild PDR. Proportion of participants who gained/lost lines of BCVA (± 5, 10, and 15 ETDRS letters) will be assessed.
• Area under the curve (AUC) for change from baseline in BCVA [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on BCVA in participants with moderately severe to severe NPDR and mild PDR. BCVA will be assessed by ETDRS letters score. A higher score represents better functioning.
• Change from baseline in central subfield thickness (CST) [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on CST in participants with moderately severe to severe NPDR and mild PDR. CST will be assessed by optical coherence tomography (OCT).
• AUC for change from baseline in CST [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on CST in participants with moderately severe to severe NPDR and mild PDR. CST will be assessed by OCT.
• Proportion of participants who met the rescue criteria [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on the need for rescue therapy in participants with moderately severe to severe NPDR and mild PDR.
• Time to meet rescue therapy criteria [ Time Frame: From Baseline (Day 1) up to Week 24 ]
  To determine the effect of OTT166 on the need for rescue therapy in participants with moderately severe to severe NPDR and mild PDR. Time required to meet rescue therapy criteria will be assessed.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: OTT166 in Diabetic Retinopathy (DR)
• Official Title: OTT166-201 A Phase 2 Randomized, Double-Masked, Vehicle-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of OTT166 Ophthalmic Solution in the Treatment of Diabetic Retinopathy (DR)
• Brief Summary: This study will evaluate the safety and efficacy of OTT166 Ophthalmic solution in participants with Diabetic Retinopathy.

Detailed Description

This randomized, double-masked, vehicle controlled, phase 2 study will evaluate the safety and efficacy of OTT166 ophthalmic solution in participants with diabetic retinopathy and select an optimum dosing regimen for Phase 3 pivotal trials. Approximately 210 participants diagnosed with moderately severe to severe non-proliferative diabetic retinopathy (NPDR) or mild proliferative diabetic retinopathy (PDR) and who are treatment naïve (ie, no prior anti-vascular endothelial growth factor [anti-VEGF] or laser [focal, grid, pan-retinal photocoagulation (PRP)] administered) will be randomized into the following groups:

OTT166 Cohort 1, OTT166 Cohort 2, Vehicle control Cohort 1, Vehicle control Cohort 2.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Diabetic Retinopathy

Intervention

• Drug: OTT166
  Participants will receive OTT166 ophthalmic solution
• Drug: Vehicle control
  Participants will receive vehicle control

Study Arms

• Experimental: OTT166 Cohort 1
  Participants will receive OTT166 low dose for 24 weeks
  Intervention: Drug: OTT166
• Experimental: OTT166 Cohort 2
  Participants will receive OTT166 high dose for 24 weeks
  Intervention: Drug: OTT166
• Placebo Comparator: Vehicle control Cohort 1
  Participants will receive vehicle control for 24 weeks
  Intervention: Drug: Vehicle control
• Placebo Comparator: Vehicle control Cohort 2
  Participants will receive vehicle control for 24 weeks
  Intervention: Drug: Vehicle control

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 26, 2023): 225
• Original Estimated Enrollment (submitted: June 3, 2022): 210
• Estimated Study Completion Date: December 29, 2023
• Estimated Primary Completion Date: December 29, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Men or women ≥ 18 years of age with type 1 or 2 diabetes mellitus who have moderately severe to severe NPDR [DRSS levels 47 or 53], or mild PDR [DRSS level 61] NVE < 0.5 DA in 1 + quadrants], in whom PRP and/or anti-VEGF IVT can be safely deferred for at least 6 months per the Investigator
2. BCVA ETDRS letter score in the study eye of ≥ 69 letters (approximate Snellen equivalent of 20/40 or better)
3. Normal foveal contour
4. Treatment naïve (ie, no previous anti-VEGF or steroid treatment or PRP or laser)
5. Willing and able to return for all study visits and comply with study-related procedures
6. Able to adhere to the study dosing requirements
7. Understands and signs the written Informed Consent Form

Exclusion Criteria:

1. CST of > 325 μm

   a. Fluid in the central subfield is allowed so long as CST is ≤325 μm and there is a normal foveal contour as determined by the Central Reading Center

2. Any prior focal or grid laser photocoagulation or any prior PRP in the study eye as it pertains to treatment of DME or DR (peripheral retinal hole treated with laser is allowed)
3. Eyes with DRSS score 61 with fibrous proliferations at disc or fibrous proliferations elsewhere a. DRSS score 61B with NVE only is allowed. Any sign of fibrosis proliferation is exclusionary
4. Any prior systemic anti-VEGF treatment or IVT anti-VEGF treatment in the study eye
5. Any prior intraocular steroid injection in the study eye, inclusive of Iluvien® and Retisert® a. History of Ozurdex® and triamcinolone use prior to 12 months before study enrollment is allowed
6. Current ASNV, vitreous hemorrhage, or tractional retinal detachment visible at the screening assessments in the study eye
7. Uncontrolled glaucoma or ocular hypertension in the study eye defined as an IOP > 25 mmHg regardless of concomitant treatment with IOP-lowering medications
8. Hypertension defined as systolic > 180 mmHg or > 160 mmHg on 2 consecutive measurements (during the same visit) or diastolic > 100 mmHg
9. Screening HbA1c blood test > 12.0%
10. Renal failure (stage 4 or end-stage), dialysis, or history of renal transplant
11. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect interpretation of the results of the study or render the participant at high risk for treatment complications
12. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months
13. Epiretinal membrane, posterior hyaloidal traction, and/or vitreomacular traction in the study eye as determined to be significant by the Investigator
14. Previous pars plana vitrectomy in the study eye
15. Any intraocular surgery in the study eye within 90 days (3 months) prior to study enrollment
16. YAG laser treatment in the study eye within 90 days prior to study enrollment
17. Concomitant use of any topical ophthalmic medications in the study eye, including dry eye or glaucoma medications, unless on a stable dose for at least 90 days prior to study enrollment and expected to stay on stable dose throughout study participation. Topical eyedrops are allowed but not within ±10 minutes of study drop application
18. Contact lens use from time of screening throughout the study
19. Central corneal changes from dry eye that are visually significant and/or Sjogren's syndrome
20. Visually significant Fuchs endothelial dystrophy or other diagnosed conditions of corneal compromise including Anterior Basement Membrane Dystrophy, or any corneal dystrophy affecting central vision (peripheral processes are not exclusionary)
21. Chronic or recurrent uveitis in the study eye
22. Ongoing ocular infection or inflammation in either eye
23. A history of cataract surgery complicated by vitreous loss in the study eye
24. Congenital eye malformations in the study eye
25. A history of penetrating ocular trauma in the study eye
26. Cognitive impairment that, in the opinion of the investigator, could compromise compliance with the requirements of the study
27. Females of childbearing potential (ie, who are not postmenopausal for at least 1 year or surgically sterile for at least 6 weeks prior to Visit 1 - Screening/Randomization) who are lactating, or who are pregnant as determined by a positive serum pregnancy test at Visit 1 -Screening/Randomization. Women of childbearing potential must agree to use acceptable methods of birth control throughout the study a. Women who are breastfeeding or who have a positive serum hCG/urine pregnancy test at the screening or BL Visit
28. Females and males of childbearing potential unwilling or unable to utilize the following acceptable methods of birth control: tubal ligation, transdermal patch, intrauterine devices/systems, oral/implantable/injectable or contraceptives, diaphragm or cervical cap with spermicide, or vasectomized partner for females; condoms with spermicidal agent and vasectomy for males; or sexual abstinence for males and females
29. Participation in any other investigational device or drug clinical research study within 12 weeks of Visit 1 - Screening/Randomization and during the duration of enrollment
30. Contraindication to the study medications or fluorescein dye
31. Other ocular pathologies that, in the investigator's opinion, would interfere with the participant's vision in the study eye
32. Ocular media of insufficient quality to obtain fundus photographs, fluorescein angiography, and OCT images in the study eye
33. Concomitant use of Semaglutide (Wegovy®, Ozempic®, Rybelsus®), Thiazolidinediones (Actos®, Avandia®), Liraglutides (Victoza®, Saxenda®), Dulaglutide (Trulicity®), or Tirzepatide (Mounjaro®) within 12 months prior to Visit 1 (allowed if a stable dose has been established for at least 1 year of use) a. Plans to start concomitant use of Semaglutide or Thiazolidinediones during the study duration is exclusionary

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Puerto Rico, United States

Administrative Information

• NCT Number: NCT05409235
• Other Study ID Numbers: OTT166-201
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: OcuTerra Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: OcuTerra Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Parexel

Investigators

• Principal Investigator: Carl Regillo, MD; Principal Investigator

• PRS Account: OcuTerra Therapeutics, Inc.
• Verification Date: November 2023