| Protocol No: | ECCT/22/03/07 | Date of Protocol: | 08-07-2021 |
| Study Title: |
A PHASE IIIB/IV, MULTICENTER, OPEN-LABEL, SINGLE-ARM STUDY TO INVESTIGATE FARICIMAB (RO6867461) TREATMENT RESPONSE IN TREATMENT-NAÏVE, UNDERREPRESENTED PATIENTS WITH DIABETIC MACULAR EDEMA
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A PHASE IV, MULTICENTER, OPEN-LABEL, SINGLE-ARM STUDY TO INVESTIGATE FARICIMAB (RO6867461) TREATMENT RESPONSE IN TREATMENT-NAÏVE, UNDERREPRESENTED PATIENTS WITH DIABETIC MACULAR EDEMA
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| Study Objectives: |
The primary objective of this study is to evaluate the treatment response in patients treated with intravitreal (IVT) injections of a 6-mg dose of faricimab based on the following endpoint:
The secondary objective of this study is to evaluate treatment response on DR and DME severity outcomes in patients treated with faricimab based on the following endpoints:
Proportion of patients gaining:
Proportion of patients avoiding a loss of:
The exploratory objectives of this study are to explore the following patient-reported outcome (PRO) assessments in patients treated with faricimab:
– Change from baseline in NEI VFQ-25 composite, Near Activities, Distance Activities, and Driving subscale scores at Week 52
– Proportion of patients with a more than or equaal to 4-point improvement from baseline in NEI VFQ-25 composite, Near Activities, Distance Activities, and Driving subscale scores at Week 52
– Change from baseline in DDS subscale scores at Week 56 Faricimab—Genentech, Inc. 25/Protocol ML43435, Version 1
– Time and intensity level of physical activity as measured by the IPAQ-SF every 12 to 16 weeks
– Change from baseline in DSC-R symptom scales at Week 56
– Diet quality as measured by the MEDAS every 12 to 16 weeks
The safety objectives for this study are to evaluate the ocular and systemic safety and tolerability of faricimab on the basis of the following endpoints:
The immunogenicity objectives of this study are to evaluate the immune response to faricimab and potential effects of anti-drug antibodies (ADAs), on the basis of the following endpoints:
The exploratory biomarker objectives of this study are to identify biomarkers that are predictive of response to faricimab, are associated with progression to a more severe disease state, are associated with susceptibility to developing adverse events, can provide evidence of faricimab activity, or can increase the knowledge and understanding of disease biology, on the basis of the following endpoints:
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| Laymans Summary: |
This Phase IIIb/IV study is designed to investigate treatment response in treatmentnaïve underrepresented patients with DME (Diabetic Macular Edema) who are treated with faricimab (RO6867461).
The study population will consist of patients 18 years of age who self-identify as Black/African American, Hispanic/Latino American, or Native American/Alaska Native/Native Hawaiian or other Pacific Islander.
All DME patients enrolled will be treatment-naïve in the study eye. Hypothesis-generating signals will be assessed via associations in visual function, retinal anatomy, and AH protein/metabolite composition.
Approximately 40 study sites in the United States (including Puerto Rico) will enroll approximately 120 patients who are treatment-naïve in the study eye. Additional sites outside of the United States may be added.
This Phase IV study will investigate treatment response (clinically assessed and patient-reported), and safety in treatment-naïve, underrepresented patients with diabetic macular edema (DME) who are treated with faricimab (RO6867461). In addition to evaluating impact on visual function, the effect of faricimab on retinal anatomy will be evaluated by retinal imaging (spectral-domain optical coherence tomography [SD-OCT], color fundus photographs [CFPs], fundus fluorescein angiography [FFA]) and other imaging modalities to assess both DME and diabetic retinopathy (DR) outcomes. Safety, patient-reported outcomes (PROs), and aqueous humor (AH) biomarker patterns also will be assessed. The study will be conducted in the United States and in Kenya and is expected to enroll up to approximately 120 subjects. The study duration is approximately 26 months.
The study population will consist of patients over18 years of age who self-identify as Black/African American, Hispanic/Latino American, or Native American/Alaska Native/Native Hawaiian or another Pacific Islander. Detailed by race/ethnicity, the estimated age-adjusted prevalence of diabetes is highest in adults who are Native American/Alaska Native (14.7%), Hispanic (12.5%), and non-Hispanic Black (11.7%), and lowest in adults who are non- Hispanic White (7.5%).
All DME patients enrolled will be treatment-naïve in the study eye. Hypothesis-generating signals will be assessed via associations in visual function, retinal anatomy, and AH protein/metabolite composition.
Prior to enrollment, all subjects will undergo screening to determine study eligibility. Eligibility will be assessed based on inclusion and exclusion criteria (Sections 4.1.1 and 4.1.2 of the Protocol). The screening evaluation will be performed within 28 days preceding the baseline visit (Day 1), i.e., the day of the first study treatment.
After screening has been completed, including all assessments listed for the Day 1 visit, eligible patients will receive 6-mg intravitreal (IVT) faricimab injections Q4W up to Week 20 (i.e., Day 1 and Weeks 4, 8, 12, 16, and 20 visits), followed by 6-mg IVT faricimab injections Q8W up to Week 52 (i.e., Weeks 28, 36, 44, and 52 visits). Patients will return for Week 56 safety follow-up visit (SFV) after more than or equal to 28 days following their last study treatment.
Patients who are discontinuing from the study or treatment early (prior to the SFV at Week 56), should return for an early termination visit (ETV) more than or equal to 28 days after their last study treatment.
Patients who complete study treatment (i.e., the Week 52 visit) will return for the final study visit (Week 56) after a minimum of 28 days have elapsed from their last study treatment, for monitoring of adverse events and final study visit assessments.
The total duration of the study for an individual patient will be approximately 61 weeks, described as follows:
A patient is considered to have completed the study if he/she has completed the SFV at Week 56.
The end of study (EoS) is defined as the date when the last patient completes their last visit (i.e., last patient, last visit [LPLV]). The end of the study is expected to occur approximately 56 to 57 weeks after the last patient is enrolled. The total length of the study, from the screening visit of the first patient to the EoS, is expected to be approximately 26 months. Alternatively, the Sponsor may decide to terminate the study at any time; in this case, the termination date will be considered the EoS.
In addition, two administrative letters are available, clarifying certain protocol sections such as study phase, IND exemption and exclusion criteria.
The trial is not part of a Paediatric Investigation Plan (PIP).
No scientific advice related to the clinical trial/IMP has been obtained.
Nonclinical Information
A comprehensive nonclinical testing strategy was developed to evaluate the pharmacology, PK, safety pharmacology, and toxicity of faricimab, and to enable the selection of a safe starting dose for clinical studies in DME.
For a description of the Sponsor’s non-clinical experience with faricimab, please refer to the enclosed Investigator’s Brochure (IB) Edition 11.0, section 4.
Clinical Information
The Roche-sponsored clinical program consists of studies investigating faricimab as a treatment for DME/ DR, neovascular age-related macular degeneration (nAMD) and retinal vein occlusion (RVO), including branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). Clinical data is available for DME patients in 9 completed and ongoing Phase I, II, and III clinical studies. The Phase III clinical development program in DME (Study GR40398[RHINE] and Study GR40349[YOSEMITE]) is evaluating the efficacy, safety, and pharmacokinetics of faricimab administered to patients every 8 weeks (Q8W) and with a personalized treatment interval regimen. Study populations include patients who are naïve to anti-VEGF therapy in the study eye as well as patients previously treated with anti-VEGF therapy in the study eye, in order to further explore outcomes on DME in both groups. Both studies met their primary endpoint.
Data from the Phase III RHINE and YOSEMITE studies have consistently shown that 6.0 mg of faricimab, given at intervals of up to 4 months, offered non-inferior vision gains versus 2.0 mg of aflibercept, given every 2 months, for treatment of DME. In addition, faricimab showed rapid and consistent improvements in anatomical outcomes, including central subfield thickness. These positive results indicate the potential for faricimab to improve vision outcomes over longer periods between treatments compared with IVT anti-VEGF monotherapy, and in turn reduce the frequency and burden of injections required. Imaging and biomarker data from this study will improve our understanding of DME and treatment response in traditionally underrepresented populations and may potentially lead to more personalized treatment options for such patients in the future. Enrolment into the RHINE and YOSEMITE studies completed in 2019; both studies are ongoing.
The faricimab Investigator’s Brochure Section 6.4.1 will be used as the Reference Safety information (RSI) for assessing whether an adverse reaction is a suspected unexpected serious adverse reaction (SUSAR).
The Sponsor’s Overall Risk/Benefit Assessment can be found in the Section 1.3 of the Protocol.
Investigational Medicinal Product (IMP):
Faricimab
Faricimab (RO6867461) is a humanized bispecific immunoglobulin G1 (IgG1) antibody that selectively binds angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A). Vitreous concentrations of both Ang-2 and VEGF-A are upregulated in patients with diabetic eye disease, RVO and, to a lesser extent, in patients with nAMD. Therefore, selective neutralization of both Ang-2 and VEGF may better stabilize pathological ocular vasculature in addition to further reducing leakage when compared to anti-VEGF monotherapy. This may result in further improvement of retinal function and durability of response for patients with DME/DR, nAMD and RVO.
Faricimab (RO6867461) single-dose 2-mL glass vials (6mg/0.05mL) are manufactured by F. Hoffmann-La Roche AG, Wurmisweg 4303 Kaiseraugst, Switzerland and will be directly supplied to Kenya sites.
Product shelf life is 48 months when stored at at 5 degrees C (2-8 degrees C), protected from light.
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| 1 | This study is designed to investigate treatment response in treatment naïve underrepresented patients with DME (Diabetic Macular Edema) who are treated with faricimab (RO6867461). The study population will consist of patients 18 years of age who self-identify as Black/African American, Hispanic/Latino American, or Native American/Alaska Native/Native Hawaiian or other Pacific Islander. All DME patients enrolled will be treatment-naïve in the study eye. Hypothesis-generating signals will be assessed via associations in visual function, retinal anatomy, and AH protein/metabolite composition. An estimated 40 study sites in the United States (including Puerto Rico) will enroll approximately 120 patients. In addition, an estimated 2 study sites in Kenya will enrol approximately 8 patients. Additional sites may be added. (Note that a separate, India-specific version of this protocol [v2] will have an estimated 7 study sites in India and will enroll approximately 40 patients.) This study will investigate treatment response (clinically assessed and patient-reported), and safety in treatment-naïve, patients with diabetic macular edema (DME) who are treated with faricimab (RO6867461). In addition to evaluating impact on visual function, the effect of faricimab on retinal anatomy will be evaluated by retinal imaging (spectral-domain optical coherence tomography [SD-OCT], color fundus photographs [CFPs], fundus fluorescein angiography [FFA]) and other imaging modalities to assess both DME and diabetic retinopathy (DR) outcomes. Safety, patient-reported outcomes (PROs), and aqueous humor (AH) biomarker patterns also will be assessed. Prior to enrollment, all subjects will undergo screening to determine study eligibility. Eligibility will be assessed based on inclusion and exclusion criteria (Sections 4.1.1 and 4.1.2 of the Protocol). The screening evaluation will be performed within 28 days preceding the baseline visit (Day 1), i.e., the day of the first study treatment. After screening has been completed, including all assessments listed for the Day 1 visit, eligible patients will receive 6-mg intravitreal (IVT) faricimab injections Q4W up to Week 20 (i.e., Day 1 and Weeks 4, 8, 12, 16, and 20 visits), followed by 6-mg IVT faricimab injections Q8W up to Week 52 (i.e., Weeks 28, 36, 44, and 52 visits). Patients will return for Week 56 safety follow-up visit (SFV) after more than or equal to 28 days following their last study treatment. Patients who are discontinuing from the study or treatment early (prior to the SFV at Week 56), should return for an early termination visit (ETV) more than or equal to 28 days after their last study treatment. Patients who complete study treatment (i.e., the Week 52 visit) will return for the final study visit (Week 56) after a minimum of 28 days have elapsed from their last study treatment, for monitoring of adverse events and final study visit assessments. The total duration of the study for an individual patient will be approximately 61 weeks, described as follows: Screening period: Up to 28 days (i.e., up to 4 weeks) Treatment period: 364 days (plus or minus 7 days) (i.e., approximately 52 weeks) Safety follow-up period: Minimum of 28 days (i.e., approximately 4 to 5 weeks) A patient is considered to have completed the study if he/she has completed the SFV at Week 56. The end of study (EoS) is defined as the date when the last patient completes their last visit (i.e., last patient, last visit [LPLV]). The end of the study is expected to occur approximately 56 to 57 weeks after the last patient is enrolled. The total length of the study, from the screening visit of the first patient to the EoS, is expected to be approximately 26 months. Alternatively, the Sponsor may decide to terminate the study at any time; in this case, the termination date will be considered the EoS. Investigational Medicinal Product (IMP): Faricimab Faricimab (RO6867461) is a humanized bispecific immunoglobulin G1 (IgG1) antibody that selectively binds angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A). Vitreous concentrations of both Ang-2 and VEGF-A are upregulated in patients with diabetic eye disease, RVO and, to a lesser extent, in patients with nAMD. Therefore, selective neutralization of both Ang-2 and VEGF may better stabilize pathological ocular vasculature in addition to further reducing leakage when compared to anti-VEGF monotherapy. This may result in further improvement of retinal function and durability of response for patients with DME/DR, nAMD and RVO. Faricimab (RO6867461) single-dose 2-mL glass vials (6mg/0.05mL) are manufactured by F. Hoffmann-La Roche AG, Wurmisweg 4303 Kaiseraugst, Switzerland and will be directly supplied to Kenya sites. Product shelf life is 48 months when stored at at 5 degrees C (2-8 degrees C), protected from light. |
| Abstract of Study: |
This Phase IIIb/IV study is designed to investigate treatment response in treatmentnaïve underrepresented patients with DME (Diabetic Macular Edema) who are treated with faricimab (RO6867461).
PROTOCOL NUMBER: ML43435
TEST PRODUCTS: Faricimab (RO6867461)
PHASE: Phase IV
RATIONALE
Diabetic macular edema (DME), a complication of diabetic retinopathy (DR), can develop at any stage of the underlying disease of retinal microvasculature (Fong et al. 2004). DME occurs with increasing frequency as the underlying DR worsens (Henricsson et al. 1999; Johnson 2009) from non-proliferative DR (NPDR) to
proliferative DR (PDR). DME is the most common cause of moderate and severe visual impairment in patients with DR (Ciulla et al. 2003; Davidson et al. 2007;
Leasher et al. 2016), and if left untreated can lead to a loss of 10 or more letters in visual acuity (VA) within 2 years in approximately 50% of patients (Ferris and Patz 1984; Ciulla et al. 2003). DME affects approximately 14% of patients with diabetes and can be found in patients with both type 1 and type 2 diabetes (Girach and Lund- Andersen 2007). In 2019, the worldwide population of people with diabetes was approximately 463 million, and it is estimated to grow to 700 million by the year 2045 (International Diabetes Federation 2019).
As this exploratory study is not comparative and most variables are objectively assessed, an open-label study design is acceptable.
OBJECTIVES AND ENDPOINTS
The primary objective of this study is to evaluate the treatment response in patients treated with intravitreal (IVT) injections of a 6-mg dose of faricimab based on the following endpoint:
The secondary objective of this study is to evaluate treatment response on DR and DME severity outcomes in patients treated with faricimab based on the following endpoints:
Proportion of patients gaining:
Proportion of patients avoiding a loss of:
The exploratory objectives of this study are to explore the following patient-reported outcome (PRO) assessments in patients treated with faricimab:
National Eye Institute Visual Functioning Questionnaire25 (NEI VFQ-25)
– Change from baseline in NEI VFQ-25 composite, Near Activities, Distance Activities, and Driving subscale scores at Week 52
– Proportion of patients with a more than or equaal to 4-point improvement from baseline in NEI VFQ-25 composite, Near Activities, Distance Activities, and Driving subscale scores at Week 52 Diabetes Distress Scale (DDS)
– Change from baseline in DDS subscale scores at Week 56 Faricimab—Genentech, Inc. 25/Protocol ML43435, Version 1 International Physical Activity QuestionnaireShort Form (IPAQ-SF)
– Time and intensity level of physical activity as measured by the IPAQ-SF every 12 to 16 weeks Diabetes Symptom ChecklistRevised (DSC-R) questionnaire
– Change from baseline in DSC-R symptom scales at Week 56 Mediterranean Diet Adherence Screener (MEDAS)
– Diet quality as measured by the MEDAS every 12 to 16 weeks
The safety objectives for this study are to evaluate the ocular and systemic safety and tolerability of faricimab on the basis of the following endpoints:
The immunogenicity objectives of this study are to evaluate the immune response to faricimab and potential effects of anti-drug antibodies (ADAs), on the basis of the following endpoints:
The exploratory biomarker objectives of this study are to identify biomarkers that are predictive of response to faricimab, are associated with progression to a more severe disease state, are associated with susceptibility to developing adverse events, can provide evidence of faricimab activity, or can increase the knowledge and understanding of disease biology, on the basis of the following endpoints:
Study design
This Phase IIIb/IV study is designed to investigate treatment response in treatmentnaïve underrepresented patients with DME who are treated with faricimab (RO6867461). The study population will consist of patients 18 years of age who self-identify as Black/African American, Hispanic/Latino American, or Native American/Alaska Native/Native Hawaiian or other Pacific Islander. All DME patients enrolled will be treatment-naïve in the study eye. Hypothesis-generating signals will be assessed via associations in visual function, retinal anatomy, and AH protein/metabolite composition
Approximately 40 study sites in the United States (including Puerto Rico) will enroll approximately 120 patients who are treatment-naïve in the study eye. Additional sites outside of the United States may be added.
State-of-the-art imaging technologies and new immunoassay platforms will be utilized in this study. Advanced analytics and multivariate analysis will also be used to show the relationships between AH and imaging biomarkers as well as genetic polymorphisms. Mandatory AH taps will be collected from the study eye prior to administering treatment at three study visits, and optional AH samples may be collected at three additional visits (see Appendix 2 of the protocol).
Multimodal retinal imaging will be applied at the screening visit, Day 1 (baseline), and throughout the study (see Appendix 1 for the complete schedule of activities [SOA]). Data from adaptive optics (AO) instruments and flavoprotein fluorescence (FPF) will be collected from selected study sites that have the technology available and agree to participate. The purpose of this data collection is to conduct a feasibility test of this technology for future studies.
If both eyes are considered eligible, the eye with the worse BCVA, as assessed at screening, will be selected for the study eye unless the investigator deems the other eye to be more appropriate for treatment in the study.
Patients who use concomitant medications should continue their use during study participation, unless a medication is listed as prohibited therapy
Patients who receive prohibited therapies may be discontinued from the study treatment and study.
Patients who discontinue the study prematurely will not be replaced and will not be allowed to restart study treatment.
Any evaluations of ocular assessments and decisions to administer study treatment will be made by site investigators who are retinal specialists (or equivalent, in ex-U.S. countries).
Inclusion Criteria:
General Inclusion Criteria:
Ocular Inclusion Criteria for Study Eye:
Exclusion Criteria:
General Exclusion Criteria:
Ocular Exclusion Criteria for Study Eye:
Ocular Exclusion Criteria for Non-Study Eye:
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| 1 | This Phase IV study is designed to investigate treatment response in treatmentnaïve underrepresented patients with DME (Diabetic Macular Edema) who are treated with faricimab (RO6867461).
PROTOCOL NUMBER: ML43435 TEST PRODUCTS: Faricimab (RO6867461) PHASE: Phase IV
RATIONALE
Diabetic macular edema (DME), a complication of diabetic retinopathy (DR), can develop at any stage of the underlying disease of retinal microvasculature (Fong et al. 2004). DME occurs with increasing frequency as the underlying DR worsens (Henricsson et al. 1999; Johnson 2009) from non-proliferative DR (NPDR) to proliferative DR (PDR). DME is the most common cause of moderate and severe visual impairment in patients with DR (Ciulla et al. 2003; Davidson et al. 2007; Leasher et al. 2016), and if left untreated can lead to a loss of 10 or more letters in visual acuity (VA) within 2 years in approximately 50% of patients (Ferris and Patz 1984; Ciulla et al. 2003). DME affects approximately 14% of patients with diabetes and can be found in patients with both type 1 and type 2 diabetes (Girach and Lund- Andersen 2007). In 2019, the worldwide population of people with diabetes was approximately 463 million, and it is estimated to grow to 700 million by the year 2045 (International Diabetes Federation 2019).
As this exploratory study is not comparative and most variables are objectively assessed, an open-label study design is acceptable.
OBJECTIVES AND ENDPOINTS
The primary objective of this study is to evaluate the treatment response in patients treated with intravitreal (IVT) injections of a 6-mg dose of faricimab based on the following endpoint:
The secondary objective of this study is to evaluate treatment response on DR and DME severity outcomes in patients treated with faricimab based on the following endpoints:
Proportion of patients gaining:
Proportion of patients avoiding a loss of:
The exploratory objectives of this study are to explore the following patient-reported outcome (PRO) assessments in patients treated with faricimab:
National Eye Institute Visual Functioning Questionnaire25 (NEI VFQ-25) – Change from baseline in NEI VFQ-25 composite, Near Activities, Distance Activities, and Driving subscale scores at Week 52 – Proportion of patients with a more than or equaal to 4-point improvement from baseline in NEI VFQ-25 composite, Near Activities, Distance Activities, and Driving subscale scores at Week 52 Diabetes Distress Scale (DDS) – Change from baseline in DDS subscale scores at Week 56 Faricimab—Genentech, Inc. 25/Protocol ML43435, Version 1 International Physical Activity QuestionnaireShort Form (IPAQ-SF) – Time and intensity level of physical activity as measured by the IPAQ-SF every 12 to 16 weeks Diabetes Symptom ChecklistRevised (DSC-R) questionnaire – Change from baseline in DSC-R symptom scales at Week 56 Mediterranean Diet Adherence Screener (MEDAS) – Diet quality as measured by the MEDAS every 12 to 16 weeks
The safety objectives for this study are to evaluate the ocular and systemic safety and tolerability of faricimab on the basis of the following endpoints:
The immunogenicity objectives of this study are to evaluate the immune response to faricimab and potential effects of anti-drug antibodies (ADAs), on the basis of the following endpoints:
The exploratory biomarker objectives of this study are to identify biomarkers that are predictive of response to faricimab, are associated with progression to a more severe disease state, are associated with susceptibility to developing adverse events, can provide evidence of faricimab activity, or can increase the knowledge and understanding of disease biology, on the basis of the following endpoints:
Study design
This Phase study is designed to investigate treatment response in treatmentnaïve underrepresented patients with DME who are treated with faricimab (RO6867461). The study population will consist of patients 18 years of age who self-identify as Black/African American, Hispanic/Latino American, or Native American/Alaska Native/Native Hawaiian or other Pacific Islander. All DME patients enrolled will be treatment-naïve in the study eye. Hypothesis-generating signals will be assessed via associations in visual function, retinal anatomy, and AH protein/metabolite composition
An estimated 40 study sites in the United States (including Puerto Rico) will enroll approximately 120 patients. In addition, an estimated 2 study sites in Kenya will enroll approximately 8 patients. Additional sites outside of the United States may be added. (Note that a separate, India-specific version of this protocol [v2] will have an estimated 7 study sites in India and will enroll approximately 40 patients.)
State-of-the-art imaging technologies and new immunoassay platforms will be utilized in this study. Advanced analytics and multivariate analysis will also be used to show the relationships between AH and imaging biomarkers as well as genetic polymorphisms. Mandatory AH taps will be collected from the study eye prior to administering treatment at three study visits, and optional AH samples may be collected at three additional visits (see Appendix 2 of the protocol).
Multimodal retinal imaging will be applied at the screening visit, Day 1 (baseline), and throughout the study (see Appendix 1 for the complete schedule of activities [SOA]). Data from adaptive optics (AO) instruments and flavoprotein fluorescence (FPF) will be collected from selected study sites that have the technology available and agree to participate. The purpose of this data collection is to conduct a feasibility test of this technology for future studies.
If both eyes are considered eligible, the eye with the worse BCVA, as assessed at screening, will be selected for the study eye unless the investigator deems the other eye to be more appropriate for treatment in the study.
Patients who use concomitant medications should continue their use during study participation, unless a medication is listed as prohibited therapy
Patients who receive prohibited therapies may be discontinued from the study treatment and study.
Patients who discontinue the study prematurely will not be replaced and will not be allowed to restart study treatment.
Any evaluations of ocular assessments and decisions to administer study treatment will be made by site investigators who are retinal specialists (or equivalent, in ex-U.S. countries).
Inclusion Criteria:
General Inclusion Criteria:
Ocular Inclusion Criteria for Study Eye:
Exclusion Criteria:
General Exclusion Criteria:
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