Treat & Extend Treatment With 0.5mg Ranibizumab vs Monthly Treatment With 0.5mg Ranibizumab

Study Overview
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Brief Summary
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TREX is a phase IIIb, multicenter, randomized, controlled clinical study. Subjects will be randomized 1:2 to monthly (control arm) or treat and extend protocol (comparator arm) respectively. TREX assess the safety, tolerability and efficacy of intravitreal injections (IVT) of 0.5mg ranibizumab given monthly for up to 100 weeks followed by pro re nata (PRN) treatment for 56 weeks compared to a Treat and Extend protocol for 156 weeks in patients with wet age-related macular degeneration (AMD). Subjects treated in a treat and extend protocol receive 3 consecutive IVT 0.5 mg ranibizumab (visits 2, 4 and 5). Starting at week 8, if a subject has achieved a dry macula; signs of active exudation have resolved will begin a Treat and Extend protocol (visits lengthened by 2 week intervals every visit a dry macular is maintained). At the beginning of the 104-week endpoint subjects initially randomized to the TREX cohort will transition to PRN re-treatment when there is no exudative disease activity at the 12-week interval.

Detailed Description
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This trial will compare the results of 2 cohorts, with different treatment intervals, to assess the safety, tolerability and efficacy of IVT of ranibizumab for the treatment of wet AMD. Specifically, this trial will evaluate the ability to reduce the amount of visits and IVT ranibizumab treatments needed all while maintaining an exudation-free macula. Subjects in both cohorts will be followed for a total of 156 weeks. Cohort A (control arm, monthly, n=20) Subjects will receive monthly treatment of IVT 0.5 mg ranibizumab from Day 0 to week 100. Monthly treatment is defined as every 28 days (±7 days). Dosing should not occur earlier than 21 days after the previous treatment. Week 104 - Week 156 Starting at week 104 subjects will be seen monthly and treated with IVT ranibizumab pro re nata (PRN) based on pre-defined re-treatment criteria. Retreatment criteria for PRN phase Re-treatment will be initiated if any of the following criteria are meet: Presence of any abnormal intraretinal or subretinal fluid on high resolution SD-OCT. Presence of new intraretinal or subretinal hemorrhage related to AMD on examination. 10 letter loss from previous visit, related to active wet AMD in the opinion of the treating investigator Cohort B (comparator arm, TREX, n=40) Subjects will receive a minimum of 3 consecutive IVT 0.5 mg ranibizumab (visits 2, 4 and 5). Starting at week 8, if a subject has achieved a dry macula; signs of active exudation have resolved by both ophthalmic exam and SD-OCT evaluation they will begin a Treat and Extend protocol. For a macula to be considered dry it must meet both the following criteria: Resolution of intraretinal and subretinal fluid Resolution of all subretinal hemorrhage related to active exudative AMD Resolution of pigment epithelial detachments (PED) is not required for a macula to be considered dry. Small intraretinal cystic areas observed on SD-OCT are acceptable and the corresponding macula can be considered dry. The criteria for these are specific; see reference images (Appendix D) for examples of acceptable intraretinal cystic spaces. When cysts described in Appendix D are present the macula should be considered dry and should be notated on the SD-OCT interpretation. Also, minimal increased retinal thickening on SD-OCT without definitive intraretinal or subretinal exudative fluid can be observed and the corresponding macula will be considered dry. Once a dry macula is achieved the interval between visits is then lengthened by 2-week increments, at every visit the macula is dry. IVT ranibizumab will be rendered at every visit, no earlier than 7 days before the target date and no later than 7 days after the target date; the interval between visits is individualized based on each patient's response to treatment. The interval between injections will not exceed 12 weeks After a subject is extended beyond 4-weeks and develops recurrent exudative disease activity, the eye is treated and the treatment interval for the next visit is reduced by 2 weeks, compared to the previous treatment interval. The interval between treatments will be reduced by 2-week intervals until a dry macula is again established. Once a dry macula is again achieved, the interval between visits will be extended by 1-week intervals, instead of 2-week intervals. For example: If recurrent exudative disease activity is detected after an 8-week interval, the eye is treated and the interval for the next visit is reduced to 6 weeks; if the macula is then dry after the 6-week interval, the interval is increased to 7 weeks. If the macula is then dry after the 7-week interval, the interval is increased to 8 weeks, etc. Once an eye is extended by 1-week intervals, if recurrent exudative disease is detected again, the treatment interval for the next visit is reduced by 1 week, compared to the previous treatment interval, and will continue to be decreased by 1-week intervals until dry or the 4-week interval is reached. Once a dry macula is again established, the most recent interval between treatments is maintained for one additional visit; if the macula remains dry at this time, the interval will then be extended by 1-week increments. If an eye exhibits recurrent exudative disease activity 3 times at a given interval and is unable to extend beyond that interval, the eye will continue treatment at the next shorter interval for 3 consecutive visits. After these 3 visits, the interval between visits will again be extended by 1-week intervals, while the macula remains dry. If the eye exhibits recurrent exudative disease activity, the interval will be decreased by 1-week intervals until the macula is again dry. The eye will then continue treatment at this interval for 3 consecutive visits before extending by 1-week again. This pattern of repeating 3 visits at the same dry interval will be repeated each time after the eye becomes wet before again attempting another 1-week extension. Evidence of recurrent exudative activity Clinical evidence of recurrent exudative disease activity requiring reducing the interval between treatments includes any of the following: Evidence of subretinal or intraretinal fluid on SD-OCT which is not classified as small intraretinal cystic areas unrelated to active exudative AMD (Appendix D) or minimal increased retinal thickening by SD-OCT without definitive intraretinal or subretinal fluid New macular hemorrhage related to active exudative AMD. ETDRS VA loss of 5 letters from the previous measurement due to neovascular AMD disease process with corresponding SD-OCT evidence of fluid in the macula. Increase in CRT of 50 microns due to active exudative AMD. The isolated presence of a PED, or enlargement of a PED, does not constitute evidence of exudative disease activity. If an eye has an ETDRS VA decrease of ≥ 4 lines (20 letters) or a subretinal macular hemorrhage of 1DD or larger, at any point during the trial, the subject will subsequently be treated with ranibizumab every 4 weeks. Week 104 - Week 156 Starting at Week 104 subjects who have achieved a dry macula, at the 12 week interval will be seen monthly and treated pro re nata (PRN) based on pre-defined re-treatment criteria. Study visits should be scheduled to occur every 28 (±7) days relative to the date of week 104 visit. Retreatment criteria for PRN phase Re-treatment will be initiated if any of the following criteria are met: Presence of any abnormal intraretinal or subretinal fluid on high resolution SD- OCT. Presence of new intraretinal or subretinal hemorrhage related to AMD on examination. 10 letter loss from previous visit, related to active wet AMD in the opinion of the treating investigator Starting at Week 104, subjects who have NOT achieved extension to the 12-week treatment interval will continue with the treat and extend protocol. At any time during weeks 104 to 156 if a subject achieves a dry macula, at the 12-week interval, they will immediately begin monthly PRN treatment based on pre-defined re-treatment criteria. Study visits should be scheduled to occur every 28 (±7) days, relative to the date the 12-week interval is achieved. Subjects will not be treated at the visit they achieve the 12 week interval (this is the date PRN treatment will begin).

Official Title
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A Phase IIIb, Multicenter, Randomized, Controlled Study of the Safety, Tolerability and Efficacy of IVT 0.5mg Ranibizumab Monthly Compared to a Treat & Extend Protocol in Patients With Wet Age-related Macular Degeneration (T-REX)

Conditions
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Macular Degeneration

Intervention / Treatment
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* Drug: 0.5 mg ranibizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide written informed consent and comply with study assessments for the full duration of the study Age > 50 years Ability and willingness to return for all scheduled visits and assessments Any CNVM lesion (Occult, Minimally Classic or Classic) (i.e., leakage on fluorescein angiography or subretinal, intraretinal activity on SDOCT) secondary to age-related macular degeneration. Best corrected visual acuity in the study eye, using ETDRS testing, between 20/32 and 20/400 (Snellen equivalent), inclusive. -The total area of subretinal hemorrhage and fibrosis must comprise less than 50% of the total lesion. Clear ocular media and adequate pupillary dilation to permit good quality fundus imaging. Exclusion Criteria: Subretinal hemorrhage in the study eye that involves the center of the fovea, if the size of the hemorrhage is either > 50% of the total area of the lesion or > 1 disc area (2.54 mm2) in size Subfoveal fibrosis or atrophy in the study eye CNV in either eye due to other causes, such as ocular histoplasmosis, trauma, or pathologic myopia

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Monthly IVT ranibizumab<br>Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart | Drug: 0.5 mg ranibizumab<br>* Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.<br>* Other names: Lucentis;|
| Experimental: Treat and Extend IVT ranibizumab<br>0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) | Drug: 0.5 mg ranibizumab<br>* Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.<br>* Other names: Lucentis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in BCVA by ETDRS Letter Score From Baseline | Mean change in Best-Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) letter score from baseline through weeks 24-28, baseline through weeks 48-56, baseline through weeks 72-82, baseline to week 104, baseline through weeks 128-132 and baseline to week 156. The ETDRS protocol is a widely accepted international standard for macular laser photocoagulation treatment. A higher score represents better functioning. The scale ranges from 0 to 100 letters | 6, 12, 18, 24, 30, and 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Adverse Events (Ocular and Non-ocular) | Incidence and severity of adverse events both ocular and non-ocular | 36 months | 
| Total Number of Intravitreal Injections Required | Total number of intravitreal injections required from baseline through weeks 48-57 (week closest to week 52), baseline through week 104 and baseline through week 156. | 12, 24, and 36 months | 
| Total Number of Office Visits and Imaging Studies Performed During Study Period | Total number of office visits and imaging studies performed from baseline through weeks 24-28 (week closest to week 26), baseline through weeks 48-56 (week closest to week 52), baseline through weeks 72-82 (week closest to week 78), baseline through week 104, baseline through weeks 128-132 (week closest to week 132) and baseline through week 156 | 6, 12, 18, 24, 30, and 36 months | 
| Percentage of Subjects With Persistent Active Exudation on SD-OCT | Percentage of subjects with persistent active exudation on SD-OCT from baseline through weeks 48-57 (week closest to week 52), baseline through week 104 and baseline through week 156. | 12, 24, and 36 months | 
| Mean Change in Central Foveal Thickness | Mean change in central foveal thickness by SD-OCT from baseline to weeks 48-57, baseline to week 104 and baseline to week 156. | 12, 24, and 36 months | 
| Percentage of Patients With Persistent Leakage on Fluorescein Angiography | Percentage of subjects with persistent leakage on fluorescein angiography from baseline through weeks 24-28, baseline to weeks 48-56, baseline to weeks 72-82, baseline to week 104, baseline to weeks 128- 132 and baseline to week 156. | 6, 12, 18, 24, 30, and 36 months | 
| CNVM Lesion Size | CNVM lesion size at baseline, compared to baseline to weeks 24-28, baseline to weeks 48-56, baseline to weeks 72-82, baseline to week 104, baseline to weeks 128-132 and baseline to week 156, as determined by fluorescein angiography. | 6, 12, 18, 24, 30, and 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Age related, Macular, sub retinal fluid, Age related Macular degeneration