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T-REX: Treat & Extend Treatment With 0.5mg Ranibizumab vs Monthly Treatment With 0.5mg Ranibizumab

Sponsor
Charles C Wykoff, PhD, MD (Other)
Overall Status
Completed
CT.gov ID
NCT01748292
Collaborator
Genentech, Inc. (Industry)
60
Enrollment
4
Locations
2
Arms
50
Actual Duration (Months)
15
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: 0.5 mg ranibizumab
 Phase 3

Detailed Description

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:

  1. Resolution of intraretinal and subretinal fluid

  2. 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:

  1. 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

  2. New macular hemorrhage related to active exudative AMD.

  3. 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.

  4. 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).

Study Design

Study Type:
Interventional
Actual Enrollment :
60 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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)
Actual Study Start Date :
Dec 1, 2012
Actual Primary Completion Date :
Feb 1, 2017
Actual Study Completion Date :
Feb 1, 2017

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Monthly IVT ranibizumab

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
Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
Other Names:
  • Lucentis

    		•
    Experimental: Treat and Extend IVT ranibizumab

    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
    Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
    Other Names:
  • Lucentis

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Mean Change in BCVA by ETDRS Letter Score From Baseline [6, 12, 18, 24, 30, and 36 months]

      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

    Secondary Outcome Measures

    1. Incidence and Severity of Adverse Events (Ocular and Non-ocular) [36 months]

      Incidence and severity of adverse events both ocular and non-ocular

    2. Total Number of Intravitreal Injections Required [12, 24, and 36 months]

      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.

    3. Total Number of Office Visits and Imaging Studies Performed During Study Period [6, 12, 18, 24, 30, and 36 months]

      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

    4. Percentage of Subjects With Persistent Active Exudation on SD-OCT [12, 24, and 36 months]

      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.

    5. Mean Change in Central Foveal Thickness [12, 24, and 36 months]

      Mean change in central foveal thickness by SD-OCT from baseline to weeks 48-57, baseline to week 104 and baseline to week 156.

    6. Percentage of Patients With Persistent Leakage on Fluorescein Angiography [6, 12, 18, 24, 30, and 36 months]

      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.

    7. CNVM Lesion Size [6, 12, 18, 24, 30, and 36 months]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    50 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Palmetto Retina Center West Columbia South Carolina United States 29169
    2 Retina Consultants of Houston/The Medical Center Houston Texas United States 77030
    3 Retina Consultants of Houston/Katy office Katy Texas United States 77494
    4 Retina Consultants of Houston The Woodlands Texas United States 77384

    Sponsors and Collaborators

    • Charles C Wykoff, PhD, MD
    • Genentech, Inc.

    Investigators

    • Principal Investigator: Charles C Wykoff, PhD, MD, Retinal Consultants of Houston

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Charles C Wykoff, PhD, MD, Deputy Director of Research, Greater Houston Retina Research
    ClinicalTrials.gov Identifier:
    NCT01748292
    Other Study ID Numbers:
    • ML28513
    First Posted:
    Dec 12, 2012
    Last Update Posted:
    Jun 4, 2019
    Last Verified:
    May 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Charles C Wykoff, PhD, MD, Deputy Director of Research, Greater Houston Retina Research
    Age related
    Macular
    sub retinal fluid
    Age related Macular degeneration
    Additional relevant MeSH terms:
    Macular Degeneration
    Ranibizumab

    Study Results

    Participant Flow

    Recruitment Details Sixty patients were enrolled between February 2013 and January 2014.
    Pre-assignment Detail
    Arm/Group Title Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Arm/Group Description Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. 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) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
    Period Title: Overall Study
    STARTED 20 40
    COMPLETED 18 28
    NOT COMPLETED 2 12

    Baseline Characteristics

    Arm/Group Title Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab Total
    Arm/Group Description Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. 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) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. Total of all reporting groups
    Overall Participants 20 40 60
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    79
    76
    77
    Sex: Female, Male (Count of Participants)
    Female
    12
    60%
    26
    65%
    38
    63.3%
    Male
    8
    40%
    14
    35%
    22
    36.7%
    Race and Ethnicity Not Collected (Count of Participants)
    Count of Participants [Participants]
    0
    0%
    Number of Right Eyes Enrolled (Count of Participants)
    Count of Participants [Participants]
    10
    50%
    16
    40%
    26
    43.3%
    Number of Participants with Posterior Chamber Intraocular Lenses (Count of Participants)
    Count of Participants [Participants]
    10
    50%
    22
    55%
    32
    53.3%
    Diabetes Mellitus (Count of Participants)
    Count of Participants [Participants]
    2
    10%
    9
    22.5%
    11
    18.3%
    Hypertension (Count of Participants)
    Count of Participants [Participants]
    16
    80%
    31
    77.5%
    47
    78.3%
    Early Treatment Diabetic Retinopathy Study Best-Corrected Visual Acuity (letters) [Mean (Full Range) ]
    Mean (Full Range) [letters]
    60.3
    59.9
    60.0
    Central Retinal Thickness (microns) [Mean (Full Range) ]
    Mean (Full Range) [microns]
    533
    489
    511

    Outcome Measures

    1. Primary Outcome
    Title Mean Change in BCVA by ETDRS Letter Score From Baseline
    Description 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
    Time Frame 6, 12, 18, 24, 30, and 36 months

    Outcome Measure Data

    Analysis Population Description
    All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals in the Treat and Extend arm, the population analyzed at each time point is equal to or smaller than the population still enrolled at that time point.
    Arm/Group Title Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Arm/Group Description Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. 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) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
    Measure Participants 20 40
    Month 6
    10.5
    (1.3)
    7.3
    (1.9)
    Month 12
    9.2
    (1.4)
    10.5
    (2.0)
    Month 18
    10.4
    (1.9)
    9.0
    (3.2)
    Month 24
    10.5
    (1.9)
    8.7
    (3.6)
    Month 30
    9.7
    (2.3)
    .95
    (4.4)
    Month 36
    8.6
    (2.8)
    4.1
    (4.0)
    2. Secondary Outcome
    Title Incidence and Severity of Adverse Events (Ocular and Non-ocular)
    Description Incidence and severity of adverse events both ocular and non-ocular
    Time Frame 36 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Arm/Group Description Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. 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) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
    Measure Participants 20 40
    Participants Experiencing Serious Ocular AE
    2
    10%
    6
    15%
    Participants Experiencing Serious Systemic AE
    7
    35%
    20
    50%
    3. Secondary Outcome
    Title Total Number of Intravitreal Injections Required
    Description 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.
    Time Frame 12, 24, and 36 months

    Outcome Measure Data

    Analysis Population Description
    All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals in the Treat and Extend arm, the population analyzed at each time point is equal to or smaller than the population still enrolled at that time point.
    Arm/Group Title Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Arm/Group Description Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. 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) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
    Measure Participants 20 40
    Month 12
    13.0
    10.1
    Month 24
    25.5
    18.6
    Month 36
    31.5
    25
    4. Secondary Outcome
    Title Total Number of Office Visits and Imaging Studies Performed During Study Period
    Description 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
    Time Frame 6, 12, 18, 24, 30, and 36 months

    Outcome Measure Data

    Analysis Population Description
    Per protocol, imaging was conducted at each study visit and is assumed to be perfectly correlated with the number of visits. Therefore, only visits were specifically analyzed. Additionally, given the high correlation between number of visits and injections administered (reported previously), this analysis was performed only at M12, M24, and M36.
    Arm/Group Title Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Arm/Group Description Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. 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) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
    Measure Participants 20 40
    Number of Visits through Month 12
    262
    364
    Number of Visits through Month 24
    560
    838
    Number of Visits through Month 36
    801
    1143
    5. Secondary Outcome
    Title Percentage of Subjects With Persistent Active Exudation on SD-OCT
    Description 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.
    Time Frame 12, 24, and 36 months

    Outcome Measure Data

    Analysis Population Description
    All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals in the Treat and Extend arm, the population analyzed at each time point is equal to or smaller than the population still enrolled at that time point.
    Arm/Group Title Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Arm/Group Description Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. 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) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
    Measure Participants 20 40
    Month 12
    3
    15%
    9
    22.5%
    Month 24
    5
    25%
    9
    22.5%
    Month 36
    9
    45%
    8
    20%
    6. Secondary Outcome
    Title Mean Change in Central Foveal Thickness
    Description Mean change in central foveal thickness by SD-OCT from baseline to weeks 48-57, baseline to week 104 and baseline to week 156.
    Time Frame 12, 24, and 36 months

    Outcome Measure Data

    Analysis Population Description
    All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals in the Treat and Extend arm, the population analyzed at each time point is equal to or smaller than the population still enrolled at that time point.
    Arm/Group Title Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Arm/Group Description Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. 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) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
    Measure Participants 20 40
    Month 12
    -246
    (43)
    -173
    (31)
    Month 24
    -170
    (37)
    -170
    (37)
    Month 36
    -188
    (42)
    -183
    (32)
    7. Secondary Outcome
    Title Percentage of Patients With Persistent Leakage on Fluorescein Angiography
    Description 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.
    Time Frame 6, 12, 18, 24, 30, and 36 months

    Outcome Measure Data

    Analysis Population Description
    This analysis was never performed because we were logistically unable to collect the data.
    Arm/Group Title Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Arm/Group Description Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. 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) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
    Measure Participants 0 0
    8. Secondary Outcome
    Title CNVM Lesion Size
    Description 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.
    Time Frame 6, 12, 18, 24, 30, and 36 months

    Outcome Measure Data

    Analysis Population Description
    This analysis was never performed because we were logistically unable to collect the data.
    Arm/Group Title Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Arm/Group Description Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. 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) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
    Measure Participants 0 0

    Adverse Events

    Time Frame 3 years (entire study period)
    Adverse Event Reporting Description Adverse events were assessed at every study visit during the 3-year study
    Arm/Group Title Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Arm/Group Description Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit. 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) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
    All Cause Mortality
    Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/20 (0%) 3/40 (7.5%)
    Serious Adverse Events
    Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 7/20 (35%) 23/40 (57.5%)
    Cardiac disorders
    Myocardial infarction 0/20 (0%) 0 1/40 (2.5%) 1
    Atrial fibrillation 0/20 (0%) 0 1/40 (2.5%) 1
    Coronary artery disease 0/20 (0%) 0 1/40 (2.5%) 1
    Eye disorders
    Unexplained vision loss, left eye 0/20 (0%) 0 1/40 (2.5%) 1
    Retinal pigment epithelium tear 0/20 (0%) 0 1/40 (2.5%) 1
    Subretinal hemorrhage 0/20 (0%) 0 1/40 (2.5%) 1
    Gastrointestinal disorders
    (Death) hypoxemia; gastrointestinal bleed; duodenal ulcer 0/20 (0%) 0 1/40 (2.5%) 1
    General disorders
    Leukocytosis 1/20 (5%) 1 0/40 (0%) 0
    Abdominal pain 0/20 (0%) 0 1/40 (2.5%) 1
    Hepatobiliary disorders
    Acute cholecystitis with abnormal liver function tests 0/20 (0%) 0 1/40 (2.5%) 1
    Infections and infestations
    Acute varicella zoster encephalitis 0/20 (0%) 0 1/40 (2.5%) 1
    Meningitis, urinary tract infection, and congestive heart failure 0/20 (0%) 0 1/40 (2.5%) 1
    Influenza B 0/20 (0%) 0 1/40 (2.5%) 1
    Injury, poisoning and procedural complications
    Fall 1/20 (5%) 1 4/40 (10%) 4
    Broken ribs 1/20 (5%) 1 0/40 (0%) 0
    (Death) High cervical vertebral fracture w/ severed spinal cord tear in descending aorta 0/20 (0%) 0 1/40 (2.5%) 1
    Motor vehicle accident 0/20 (0%) 0 1/40 (2.5%) 1
    Musculoskeletal and connective tissue disorders
    Worsening of gout, cellulitis 1/20 (5%) 1 0/40 (0%) 0
    Osteoarthritis 0/20 (0%) 0 1/40 (2.5%) 1
    Worsening of arthritis 1/20 (5%) 1 0/40 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer 0/20 (0%) 0 1/40 (2.5%) 1
    Breast cancer 1/20 (5%) 1 1/40 (2.5%) 1
    Small cell lung cancer 0/20 (0%) 0 1/40 (2.5%) 1
    Nervous system disorders
    Cerebrovascular accident 2/20 (10%) 2 1/40 (2.5%) 1
    (Death) Hemorrhagic stroke 0/20 (0%) 0 1/40 (2.5%) 1
    Respiratory, thoracic and mediastinal disorders
    Severe pneumonia, dehydration, anemia, COPD, emphysema, lung cancer 0/20 (0%) 0 1/40 (2.5%) 1
    Bronchitis and Pleural Effusion 1/20 (5%) 1 0/40 (0%) 0
    Worsening of COPD 0/20 (0%) 0 1/40 (2.5%) 1
    Interstitial lung disease 1/20 (5%) 1 0/40 (0%) 0
    Vascular disorders
    Temporal arteritis 0/20 (0%) 0 1/40 (2.5%) 1
    Hypotension 0/20 (0%) 0 1/40 (2.5%) 1
    Other (Not Including Serious) Adverse Events
    Monthly IVT Ranibizumab Treat and Extend IVT Ranibizumab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/20 (10%) 4/40 (10%)
    Eye disorders
    Subretinal hemorrhage 1/20 (5%) 1 1/40 (2.5%) 1
    Progressive macular atrophy 0/20 (0%) 0 3/40 (7.5%) 3
    Hollenhorst plaque 1/20 (5%) 1 0/40 (0%) 0

    Limitations/Caveats

    The key limitation is the small population analyzed through 3 complete years; subject attrition due to elderly population.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Charles C. Wykoff, MD, PhD
    Organization Retina Consultants of Houston
    Phone 713-524-3434
    Email ccwmd@houstonretina.com
    Responsible Party:
    Charles C Wykoff, PhD, MD, Deputy Director of Research, Greater Houston Retina Research
    ClinicalTrials.gov Identifier:
    NCT01748292
    Other Study ID Numbers:
    • ML28513
    First Posted:
    Dec 12, 2012
    Last Update Posted:
    Jun 4, 2019
    Last Verified:
    May 1, 2019