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Long-Term Efficacy & Safety of Aflibercept IVT for the Treatment of DME in Subjects Who Completed the VISTA-DME Trial

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ClinicalTrials.gov Identifier: NCT02299336
Recruitment Status : Completed
First Posted : November 24, 2014
Results First Posted : June 7, 2018
Last Update Posted : June 4, 2019
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Charles C Wykoff, PhD, MD, Greater Houston Retina Research

Tracking Information
First Submitted Date  ICMJE October 15, 2014
First Posted Date  ICMJE November 24, 2014
Results First Submitted Date  ICMJE January 9, 2018
Results First Posted Date  ICMJE June 7, 2018
Last Update Posted Date June 4, 2019
Actual Study Start Date  ICMJE November 24, 2014
Actual Primary Completion Date January 9, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 7, 2018)
Mean Number of Intravitreal Aflibercept Injections for Subjects Who Were Enrolled and Completed the 3-year VISTA DME (VGFT-OD-1009) Trial [ Time Frame: Week 104 ]
Measured by evaluating mean number of injections required for subjects who were enrolled and completed the 3-year VISTA DME (VGFT-OD-1009) trial
Original Primary Outcome Measures  ICMJE
 (submitted: November 20, 2014)
Assess the need for ongoing intravitreal aflibercept injections for subjects who were enrolled and completed the 3-year VISTA DME (VGFT-OD-1009) trial [ Time Frame: 52 weeks ]
Measureed by evaluating proportion of subjects receiving 0 injections and o mean number of injections.
Change History Complete list of historical versions of study NCT02299336 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 15, 2019)
  • Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity From Baseline to Week 52 and Baseline to Week 104 [ Time Frame: Week 52, Week 104 ]
    Evaluate the mean change over time in Early Treatment Diabetic Retinopathy Study best-corrected visual acuity at week 52 from baseline and at week 104 from baseline. Participants were challenged with reading letters on lines of an eye chart (5 letters per line) in standardized lighting conditions. Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until they reached a row where a minimum of three letters on a line could be read, and were scored by how many letters could be correctly identified.
  • Mean Number of Intravitreal Aflibercept Injections Before and After Receiving First Focal Laser Application. [ Time Frame: Before First Focal Laser Treatment (FLT) at Week 12 or later; After First FLT at up to 104 weeks ]
    Measure the role of focal laser treatment (fluorescein angiography-guided, if applicable) in decreasing the treatment burden among subjects who require ongoing aflibercept treatment in the management of diabetic macular edema.
  • Percentage of Subjects With Gain or Loss of 0 to 5 Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity Letters From Baseline to Week 52 and Baseline to Week 104 [ Time Frame: Week 52, Week 104 ]
    Evaluate the percentage of subjects with a gain or loss in Early Treatment Diabetic Retinopathy Study best-corrected visual acuity letters in patients treated with aflibercept from baseline to week 52 and baseline to week 104
  • Mean Change in Central Retinal Thickness From Baseline to Week 52 and Baseline to Week 104. [ Time Frame: Week 52, Week 104 ]
    Evaluate the mean change in central retinal thickness from baseline to week 52 and baseline to week 104 in patients treated with aflibercept.
  • Number of Subjects With no Clinically-relevant Diabetic Macular Edema (as Defined in the Protocol) on Spectral Domain Optical Coherence Tomography From Baseline to Week 52 and Baseline to Week 104. [ Time Frame: Week 52, Week 104 ]
    Evaluate the number of subjects with no clinically-relevant diabetic macular edema (as defined in the protocol) on spectral domain optical coherence tomography from baseline to week 52 and baseline to week 104 in patients treated with aflibercept.
  • Number of Subjects With Stable, Worsened, or Improved Diabetic Retinopathy [ Time Frame: Week 52, Week 104 ]
    Number of subjects with stable, worsened, or improved diabetic retinopathy through 104 weeks.
  • Number of Subjects That Receive Focal Laser Treatment. [ Time Frame: Week 52, Week 104 ]
    Number of subjects that receive focal laser treatment from baseline to week 52 and from baseline to week 104.
  • Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity Before and After Focal Laser Therapy [ Time Frame: 104 weeks ]
    Evaluation of the effect of laser on Early Treatment Diabetic Retinopathy Study best-corrected visual acuity outcomes. Participants were challenged with reading letters on lines of an eye chart (5 letters per line) in standardized lighting conditions. Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until they reached a row where a minimum of three letters on a line could be read, and were scored by how many letters could be correctly identified.
  • Mean Change in Central Retinal Thickness Before and After First Focal Laser Treatment [ Time Frame: 104 weeks ]
    Evaluate the mean change in central retinal thickness before and after first focal laser treatment in patients treated with pro re nata aflibercept.
  • Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Past and Future Anti-VEGF Treatment Burden [ Time Frame: Week 52, Week 104 ]
    Mean number of injections in 52 weeks and 104 weeks based on quantification of ischemic areas
  • Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Visual Outcomes [ Time Frame: Week 52, Week 104 ]
    Mean change in visual acuity from baseline to week 52 and baseline to week 104 based on quantification of ischemic areas
  • Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Anatomic Outcomes [ Time Frame: Week 52, Week 104 ]
    Mean change in central retinal thickness from baseline to week 52 based on quantification of ischemic areas
Original Secondary Outcome Measures  ICMJE
 (submitted: November 20, 2014)
  • Characterize longer-term efficacy of intravitreal aflibercept injections in the management of DME [ Time Frame: 52 weeks ]
    By evaluating:
    • Mean change in visual acuity from baseline to week 52
    • Proportion of subjects with gain or loss of 0 to 5 letters from baseline to week 52
    • Mean change in central retinal thickness from baseline to week 52
    • Percentage of subjects with no CR-DME (as defined in the protocol) on SD-OCT from baseline to week 52
    • Proportion of subjects with stable, worsened, or improved diabetic retinopathy
    • Incidence and severity of ocular and systemic adverse events
  • Characterize longer-term safety of intravitreal aflibercept injections in the management of DME by evaluating [ Time Frame: 52 weeks ]
    By evaluating:
    • Mean change in visual acuity from baseline to week 52
    • Proportion of subjects with gain or loss of 0 to 5 letters from baseline to week 52
    • Mean change in central retinal thickness from baseline to week 52
    • Percentage of subjects with no CR-DME (as defined in the protocol) on SD-OCT from baseline to week 52
    • Proportion of subjects with stable, worsened, or improved diabetic retinopathy
    • Incidence and severity of ocular and systemic adverse events
  • Evaluate the role of focal laser treatment (fluorescein angiography-guided, if applicable) in decreasing the treatment burden among subjects who require ongoing aflibercept treatment in the management of DME [ Time Frame: 52 weeks ]
    Measured by:
    • Proportion of subjects that receive focal laser treatment (FLT)
    • Mean number of intravitreal aflibercept injections before and after receiving FLT
    • Mean change in visual acuity from baseline to week 52
    • Mean change in central retinal thickness from baseline to week 52
    • Incidence and severity of ocular and systemic adverse events
  • Evaluate the role of (ultrawide-field, if available) baseline vs 52 week fluorescein angiography-determined retina ischemia in predicting past and future anti-VEGF treatment burden, anatomic and visual outcomes: [ Time Frame: 52 weeks ]
    Measured by:
    • Mean number of injections in 52 weeks based on quantification of ischemic areas
    • Mean change in visual acuity from baseline to week 52 based on quantification of ischemic areas
    • Mean change in central retinal thickness from baseline to week 52 based on quantification of ischemic areas
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Long-Term Efficacy & Safety of Aflibercept IVT for the Treatment of DME in Subjects Who Completed the VISTA-DME Trial
Official Title  ICMJE Long-Term Efficacy and Safety of Intravitreal Aflibercept Injections for the Treatment of Diabetic Macular Edema in Subjects Who Completed the Three Year VISTA-DME Trial .
Brief Summary The Endurance Trial is a phase IV open label clinical study to assess the need for ongoing intravitreal aflibercept injections after the 3-year VISTA DME (VGFT-OD-1009; NCT01363440) end-point. Subjects will be treated with intravitreal aflibercept injections pro re nata (PRN) based on the presence of CR-DME (Clinically Relevant-DME). In addition, subjects who meet re-treatment criteria will be eligible for focal laser treatment every 90 days.
Detailed Description

The investigational product is aflibercept, which will be supplied by Regeneron Pharmaceuticals, Inc. in sterile vials for intravitreal (IVT) injection. Vials must be used (defined as entered with needle) only once. All drug supplies are to be kept under recommended storage conditions.

The injection volume will be 50μL (0.05 mL) and will be administered to the subjects by IVT injection.

Throughout the trial, subjects will be treated with intravitreal aflibercept injections PRN in the presence of CR-DME; this is defined as DME that the treating investigator believes is limiting visual function.

All subjects will initially be evaluated every 4 weeks (28 days) for CR-DME and treated PRN. If CR-DME is present the subject will receive IVT aflibercept injection. If CR-DME is not present the subject will not receive an IVT aflibercept injection and will be observed.

At any point throughout the study, once a subject has been evaluated and observed (with no IVT aflibercept) for a total of 8 weeks (3 consecutive monthly visits), the interval between visits will be increased to 8 weeks.

After an additional 24 weeks (3 consecutive visits, every 8 weeks) without an IVT aflibercept injection, the interval between visits will be increased to 12 weeks.

If a subject has recurrent CR-DME they will receive an IVT aflibercept injection and the interval between visits will reduce back to 4 weeks. Subjects can again extend the interval between visits to 8 weeks once they have not received an IVT aflibercept injection for a total of 8 weeks (3 consecutive visits) as described above. Extension to 12 weeks is then performed as above.

Starting at week 52, once a subject has extended to a 12 week interval, if CR-DME is not present the subject will not receive an IVT aflibercept injection and will be extended to a 16 week interval. Once at a 16 week interval, if CR-DME is not present the subject will not receive an IVT aflibercept injection and will be extended to a 20 week interval. At any point past a 12 week interval extension, if a subject has recurrent CR-DME they will receive an IVT aflibercept injection and the interval for the next visit will be reduced at investigator discretion to be either 12 or 16 weeks. If the interval is needed to be reduced to below 12 weeks, the subject will return to a 4 or 8 week interval, at investigator discretion and return to the protocol above.

All subjects receiving PRN IVT aflibercept injections will be evaluated for focal laser treatment beginning at week 12 through the end of the study. If the subject meets any of the criteria for focal laser treatment (FLT), fluorescein angiography (FA) will be performed to guide the focal laser treatment. Focal laser treatment and focal laser re-treatment will be administered no more than once every 90 days.

When a subject receives ≥ 2 IVT aflibercept injections in ≤ 24 weeks FLT will be applied. Once the initial session of FLT is applied subjects are eligible for FLT re-treatment after 90 days, when they have received ≥ 2 IVT aflibercept injections within the prior 90 day period.

FLT will be applied to:

  1. All leaking microaneurysms.
  2. Grid to all areas of diffuse leakage.
  3. Grid to all areas of retinal ischemia outside of the FAZ (once ischemic areas are treated once with grid FLT, these same areas should not be treated again).
  4. Laser will not be applied within the capillaries of the FAZ.

FLT will not be applied if any of the following apply and are identified:

  1. Significant macular ischemia involving the foveal avascular zone (once this has been determine additional fluorescein angiography for FLT planning should not be performed and subjects will not longer be eligible for rescue FLT).
  2. Treatment would be too close to the foveal avascular zone.
  3. Macular edema is not related to DME (eg: postoperative CME, etc).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Diabetic Macular Edema
Intervention  ICMJE
  • Drug: Aflibercept
    pro re nata (PRN)
    Other Name: Eylea
  • Procedure: Focal Laser
    Focal laser administered based on pre-specified criteria
Study Arms  ICMJE PRN (pro re nata)
2 mg intravitreal aflibercept (Eylea) PRN, focal laser administered based on pre-specified criteria, 104 weeks
Interventions:
  • Drug: Aflibercept
  • Procedure: Focal Laser
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 7, 2018)
60
Original Estimated Enrollment  ICMJE
 (submitted: November 20, 2014)
35
Actual Study Completion Date  ICMJE January 9, 2017
Actual Primary Completion Date January 9, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • A subject must meet the following criteria to be eligible for inclusion in the study:

    1. Enrolled and Completed VISTA DME (VGFT-OD-1009) clinical trial
    2. Willing and able to comply with clinic visits and study-related procedures
    3. Provide signed informed consent
    4. Enrollment in the trial within 12 weeks of trial activation.

Exclusion Criteria:

  • A subject who meets any of the following criteria will be excluded from the study:

    1. Prior treatment with anti-VEGF therapy in the study eye within 28 days of baseline
    2. Pregnant or breast-feeding women
    3. Sexually active men* or women of childbearing potential** who are unwilling to practice adequate contraception during the study (adequate contraceptive measures include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device [IUD]; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly).

      • Contraception is not required for men with documented vasectomy. **Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of child bearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02299336
Other Study ID Numbers  ICMJE The Endurance 1 Trial
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
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Charles C Wykoff, PhD, MD, Greater Houston Retina Research
Study Sponsor  ICMJE Greater Houston Retina Research
Collaborators  ICMJE Regeneron Pharmaceuticals
Investigators  ICMJE
Principal Investigator: Charles C Wykoff, MD Greater Houston Retina Research
PRS Account Greater Houston Retina Research
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP