Macular Edema Associated With Diabetes Mellitus
Conditions
Keywords
randomized sham-controlled multicenter macular edema
Brief summary
The purpose of the study is to test whether Macugen injected into the eye improves vision in more patients than the currently existing standard of care laser therapy. The safety of Macugen compared to standard of care laser will also be evaluated.
Interventions
DRUGStandard of Care
Clinicians decision to use optional laser therapy.
DRUGMacugen
Intravitreal injection of Macugen 0.3mg/90ul every 6 weeks up to 2 years.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* macular edema associated with diabetes * visual acuity between 20/50 and 20/200
Exclusion criteria
* recent laser therapy in the eye * recent signs of uncontrolled diabetes * blood pressure worse than 160/100 * severe cardiac disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Greater Than or Equal to ≥10 Letter (or 2 Line) Improvement in Vision at 1 Year | Baseline, Year 1 | Refraction and best-corrected visual acuity (VA) measurements were performed using retro-illuminated, modified Ferris-Bailey Early Treatment Diabetic Retinopathy Study (ETDRS) charts |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a ≥ 15 Letter Improvement in Vision at 1 Year | Baseline, Year 1 | Refraction and best-corrected VA measurements were performed using retro-illuminated, modified Ferris-Bailey ETDRS charts |
| Number of Participants With a ≥ 15 Letter Improvement in Vision at 2 Years | Baseline, Year 2 | Refraction and best-corrected VA measurements were performed using retro-illuminated, modified Ferris-Bailey ETDRS charts |
| Number of Eyes With a 2 or More Step Increase in Degree of Retinopathy at 1 Year | Baseline, Year 1 | Retinopathy changes were monitored using fundus photography and fluorescein angiograph (FA) assessments. An Independent Reading Center, using trained graders, evaluated the presence of retinopathy using a modified 12-step version of the ETDRS Final Retinopathy Severity Scale, that ranged from step 1 (retinopathy level of 10 or 12) to step 12 (retinopathy level of 85A or 85B) where an increase in the step or retinopathy level indicated a worsening of the condition. |
| Number of Eyes With a 2 or More Step Decrease in Degree of Retinopathy at 1 Year | Baseline, Year 1 | Retinopathy changes were monitored using fundus photography and FA assessments. An Independent Reading Center, using trained graders, evaluated the presence of retinopathy using a modified 12-step version of the ETDRS Final Retinopathy Severity Scale, that ranged from step 1 (retinopathy level of 10 or 12) to step 12 (retinopathy level of 85A or 85B) where a decrease in the step or retinopathy level indicated an improvement. |
| Number of Eyes With a 2 or More Step Increase in Degree of Retinopathy at 2 Years | Baseline, Year 2 | Retinopathy changes were monitored using fundus photography and FA assessments. An Independent Reading Center, using trained graders, evaluated the presence of retinopathy using a modified 12-step version of the ETDRS Final Retinopathy Severity Scale, that ranged from step 1 (retinopathy level of 10 or 12) to step 12 (retinopathy level of 85A or 85B) where an increase in the step or retinopathy level indicated a worsening of the condition. |
| Number of Participants With a ≥ 10 Letter (or 2 Line) Improvement in Vision at 2 Years | Baseline, Year 2 | Refraction and best-corrected VA measurements were performed using retro-illuminated, modified Ferris-Bailey ETDRS charts |
| Change From Baseline in Mean VA Score at 1 Year | Baseline, Year 1 | Changes in VA monitored through refraction and best-corrected VA measurements using retro-illuminated, modified Ferris-Bailey ETDRS chart with participants at a 4-meter distance from chart. Distance VA expressed as an ETDRS score (number of letters correctly read) ranging from 0 to 60, where higher ETDRS scores represented better vision. Change from baseline for each patient equaled the visual acuity obtained at the observation minus the visual acuity at baseline. |
| Change From Baseline in Mean VA Score at 2 Years | Baseline, Year 2 | Changes in VA monitored through refraction and best-corrected VA measurements using retro-illuminated, modified Ferris-Bailey ETDRS chart with participants at a 4-meter distance from chart. Distance VA expressed as an ETDRS score (number of letters correctly read) ranging from 0 to 60, where higher ETDRS scores represented better vision. Change from baseline for each patient equaled the visual acuity obtained at the observation minus the visual acuity at baseline. |
| Number of Participants Requiring Focal or Grid Laser Treatment During Year 1 | 1 year | Included focal laser coagulation, focal laser photocoagulation, panretinal laser photocoagulation, retinal laser coagulation, and retinal laser photocoagulation |
| Number of Participants Requiring Focal or Grid Laser Treatment During Year 2 | 2 years | Included focal laser coagulation, focal laser photocoagulation, panretinal laser photocoagulation, retinal laser coagulation, and retinal laser photocoagulation |
| Number of Eyes With a 2 or More Step Decrease in Degree of Retinopathy at 2 Years | Baseline, Year 2 | Retinopathy changes were monitored using fundus photography and FA assessments. An Independent Reading Center, using trained graders, evaluated the presence of retinopathy using a modified 12-step version of the ETDRS Final Retinopathy Severity Scale, that ranged from step 1 (retinopathy level of 10 or 12) to step 12 (retinopathy level of 85A or 85B) where a decrease in the step or retinopathy level indicated an improvement. |
Countries
Australia, Austria, Brazil, Canada, Colombia, Czechia, Denmark, France, Germany, Greece, India, Italy, Netherlands, Portugal, South Africa, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Original protocol included 0.3, 0.03, and 0.003 milligram (mg) pegaptanib sodium and sham treatment groups; the 0.03 and 0.003 mg doses were removed, affected participants given option of receiving 0.3 mg injections of pegaptanib sodium or study withdraw. Later, participants who hadn't completed Year 2 were eligible to enroll in Year 3 extension.
Participants by arm
| Arm | Count |
|---|---|
| 0.3 mg Pegaptanib Sodium Intravitreal injection of pegaptanib sodium, 0.3 mg every 6 weeks up to 2 years. Eligible participants had option to enroll in Year 3, open-label, extension phase during which participants received intravitreal injections of pegaptanib sodium, 0.3 mg every 6 weeks for 1 year. | 145 |
| Sham Standard of care and sham injection (the application of an empty barrel of a needleless syringe). Eligible participants had option to enroll in Year 3, open-label, extension phase during which participants received intravitreal injections of pegaptanib sodium, 0.3 mg every 6 weeks for 1 year. | 143 |
| 0.03 mg Pegaptanib Sodium Intravitreal injection of pegaptanib sodium, 0.03 mg every 6 weeks was planned for up to 2 years. The 0.03 mg dose was removed and participants given option of receiving 0.3 mg injection of pegaptanib sodium every 6 weeks up to 2 years or withdrawing from study. | 22 |
| 0.003 mg Pegaptanib Sodium Intravitreal injection of pegaptanib sodium, 0.003 mg every 6 weeks was planned for up to 2 years. The 0.003 mg dose was removed and participants given option of receiving 0.3 mg injection of pegaptanib sodium every 6 weeks up to 2 years or withdrawing from study. | 7 |
| Total | 317 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Year 1 | Adverse Event | 3 | 1 | 1 | 5 |
| Year 1 | Lost to Follow-up or Patient non-comply | 5 | 1 | 0 | 2 |
| Year 1 | Other | 2 | 1 | 0 | 1 |
| Year 1 | Physician Decision | 7 | 4 | 0 | 6 |
| Year 1 | Protocol Violation | 0 | 0 | 0 | 1 |
| Year 1 | Withdrawal by Subject | 2 | 4 | 0 | 4 |
| Year 2 | Adverse Event | 4 | 0 | 2 | 4 |
| Year 2 | Lost to Follow-up or Patient non-comply | 4 | 0 | 0 | 2 |
| Year 2 | Other | 1 | 0 | 0 | 1 |
| Year 2 | Physician Decision | 11 | 6 | 4 | 11 |
| Year 2 | Withdrawal by Subject | 4 | 0 | 0 | 4 |
| Year 3 Extension | Adverse Event | 2 | 0 | 0 | 2 |
| Year 3 Extension | Lost to Follow-up or Patient non-comply | 2 | 0 | 0 | 0 |
| Year 3 Extension | Other | 2 | 0 | 0 | 0 |
| Year 3 Extension | Physician Decision | 0 | 0 | 0 | 2 |
| Year 3 Extension | Withdrawal by Subject | 2 | 0 | 0 | 5 |
Baseline characteristics
| Characteristic | 0.3 mg Pegaptanib Sodium | Sham | 0.03 mg Pegaptanib Sodium | 0.003 mg Pegaptanib Sodium | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.5 Years STANDARD_DEVIATION 9.2 | 62.4 Years STANDARD_DEVIATION 10.3 | 64.7 Years STANDARD_DEVIATION 8.6 | 57.3 Years STANDARD_DEVIATION 10.1 | 62.5 Years STANDARD_DEVIATION 9.7 |
| Sex: Female, Male Female | 59 Participants | 65 Participants | 11 Participants | 4 Participants | 139 Participants |
| Sex: Female, Male Male | 86 Participants | 78 Participants | 11 Participants | 3 Participants | 178 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 110 / 174 | 15 / 22 | 7 / 7 | 100 / 143 | 11 / 46 | 10 / 54 |
| serious Total, serious adverse events | 42 / 174 | 4 / 22 | 0 / 7 | 35 / 143 | 4 / 46 | 6 / 54 |
Outcome results
Primary
Number of Participants With Greater Than or Equal to ≥10 Letter (or 2 Line) Improvement in Vision at 1 Year
Refraction and best-corrected visual acuity (VA) measurements were performed using retro-illuminated, modified Ferris-Bailey Early Treatment Diabetic Retinopathy Study (ETDRS) charts
Time frame: Baseline, Year 1
Population: Modified Intent-to-Treat (MITT)1 population:participants with at least 1 dose of study treatment who completed baseline VA, had at least 1 post baseline VA assessment within 1 year; 2 sites not analyzed due to Good Clinical Practice deviations; the 0.03 and 0.003mg pegaptanib arms not analyzed for efficacy. Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Pegaptanib Sodium | Number of Participants With Greater Than or Equal to ≥10 Letter (or 2 Line) Improvement in Vision at 1 Year | 49 Participants |
| Sham | Number of Participants With Greater Than or Equal to ≥10 Letter (or 2 Line) Improvement in Vision at 1 Year | 25 Participants |
p-value: 0.004795% CI: [1.32, 4.3]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Mean VA Score at 1 Year
Changes in VA monitored through refraction and best-corrected VA measurements using retro-illuminated, modified Ferris-Bailey ETDRS chart with participants at a 4-meter distance from chart. Distance VA expressed as an ETDRS score (number of letters correctly read) ranging from 0 to 60, where higher ETDRS scores represented better vision. Change from baseline for each patient equaled the visual acuity obtained at the observation minus the visual acuity at baseline.
Time frame: Baseline, Year 1
Population: MITT1 population. LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.3 mg Pegaptanib Sodium | Change From Baseline in Mean VA Score at 1 Year | Baseline | 57.0 scores on a scale | Standard Deviation 8.85 |
| 0.3 mg Pegaptanib Sodium | Change From Baseline in Mean VA Score at 1 Year | Change at 1 year | 5.2 scores on a scale | Standard Deviation 9.94 |
| Sham | Change From Baseline in Mean VA Score at 1 Year | Baseline | 57.5 scores on a scale | Standard Deviation 8.11 |
| Sham | Change From Baseline in Mean VA Score at 1 Year | Change at 1 year | 1.2 scores on a scale | Standard Deviation 11.77 |
p-value: 0.00495% CI: [1.25, 6.54]ANCOVA
Secondary
Change From Baseline in Mean VA Score at 2 Years
Changes in VA monitored through refraction and best-corrected VA measurements using retro-illuminated, modified Ferris-Bailey ETDRS chart with participants at a 4-meter distance from chart. Distance VA expressed as an ETDRS score (number of letters correctly read) ranging from 0 to 60, where higher ETDRS scores represented better vision. Change from baseline for each patient equaled the visual acuity obtained at the observation minus the visual acuity at baseline.
Time frame: Baseline, Year 2
Population: FAS2 population. LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.3 mg Pegaptanib Sodium | Change From Baseline in Mean VA Score at 2 Years | Baseline | 57.0 Scores on a scale | Standard Deviation 8.85 |
| 0.3 mg Pegaptanib Sodium | Change From Baseline in Mean VA Score at 2 Years | Change at Year 2 | 6.2 Scores on a scale | Standard Deviation 10.58 |
| Sham | Change From Baseline in Mean VA Score at 2 Years | Baseline | 57.4 Scores on a scale | Standard Deviation 8.2 |
| Sham | Change From Baseline in Mean VA Score at 2 Years | Change at Year 2 | 1.7 Scores on a scale | Standard Deviation 11.68 |
p-value: 0.001195% CI: [1.85, 7.29]ANCOVA
Secondary
Number of Eyes With a 2 or More Step Decrease in Degree of Retinopathy at 1 Year
Retinopathy changes were monitored using fundus photography and FA assessments. An Independent Reading Center, using trained graders, evaluated the presence of retinopathy using a modified 12-step version of the ETDRS Final Retinopathy Severity Scale, that ranged from step 1 (retinopathy level of 10 or 12) to step 12 (retinopathy level of 85A or 85B) where a decrease in the step or retinopathy level indicated an improvement.
Time frame: Baseline, Year 1
Population: Evaluable participants from MITT1 population. Only 1 eye per participant was assessed in this study. LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Pegaptanib Sodium | Number of Eyes With a 2 or More Step Decrease in Degree of Retinopathy at 1 Year | 10 Eyes |
| Sham | Number of Eyes With a 2 or More Step Decrease in Degree of Retinopathy at 1 Year | 3 Eyes |
p-value: 0.112495% CI: [0.73, 11.55]Cochran-Mantel-Haenszel
Secondary
Number of Eyes With a 2 or More Step Decrease in Degree of Retinopathy at 2 Years
Retinopathy changes were monitored using fundus photography and FA assessments. An Independent Reading Center, using trained graders, evaluated the presence of retinopathy using a modified 12-step version of the ETDRS Final Retinopathy Severity Scale, that ranged from step 1 (retinopathy level of 10 or 12) to step 12 (retinopathy level of 85A or 85B) where a decrease in the step or retinopathy level indicated an improvement.
Time frame: Baseline, Year 2
Population: FAS2 population. Number of participants analyzed (N) = participants with evaluable data. Only 1 eye per participant was assessed in this study. LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Pegaptanib Sodium | Number of Eyes With a 2 or More Step Decrease in Degree of Retinopathy at 2 Years | 17 Eyes |
| Sham | Number of Eyes With a 2 or More Step Decrease in Degree of Retinopathy at 2 Years | 3 Eyes |
p-value: 0.004895% CI: [1.45, 18.06]Cochran-Mantel-Haenszel
Secondary
Number of Eyes With a 2 or More Step Increase in Degree of Retinopathy at 1 Year
Retinopathy changes were monitored using fundus photography and fluorescein angiograph (FA) assessments. An Independent Reading Center, using trained graders, evaluated the presence of retinopathy using a modified 12-step version of the ETDRS Final Retinopathy Severity Scale, that ranged from step 1 (retinopathy level of 10 or 12) to step 12 (retinopathy level of 85A or 85B) where an increase in the step or retinopathy level indicated a worsening of the condition.
Time frame: Baseline, Year 1
Population: Evaluable participants from MITT1 population. Only 1 eye per participant was assessed in this study. LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Pegaptanib Sodium | Number of Eyes With a 2 or More Step Increase in Degree of Retinopathy at 1 Year | 4 Eyes |
| Sham | Number of Eyes With a 2 or More Step Increase in Degree of Retinopathy at 1 Year | 12 Eyes |
p-value: 0.046895% CI: [0.07, 0.99]Cochran-Mantel-Haenszel
Secondary
Number of Eyes With a 2 or More Step Increase in Degree of Retinopathy at 2 Years
Retinopathy changes were monitored using fundus photography and FA assessments. An Independent Reading Center, using trained graders, evaluated the presence of retinopathy using a modified 12-step version of the ETDRS Final Retinopathy Severity Scale, that ranged from step 1 (retinopathy level of 10 or 12) to step 12 (retinopathy level of 85A or 85B) where an increase in the step or retinopathy level indicated a worsening of the condition.
Time frame: Baseline, Year 2
Population: FAS2 population. Number of participants analyzed (N) = participants with evaluable data. Only 1 eye per participant was assessed in this study. LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Pegaptanib Sodium | Number of Eyes With a 2 or More Step Increase in Degree of Retinopathy at 2 Years | 6 Eyes |
| Sham | Number of Eyes With a 2 or More Step Increase in Degree of Retinopathy at 2 Years | 13 Eyes |
p-value: 0.178895% CI: [0.16, 1.42]Cochran-Mantel-Haenszel
Secondary
Number of Participants Requiring Focal or Grid Laser Treatment During Year 1
Included focal laser coagulation, focal laser photocoagulation, panretinal laser photocoagulation, retinal laser coagulation, and retinal laser photocoagulation
Time frame: 1 year
Population: MITT1 population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Pegaptanib Sodium | Number of Participants Requiring Focal or Grid Laser Treatment During Year 1 | 31 Participants |
| Sham | Number of Participants Requiring Focal or Grid Laser Treatment During Year 1 | 53 Participants |
p-value: 0.002395% CI: [0.24, 0.74]Cochran-Mantel-Haenszel
Secondary
Number of Participants Requiring Focal or Grid Laser Treatment During Year 2
Included focal laser coagulation, focal laser photocoagulation, panretinal laser photocoagulation, retinal laser coagulation, and retinal laser photocoagulation
Time frame: 2 years
Population: FAS2 population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Pegaptanib Sodium | Number of Participants Requiring Focal or Grid Laser Treatment During Year 2 | 34 Participants |
| Sham | Number of Participants Requiring Focal or Grid Laser Treatment During Year 2 | 57 Participants |
p-value: 0.000895% CI: [0.23, 0.69]Cochran-Mantel-Haenszel
Secondary
Number of Participants With a ≥ 10 Letter (or 2 Line) Improvement in Vision at 2 Years
Refraction and best-corrected VA measurements were performed using retro-illuminated, modified Ferris-Bailey ETDRS charts
Time frame: Baseline, Year 2
Population: Full Analysis Set (FAS)2 population:participants who had same treatment for 102 weeks (pegaptanib sodium or sham on/before Week 96) with baseline VA assessment, who met the following: had at least 1 post baseline VA within 2 years, before entry into the Year 3 open-label extension phase, or before withdrawing from the study prior to Week 102. LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Pegaptanib Sodium | Number of Participants With a ≥ 10 Letter (or 2 Line) Improvement in Vision at 2 Years | 51 Participants |
| Sham | Number of Participants With a ≥ 10 Letter (or 2 Line) Improvement in Vision at 2 Years | 37 Participants |
p-value: 0.190495% CI: [0.85, 2.53]Cochran-Mantel-Haenszel
Secondary
Number of Participants With a ≥ 15 Letter Improvement in Vision at 1 Year
Refraction and best-corrected VA measurements were performed using retro-illuminated, modified Ferris-Bailey ETDRS charts
Time frame: Baseline, Year 1
Population: MITT1 population. LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Pegaptanib Sodium | Number of Participants With a ≥ 15 Letter Improvement in Vision at 1 Year | 22 Participants |
| Sham | Number of Participants With a ≥ 15 Letter Improvement in Vision at 1 Year | 13 Participants |
p-value: 0.246695% CI: [0.74, 3.34]Cochran-Mantel-Haenszel
Secondary
Number of Participants With a ≥ 15 Letter Improvement in Vision at 2 Years
Refraction and best-corrected VA measurements were performed using retro-illuminated, modified Ferris-Bailey ETDRS charts
Time frame: Baseline, Year 2
Population: FAS2 population. LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Pegaptanib Sodium | Number of Participants With a ≥ 15 Letter Improvement in Vision at 2 Years | 30 Participants |
| Sham | Number of Participants With a ≥ 15 Letter Improvement in Vision at 2 Years | 18 Participants |
p-value: 0.138895% CI: [0.86, 3.26]Cochran-Mantel-Haenszel