Diabetic Macular Edema
Conditions
Keywords
Diabetic macular edema, DME, ranibizumab, wait and extend
Brief summary
To explore a more clinical feasible treatment regime with ranibizumab for DME to provide satisfactory treatment effect with a lower number of visits and injections.
Detailed description
Diabetes mellitus (DM) is the most common endocrine disease in developed countries, with prevalence estimates ranging between 2 to 5% of the world's population. Diabetic retinopathy (DR) and diabetic macular edema (DME) are common microvascular complications in patients with diabetes and may have a sudden and debilitating impact on visual acuity (VA), eventually leading to blindness. DME is a frequent manifestation of DR and is the major cause of visual loss in patients with DR. If left untreated, \>50% of patients lose \>2 lines of visual acuity (VA) within 2 years. DME mostly affects the working-age population, imposing a significant burden both on society and on individual patients - a burden that is expected to increase with the rising prevalence of diabetes.
Interventions
DRUGLabeled regime arm
Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month.
DRUGWait and Extend regime arm
Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent must be obtained before any assessment is performed. * M or F patients \>18 years of age who have signed an informed consent * Patients with Type 1 or Type 2 DM (according to ADA or WHO guidelines) with HbA1c not more than 12.0% at screening (Visit 1). Patients should be on diet, exercise, and/or pharmacological treatment for diabetes. * Patients with visual impairment due to focal or diffuse macular edema with center involvement in at least one eye, as demonstrated with color fundus photography, fluorescein angiography and OCT within 28 days of the baseline treatment. If both eyes are eligible, the one with the worse visual acuity, as assessed at Visit 1, will be selected for study treatment unless, based on medical reasons, the investigator deems the other eye the more appropriate candidate for study treatment. The study eye must fulfill the following criteria at Visit 1: * BCVA score between 78 and 39 letters, inclusively, using ETDRS-like visual acuity testing charts at a testing distance of 4 meters (approximate Snellen equivalent of 20/32 to 20/160) * Decrease in vision is due to DME and not due to other causes, in the opinion of the investigator
Exclusion criteria
* Concomitant conditions in the study eye according to defined criteria such as infection, inflammation, uncontrolled glaucoma * Active PDR in the study eye or evidence of vitreomacular traction in either eye * Patients who are monocular or have a BCVA score in the non-study eye (fellow eye) £ 24 letters at Visit 1 * Concomitant systemic condition according to defined criteria, eg. history of stroke, uncontrolled diabetes, renal failure, unsatisfactory controlled hypertension * Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days until the expected PD effect has returned to baseline, whichever is longer. * History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes. * History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Best-corrected Visual Acuity at Month 12 | 12 months | Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Injections | 12 months | Mean number of injections over a 12-month treatment period |
| Mean Number of Visits | 12 months | Mean number of visits over a 12-month treatment period |
| Mean Change in Central Retinal Thickness (CRT) | 12 months | CRT was assessed by Optical Coherence Tomography (OCT). |
| Proportion of Patients Who Gained ≥10 Letters | 12 months | BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥10 letters of visual acuity at month 12 as compared with baseline |
| Proportion of Patients Who Gained ≥15 Letters | 12 months | BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥15 letters of visual acuity at month 12 as compared with baseline |
| Proportion of Patients Who Gained ≥5 Letters | 12 months | BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥5 letters of visual acuity at month 12 as compared with baseline |
Countries
Turkey (Türkiye)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Labeled Regime Arm Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month | 45 |
| Wait and Extend Regime Arm Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks. | 42 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Protocol deviation | 2 | 5 |
| Overall Study | Withdrawal of consent | 4 | 2 |
Baseline characteristics
| Characteristic | Labeled Regime Arm | Wait and Extend Regime Arm | Total |
|---|---|---|---|
| Age, Continuous | 61 Years STANDARD_DEVIATION 9.93 | 59.5 Years STANDARD_DEVIATION 9.68 | 60.3 Years STANDARD_DEVIATION 9.78 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 16 Participants | 15 Participants | 31 Participants |
| Sex: Female, Male Male | 29 Participants | 27 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 45 | 0 / 42 |
| other Total, other adverse events | 12 / 45 | 9 / 42 |
| serious Total, serious adverse events | 10 / 45 | 7 / 42 |
Outcome results
Primary
Mean Change in Best-corrected Visual Acuity at Month 12
Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement
Time frame: 12 months
Population: Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Labeled Regime Arm | Mean Change in Best-corrected Visual Acuity at Month 12 | 76.44 Letters | Standard Error 1.78 |
| Wait and Extend Regime Arm | Mean Change in Best-corrected Visual Acuity at Month 12 | 73.09 Letters | Standard Error 1.68 |
p-value: 0.5Wilcoxon (Mann-Whitney)
Secondary
Mean Change in Central Retinal Thickness (CRT)
CRT was assessed by Optical Coherence Tomography (OCT).
Time frame: 12 months
Population: Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Labeled Regime Arm | Mean Change in Central Retinal Thickness (CRT) | 315.7 Micrometers | Standard Error 15.07 |
| Wait and Extend Regime Arm | Mean Change in Central Retinal Thickness (CRT) | 348.9 Micrometers | Standard Error 16.54 |
p-value: 0.082Wilcoxon (Mann-Whitney)
Secondary
Mean Number of Injections
Mean number of injections over a 12-month treatment period
Time frame: 12 months
Population: Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers. Statistical analysis not performed for the injection numbers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Labeled Regime Arm | Mean Number of Injections | 7.4 Injections | Standard Error 0.44 |
| Wait and Extend Regime Arm | Mean Number of Injections | 7.5 Injections | Standard Error 0.44 |
Secondary
Mean Number of Visits
Mean number of visits over a 12-month treatment period
Time frame: 12 months
Population: Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers. Statistical analysis not performed to compare visits
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Labeled Regime Arm | Mean Number of Visits | 11.2 Number of visits | Standard Error 0.19 |
| Wait and Extend Regime Arm | Mean Number of Visits | 10.2 Number of visits | Standard Error 0.24 |
Secondary
Proportion of Patients Who Gained ≥10 Letters
BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥10 letters of visual acuity at month 12 as compared with baseline
Time frame: 12 months
Population: Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Labeled Regime Arm | Proportion of Patients Who Gained ≥10 Letters | 23 Participants |
| Wait and Extend Regime Arm | Proportion of Patients Who Gained ≥10 Letters | 15 Participants |
p-value: 0.072Chi-squared
Secondary
Proportion of Patients Who Gained ≥15 Letters
BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥15 letters of visual acuity at month 12 as compared with baseline
Time frame: 12 months
Population: Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Labeled Regime Arm | Proportion of Patients Who Gained ≥15 Letters | 12 Participants |
| Wait and Extend Regime Arm | Proportion of Patients Who Gained ≥15 Letters | 10 Participants |
p-value: 0.466Chi-squared
Secondary
Proportion of Patients Who Gained ≥5 Letters
BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥5 letters of visual acuity at month 12 as compared with baseline
Time frame: 12 months
Population: Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Labeled Regime Arm | Proportion of Patients Who Gained ≥5 Letters | 29 Participants |
| Wait and Extend Regime Arm | Proportion of Patients Who Gained ≥5 Letters | 22 Participants |
p-value: 0.095Chi-squared