Safety, Efficacy and Cost-efficacy of Ranibizumab (Monotherapy or Combination With Laser) in the Treatment of Diabetic Macular Edema (DME)

Study Overview
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Brief Summary
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To evaluate, specifically within the Canadian medical environment, the efficacy, safety and cost-efficacy of ranibizumab administered either as combination therapy (ranibizumab plus laser photocoagulation), or as monotherapy in comparison with the current standard of care (laser photocoagulation monotherapy), in patients with visual impairment due to DME.

Official Title
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A Canadian 12-month, Prospective, Randomized, Open-label, Multicenter, Laser-controlled Phase IIIb Study Assessing the Efficacy, Safety and Cost-efficacy of Ranibizumab as Combination and Monotherapy in Patients With Visual Impairment Due to Diabetic Macular Edema.

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: ranibizumab
* Procedure: Laser


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stable Type 1 or Type 2 diabetes mellitus Visual impairment due to focal or diffuse DME in at least one eye Exclusion Criteria: Active conditions in the study eye that could prevent the improvement of visual acuity on study treatment Active eye infection or inflammation History of stroke, renal failure or uncontrolled hypertension Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: Combination Therapy<br>Participants received ranibizumab intravitreal injection and laser photocoagulation treatments | Drug: ranibizumab<br>* Ranibizumab 0.5 mg fixed loading dose via intravitreal injection, given once per month for 3 consecutive months (Day 1, Month 1 and Month 2). This treatment could be reapllied, depending on symptoms.<br>Procedure: Laser<br>* Laser photocoagulation treatment was administered on Day 1. Subsequent laser treatments could be administered if needed, in accordance with Early Treatment Diabetic Retinopathy Study (ETDRS) guidelines.<br>|
| Experimental: Ranibizumab Monotherapy<br>Participants received ranibizumab intravitreal injection therapy only | Drug: ranibizumab<br>* Ranibizumab 0.5 mg fixed loading dose via intravitreal injection, given once per month for 3 consecutive months (Day 1, Month 1 and Month 2). This treatment could be reapllied, depending on symptoms.<br>|
| Active Comparator: Laser Monotherapy<br>Participants received Laser photocoagulation therapy only | Procedure: Laser<br>* Laser photocoagulation treatment was administered on Day 1. Subsequent laser treatments could be administered if needed, in accordance with Early Treatment Diabetic Retinopathy Study (ETDRS) guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Best Corrected Visual Acuity- (BCVA) at Month 12 | Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (EDTRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of BCVA (EDTRS) is 0 to 100 letters. A positive change from baseline of BCVA indicates improvement. | Baseline and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Months 3,6 and 9 | Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (EDTRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of BCVA (EDTRS)is 0 to 100 letters. A positive change from baseline of BCVA indicates improvement. | Baseline, 3, 6 and 9 months | 
| Change From Baseline in Central Retinal Thickness (CRT) at Months 3,6,9 and 12 | OCT is a diagnostic imaging technique using low-coherence interferometry to produce cross-sectional tomograms of the posterior segment eye structures. OCT was performed prior to study treatment to assess CRT, presence of fluid in the macula (intra-retinal cyst or fluid) and evaluation of image to monitor disease progression/treatment effect and to determine the need to stop/re-initiate ranibizumab treatment | Baseline, 3, 6, 9 and 12 months | 
| Percentage of Patients Achieving a Gain of 15-letters or More (3-lines) in BCVA From Baseline | Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (EDTRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of BCVA (EDTRS) is 0 to 100 letters. A higher percent of patients achieving a gain of ≥15 letters BCVA indicates a better response. | Baseline, 3, 6, 9 and 12 months | 
| Percentage of Patients Achieving Gain of Letters From Baseline in BCVA | Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (EDTRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of BCVA (EDTRS) is 0 to 100 letters. A gain of 5,10,15 or more BCVA letters from baseline indicates improvement. | 12 months | 
| National Eye Institute Visual Functioning Questionnaire - 25 (VFQ-25) Composite Score at Month 12 | The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) was used to measure the influence of visual disability and visual symptoms on general health domains. The 12 subscales in the VFQ-25 are general health, general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. For each question, the patient was asked to rate their condition on a scale of 1-5 or 1-6, where a low number reflects a better outcome. A composite score for a patient is calculated by aggregating and averaging the scores from the 11 sub-scales (excluding general health sub-scale), and an algorithm is apply to give equal weight to each sub-scale. Sub-scales and composite scores are calculated by converting the response from questionnaires into a 0-100 scale, with 0 as the worst possible outcome and 100 as the best. Missing data was not imputed | 12 month | 
| EuroQoL (EQ-5D) Utility Score at Month 12 | The Euro Quality of Life Questionnaire (EQ-5D) standardized instrument was utilized to measure health outcomes related to 5 dimensions, namely: mobility, self-care, usual activities, pain-discomfort, and anxiety/depression. The possible range for each dimension was 1 to 3, where 1=no problems, 2=some problems and 3=extreme problems. Missing values were not imputed. Using the scoring algorithm derived from the Canadian value sets (Bansback et al., 2012), a utility score for a patient was calculated based on the EQ-5D responses for a given time-point at which the questionnaire was presented to the patient. This mean EQ-5D utility score ranged between 0 (worst health) to 1 (perfect health). | 12 month | 
| Time Trade-Off Questionnaire - 25 (TTO) Composite Score at Month 12 | (TTO) questionnaire was used to help determine the patients' health utility. Reported health utility represents the patients' quality of life at the current health state, and is a cardinal value that ranges from 0 (worst possible health or death) to 1 (best possible health). In this questionnaire, patients were first asked to estimate their remaining life expectancy. Second, the patients were presented with a hypothetical situation where a technology existed that could permanently return their vision to normal. This technology would always work, but would decrease their length of survival. Patients were then asked how much of their remaining life expectancy, if any, they would be willing to trade in return for use of the technology and thus for normal vision. The principle of this measure is that if patients were content with their current vision status (i.e., have a utility value of 1.0), they would not want to trade any of their remaining life years to improve their vision. | 12 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DME, visual impairment, diabetes, macular edema, diabetic macular edema, ranibizumab, laser, photocoagulation, retinopathy, retina