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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Diabetic Macular Edema	Drug: ranibizumab; Procedure: Laser	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	241 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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.
Study Start Date :	July 2010
Actual Primary Completion Date :	March 2013
Actual Study Completion Date :	March 2013

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Combination Therapy; Participants received ranibizumab intravitreal injection and laser photocoagulation treatments	Drug: ranibizumab; 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.; Procedure: Laser; 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.
Experimental: Ranibizumab Monotherapy; Participants received ranibizumab intravitreal injection therapy only	Drug: ranibizumab; 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.
Active Comparator: Laser Monotherapy; Participants received Laser photocoagulation therapy only	Procedure: Laser; 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.

Outcome Measures

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Primary Outcome Measures :

1. Mean Change From Baseline in Best Corrected Visual Acuity- (BCVA) at Month 12 [ Time Frame: Baseline and 12 months ]
   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.

Secondary Outcome Measures :

1. Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Months 3,6 and 9 [ Time Frame: Baseline, 3, 6 and 9 months ]
   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.
2. Change From Baseline in Central Retinal Thickness (CRT) at Months 3,6,9 and 12 [ Time Frame: Baseline, 3, 6, 9 and 12 months ]
   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
3. Percentage of Patients Achieving a Gain of 15-letters or More (3-lines) in BCVA From Baseline [ Time Frame: Baseline, 3, 6, 9 and 12 months ]
   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.
4. Percentage of Patients Achieving Gain of Letters From Baseline in BCVA [ Time Frame: 12 months ]
   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.
5. National Eye Institute Visual Functioning Questionnaire - 25 (VFQ-25) Composite Score at Month 12 [ Time Frame: 12 month ]
   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
6. EuroQoL (EQ-5D) Utility Score at Month 12 [ Time Frame: 12 month ]
   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).
7. Time Trade-Off Questionnaire - 25 (TTO) Composite Score at Month 12 [ Time Frame: 12 month ]
   (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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

Canada, Alberta
Calgary Retina Consultants
Calgary, Alberta, Canada
Canada, British Columbia
UBC - Eye Care Center
Vancouver, British Columbia, Canada
Retina Consultants of Victoria
Victoria, British Columbia, Canada
Canada, Newfoundland and Labrador
Memorial University Health Sciences Centre / Bense Eye Centre
St-John's, Newfoundland and Labrador, Canada
Canada, Nova Scotia
Victoria General Hospital, Department of Ophthalmology
Halifax, Nova Scotia, Canada
Canada, Ontario
Ivey Eye Institute
London, Ontario, Canada
Canadian Centre for Advanced Eye Therapeutics
Mississauga, Ontario, Canada
The Ottawa Hospital - General Campus
Ottawa, Ontario, Canada
St-Michael's Hospital - Dept of Ophthalmology
Toronto, Ontario, Canada
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada
Toronto Western Hospital
Toronto, Ontario, Canada
Canada, Quebec
Clinique ChirurgiVision
Drummondville, Quebec, Canada
Hôpital Maisonneuve-Rosemont
Montreal, Quebec, Canada
Hôpital Notre Dame (CHUM)
Montreal, Quebec, Canada
Royal Victoria Hospital
Montreal, Quebec, Canada
Centre Oculaire de Québec
Québec, Quebec, Canada
Dr.Michel Giunta Clinique Médicale
Sherbrooke, Quebec, Canada
Canada, Saskatchewan
Saskatoon City Hospital / Spadina Clinic
Saskatoon, Saskatchewan, Canada
Canada
Institut de l'oeil des Laurentides
Quebec, Canada
Memorial University Health Sciences Centre / Newfoundland Drive Medical Clinic
St-John's, Canada

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

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Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT01135914 History of Changes
Other Study ID Numbers:	CRFB002DCA05
First Posted:	June 3, 2010
Results First Posted:	October 23, 2014
Last Update Posted:	October 23, 2014
Last Verified:	October 2014

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

DME; visual impairment; diabetes; macular edema; diabetic macular edema	ranibizumab; laser; photocoagulation; retinopathy; retina

Additional relevant MeSH terms:

Edema; Macular Edema; Vision Disorders; Signs and Symptoms; Macular Degeneration; Retinal Degeneration; Retinal Diseases; Eye Diseases; Sensation Disorders; Neurologic Manifestations	Nervous System Diseases; Ranibizumab; Immunologic Factors; Physiological Effects of Drugs; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antineoplastic Agents