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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01135914
• Collaborator: (none)
• Enrollment: 241
• Locations: 20
• Arms: 3
• Duration (Months): 32
• Patients Per Site: 12.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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

• Study Type: Interventional
• 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: Jul 1, 2010
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

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

Primary Outcome Measures

1. Mean Change From Baseline in Best Corrected Visual Acuity- (BCVA) at Month 12 [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 [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 [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 [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 [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 [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 [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 [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Calgary Retina Consultants	Calgary	Alberta	Canada
2	UBC - Eye Care Center	Vancouver	British Columbia	Canada
3	Retina Consultants of Victoria	Victoria	British Columbia	Canada
4	Memorial University Health Sciences Centre / Bense Eye Centre	St-John's	Newfoundland and Labrador	Canada
5	Victoria General Hospital, Department of Ophthalmology	Halifax	Nova Scotia	Canada
6	Ivey Eye Institute	London	Ontario	Canada
7	Canadian Centre for Advanced Eye Therapeutics	Mississauga	Ontario	Canada
8	The Ottawa Hospital - General Campus	Ottawa	Ontario	Canada
9	St-Michael's Hospital - Dept of Ophthalmology	Toronto	Ontario	Canada
10	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada
11	Toronto Western Hospital	Toronto	Ontario	Canada
12	Clinique ChirurgiVision	Drummondville	Quebec	Canada
13	Hôpital Maisonneuve-Rosemont	Montreal	Quebec	Canada
14	Hôpital Notre Dame (CHUM)	Montreal	Quebec	Canada
15	Royal Victoria Hospital	Montreal	Quebec	Canada
16	Centre Oculaire de Québec	Québec	Quebec	Canada
17	Dr.Michel Giunta Clinique Médicale	Sherbrooke	Quebec	Canada
18	Saskatoon City Hospital / Spadina Clinic	Saskatoon	Saskatchewan	Canada
19	Institut de l'oeil des Laurentides	Quebec		Canada
20	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01135914
• Other Study ID Numbers: CRFB002DCA05
• First Posted: Jun 3, 2010
• Last Update Posted: Oct 23, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Novartis Pharmaceuticals: DME; visual impairment; diabetes; macular edema; diabetic macular edema; ranibizumab; laser; photocoagulation; retinopathy; retina
• Additional relevant MeSH terms: Macular Edema; Edema; Ranibizumab

Study Results

Participant Flow

Recruitment Details	A total of 239 patients were enrolled in the study. An additional 2 patients were enrolled but were removed from the database because consent was not signed in accordance with GCP principles."
Pre-assignment Detail	3 treatment arms: Group C - laser photocoagulation per ETDRS guidelines, Group B - ranibizumab intravitreal injections (3 monthly injections during loading phase, and subsequent treatments per protocol-defined criteria), or Group A - combination therapy, where decisions to treat with laser were independent of decisions to treat with ranibizumab.

Arm/Group Title	Combination Therapy	Ranibizumab Monotherapy	Laser Monotherapy
Arm/Group Description	Participants received both a ranibizumab intravitreal injection and laser photocoagulation treatments.	Participants received ranibizumab intravitreal injection therapy only	Participants received Laser photocoagulation therapy only
Period Title: Overall Study
STARTED	78	80	81
Intent to Treat (ITT) Population	73	75	72
Safety Population	73	75	74
COMPLETED	74	75	59
NOT COMPLETED	4	5	22

Baseline Characteristics

Arm/Group Title	Combination Therapy	Ranibizumab Monotherapy	Laser Monotherapy	Total
Arm/Group Description	Participants received both a ranibizumab intravitreal injection and laser photocoagulation treatments.	Participants received ranibizumab intravitreal injection therapy only	Participants received Laser photocoagulation therapy only	Total of all reporting groups
Overall Participants	73	75	72	220
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.8 (10.21)	61.5 (9.86)	62.8 (9.44)	61.7 (9.83)
Sex: Female, Male (Count of Participants)
Female	26 35.6%	33 44%	29 40.3%	88 40%
Male	47 64.4%	42 56%	43 59.7%	132 60%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in Best Corrected Visual Acuity- (BCVA) at Month 12
Description	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.
Time Frame	Baseline and 12 months

Outcome Measure Data

Analysis Population Description

ITT defined as all patients receiving at least one dose of either study treatment for monotherapy treatment arms, or one of the two study treatments for the combination therapy arm, and having at least 1 post-baseline assessment. Patients from one study site were excluded from ITT. patients with both baseline and 12 month data were included.

Arm/Group Title	Combination Therapy	Ranibizumab Monotherapy	Laser Monotherapy
Arm/Group Description	Participants received both a ranibizumab intravitreal injection and laser photocoagulation treatments.	Participants received ranibizumab intravitreal injection therapy only	Participants received Laser photocoagulation therapy only
Measure Participants	70	71	62
Mean (Standard Deviation) [Letters]	8.2 (9.20)	8.9 (7.78)	0.3 (12.47)

2. Secondary Outcome

Title	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Months 3,6 and 9
Description	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.
Time Frame	Baseline, 3, 6 and 9 months

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all patients receiving at least one dose of either study treatment for monotherapy treatment arms, or one of the two study treatments for the combination therapy arm, and having at least 1 post-baseline assessment. Patients from one site were excluded from ITT.

Arm/Group Title	Combination Therapy	Ranibizumab Monotherapy	Laser Monotherapy
Arm/Group Description	Participants received both a ranibizumab intravitreal injection and laser photocoagulation treatments.	Participants received ranibizumab intravitreal injection therapy only	Participants received Laser photocoagulation therapy only
Measure Participants	73	75	72
Month 3 (n=71, 75, 69)	3.7 (10.71)	5.3 (7.58)	1.4 (6.55)
Month 6 (n= 70, 72, 65)	5.6 (8.45)	7.1 (7.74)	0.9 (7.23)
Month 9 (n=69, 71, 59)	7.1 (7.92)	6.9 (12.45)	-0.2 (10.71)

3. Secondary Outcome

Title	Change From Baseline in Central Retinal Thickness (CRT) at Months 3,6,9 and 12
Description	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
Time Frame	Baseline, 3, 6, 9 and 12 months

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all patients receiving at least one dose of either study treatment for monotherapy treatment arms, or one of the two study treatments for the combination therapy arm, and having at least 1 post-baseline assessment. Patients from one site were excluded from ITT.

Arm/Group Title	Combination Therapy	Ranibizumab Monotherapy	Laser Monotherapy
Arm/Group Description	Participants received both a ranibizumab intravitreal injection and laser photocoagulation treatments.	Participants received ranibizumab intravitreal injection therapy only	Participants received Laser photocoagulation therapy only
Measure Participants	73	75	72
Baseline	422.1 (142.26)	448.5 (136.64)	458.0 (133.07)
Month 3 (n=71,75, 69)	-105.7 (127.74)	-108.9 (113.38)	-32.5 (114.15)
Month 6 (n= 70,72,65)	-114.2 (110.88)	-129.3 (116.50)	-64.4 (110.77)
Month 9 (69,70,58)	-138.1 (125.86)	-135.9 (140.90)	-85.8 (128.00)
Month 12 (70,71,61)	-152.2 (139.27)	-143.5 (143.95)	-107.1 (143.86)

4. Secondary Outcome

Title	Percentage of Patients Achieving a Gain of 15-letters or More (3-lines) in BCVA From Baseline
Description	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.
Time Frame	Baseline, 3, 6, 9 and 12 months

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all patients receiving at least one dose of either study treatment for monotherapy treatment arms, or one of the two study treatments for the combination therapy arm, and having at least 1 post-baseline assessment. Patients from one site were excluded from ITT

Arm/Group Title	Combination Therapy	Ranibizumab Monotherapy	Laser Monotherapy
Arm/Group Description	Participants received both a ranibizumab intravitreal injection and laser photocoagulation treatments.	Participants received ranibizumab intravitreal injection therapy only	Participants received Laser photocoagulation therapy only
Measure Participants	73	75	72
Month 3 (n=71,75,69)	8.5	9.3	2.9
Month 6 (n=70,72,65)	11.4	13.9	1.5
Month 9 (69,71,59)	13.0	21.1	0
Month 12 (70,71,62)	24.3	21.1	6.5

5. Secondary Outcome

Title	Percentage of Patients Achieving Gain of Letters From Baseline in BCVA
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

ITT defined as all patients receiving at least one dose of either study treatment for monotherapy treatment arms, or one of the two study treatments for the combination therapy arm, and having at least 1 post-baseline assessment. Patients from one study site were excluded from ITT. Patients with 12 month data were included

Arm/Group Title	Combination Therapy	Ranibizumab Monotherapy	Laser Monotherapy
Arm/Group Description	Participants received both a ranibizumab intravitreal injection and laser photocoagulation treatments.	Participants received ranibizumab intravitreal injection therapy only	Participants received Laser photocoagulation therapy only
Measure Participants	70	71	62
5 letter gain	61.4	70.4	40.3
10 letter gain	34.3	52.1	16.1
15 letter gain	24.3	21.1	6.5

6. Secondary Outcome

Title	National Eye Institute Visual Functioning Questionnaire - 25 (VFQ-25) Composite Score at Month 12
Description	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
Time Frame	12 month

Outcome Measure Data

Analysis Population Description

ITT defined as all patients receiving at least one dose of either study treatment for monotherapy treatment arms, or one of the two study treatments for the combination therapy arm, and having at least 1 post-baseline assessment. Patients from one study site were excluded from ITT. Patients with both baseline and 12 month data were included

Arm/Group Title	Combination Therapy	Ranibizumab Monotherapy	Laser Monotherapy
Arm/Group Description	Participants received both a ranibizumab intravitreal injection and laser photocoagulation treatments.	Participants received ranibizumab intravitreal injection therapy only	Participants received Laser photocoagulation therapy only
Measure Participants	70	71	62
Mean (Standard Deviation) [Units on a Scale]	85.21 (12.77)	84.29 (11.78)	78.20 (17.27)

7. Secondary Outcome

Title	EuroQoL (EQ-5D) Utility Score at Month 12
Description	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).
Time Frame	12 month

Outcome Measure Data

Analysis Population Description

ITT defined as all patients receiving at least one dose of either study treatment for monotherapy treatment arms, or one of the two study treatments for the combination therapy arm, and having at least 1 post-baseline assessment. Patients from one study site were excluded from ITT. Patients with both baseline and 12 month data were included

Arm/Group Title	Combination Therapy	Ranibizumab Monotherapy	Laser Monotherapy
Arm/Group Description	Participants received both a ranibizumab intravitreal injection and laser photocoagulation treatments.	Participants received ranibizumab intravitreal injection therapy only	Participants received Laser photocoagulation therapy only
Measure Participants	68	71	60
Mean (Standard Deviation) [Units on a scale]	0.88 (0.15)	0.88 (0.17)	0.87 (0.17)

8. Secondary Outcome

Title	Time Trade-Off Questionnaire - 25 (TTO) Composite Score at Month 12
Description	(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.
Time Frame	12 month

Outcome Measure Data

Analysis Population Description

ITT defined as all patients receiving at least one dose of either study treatment for monotherapy treatment arms, or one of the two study treatments for the combination therapy arm, and having at least 1 post-baseline assessment. Patients from one study site were excluded from ITT. Patients with both baseline and 12 month data were included

Arm/Group Title	Combination Therapy	Ranibizumab Monotherapy	Laser Monotherapy
Arm/Group Description	Participants received both a ranibizumab intravitreal injection and laser photocoagulation treatments.	Participants received ranibizumab intravitreal injection therapy only	Participants received Laser photocoagulation therapy only
Measure Participants	69	68	60
Mean (Standard Deviation) [Units on a scale]	0.83 (0.28)	0.78 (0.23)	0.80 (0.24)

Adverse Events

Adverse Event Reporting Description	The Safety population was defined as all patients who received at least 1 administration of ranibizumab/laser treatment for monotherapy, or at least one of the two treatments for combination therapy, excluding patients from one site
Arm/Group Title	Combination Therapy		Ranibizumab Monotherapy		Laser Monotherapy
Arm/Group Description	Participants received both a ranibizumab intravitreal injection and laser photocoagulation treatments.		Participants received ranibizumab intravitreal injection therapy only		Participants received Laser photocoagulation therapy only
All Cause Mortality
	Combination Therapy		Ranibizumab Monotherapy		Laser Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Combination Therapy		Ranibizumab Monotherapy		Laser Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/73 (12.3%)		10/75 (13.3%)		5/74 (6.8%)
Cardiac disorders
Acute myocardial infarction	0/73 (0%)		0/75 (0%)		1/74 (1.4%)
Atrial fibrillation	1/73 (1.4%)		0/75 (0%)		0/74 (0%)
Cardiac failure congestive	0/73 (0%)		0/75 (0%)		2/74 (2.7%)
Endocrine disorders
Hyperthyroidism	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Eye disorders
Vitreous haemorrhage (Fellow eye)	0/73 (0%)		0/75 (0%)		2/74 (2.7%)
Vitreous haemorrhage (Study eye)	0/73 (0%)		0/75 (0%)		2/74 (2.7%)
Gastrointestinal disorders
Abdominal pain	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Colitis ischaemic	1/73 (1.4%)		0/75 (0%)		0/74 (0%)
Impaired gastric emptying	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Intestinal obstruction	1/73 (1.4%)		0/75 (0%)		0/74 (0%)
General disorders
Hypothermia	1/73 (1.4%)		0/75 (0%)		0/74 (0%)
Immune system disorders
Sarcoidosis	1/73 (1.4%)		0/75 (0%)		0/74 (0%)
Infections and infestations
Cellulitis	0/73 (0%)		2/75 (2.7%)		0/74 (0%)
Diabetic foot infection	1/73 (1.4%)		0/75 (0%)		0/74 (0%)
Lobar pneumonia	0/73 (0%)		0/75 (0%)		1/74 (1.4%)
Localised infection	1/73 (1.4%)		0/75 (0%)		0/74 (0%)
Osteomyelitis	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Viral infection	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Injury, poisoning and procedural complications
Rib fracture	1/73 (1.4%)		0/75 (0%)		0/74 (0%)
Metabolism and nutrition disorders
Diabetic ketoacidosis	0/73 (0%)		0/75 (0%)		1/74 (1.4%)
Hypoglycaemia	1/73 (1.4%)		0/75 (0%)		0/74 (0%)
Hypokalaemia	1/73 (1.4%)		0/75 (0%)		0/74 (0%)
Musculoskeletal and connective tissue disorders
Tendonitis	1/73 (1.4%)		0/75 (0%)		0/74 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial cancer stage II	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Nervous system disorders
Cerebrovascular accident	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Transient ischaemic attack	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Renal and urinary disorders
Neurogenic bladder	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Dyspnoea	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Haemoptysis	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Lung disorder	0/73 (0%)		1/75 (1.3%)		0/74 (0%)
Other (Not Including Serious) Adverse Events
	Combination Therapy		Ranibizumab Monotherapy		Laser Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/73 (35.6%)		26/75 (34.7%)		17/74 (23%)
Eye disorders
Cataract (Fellow eye)	0/73 (0%)		5/75 (6.7%)		3/74 (4.1%)
Cataract (Study eye)	0/73 (0%)		5/75 (6.7%)		0/74 (0%)
Conjunctival haemorrhage (Study eye)	9/73 (12.3%)		6/75 (8%)		1/74 (1.4%)
Eye irritation (Study eye)	4/73 (5.5%)		0/75 (0%)		0/74 (0%)
Vision blurred (Study eye)	4/73 (5.5%)		0/75 (0%)		0/74 (0%)
Vitreous haemorrhage (Fellow eye)	4/73 (5.5%)		2/75 (2.7%)		1/74 (1.4%)
Vitreous haemorrhage (Study eye)	1/73 (1.4%)		0/75 (0%)		4/74 (5.4%)
Infections and infestations
Nasopharyngitis	5/73 (6.8%)		5/75 (6.7%)		4/74 (5.4%)
Investigations
Intraocular pressure increased (Fellow eye)	4/73 (5.5%)		4/75 (5.3%)		3/74 (4.1%)
Intraocular pressure increased (Study eye)	8/73 (11%)		10/75 (13.3%)		0/74 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/73 (0%)		4/75 (5.3%)		0/74 (0%)
Nervous system disorders
Headache	1/73 (1.4%)		4/75 (5.3%)		1/74 (1.4%)
Neuropathy peripheral	5/73 (6.8%)		1/75 (1.3%)		0/74 (0%)
Vascular disorders
Hypertension	2/73 (2.7%)		5/75 (6.7%)		5/74 (6.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until publication of the pooled data (i.e. data from all sites) in the clinical trial or dislcosure of trial results in their entirety.