Safety and Efficacy of Ranibizumab in Japanese Patients With Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration

This study has been completed.

Sponsor:

Information provided by:

Novartis

ClinicalTrials.gov Identifier:

NCT00284089

First received: January 30, 2006

Last updated: February 22, 2011

Last verified: February 2011

History of Changes

Results First Received: January 20, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Subfoveal Choroidal Neovascularization(CNV) Secondary to Age-related Macular Degeneration (AMD)
Intervention:	Drug: Ranibizumab

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
In total, 88 patients were enrolled in the study, 12 in Group A and 76 in Group B. The single dose phase of the study (Group A patients only) was completed prior to initiation of the multiple dose phase (Groups A and B).

Reporting Groups

	Description
Group A: Ranibizumab 0.3 mg	In the single dose phase, all patients randomized in Group A received a single intravitreal injection of 0.3 mg of ranibizumab into the study eye. Those patients who successfully completed this phase entered the multiple dose phase, where they received an intravitreal injection of 0.3 mg of ranibizumab once a month for an additional 11 months. Subsequently patients enrolling in the extension phase received an intravitreal injection of 0.3 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.70 years.
Group A: Ranibizumab 0.5 mg	In the single dose phase, all patients randomized in Group A received a single intravitreal injection of 0.5 mg of ranibizumab into the study eye. Those patients who successfully completed this phase entered the multiple dose phase, where they received an intravitreal injection of 0.5 mg of ranibizumab once a month for an additional 11 months. Subsequently Group A patients enrolling in the extension phase received an intravitreal injection of 0.5 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.93 years.
Group B: Ranibizumab 0.3 mg	Group B patients received a total of 12 monthly intravitreal injections of 0.3 mg of ranibizumab into the study eye in the multiple dose phase of the study. Group B patients who enrolled in the extension phase received an intravitreal injection of 0.3 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.45 years.
Group B: Ranibizumab 0.5 mg	Group B patients received a total of 12 monthly intravitreal injections of 0.5 mg of ranibizumab into the study eye in the multiple dose phase of the study. Group B patients who enrolled in the extension phase received an intravitreal injection of 0.5 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.36 years.

Participant Flow for 3 periods

Period 1: Single Dose Phase

	Group A: Ranibizumab 0.3 mg	Group A: Ranibizumab 0.5 mg	Group B: Ranibizumab 0.3 mg	Group B: Ranibizumab 0.5 mg
STARTED	6	6	0 ^[1]	0 ^[1]
COMPLETED	6	6	0	0
NOT COMPLETED	0	0	0	0

[1]	Group B patients did not participate in the Single Dose Phase of the study.

Period 2: Multiple Dose Phase

	Group A: Ranibizumab 0.3 mg	Group A: Ranibizumab 0.5 mg	Group B: Ranibizumab 0.3 mg	Group B: Ranibizumab 0.5 mg
STARTED	5 ^[1]	6	35	41
COMPLETED	4	6	31	37
NOT COMPLETED	1	0	4	4
Adverse Event	1	0	1	1
Protocol Violation	0	0	1	0
Withdrawal by Subject	0	0	1	2
Death	0	0	1	1

[1]	1 subject chose to receive other treatment & discontinued before starting the multiple dose phase.

Period 3: Extension Phase

	Group A: Ranibizumab 0.3 mg	Group A: Ranibizumab 0.5 mg	Group B: Ranibizumab 0.3 mg	Group B: Ranibizumab 0.5 mg
STARTED	3 ^[1]	6 ^[1]	28 ^[1]	33 ^[1]
COMPLETED	1	6	22	21
NOT COMPLETED	2	0	6	12
Adverse Event	0	0	2	2
condition no longer requires study drug	2	0	2	7
Protocol Violation	0	0	1	0
Withdrawal by Subject	0	0	1	3

[1]	Patients providing written consent & satisfying eligibility criteria could enter the extension phase

Baseline Characteristics

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Reporting Groups

	Description
Group A: Ranibizumab 0.3 mg	In the single dose phase, all patients randomized in Group A received a single intravitreal injection of 0.3 mg of ranibizumab into the study eye. Those patients who successfully completed this phase entered the multiple dose phase, where they received an intravitreal injection of 0.3 mg of ranibizumab once a month for an additional 11 months. Subsequently patients enrolling in the extension phase received an intravitreal injection of 0.3 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.70 years.
Group A: Ranibizumab 0.5 mg	In the single dose phase, all patients randomized in Group A received a single intravitreal injection of 0.5 mg of ranibizumab into the study eye. Those patients who successfully completed this phase entered the multiple dose phase, where they received an intravitreal injection of 0.5 mg of ranibizumab once a month for an additional 11 months. Subsequently Group A patients enrolling in the extension phase received an intravitreal injection of 0.5 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.93 years.
Group B: Ranibizumab 0.3 mg	Group B patients received a total of 12 monthly intravitreal injections of 0.3 mg of ranibizumab into the study eye in the multiple dose phase of the study. Group B patients enrolled in the extension phase received an intravitreal injection of 0.3 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.45 years.
Group B: Ranibizumab 0.5 mg	Group B patients received a total of 12 monthly intravitreal injections of 0.5 mg of ranibizumab into the study eye in the multiple dose phase of the study. Group B patients who enrolled in the extension phase received an intravitreal injection of 0.5 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.36 years.
Total	Total of all reporting groups

Baseline Measures

	Group A: Ranibizumab 0.3 mg	Group A: Ranibizumab 0.5 mg	Group B: Ranibizumab 0.3 mg	Group B: Ranibizumab 0.5 mg	Total
Number of Participants [units: participants]	6	6	35	41	88
Age, Customized ^[1] [units: Participants]
50 to <65 years	2	0	8	10	20
65 to <75 years	2	4	16	13	35
75 to <85 years	2	2	10	15	29
>= 85 years	0	0	1	3	4
Age, Customized ^[2] [units: Participants]
50 to <65 years	1	0	7	10	18
65 to <75 years	1	4	14	10	29
75 to <85 years	1	2	6	12	21
>= 85 years	0	0	1	1	2
Gender ^[3] [units: Participants]
Female	1	1	9	8	19
Male	5	5	26	33	69
Gender ^[4] [units: participants]
Female	0	1	9	5	15
Male	3	5	19	28	55

[1]	Age demographics for those subjects enrolled in the single and multiple dose phases of the study.
[2]	Age demographics for those subjects enrolled in the extension phase of the study.
[3]	Gender demographics for those subjects enrolled in the single and multiple dose phases of the study.
[4]	Gender demographics for those subjects enrolled in the extension phase of the study.

Outcome Measures

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1. Primary:

Mean Change From Baseline in the Best Corrected Visual Acuity Score of the Study Eye at Month 6 in Group B [ Time Frame: Baseline and Month 6 ]

Show Outcome Measure 1

2. Secondary:

Mean Change From Baseline in the Best Corrected Visual Acuity Score of the Study Eye at Month 12 in Group B [ Time Frame: Baseline and Month 12 ]

Show Outcome Measure 2

3. Secondary:

Categorical Analysis of Best Corrected Visual Acuity of the Study Eye at Month 6 and Month 12 in Group B [ Time Frame: Baseline, Month 6 and Month 12 ]

Show Outcome Measure 3

4. Secondary:

Extension Phase: Mean Change From Month 12 (Start of Extension Phase) in Best Corrected Visual Acuity Score of the Study Eye at Last Visit of Extension Phase in Group B. [ Time Frame: Month 12 (start of extension phase) and last visit of extension phase. Duration in the extension phase varied depending on the study entry. The mean duration of treatment was 1.45 years in the 0.3 mg group and 1.36 years in the 0.5 mg dose group. ]

Show Outcome Measure 4

5. Secondary:

Extension Phase: Categorical Analysis of Best Corrected Visual Acuity of the Study Eye at Last Visit of Extension Phase in Group B [ Time Frame: Baseline and last visit of extension phase - Duration in the extension phase varied depending on the study entry. The mean duration of treatment was 1.45 years in the 0.3 mg group and 1.36 years in the 0.5 mg dose group. ]

Show Outcome Measure 5

6. Secondary:

Mean Change From Baseline in Total Area of Choroidal Neovascularization of the Study Eye in Group B [ Time Frame: Baseline, Months 3, 6, 9 and 12 ]

Show Outcome Measure 6

7. Secondary:

Mean Change From Baseline in Total Area of Leakage From CNV Plus Staining of Retinal Pigment Epithelium of the Study Eye in Group B [ Time Frame: Baseline, Months 3, 6, 9 and 12 ]

Show Outcome Measure 7

8. Secondary:

Percentage of Participants in Group B With Absence of Leakage in the Study Eye at Month 3, 6, 9 and 12. [ Time Frame: Months 3, 6, 9 and 12 ]

Show Outcome Measure 8

9. Secondary:

Mean Change From Baseline in Foveal Retinal Thickness of the Study Eye in Group B [ Time Frame: Baseline, Months 3, 6, 9 and 12 ]

Show Outcome Measure 9

10. Secondary:

Mean Change From Baseline in Total Retinal Volume of the Study Eye in Group B [ Time Frame: Baseline, Months 3, 6, 9 and 12 ]

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Serious Adverse Events

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Time Frame	The timeframe for the Core Phase (Single and Multiple Dose Phases) was 12 months. For the Extension Phase adverse event data was collected from Month 12 through to the Last Visit (the maximum time on study was 35 months total).
Additional Description	No text entered.

Reporting Groups

	Description
Core Group A+B: Ranibizumab 0.3 mg	“Core” means Single and Multiple Dose Phases. Group A patients received a single intravitreal injection of 0.3 mg of ranibizumab into the study eye, followed by 11 additional intravitreal injections of 0.3 mg of ranibizumab once a month. Group B patients received a total of 12 monthly intravitreal injections of 0.3 mg of ranibizumab into the study eye.
Core Group A+B: Ranibizumab 0.5 mg	“Core” means Single and Multiple Dose Phases. Group A patients received a single intravitreal injection of 0.5 mg of ranibizumab into the study eye, followed by 11 additional intravitreal injections of 0.5 mg of ranibizumab once a month. Group B patients received a total of 12 monthly intravitreal injections of 0.5 mg of ranibizumab into the study eye.
Extension Group A+B: Ranibizumab 0.3 mg	In the extension phase, enrolled patients received an intravitreal injection of 0.3 mg ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.45 years.
Extension Group A+B: Ranibizumab 0.5 mg	In the extension phase, all patients received an intravitreal injection of 0.5 mg ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.36 years.

Serious Adverse Events

	Core Group A+B: Ranibizumab 0.3 mg	Core Group A+B: Ranibizumab 0.5 mg	Extension Group A+B: Ranibizumab 0.3 mg	Extension Group A+B: Ranibizumab 0.5 mg
Total, serious adverse events
# participants affected / at risk	5/41 (12.20%)	8/47 (17.02%)	5/31 (16.13%)	8/39 (20.51%)
Cardiac disorders
Angina pectoris ^{† 1}
# participants affected / at risk	0/41 (0.00%)	1/47 (2.13%)	0/31 (0.00%)	0/39 (0.00%)
Eye disorders
Cataract (Fellow eye) ^{† 1}
# participants affected / at risk	1/41 (2.44%)	1/47 (2.13%)	0/31 (0.00%)	0/39 (0.00%)
Corneal oedema (Study eye) ^{† 1}
# participants affected / at risk	0/41 (0.00%)	1/47 (2.13%)	0/31 (0.00%)	0/39 (0.00%)
Eye pain (Study eye) ^{† 1}
# participants affected / at risk	0/41 (0.00%)	1/47 (2.13%)	0/31 (0.00%)	0/39 (0.00%)
Glaucomatocyclitic crises (Study eye) ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	1/31 (3.23%)	0/39 (0.00%)
Macular degeneration (Fellow eye) ^{† 1}
# participants affected / at risk	1/41 (2.44%)	0/47 (0.00%)	0/31 (0.00%)	0/39 (0.00%)
Macular degeneration (Study eye) ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	1/31 (3.23%)	0/39 (0.00%)
Retinal detachment (Study eye) ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	1/31 (3.23%)	0/39 (0.00%)
Visual acuity reduced (Fellow eye) ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	0/31 (0.00%)	1/39 (2.56%)
Visual acuity reduced (Study eye) ^{† 1}
# participants affected / at risk	1/41 (2.44%)	0/47 (0.00%)	0/31 (0.00%)	0/39 (0.00%)
Visual acuity reduced transiently (Study eye) ^{† 1}
# participants affected / at risk	0/41 (0.00%)	2/47 (4.26%)	0/31 (0.00%)	0/39 (0.00%)
Vitreous haemorrhage (Study eye) ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	1/31 (3.23%)	0/39 (0.00%)
Gastrointestinal disorders
Colonic polyp ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	0/31 (0.00%)	1/39 (2.56%)
Enterocele ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	1/31 (3.23%)	0/39 (0.00%)
Gastric polyps ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	0/31 (0.00%)	1/39 (2.56%)
Infections and infestations
Abscess neck ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	0/31 (0.00%)	1/39 (2.56%)
Injury, poisoning and procedural complications
Overdose (Study eye) ^{† 1}
# participants affected / at risk	0/41 (0.00%)	2/47 (4.26%)	0/31 (0.00%)	0/39 (0.00%)
Investigations
Intraocular pressure increased (Study eye) ^{† 1}
# participants affected / at risk	0/41 (0.00%)	2/47 (4.26%)	0/31 (0.00%)	0/39 (0.00%)
Metabolism and nutrition disorders
Anorexia ^{† 1}
# participants affected / at risk	0/41 (0.00%)	1/47 (2.13%)	0/31 (0.00%)	0/39 (0.00%)
Diabetes mellitus ^{† 1}
# participants affected / at risk	1/41 (2.44%)	0/47 (0.00%)	0/31 (0.00%)	0/39 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm ^{† 1}
# participants affected / at risk	1/41 (2.44%)	0/47 (0.00%)	0/31 (0.00%)	0/39 (0.00%)
Colon cancer ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	1/31 (3.23%)	0/39 (0.00%)
Gastric cancer ^{† 1}
# participants affected / at risk	0/41 (0.00%)	1/47 (2.13%)	0/31 (0.00%)	1/39 (2.56%)
Lung carcinoma cell type unspecified recurrent ^{† 1}
# participants affected / at risk	0/41 (0.00%)	1/47 (2.13%)	0/31 (0.00%)	0/39 (0.00%)
Small cell lung cancer stage unspecified ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	0/31 (0.00%)	1/39 (2.56%)
Nervous system disorders
Ataxia ^{† 1}
# participants affected / at risk	0/41 (0.00%)	1/47 (2.13%)	0/31 (0.00%)	0/39 (0.00%)
Cerebral haemorrhage ^{† 1}
# participants affected / at risk	0/41 (0.00%)	1/47 (2.13%)	0/31 (0.00%)	0/39 (0.00%)
Cerebral infarction ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	1/31 (3.23%)	1/39 (2.56%)
Hypoaesthesia ^{† 1}
# participants affected / at risk	0/41 (0.00%)	1/47 (2.13%)	0/31 (0.00%)	0/39 (0.00%)
Spondylitic myelopathy ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	0/31 (0.00%)	1/39 (2.56%)
Psychiatric disorders
Depression ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	0/31 (0.00%)	1/39 (2.56%)
Respiratory, thoracic and mediastinal disorders
Emphysema ^{† 1}
# participants affected / at risk	0/41 (0.00%)	0/47 (0.00%)	0/31 (0.00%)	1/39 (2.56%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA

Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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 the publication of the pooled data (i.e., data from all sites) in the clinical trial.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Study Director
Organization: Novartis Pharmaceuticals
phone: 862 778-8300

Publications of Results:

Tano Y, Ohji M; EXTEND-I Study Group. EXTEND-I: safety and efficacy of ranibizumab in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Acta Ophthalmol. 2010 May;88(3):309-16. Epub 2010 Feb 16.

Responsible Party:	External Affairs, Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT00284089 History of Changes
Other Study ID Numbers:	CRFB002A1201
Study First Received:	January 30, 2006
Results First Received:	January 20, 2011
Last Updated:	February 22, 2011
Health Authority:	Japan: Ministry of Health, Labor and Welfare

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