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Clinical Trial Results:
An open-label, multi-center, expanded access program of ranibizumab in patients with visual impairment due to diabetic macular edema for whom no suitable therapeutic alternatives exist.

Summary
EudraCT number	2011-002731-26
Trial protocol	IT
Global end of trial date	08 Oct 2013

Results information
Results version number	v1(current)
This version publication date	17 Dec 2020
First version publication date	17 Dec 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CRFB002DIT01

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, +41 +39 02 96541,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, +41 +39 02 96541,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

08 Oct 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Oct 2013

Was the trial ended prematurely?

Main objective of the trial

To provide early access to ranibizumab in patients with macular edema and visual impairment secondary to diabetes mellitus for whom no suitable therapeutic alternatives exist (i.e. existing therapies, e.g. laser photocoagulation, have failed or are not indicated).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

07 Nov 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Italy: 617

Worldwide total number of subjects

617

EEA total number of subjects

617

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

275

From 65 to 84 years

338

85 years and over

Subject disposition

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Recruitment details

A total of 620 subjects were screened and 617 subjects were enrolled in the study.

Screening details

Subjects were enrolled at 33 sites in Italy. The first subject was screened on 7 November 2011. The last study visit occurred on 8 October 2013

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Overall Study

Arm description

Subjects received 0.5 mg ranibizumab intravitreal injection according to the approved label: the treatment was given monthly until maximum visual acuity (VA) was achieved (the subjects VA was stable for three consecutive monthly assessments).

Arm type

Experimental

Investigational medicinal product name

Ranibizumab

Investigational medicinal product code

Other name

Lucentis®

Pharmaceutical forms

Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

Subjects received 0.5 mg ranibizumab as intravitreal injection monthly until maximum VA was achieved.

Number of subjects in period 1	Overall Study
Started	617
Completed	515
Not completed	102
Adverse event, serious fatal	3
Consent withdrawn by subject	32
Subject's condition not required program drug	4
Adverse event, non-fatal	19
Protocol violation	8
Unsatisfactory therapeutic effect	8
Lost to follow-up	27
Abnormal test procedure result(s)	1

Baseline characteristics

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Reporting group title

Overall Study

Reporting group description

Reporting group values	Overall Study	Total
Number of subjects	617	617
Age categorical
Units: Subjects
In utero		0
Preterm newborn infants (gestational age < 37 wks)		0
Newborns (0-27 days)		0
Infants and toddlers (28 days-23 months)		0
Children (2-11 years)		0
Adolescents (12-17 years)		0
Adults (18-64 years)		0
From 65-84 years		0
85 years and over		0
Age continuous
Units: years
arithmetic mean (standard deviation)	65.525 ( 9.145 )	-
Gender categorical
Please note, the data in the CSR that was provided for the gender was for the Full Analysis Set (FAS), 612. All other Baseline categories were supplied for the Enrolled patient (617). Data was provided for the actual number of subjects enrolled in the study by gender for consistency.
Units: Subjects
Female	228	228
Male	389	389

End points

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Reporting group title

Overall Study

Reporting group description

Primary: Percentage of Subjects Experiencing any Serious Adverse Events (SAEs)

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End point title

Percentage of Subjects Experiencing any Serious Adverse Events (SAEs) ^[1]

End point description

End point type

Primary

End point timeframe

Baseline up to end of program (Up to approximately 23 months)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed.

End point values	Overall Study
Number of subjects analysed	612 ^[2]
Units: Percentage of subjects
number (not applicable)	29

Notes
[2] - All subjects who received at least one dose of ranibizumab and had at least one post-baseline safety

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to end of program (Up to approximately 23 months)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

14.0

Reporting group title

Unilateral DME

Reporting group description

Unilateral DME

Reporting group title

Bilateral DME

Reporting group description

Bilateral DME

Serious adverse events	Unilateral DME	Bilateral DME
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 157 (4.46%)	22 / 455 (4.84%)
number of deaths (all causes)	1	2
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder papilloma
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal neoplasm
subjects affected / exposed	1 / 157 (0.64%)	0 / 455 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic neoplasm
subjects affected / exposed	1 / 157 (0.64%)	0 / 455 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Non-Hodgkin's lymphoma
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Arterial disorder
subjects affected / exposed	1 / 157 (0.64%)	0 / 455 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Cataract operation
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Inflammation
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleurisy
subjects affected / exposed	1 / 157 (0.64%)	0 / 455 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 157 (0.64%)	0 / 455 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	0 / 157 (0.00%)	3 / 455 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congestive cardiomyopathy
subjects affected / exposed	1 / 157 (0.64%)	0 / 455 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 157 (0.64%)	0 / 455 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	1 / 157 (0.64%)	0 / 455 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic cerebral infarction
subjects affected / exposed	1 / 157 (0.64%)	0 / 455 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Ocular hypertension
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vitreous haemorrhage
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	1 / 157 (0.64%)	0 / 455 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Urethral obstruction
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Unilateral DME	Bilateral DME
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 157 (3.18%)	30 / 455 (6.59%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Vascular disorders
Hypertension
subjects affected / exposed	0 / 157 (0.00%)	2 / 455 (0.44%)
occurrences all number	0	2
Hypertensive crisis
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Surgical and medical procedures
Cataract operation
subjects affected / exposed	0 / 157 (0.00%)	2 / 455 (0.44%)
occurrences all number	0	2
Cholecystectomy
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Investigations
Intraocular pressure increased
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Injury, poisoning and procedural complications
Toxicity to various agents
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Nervous system disorders
Diabetic neuropathy
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Presyncope
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Eye disorders
Cataract
subjects affected / exposed	2 / 157 (1.27%)	4 / 455 (0.88%)
occurrences all number	3	4
Conjunctival haemorrhage
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Conjunctivitis
subjects affected / exposed	2 / 157 (1.27%)	0 / 455 (0.00%)
occurrences all number	2	0
Diabetic retinal oedema
subjects affected / exposed	0 / 157 (0.00%)	6 / 455 (1.32%)
occurrences all number	0	6
Diabetic retinopathy
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Lacrimation increased
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Macular ischaemia
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Macular oedema
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Ocular hypertension
subjects affected / exposed	1 / 157 (0.64%)	1 / 455 (0.22%)
occurrences all number	1	1
Retinal exudates
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Uveitis
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Vitreous haemorrhage
subjects affected / exposed	1 / 157 (0.64%)	0 / 455 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Skin ulcer
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Renal and urinary disorders
Microalbuminuria
subjects affected / exposed	0 / 157 (0.00%)	1 / 455 (0.22%)
occurrences all number	0	1
Infections and infestations
Influenza
subjects affected / exposed	0 / 157 (0.00%)	3 / 455 (0.66%)
occurrences all number	0	3
Labyrinthitis
subjects affected / exposed	0 / 157 (0.00%)	2 / 455 (0.44%)
occurrences all number	0	2

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
An open-label, multi-center, expanded access program of ranibizumab in patients with visual impairment due to diabetic macular edema for whom no suitable therapeutic alternatives exist.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects Experiencing any Serious Adverse Events (SAEs)

Primary: Percentage of Subjects Experiencing any Serious Adverse Events (SAEs)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: An open-label, multi-center, expanded access program of ranibizumab in patients with visual impairment due to diabetic macular edema for whom no suitable therapeutic alternatives exist.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects Experiencing any Serious Adverse Events (SAEs)

Primary: Percentage of Subjects Experiencing any Serious Adverse Events (SAEs)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An open-label, multi-center, expanded access program of ranibizumab in patients with visual impairment due to diabetic macular edema for whom no suitable therapeutic alternatives exist.