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Clinical Trial Results:
Wirksamkeit von Ranibizumab bei Patienten mit CHORIOIDALER NEOVASKULARISATION (CNV), als Folge einer altersbedingten Makuladegeneration (AMD), bei einer Gabe alle zwei Monate gegenüber der Behandlung bei Bedarf Efficacy of Ranibizumab Treatment Every 2 Month Compared to Treatment on Demand on Patients With Choroidal Neo-vascularization (CNV) as a Consequence of Age-related Macular Degeneration (AMD) [ClinicalTrials.gov ] Efficacy and safety of a fixed bimonthly ranibizumab treatment regimen in eyes with neovascular age-related macular degeneration - RABIMO trial [Paper 2017]

Summary
EudraCT number	2009-017324-11
Trial protocol	DE
Global end of trial date	06 Aug 2013

Results information
Results version number	v1(current)
This version publication date	05 Nov 2021
First version publication date	05 Nov 2021
Other versions
Summary report(s)	Summary results

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

CRFB002ADE09T

ISRCTN number

US NCT number

NCT01831947

WHO universal trial number (UTN)

Other trial identifiers

RABIMO: IFS-218

Sponsor organisation name

Universitätsmedizin Göttingen (UMG), Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts

Sponsor organisation address

Robert-Koch-Straße 40, Göttingen, Germany, 37075

Public contact

Studienzentrum UMG, Universitätsmedizin Göttingen (UMG), +49 5513960812, sz-umg.sponsor-qm@med.uni-goettingen.de

Scientific contact

Prof. Dr. Hans Michael Hoerauf, Klinik für Augenheilkunde, Universitätsmedizin Göttingen (UMG), +49 5513963580, augenklinik@med.uni-goettingen.de

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

10 Nov 2013

Is this the analysis of the primary completion data?

Yes

Primary completion date

06 Aug 2013

Global end of trial reached?

Yes

Global end of trial date

06 Aug 2013

Was the trial ended prematurely?

Main objective of the trial

Ziel der klinischen Prüfung ist die Überprüfung des Einflusses von intravitreal injiziertem Ranibizumab in unterschiedlichen Intervallen auf die Sehschärfe von Patienten mit neovaskulärer CNV im Rahmen einer AMD. Dabei erhalten alle Patienten zunächst 3 Injektionen in monatlichem Abstand und im weiteren Verlauf entweder 2-monatlich als fixes Schema oder lediglich bei Befundverschlechterung („on demand―). Evaluation prospectively the efficacy and safety of a fixed bimonthly ranibizumab treatment regimen (RABIMO) in eyes with neovascular age-related macular degeneration (nAMD) and comparison of results with a pro re nata (PRN) treatment scheme. Impact of injection frequency of ranibizumab on visual acuity development / BCVA - best corrected visual acuity after 12 months in comparison to baseline / ...[Paper 2017]

Protection of trial subjects

To minimize the risk of AMD worsening in all patients, monthly assessments were introduced to identify patients for whom bi-monthly injection intervals were inadequate. [Dissertation 2017]

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Apr 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 39

Worldwide total number of subjects

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment period: 12 months / First patient in: 28.04.2010 / Last patient in: 29.03.2012

Screening details

Inclusion and exclusion criteria / Demographic data / Medical history / Concomitant diseases / Physical examination and vital signs / Blood count / Visual acuity / Ophthalmological examination / Optical coherence tomography (OCT) / Fundus photography Fluorescein angiography / Accompanying medication / Tonometry

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

RABIMO group (randomized)

Arm description

Experimental: Ranibizumab fixed dose / fixed bimonthly ranibizumab treatment regimen (RABIMO) / Injection of 0.5 mg Ranibizumab every 2 months for one year, following a monthly injection during the first 3 months.

Arm type

Experimental

Investigational medicinal product name

Ranibizumab

Investigational medicinal product code

Other name

Lucentis

Pharmaceutical forms

Suspension for injection

Routes of administration

Injection

Dosage and administration details

Ranibizumab 0.5 mg, eight injections After three initial monthly injections, patients were randomised to receive ranibizumab bimonthly.

PRN group (randomized)

Arm description

Experimental: Ranibizumab on demand / pro re nata (PRN) treatment scheme / Injection of 0.5 mg Ranibizumab on demand for one year, following a monthly injection during the first 3 months.

Arm type

Experimental

Investigational medicinal product name

Ranibizumab

Investigational medicinal product code

Other name

Lucentis

Pharmaceutical forms

Suspension for injection

Routes of administration

Injection

Dosage and administration details

0.5 mg/eye, intravitreal injection

Number of subjects in period 1	RABIMO group (randomized)	PRN group (randomized)
Started	19	20
Completed	18	15
Not completed	1	5
Adverse event, serious fatal	1	2
Consent withdrawn by subject	-	1
Adverse event, non-fatal	-	2

Baseline characteristics

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Reporting group title

overall trial (overall period)

Reporting group description

Reporting group values	overall trial (overall period)	Total
Number of subjects	39	39
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	1	1
From 65-84 years	29	29
85 years and over	9	9
Gender categorical
Units: Subjects
Female	25	25
Male	14	14

End points

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Reporting group title

RABIMO group (randomized)

Reporting group description

Reporting group title

PRN group (randomized)

Reporting group description

Experimental: Ranibizumab on demand / pro re nata (PRN) treatment scheme / Injection of 0.5 mg Ranibizumab on demand for one year, following a monthly injection during the first 3 months.

Primary: BCVA: best-corrected visual acuity

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End point title

BCVA: best-corrected visual acuity

End point description

Impact of injection frequency on visual acuity development (best-corrected visual acuity (BCVA) after 12 months in comparison to baseline.

End point type

Primary

End point timeframe

after 12 months (in comparison to baseline)

End point values	RABIMO group (randomized)	PRN group (randomized)
Number of subjects analysed	19 ^[1]	20 ^[2]
Units: interquartile range (IQR)
median (inter-quartile range (Q1-Q3))
significant difference in BCVA	6.5 (4 to 19)	9 (0.5 to 15.5)

Attachments

Untitled (Filename: Median (IQR) BCVA.jpg)

Notes
[1] - fixed-dose / RABIMO group
[2] - pro re nata (as needed) / PRN group

intention to treat (ITT)

Statistical analysis description

non-inferiority design

Comparison groups

PRN group (randomized) v RABIMO group (randomized)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

P-value

< 0.0001 ^[4]

Method

t-test, 1-sided

Confidence interval

level

95%

sides

1-sided

lower limit

upper limit

Variability estimate

Standard deviation

Notes
[3] - non-inferiority design for the difference μB-μ2 / μB: expected value in "on-demand" group / μ2: expected value in "fixed dose" group / difference between 12-month visit (visit 14) and baseline visit, under therapy μ2 denotes the fixed 2-month injection
[4] - one-sided t-test (alpha = 5%) on the ITT

Adverse events

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Timeframe for reporting adverse events

Adverse events were recorded during the entire study period.

Assessment type

Systematic

Dictionary name

ICD-10

Dictionary version

2019

Reporting group title

PRN group

Reporting group description

Reporting group title

RABIMO group

Reporting group description

Serious adverse events	PRN group	RABIMO group
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 20 (35.00%)	6 / 19 (31.58%)
number of deaths (all causes)	2	1
number of deaths resulting from adverse events	2	1
Vascular disorders
Benigne essential hypertension
Additional description: 577
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stroke, not specified as haemorrhage or infarction
Additional description: 740 (Dysphasia and aphasia), sudden cardiac Death
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Abdominal aortic aneurysm, without mention of rupture
Additional description: 741
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atherosclerosis of arteries of extremities
Additional description: 545 (left leg)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Mitral (valve) insufficiency
Additional description: 573 (Paroxysmal atrial fibrillation)
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Acquired absence of leg at or below knee
Additional description: 572 (left site, amputation)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (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
Other transient cerebral ischaemic attacks and related syndromes
Additional description: 598
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphocyte-rich (classical) Hodgkin lymphoma
Additional description: 257, Relapse M. Hodgkin
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diffuse large B-cell lymphoma
Additional description: 801 (Diffuse follicle centre lymphoma)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Other ill-defined and unspecified causes of mortality
Additional description: 1063, Other ill-defined and unspecified causes of mortality, Death
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Eye disorders
Retinal haemorrhage
Additional description: 1044
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Degeneration of macula and posterior pole
Additional description: 1185, 1186 (both 218_0001)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Enterocolitis due to Clostridium difficile
Additional description: 547
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Fracture of pubis
Additional description: 537
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis of vertebra
Additional description: 497, cervical, Discitis, unspecified (spondylodiscitis V2-3, V3-4)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyogenic arthritis, unspecified
Additional description: 550 (knee)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Influenza, virus not identified
Additional description: 943, severe infection, (Urinary tract infection, site not specified)
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Conjunctivitis due to adenovirus
Additional description: 417 worsening of infectious keratitis
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic Inflammatory Response Syndrome of infectious origin with organ failure
Additional description: 599, Septic shock, Cardiac arrest, unspecified, Death
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Syncope and collapse
Additional description: 922 (Other infectious diseases)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0.05%

Non-serious adverse events	PRN group	RABIMO group
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 20 (45.00%)	13 / 19 (68.42%)
Vascular disorders
Essential (primary) hypertension
Additional description: 297, 546 progression) (both 218_0002)
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	2
Cardiac disorders
Paroxysmal atrial fibrillation
Additional description: 700 (tachycardiac arrhythmia)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences all number	1	0
Nervous system disorders
Restlessness and agitation
Additional description: 1123
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences all number	1	0
Blood and lymphatic system disorders
Other iron deficiency anaemias
Additional description: 1205
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Eye disorders
Blepharitis
Additional description: 1046, 1083, 1045, 1047, 1165
subjects affected / exposed	2 / 20 (10.00%)	3 / 19 (15.79%)
occurrences all number	2	3
Conjunctival haemorrhage
Additional description: 1043 (up, resorption), 1064, 1042 (down, temporal)
subjects affected / exposed	2 / 20 (10.00%)	1 / 19 (5.26%)
occurrences all number	2	1
Corneal ulcer
Additional description: 538
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Hereditary corneal dystrophies
Additional description: 781
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Other disorders of choroid
Additional description: 983
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Degeneration of macula and posterior pole
Additional description: 842
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Other degeneration of macula and posterior pole
Additional description: 822
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Peripheral retinal degeneration
Additional description: 862 (defects)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences all number	1	0
Separation of retinal layers
Additional description: 982 (RPE seperation)
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Retinal disorder, unspecified
Additional description: 1103 (RPE abnormalities, down)
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Other vitreous opacities
Additional description: 823, 942, 1166
subjects affected / exposed	0 / 20 (0.00%)	3 / 19 (15.79%)
occurrences all number	0	3
Ocular pain
Additional description: 551
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion, not elsewhere classified
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences all number	1	0
Cough
Additional description: 1003 (after fluorescence angiography)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences all number	1	0
Psychiatric disorders
Other depressive episodes
Additional description: 882
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Endocrine disorders
Generalized hyperhidrosis
Additional description: 883, Ectopic hormone secretion, not elsewhere classified (increased sweating / hormones liver )
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Other dorsalgia
Additional description: 457, 802
subjects affected / exposed	1 / 20 (5.00%)	1 / 19 (5.26%)
occurrences all number	1	1
Osseous and subluxation stenosis of intervertebral foramina
Additional description: 1023
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Localized oedema
Additional description: 517 (Ankle, both sides)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences all number	1	0
Fracture of thoracic vertebra
Additional description: 660 (thoracic vertebra 12)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences all number	1	0
Injury of Achilles tendon
Additional description: 541 (left site)
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences all number	1	0
Infections and infestations
Zoster without complication
Additional description: 1022
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
nasopharyngitis [common cold]
Additional description: 574, 600, 1002
subjects affected / exposed	1 / 20 (5.00%)	2 / 19 (10.53%)
occurrences all number	1	2
Acute upper respiratory infections of multiple and unspecified sites
Additional description: 620
subjects affected / exposed	1 / 20 (5.00%)	0 / 19 (0.00%)
occurrences all number	1	0
Pneumonia, unspecified
Additional description: 720
subjects affected / exposed	0 / 20 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Bronchitis, not specified as acute or chronic
Additional description: 761, 544, 640
subjects affected / exposed	1 / 20 (5.00%)	2 / 19 (10.53%)
occurrences all number	1	2

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Were there any global substantial amendments to the protocol? Yes

08 Apr 2010

Protocol Version 1.3 and ICF modification

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

http://www.ncbi.nlm.nih.gov/pubmed/28102456

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Primary: BCVA: best-corrected visual acuity

Primary: BCVA: best-corrected visual acuity

Adverse events

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