Clinical Trial Results:
Phase IV study to evaluate genetic variants of VEGF pathway as biomarkers of VEGF Trap-Eye treatment efficacy in subjects with neovascular age-related macular degeneration (wAMD).
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Summary
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EudraCT number |
2013-002124-17 |
Trial protocol |
ES |
Global end of trial date |
30 Mar 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
25 Nov 2021
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First version publication date |
25 Nov 2021
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Other versions |
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Summary report(s) |
Relationship between Aflibercept Efficacy and Genetic Variants of Genes Associated with Neovascular Age-Related Macular Degeneration: The BIOIMAGE Trial CT results |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
IMO-AFLI-2013-01
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Additional study identifiers
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ISRCTN number |
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US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Fundació IMO
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Sponsor organisation address |
Josep Maria Lladó 3, Barcelona, Spain,
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Public contact |
Elisabet Molina, Trial Form Support, +34 931850200, elisabet.molina@tfscro.com
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Scientific contact |
Elisabet Molina, Trial Form Support, +34 931850200, elisabet.molina@tfscro.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
20 Dec 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Mar 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Mar 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To study genetic variants of VEGF pathway (SNP markers located within the coding and regulatory regions of the genes of the VEGF pathway) and its relation to VEGF trap-Eye treatment efficacy in terms of the percentage of patients with ? 15 letters gain in visual acuity.
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Protection of trial subjects |
Patients were treated according to routine clinical practice (phase IV trial). They were informed of all additional tests that had to be performed.
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
16 Dec 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 194
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Worldwide total number of subjects |
194
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EEA total number of subjects |
194
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
70
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From 65 to 84 years |
100
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85 years and over |
24
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Recruitment
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Recruitment details |
The investigator had to ensure that all patients who were offered the possibility to participate in the study met the following inclusion criteria and none of the exclusion criteria. In order to ensure that the study population was representative of all eligible patients, the investigator could not apply any additional exclusion criteria. | ||||||||||||||||||
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Pre-assignment
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Screening details |
The subjects met all of the following inclusion criteria: 1. Males or females aged 50 or over. 2. Patients with active primary subfoveal CNV (secondary to the AMD), including juxtafoveal lesions affecting the fovea (confirmed through angiography) in the study eye. 3. Patients with a baseline BCVA per ETDRS optotype of 20/40 to 20/320 | ||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
194 | ||||||||||||||||||
Number of subjects completed |
194 | ||||||||||||||||||
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Period 1
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Period 1 title |
visual acuity and genetic variations (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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Single arm | ||||||||||||||||||
Arm description |
Single arm To identify the genetic variants of the vascular endothelial growth factor (VEGF) pathway genes and other genes associated with neovascular age-related macular degeneration (nAMD) as possible predictive biomarkers of a favorable treatment response to aflibercept | ||||||||||||||||||
Arm type |
Tratment according to labelling | ||||||||||||||||||
Investigational medicinal product name |
Aflibercept
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Investigational medicinal product code |
authorized drug
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Other name |
Eylea
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Pharmaceutical forms |
Suspension for injection in pre-filled injector
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Routes of administration |
Intravitreal use
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Dosage and administration details |
Patients were treated with aflibercept 2 mg (40 mg/mL) IVT
during a 52-week study period, receiving 1 IVT injection once
monthly for the first 3 months (loading phase: weeks 0, 4, and 8),
and then 1 IVT injection every 8 weeks (q8) until week 48 (scheduled treatment). All patients concluded the study period at week
52. At week 48, patients were invited to participate in a 52-week
extension phase. In the extension phase, the interval between visits for aflibercept administration was extended by 2 weeks
per visit (in relation to the period since the last visit) to a maximum
of 12 weeks if no evidence of disease activity was observed (treatand-extend regimen). If there were signs of activity, patients were
retreated, and the next visit was reduced by 2 weeks, with a minimum of 8 weeks between visits. Patients concluded the extension
phase after 104 weeks
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Baseline characteristics reporting groups
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Reporting group title |
visual acuity and genetic variations
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Reporting group description |
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End points reporting groups
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Reporting group title |
Single arm
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Reporting group description |
Single arm To identify the genetic variants of the vascular endothelial growth factor (VEGF) pathway genes and other genes associated with neovascular age-related macular degeneration (nAMD) as possible predictive biomarkers of a favorable treatment response to aflibercept | ||
Subject analysis set title |
correlation between aflibercept and gene variants
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All data were descriptively analysed. Continuous variables were presented with mean and corresponding
95% CI, median, standard deviation
(SD) and range (minimum, maximum) while categorical variables with frequencies and percentages.
Differences between categorical variables were analysed with Chi-square or Fisher’s exact tests, as
applicable.
For continuous variables, changes from baseline were analysed using Student's t-test for paired data.
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End point title |
to determine genetic variants of VEGF pathway and its correlation with patients who presented an increase in VA of more than 15 letters at week 52 | |||||||||
End point description |
Multivariate logistic regression revealed significant effect of six SNPs (in six genes) on gaining≥15 letters in BCVA at week 52. Thus, the odds of gaining ≥15 letters in BCVA after 52 weeks of aflibercept treatment were higher in patients with genotypes TT in rs12366035 (VEGFB) (OR=216.9; p<0.001), AA/AG in rs25681 (C5) (OR=19.7/8.3; p<0.001/ 0.01), CT/CC in rs17793056 (CX3CR1) (OR=8.1/6.2; p<0.01/0.05), CC in rs1800775 (CETP) (OR=6.6; p<0.01), GG/AA in rs2069845 (IL6) (OR=5.6/3.3; p<0.05/0.05), and CT in rs13900 (CCL2) (OR=4.0; p<0.01).
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End point type |
Primary
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End point timeframe |
52 weeks
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Statistical analysis title |
correlation between aflibercept and gene variants | |||||||||
Statistical analysis description |
Justification: This being an exploratory study, no hypothesis confirmation tests were
performed. However,
as an initial approximation of the efficacy of aflibercept in the treatment of wAMD based on
the genetic variants in the VEGF pathway, the allelic variants and their correlations with
aflibercept treatment efficacy were analysed. Treatment efficacy was defined as an
increase
in VA ≥ 15 letters vs. the baseline visit.
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Comparison groups |
Single arm v correlation between aflibercept and gene variants
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Number of subjects included in analysis |
388
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||
P-value |
< 5 | |||||||||
Method |
ANOVA | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Confidence interval |
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End point title |
percentage of patients who presented a gain or loss of more than 15 letters at week 52 | ||||
End point description |
the percentage of patients who gained 15 or more letters at week 52 was 33,0%
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End point type |
Secondary
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End point timeframe |
52 weeks
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Adverse events information
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Timeframe for reporting adverse events |
24 hours for Serious adverse events
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
SOC | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
27
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Reporting groups
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Reporting group title |
adverse event reporting
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Reporting group description |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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31 Oct 2013 |
included a new participant centre (Hospital de Cruces,
Vizcaya) into the study. |
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03 Dec 2013 |
changed the principal investigator in the Hospital Universitario
y Politécnico La Fe de Valencia. |
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17 Feb 2014 |
This amendment (17 Feb 2014) modified three different aspects of the protocol.
First, the exclusion criteria num 2. “Patients previously treated with anti-VEGF in the
study eye” was modified. The following new exclusion criteria was included: “Previous
systemic anti-VEGF treatment, approved or experimental, during the three months
prior to the first dose of the study is not allowed during the study”.
Second, the amendment added that during the bimonthly administration phase
Clinical Study Report Sponsor: Fundació IMO
Version: Final Study Code: IMO-AFLI-2013-01
Date: 20/12/2017 EudraCT No.: 2013-002124-17
Confidential Page 50 of 171
(weeks 16, 24 and 32), patients were allowed to receive unscheduled treatment
(never before 4 weeks) if the following rescue criteria were strictly met:
Loss of > 5 letters
AND
Increase of at least 100 micras in retinal thickness attributable to the baseline
disease.
Third, there were two changes in terms of participant centers:
The Fundación Oftalmológica del Mediterráneo (FOM) has changed the name
to FISABIO-Oftalmología Médica
Dr Mª Isabel López Sánchez will perform the study in the Hospital Clínico
Universitario de Valladolid, not in the IOBA center, as initially exposed |
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15 Feb 2015 |
adds the period “treat and extend” by which all patients with
a bimonthly regimen with aflibercept the whole first year of treatment (week 48) were
included in the study after gave their informed consent |
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30 Sep 2015 |
A change in the principal investigator in The Hospital La Paz was done.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
