Multicenter, Non-interventional Study, Describing Patients With Inherited Retinal Disease (IRD) in France
Conditions: Inherited Retinal Disease
Sponsor: University Hospital, Strasbourg, France

 
Department of Clinical Research and Innovations 
RIPH3  
PRI 2021 - HUS N° 8173 
 
V1.1 of 25/06/2021 approved by the CPP Ile de France X on 31/08/2021 
And sent for information to the competent authority on 03/09/2021               1/7            
                                                                                                                                              
 
STUDY SYNOPSIS 
 
Study title 
MULTICENTER, 
NON-INTERVENTIONAL 
STUDY, 
DESCRIBING 
PATIENTS WITH INHERITED RETINAL DISEASE (IRD) IN FRANCE 
Short title 
EPI-GenRet 
Sponsor 
Strasbourg University Hospitals 
Coordinating/Principal Investigator 
Pr Hélène DOLLFUS 
Collaborative partner 
Novartis Pharma SAS 
HUS n° 
8173 
ID RCB n° 
2021-A01786-35 
NCT 
NCT05122442 
Study rationale 
Genetic diagnostic testing becomes increasingly important for 
enhancing our understanding of the disease notably the genetics 
and providing the best care to the patients(“Recommendations on 
Clinical 
Assessment 
of 
Patients 
with 
Inherited 
Retinal 
Degenerations - 2016,” 2016), and several initiatives seek to gather 
more data in order to better understand and treat those diseases.  
 
Within this context, Novartis and SENSGENE/Strasbourg 
University Hospitals (HUS) want to set up, through a research 
collaboration, a non-interventional study in France to better 
understand the epidemiology of IRDs, particularly the 
distribution of pathogenic variants in patients. This study aims to 
serve as a starter study to implement an IRD national registry led 
by SENSGENE/Strasbourg University Hospitals (HUS). The data 
collected might also be used to populate global European registries 
(cf ERN-EYE initiatives). The primary objective has been defined in 
a sufficient broad way to address this perspective of registries.  
 
As IRDs can present from birth to late middle age, this study will 
include both children and adult patients regardless of age, sex, and 
the type of IRD.  
Primary Objective  
The primary objective of this study is to describe the type of IRD of 
patients clinically diagnosed and who attended a consultation at 
one of participating centers from SENSGENE network over the 
inclusion period. 
Secondary Objectives 
The secondary objectives are stated for patients with IRD who 
attended a consultation at one of the participating centers from 
SENSGENE network over the inclusion period.  
 
 
 
To describe the genetic diagnosis  
o 
To describe the genetic testing characteristics  
o 
To describe the distribution of genes and 
pathogenic variants (class 4 and class 5) associated 
with IRDs  
o 
To describe the distribution of variant of uncertain 
significance (VUS - class 3 variants) in IRD-
associated genes  
o 
To describe the proportion of unsolved patients  
o 
To describe the type of pathogenic variants in 
each IRD-associated gene identified  
 

 
Department of Clinical Research and Innovations 
RIPH3  
PRI 2021 - HUS N° 8173 
 
V1.1 of 25/06/2021 approved by the CPP Ile de France X on 31/08/2021 
And sent for information to the competent authority on 03/09/2021               2/7            
                                                                                                                                              
 
 
To evaluate the potential correlation between the patient’s 
genotype and the IRD phenotype  
 
To describe the clinical characteristics  
 
To describe the diagnosis pathway  
 
To describe the socio-demographic characteristics of 
patients  
 
To describe the therapeutic care of patients  
Primary endpoint 
Proportion of patients by type of IRD (based on ORPHA classification 
for IRD) 
Secondary endpoints  
 
• 
Proportion of patients by type of analysis performed for 
definitive molecular genetic diagnosis 
• 
Proportion of each type of genetic analysis performed and 
duration between clinical diagnosis and definitive molecular 
genetic diagnosis 
• 
Proportion of genes with at least 1 pathogenic variant identified 
(classified as class 4 likely pathogenic and class 5 pathogenic) 
according to transmission mode 
• 
Proportion of variants according to their classification (class 4 
and 5) in a specific gene and in all IRD genes 
• 
Proportion of variants of uncertain significance (VUS-class 3 
variants) 
• 
Proportion of unsolved patients 
• 
Proportion of pathogenic variants according to the:  
o 
Mutation’s nomenclature 
o 
Nature of gene mutation 
o 
Allelic status 
o 
Origin of the allele 
 
• 
Proportion of patient with family segregation assessment 
• 
Proportion of similar genotype in other family members 
• 
Proportion of “classic cases”, i.e. patients whose clinical 
phenotype is associated with the expected genotype 
• 
Proportion of “atypic cases”, i.e. patients whose clinical 
phenotype is associated with unusual/unexpected genotype 
• 
Proportion of patients whose type of IRD (ORPHA classification) 
was modified after definitive molecular genetic diagnosis 
• 
Proportion of patients by: 
o 
Age at first symptom onset 
o 
Circumstances of discovery 
o 
Type of clinical assessments to confirm the clinical 
diagnosis 
o 
Age at date of clinical diagnosis 
o 
Type and number of current symptoms related to 
IRD at consultation 
o 
Associated clinical signs 

 
Department of Clinical Research and Innovations 
RIPH3  
PRI 2021 - HUS N° 8173 
 
V1.1 of 25/06/2021 approved by the CPP Ile de France X on 31/08/2021 
And sent for information to the competent authority on 03/09/2021               3/7            
                                                                                                                                              
 
o 
Medical history of interest 
• 
Proportion of patients according to the values of visual acuity 
(VA) and visual field (VF) by patients’ clinical characteristics 
• 
Proportion of patients with a cystoid macular oedema (CME) on 
last coherence tomography (OCT) done 
• 
Proportion of patients with preserved macular area appearance 
by autofluorescence at consultation 
• 
Proportion of patients according to lens status 
• 
Proportion of patients with cataract at consultation 
• 
Proportion of patients with posterior capsular opacification 
• 
Proportion of patients with cataract (phakic and pseudophakic) 
with an impact on VA 
• 
Proportion of patients by type of clinical assessments performed 
• 
Diagnostic odyssey (Length of time from the first symptoms 
onset to the clinical diagnosis and Length of time from the 
previous molecular genetic test and the definitive molecular 
genetic diagnosis for patient who already had a molecular 
genetic test) 
• 
Proportion of patients by age class, gender, type of occupation 
and geographical origin 
• 
Proportion of patients by type of treatments administered for 
IRD 
Study design 
This study is a multicenter, cross-sectional non-interventional study 
that aims to set up a registry of patients with IRD in France. 
 
This study relies on primary data collection and a cross sectional 
design. Data will be collected for both patients with prevalent IRD 
(patients who were already clinically diagnosed with IRD before the 
inclusion in the study) and patients with incident IRD (patients who 
were clinically diagnosed with IRD upon their inclusion in the study). 
To address the primary objective, all patients seen by the physician 
over the inclusion period following site initiation will be included into 
the study, on a consecutive and exhaustive basis until a maximum of 
1000 patients is reached (registry starter). 
 
Given the capacity of sites to screen patients over one year (around 
3000 patients), the inclusion of patients into the study will be limited 
to the first 1000 patients in order to favor the data collection quality 
by limiting the sites workload. This will also encourage the inclusion 
of the patients exhaustively, especially for high volume sites for which 
this registry represents a deep work. However, it should be reminded 
that this study is a starter study that is planned to be extended to a 
larger national registry. 
 
Since this study is non-interventional, nor clinical interventions 
neither genetic tests, imaging and assessment schedule will be 

 
Department of Clinical Research and Innovations 
RIPH3  
PRI 2021 - HUS N° 8173 
 
V1.1 of 25/06/2021 approved by the CPP Ile de France X on 31/08/2021 
And sent for information to the competent authority on 03/09/2021               4/7            
                                                                                                                                              
 
required as part of this study, and all data will be collected as per 
physicians’ routine practice. 
Patients included in this study must have either available genetic 
results upon their inclusion in the study (whether the result of this 
test is positive or negative) or a genetic testing prescription for IRD 
(genetic testing through PFMG platform or from a traditional 
reference public laboratory). Given the delay for obtaining genetic 
results, the data may be available within approximately 12 months 
after the test prescription. 
Inclusion and non-inclusion criteria 
Only the patients who meet all the following inclusion criteria can be 
included in this study: 
 
All patients, whatever age or gender, clinically diagnosed 
with IRD or with high suspicion for IRDs based on clinical 
examination and functional tests (such as fundus exam and 
ERG), regardless of genetic testing 
 
Patients who attended a consultation at one of the 
participating centers from SENSGENE network over the 
inclusion period starting from sites initiation 
 
Patients who had been prescribed a genetic test for IRD prior 
to or at the date of inclusion. 
 
 
Patients who present at least one of the following non-inclusion 
criteria cannot be included in this study: 
 
Patients/Parents/Legally authorized representatives (LAR) 
opposed to the collection and processing of their medical 
data/the medical data of their children/the medical data of 
the person for whom they are LAR; 
 
Patients who are suffering from any other retinal disorder or 
optic neuropathy that may clinically or genetically overlap 
with IRD or non-genetic (phenocopy); 
 
Patients/parents/Legally authorized representatives (LAR) 
refusing genetic testing; 
 
Patients 
lacking 
decision-making 
capacity: 
Mental 
incapacity, unwillingness, or language barriers precluding 
adequate understanding or cooperation. 
Conduct of the study 
French reference and competence centers for rare eye diseases are 
gathered within the SENSGENE network. The Filière de santé 
maladies rares (FSMR) SENSGENE fulfills national missions around 
rare sensory diseases with the aim of improving the care of patients, 
coordinating and encouraging research and developing training and 
information. Seven French reference and competence centers from 
the SENSGENE network will be contacted to participate in the study. 
 
Five coordinating or constitutive reference centers for rare 
eye diseases: HU-Necker-Enfants Malades-APHP (Paris), 
CHNO XV-XX (Paris), CHI Créteil, HU Strasbourg, CHU 
Montpelier. 
 
Two competence centers for rare eye diseases: CHU 
Nantes and CHU Lille 
 
Required sample size 
This study will set up a registry that will include all eligible patients 
with IRD who attended a consultation at one of the participating 
centers from SENSGENE network. 
 

 
Department of Clinical Research and Innovations 
RIPH3  
PRI 2021 - HUS N° 8173 
 
V1.1 of 25/06/2021 approved by the CPP Ile de France X on 31/08/2021 
And sent for information to the competent authority on 03/09/2021               5/7            
                                                                                                                                              
 
For the Cross-sectional registry no sample size calculation is required 
as this registry will record patient fulfilling the sets of criteria defined 
and will allow to have an estimation of the target population at the 
national level. 
 
Given the capacity of sites to screen patients over one year (around 
3000 patients), the inclusion of patients into the study will be limited 
to the first 1000 patients in order to favor the data collection quality 
by limiting the sites workload. This will encourage the inclusion of the 
patients exhaustively, especially for high volume sites for which this 
registry represents a deep work. However, it should be reminded that 
this study is a starter study that is planned to be extended to a larger 
national registry. 
 
The precision can be estimated for a sample size of 1000 patients 
while considering 5% loss (patients not evaluable for the primary 
objective or not meeting all selection criteria). 
 
The following table presents the precision and the corresponding 2-
sided 95% confidence interval (CI) to describe the distribution of IRD 
type (proportions varying from 10% to 50% for each modality) and a 
sample size of 1000 patients. 
 
Table. Precision and corresponding 2-sided 95% CI given the 
proportion of a modality varying from 10% to 50% and a sample size 
of 1000 patients (5% of non-evaluable patients) 
 
 
Proportion 
10% 
20% 
30% 
40% 
50% 
n  
Precision  Precision Precision Precision Precision 
Précision 
(%)  
1.9 
2.5 
2.9 
3.1 
3.2 
95% CI 
8.1; 11.9 17.5; 22.5 27.1; 32.9 36.9; 43.1 46.8; 53.2 
 
The precision (e) is calculated based on the normal approximation 
using the following formula: 
 
𝑒= √1,96² ∗(𝑝−𝑝²)
𝑛
 
 
where p is the proportion of a given modality and n is the number of 
patients. 
Statistical method 
A descriptive analysis will be conducted on all study endpoints for 
which data has been collected both for the overall study population 
and per subgroups of interest where relevant (e.g. patients’ clinical 
characteristics, classification (class 4 and 5), nature of the mutation, 
the values of visual acuity (VA) and visual field (VF), date of genetic 
testing, clinical phenotype, type of genetic analysis performed and 
unsolved patients) as long as that the sizes of the sub-groups are 
relevant for statistical estimations. The subgroups’ modalities and 
associated endpoints will be detailed in the Statistical Analysis Plan. 
 
The following statistics will be provided for quantitative variables: 
number and proportion of patients with non-missing and missing 

 
Department of Clinical Research and Innovations 
RIPH3  
PRI 2021 - HUS N° 8173 
 
V1.1 of 25/06/2021 approved by the CPP Ile de France X on 31/08/2021 
And sent for information to the competent authority on 03/09/2021               6/7            
                                                                                                                                              
 
values per variable, mean, standard deviation (StD), median, first 
quartile (Q1), third quartile (Q3), minimum and maximum value, the 
mode (especially for discrete quantitative variables with limited 
variability). 
 
For qualitative variables, the number and proportion of each variable 
modality will be provided together with the number of missing 
values. Proportion will be computed based on the population with 
non-missing data. 
 
Exploratory comparison between study subgroups might be 
considered. Statistical tests will be based on the type and distribution 
of the variables. All comparison tests will be two-tailed with a 
standard type 1 error threshold of 5% (significance level). 
 
The enrollment of patients in the study will be limited to a maximum 
of 1000 patients, registered over a variable period of time limited to 
12 months. 
 
This study design therefore presents bias related to the 
heterogeneous duration of patients’ inclusion which depends on the 
activity size of each participating physician. 
 
In order to take into account the biases associated with this study 
design and be able to extrapolate results at the national level, an 
adjustment is planned for descriptive analyses over the registry using 
a weight applied at center level. 
Expected benefits 
Implementation of an IRD national registry including all data related 
to IRD and presenting their clinical features may help to deepen the 
epidemiologic and genetics knowledge of IRDs. No direct benefit to 
the participating patient is expected from this study but the 
knowledge generated from this study may benefit future patients. 
Provisional schedule 
-Maximum duration of the inclusion phase: 12 months or 
themaximum of 1000 patients is reached, whatever occurs first (a) 
-Maximum duration of participation of each patient: 12months (b) 
-Maximum total duration of the study: 24 months (= a+b) 
-Exclusion from other interventional studies while patientsparticipate 
to the present clinical trial: None 
-End of trial: The study end corresponds to the end of thecollection 
of gene testing results of the participation of the lastsubject in the 
study.