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Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM) (CILLICORIRCM)

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ClinicalTrials.gov Identifier: NCT04874909
Recruitment Status : Not yet recruiting
First Posted : May 6, 2021
Last Update Posted : May 6, 2021
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

The purpose of the C'IL-LICO RICM study is to develop innovative and transformative diagnostic and prognostic for patients suffering from ciliopathies leading to renal failure.

The objectives is to decipher disease mechanisms and highlight signaling pathways altered in at-risk to develop renal failure patient groups and to produce a prognostic biomarker-based kit to predict the evolution of ciliopathy patients towards renal impairment.


Condition or disease Intervention/treatment Phase
Ciliopathies Nephronophthisis Senior-Loken Syndrome Joubert Syndrome Jeune Syndrome Bardet-Biedl Syndrome Other: Blood sample Other: Urine sample Not Applicable

Detailed Description:

Ciliopathies are a large group of rare and severe genetic diseases caused by ciliary dysfunction, in which nearly all organs can be affected. In spite of being individually rare, they affect collectively up to one per 2000 people. Over the past two decades, more than 90 genes have been reported as mutated in ciliopathy patients. Most proteins encoded by these genes play key roles in the biogenesis or function of cilia, in which they define different functional subdomains. Genetic analyses of ciliopathies revealed a vast clinical variability and a broad genetic heterogeneity as: 1) mutations of the same disease-causing gene can result in distinct clinical entities and, conversely, 2) mutations in several independent genes can lead to similar clinical features, implying both phenotypic and genetic overlaps. The extent and severity of organ involvement may be correlated in part with the nature or location of the mutational event, the cell/tissue specific expression and effect of the mutated protein on cilia dysfunction.

Renal involvement is one of the most frequent manifestations in ciliopathies, and it leads to excessive morbidity and mortality. This includes renal cystic dysplasia (RCD), a kidney developmental defect, and nephronophthisis (NPHP), a chronic tubulointerstitial nephritis, both disorders representing frequent causes of end-stage renal disease (ESRD) during childhood to early adulthood. This makes ESRD a terminal endpoint of either isolated or syndromic ciliopathies, with, hitherto, no available curative treatment of chronic kidney disease whatsoever. The only bearable option is renal transplantation. As the average life-span of a functioning kidney transplant is about 10-15 years, it is urgent to identify therapeutic solutions that slow down progression of CKD in ciliopathies, and delay or avoid dialysis or transplantation. Today, the diagnosis of ciliopathies is first based on primary clinical manifestations, and then confirmed by gene mutation identification. However, even in patients with identified causative mutations, it is impossible to predict the severity of the disease, the risk of appearance (if not present at diagnosis), and/or the rate of progression of CKD. Thus, a crucial issue in the field of ciliopathies is to be able to perform early detection of at-risk patients prior to development of CKD as well as to predict disease progression rate.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Classification and Functional Stratification of the Patients With Ciliopathy and Identification of Biomarkers to Improve Their Prognosis
Estimated Study Start Date : June 2021
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : June 2024


Arm Intervention/treatment
"Case" Patient
Patient with ciliopathy
Other: Blood sample

Blood sample of 15ml max by subject (case, related individual, control) once time:

  • subject less than 5 kg : 1.8 to 4.5 ml max
  • subject 5 kg to 10 kg : 4.5 to 9 ml max
  • subject 10 kg to 15 kg : 9 to 13.5 ml
  • subject 15 kg to 20 kg : 13.5 to 15 ml max

Other: Urine sample
Urine sample (500 ml) once time

Healthy related individual
Individual without ciliopathy but related to a patient with ciliopathy (father, mother, brother, sister)
Other: Blood sample

Blood sample of 15ml max by subject (case, related individual, control) once time:

  • subject less than 5 kg : 1.8 to 4.5 ml max
  • subject 5 kg to 10 kg : 4.5 to 9 ml max
  • subject 10 kg to 15 kg : 9 to 13.5 ml
  • subject 15 kg to 20 kg : 13.5 to 15 ml max

Other: Urine sample
Urine sample (500 ml) once time

"Negative Control" patient
patient without renal disease
Other: Blood sample

Blood sample of 15ml max by subject (case, related individual, control) once time:

  • subject less than 5 kg : 1.8 to 4.5 ml max
  • subject 5 kg to 10 kg : 4.5 to 9 ml max
  • subject 10 kg to 15 kg : 9 to 13.5 ml
  • subject 15 kg to 20 kg : 13.5 to 15 ml max

Other: Urine sample
Urine sample (500 ml) once time

"Positive Control" patient
patient with renal disease other that ciliopathy but with a similar renal function to the ciliopathy group ("case" patient)
Other: Blood sample

Blood sample of 15ml max by subject (case, related individual, control) once time:

  • subject less than 5 kg : 1.8 to 4.5 ml max
  • subject 5 kg to 10 kg : 4.5 to 9 ml max
  • subject 10 kg to 15 kg : 9 to 13.5 ml
  • subject 15 kg to 20 kg : 13.5 to 15 ml max

Other: Urine sample
Urine sample (500 ml) once time




Primary Outcome Measures :
  1. Change in transcriptional profiles in different subtypes of ciliopathy patients and control subjects [ Time Frame: 3 years ]

    RNA-sequencing analysis will be utilized to identify changes in transcriptional profiles and biological pathways in subgroups of patients to research whether the target mutation gene combination analyzed by transcription group was consistent with clinical cell morphological diagnosis and disease progression.

    Different human models will be used: Urine-derived Renal Epithelial Cells (URECs), renal organoids from patients derived induced Pluripotent Stem Cells (iPSCs) and urines.



Secondary Outcome Measures :
  1. Change in proteome profiles in different subtypes of ciliopathy patients and control subjects [ Time Frame: 3 years ]

    Proteomics analysis will be utilized to identify changes in proteome profiles in subgroups of patients to research whether the target mutation gene combination analyzed by proteomics group was consistent with clinical cell morphological diagnosis and disease progression.

    Different human models will be used: Urine-derived Renal Epithelial Cells (URECs), renal organoids from patients derived induced Pluripotent Stem Cells (iPSCs) and urines.


  2. Change in metabolome profiles in different subtypes of ciliopathy patients and control subjects [ Time Frame: 3 years ]

    Metabolomics analysis will be utilized to identify changes in metabolome profiles in subgroups of patients to research whether the target mutation gene combination analyzed by metabolomics group was consistent with clinical cell morphological diagnosis and disease progression.

    Different human models will be used: Urine-derived Renal Epithelial Cells (URECs), renal organoids from patients derived induced Pluripotent Stem Cells (iPSCs) and urines.




Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

"Case" Patient :

  • with nephronophthisis or ciliopathy with known genetic diagnosis or not
  • signed the Informed consent form (patient or legal guardians if minor/incapable major)
  • no limit of age, this patients could be recruited from the birth
  • social insurance affiliation

Healthy related individual :

  • related with a included patient (father, mother, brother, sister)
  • signed the Informed consent form (major or legal guardians if minor/incapable major)
  • no limit of age, this patients could be recruited from the birth
  • social insurance affiliation

"Negative Control" patient :

  • without chronic renal failure
  • signed the Informed consent form (major or legal guardians if minor/incapable major)
  • no limit of age, this patients could be recruited from the birth
  • social insurance affiliation

"Positive Control" patient :

  • with chronic renal failure not related with a ciliary dysfunction
  • signed the Informed consent form (major or legal guardians if minor/incapable major)
  • no limit of age, this patients could be recruited from the birth
  • social insurance affiliation

Exclusion Criteria "Case" Patient :

  • pregnant, parturious and nursing mothers.
  • with functional renal graft
  • use an experimental treatment during 30 days before inclusion date

Healthy related individual :

- pregnant, parturious and nursing mothers.

"Negative Control" patient :

- pregnant, parturious and nursing mothers.

"Positive Control" patient :

  • pregnant, parturious and nursing mothers.
  • with functional renal graft
  • use an experimental treatment during 30 days before inclusion date

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04874909


Contacts
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Contact: Stanislas LYONNET, MD, PhD (33) 1 42 75 49 96 stanislas.lyonnet@aphp.fr
Contact: Sandra COLAS +33 1 71 19 64 32 sandra.colas@aphp.fr

Locations
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France
Hôpital Necker-Enfants Malades
Paris, France, 75015
Contact: Stanislas LYONNET, MD, PhD    (33) 1 42 75 49 96    stanislas.lyonnet@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Study Chair: Sophie SAUNIER, PhD Imagine Institute
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04874909    
Other Study ID Numbers: APHP200896
ID-RCB Number ( Other Identifier: 2020-A02356-33 )
First Posted: May 6, 2021    Key Record Dates
Last Update Posted: May 6, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Ciliopathies
Pediatrics
Genetic diseases
Chronic Kidney Disease
Biomarkers
Additional relevant MeSH terms:
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Bardet-Biedl Syndrome
Laurence-Moon Syndrome
Ciliopathies
Syndrome
Disease
Pathologic Processes
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Retinitis Pigmentosa
Eye Diseases, Hereditary
Eye Diseases
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, Inborn