Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Polygen Defi-Alpha: Genetic Polymorphisms Study in Children With Alpha-1 Antitrypsin Deficiency, Included in the DEFI-ALPHA Cohort

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Hospices Civils de Lyon
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon
ClinicalTrials.gov Identifier:
NCT01862211
First received: May 22, 2013
Last updated: September 11, 2014
Last verified: September 2014
  Purpose

The deficiency of alpha-1 antitrypsin (DA1AT) is a genetic disorder of variable clinical expression, initially described in adults with pulmonary emphysema patients. In children, it is the second cause of neonatal cholestasis after biliary atresia and is a common indication for liver transplantation.

Several genotypes for SERPINA1 gene coding for alpha-1 anti-trypsin were identified. The main ones are M / M, M / Z, M / S and Z / Z and each genotype is closely correlated with the concentration of blood A1AT. The estimate for France suggests a prevalence of genotype deficit Z / Z of the order of 1/6054, (9982 patients), which in 11% of cases, have liver disease (prolonged neonatal jaundice). Half of them will move towards the development of cirrhosis with portal hypertension, at worst liver transplantation.

Currently, we do not know what are the clinical and genetic factors that predispose a patient A1AT deficiency develop liver damage. Recent studies have led us to think that polymorphisms in the gene SERPINA1, as well as that of the alpha-mannosidase 1 endoplasmic reticulum (Erman gene) could be a predictive marker of liver complications. Another possible candidate gene is one of the importin beta (KPNB1), a protein involved in the elimination of misfolded proteins. These data lead us to propose the study of genetic polymorphisms.

The main objective of the study is to compare the allele frequencies of these polymorphisms between (i) a cohort of A1AT deficient patients and with hepatic symptoms (portal hypertension and its complications, severe liver failure leading to transplant or not, or an indication for liver transplantation) and (ii) a cohort of A1AT deficient patients without signs of hepatic call. To build this last cohort, we will include in the genetic study the family members of deficient patients, some of whom probably carrying a deficit genotype Z / Z but without any associated clinical manifestations. This will allow us to facilitate the establishment of genotype profiles / phenotype clearly identified, which then allow a more appropriate care for children who may have such a development, we will strive to achieve a haplotype interpretation of polymorphisms found.

This study will be conducted in association with the DEFI-ALPHA study to identify clinical and biological prognostic factors such as age at diagnosis, the diagnostic mode, the results of liver biopsy (when available), the clinical course, family history, the existence of IUGR and long-term treatment.

The secondary objectives of the study are :

  • The measurement and interpretation of serum IL-8 in A1AT-deficient patients. Indeed, one study showed a higher IL-8 in patients with ulcerative colitis compared with healthy patients' serum. These considerations led us to hypothesize that IL-8 may be a marker of liver disease in A1AT deficiency.
  • Preservation of blood samples for further study of other genes, which may be in the future suspected to be associated with the occurrence of liver complications. To this end, a DNA bank will be created. It will involve the children with a deficiency of alpha-1 antitrypsin and their family of 1st and 2nd degree in civil law (parents and siblings).

This study is a continuation of the cohort DEFI-ALPHA (descriptive study of a cohort of children with DA1AT) and sought to identify the clinical and biological factors such as age at diagnosis, diagnosis mode, the result sets of the liver biopsy (when available), clinical course, family history, the presence of IUGR and long-term treatment.

The only criterion for not-inclusion is, according to the subject, the lack of consent of the child and his parents, the lack of consent of the adult patient, or the lack of consent of the witness. Demographic and clinical history data (for parents and brothers/sisters showing no DA1AT) will be collected.

Currently, the cohort of patients with DA1AT is being set up in the framework of the "Cohort DEFI-ALPHA." This multicenter project is realized with the help of french pediatric hepatology centers that regularly follow patients DA1AT. Today, over 100 patients DA1AT have already been identified, and the collection of historical data has already begun on several centers since September 2009. This study is therefore a continuation of this work.

Over a period of 30 months, the total number of potentially includable subjects is estimated at about 400 in this study (100 patients and 300 related to the first degree such as parents, brothers and sisters).

This study will be promoted by the Hospices Civils de Lyon. Authorization of the competent authority and the ethical committee will be obtained as well as informed consent from families before blood sampling.


Condition Intervention
Children With a Deficiency of Alpha-1 Antitrypsin
Other: blood sampling

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: POLYGEN DEFI-ALPHA : Genetic Polymorphisms Study in Children With Alpha-1 Antitrypsin Deficiency, Included in the DEFI-ALPHA Cohort

Resource links provided by NLM:


Further study details as provided by Hospices Civils de Lyon:

Primary Outcome Measures:
  • presence of mutations / polymorphisms in genes SERPINA1, Ermani and KPNB1 (with haplotype interpretation) in children with hepatic complications [ Time Frame: 1 day ] [ Designated as safety issue: No ]
    The main objective of the study is to compare the allele frequencies of these polymorphisms between (i) a cohort of A1AT deficient patients and with hepatic symptoms (portal hypertension and its complications, severe liver failure leading to transplant or not, or an indication for liver transplantation) and (ii) a cohort of A1AT deficient patients without signs of hepatic call.


Secondary Outcome Measures:
  • measurement and interpretation of serum IL-8 [ Time Frame: 1 day ] [ Designated as safety issue: No ]
    The measurement and interpretation of serum IL-8 in A1AT-deficient patients. Indeed, one study showed a higher IL-8 in patients with ulcerative colitis compared with healthy patients' serum. These considerations led us to hypothesize that IL-8 may be a marker of liver disease in A1AT deficiency.


Estimated Enrollment: 400
Study Start Date: May 2013
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: members of family of children with a DA1AT Other: blood sampling
A blood sampling will be performed for the genetic analysis and the measurement of serum IL-8.
Experimental: children with a DA1AT Other: blood sampling
A blood sampling will be performed for the genetic analysis and the measurement of serum IL-8.

  Eligibility

Ages Eligible for Study:   7 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Children included in the DefiAlpha cohort or adult aged under 18 years at the time of inclusion in the cohort Defi-Alpha, with a deficiency of of alpha-1 antitrypsin
  • Beneficiaries subjects of a social security system
  • Presence of a signed informed consent (patient or parents) at the time of inclusion

Exclusion Criteria:

- Lack of consent

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01862211

Contacts
Contact: Alain Lachaux, Pr 427 856 020 ext +33 alain.lachaux@chu-lyon.fr

Locations
France
Hôpital Pellegrin Not yet recruiting
Bordeaux, France
Contact: Thierry LAMIREAU, PU-PH       thierru.lamireau@chu-bordeaux.fr   
Principal Investigator: Thierry LAMIREAU, PU-PH         
Hôpital Femme Mère Enfant de Lyon Recruiting
Bron, France
Contact: Alain Lachaux, Pr    427 856 020 ext +33    alain.lachaux@chu-lyon.fr   
Principal Investigator: Alain Lachaux, Pr         
CHU Estaing Not yet recruiting
Clermont-Ferrand, France
Contact: Corinne BORDERON, PU-PH       cborderon@chu-clermontferrand.fr   
Principal Investigator: Corinne BORDERON, PU-PH         
Hôpital Couple Enfant Not yet recruiting
La Tronche, France
Contact: Jean-Pierre CHOURAQUI, PH       JPChouraqui@chu-grenoble.fr   
Principal Investigator: Jean-Pierre CHOURAQUI, PH         
AP-HP - Kremlin Bicêtre Not yet recruiting
Le Kremlin Bicetre, France
Contact: Emmanuel JACQUEMIN, PU-PH       emmanuel.jacquemin@bct.aphp.fr   
Principal Investigator: Emmanuel JACQUEMIN, PU-PH         
Hôpital Jeanne de Flandre Not yet recruiting
Lille, France
Contact: Frédéric GOTTRAND, PU-PH       frederic.gottrand@chru-lille.fr   
Principal Investigator: Frédéric GOTTRAND, PU-PH         
Hôpital Brabois Enfants Not yet recruiting
Nancy, France
Contact: Alain MORALI, PH       a.morali@chu-nancy.fr   
Principal Investigator: Alain MORALI, PH         
Hôpital Mère Enfant Not yet recruiting
Nantes, France
Contact: Agathe JOBERT GIRAUD, PH       a.jobert@ch-saintnazaire.fr   
Principal Investigator: Agathe JOBERT GIRAUD, PH         
AP-HP Hôpital Necker Recruiting
Paris, France
Contact: Florence LACAILLE, PU-PH       florence.lacaille@nck.aphp.fr   
Principal Investigator: Florence LACAILLE, PU-PH         
Hôpital Anne de Bretagne Recruiting
Rennes, France
Contact: Alain DABADIE, PH         
Principal Investigator: Alain DABADIE, PH         
Hôpital Charles Nicolle Not yet recruiting
Rouen, France
Contact: Olivier MOUTERDE, PH       olivier.mouterde@chu-rouen.fr   
Principal Investigator: Olivier MOUTERDE, PH         
Hôpital Nord Recruiting
Saint Etienne, France
Contact: Clara CREMILLIEUX, PH       clara.cremillieux@chu-st-etienne.fr   
Principal Investigator: Clara CREMILLIEUX, PH         
CH Saint Nazaire Not yet recruiting
Saint Nazaire, France
Contact: Agathe JOBERT GIRAUD, PH       .jobert@ch-saintnazaire.fr   
Principal Investigator: Agathe JOBERT GIRAUD, PH         
Hôpital des Enfants Not yet recruiting
Toulouse, France
Contact: Pierrre BROUE       broue.p@chu-toulouse.fr   
Principal Investigator: Pierre BROUE, PU-PH         
Centre de Pédiatrie Gatien de Clocheville Recruiting
Tours, France
Contact: Bernard CAURIER, PH       bernard.caurier@free.fr   
Principal Investigator: Bernard CAURIER, PH         
Sponsors and Collaborators
Hospices Civils de Lyon
  More Information

No publications provided

Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT01862211     History of Changes
Other Study ID Numbers: 2011.663
Study First Received: May 22, 2013
Last Updated: September 11, 2014
Health Authority: France: Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé
France: The Commission nationale de l’informatique et des libertés
France: Committee for the Protection of Personnes
France: Agence Nationale de Sécurité du Médicament et des produits de santé

Keywords provided by Hospices Civils de Lyon:
alpha antitrypsin, hepatic disease, genetic, polymorphism

Additional relevant MeSH terms:
Alpha 1-Antitrypsin Deficiency
Digestive System Diseases
Emphysema
Genetic Diseases, Inborn
Liver Diseases
Lung Diseases
Pathologic Processes
Respiratory Tract Diseases
Subcutaneous Emphysema
Alpha 1-Antitrypsin
Protein C Inhibitor
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protease Inhibitors
Serine Proteinase Inhibitors
Trypsin Inhibitors

ClinicalTrials.gov processed this record on November 25, 2014