Children With a Deficiency of Alpha-1 Antitrypsin Clinical Trial
— PolygenOfficial title:
POLYGEN DEFI-ALPHA : Genetic Polymorphisms Study in Children With Alpha-1 Antitrypsin Deficiency, Included in the DEFI-ALPHA Cohort
| NCT number | NCT01862211 |
| Other study ID # | 2011.663 |
| Secondary ID | ID RCB |
| Status | Completed |
| Phase | N/A |
| First received | |
| Last updated | |
| Start date | May 2013 |
| Est. completion date | November 2017 |
| Verified date | November 2018 |
| Source | Hospices Civils de Lyon |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 296 |
| Est. completion date | November 2017 |
| Est. primary completion date | November 2017 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 7 Years and older |
| Eligibility |
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 |
| Country | Name | City | State |
|---|---|---|---|
| France | CHU d'Amiens - Hopital Nord | Amiens | |
| France | CHU de BESANCON | Besancon | |
| France | Hôpital Pellegrin | Bordeaux | |
| France | Hôpital Femme Mère Enfant de Lyon | Bron | |
| France | CHU Estaing | Clermont-Ferrand | |
| France | Hôpital Couple Enfant | La Tronche | |
| France | CHG Le HAVRE | Le Havre | |
| France | AP-HP - Kremlin Bicêtre | Le Kremlin Bicetre | |
| France | Hôpital Jeanne de Flandre | Lille | |
| France | Hopital de la Timone | Marseille | |
| France | Hôpital Brabois Enfants | Nancy | |
| France | Hôpital Mère Enfant | Nantes | |
| France | AP-HP Hôpital Necker | Paris | |
| France | Hôpital Anne de Bretagne | Rennes | |
| France | Hôpital Charles Nicolle | Rouen | |
| France | Hôpital Nord | Saint Etienne | |
| France | CH Saint Nazaire | Saint Nazaire | |
| France | Hopital Hautepierre | Strasbourg | |
| France | Hôpital des Enfants | Toulouse | |
| France | Centre de Pédiatrie Gatien de Clocheville | Tours |
| Lead Sponsor | Collaborator |
|---|---|
| Hospices Civils de Lyon |
France,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | presence of mutations / polymorphisms in genes SERPINA1, Ermani and KPNB1 (with haplotype interpretation) in children with hepatic complications | 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. | 1 day | |
| Secondary | measurement and interpretation of serum IL-8 | 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. | 1 day | |
| Secondary | Identification of modifier genes or mutations responsible of hepatic complications | Find genes responsible of hepatic complications in A1AT-deficient patients by sequencing whole exome | 1 year |