EWOG-SAA 2010 Genetic and Immunological Characterization of Acquired Severe Aplastic Anemia (SAA) in Children and Adolescents
Organizational Data
- DRKS-ID:
- DRKS00000610
- Recruitment Status:
- Recruiting suspended on temporary hold
- Date of registration in DRKS:
- 2011-08-25
- Last update in DRKS:
- 2023-07-05
- Registration type:
- Prospective
Acronym/abbreviation of the study
EWOG-SAA 2010
URL of the study
No Entry
Brief summary in lay language
In severe aplastic anemia (SAA), the normal blood cells (white and red blood cells as well as platelets) are very low.The study EWOG-SAA 2010 is a clinical trial that is part of clinical research. This study analyses scientific questions concerning origin and characteristics of the disease independent of the treatment. In order to better understand this rare disease and thereby develop better therapies, this study aims at answering a set of questions. Our hypothesis is that congenital and/or acquired genetic defects may be causative for the disease. The main focus of the project is the search for genetic triggers applying modern techniques to analyse the whole genome (i.e. the genetic information) and consecutively the function of the genes. First, the DNA samples will be made anonymous for analysis with so-called SNP-chips to detect new alterations in the genome associated with the disease. With SNP-chips thousands to millions of genetic variants in the DNA of an individual can be detected and shed light on minimal changes of the genome. The newly detected alterations will be further investigated in a second step by modern methods of analysing the genetic information (DNA sequencing) in order to detect alterations in as many possibly affected genes as possible. Later selected genes will be analyzed in cell biological experiments. Here, the consequences of loss and gain of function of a certain gene on the function of the blood stem cell will be investigated. Eventually, we want to elucidate the clinical relevance of the newly identified genetic alterations and their role for diagnosis and prognosis of the disease.
Brief summary in scientific language
The proposed EWOG-SAA 2010 study is the first SAA research study of the group. Besides the rationale to better understand the pathophysiologic aspects of the disease, this study will give the newly formed cooperative study group the possibility to test its infrastructure including Reference Centers and the Coordinating Study Center in Freiburg. The objectives of this study are the evaluation of whole genome SNP genotypes/ karyotypes, frequency of PNH clones, TCRVβ repertoire, overall telomere length and in vitro activation status prior and post ATG exposure.
Health condition or problem studied
- ICD10:
- D61.9 - Aplastic anaemia, unspecified
- Healthy volunteers:
- No Entry
Interventions, Observational Groups
- Arm 1:
- Within the framework of this study we will determine the length of so called telomeres. Telomeres are repetitive DNA structures at the ends of chromosomes stabilizing the human genome. The longer the telomeres the more long-lasting the cell will be. With each cell division telomeres are shortening in most cells except special long-lasting cells, e.g. stem cells. From previous research we know that telomeres are shortened in patients with severe aplastic anemia compared to healthy control subjects of same age. It is not clear if telomere length is associated with probability of response to immunosuppressive therapy or with the risk of developing leukemia. We will address this question. We also know that in a certain proportion of patients with severe aplastic anemia a PNH-clone can be found. PNH-clones are a group of blood producing cells which lack certain proteins on their surface and are therefore prone to attacks of the immune system. We do not know how often these clones are present in children and adults with severe aplastic anemia. Moreover, these clones can change during the course of therapy, they can become smaller or larger. As mentioned before, a certain proportion of patients responds to immunosuppressive therapy. If it is medically indicated your child will receive several drugs suppressing the immune system, amongst others an antibody against T-lymphocytes (anti-thymocyte globulin, ATG). To analyze the possible response to immunosuppressive therapy, especially the response to ATG, the reaction of T-lymphocytes to ATG will be investigated in vitro, i.e. in a test tube. Activation of T-lymphocytes before and after administration of ATG will be measured. Additionally, survival of over activated T-lymphocytes during the treatment with ATG will be determined in vitro. Another study question is if response to immunosuppressive therapy is associated with defects in the T-lymphocytes. Therefore, certain features on T-lymphocytes (T-cell receptors, TCR) will be analyzed. It might be possible that a certain subtype of T-lymphocytes is associated with response to immunosuppressive therapy. In this study, epidemiological data are collected and response to immunosuppressive therapy is recorded. Special side effects will also be recorded. Eventually, genetic analyses are performed within this study. The aim of these analyses is to examine the genetic information (DNA) with respect to genetic characteristics that could be causative for the disease or may contribute to the understanding of the development of the disease.
Endpoints
- Primary outcome:
- • To detect specific genomic lesions/ genotypes by whole genome SNP-arrays and thus to identify patients at high risk for clonal evolution and/or putative non response • To measure telomere length • To study the frequency of clinically manifest EBV-related lymphoproliferation • To analyze the epidemiology of SAA in children and adolescents
- Secondary outcome:
- • To explore the presence and frequency of PNH clones • To detect T cell oligoclonality in BM derived T lymphocytes • To investigate the association of immunophenotypic subclones with oligoclonal T cellexpansion in SAA • To assess the PBMC activation status and capacity of in vitro cellular response to ATG • To compare hematologic response and clinical outcome following IST with immunological and genetic parameters (genomic lesions, telomere length, presence of PNH clones, T cell oligoclonality, in vitro cellular response to ATG)
Study Design
- Purpose:
- Diagnostic
- Retrospective/prospective:
- No Entry
- Study type:
- Non-interventional
- Longitudinal/cross-sectional:
- No Entry
- Study type non-interventional:
- No Entry
Recruitment
- Recruitment Status:
- Recruiting suspended on temporary hold
- Reason if recruiting stopped or withdrawn:
- No Entry
Recruitment Locations
- Recruitment countries:
-
- Austria
- Belgium
- Czechia
- Denmark
- Finland
- Germany
- Ireland
- Italy
- Netherlands
- Norway
- Poland
- Spain
- Sweden
- Switzerland
- Number of study centers:
- Multicenter study
- Recruitment location(s):
- No Entry
Recruitment period and number of participants
- Planned study start date:
- 2011-08-29
- Actual study start date:
- 2011-08-29
- Planned study completion date:
- No Entry
- Actual Study Completion Date:
- No Entry
- Target Sample Size:
- 120
- Final Sample Size:
- No Entry
Inclusion Criteria
- Sex:
- All
- Minimum Age:
- 6 Months
- Maximum Age:
- 17 Years
- Additional Inclusion Criteria:
- • Written informed consent by the caretakers and whenever possible the patient’s assent. • Confirmed diagnosis of SAA (Appendix 3) • Age: 6 months to less than 18 years
Exclusion Criteria
• Previous therapy with IST for SAA • Inherited bone marrow failure (IBMF) disorder (e.g. Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia) • Chromosomal aberration detected by metaphase cytogenetics and/ or FISH (for chromosome 7 and 8), except trisomy of chromosome 8 • Diagnosis of refractory cytopenia (RC)
Addresses
Primary Sponsor
- Address:
- Universitätsklinikum FreiburgHugstetterstr. 5579106 FreiburgGermany
- Telephone:
- No Entry
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- No Entry
- Investigator Sponsored/Initiated Trial (IST/IIT):
- Yes
Contact for Scientific Queries
- Address:
- Zentrum für Kinder- und Jugendmedizin des Universitätsklinikums Freiburg, Klinik IV, Pädiatrische Hämatologie/OnkologieDr. Brigitte StrahmMathildenstr.179106 FreiburgGermany
- Telephone:
- 0761-270-46250
- Fax:
- 0761-270-46230
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- No Entry
Contact for Public Queries
- Address:
- Zentrum für Kinder- und Jugendmedizin des Universitätsklinikums Freiburg, Klinik IV, Pädiatrische Hämatologie/OnkologieDr. Brigitte StrahmMathildenstr.179106 FreiburgGermany
- Telephone:
- 0761-270-46250
- Fax:
- 0761-270-46230
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- No Entry
Principal Investigator
- Address:
- Universitätsklinikum Freiburg, Zentrum für Kinder- und JugendmedizinBrigitte StrahmMathildenstraße 179106 Freiburg im BreisgauGermany
- Telephone:
- +49 761 270 46280
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- No Entry
Sources of Monetary or Material Support
Institutional budget, no external funding (budget of sponsor/PI)
- Address:
- Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin, Klinik IV, Pädiatrische Hämatologie/OnkologieMathildenstr. 179106 FreiburgGermany
- Telephone:
- No Entry
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- No Entry
Ethics Committee
Address Ethics Committee
- Address:
- Ethik-Kommission der Albert-Ludwigs-Universität FreiburgEngelberger Str. 2179106 FreiburgGermany
- Telephone:
- +49-761-27072600
- Fax:
- +49-761-27072630
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- No Entry
Vote of leading Ethics Committee
- Vote of leading Ethics Committee
- Date of ethics committee application:
- 2010-10-13
- Ethics committee number:
- 315/10
- Vote of the Ethics Committee:
- Approved
- Date of the vote:
- 2010-10-18
Further identification numbers
- Other primary registry ID:
- No Entry
- EudraCT Number:
- No Entry
IPD - Individual Participant Data
- Do you plan to make participant-related data (IPD) available to other researchers in an anonymized form?:
- No
- IPD Sharing Plan:
- No Entry
Study protocol and other study documents
- Study protocols:
- No Entry
- Study abstract:
- No Entry
- Other study documents:
- No Entry
- Background literature:
- No Entry
- Related DRKS studies:
- No Entry
Publication of study results
- Planned publication:
- No Entry
- Publikationen/Studienergebnisse:
- No Entry
- Date of first publication of study results:
- No Entry
- DRKS entry published for the first time with results:
- No Entry
Basic reporting
- Basic Reporting / Results tables:
- No Entry
- Brief summary of results:
- No Entry