Susceptibility to Infections in Ataxia Telangiectasia
Primary Purpose
Ataxia Telangiectasia, Infections, Immunodeficiency
Status
Completed
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Blood collection
Lung function measurement
Symptom diary
Sponsored by
About this trial
This is an interventional supportive care trial for Ataxia Telangiectasia
Eligibility Criteria
Inclusion Criteria:
- A-T: clinically and/or genetically diagnosed A-T
- No IgG treatment from the point of being included into the study
- Healthy controls: healthy children or adults matched for gender and age
- age 2 - 45 years
- written informed consent
Exclusion Criteria:
- age < 2 or > 45 years
- patient has to be treated with IgG-replacement regularly
- Other diseases with influence on the immune system (e.g. diabetes mellitus, malignancy, dialysis-dependent renal failure)
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Ataxia Telangiectasia
Healthy Control
Arm Description
All A-T patients presented for 3 study visits. In all visits patients had a clinical examination, a blood collection and a lung function measurement. Furthermore symptom diaries were distributed and collected on these visits.
All healthy controls presented for 3 study visits. In all visits patients had a clinical examination and a lung function measurement. Furthermore symptom diaries were distributed and collected on these visits.
Outcomes
Primary Outcome Measures
Number of days with a symptom score > 3 compared to healthy subjects matched for age.
Secondary Outcome Measures
Number of days of absence in kindergarten, school or at work
Number of cold periods
Number of antibiotic therapies
Number of severe infections
Number of severe infections defined as abscess-forming pneumonia/meningitis and/or other infection with need for hospitalization compared to healthy controls.
Full Information
NCT ID
NCT02345135
First Posted
January 19, 2015
Last Updated
November 29, 2017
Sponsor
Johann Wolfgang Goethe University Hospital
Collaborators
CSL Behring
1. Study Identification
Unique Protocol Identification Number
NCT02345135
Brief Title
Susceptibility to Infections in Ataxia Telangiectasia
Official Title
Susceptibility to Infections in Patients With Ataxia Telangiectasia : A Prospective Follow-up Study
Study Type
Interventional
2. Study Status
Record Verification Date
November 2017
Overall Recruitment Status
Completed
Study Start Date
September 2012 (undefined)
Primary Completion Date
January 31, 2016 (Actual)
Study Completion Date
July 31, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Johann Wolfgang Goethe University Hospital
Collaborators
CSL Behring
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Death in Ataxia telangiectasia (A-T) is usually due to cancer or chronic lung failure around 20 years of age. Despite low lymphocyte counts (CD3, CD4, CD8 and CD19), IgA and IgG subclass deficiency opportunistic and acute severe respiratory infections are rare. The prevailing wisdom is that an immunoglobulin replacement therapy is not necessary in most of the patients. However no placebo controlled trials have been performed so far. The aim of this trial was to investigate the prevalence of mild and severe respiratory infections and / or chronic cough in classical A-T patients compared to healthy controls.
Detailed Description
Ataxia telangiectasia is an autosomal recessive multisystem disorder which is characterized by a progressive ataxia, conjunctival telangiectasia, a humoral and cellular immunodeficiency, an increased radiosensitivity and an increased risk for cancer (Boder E, Pediatrics, 1957). Most patients die in their 2nd or 3rd decade of life due to a respiratory failure caused by progressive (interstitial) lung disease or due to malignancies (Schroeder SA, Pediatr Pulmonol, 2010). In 1995 the sequence of the mutated AT gene (ATM) on chromosome 11q22-23 was identified. Main problems besides the progressive neurodegeneration are recurrent infections of upper and lower respiratory tract and a growth retardation and malnutrition. These problems are caused by a mutation in the ATM gene on chromosome 11, which encodes for a protein with several key functions in control of cell cycle and apoptosis (Savitsky K et al., Hum Mol Gen, 1995). Several works already showed that patients with AT have a variable immunodeficiency which is characterized by low lymphocyte counts, a lack of Immunoglobulin A (IgA), Immunoglobulin G subclasses (IgG2 and 4) and specific pneumococcal antibodies (Schubert R, Clin Exp Immunol, 2002). The course of disease is dependent on the AT mutation respectively the residual kinase activity of ATM which is found in about 10% of A-T patients. These patients are described as 'variant ATs´ and have a better prognosis regarding immunodeficiency, susceptibility to infections and a possible growth retardation and malnutrition (Verhagen M, Hum Mutat, 2012). Despite the evidence for a humoral immunodeficiency a treatment with polyvalent immunoglobulins (IgG) is not practiced in generally. In the 'Clinical Workshop on Ataxia Teleangiectasia´, that took place in Frankfurt in January 2011, the investigators found out that the percentage of A-T patient, that are supplemented with immunoglobulins was only 10% to 60% depending on the different clinical centres.The Goethe University Childrens Hospital in Frankfurt, the biggest A-T centre in Germany, takes care for more than 40 A-T patients. At the moment about 15% of these patients are treated with immunoglobulins. Some observations show that the progress of the chronic lung disease cannot be prevented the usage of immunoglobulins. By now it´s not clear in what way patients suffer from an increased susceptibility to infections and if a substitution with immunoglobulins is needed. The aim of this trial is to investigate the incidence, intensity and duration of infections in patients with A-T compared to age matched healthy controls.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ataxia Telangiectasia, Infections, Immunodeficiency, Lung Disease
7. Study Design
Primary Purpose
Supportive Care
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
41 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ataxia Telangiectasia
Arm Type
Active Comparator
Arm Description
All A-T patients presented for 3 study visits. In all visits patients had a clinical examination, a blood collection and a lung function measurement. Furthermore symptom diaries were distributed and collected on these visits.
Arm Title
Healthy Control
Arm Type
Active Comparator
Arm Description
All healthy controls presented for 3 study visits. In all visits patients had a clinical examination and a lung function measurement. Furthermore symptom diaries were distributed and collected on these visits.
Intervention Type
Procedure
Intervention Name(s)
Blood collection
Intervention Description
In all patients with Ataxia telangiectasia blood was collected at each visit date to determine blood count, lymphocyte subpopulation count and immunoglobulin levels in serum (IgA, IgG, IgM, IgE), as well as alpha feto protein (AFP).
Intervention Type
Procedure
Intervention Name(s)
Lung function measurement
Intervention Description
In all patients - Ataxia telangiectasia and healthy controls - a lung function measurement was done to determine vital capacity (VC), forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF) and Tiffenau index.
Intervention Type
Behavioral
Intervention Name(s)
Symptom diary
Intervention Description
All patients - Ataxia telangiectasia and healthy controls - were requested to keep a symptom diary for the months September to March of the years 2012/2013 and 2013/2014 to determine days with symptoms as coughing during day and night, cold and fever, as well missing days at kindergarten/school/work, intake of medication (especially antibiotic treatment) and hospitalisations.
Primary Outcome Measure Information:
Title
Number of days with a symptom score > 3 compared to healthy subjects matched for age.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Number of days of absence in kindergarten, school or at work
Time Frame
24 months
Title
Number of cold periods
Time Frame
24 months
Title
Number of antibiotic therapies
Time Frame
24 months
Title
Number of severe infections
Description
Number of severe infections defined as abscess-forming pneumonia/meningitis and/or other infection with need for hospitalization compared to healthy controls.
Time Frame
24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
A-T: clinically and/or genetically diagnosed A-T
No IgG treatment from the point of being included into the study
Healthy controls: healthy children or adults matched for gender and age
age 2 - 45 years
written informed consent
Exclusion Criteria:
age < 2 or > 45 years
patient has to be treated with IgG-replacement regularly
Other diseases with influence on the immune system (e.g. diabetes mellitus, malignancy, dialysis-dependent renal failure)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stefan Zielen, Prof. Dr.
Organizational Affiliation
Johann Wolfgang Goethe University, Childrens Hospital
Official's Role
Principal Investigator
12. IPD Sharing Statement
Citations:
PubMed Identifier
23761391
Citation
Schroeder SA, Zielen S. Infections of the respiratory system in patients with ataxia-telangiectasia. Pediatr Pulmonol. 2014 Apr;49(4):389-99. doi: 10.1002/ppul.22817. Epub 2013 Jun 13.
Results Reference
background
PubMed Identifier
15014308
Citation
Schubert R, Reichenbach J, Rose M, Zielen S. Immunogenicity of the seven valent pneumococcal conjugate vaccine in patients with ataxia-telangiectasia. Pediatr Infect Dis J. 2004 Mar;23(3):269-70. doi: 10.1097/01.inf.0000115737.35353.55.
Results Reference
background
PubMed Identifier
20583220
Citation
McGrath-Morrow SA, Gower WA, Rothblum-Oviatt C, Brody AS, Langston C, Fan LL, Lefton-Greif MA, Crawford TO, Troche M, Sandlund JT, Auwaerter PG, Easley B, Loughlin GM, Carroll JL, Lederman HM. Evaluation and management of pulmonary disease in ataxia-telangiectasia. Pediatr Pulmonol. 2010 Sep;45(9):847-59. doi: 10.1002/ppul.21277.
Results Reference
background
PubMed Identifier
15789441
Citation
Schroeder SA, Swift M, Sandoval C, Langston C. Interstitial lung disease in patients with ataxia-telangiectasia. Pediatr Pulmonol. 2005 Jun;39(6):537-43. doi: 10.1002/ppul.20209.
Results Reference
background
PubMed Identifier
23566627
Citation
Driessen GJ, Ijspeert H, Weemaes CM, Haraldsson A, Trip M, Warris A, van der Flier M, Wulffraat N, Verhagen MM, Taylor MA, van Zelm MC, van Dongen JJ, van Deuren M, van der Burg M. Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity. J Allergy Clin Immunol. 2013 May;131(5):1367-75.e9. doi: 10.1016/j.jaci.2013.01.053. Epub 2013 Apr 6.
Results Reference
background
PubMed Identifier
22017321
Citation
Verhagen MM, Martin JJ, van Deuren M, Ceuterick-de Groote C, Weemaes CM, Kremer BH, Taylor MA, Willemsen MA, Lammens M. Neuropathology in classical and variant ataxia-telangiectasia. Neuropathology. 2012 Jun;32(3):234-44. doi: 10.1111/j.1440-1789.2011.01263.x. Epub 2011 Oct 24.
Results Reference
background
PubMed Identifier
34477998
Citation
Zielen S, Duecker RP, Woelke S, Donath H, Bakhtiar S, Buecker A, Kreyenberg H, Huenecke S, Bader P, Mahlaoui N, Ehl S, El-Helou SM, Pietrucha B, Plebani A, van der Flier M, van Aerde K, Kilic SS, Reda SM, Kostyuchenko L, McDermott E, Galal N, Pignata C, Perez JLS, Laws HJ, Niehues T, Kutukculer N, Seidel MG, Marques L, Ciznar P, Edgar JDM, Soler-Palacin P, von Bernuth H, Krueger R, Meyts I, Baumann U, Kanariou M, Grimbacher B, Hauck F, Graf D, Granado LIG, Prader S, Reisli I, Slatter M, Rodriguez-Gallego C, Arkwright PD, Bethune C, Deripapa E, Sharapova SO, Lehmberg K, Davies EG, Schuetz C, Kindle G, Schubert R. Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia. J Clin Immunol. 2021 Nov;41(8):1878-1892. doi: 10.1007/s10875-021-01090-8. Epub 2021 Sep 3.
Results Reference
derived
Links:
URL
http://www.info-at.de
Description
German AT-website
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Susceptibility to Infections in Ataxia Telangiectasia
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