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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
Johann Wolfgang Goethe University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Ataxia Telangiectasia

Eligibility Criteria

2 Years - 45 Years (Child, Adult)All SexesAccepts Healthy Volunteers

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

    First Posted
    January 19, 2015
    Last Updated
    November 29, 2017
    Sponsor
    Johann Wolfgang Goethe University Hospital
    Collaborators
    CSL Behring
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    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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