- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02345135
Susceptibility to Infections in Ataxia Telangiectasia
November 29, 2017 updated by: Stefan Zielen, Johann Wolfgang Goethe University Hospital
Susceptibility to Infections in Patients With Ataxia Telangiectasia : A Prospective Follow-up Study
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.
Study Overview
Status
Completed
Intervention / Treatment
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.
Study Type
Interventional
Enrollment (Actual)
41
Phase
- Not Applicable
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
2 years to 45 years (ADULT, CHILD)
Accepts Healthy Volunteers
Yes
Genders Eligible for Study
All
Description
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)
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: SUPPORTIVE_CARE
- Allocation: NON_RANDOMIZED
- Interventional Model: PARALLEL
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
ACTIVE_COMPARATOR: Ataxia Telangiectasia
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.
|
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).
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.
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.
|
ACTIVE_COMPARATOR: Healthy Control
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.
|
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.
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.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Number of days with a symptom score > 3 compared to healthy subjects matched for age.
Time Frame: 24 months
|
24 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of days of absence in kindergarten, school or at work
Time Frame: 24 months
|
24 months
|
|
Number of cold periods
Time Frame: 24 months
|
24 months
|
|
Number of antibiotic therapies
Time Frame: 24 months
|
24 months
|
|
Number of severe infections
Time Frame: 24 months
|
Number of severe infections defined as abscess-forming pneumonia/meningitis and/or other infection with need for hospitalization compared to healthy controls.
|
24 months
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Collaborators
Investigators
- Principal Investigator: Stefan Zielen, Prof. Dr., Johann Wolfgang Goethe University, Childrens Hospital
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Helpful Links
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
September 1, 2012
Primary Completion (ACTUAL)
January 31, 2016
Study Completion (ACTUAL)
July 31, 2016
Study Registration Dates
First Submitted
January 19, 2015
First Submitted That Met QC Criteria
January 22, 2015
First Posted (ESTIMATE)
January 26, 2015
Study Record Updates
Last Update Posted (ACTUAL)
November 30, 2017
Last Update Submitted That Met QC Criteria
November 29, 2017
Last Verified
November 1, 2017
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Metabolic Diseases
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Respiratory Tract Diseases
- Immunologic Deficiency Syndromes
- Immune System Diseases
- Neurologic Manifestations
- Disease Attributes
- Genetic Diseases, Inborn
- Dyskinesias
- DNA Repair-Deficiency Disorders
- Neurocutaneous Syndromes
- Cerebellar Diseases
- Primary Immunodeficiency Diseases
- Spinocerebellar Ataxias
- Lung Diseases
- Infections
- Communicable Diseases
- Ataxia
- Telangiectasis
- Cerebellar Ataxia
- Ataxia Telangiectasia
Other Study ID Numbers
- INFECTION_AT2012
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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