Susceptibility to Infections, Tumor Risk and Liver Disease in Patients With Ataxia Telangiectasia

Susceptibility to Infections, Tumor Risk and Liver Disease in Patients With Ataxia Telangiectasia With and Without Substitution of Immunoglobulin G: a Prospective Observational Study

Ataxia telangiectasia (A-T) is a rare devastating human recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability and cancer susceptibility. The immunodeficiency is expressed by recurring infections. It's characterised by decreased lymphocytes data as well as lack of immunglobulin A, immunglobulin G subclasses and specific antibodies against pneumococcus. Aim of the present clinical trial is to investigate frequency-, intensity- and duration of the infections as well as changes oft immune status, dimension of liver disease and tumor risk in patients with A-T, with and without immunoglobulin G substitution therapy. Transient elastography (FibroScan) will be performed in order to measure liver stiffness as an indication of fatty liver and liver fibrosis. A bioelectrical impedance analysis (BIA) is conducted to investigate the exact body composition. Ataxia Score is determined to define neurological problems. Every subject receives a diary to compile symptoms of infection.

Study Overview

• Status: Unknown
• Conditions: Ataxia Telangiectasia
• Intervention / Treatment: Diagnostic test: bioelectrical impedance analysis; Diagnostic test: blood draw; Diagnostic test: transient elastography (FibroScan); Diagnostic test: ataxia score; Diagnostic test: Five-Times-Sit-to-Stand Test

Detailed Description

Ataxia teleangiectasia (A-T) is a rare devastating human recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability and cancer susceptibility. The immunodeficiency is expressed by recurring infections. It's characterised by decreased lymphocytes data as well as lack of immunglobulin A, immunglobulin G subclasses and specific antibodies against pneumococcus as shown in many trials. Additionally the patients suffer from a fatty liver with increased transaminases and have the risk for a cirrhosis of the liver and a hepatocellular carcinoma. It's known that the dimension of the liver disease affects susceptibility to infection. Nevertheless there are only a few studies treating this problem.

Despite the proof of the immunodeficiency polyvalent immunoglobulins (IgG) are not given regularly. Own observations show that in spite of the treatment with immunoglobulins the progression of a chronic destructive lung disease with development of bronchiectasis hardly can prohibited.

Up to now it isn't cleared if a substitution therapy with immunoglobulins reduces the susceptibility to infection. Therefore the aim oft the present clinical trial ist to explore frequency-, intensity, and duration oft the infections as well as changes oft the immune status, measure of liver disease and tumor risk in patients with A-T, with and without immunoglobulin therapy. The study includes five visits, which are performed in all A-T patients. Visit 1, 3, 5 are realized in the context of annual follow ups:

• To evaluate weight and length of all subjects
• To analyze the exact structure of single body compartments such as the lean mass, the water compartment or the fat compartment using bioelectrical impedance analysis
• To define the neurological status by ataxia score
• To get a detailed immune status, vaccination status and liver values as well as special tumor markers in blood
• To check the lung function using spirometry
• To measure liver stiffness using transient elastography (FibroScan)
• To compile any symptoms of infection by diary
• To investigate the ataxia status and physical condition by means of the Five-Times-Sit-to-Stand Test

Visit 2 and 4 are additionally conducted as study visits:

• To get a detailed immune status in blood
• To check the lung function using spirometry

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sandra Woelke, Dr.; Phone Number: 00496930183063; Email: sandra.voss@kgu.de
• Study Contact Backup: Name: Stefan Zielen, Prof. Dr.; Phone Number: 00496930183063; Email: stefan.zielen@kgu.de

Study Locations

• Germany
  • Hessen
    • Frankfurt, Hessen, Germany, 60590
      • Recruiting
      • Children's Hospital, Allergology, Pneumology and Cystic Fibrosis, Goethe University Frankfurt
      • Contact: Sandra Wölke, Dr.; Phone Number: 004969630183063; Email: sandra.voss@kgu.de
      • Contact: Stefan Zielen, Prof. Dr.; Phone Number: 004969630183063; Email: stefan.zielen@kgu.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 months to 43 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• aim group: genetically and/or clinically diagnosed A-T
• age 2-45 years
• written informed consent

Exclusion Criteria:

• age < 2 or > 45 years
• other diseases with influence on the immune system (i.e. diabetes mellitus, malignoma, dialysis-dependent renal failure)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: A-T patients; A-T patients aged 2 to 45 years with and without immunoglobulin G Substitution; bioelectrical impedance Analysis; blood draw; transient elastography (FibroScan); ataxia score; Five-Times-Sit-to-Stand Test

Diagnostic test: bioelectrical impedance analysis; Electrophysical measurement that allows to determine the exact composition of single body compartments by producing a magnetic field and detecting the potential difference through the body; Diagnostic test: blood draw; Blood samples are taken from sober patients; Diagnostic test: transient elastography (FibroScan); FibroScan is a noninvasive tool to measure liver stiffness as an indication of fatty liver and liver fibrosis using ultrasound; Diagnostic test: ataxia score; Klockgether ataxia score ranges from 0 to 35 points in which 0 means no symptoms and 35 stands for final stage of disease. It includes seven ataxia associated symptoms: dysarthria, intention tremor, ataxia of gait, stance, dysdiadochokinesia, upper limb and lower limb; Diagnostic test: Five-Times-Sit-to-Stand Test; The test measures the complete time which is necessary for an individual to stand up and sit down on a chair five times in series

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infections in A-T	Evaluation of frequency, severity and intensity of infections in A-T patients with and without immunoglobulin G substitution	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver disease	Evaluation of the degree of liver disease measured by liver enzymes and structural changes by transient elastography (Fibroscan) in A-T patients	24 months
Cancer risk	Evaluation of tumor markers in A-T patients	24 months

Collaborators and Investigators

• Sponsor: Johann Wolfgang Goethe University Hospital
• Investigators: Principal Investigator: Stefan Zielen, Prof. Dr., Children's Hospital, Allergology, Pneumology and Cystic Fibrosis, Goethe-University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2016
• Primary Completion (Anticipated): September 30, 2018
• Study Completion (Anticipated): September 30, 2019

Study Registration Dates

• First Submitted: April 24, 2017
• First Submitted That Met QC Criteria: November 29, 2017
• First Posted (Actual): November 30, 2017

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

• Keywords: liver disease; immunodeficiency; cancer risk
• Additional Relevant MeSH Terms: Digestive System Diseases; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Neurologic Manifestations; Genetic Diseases, Inborn; Dyskinesias; DNA Repair-Deficiency Disorders; Neurocutaneous Syndromes; Cerebellar Diseases; Primary Immunodeficiency Diseases; Spinocerebellar Ataxias; Liver Diseases; Ataxia; Telangiectasis; Cerebellar Ataxia; Ataxia Telangiectasia
• Other Study ID Numbers: InfectionandLiver_AT2016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No