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Status of Growth Hormone/ Insulin-like Growth Factor-1 (GH/IGF-1) Axis and Growth Failure in Ataxia Telangiectasia (AT) (GHAT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01052623
Recruitment Status : Unknown
Verified July 2010 by Johann Wolfgang Goethe University Hospital.
Recruitment status was:  Recruiting
First Posted : January 20, 2010
Last Update Posted : July 5, 2010
Information provided by:
Johann Wolfgang Goethe University Hospital

Brief Summary:
This study will evaluate the status of the growth hormone/ insulin-like growth factor-1 (GH/IGF-1) axis in relation to growth failure, body weight and composition and neuroprotection in children with Ataxia telangiectasia (AT).

Condition or disease Intervention/treatment Phase
Ataxia Telangiectasia Growth Failure Drug: Somatropin, Clonidine, L-Arginin-Hydrochloride, Estradiol valerate Phase 4

Detailed Description:

Growth failure and GH/IgF-1 deficiency has been described in patients diagnosed with Ataxia telangiectasia (AT) [Boder et al.,1958]. This condition is a fatal inherited disease caused by a mutation of the ATM gene on chromosome 11 leading to chromosomal instability, immunodeficiency, cancer susceptibility and and endocrinological abnormalities. In this regard, several groups demonstrated a cross-linking of ATM with growth factor pathways. Participation of the ATM protein in insulin signaling through phosphorylation of eIF-4E-binding protein 1 has been postulated [Yang et al.,2000]. Peretz et al.[2001] described that expression of the insulin-like growth factor-I receptor is (IGF-I R) ATM dependent in a pathway regulating radiation response. In addition, Shahrabani-Gargir et al.[2004] found that the ATM gene controls IGF-I R gene expression in a DNA damage response pathway. Suzuki et al.[2004] described that IGF-I phosphorylates AMPK-alpha, a key regulator of cholesterol and fatty acid synthesis, acts in an ATM-dependent manner . We have recently demonstrated reduced levels of circulating Insulin-like growth factor-I (IGF-I) and its main binding protein 3 (IGFBP-3) in AT patients accompanied with decreased body mass index [Schubert et al.,2005]. Furthermore, apart from regulating somatic growth and metabolism, evidence suggests that the GH/IGF-I axis is involved in the regulation of brain growth, development and myelination. Moreover, GH and particularly IGF-1 have potential neuroprotective effects in different in vitro and in vivo experimental models. In addition we have recently shown that extracerebellar MRI-lesions in AT go along with deficiency of the GH/IGF-1 Axis, markedly reduced body weight, high ataxia scores and advanced age [Kieslich et al.,2009]. Supplementation with these growth hormones might overcome the progressive dystrophy and may have clinical benefits against the progression of neurodegeneration and immunodeficiency.

We found that supplementation with GH significantly increased longevity of Atm-deficient mice and improve T-cell immunity and locomotor behaviour [Schubert et al.,2009]. Surprisingly IGF-1 was not generated in the ATM deficient mice, indicating that the GH/IGF-1 signalling is impaired. Taken this into account a accurate diagnostic approach of the GH/IGF-1 axis is mandatory including a IGF-1 generation test before long term treatment either with GH or IGF-1 is justified in humans.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Status of the Growth Hormone/ Insulin-like Growth Factor-1 (GH/IGF-1) Axis in Relation to Growth Failure, Body Weight and Neuroprotection in Children With Ataxia Telangiectasia
Study Start Date : January 2010
Estimated Primary Completion Date : December 2011
Estimated Study Completion Date : September 2012

Arm Intervention/treatment
Experimental: Growth hormone-testing (GH/IGF-1-testing)

Patients (girls over 8 years and boys over 10 years) are primed with estradiol 1 mg orally for 2 days, to help avoid false results of growth hormone (GH) levels in blood samples. Then provocation testing is done, with two tests back to back. It determines blood levels of GH and the body's response to testing with drugs called arginine and clonidine. Patients are admitted to the pediatric inpatient unit and will have an intravenous (IV) line placed in the arm. Arginine is given by IV over 30 minutes, and blood samples are taken as indicated.

The next day, the clonidine test is performed according to current guidelines. Then the IGF-1 generation test is done to see if the patient has the ability to generate IGF-1 in response to injections of GH for 5 consecutive days.

Drug: Somatropin, Clonidine, L-Arginin-Hydrochloride, Estradiol valerate
1 mg Estradiol valerate with for two days before GH-testing pre pubertal girls older than 8 years and pre pubertal boys older than 10 years. L-Arginin-Hydrochloride in the vein (0.5 g/kg KG maximum dose 30g) over 30 minutes. Clonidine orally (0,075 mg/m2 BSA). Somatropin-NutropinAq subcutaneum,a single one shot (dose 0.03 mg/KG, daily, over five days).
Other Names:
  • Catapressan
  • Growth hormone
  • NutropinAq
  • Progynova 21 mite
  • L-Arginin_hydrochlorid-einmolar

Primary Outcome Measures :
  1. To evaluate the GH increase after Arginine Provocation Test [ Time Frame: at minute 0, 30, 60, 90 und 120 after infusion ]

Secondary Outcome Measures :
  1. The GH increase after Clonidine Provocation Test. To evaluate the safety and efficacy of the IGF-1 generation test. To correlate GH/IgF-1 deficiency to BMI To correlate GH/IgF-1 deficiency to MRI findings [ Time Frame: at minute 0, 30, 60, 90 und 120 after dosing of Clonidin. IgF-1 generation test after 5 days. ]

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Have a diagnosis of AT
  • Have no fusion of epiphyses/closed growth plates as determined by X-ray of left wrist and hand (special skeletal age film)
  • Be between 3 years to 18 years old and have not completed puberty
  • Consent to permit blood and/or tissue samples for storage
  • Demonstrate growth failure: height below the 10th percentile for chronological age
  • Have a primary care physician at home
  • Demonstrate growth failure, defined as growth velocity (measured as linear growth) that is less than 5% to 10% of that expected for children of the same age group, over the past 12 months
  • Willingness to remain hospitalized for several days
  • Provide evidence of serum IGF-1 level performed within the preceding 6 months and the results fall below 25% range of normal limits for age

Exclusion Criteria:

  • Have fusion of epiphyseal plates
  • Be under the age of 3 years or have reached completion of puberty
  • Have a serum IGF-1 level that is above the 25% range of normal limits for age
  • Be above the 10th percentile height for chronological age
  • Demonstrate any history of anaphylactic reaction or hypersensitivity to one of the GH formulation
  • Have any active or suspected neoplasia
  • Demonstrate signs of intracranial hypertension as evidenced by papilledema upon examination by fundoscopy
  • Have any condition that, in the investigator's opinion, places the patient at undue risk by participating in the study
  • Be unwilling to undergo testing or procedures associated with this protocol
  • Have acute or chronic infections
  • Have a hypersensitivity to one of the drugs: Clonidine hydrochlorid, Arginine hydrochlorid, Estradiol valerate, Somatropin
  • Have a presence of bradycardia, cardiac arrhythmia, have symptoms of a sick sinus syndrome
  • Suffer from depression
  • Have acute or recurrent thrombosis
  • Have acute liver diseases

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01052623

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Contact: Stefan Zielen, Prof. Dr. 0049-69-6301-83063
Contact: Ralf Schubert, Dr. 0049-69-6301-83611

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Children's Hospital, Goethe-University Recruiting
Frankfurt am Main, Germany, 60590
Contact: Stefan Zielen, Prof. Dr.    0049-69-6301-83063   
Contact: Ralf Schubert, Dr.    0049-69-6301-83611   
Principal Investigator: Stefan Zielen, Prof.Dr.         
Sub-Investigator: Ruth Dresel, Dr.         
Sub-Investigator: Franziska Hoche, Dr.         
Sub-Investigator: Martin Christman, Dr.         
Sponsors and Collaborators
Johann Wolfgang Goethe University Hospital
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Principal Investigator: Stefan Zielen, Prof. Dr. Children´s Hospital, Goethe-University
Additional Information:

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Responsible Party: Prof. Dr. Stefan Zielen, Johann Wolfgang Goethe University Hospitals Identifier: NCT01052623    
Other Study ID Numbers: FRA.GHAT.2009
First Posted: January 20, 2010    Key Record Dates
Last Update Posted: July 5, 2010
Last Verified: July 2010
Keywords provided by Johann Wolfgang Goethe University Hospital:
Ataxia telangiectasia (AT)
IGF-1 Generation Test
Growth hormone
Additional relevant MeSH terms:
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Cerebellar Ataxia
Ataxia Telangiectasia
Failure to Thrive
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Cerebellar Diseases
Brain Diseases
Central Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Spinocerebellar Ataxias
Neurocutaneous Syndromes
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Polyestradiol phosphate
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs