Status of Growth Hormone/ Insulin-like Growth Factor-1 (GH/IGF-1) Axis and Growth Failure in Ataxia Telangiectasia (AT) (GHAT)
Recruitment status was: Recruiting
|Ataxia Telangiectasia Growth Failure||Drug: Somatropin, Clonidine, L-Arginin-Hydrochloride, Estradiol valerate||Phase 4|
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: 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|
- To evaluate the GH increase after Arginine Provocation Test [ Time Frame: at minute 0, 30, 60, 90 und 120 after infusion ]
- 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. ]
|Study Start Date:||January 2010|
|Estimated Study Completion Date:||September 2012|
|Estimated Primary Completion Date:||December 2011 (Final data collection date for primary outcome measure)|
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).
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. 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. found that the ATM gene controls IGF-I R gene expression in a DNA damage response pathway. Suzuki et al. 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01052623
|Contact: Stefan Zielen, Prof. Dr.||0049-69-6301-83063||Stefan.Zielen@kgu.de|
|Contact: Ralf Schubert, Dr.||0049-69-6301-83611||Ralf.Schubert@kgu.de|
|Children's Hospital, Goethe-University||Recruiting|
|Frankfurt am Main, Germany, 60590|
|Contact: Stefan Zielen, Prof. Dr. 0049-69-6301-83063 Stefan.Zielen@kgu.de|
|Contact: Ralf Schubert, Dr. 0049-69-6301-83611 Ralf.Schubert@kgu.de|
|Principal Investigator: Stefan Zielen, Prof.Dr.|
|Sub-Investigator: Ruth Dresel, Dr.|
|Sub-Investigator: Franziska Hoche, Dr.|
|Sub-Investigator: Martin Christman, Dr.|
|Principal Investigator:||Stefan Zielen, Prof. Dr.||Children´s Hospital, Goethe-University|