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

NCT01052623 | Unknown Phase 4

• 1 other identifier: FRA.GHAT.2009
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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).

Conditions

Ataxia Telangiectasia; Growth Failure

Keywords

GH/IGF-1; Ataxia telangiectasia (AT); IGF-1 Generation Test; Growth hormone

Outcome Measures

Primary Outcomes (1)

• To evaluate the GH increase after Arginine Provocation Test

  at minute 0, 30, 60, 90 und 120 after infusion

Secondary Outcomes (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

  at minute 0, 30, 60, 90 und 120 after dosing of Clonidin. IgF-1 generation test after 5 days.

Study Arms (1)

Growth hormone-testing (GH/IGF-1-testing)

EXPERIMENTAL

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

Interventions

Somatropin, Clonidine, L-Arginin-Hydrochloride, Estradiol valerate DRUG

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).

Also known as: Catapressan, Growth hormone, NutropinAq, Progynova 21 mite, L-Arginin_hydrochlorid-einmolar

Growth hormone-testing (GH/IGF-1-testing)

Eligibility Criteria

• Age: 3 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Johann Wolfgang Goethe University Hospital: lead

Study Sites (1)

Children's Hospital, Goethe-University

Frankfurt am Main, 60590, Germany

RECRUITING

Related Publications (10)

• BODER E, SEDGWICK RP. Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics. 1958 Apr;21(4):526-54. No abstract available.

  PMID: 13542097 BACKGROUND

• Lavin MF. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol. 2008 Oct;9(10):759-69. doi: 10.1038/nrm2514.

  PMID: 18813293 BACKGROUND

• Schubert R, Reichenbach J, Zielen S. Growth factor deficiency in patients with ataxia telangiectasia. Clin Exp Immunol. 2005 Jun;140(3):517-9. doi: 10.1111/j.1365-2249.2005.02782.x.

  PMID: 15932513 BACKGROUND

• Isgaard J, Aberg D, Nilsson M. Protective and regenerative effects of the GH/IGF-I axis on the brain. Minerva Endocrinol. 2007 Jun;32(2):103-13.

  PMID: 17557036 BACKGROUND

• Yang DQ, Kastan MB. Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1. Nat Cell Biol. 2000 Dec;2(12):893-8. doi: 10.1038/35046542.

  PMID: 11146653 BACKGROUND

• Peretz S, Jensen R, Baserga R, Glazer PM. ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1676-81. doi: 10.1073/pnas.98.4.1676. Epub 2001 Feb 6.

  PMID: 11172010 BACKGROUND

• Shahrabani-Gargir L, Pandita TK, Werner H. Ataxia-telangiectasia mutated gene controls insulin-like growth factor I receptor gene expression in a deoxyribonucleic acid damage response pathway via mechanisms involving zinc-finger transcription factors Sp1 and WT1. Endocrinology. 2004 Dec;145(12):5679-87. doi: 10.1210/en.2004-0613. Epub 2004 Sep 2.

  PMID: 15345673 BACKGROUND

• Suzuki A, Kusakai G, Kishimoto A, Shimojo Y, Ogura T, Lavin MF, Esumi H. IGF-1 phosphorylates AMPK-alpha subunit in ATM-dependent and LKB1-independent manner. Biochem Biophys Res Commun. 2004 Nov 19;324(3):986-92. doi: 10.1016/j.bbrc.2004.09.145.

  PMID: 15485651 BACKGROUND

• Kieslich M, Hoche F, Reichenbach J, Weidauer S, Porto L, Vlaho S, Schubert R, Zielen S. Extracerebellar MRI-lesions in ataxia telangiectasia go along with deficiency of the GH/IGF-1 axis, markedly reduced body weight, high ataxia scores and advanced age. Cerebellum. 2010 Jun;9(2):190-7. doi: 10.1007/s12311-009-0138-0.

  PMID: 19898915 BACKGROUND

• Schubert R, Schmitz N, Pietzner J, Tandi C, Theisen A, Dresel R, Christmann M, Zielen S. Growth hormone supplementation increased latency to tumourigenesis in Atm-deficient mice. Growth Factors. 2009 Oct;27(5):265-73. doi: 10.1080/08977190903112663.

  PMID: 19626507 BACKGROUND

Related Links

• Related Info

MeSH Terms

Conditions

Ataxia Telangiectasia; Failure to Thrive

Interventions

Human Growth Hormone; Clonidine; Estradiol; Growth Hormone

Condition Hierarchy (Ancestors)

Spinocerebellar Ataxias; Cerebellar Ataxia; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocutaneous Syndromes; Ataxia; Dyskinesias; Neurologic Manifestations; Telangiectasis; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Primary Immunodeficiency Diseases; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pituitary Hormones, Anterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Imidazolines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones

Study Officials

• Stefan Zielen, Prof. Dr.

  Children´s Hospital, Goethe-University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Stefan Zielen, Prof. Dr.

CONTACT

0049-69-6301-83063; Stefan.Zielen@kgu.de

Ralf Schubert, Dr.

CONTACT

0049-69-6301-83611; Ralf.Schubert@kgu.de

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: January 19, 2010
• First Posted: January 20, 2010
• Study Start: January 1, 2010
• Primary Completion: December 1, 2011
• Study Completion: September 1, 2012
• Last Updated: July 5, 2010

Record last verified: 2010-07

Locations

DE (1)