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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)

Primary Purpose

Ataxia Telangiectasia, Growth Failure

Status
Unknown status
Phase
Phase 4
Locations
Germany
Study Type
Interventional
Intervention
Somatropin, Clonidine, L-Arginin-Hydrochloride, Estradiol valerate
Sponsored by
Johann Wolfgang Goethe University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Ataxia Telangiectasia focused on measuring GH/IGF-1, Ataxia telangiectasia (AT), IGF-1 Generation Test, Growth hormone

Eligibility Criteria

3 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Hospital, Goethe-UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

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

Arm Description

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.

Outcomes

Primary Outcome Measures

To evaluate the GH increase after Arginine Provocation Test

Secondary Outcome Measures

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

Full Information

First Posted
January 19, 2010
Last Updated
July 2, 2010
Sponsor
Johann Wolfgang Goethe University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01052623
Brief Title
Status of Growth Hormone/ Insulin-like Growth Factor-1 (GH/IGF-1) Axis and Growth Failure in Ataxia Telangiectasia (AT)
Acronym
GHAT
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 Type
Interventional

2. Study Status

Record Verification Date
July 2010
Overall Recruitment Status
Unknown status
Study Start Date
January 2010 (undefined)
Primary Completion Date
December 2011 (Anticipated)
Study Completion Date
September 2012 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
Johann Wolfgang Goethe University Hospital

4. Oversight

Data Monitoring Committee
No

5. Study Description

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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ataxia Telangiectasia, Growth Failure
Keywords
GH/IGF-1, Ataxia telangiectasia (AT), IGF-1 Generation Test, Growth hormone

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Growth hormone-testing (GH/IGF-1-testing)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Somatropin, Clonidine, L-Arginin-Hydrochloride, Estradiol valerate
Other Intervention Name(s)
Catapressan, Growth hormone, NutropinAq, Progynova 21 mite, L-Arginin_hydrochlorid-einmolar
Intervention Description
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).
Primary Outcome Measure Information:
Title
To evaluate the GH increase after Arginine Provocation Test
Time Frame
at minute 0, 30, 60, 90 und 120 after infusion
Secondary Outcome Measure Information:
Title
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Stefan Zielen, Prof. Dr.
Phone
0049-69-6301-83063
Email
Stefan.Zielen@kgu.de
First Name & Middle Initial & Last Name or Official Title & Degree
Ralf Schubert, Dr.
Phone
0049-69-6301-83611
Email
Ralf.Schubert@kgu.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stefan Zielen, Prof. Dr.
Organizational Affiliation
Children´s Hospital, Goethe-University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital, Goethe-University
City
Frankfurt am Main
ZIP/Postal Code
60590
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stefan Zielen, Prof. Dr.
Phone
0049-69-6301-83063
Email
Stefan.Zielen@kgu.de
First Name & Middle Initial & Last Name & Degree
Ralf Schubert, Dr.
Phone
0049-69-6301-83611
Email
Ralf.Schubert@kgu.de
First Name & Middle Initial & Last Name & Degree
Stefan Zielen, Prof.Dr.
First Name & Middle Initial & Last Name & Degree
Ruth Dresel, Dr.
First Name & Middle Initial & Last Name & Degree
Franziska Hoche, Dr.
First Name & Middle Initial & Last Name & Degree
Martin Christman, Dr.

12. IPD Sharing Statement

Citations:
PubMed Identifier
13542097
Citation
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.
Results Reference
background
PubMed Identifier
18813293
Citation
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. Erratum In: Nat Rev Mol Cell Biol. 2008 Dec;9(12). doi: 10.1038/nrm2514.
Results Reference
background
PubMed Identifier
15932513
Citation
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.
Results Reference
background
PubMed Identifier
17557036
Citation
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.
Results Reference
background
PubMed Identifier
11146653
Citation
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.
Results Reference
background
PubMed Identifier
11172010
Citation
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.
Results Reference
background
PubMed Identifier
15345673
Citation
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.
Results Reference
background
PubMed Identifier
15485651
Citation
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.
Results Reference
background
PubMed Identifier
19898915
Citation
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.
Results Reference
background
PubMed Identifier
19626507
Citation
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.
Results Reference
background
Links:
URL
http://www.info-at.de
Description
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Status of Growth Hormone/ Insulin-like Growth Factor-1 (GH/IGF-1) Axis and Growth Failure in Ataxia Telangiectasia (AT)

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