children with short stature of unknown cause idiopathic short stature
Conditions
Interventions
The intervention consists of a diagnostic procedure to assess GH
responsiveness: the dose-escalation IGF-I generation test. This procedure will
be followed by GH treatment in the context of regular
It is assumed that a
maximum of 2 children will fall in this category.
The IMP in the IGF-I generation test is: NutropinAq (somatropin, 5 mg/ml, 2 ml
per cartridge). Doses in the diagnostic protoco
Sponsors
Ipsen Pharmaceuticals
Eligibility
Age
2 Years to 11 Years
Inclusion criteria
Inclusion criteria: Prepubertal children aged 2.0-9.0 (females) or 2.0-10.0 (males) years, bone age 30 mU/L, IGF-I SDS
Exclusion criteria
Exclusion criteria: * Has a history of hypersensitivity to growth hormone or phenol (conservative added to GH in NutropinAq), or drugs with a similar chemical structure. * Was treated with any other Investigational Medicinal Product (IMP) within the last 30 days before study entry. * Has any mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude. * Has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the Investigator, might jeopardise the subject*s safety or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study. * Has a birth weight and/or length below -2 SDS for Swedish reference charts. Patients will not be excluded due to an unknown birth weight or length. * Has a known cause of short stature, or any significant concomitant disease that is likely to interfere with growth or with the study schedule/objectives, or is a known contraindication to GH treatment such as: chromosomal abnormalities (known syndromes associated with short stature, and skeletal dysplasias); growth failure due to high doses of glucocorticosteroids, hypothyroidism, chronic illnesses; malignancy, intra-cranial tumor; chronic disease such as insulin-dependent diabetes mellitus; chronic infectious disease; chronic renal insufficiency; chronic heart failure; chronic hepatic disease; celiac disease; chronic pulmonary disease; active rheumatic disease; psychosis; neurofibromatosis; McCune Albright syndrome; dysmorphic syndromes such as Russell-Silver syndrome, Leri-Weill syndrome, achondroplasia, etc; and emotional deprivation. Hypothyroidism adequately substituted with thyroid hormone replacement therapy is not an exclusion criterion. For girls, the karyotype, to eliminate a Turner syndrome, is mandatory. In case of a positive Rappold score (> 4), a SHOX defect has to be excluded. * Has dysmorphic features suspect for chromosomal breakage syndromes. * Has known causes of decreased IGF-I (e.g. undernutrition). * Has an abnormal sitting height:height ratio SDS (+2), corrected for bone age, according to Dutch references. * Has any abnormality at laboratory screening according to the Dutch consensus protocol (see appendix 3). * Is likely to require treatment during the study with drugs that are not permitted by the study protocol (see appendix 4). * Has active neoplasia or suspected neoplasia. * The parents are investigator site personnel directly affiliated with the study, or are the immediate family of investigator site personnel directly affiliated with the study. Immediate family is defined as spouse, parent, child, or sibling, whether biological or legally adopted. * Is unable or unwilling to comply with the study visits or the test schedule required by the protocol. * Patients not affiliated to the health insurance system will not be allowed to participate in this trial.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Assessment of the value of the short-term response of IGF-I (peak IGF-I SDS) to different two weeks dose regiments (0.7 and 1.4 mg/mm2/day respectively) of GH (somatropine) in comparison to baseline IGF-I to predict the 1 year growth response to GH in a dose of 1.4 mg/m2/day. Two approaches will be taken. First, in a multiple regression analysis the explained variance will be calculated of the studentized residual of growth response (according to Ranke et al (1) (dependent variable) and baseline IGF-I SDS and peak IGF-I (after 1.4 mg/m2/day for 2 weeks) will be calculated. The second approach is to define a good response as a studentized residual > -1, and prepare ROC curves for clinical predictors, baseline IGF-I SDS, and peak IGF-I SDS after 1.4 mg/m2/day. The IGF-I generation test in this study is a modification of the test currently used in clinical practise (two weeks per dose instead of one), with measurements of IGF-I, IGFBP-3 and IGFBP-2 before and after 2 weeks of GH in dosages of 0.7, 1.4 and (if these dosages result in an insufficient response (IGF-I SDS | — |
Secondary
| Measure | Time frame |
|---|---|
| Assessment of the value of other parameters of the dose-escalation IGF-I generation test (peak values and changes versus baseline of IGF-I, IGFBP-3, IGF-I/IGFBP-3 ratio, and IGF-I/IGFBP-2 ratio) in comparison to baseline IGF-I to predict the 1 year growth response to GH in a dose of 1.4 mg/m2/day. The other parameters include peak values and changes (before-after 2 weeks of GH) of IGF-I, IGFBP-3, IGF-I/IGFBP-3 ratio and IGF-I/IGFBP-2 ratio, on the dosages of 0.7 and 1.4 mg/m2/day. Explorative objectives: a) Assessment of the value of the various parameters of the dose-escalation IGF-I generation test in comparison to baseline IGF-I to predict the 1 year growth response. b) Assess the predictive value of the short-term IGF-I SDS response to the highest GH dosage in those children in whom serum IGF-I does not sufficiently respond to the two lower dosages. c) The correlation between serum GHBP and long-term growth response will be assessed. d) Biochemical and genetic analysis of the GH-IGF-I axis and genome-wide SNP-array. Besides IGF-I and IGFBP-3, patients will be tested for an ALS defect. Genetic analysis of the GH-IGF-I axis: for all participating patients DNA will be collected from blood lymphocytes for genetic studies. Safety Endpoints and Evaluations: Patients will be seen by the paediatric endocrinologist before the IGF-I generation test, at start of long-term GH therapy, and after 3, 6, 9, and 12 months. | — |
Countries
Netherlands
Outcome results
None listed