Clinical trial NCT01196156: Follow-up to Adult Height of a Cohort of Subjects Born Small for the Gestational Age and Treated With Growth Hormone
Official title: An Observational Phase IV Study for Prospective Follow-up to Adult Height of a Cohort of Subjects Born Small for the Gestational Age and Treated With Growth Hormone
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Infant, Small for Gestational Age
Keywords: Infant, Small for Gestational Age
Dwarfism Pituitary
Saizen
Somatropin; Growth Hormone
Insulin resistance
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
Collaborators: name: Merck, S.L., Spain
First posted: 2010-09-08
Enrollment: 443
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Children with growth disorder (current height \<-2.5 SD and height adjusted to parental stature \<-1 SD) in children born SGA with a weight and/or length at birth below -2 SD, that has not experimented a growth catch-up (growth speed \<0 SD during the last year) at 4 years old or afterwards.

Brief summary: This non-interventional study for prospective follow up of a cohort of 220 subjects born small for gestational age (SGA) is planned for the purpose of finding out if normalisation of adult height is associated or not with metabolic alterations and if true, their magnitude and relevance as well as to detect warnings throughout the treatment period that may be useful for prevention or therapy. This study would help in answering the question if the SGA and growth hormone (GH) association results in insulin resistance and if affirmative, who develops it as well as its impact on other metabolic parameters that precedes type 2 diabetes.

Detailed description: The small for gestational age (SGA) concept includes babies born to term whose weight and/or height is lower than two standard deviations (SD) below the mean. Pathologically short stature is understood as a stature of 2.5 SD below the mean for their age and an expected adult height adjusted to the parental height of one SD below the mean. These SGA children with a pathological short stature after four years of age are unsuitable for GH treatment. In fact, there is no other efficient treatment for short stature and insufficient development of these children other than GH. In addition to short stature, the SGA syndrome also includes resistance to insulin with the consequent risk of developing type 2 diabetes and other interrelated metabolic alterations like dyslipidemia and hypertension; and the glucose-insulin-insulin growth factors (IGFs)-proteins transport axis regulate growth as well as foetal metabolism and development. Independent from the possible maternal environmental causes, those born with SGA have low levels of somatomedin C (IGF-I) and its transport protein \[Insulin-like growth factor binding protein 3 (IGFBP-3)\] as well as fasting hyperinsulinemia. The low levels of IGF-1 and IGFBP-3 persist in those that do not present a catch-up growth and the insulin resistance is secondary to the somatotrope axis. Treatment with GH increases IGF-I and IGFBP3 levels but also the plasmatic level of fasting insulin and the long term net result of this combination is unknown.

An analysis has shown, that although during the first 2 years of GH treatment, there are no signs of glucose intolerance even though there is less sensitivity to insulin, there could be a greater incidence of type 2 diabetes in deficient children that have been treated with GH for a longer period. Treatment with GH, of children born SGA that have not caught-up their growth at 4 years of age, in the majority of cases achieves a good initial growth speed increase in order to continue to grow within normal limits and end up with an adult height that falls within normal. This is achieved with an authorised daily dose of 0.035 mg/kg (1 mg/m2/day). However, the question regarding the possible metabolic consequences of GH treatment of those born SGA remains unanswered in both forms, to find out if GH treatment increases or reduces resistance to insulin and other associated metabolic parameters and therefore, the risk of developing type 2 diabetes. Continued monitoring to adult height of a cohort of subjects born with SGA and treated with GH is the most efficient, easy and comfortable tool for answering that question.

OBJECTIVES

Primary objective:

* To quantify the evolution of insulin sensitivity from the start of treatment with GH until adult stature is reached. Sensitivity or resistance to insulin is calculated using the HOMA-IR model (Homeostasis Model Assessment for Insulin Resistance) which is a reliable and easy mathematical model that uses the following formula: insulinemia (μU/ml) x glycemia (mmol/l)/22.5.

Secondary objectives:

* To find predictive factors for the possible changes in insulin sensitivity and its complex associated obesity, hypertension and high triglycerides type dyslipidemia with low high density lipoprotein (HDL)-cholesterol. For this, a relation between these metabolic factors and auxological parameters is to be identified.

  a. The following are considered independent or predictive variables:
* Speed of growth in cm/ year
* Standard deviations of height
* IGF-I in ng/ml
* IGFBP-3 in ng/ml b. The dependent variables will be:
* HOMA-IR value
* Triglycerides rate in mg/dl / HDL-cholesterol in mg/dl
* Blood pressure in mmHG
* Body mass index

This is an observational study of a single cohort, without the possibility of a control group because those born with SGA, who experience a catch-up growth and enter normal auxology within the first four years of life are not subjected to a paediatric follow-up similar to those that do not catch-up to normal auxology and are treated with GH. Therefore, the same auxological and metabolic test results are not available in standard care. The collection of said parameters requires an "ad hoc" intervention and the study would be experimental or interventional. The observation period of this study encompasses from the start of treatment with GH up to a year after finishing the treatment for any reason. The starting age as well as the time treatment is ended will vary per subject. However, most subjects finish treatment once adulthood is reached. In accordance with clinical studies, the average observation period will probably be about 10 years. After the basal data is made available, the collection of data afterwards will be carried out once a year per subject.

Eligibility criteria: Inclusion Criteria:

* Children with growth disorder (current height \<-2.5 SD and height adjusted to parental stature \<-1 SD) in children born SGA with a weight and/or length at birth below -2 SD, that has not experimented a growth catch-up (growth speed \<0 SD during the last year) at 4 years old or afterwards were enrolled in the study
* Children undergoing treatment with somatropin from Serono
* Children whose parent or legal guardians, as well as the subject himself if 12 or more years old have given written permission to access their records

Exclusion Criteria:

* Children with closed epiphysis
* Children with known hypersensitivity to somatropin or to any excipients present in the injection powder or solvent
* Subjects with active neoplasms. Any anti-tumoral treatment must be completed prior to starting treatment with somatropin
* Subjects with evidence of progression or relapse of a subjacent intracranial lesion
* Subjects with acute critical diseases such as those that present complications after open heart surgery, abdominal surgery, polytraumatisms, acute respiratory failure or similar conditions

Primary outcomes:
measure: Changes in the insulin sensitivity index measured using HOMA-IR (Homeostasis Model Assessment for Insulin Resistance)
timeFrame: up to 10 years
Secondary outcomes:
measure: Auxological parameter - Growth speed
timeFrame: up to 10 years
measure: Auxological parameter - Height
timeFrame: up to 10 years
measure: Auxological parameter - Weight in kilogram
timeFrame: up to 10 years
measure: Auxological parameter - Plasma insulin growth factor (IGF-I), measured at the local laboratory
timeFrame: up to 10 years
measure: Auxological parameter - Plasma insulin growth factor (IGF-I), measured at the central laboratory
timeFrame: up to 10 years
measure: Metabolic parameter - Fasting plasma insulin measured at the local laboratory
timeFrame: up to 10 years
measure: Metabolic parameter - Fasting plasma glucose measured at the local laboratory
timeFrame: up to 10 years
measure: Metabolic parameter - Plasma triglycerides measured locally
timeFrame: up to 10 years
measure: Metabolic parameter - High density lipoproteins (HDL) cholesterol measured locally
timeFrame: up to 10 years
measure: Metabolic parameter - Glycosylated haemoglobin (HbA1c)
timeFrame: up to 10 years
measure: Metabolic parameter - Blood pressure (BP)
timeFrame: up to 10 years
Other outcomes:
Locations:
city: Alcalá De Henares, Madrid
country: Spain
facility: Hospital Universitario Príncipe de Asturias
city: Alicante
country: Spain
facility: Hospital General de Alicante
city: Andorra
country: Spain
facility: Hospital Nostra Senyora de Meritxell
city: Avilés)
country: Spain
facility: Hospital San Agustin
city: Avilés
country: Spain
facility: Hospital San Agustín
city: Badajoz
country: Spain
facility: Hospital Materno Infantil de Badajoz
city: Baracaldo
country: Spain
facility: Hospital de Cruces-Baracaldo
city: Barcelona
country: Spain
facility: Hospital Sagrado Corazón
city: Cadiz
country: Spain
facility: Hospital Puerta del Mar de Cádiz
city: Don Benito
country: Spain
facility: Hospital Comarcal de Don Benito
city: Elche
country: Spain
facility: Hospital de Elche
city: Elda
country: Spain
facility: Hospital General de Elda
city: Granada
country: Spain
facility: Hospital Clínico San Cecilio
city: Jerez de la Frontera
country: Spain
facility: Hospital SAS Jerez de la Frontera
city: Leganés, Madrid
country: Spain
facility: Hospital Severo Ochoa
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova
city: Madrid
country: Spain
facility: Hospital Univ. La Paz
city: Malaga
country: Spain
facility: Hospital Materno Infantil de
city: Murcia
country: Spain
facility: Hospital Virgen de la Arrixaca
city: Oviedo
country: Spain
facility: Hospital Central de Asturias
city: Palma de Mallorca
country: Spain
facility: Hospital Son Espases
city: Pamplona
country: Spain
facility: Hospital Virgen del Camino
city: Reus
country: Spain
facility: Hospital Sant Joan de Reus
city: Sabadell
country: Spain
facility: Hospital Parc Taulí de Sabadell
city: Salamanca
country: Spain
facility: Hospital Clínico de Salamanca
city: Santiago
country: Spain
facility: Hospital Clínico Universitario
city: Sevilla
country: Spain
facility: Hospital de Valme. Seville
city: Sevilla
country: Spain
facility: Hospital Virgen Macarena
Study officials:
affiliation: Merck, S.L., Spain
name: Medical Director
role: STUDY_DIRECTOR
References: