Follow-up to Adult Height of a Cohort of Subjects Born Small for the Gestational Age and Treated With Growth Hormone

Infant, Small for Gestational Age Clinical Trial

— SGA  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01196156
• Other study ID #: IMP 27143
• Status: Completed
• Start date: September 30, 2005
• Est. completion date: December 31, 2018

Study information

• Verified date: February 2019
• Source: Merck KGaA, Darmstadt, Germany
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 443
• Est. completion date: December 31, 2018
• Est. primary completion date: December 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Infant, Small for Gestational Age

Locations

Country	Name	City	State
Spain	Hospital Universitario Príncipe de Asturias	Alcalá De Henares, Madrid
Spain	Hospital General de Alicante	Alicante
Spain	Hospital Nostra Senyora de Meritxell	Andorra
Spain	Hospital San Agustín	Avilés
Spain	Hospital San Agustin	Avilés)
Spain	Hospital Materno Infantil de Badajoz	Badajoz
Spain	Hospital de Cruces-Baracaldo	Baracaldo
Spain	Hospital Sagrado Corazón	Barcelona
Spain	Hospital Puerta del Mar de Cádiz	Cadiz
Spain	Hospital Comarcal de Don Benito	Don Benito
Spain	Hospital de Elche	Elche
Spain	Hospital General de Elda	Elda
Spain	Hospital Clínico San Cecilio	Granada
Spain	Hospital SAS Jerez de la Frontera	Jerez de la Frontera
Spain	Hospital Severo Ochoa	Leganés, Madrid
Spain	Hospital Universitari Arnau de Vilanova	Lleida
Spain	Hospital Univ. La Paz	Madrid
Spain	Hospital Materno Infantil de	Malaga
Spain	Hospital Virgen de la Arrixaca	Murcia
Spain	Hospital Central de Asturias	Oviedo
Spain	Hospital Son Espases	Palma de Mallorca
Spain	Hospital Virgen del Camino	Pamplona
Spain	Hospital Sant Joan de Reus	Reus
Spain	Hospital Parc Taulí de Sabadell	Sabadell
Spain	Hospital Clínico de Salamanca	Salamanca
Spain	Hospital Clínico Universitario	Santiago
Spain	Hospital de Valme. Seville	Sevilla
Spain	Hospital Virgen Macarena	Sevilla

Sponsors (2)

Lead Sponsor	Collaborator
Merck KGaA, Darmstadt, Germany	Merck, S.L., Spain

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in the insulin sensitivity index measured using HOMA-IR (Homeostasis Model Assessment for Insulin Resistance)	Once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason	up to 10 years
Secondary	Auxological parameter - Growth speed	Growth speed will be measured using a wall stadiometer and quantified and assessed in cm/year. Measurement occurs once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason.	up to 10 years
Secondary	Auxological parameter - Height	Height will be measured using a wall stadiometer and quantified in standard deviations (SDS). Measurement occurs once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason.	up to 10 years
Secondary	Auxological parameter - Weight in kilogram	Measurement occurs once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason.	up to 10 years
Secondary	Auxological parameter - Plasma insulin growth factor (IGF-I), measured at the local laboratory	Plasma IGF-1 will be quantified in ng/ml. Measurement occurs once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason.	up to 10 years
Secondary	Auxological parameter - Plasma insulin growth factor (IGF-I), measured at the central laboratory	Plasma IGF-1 will be quantified in ng/ml. Measurement occurs once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason.	up to 10 years
Secondary	Metabolic parameter - Fasting plasma insulin measured at the local laboratory	Fasting plasma insulin will be quantified in µU/ml. Measurement occurs once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason.	up to 10 years
Secondary	Metabolic parameter - Fasting plasma glucose measured at the local laboratory	Fasting plasma insulin will be quantified in mmol/l. Measurement occurs once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason.	up to 10 years
Secondary	Metabolic parameter - Plasma triglycerides measured locally	Plasma triglycerides will be quantified in mg/dl. Measurement occurs once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason.	up to 10 years
Secondary	Metabolic parameter - High density lipoproteins (HDL) cholesterol measured locally	HDL-cholesterol will be quantified in mg/dl. Measurement occurs once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason.	up to 10 years
Secondary	Metabolic parameter - Glycosylated haemoglobin (HbA1c)	HbA1c will be quantified in % over total Hb. Measurement occurs once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason.	up to 10 years
Secondary	Metabolic parameter - Blood pressure (BP)	BP will be measured in mmHg. Measurement occurs once a year per subject from the start of treatment with GH up to a year after finishing the treatment for any reason.	up to 10 years