Infant, Small for Gestational Age
Conditions
Keywords
Infant, small for gestational age, Growth hormone, Saizen
Brief summary
This open, multicentric, randomized, controlled study is planned to evaluate the correlation between gene expression, spontaneous catch-up growth and therapeutic response to Saizen in SGA children.
Detailed description
This open, multicentric, randomized, controlled study was planned to identify genes activated by hGH in SGA children responders to treatment (making it possible in the near future to better identify SGA children likely to benefit from hGH treatment). Furthermore, the study would hopefully allow to verify which genes were responsible of spontaneous catch-up growth in children with diagnosis of SGA at birth but above the third percentile for height at the age of 24 months, and if these genes were the same activated by hGH during the treatment in participants responders. Sixty children born at term (i.e. after the 37th completed week of gestation) and with a diagnosis of SGA (defined as a length less than tenth percentile according to the Italian reference table published by Bertini and Fabris) were planned to be enrolled in the study. Forty participants (group A) were still less than third percentile for height (according to the Tanner reference table) at the age of 24 months, the remaining 20 (group B) being more than or equal to third percentile (thus showing a spontaneous catch-up growth). Group A was randomized to receive Saizen at the daily dose of 0.067 mg/kg (Group A1) or no treatment (Group A2) for two years. All participants were to undergo full clinical examination and blood chemistry at baseline visit and visit after 1,6,12,18 and 24 months for a period of two years. Gene expression analysis using the Clontech Atlas Human Array was performed in all participants at baseline and after one year in order to identify the possible correlation between catch-up growth (either spontaneous or drug-induced) and expression of some genes. OBJECTIVES Primary objective: * To evaluate the correlation between gene expression profiling and catch-up growth (either spontaneous or drug induced after one year of treatment) in SGA children. Secondary Objectives: * To evaluate the percentage of participants not treated who show a spontaneous catch-up growth during the two years of observation. * To assess the safety and tolerability of early treatment with Saizen
Interventions
Recombinant human GH were administered subcutaneously (s.c) at the daily dose of 0.067 mg/kg of body weight to Group A1.
Sponsors
Merck Serono S.P.A., Italy
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 6 Years
Healthy volunteers
No
Inclusion criteria
* SGA at birth (defined as a length at birth equal or below the tenth percentile according to the Italian reference table of Bertini and Fabris) * Age of 24 Months * Caucasic * Born at term (i.e. after the 37th completed week of gestation) * Height equal or below (Group A) or up (Group B) the third percentile at the age of 24 months according to the Tanner reference table * Sufficient GH secretion (more than 10 nanogram (ng)/milliliter (ml)) at least to one of the tests commonly used at that age (glucagon, Levo-dopa, arginine, clonidine, Growth Hormone Releasing Hormone (GHRH), GH integrated secretion) * Normal level of Thyroid-stimulating hormone (THS), Free Triiodothyronine (FT3), Free Thyroxine (FT4), Insulin-like growth factor 1(IGF-1), insulin and haemoglobin A1c (HbA1c) * Normal level of Immunoglobulin A (IgA) * Children parents willing to comply with the protocol for the whole duration of the study * A written Informed Consent before the baseline visit must be obtained from the parent(s) / legal guardian(s)
Exclusion criteria
* Congenital malformations (including Silver-Russel syndrome) * Known abnormal karyotype, especially in girls * Twins * Severe psychomotor retardation * Previous or ongoing treatment with anabolic steroids or r-hGH * Treatments interfering with the immune system (including bacterial lysate) * Severe chronic illnesses * Autoimmune diseases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Correlation Between Gene Expression Profiling and Catch-up Growth in Small for Gestational Age (SGA) Children | Baseline and Week 48 | Gene expression profiling:analysis of ribonucleic acid (RNA) extracted from body tissue or fluids using Clontech Atlas Human Array to study level of activation of genes in tissue analyzed. Analysis was performed to identify possible correlation between catch-up growth (either spontaneous or drug-induced after Week 48) and therapeutic response to rhGH. Spontaneous catch up growth:shown by SGA participants having length more than third percentile at Week 96 without any treatment;drug induced growth was by SGA participants having length more than third percentile at Week 96 with drug treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Untreated Participants Who Showed a Spontaneous Catch-up Growth | Baseline through Week 96 | Spontaneous catch up growth was the growth shown by SGA participants having length more than third percentile at Week 96 without any study drug treatment. |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | Baseline through Week 96 | AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug , SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued from the study due to AE were also recorded. |
Countries
Italy
Participant flow
Recruitment details
Participants were recruited in 12 study centers in Italy from 20 Feb 2004 to 10 Jul 2009.
Participants by arm
| Arm | Count |
|---|---|
| Group A, Less Than Third Percentile (Saizen) Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (s.c) at the daily dose of 0.035 milligram(mg)/kilogram(kg) for 2 years. | 9 |
| Group A2, Less Than Third Percentile (No Treatment) Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years. | 6 |
| Group B, More Than Third Percentile (No Treatment) Participants with more than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years. | 10 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 1 |
Baseline characteristics
| Characteristic | Group A, Less Than Third Percentile (Saizen) | Group A2, Less Than Third Percentile (No Treatment) | Group B, More Than Third Percentile (No Treatment) | Total |
|---|---|---|---|---|
| Age, Continuous | 5.7 years STANDARD_DEVIATION 1.2 | 5.0 years STANDARD_DEVIATION 0.7 | 5.2 years STANDARD_DEVIATION 0.4 | 5.3 years STANDARD_DEVIATION 0.9 |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 5 Participants | 13 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 5 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 8 | 4 / 4 | 9 / 10 |
| serious Total, serious adverse events | 0 / 8 | 0 / 4 | 0 / 10 |
Outcome results
Primary
Correlation Between Gene Expression Profiling and Catch-up Growth in Small for Gestational Age (SGA) Children
Gene expression profiling:analysis of ribonucleic acid (RNA) extracted from body tissue or fluids using Clontech Atlas Human Array to study level of activation of genes in tissue analyzed. Analysis was performed to identify possible correlation between catch-up growth (either spontaneous or drug-induced after Week 48) and therapeutic response to rhGH. Spontaneous catch up growth:shown by SGA participants having length more than third percentile at Week 96 without any treatment;drug induced growth was by SGA participants having length more than third percentile at Week 96 with drug treatment.
Time frame: Baseline and Week 48
Population: Gene expression profiling was not performed due to RNA degradation in nearly all of the blood samples and hence no comparison between gene expression and growth was made.
Secondary
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation
AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug , SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued from the study due to AE were also recorded.
Time frame: Baseline through Week 96
Population: Safety analysis population included all randomized participants with at least 1 post-baseline assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A, Less Than Third Percentile (Saizen) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 0 participants |
| Group A, Less Than Third Percentile (Saizen) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 6 participants |
| Group A, Less Than Third Percentile (Saizen) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | Discontinuation due to AEs | 0 participants |
| Group A2, Less Than Third Percentile (No Treatment) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 0 participants |
| Group A2, Less Than Third Percentile (No Treatment) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 4 participants |
| Group A2, Less Than Third Percentile (No Treatment) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | Discontinuation due to AEs | 0 participants |
| Group B, More Than Third Percentile (No Treatment) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | AEs | 9 participants |
| Group B, More Than Third Percentile (No Treatment) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | Discontinuation due to AEs | 0 participants |
| Group B, More Than Third Percentile (No Treatment) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation | SAEs | 0 participants |
Secondary
Percentage of Untreated Participants Who Showed a Spontaneous Catch-up Growth
Spontaneous catch up growth was the growth shown by SGA participants having length more than third percentile at Week 96 without any study drug treatment.
Time frame: Baseline through Week 96
Population: Data was not analyzed due to small number of evaluable participants.