Dwarfism, Pituitary
Conditions
Keywords
Dwarfism, pituitary, Growth hormone
Brief summary
This is an open-label, prospective, multicentric, non-comparative, non-randomized Phase IV interventional study in which subjects pre-diagnosed with Growth Hormone Deficiency (GHD) were treated for 4 weeks with Saizen to compare the response between GHD children born appropriate for gestational age (AGA) and those born small for gestation age (SGA) after 4 weeks of Saizen therapy.
Detailed description
The response to growth hormone (GH) treatment, short-term as well as long-term, displays considerable inter individual variability. This is particularly evident for the endpoint of paediatric GH administration, that is (i.e.) the growth response, which is pronounced in children who are affected by GHD. This is an open-label, multicentric study in which subjects pre-diagnosed with GHD were treated for 4 weeks with Saizen. Two hundred fourteen GHD evaluable pre-pubertal subjects were planned to be recruited in approximately 9 sites in China. Demographic data, medical history, tanner stage, physical examination, body weight, height, bone age measurement, body mass index, review of baseline medications and procedures and blood sampling were performed at baseline visit, end of treatment visit (week 4) and at 4 week follow-up visit. OBJECTIVES Primary objective: * To compare the response between GHD children born AGA and those born SGA after 4 weeks of Saizen therapy Secondary Objectives: * To explore the contribution of selected genes to the phenotype of GHD children * To explore the impact of gene polymorphisms on the levels of specific serum biomarkers in GHD children after 4 weeks of Saizen therapy * To explore the relationships between changes in gene expression and changes in serum biomarkers after 4 weeks of Saizen therapy and the spectrum of gene polymorphisms in GHD children
Interventions
Recombinant human growth hormone (r-hGH) administered at dose of 0.033 milligram/kilogram (mg/kg) body weight (0.1 International Unit \[IU\]/kg body weight) per day by subcutaneous injection.
Sponsors
Merck Serono Co., Ltd., China
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Male and female subjects with documented pre-established diagnosis of GHD with a GH peak response of \<10 microgram/liter (mcg/L) with 2 GH stimulation tests, without priming with estradiol * Subjects with SGA defined as birth weight and/or length at least 2 standard deviations (SDs) below the mean for gestational age * Subjects with prepubertal status according to Tanner * Subjects with pre-established history of normal thyroid function or adequate substitution for at least 3 months * Subjects with weight for stature within the population specific normal range (\>5th and \<95th percentiles) for gender * Subjects with willingness and ability to comply with the protocol for the duration of the study * Subjects whose parents or guardians written informed consent given before any study-related procedure that was not part of the subjects normal medical care, with the understanding that the subject or parent/guardian might withdraw consent at any time without prejudice to future medical care. If the child was old enough to read and write, a separate assent form was given
Exclusion criteria
* Subjects who acquired GHD due to central nervous system tumor, trauma, infection, infiltration (documented by imaging), and history of irradiation or cranial surgery * Subjects with previous treatment with GH, growth hormone releasing hormone (GHRH), anabolic steroids or any treatment affecting growth * Subjects who had previous treatment with corticosteroids, except in case of topical or inhaled corticosteroid administration for atopic disease. Corticosteroids for hormonal substitution were also allowed if the condition and the treatment regimen had been stable for at least 3 months * Subjects with severe associated pathology affecting growth such as malnutrition, malabsorption, or bone dysplasia * Subjects with chronic severe kidney disease * Subjects with chronic severe liver disease * Subjects with chronic infectious disease * Subjects with acute or severe illness during the previous 6 months * Subjects with significant concomitant illness that would interfere with participation or assessment in this study * Subjects who had active malignancy (except non-melanomatous skin malignancies that had undergone surgical excision and/or biopsy, diagnosis and treatment to resolution) * Subjects with history or active idiopathic intra-cranial hypertension (benign intracranial hypertension or pseudo-tumor cerebri) * Subjects with diabetes mellitus type I & II * Subjects with any autoimmune disease * Subjects who had previous screening failure in this study * Subjects who had used an investigational drug or participated in another clinical study within the last 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Serum Insulin Like Growth Factor-1 Standard Deviation Score (IGF-1 SDS) Levels at Week 4 | Baseline and Week 4 | Insulin Like Growth Factor-1 Standard Deviation Score (IGF-1 SDS) was calculated as logarithm (log) 10 actual value of IGF-1 - log 10 (mean reference value of IGF-1) divided by log10 reference standard deviation of IGF-1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels at Week 4 | Baseline and Week 4 | — |
| Change From Baseline in Fasting Glucose at Week 4 | Baseline and Week 4 | — |
| Change From Baseline in Fasting Insulin at Week 4 | Baseline and Week 4 | — |
| Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Test at Week 4 | Baseline and Week 4 | HOMA-IR is used to assess insulin resistance and calculated by an empirical mathematical formula based on fasting plasma glucose and fasting plasma insulin levels. HOMA-IR = fasting plasma insulin (picomole/liter \[pmol/L\]) \* fasting plasma glucose (millimole/liter \[mmol/L\]) divided by 22.5. |
| Change From Baseline in Lipid Profile at Week 4 | Baseline and Week 4 | Total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides levels were evaluated. |
Participant flow
Pre-assignment details
Out of 214 participants enrolled in the study, 1 participant could not be categorized as appropriate for gestational age (AGA) or small for gestational age (SGA) since weight and height at birth was not available.
Participants by arm
| Arm | Count |
|---|---|
| Appropriate for Gestational Age (AGA) Participants in AGA group received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (sc) at the daily dose of 0.033 milligram/kilogram (mg/kg) body weight for 4 weeks. | 175 |
| Small for Gestational Age (SGA) Participants in SGA group received Saizen (r-hGH) sc at the daily dose of 0.033 mg/kg body weight for 4 weeks. | 30 |
| Total | 205 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Other | 3 | 0 |
| Overall Study | Protocol Violation | 3 | 1 |
| Overall Study | Randomized but not treated | 8 | 0 |
Baseline characteristics
| Characteristic | Appropriate for Gestational Age (AGA) | Small for Gestational Age (SGA) | Total |
|---|---|---|---|
| Age, Continuous | 10.52 years STANDARD_DEVIATION 3.844 | 9.39 years STANDARD_DEVIATION 4.349 | 10.35 years STANDARD_DEVIATION 3.931 |
| Sex: Female, Male Female | 46 Participants | 6 Participants | 52 Participants |
| Sex: Female, Male Male | 129 Participants | 24 Participants | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 175 | 3 / 30 |
| serious Total, serious adverse events | 1 / 175 | 0 / 30 |
Outcome results
Primary
Change From Baseline in Serum Insulin Like Growth Factor-1 Standard Deviation Score (IGF-1 SDS) Levels at Week 4
Insulin Like Growth Factor-1 Standard Deviation Score (IGF-1 SDS) was calculated as logarithm (log) 10 actual value of IGF-1 - log 10 (mean reference value of IGF-1) divided by log10 reference standard deviation of IGF-1.
Time frame: Baseline and Week 4
Population: The intent-to-treat (ITT) population set included all the participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Appropriate for Gestational Age (AGA) | Change From Baseline in Serum Insulin Like Growth Factor-1 Standard Deviation Score (IGF-1 SDS) Levels at Week 4 | Baseline | -2.04 nanogram/millilter (ng/mL) | Standard Deviation 2.341 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Serum Insulin Like Growth Factor-1 Standard Deviation Score (IGF-1 SDS) Levels at Week 4 | Change at Week 4 | 1.38 nanogram/millilter (ng/mL) | Standard Deviation 1.358 |
| Small for Gestational Age (SGA) | Change From Baseline in Serum Insulin Like Growth Factor-1 Standard Deviation Score (IGF-1 SDS) Levels at Week 4 | Baseline | -2.22 nanogram/millilter (ng/mL) | Standard Deviation 2.39 |
| Small for Gestational Age (SGA) | Change From Baseline in Serum Insulin Like Growth Factor-1 Standard Deviation Score (IGF-1 SDS) Levels at Week 4 | Change at Week 4 | 0.85 nanogram/millilter (ng/mL) | Standard Deviation 1.257 |
p-value: 0.194Wilcoxon rank sum test
Secondary
Change From Baseline in Fasting Glucose at Week 4
Time frame: Baseline and Week 4
Population: ITT population set included all the participants who received at least 1 dose of study medication. Here 'N' (Number of participants analyzed) signified those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Appropriate for Gestational Age (AGA) | Change From Baseline in Fasting Glucose at Week 4 | Baseline | 4.83 millimole/liter (mmol/L) | Standard Deviation 0.471 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Fasting Glucose at Week 4 | Change at Week 4 | 0.17 millimole/liter (mmol/L) | Standard Deviation 0.578 |
| Small for Gestational Age (SGA) | Change From Baseline in Fasting Glucose at Week 4 | Baseline | 4.46 millimole/liter (mmol/L) | Standard Deviation 1.106 |
| Small for Gestational Age (SGA) | Change From Baseline in Fasting Glucose at Week 4 | Change at Week 4 | 0.22 millimole/liter (mmol/L) | Standard Deviation 0.886 |
p-value: 0.71Wilcoxon rank sum test
Secondary
Change From Baseline in Fasting Insulin at Week 4
Time frame: Baseline and Week 4
Population: ITT population set included all the participants who received at least 1 dose of study medication. Here 'N' (Number of participants analyzed) signified those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Appropriate for Gestational Age (AGA) | Change From Baseline in Fasting Insulin at Week 4 | Baseline | 36.17 picomole/L (pmol/L) | Standard Deviation 74.575 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Fasting Insulin at Week 4 | Change at Week 4 | 10.08 picomole/L (pmol/L) | Standard Deviation 81.674 |
| Small for Gestational Age (SGA) | Change From Baseline in Fasting Insulin at Week 4 | Baseline | 23.58 picomole/L (pmol/L) | Standard Deviation 14.892 |
| Small for Gestational Age (SGA) | Change From Baseline in Fasting Insulin at Week 4 | Change at Week 4 | 12.04 picomole/L (pmol/L) | Standard Deviation 32.389 |
p-value: 0.265Wilcoxon rank sum test
Secondary
Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Test at Week 4
HOMA-IR is used to assess insulin resistance and calculated by an empirical mathematical formula based on fasting plasma glucose and fasting plasma insulin levels. HOMA-IR = fasting plasma insulin (picomole/liter \[pmol/L\]) \* fasting plasma glucose (millimole/liter \[mmol/L\]) divided by 22.5.
Time frame: Baseline and Week 4
Population: ITT population set included all the participants who received at least 1 dose of study medication. Here 'N' (Number of participants analyzed) signified those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Appropriate for Gestational Age (AGA) | Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Test at Week 4 | Baseline | 7.91 pmol/L*mmol/L | Standard Deviation 15.662 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Test at Week 4 | Change at Week 4 | 2.96 pmol/L*mmol/L | Standard Deviation 18.458 |
| Small for Gestational Age (SGA) | Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Test at Week 4 | Baseline | 5.06 pmol/L*mmol/L | Standard Deviation 3.29 |
| Small for Gestational Age (SGA) | Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Test at Week 4 | Change at Week 4 | 2.48 pmol/L*mmol/L | Standard Deviation 6.527 |
p-value: 0.308Wilcoxon rank sum test
Secondary
Change From Baseline in Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels at Week 4
Time frame: Baseline and Week 4
Population: ITT population set included all the participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Appropriate for Gestational Age (AGA) | Change From Baseline in Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels at Week 4 | Baseline | 3.16 microgram/mL (mcg/mL) | Standard Deviation 1.386 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels at Week 4 | Change at Week 4 | 0.58 microgram/mL (mcg/mL) | Standard Deviation 0.869 |
| Small for Gestational Age (SGA) | Change From Baseline in Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels at Week 4 | Baseline | 2.57 microgram/mL (mcg/mL) | Standard Deviation 1.525 |
| Small for Gestational Age (SGA) | Change From Baseline in Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels at Week 4 | Change at Week 4 | 0.51 microgram/mL (mcg/mL) | Standard Deviation 0.805 |
p-value: 0.752Wilcoxon rank sum test
Secondary
Change From Baseline in Lipid Profile at Week 4
Total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides levels were evaluated.
Time frame: Baseline and Week 4
Population: ITT population set included all the participants who received at least 1 dose of study medication. Here 'N' (Number of participants analyzed) signified those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Appropriate for Gestational Age (AGA) | Change From Baseline in Lipid Profile at Week 4 | Baseline (Total Cholesterol) | 4.16 mmol/L | Standard Deviation 0.752 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Lipid Profile at Week 4 | Baseline (HDL-Cholesterol) | 1.56 mmol/L | Standard Deviation 0.452 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Lipid Profile at Week 4 | Baseline (LDL-Cholesterol) | 2.18 mmol/L | Standard Deviation 0.672 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Lipid Profile at Week 4 | Baseline (Triglycerides) | 0.99 mmol/L | Standard Deviation 0.527 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Lipid Profile at Week 4 | Change at Week 4 (Total Cholesterol) | -0.28 mmol/L | Standard Deviation 0.601 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Lipid Profile at Week 4 | Change at Week 4 (HDL-Cholesterol) | -0.10 mmol/L | Standard Deviation 0.317 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Lipid Profile at Week 4 | Change at Week 4 (LDL-Cholesterol) | -0.24 mmol/L | Standard Deviation 0.546 |
| Appropriate for Gestational Age (AGA) | Change From Baseline in Lipid Profile at Week 4 | Change at Week 4 (Triglycerides) | 0.12 mmol/L | Standard Deviation 0.551 |
| Small for Gestational Age (SGA) | Change From Baseline in Lipid Profile at Week 4 | Change at Week 4 (Triglycerides) | -0.09 mmol/L | Standard Deviation 0.831 |
| Small for Gestational Age (SGA) | Change From Baseline in Lipid Profile at Week 4 | Baseline (Total Cholesterol) | 4.22 mmol/L | Standard Deviation 0.833 |
| Small for Gestational Age (SGA) | Change From Baseline in Lipid Profile at Week 4 | Change at Week 4 (Total Cholesterol) | -0.03 mmol/L | Standard Deviation 0.612 |
| Small for Gestational Age (SGA) | Change From Baseline in Lipid Profile at Week 4 | Baseline (HDL-Cholesterol) | 1.59 mmol/L | Standard Deviation 0.443 |
| Small for Gestational Age (SGA) | Change From Baseline in Lipid Profile at Week 4 | Change at Week 4 (LDL-Cholesterol) | 0.02 mmol/L | Standard Deviation 0.502 |
| Small for Gestational Age (SGA) | Change From Baseline in Lipid Profile at Week 4 | Baseline (LDL-Cholesterol) | 2.19 mmol/L | Standard Deviation 0.709 |
| Small for Gestational Age (SGA) | Change From Baseline in Lipid Profile at Week 4 | Change at Week 4 (HDL-Cholesterol) | 0.02 mmol/L | Standard Deviation 0.329 |
| Small for Gestational Age (SGA) | Change From Baseline in Lipid Profile at Week 4 | Baseline (Triglycerides) | 1.02 mmol/L | Standard Deviation 0.638 |
Comparison: For total cholesterol: Wilcoxon rank sum test was used to calculate p-value.p-value: 0.078Wilcoxon rank sum test
Comparison: For HDL-cholesterol: Wilcoxon rank sum test was used to calculate p-value.p-value: 0.033Wilcoxon rank sum test
Comparison: For LDL-cholesterol: Wilcoxon rank sum test was used to calculate p-value.p-value: 0.041Wilcoxon rank sum test
Comparison: For triglycerides: Wilcoxon rank sum test was used to calculate p-value.p-value: 0.091Wilcoxon rank sum test