Predictive Markers in Chinese Growth Hormone Deficiency (GHD) Children Treated With Saizen®

• Change From Baseline in Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Levels at Week 4 [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]
• Change From Baseline in Fasting Glucose at Week 4 [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]
• Change From Baseline in Fasting Insulin at Week 4 [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]
• Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Test at Week 4 [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]
  Total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides levels were evaluated.

• Insulin like Growth Factor binding protein-3 (IGFBP-3) levels [ Time Frame: At 4 weeks ] [ Designated as safety issue: No ]
• Fasting glucose, fasting insulin, insulin resistance [ Time Frame: At 4 weeks ] [ Designated as safety issue: No ]
• Lipid profile [ Time Frame: At 4 weeks ] [ Designated as safety issue: No ]

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.

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

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