Idiopathic Short Stature
Conditions
Keywords
Saizen®, Recombinant human growth hormone (r-hGH), Idiopathic short stature, Height velocity, Bone age
Brief summary
This is an open-label, multi-center, randomized, two-arm parallel, no-treatment group controlled (only for the first 6 months), Phase 3 study in children with ISS. The subjects will be treated with 0.067 milligram/kilogram/day (mg/kg/day) of Saizen®, weight base dose, for 12 months (12 months of treatment in the test group, and 6 months of no treatment and then 6 months of treatment in the control group).
Interventions
DRUGSaizen®
Subjects in the Saizen test group will receive Saizen (recombinant-human growth hormone \[r-hGH\]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age greater than or equal to 5 years * Pre-pubertal; testicular volume less than 4 milliliter (in males) and breast Stage 1 (in females) * The official records of height (for example records measured in hospitals or schools) during previous 6 months or more preceding inclusion in the study (self-measurement of the height at home will not be considered as a valid record) * Height less than or equal to 3rd percentile compared to same sex, same age * Peak serum growth hormone (GH) greater than 10 microgram per liter (mcg/L) in GH stimulation test (results of peak serum GH greater than 10 mcg/L in GH stimulation test within 1 year can be used instead) * Naive to GH therapy * Normal birth weight (that is greater than or equal to 3rd percentile when compared to same sex) * Normal thyroid function * Normal karyotype in girls * Written informed consent from parent/guardian * Written informed consent from the subject who speaks, understand, read, and write Korean * Bone age less than 10 years in boys and less than 9 years in girls, whose difference between the bone and chronological age is no more than 3 years
Exclusion criteria
* Puberty development (Tanner stage greater than or equal to 2) * Skeletal dysplasia or abnormal body proportions * Chronic systemic illness * Dysmorphic syndrome * Growth Hormone Deficiency * Small for Gestational Age (SGA) * Current medication for Attention deficit hyperactivity disorder (ADHD) or hyperactivity disorder * Current medication with drugs that may influence secretion or action of growth hormone (such as estrogen, androgen, anabolic steroid, corticosteroid, thyroxine, aromatase inhibitors) * Diabetes mellitus * Kidney transplantation * Acute critical illness, including complications following open heart surgery, abdominal surgery or multiple accidental trauma * Acute respiratory failure * Malignancy or previous therapy for malignancy * Known hypersensitivity to somatotropin or any of its excipients including cresol or glycerol * Closed epiphyses, progression or recurrence of an underlying intracranial tumor, chronic renal disease * Endocrinologic or metabolic disorders such as Prader-Willi syndrome; Russel-Silver syndrome; Seckel syndrome; Down syndrome; Cushing syndrome; Noonan syndrome; short stature caused by other chromosomal abnormalities * The disorders that explain short stature such as psychiatric disorders, nutritional disorders, and chronic debilitating diseases * Participation in another clinical trial within the past 3 months * Status of legal incapacity or limited legal capacity of the parents or legal guardian
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Height Velocity at Month 6 Using Last Observation Carried Forward (LOCF) Method | Baseline, Month 6 | Baseline height is defined as the last available height measurement before randomization. Baseline height velocity = (\[Baseline height minus height measurement obtained at least 6 months prior\] / 6) \* 12. Height velocity at Month 6 = (\[Month 6 height minus height measurement obtained at least 6 months prior\] / 6) \* 12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Height at Month 6 and 12 | Baseline, Month 6, Month 12 | — |
| Change From Baseline in Height Standard Deviation Score (SDS) at Month 6 and 12 | Baseline, Month 6, Month 12 | Height SDS was calculated as: Height SDS = (measured height - population mean) / population standard deviation, where mean and standard deviation were based on the Korean standard growth charts. SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a subject's value was relative to the mean of the reference population. The scores were centred around zero. Negative score indicated a subject was smaller for their age/gender. |
| Change From Baseline in Serum Concentration of Insulin-like Growth Factor-I (IGF-I) at Month 6 and 12 | Baseline, Month 6, Month 12 | — |
| Change From Baseline in Height Velocity at Month 12 | Baseline, Month 12 | Baseline height is defined as the last available height measurement before randomization. Baseline height velocity = (\[Baseline height minus height measurement obtained at least 12 months prior\] / 12) \* 12. Height velocity at Month 12 = (\[Month 12 height minus height measurement obtained at least 12 months prior\] / 12) \* 12. |
| Percentage of Adherence to Study Treatment | 6 months post-dose (Saizen Test Group and Saizen Control Group); 12 months post-dose (Saizen Test Group) | Percentage of adherence to study treatment (adherence rate) was defined as the actual number of received treatments divided by the scheduled number of treatments multiplied by 100. The adherence rate for 6 months was calculated from Baseline to 6 months for the Saizen Test Group and from Month 6 to Month 12 for the Saizen Control Group. |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs | Baseline up to Month 13 | An adverse event (AE) was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. For the Saizen Test Group, TEAEs were defined as events that occurred or worsened at or after the first administration of treatment and for the Saizen Control Group, TEAEs were defined as events that occurred or worsened at or after the randomization. |
| Change From Baseline in Serum Concentration of Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) at Month 6 and 12 | Baseline, Month 6, Month 12 | — |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Saizen Test Group Subjects in the Saizen test group received Saizen (recombinant-human growth hormone \[r-hGH\]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months. | 59 |
| Saizen Control Group Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months. | 30 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Consent withdrawal by parent's guardian | 5 | 2 |
| Overall Study | Entered puberty during the study | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Saizen Test Group | Saizen Control Group | Total |
|---|---|---|---|
| Age, Continuous | 6.79 years STANDARD_DEVIATION 1.54 | 6.83 years STANDARD_DEVIATION 1.61 | 6.80 years STANDARD_DEVIATION 1.55 |
| Sex: Female, Male Female | 29 Participants | 13 Participants | 42 Participants |
| Sex: Female, Male Male | 30 Participants | 17 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 42 / 59 | 18 / 30 |
| serious Total, serious adverse events | 3 / 59 | 1 / 30 |
Outcome results
Primary
Change From Baseline in Height Velocity at Month 6 Using Last Observation Carried Forward (LOCF) Method
Baseline height is defined as the last available height measurement before randomization. Baseline height velocity = (\[Baseline height minus height measurement obtained at least 6 months prior\] / 6) \* 12. Height velocity at Month 6 = (\[Month 6 height minus height measurement obtained at least 6 months prior\] / 6) \* 12.
Time frame: Baseline, Month 6
Population: Intent-to-treat (ITT) analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here n signifies those subjects who were evaluable for this outcome measure at the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen Test Group | Change From Baseline in Height Velocity at Month 6 Using Last Observation Carried Forward (LOCF) Method | Baseline (n=59,30) | 5.63 centimeter/year (cm/yr) | Standard Deviation 1.62 |
| Saizen Test Group | Change From Baseline in Height Velocity at Month 6 Using Last Observation Carried Forward (LOCF) Method | Change at Month 6 (n=59,29) | 4.45 centimeter/year (cm/yr) | Standard Deviation 2.7 |
| Saizen Control Group | Change From Baseline in Height Velocity at Month 6 Using Last Observation Carried Forward (LOCF) Method | Baseline (n=59,30) | 4.94 centimeter/year (cm/yr) | Standard Deviation 1.91 |
| Saizen Control Group | Change From Baseline in Height Velocity at Month 6 Using Last Observation Carried Forward (LOCF) Method | Change at Month 6 (n=59,29) | 1.01 centimeter/year (cm/yr) | Standard Deviation 3.15 |
p-value: <0.000195% CI: [2.17, 4.78]ANCOVA
Secondary
Change From Baseline in Height at Month 6 and 12
Time frame: Baseline, Month 6, Month 12
Population: ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here n signifies those subjects who were evaluable for this outcome measure at the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen Test Group | Change From Baseline in Height at Month 6 and 12 | Change at Month 6 (n=55, 27) | 5.41 centimeter (cm) | Standard Deviation 1.04 |
| Saizen Test Group | Change From Baseline in Height at Month 6 and 12 | Change at Month 12 (n=52, 27) | 9.78 centimeter (cm) | Standard Deviation 1.35 |
| Saizen Test Group | Change From Baseline in Height at Month 6 and 12 | Baseline (n=60, 30) | 108.27 centimeter (cm) | Standard Deviation 7.67 |
| Saizen Control Group | Change From Baseline in Height at Month 6 and 12 | Change at Month 6 (n=55, 27) | 3.10 centimeter (cm) | Standard Deviation 0.84 |
| Saizen Control Group | Change From Baseline in Height at Month 6 and 12 | Change at Month 12 (n=52, 27) | 8.24 centimeter (cm) | Standard Deviation 1.47 |
| Saizen Control Group | Change From Baseline in Height at Month 6 and 12 | Baseline (n=60, 30) | 108.07 centimeter (cm) | Standard Deviation 8.36 |
Secondary
Change From Baseline in Height Standard Deviation Score (SDS) at Month 6 and 12
Height SDS was calculated as: Height SDS = (measured height - population mean) / population standard deviation, where mean and standard deviation were based on the Korean standard growth charts. SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a subject's value was relative to the mean of the reference population. The scores were centred around zero. Negative score indicated a subject was smaller for their age/gender.
Time frame: Baseline, Month 6, Month 12
Population: ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here n signifies those subjects who were evaluable for this outcome measure at the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen Test Group | Change From Baseline in Height Standard Deviation Score (SDS) at Month 6 and 12 | Baseline (n=60,30) | -2.26 standard deviation score | Standard Deviation 0.36 |
| Saizen Test Group | Change From Baseline in Height Standard Deviation Score (SDS) at Month 6 and 12 | Change at Month 6 (n=55, 27) | 0.59 standard deviation score | Standard Deviation 0.21 |
| Saizen Test Group | Change From Baseline in Height Standard Deviation Score (SDS) at Month 6 and 12 | Change at Month 12 (n=52, 27) | 0.96 standard deviation score | Standard Deviation 0.27 |
| Saizen Control Group | Change From Baseline in Height Standard Deviation Score (SDS) at Month 6 and 12 | Baseline (n=60,30) | -2.34 standard deviation score | Standard Deviation 0.34 |
| Saizen Control Group | Change From Baseline in Height Standard Deviation Score (SDS) at Month 6 and 12 | Change at Month 6 (n=55, 27) | 0.08 standard deviation score | Standard Deviation 0.19 |
| Saizen Control Group | Change From Baseline in Height Standard Deviation Score (SDS) at Month 6 and 12 | Change at Month 12 (n=52, 27) | 0.62 standard deviation score | Standard Deviation 0.27 |
Secondary
Change From Baseline in Height Velocity at Month 12
Baseline height is defined as the last available height measurement before randomization. Baseline height velocity = (\[Baseline height minus height measurement obtained at least 12 months prior\] / 12) \* 12. Height velocity at Month 12 = (\[Month 12 height minus height measurement obtained at least 12 months prior\] / 12) \* 12.
Time frame: Baseline, Month 12
Population: ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here Number of participants analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saizen Test Group | Change From Baseline in Height Velocity at Month 12 | 3.77 cm/year | Standard Deviation 2.21 |
| Saizen Control Group | Change From Baseline in Height Velocity at Month 12 | 2.86 cm/year | Standard Deviation 1.95 |
Secondary
Change From Baseline in Serum Concentration of Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) at Month 6 and 12
Time frame: Baseline, Month 6, Month 12
Population: ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here n signifies those subjects who were evaluable for this outcome measure at the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen Test Group | Change From Baseline in Serum Concentration of Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) at Month 6 and 12 | Baseline (n=60, 30) | 3,783.33 mcg/L | Standard Deviation 915.2 |
| Saizen Test Group | Change From Baseline in Serum Concentration of Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) at Month 6 and 12 | Change at Month 6 (n=55, 27) | 857.64 mcg/L | Standard Deviation 761.28 |
| Saizen Test Group | Change From Baseline in Serum Concentration of Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) at Month 6 and 12 | Change at Month 12 (n=52, 27) | 932.31 mcg/L | Standard Deviation 666.13 |
| Saizen Control Group | Change From Baseline in Serum Concentration of Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) at Month 6 and 12 | Baseline (n=60, 30) | 3,935.67 mcg/L | Standard Deviation 866.42 |
| Saizen Control Group | Change From Baseline in Serum Concentration of Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) at Month 6 and 12 | Change at Month 6 (n=55, 27) | -38.89 mcg/L | Standard Deviation 616.88 |
| Saizen Control Group | Change From Baseline in Serum Concentration of Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) at Month 6 and 12 | Change at Month 12 (n=52, 27) | 545.56 mcg/L | Standard Deviation 599.52 |
Secondary
Change From Baseline in Serum Concentration of Insulin-like Growth Factor-I (IGF-I) at Month 6 and 12
Time frame: Baseline, Month 6, Month 12
Population: ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here n signifies those subjects who were evaluable for this outcome measure at the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen Test Group | Change From Baseline in Serum Concentration of Insulin-like Growth Factor-I (IGF-I) at Month 6 and 12 | Baseline (n=60,30) | 112.62 microgram/liter (mcg/L) | Standard Deviation 43.06 |
| Saizen Test Group | Change From Baseline in Serum Concentration of Insulin-like Growth Factor-I (IGF-I) at Month 6 and 12 | Change at Month 6 (n=55, 27) | 122.57 microgram/liter (mcg/L) | Standard Deviation 96.99 |
| Saizen Test Group | Change From Baseline in Serum Concentration of Insulin-like Growth Factor-I (IGF-I) at Month 6 and 12 | Change at Month 12 (n=52, 27) | 164.48 microgram/liter (mcg/L) | Standard Deviation 95.69 |
| Saizen Control Group | Change From Baseline in Serum Concentration of Insulin-like Growth Factor-I (IGF-I) at Month 6 and 12 | Baseline (n=60,30) | 125.01 microgram/liter (mcg/L) | Standard Deviation 65.68 |
| Saizen Control Group | Change From Baseline in Serum Concentration of Insulin-like Growth Factor-I (IGF-I) at Month 6 and 12 | Change at Month 6 (n=55, 27) | 8.30 microgram/liter (mcg/L) | Standard Deviation 41.57 |
| Saizen Control Group | Change From Baseline in Serum Concentration of Insulin-like Growth Factor-I (IGF-I) at Month 6 and 12 | Change at Month 12 (n=52, 27) | 142.17 microgram/liter (mcg/L) | Standard Deviation 112.94 |
Secondary
Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs
An adverse event (AE) was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. For the Saizen Test Group, TEAEs were defined as events that occurred or worsened at or after the first administration of treatment and for the Saizen Control Group, TEAEs were defined as events that occurred or worsened at or after the randomization.
Time frame: Baseline up to Month 13
Population: Safety analysis set (SAS) included all randomized subjects who received at least 1 dose of planned trial treatment and had follow-up safety data. SAS also included the safety data for all subjects during non-treatment (the first 6 months after enrollment) period who belonged to control group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Saizen Test Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs | TEAEs | 42 subjects |
| Saizen Test Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs | Serious TEAEs | 3 subjects |
| Saizen Control Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs | TEAEs | 18 subjects |
| Saizen Control Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs | Serious TEAEs | 1 subjects |
Secondary
Percentage of Adherence to Study Treatment
Percentage of adherence to study treatment (adherence rate) was defined as the actual number of received treatments divided by the scheduled number of treatments multiplied by 100. The adherence rate for 6 months was calculated from Baseline to 6 months for the Saizen Test Group and from Month 6 to Month 12 for the Saizen Control Group.
Time frame: 6 months post-dose (Saizen Test Group and Saizen Control Group); 12 months post-dose (Saizen Test Group)
Population: ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here n signifies those subjects who were evaluable for this outcome measure at the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saizen Test Group | Percentage of Adherence to Study Treatment | Adherence for 6 months (n=60, 27) | 94.38 percentage of adherance | Standard Deviation 14.12 |
| Saizen Test Group | Percentage of Adherence to Study Treatment | Adherence for 12 months (n=60, 0) | 93.27 percentage of adherance | Standard Deviation 14.67 |
| Saizen Control Group | Percentage of Adherence to Study Treatment | Adherence for 12 months (n=60, 0) | NA percentage of adherance | — |
| Saizen Control Group | Percentage of Adherence to Study Treatment | Adherence for 6 months (n=60, 27) | 95.69 percentage of adherance | Standard Deviation 5.04 |