Growth Disorders
Conditions
Keywords
Pediatric growth disorders
Brief summary
The purpose of this multicenter, open-label, observational, post-marketing surveillance study is to collect long term safety and efficacy information on growth hormone (GH) products: Protropin (somatrem for injection), Nutropin (somatropin for injection), Nutropin AQ (somatropin for injection), and Nutropin Depot (somatropin for injectable suspension) in the treatment of pediatric growth disorders for which GH is prescribed.
Interventions
BIOLOGICALSomatrem
BIOLOGICALSomatropin
Sponsors
Genentech, Inc.
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Participants with open epiphyses * Children of either sex who are treated with Nutropin Depot, Nutropin AQ, Nutropin, or Protropin for the treatment of growth failure * Participants who are willing to keep follow up appointments throughout the study participation
Exclusion criteria
* Participants treated with a non-Genentech GH preparation * Participants with closed epiphyses * Participants with active neoplasia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died | From October 1985 to June 2010 (overall approximately 24 years and 9 months) | — |
| First Year Annualized Growth Rate | Year 1 | Annualized growth rates are expressed as centimeters per year (cm/yr), computed as the change in height (centimeters) divided by the change in age (years). Growth rates were calculated from the date of the first injection (baseline/ enrollment) to the visit closest to 365\*1 days after baseline. Visits within 90 days of 365\*1 days after baseline may be used. If multiple visits within 90 days were reported then the visit closest to 365\*1 days was used. Growth rates less than (\<) -1 or greater than (\>) 30 cm/yr were excluded. Growth rates from -1 to 0 were set to 0 cm/yr. Growth rates are summarized by etiology group and gender. Only those participants who had non-missing 1-year growth rate data were included in the analysis. |
| Second Year Annualized Growth Rate | Year 2 | Annualized growth rates are expressed as cm/yr, computed as the change in height (centimeters) divided by the change in age (years). Growth rates were calculated from the date of the visit closest to 365 days after baseline to the visit closest to 730 days. Visits within 90 days of 365 and 730 days after baseline may be used. If multiple visits within 90 days were reported then the visit closest to 365 or 730 days was used. Growth rates \<-1 or \>30 cm/yr were excluded. Growth rates from -1 to 0 were set to 0 cm/yr. Growth rates are summarized by etiology group and gender. Only those participants who had non-missing second-year growth rate data were included in the analysis. |
| Third Year Annualized Growth Rate | Year 3 | Annualized growth rates are expressed as cm/yr, computed as the change in height (centimeters) divided by the change in age (years). Growth rates were calculated from the date of the visit closest to 730 days after baseline to the visit closest to 1095 days. Visits within 90 days of 730 and 1095 days after baseline may be used. If multiple visits within 90 days were reported then the visit closest to 730 or 1095 days was used. Growth rates \<-1 or \>30 cm/yr were excluded. Growth rates from -1 to 0 were set to 0 cm/yr. Growth rates are summarized by etiology group and gender. Only those participants who had non-missing third-year growth rate data were included in the analysis. |
| Near Adult Height (NAH) | From October 1985 to June 2010 (overall approximately 24 years and 9 months) | Heights were standardized with height standardized deviation scores (SDS) to enable height comparisons across ages and sexes using methods and height standards found at: http://www.cdc.gov/growthcharts/cdc\_charts.htm. NAH were calculated overall and by etiology groups for participants who had both a non-missing value available height z-score and a non-missing enrollment height (EH) SDS, as well as for participants with 3 or more years of GH therapy (GHT ≥3y). |
Participant flow
Pre-assignment details
All participants were assigned to a growth failure etiology group. Assignment was determined from etiology and medical history data and comments from all participant forms. Etiology groups were mutually exclusive. Participants with multiple etiologies were prioritized as follows: Turner, Renal, Other, Organic GHD, IGHD, ISS, and Undefined.
Participants by arm
| Arm | Count |
|---|---|
| Idiopathic Growth Hormone Deficiency (IGHD) Participants who meet any one of the following definitions: Documented IGHD; Undocumented IGHD; Presumed IGHD. | 27,286 |
| Organic GHD Participants with conditions that have a direct effect on the ability of the pituitary gland to modulate GH production, including craniopharyngioma, CNS tumors, CNS trauma, irradiation, septo-optic dysplasia, and effects of treatments given to participants with leukemia. Inclusion was determined by enrollment form etiology and medical history checkboxes coupled with examination of all participants text. | 9,356 |
| Idiopathic Short Stature (ISS) Participants must have had a stimulation result of \>/=10 ng/mL and/or other identifiable relevant medical text related to ISS. Participants without any identifiable criterion for assignation elsewhere, coupled with a stimulation result of \>/=10 ng/mL were assigned to this group. ISS participant may have been Documented ISS, Undocumented ISS, or Presumed ISS, based on text criteria and GH stimulation result of \>/=10 ng/mL. | 12,519 |
| Turner Syndrome Participants were assigned to this group, based on medical review of selected participants text, karyotype data, and medical history in cooperation with the NCGS medical advisor. | 5,651 |
| Renal Disease Participants with CRI or ESRD prior to transplantation as indicated by the CRI/ESRD checkbox on the current NCGS enrollment form or Chronic Renal Disease checkbox (RENAL) from older versions. A search for equivalent terminology in the medical text was also done. | 2,144 |
| Other Etiology The other group represents a heterogeneous mix of participants. Classification in this grouping was determined by examination of enrollment form etiology and medical history checkboxes coupled with examination of participant medical text for selected conditions. Participants with a variety of congenital and/or genetic syndromes, such as Noonan syndrome or Prader-Willi syndrome, were largely included in this classification. | 8,010 |
| Undefined Etiology A participants meeting none of the criteria above was classified as Undefined. These included participants with no medically relevant checkbox, no relevant medical text noted on the enrollment or follow-up forms, and no stimulation result available. | 239 |
| Total | 65,205 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 78 | 133 | 37 | 27 | 30 | 59 | 1 |
| Overall Study | Death | 2 | 7 | 0 | 0 | 1 | 3 | 0 |
| Overall Study | Lack of Efficacy | 249 | 122 | 202 | 105 | 45 | 228 | 5 |
| Overall Study | Participant Non-compliant | 2,140 | 567 | 1,067 | 353 | 136 | 543 | 18 |
| Overall Study | Reason not Specified | 111 | 49 | 53 | 21 | 11 | 40 | 2 |
| Overall Study | Reasons Other Than Above | 3,602 | 1,382 | 1,757 | 692 | 361 | 1,244 | 34 |
| Overall Study | Status Unknown (Or no final evaluation) | 11,959 | 3,948 | 5,646 | 2,170 | 1,106 | 3,546 | 108 |
| Overall Study | Withdrawal by Subject | 925 | 323 | 346 | 217 | 68 | 229 | 3 |
Baseline characteristics
| Characteristic | Idiopathic Growth Hormone Deficiency (IGHD) | Organic GHD | Idiopathic Short Stature (ISS) | Turner Syndrome | Renal Disease | Other Etiology | Undefined Etiology | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 11.6 years | 10.0 years | 11.8 years | 10.2 years | 10.2 years | 10.1 years | 10.7 years | 11.1 years |
| Gender Female | 6704 Participants | 3426 Participants | 3213 Participants | 5651 Participants | 630 Participants | 3017 Participants | 81 Participants | 22722 Participants |
| Gender Male | 20582 Participants | 5930 Participants | 9306 Participants | 0 Participants | 1514 Participants | 4993 Participants | 158 Participants | 42483 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 949 / 27,286 | 523 / 9,356 | 385 / 12,519 | 328 / 5,651 | 101 / 2,144 | 357 / 8,010 | 7 / 239 |
| serious Total, serious adverse events | 322 / 27,286 | 595 / 9,356 | 100 / 12,519 | 119 / 5,651 | 141 / 2,144 | 255 / 8,010 | 4 / 239 |
Outcome results
Primary
First Year Annualized Growth Rate
Annualized growth rates are expressed as centimeters per year (cm/yr), computed as the change in height (centimeters) divided by the change in age (years). Growth rates were calculated from the date of the first injection (baseline/ enrollment) to the visit closest to 365\*1 days after baseline. Visits within 90 days of 365\*1 days after baseline may be used. If multiple visits within 90 days were reported then the visit closest to 365\*1 days was used. Growth rates less than (\<) -1 or greater than (\>) 30 cm/yr were excluded. Growth rates from -1 to 0 were set to 0 cm/yr. Growth rates are summarized by etiology group and gender. Only those participants who had non-missing 1-year growth rate data were included in the analysis.
Time frame: Year 1
Population: Safety evaluable population. Here, 'N' (number of participants analyzed) signifies the number of participants evaluable for this outcome measure and 'Number Analyzed' signifies the number of participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idiopathic Growth Hormone Deficiency (IGHD) | First Year Annualized Growth Rate | Male | 9.5 cm/yr | Standard Deviation 2.7 |
| Idiopathic Growth Hormone Deficiency (IGHD) | First Year Annualized Growth Rate | Female | 9.8 cm/yr | Standard Deviation 3.2 |
| Organic GHD | First Year Annualized Growth Rate | Male | 10.3 cm/yr | Standard Deviation 4.1 |
| Organic GHD | First Year Annualized Growth Rate | Female | 11.0 cm/yr | Standard Deviation 4.8 |
| Idiopathic Short Stature (ISS) | First Year Annualized Growth Rate | Male | 8.6 cm/yr | Standard Deviation 2.2 |
| Idiopathic Short Stature (ISS) | First Year Annualized Growth Rate | Female | 8.7 cm/yr | Standard Deviation 2.5 |
| Turner Syndrome | First Year Annualized Growth Rate | Female | 8.0 cm/yr | Standard Deviation 2.2 |
| Renal Disease | First Year Annualized Growth Rate | Male | 8.9 cm/yr | Standard Deviation 3.6 |
| Renal Disease | First Year Annualized Growth Rate | Female | 8.4 cm/yr | Standard Deviation 3.4 |
| Other Etiology | First Year Annualized Growth Rate | Male | 9.5 cm/yr | Standard Deviation 3.5 |
| Other Etiology | First Year Annualized Growth Rate | Female | 9.4 cm/yr | Standard Deviation 3.8 |
| Undefined Etiology | First Year Annualized Growth Rate | Male | 9.8 cm/yr | Standard Deviation 4.3 |
| Undefined Etiology | First Year Annualized Growth Rate | Female | 9.1 cm/yr | Standard Deviation 2.5 |
Primary
Near Adult Height (NAH)
Heights were standardized with height standardized deviation scores (SDS) to enable height comparisons across ages and sexes using methods and height standards found at: http://www.cdc.gov/growthcharts/cdc\_charts.htm. NAH were calculated overall and by etiology groups for participants who had both a non-missing value available height z-score and a non-missing enrollment height (EH) SDS, as well as for participants with 3 or more years of GH therapy (GHT ≥3y).
Time frame: From October 1985 to June 2010 (overall approximately 24 years and 9 months)
Population: Safety evaluable population. Here, 'N' (number of participants analyzed) signifies the number of participants evaluable for this outcome measure and 'Number Analyzed' signifies the number of participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idiopathic Growth Hormone Deficiency (IGHD) | Near Adult Height (NAH) | NAH | -0.9 SDS | Standard Deviation 1.1 |
| Idiopathic Growth Hormone Deficiency (IGHD) | Near Adult Height (NAH) | EH | -2.5 SDS | Standard Deviation 1 |
| Idiopathic Growth Hormone Deficiency (IGHD) | Near Adult Height (NAH) | NAH GHT ≥3y | -0.8 SDS | Standard Deviation 1 |
| Idiopathic Growth Hormone Deficiency (IGHD) | Near Adult Height (NAH) | EH GHT ≥3y | -2.6 SDS | Standard Deviation 1 |
| Organic GHD | Near Adult Height (NAH) | EH GHT ≥3y | -2.5 SDS | Standard Deviation 1.4 |
| Organic GHD | Near Adult Height (NAH) | NAH GHT ≥3y | -1.0 SDS | Standard Deviation 1.4 |
| Organic GHD | Near Adult Height (NAH) | NAH | -1.1 SDS | Standard Deviation 1.4 |
| Organic GHD | Near Adult Height (NAH) | EH | -2.4 SDS | Standard Deviation 1.4 |
| Idiopathic Short Stature (ISS) | Near Adult Height (NAH) | NAH GHT ≥3y | -1.1 SDS | Standard Deviation 1 |
| Idiopathic Short Stature (ISS) | Near Adult Height (NAH) | EH | -2.7 SDS | Standard Deviation 0.8 |
| Idiopathic Short Stature (ISS) | Near Adult Height (NAH) | NAH | -1.2 SDS | Standard Deviation 1 |
| Idiopathic Short Stature (ISS) | Near Adult Height (NAH) | EH GHT ≥3y | -2.7 SDS | Standard Deviation 0.8 |
| Turner Syndrome | Near Adult Height (NAH) | NAH | -2.0 SDS | Standard Deviation 1 |
| Turner Syndrome | Near Adult Height (NAH) | EH | -3.1 SDS | Standard Deviation 0.9 |
| Turner Syndrome | Near Adult Height (NAH) | NAH GHT ≥3y | -1.9 SDS | Standard Deviation 1 |
| Turner Syndrome | Near Adult Height (NAH) | EH GHT ≥3y | -3.2 SDS | Standard Deviation 1 |
| Renal Disease | Near Adult Height (NAH) | NAH | -2.0 SDS | Standard Deviation 1.5 |
| Renal Disease | Near Adult Height (NAH) | EH GHT ≥3y | -3.1 SDS | Standard Deviation 1.2 |
| Renal Disease | Near Adult Height (NAH) | EH | -3.1 SDS | Standard Deviation 1.3 |
| Renal Disease | Near Adult Height (NAH) | NAH GHT ≥3y | -1.7 SDS | Standard Deviation 1.4 |
| Other Etiology | Near Adult Height (NAH) | EH | -2.9 SDS | Standard Deviation 1.4 |
| Other Etiology | Near Adult Height (NAH) | NAH | -1.5 SDS | Standard Deviation 1.3 |
| Other Etiology | Near Adult Height (NAH) | NAH GHT ≥3y | -1.5 SDS | Standard Deviation 1.3 |
| Other Etiology | Near Adult Height (NAH) | EH GHT ≥3y | -3.0 SDS | Standard Deviation 1.4 |
| Undefined Etiology | Near Adult Height (NAH) | NAH GHT ≥3y | -1.2 SDS | Standard Deviation 1.2 |
| Undefined Etiology | Near Adult Height (NAH) | NAH | -1.3 SDS | Standard Deviation 1.2 |
| Undefined Etiology | Near Adult Height (NAH) | EH | -3.0 SDS | Standard Deviation 1.7 |
| Undefined Etiology | Near Adult Height (NAH) | EH GHT ≥3y | -3.2 SDS | Standard Deviation 1.8 |
Primary
Number of Participants Who Died
Time frame: From October 1985 to June 2010 (overall approximately 24 years and 9 months)
Population: Safety evaluable population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idiopathic Growth Hormone Deficiency (IGHD) | Number of Participants Who Died | 14 participants |
| Organic GHD | Number of Participants Who Died | 96 participants |
| Idiopathic Short Stature (ISS) | Number of Participants Who Died | 4 participants |
| Turner Syndrome | Number of Participants Who Died | 7 participants |
| Renal Disease | Number of Participants Who Died | 23 participants |
| Other Etiology | Number of Participants Who Died | 38 participants |
| Undefined Etiology | Number of Participants Who Died | 1 participants |
Primary
Second Year Annualized Growth Rate
Annualized growth rates are expressed as cm/yr, computed as the change in height (centimeters) divided by the change in age (years). Growth rates were calculated from the date of the visit closest to 365 days after baseline to the visit closest to 730 days. Visits within 90 days of 365 and 730 days after baseline may be used. If multiple visits within 90 days were reported then the visit closest to 365 or 730 days was used. Growth rates \<-1 or \>30 cm/yr were excluded. Growth rates from -1 to 0 were set to 0 cm/yr. Growth rates are summarized by etiology group and gender. Only those participants who had non-missing second-year growth rate data were included in the analysis.
Time frame: Year 2
Population: Safety evaluable population. Here, 'N' (number of participants analyzed) signifies the number of participants evaluable for this outcome measure and 'Number Analyzed' signifies the number of participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idiopathic Growth Hormone Deficiency (IGHD) | Second Year Annualized Growth Rate | Male | 7.7 cm/yr | Standard Deviation 1.8 |
| Idiopathic Growth Hormone Deficiency (IGHD) | Second Year Annualized Growth Rate | Female | 8.0 cm/yr | Standard Deviation 2.2 |
| Organic GHD | Second Year Annualized Growth Rate | Male | 8.0 cm/yr | Standard Deviation 2.5 |
| Organic GHD | Second Year Annualized Growth Rate | Female | 8.2 cm/yr | Standard Deviation 2.8 |
| Idiopathic Short Stature (ISS) | Second Year Annualized Growth Rate | Female | 7.3 cm/yr | Standard Deviation 1.7 |
| Idiopathic Short Stature (ISS) | Second Year Annualized Growth Rate | Male | 7.3 cm/yr | Standard Deviation 1.6 |
| Turner Syndrome | Second Year Annualized Growth Rate | Female | 6.6 cm/yr | Standard Deviation 1.5 |
| Renal Disease | Second Year Annualized Growth Rate | Male | 7.2 cm/yr | Standard Deviation 2.4 |
| Renal Disease | Second Year Annualized Growth Rate | Female | 7.2 cm/yr | Standard Deviation 2.1 |
| Other Etiology | Second Year Annualized Growth Rate | Male | 7.5 cm/yr | Standard Deviation 2.2 |
| Other Etiology | Second Year Annualized Growth Rate | Female | 7.6 cm/yr | Standard Deviation 2.4 |
| Undefined Etiology | Second Year Annualized Growth Rate | Male | 7.7 cm/yr | Standard Deviation 2.4 |
| Undefined Etiology | Second Year Annualized Growth Rate | Female | 8.0 cm/yr | Standard Deviation 2.3 |
Primary
Third Year Annualized Growth Rate
Annualized growth rates are expressed as cm/yr, computed as the change in height (centimeters) divided by the change in age (years). Growth rates were calculated from the date of the visit closest to 730 days after baseline to the visit closest to 1095 days. Visits within 90 days of 730 and 1095 days after baseline may be used. If multiple visits within 90 days were reported then the visit closest to 730 or 1095 days was used. Growth rates \<-1 or \>30 cm/yr were excluded. Growth rates from -1 to 0 were set to 0 cm/yr. Growth rates are summarized by etiology group and gender. Only those participants who had non-missing third-year growth rate data were included in the analysis.
Time frame: Year 3
Population: Safety evaluable population. Here, 'N' (number of participants analyzed) signifies the number of participants evaluable for this outcome measure and 'Number Analyzed' signifies the number of participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idiopathic Growth Hormone Deficiency (IGHD) | Third Year Annualized Growth Rate | Male | 7.0 cm/yr | Standard Deviation 1.7 |
| Idiopathic Growth Hormone Deficiency (IGHD) | Third Year Annualized Growth Rate | Female | 7.1 cm/yr | Standard Deviation 1.7 |
| Organic GHD | Third Year Annualized Growth Rate | Male | 7.1 cm/yr | Standard Deviation 2.2 |
| Organic GHD | Third Year Annualized Growth Rate | Female | 7.2 cm/yr | Standard Deviation 2.3 |
| Idiopathic Short Stature (ISS) | Third Year Annualized Growth Rate | Male | 6.6 cm/yr | Standard Deviation 1.6 |
| Idiopathic Short Stature (ISS) | Third Year Annualized Growth Rate | Female | 6.7 cm/yr | Standard Deviation 1.7 |
| Turner Syndrome | Third Year Annualized Growth Rate | Female | 5.9 cm/yr | Standard Deviation 1.5 |
| Renal Disease | Third Year Annualized Growth Rate | Male | 6.2 cm/yr | Standard Deviation 2.4 |
| Renal Disease | Third Year Annualized Growth Rate | Female | 6.1 cm/yr | Standard Deviation 2.2 |
| Other Etiology | Third Year Annualized Growth Rate | Male | 6.8 cm/yr | Standard Deviation 1.9 |
| Other Etiology | Third Year Annualized Growth Rate | Female | 6.8 cm/yr | Standard Deviation 1.9 |
| Undefined Etiology | Third Year Annualized Growth Rate | Male | 6.5 cm/yr | Standard Deviation 1.7 |
| Undefined Etiology | Third Year Annualized Growth Rate | Female | 6.3 cm/yr | Standard Deviation 2.6 |