Children Born With Serious Intra-uterine Growth Retardation
Conditions
Keywords
Intra-uterine growth retardation (IUGR), Saizen, Recombinant human growth hormone (r-hGH), Final height, Bone age, SGA (Small for Gestational Age)
Brief summary
Study of safety of Saizen® in children born with serious intra-uterine growth retardation (IUGR) treated to final height. An open, phase III study involving 17 centers in France. The study enrolled children who have completed 3 or 2 years of treatment and at least one year of post treatment observation in the Sponsor Studies GF 4001 (Safety and Efficacy of Saizen in the Treatment of Young Children Born with Severe IUGR) or GF 6283 (Effect of Intermittent versus Continuous Saizen Therapy in Young Children Born with Severe IUGR), respectively. Detailed description: Serious IUGR is a syndrome characterized by low birth length and weight for gestational age (less than 10 percentile). The secretion of growth hormone in response to provocative stimuli (e.g. arginine, insulin) is normal in these children. Apart from low birth weight, children born with IUGR may have minor or major malformations. A catch-up period with a supraphysiological growth velocity generally occurs during the first 6 to 24 months of life in 80 to 90 percent (%) of these children. This generally allows them to reach normal height. That means that conversely, approximately 10 to 20% of children do maintain a statural handicap. Puberty occurs at a normal age and the retardation in bone maturation present during the first years of life disappears very quickly. This leads to short adult stature in subjects who have not shown spontaneous catch-up during the first years of life. A safe and effective means of promoting growth without accelerating the timing or tempo of puberty would therefore be desirable.
Interventions
DRUGSaizen® A
Continuous or intermittent treatment with recombinant human Growth Hormone (r-hGH) 0.067 milligram/kilogram/day (mg/kg/day) subcutaneously (sc).
DRUGSaizen® B
Observed until the first signs of puberty and then continuous treatment with r-hGH 0.067 mg/kg/day sc or observed without treatment.
OTHERObservation only
Subjects were only observed.
Sponsors
Merck Serono S.A., Geneva
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Previous inclusion, good compliance and normal completion of GF4001 or GF6283 in the treatment of growth failure in children born with serious IUGR (3-year continuous r-hGH treatment in GF4001 or 2-year continuous or intermittent r-hGH treatment in GF6283). * Increase in height greater than 0.5 standard deviation (SD) during the first 2 years of r-hGH treatment in GF4001 or after 2 years of continuous or intermittent r-hGH treatment in GF6283. * A written Informed Consent at the beginning of the pre-study visit must be obtained from the parent(s)/legal guardian(s), with the understanding that consent may be withdrawn by the subject or parents at any time without prejudice to their future medical care. Children able to understand the trial should personally sign and date the written informed consent, too. * Other protocol-defined inclusion criteria may apply.
Exclusion criteria
* Known multiple malformation syndrome with severe psychomotor retardation and/or body hemihypertrophy. * Severe psychomotor retardation. * Severe congenital malformations. * Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Final Height | One year after final height was attained up to 10.6 years | Final height was defined as the height reached 1 year after height velocity (HV) was less than 2 centimeter/year (cm/year). Height velocity was the change in height since the previous year's measurement. Height was measured with a wall-mounted stadiometer (or in supine position if the participant's age was less than 3 years) and the measurement was repeated thrice by the same observer. The mean of the values obtained in the repeated measurements was taken for the analysis. |
| Height Standard Deviation Score (HSDS) | One year after final height was attained up to 10.6 years | HSDS was calculated as height minus reference mean height divided by SD of the reference mean height, both given by the reference growth table (Sempe) for the corresponding chronological age at the height measurement. Greater HSDS indicate greater height. (Sempe M et al., 1979) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parental Adjusted Height Standard Deviation Score (PAHSDS) | One year after final height was attained up to 10.6 years | PAHSDS is the distance between the participant's current and target heights, expressed in units of SD of the height distribution of the reference population. Target height is a measure of the height which the participant could hypothetically reach based only on his parents' heights. Target height standard deviation score (THSDS) was calculated as target height minus mean adult height of the reference population divided by SD of the mean adult height of the reference population. |
Participant flow
Recruitment details
Participants who completed 3 or 2 years treatment and at least 1 year post treatment observation in Sponsor Studies GF 4001 (Safety and Efficacy of Saizen in the Treatment of Young Children Born with Severe IUGR) or GF 6283 (Effect of Intermittent versus Continuous Saizen Therapy in Young Children Born with Severe IUGR), respectively were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Non-Final Height: Not Treated Includes all participants who did not achieve the final height during the study period and did not receive r-hGH 0.067 mg/kg/day sc either continuously or intermittently. | 10 |
| Non-Final Height: Treated Includes all participants who did not achieve the final height during the study period and received r-hGH 0.067 mg/kg/day sc either continuously or intermittently. | 13 |
| Final Height: Not Treated Includes all participants who achieved the final height during the study period and did not receive r-hGH 0.067 mg/kg/day sc either continuously or intermittently. | 22 |
| Final Height: Treated Includes all participants who achieved the final height during the study period and received r-hGH 0.067 mg/kg/day sc either continuously or intermittently. | 46 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 5 | 2 | 1 | 4 | 3 |
| Overall Study | Non-compliance | 0 | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Other | 4 | 2 | 0 | 2 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 2 | 0 | 4 | 1 | 3 |
Baseline characteristics
| Characteristic | Total | Final Height: Treated | Final Height: Not Treated | Non-Final Height: Not Treated | Non-Final Height: Treated |
|---|---|---|---|---|---|
| Age Continuous | 10.3 years STANDARD_DEVIATION 3 | 9.5 years STANDARD_DEVIATION 2.6 | 12.5 years STANDARD_DEVIATION 3.1 | 10.6 years STANDARD_DEVIATION 3 | 9.2 years STANDARD_DEVIATION 2.4 |
| Birth Height | 42.8 cm STANDARD_DEVIATION 3.7 | 42.3 cm STANDARD_DEVIATION 3.5 | 44.8 cm STANDARD_DEVIATION 3.4 | 41.8 cm STANDARD_DEVIATION 4.3 | 42.2 cm STANDARD_DEVIATION 3.5 |
| Birth Weight | 2085.3 g STANDARD_DEVIATION 551.8 | 2030.9 g STANDARD_DEVIATION 573.4 | 2312 g STANDARD_DEVIATION 451.1 | 1848 g STANDARD_DEVIATION 601.2 | 2076.9 g STANDARD_DEVIATION 520.9 |
| Length of Gestation | 37.9 weeks STANDARD_DEVIATION 2.6 | 37.9 weeks STANDARD_DEVIATION 2.8 | 38.9 weeks STANDARD_DEVIATION 1.5 | 37 weeks STANDARD_DEVIATION 2.9 | 37.3 weeks STANDARD_DEVIATION 2.6 |
| Original Study GF4001 | 52 participants | 22 participants | 18 participants | 6 participants | 6 participants |
| Original Study GF6283 | 39 participants | 24 participants | 4 participants | 4 participants | 7 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 0 participants | 0 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Black | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 88 participants | 45 participants | 22 participants | 8 participants | 13 participants |
| Sex: Female, Male Female | 41 Participants | 21 Participants | 10 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 50 Participants | 25 Participants | 12 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 32 | 52 / 59 |
| serious Total, serious adverse events | 1 / 32 | 13 / 59 |
Outcome results
Primary
Final Height
Final height was defined as the height reached 1 year after height velocity (HV) was less than 2 centimeter/year (cm/year). Height velocity was the change in height since the previous year's measurement. Height was measured with a wall-mounted stadiometer (or in supine position if the participant's age was less than 3 years) and the measurement was repeated thrice by the same observer. The mean of the values obtained in the repeated measurements was taken for the analysis.
Time frame: One year after final height was attained up to 10.6 years
Population: Intention-to-treat (ITT) population included all participants enrolled in this study. Safety population was identical in this study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Non-Final Height: Not Treated | Final Height | 145.90 cm | Standard Deviation 16.08 |
| Non-Final Height: Treated | Final Height | 150.06 cm | Standard Deviation 12.89 |
| Final Height: Not Treated | Final Height | 153.27 cm | Standard Deviation 8.71 |
| Final Height: Treated | Final Height | 155.59 cm | Standard Deviation 8.38 |
Primary
Height Standard Deviation Score (HSDS)
HSDS was calculated as height minus reference mean height divided by SD of the reference mean height, both given by the reference growth table (Sempe) for the corresponding chronological age at the height measurement. Greater HSDS indicate greater height. (Sempe M et al., 1979)
Time frame: One year after final height was attained up to 10.6 years
Population: ITT population included all participants enrolled in this study. Safety population was identical in this study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Non-Final Height: Not Treated | Height Standard Deviation Score (HSDS) | -1.45 standard deviation score | Standard Deviation 0.76 |
| Non-Final Height: Treated | Height Standard Deviation Score (HSDS) | -1.90 standard deviation score | Standard Deviation 1.73 |
| Final Height: Not Treated | Height Standard Deviation Score (HSDS) | -2.33 standard deviation score | Standard Deviation 1.01 |
| Final Height: Treated | Height Standard Deviation Score (HSDS) | -1.99 standard deviation score | Standard Deviation 0.88 |
Secondary
Parental Adjusted Height Standard Deviation Score (PAHSDS)
PAHSDS is the distance between the participant's current and target heights, expressed in units of SD of the height distribution of the reference population. Target height is a measure of the height which the participant could hypothetically reach based only on his parents' heights. Target height standard deviation score (THSDS) was calculated as target height minus mean adult height of the reference population divided by SD of the mean adult height of the reference population.
Time frame: One year after final height was attained up to 10.6 years
Population: ITT population included all participants enrolled in this study. Safety population was identical in this study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Non-Final Height: Not Treated | Parental Adjusted Height Standard Deviation Score (PAHSDS) | -0.82 standard deviation score | Standard Deviation 0.59 |
| Non-Final Height: Treated | Parental Adjusted Height Standard Deviation Score (PAHSDS) | -1.52 standard deviation score | Standard Deviation 1.92 |
| Final Height: Not Treated | Parental Adjusted Height Standard Deviation Score (PAHSDS) | -1.64 standard deviation score | Standard Deviation 1.61 |
| Final Height: Treated | Parental Adjusted Height Standard Deviation Score (PAHSDS) | -1.24 standard deviation score | Standard Deviation 1.39 |
Post Hoc
Duration of Participation in the Study
Time frame: Up to 10.6 years
Population: ITT population included all participants enrolled in this study. Safety population was identical in this study. Here, 'N' (number of participants analyzed) signifies those participants who were evaluated for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Non-Final Height: Not Treated | Duration of Participation in the Study | 2.08 years | Standard Deviation 2.27 |
| Non-Final Height: Treated | Duration of Participation in the Study | 5.29 years | Standard Deviation 2.89 |
| Final Height: Not Treated | Duration of Participation in the Study | 4.10 years | Standard Deviation 2.87 |
| Final Height: Treated | Duration of Participation in the Study | 7.02 years | Standard Deviation 2.06 |
Post Hoc
Duration of Treatment
Time frame: Up to 10.6 years
Population: ITT population included all participants enrolled in this study. Safety population was identical in this study. Here, 'N' (number of participants analyzed) signifies those participants who were treated and hence, were evaluated for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Non-Final Height: Not Treated | Duration of Treatment | 4.09 years | Standard Deviation 2.92 |
| Non-Final Height: Treated | Duration of Treatment | 4.51 years | Standard Deviation 2.2 |