Acts PEdiatr Scand [Suppl] 367: 44-48, 1990
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Biosynthetic Human Growth Hormone in the Treatment of Growth Hormone Deficiency J.H. HOLCOMBE, P.M. CONFORTI, A.C. WONG, R.G. THOMPSON and M.W. DRAPER From rhe Lilly Research Laboratories, Indianapolis, USA
ABSTRACT. Holcombe, J.H., Conforti, P.M., Wong, A.C., Thompson, R.G. and Draper, M. W. (Lilly Research Laboratories, Indianapolis, USA). Biosynthetic human growth hormone in the treatment of growth hormone deficiency. Acta Paediatr Scand [Suppl] 367: 44,1990.
A total of 309 previously untreated children with growth hormone deficiency (GHD) (219 boys, 90 girls; mean age 8.4 f 3.9 years, range 1.5-19 years) were treated for up to 3 years in an ongoing trial designed to examine the long-term efficacy and safety of biosynthetic somatropin (rhGH). The children were treated with rhGH, 0.06 mglkg (0.16 IUlkg) three times weekly. In the prepubertal children, the mean height velocity increased during the first year from 3.8 f 1.8 cmlyear to 8.9 2.2 cm/year (n = 188). During the second and third years, their height velocities were 7.1 f 1.1 (n = 147) and 6.3 f 1.2 cm/year (n = 64), respectively. The height velocity SDS increased from -2.5 f 1.9 before treatment to 3.1 f 2.6 during the first year of treatment in the
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prepubertal children. The mean pretreatment height velociity in those with idiopathic GHD (3.8 f 1.6 cmlyear) did not differ from that in children with organic GHD (3.8 f 2.3 cmlyear). In addition, the height velocities during the first year of therapy did not differ significantly with respect to the aetiology of GHD. For the children who entered puberty during the study, the mean height velocity increased from 3.0 f 1.7 cmlyear before treatment to 8.4 f 2.3 cmlyear during the first year of rhGH therapy. In the fi ra year, the height velocity of children with a bone age of less than 5 years (9.4 2.3 cmlyear) was significantly greater than that in children with a bone age of 5-10 years (8.4 1.8 cmlyear) or greater than 10 years (7.8 2.2 cmlyear: p = 0.001). However, the increase in height velocity above the pretreatment level did not differ between bone age groups ( p = 0.13). During the study, the height SDS improved from -3.4 f 1.4 before treatment to -2.1 1.1 by the end of year 3. At the start of rhGH therapy, only 38 out of 309 (12.3%) children had heights above -2 SD, but by the end of the 3 years, 44 out of 99 children (44.4%) had heights above that level. Antibodies to GH were detected in 8 out of 304 children (2.6%), but none of these children showed attenuated growth as a result. The results of this ongoing study confirm that rhGH is a safe and effective therapy in children with GHD. Key words: Somatropin, recombinant human growth hormone, growth hormone deficiency, linear growth.
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Human growth hormone (hGH) has been used in the treatment of growth hormone deficiency (GHD) for over 30 years (1). However, investigations into optimal dose regimens, new indications and long-term efficacy were restricted before recombinant DNA technology provided a potentially unlimited supply of biosynthetic hGH (rhGH) for such studies. The results of an interim analysis of an ongoing, long-term, clinical trial of rhGH in children with GHD are presented here. PATIENTS AND METHODS The study comprised 309 prepubertal, otherwise healthy, GH-deficient children (2 19 boys, 90 girls) who had never previously been treated with GH, and who had either isolated endogenous GHD (n = 226) or multiple pituitary hormone deficiencies (n = 83), but who were on appropriate hormone replacement therapy. The aetiologies of GHD were separated into idiopathic (n = 228) or organic causes (n = 81), with organic causes including postoperative (n = 19). radiation-induced (n = 20), tumour (n = 16), or other (n = 26) causes. All children had classic GHD, defined by a peak serum GH level below 10 ng/ml in response to at least two standard provocative tests, and an abnormal height velocity during pre-study evaluation (either < 4 cmlyear, or < 6 cm/year and < 3rd centile for chronological age). The protocol was approved by the Institutional Review Board of each participating institution, and written informed consent was obtained from the patients and/or their parents before enrolment into the study. Sera for measurement of insulin-like growth factor I (IGF-I) and antibodies to Escherichia coli peptide (ECP) and hGH were obtained. Therapy with rhGH, 0.06 mg/kg/dose i.m. (potency of rhGH: 1 mg = 2.6 IU,
Treatment of GHD
Acta Paediatr Scand [Suppl] 367
10 l1
L
Before treatment
Year 1
Year 2 Treatment year
Year 3
Fig. I. Height velocities of prepubertal children with GHD (grouped according to aetiology) before and during treatment with rhGH. The open bars represent idiopathic GHD, and the solid bars represent organic GHD. The error bar indicates SD. Figures in parentheses represent n values. compared with WHO human reference standard 80/505 in a rat tibia1 assay), three time weekly, was initiated. The route of administration was changed to the subcutaneous route during the second year of the study. Patients were monitored 1 month after the start of treatment and thereafter at 3-month intervals. Bone age (BA) was determined annually by the method of Greulich and Pyle (2). NCHS standards were used to calculate SDS scores (3). Stutisticul analysis. The unpaired and paired t-tests were used to compare inter- and intra-group differences, respectively. Height velocities of patients grouped according to BA or according to the aetiology of GHD were compared using a one-way analysis of variance.
RESULTS The height velocities for prepubertal children (girls, aged 3-1 1 years; boys, aged 3-13 years) are shown in Figure 1. There was no significant difference in the height velocities with respect to the aetiology of GHD (idiopathic versus organic, p > 0.05) at any time. The height velocity SDS (based on chronological age) before and during rhGH therapy are shown in Table 1. During the first year of therapy, there was a striking increase in height velocity; during the ensuing two years it decreased but remained positive, indicating continued catch-up growth. A total of 90 children entered puberty (defined as Tanner stage 2 2 on two consecutive visits) during the study, of whom 29 were treated with rhGH for 3 years (Table 2). The pubertal children with organic GHD had a significantly lower pretreatment height velocity 1.4 versus 3.5 k 1.6 cm/year, p < 0.001), but than those with idiopathic GHD (2.2
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Table 1. Height velocity and SDS in prepubertal children with GHD before and during therapy with rhGH. Year
Idiopathic GHD Height velocity (cm/year)
Pretreatment 1
2 3
3.8 8.9 7.1 6.3
f f f f
1.6 2.1 1.4 1.2
SDS
-2.4 3.1 1.3 0.5
f f f f
Organic GHD Number of patients
1.7 2.5 1.8 1.5
143 129 109 50
Height velocity (cmlyear) 3.8 8.9 7.0 6.5
f f f f
2.3 2.6 1.4 1.4
SDS
-2.6 2.8 1.1 0.9
f 2.6 f 2.8 f 1.8 f 1.9
Number of patients
45 41 38 14
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46
J.H. Holcombe et al.
Acta Paediatr Scand [Suppl] 367
Table 2. Height velocity in pubertal GH-deficient children before and during therapy with rhGH. Year
Pretreatment 1 2 3 *p
Idiopathic GHD Height velocity Number of (cdyear) patients 3.5 8.6 7.4 7.4
f f f f
1.6* 2.1 1.6 1.7
58 58 50 23
Organic GHD Height velocity Number of (cm/ year) patients 2.2 8.3 7.7 1.0
f 1.4 f 2.7 f 2.4 f 2.0
32 32 28 6
< 0.001 versus organic GHD.
during rhGH therapy the height velocities did not differ between diagnostic groups. The mean height velocity of children with a BA of less than 5 years at the start of treatment increased from 3.9 f 1.9 cm/year to 9.4 f 2.3 cm/year ( p
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Biosynthetic Human Growth Hormone in the Treatment of Growth Hormone Deficiency J.H. HOLCOMBE, P.M. CONFORTI, A.C. WONG, R.G. THOMPSON and M.W. DRAPER From rhe Lilly Research Laboratories, Indianapolis, USA
ABSTRACT. Holcombe, J.H., Conforti, P.M., Wong, A.C., Thompson, R.G. and Draper, M. W. (Lilly Research Laboratories, Indianapolis, USA). Biosynthetic human growth hormone in the treatment of growth hormone deficiency. Acta Paediatr Scand [Suppl] 367: 44,1990.
A total of 309 previously untreated children with growth hormone deficiency (GHD) (219 boys, 90 girls; mean age 8.4 f 3.9 years, range 1.5-19 years) were treated for up to 3 years in an ongoing trial designed to examine the long-term efficacy and safety of biosynthetic somatropin (rhGH). The children were treated with rhGH, 0.06 mglkg (0.16 IUlkg) three times weekly. In the prepubertal children, the mean height velocity increased during the first year from 3.8 f 1.8 cmlyear to 8.9 2.2 cm/year (n = 188). During the second and third years, their height velocities were 7.1 f 1.1 (n = 147) and 6.3 f 1.2 cm/year (n = 64), respectively. The height velocity SDS increased from -2.5 f 1.9 before treatment to 3.1 f 2.6 during the first year of treatment in the
+
prepubertal children. The mean pretreatment height velociity in those with idiopathic GHD (3.8 f 1.6 cmlyear) did not differ from that in children with organic GHD (3.8 f 2.3 cmlyear). In addition, the height velocities during the first year of therapy did not differ significantly with respect to the aetiology of GHD. For the children who entered puberty during the study, the mean height velocity increased from 3.0 f 1.7 cmlyear before treatment to 8.4 f 2.3 cmlyear during the first year of rhGH therapy. In the fi ra year, the height velocity of children with a bone age of less than 5 years (9.4 2.3 cmlyear) was significantly greater than that in children with a bone age of 5-10 years (8.4 1.8 cmlyear) or greater than 10 years (7.8 2.2 cmlyear: p = 0.001). However, the increase in height velocity above the pretreatment level did not differ between bone age groups ( p = 0.13). During the study, the height SDS improved from -3.4 f 1.4 before treatment to -2.1 1.1 by the end of year 3. At the start of rhGH therapy, only 38 out of 309 (12.3%) children had heights above -2 SD, but by the end of the 3 years, 44 out of 99 children (44.4%) had heights above that level. Antibodies to GH were detected in 8 out of 304 children (2.6%), but none of these children showed attenuated growth as a result. The results of this ongoing study confirm that rhGH is a safe and effective therapy in children with GHD. Key words: Somatropin, recombinant human growth hormone, growth hormone deficiency, linear growth.
*
*
*
*
Human growth hormone (hGH) has been used in the treatment of growth hormone deficiency (GHD) for over 30 years (1). However, investigations into optimal dose regimens, new indications and long-term efficacy were restricted before recombinant DNA technology provided a potentially unlimited supply of biosynthetic hGH (rhGH) for such studies. The results of an interim analysis of an ongoing, long-term, clinical trial of rhGH in children with GHD are presented here. PATIENTS AND METHODS The study comprised 309 prepubertal, otherwise healthy, GH-deficient children (2 19 boys, 90 girls) who had never previously been treated with GH, and who had either isolated endogenous GHD (n = 226) or multiple pituitary hormone deficiencies (n = 83), but who were on appropriate hormone replacement therapy. The aetiologies of GHD were separated into idiopathic (n = 228) or organic causes (n = 81), with organic causes including postoperative (n = 19). radiation-induced (n = 20), tumour (n = 16), or other (n = 26) causes. All children had classic GHD, defined by a peak serum GH level below 10 ng/ml in response to at least two standard provocative tests, and an abnormal height velocity during pre-study evaluation (either < 4 cmlyear, or < 6 cm/year and < 3rd centile for chronological age). The protocol was approved by the Institutional Review Board of each participating institution, and written informed consent was obtained from the patients and/or their parents before enrolment into the study. Sera for measurement of insulin-like growth factor I (IGF-I) and antibodies to Escherichia coli peptide (ECP) and hGH were obtained. Therapy with rhGH, 0.06 mg/kg/dose i.m. (potency of rhGH: 1 mg = 2.6 IU,
Treatment of GHD
Acta Paediatr Scand [Suppl] 367
10 l1
L
Before treatment
Year 1
Year 2 Treatment year
Year 3
Fig. I. Height velocities of prepubertal children with GHD (grouped according to aetiology) before and during treatment with rhGH. The open bars represent idiopathic GHD, and the solid bars represent organic GHD. The error bar indicates SD. Figures in parentheses represent n values. compared with WHO human reference standard 80/505 in a rat tibia1 assay), three time weekly, was initiated. The route of administration was changed to the subcutaneous route during the second year of the study. Patients were monitored 1 month after the start of treatment and thereafter at 3-month intervals. Bone age (BA) was determined annually by the method of Greulich and Pyle (2). NCHS standards were used to calculate SDS scores (3). Stutisticul analysis. The unpaired and paired t-tests were used to compare inter- and intra-group differences, respectively. Height velocities of patients grouped according to BA or according to the aetiology of GHD were compared using a one-way analysis of variance.
RESULTS The height velocities for prepubertal children (girls, aged 3-1 1 years; boys, aged 3-13 years) are shown in Figure 1. There was no significant difference in the height velocities with respect to the aetiology of GHD (idiopathic versus organic, p > 0.05) at any time. The height velocity SDS (based on chronological age) before and during rhGH therapy are shown in Table 1. During the first year of therapy, there was a striking increase in height velocity; during the ensuing two years it decreased but remained positive, indicating continued catch-up growth. A total of 90 children entered puberty (defined as Tanner stage 2 2 on two consecutive visits) during the study, of whom 29 were treated with rhGH for 3 years (Table 2). The pubertal children with organic GHD had a significantly lower pretreatment height velocity 1.4 versus 3.5 k 1.6 cm/year, p < 0.001), but than those with idiopathic GHD (2.2
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Table 1. Height velocity and SDS in prepubertal children with GHD before and during therapy with rhGH. Year
Idiopathic GHD Height velocity (cm/year)
Pretreatment 1
2 3
3.8 8.9 7.1 6.3
f f f f
1.6 2.1 1.4 1.2
SDS
-2.4 3.1 1.3 0.5
f f f f
Organic GHD Number of patients
1.7 2.5 1.8 1.5
143 129 109 50
Height velocity (cmlyear) 3.8 8.9 7.0 6.5
f f f f
2.3 2.6 1.4 1.4
SDS
-2.6 2.8 1.1 0.9
f 2.6 f 2.8 f 1.8 f 1.9
Number of patients
45 41 38 14
45
46
J.H. Holcombe et al.
Acta Paediatr Scand [Suppl] 367
Table 2. Height velocity in pubertal GH-deficient children before and during therapy with rhGH. Year
Pretreatment 1 2 3 *p
Idiopathic GHD Height velocity Number of (cdyear) patients 3.5 8.6 7.4 7.4
f f f f
1.6* 2.1 1.6 1.7
58 58 50 23
Organic GHD Height velocity Number of (cm/ year) patients 2.2 8.3 7.7 1.0
f 1.4 f 2.7 f 2.4 f 2.0
32 32 28 6
< 0.001 versus organic GHD.
during rhGH therapy the height velocities did not differ between diagnostic groups. The mean height velocity of children with a BA of less than 5 years at the start of treatment increased from 3.9 f 1.9 cm/year to 9.4 f 2.3 cm/year ( p
