Potential for Optimization of Growth Hormone Treatment in Children with Growth Hormone Deficiency, Small for Gestational Age, and Turner Syndrome in Germany: Data from the PATRO^® Children Study

Abstract

Introduction

Growth hormone (GH) treatment in children with growth hormone deficiency (GHD), short children born small for gestational age (SGA), and Turner syndrome (TS) is well established. However, a variety of parameters are still under discussion to achieve optimal growth results and efficiency of GH use in real-world treatment.

Methods

German GH-treatment naïve patients of the PATRO Children database were grouped according to their start of treatment into groups of 3 years from 2007 to 2018. Time trends in age, gender, GH dose, height standard deviation score (SDS), first-year growth response, and Index of Responsiveness (IoR) were investigated in children with GHD, short children born SGA, and TS starting GH treatment in the German patient population of the PATRO Children database from 2007 to 2018 to determine specific parameters for GH treatment optimization.

Results

All patient groups started GH treatment at a relatively high chronological age (2007–2009: GHD 8.33 ± 3.19, SGA 7.32 ± 2.52, TS 8.65 ± 4.39) with a slight but not significant trend towards younger therapy start up to 2016–2018 (GHD 8.04 ± 3.36, SGA 6.67 ± 2.65, TS 7.85 ± 3.38). In the GHD and SGA groups, female patients were underrepresented compared to male patients (GHD 32.3%, SGA 43.6%) with no significant change over the 4 time periods. Patients with GHD started GH treatment at a low dose (0.026 mg/kg/day). In SGA and TS patients, GH therapy was started below the registered dose recommendation (30.0 μg/kg/day and 33.7 μg/kg/day, respectively). In the first year of treatment, the mean GH dose was increased moderately (GHD: 30.7, SGA: 35.7, TS: 40.8 μg/kg/day). There was no significant change of GH dosing over time from 2007 to 2018. The IoR was comparable between time-groups for all 3 diagnoses.

Discussion

This study shows potential for improvement of GH treatment results in GHD, SGA, and TS patients in terms of early dose adjustment and younger age at the start of treatment. This is in accordance with important parameters used in prediction models.

Introduction

Since the approval of the first recombinant human growth hormone (GH) in the late 1980s, a large amount of data has been collected from randomized controlled trials as well as from observational studies resulting in several treatment guidelines [1–4]. The aim of all observations was to show the efficacy and safety of a number of GH products that were used in the treatment of several pediatric indications, including growth hormone deficiency (GHD), Turner syndrome (TS), and short children born small for gestational age (SGA) [1, 4–7]. The biosimilar recombinant human GH (Omnitrope^®, Sandoz GmbH, Kundl, Austria) was the first medicine to be approved via the EMA biosimilar approval pathway in 2006, which was followed by the start of the post-marketing surveillance (PMS) to monitor the long-term safety and efficacy of Omnitrope^® in infants, children, and adolescents (PATRO Children) in several countries [8]. Long-term data over more than 10 years of treatment from PATRO Children indicate that the biosimilar GH is well tolerated and effective in real-world clinical practice [9].

The modalities for the treatment with GH vary between countries [10], and there is an ongoing discussion about optimal individual GH dosing [11]. The comparison of treatment strategies between countries is difficult not least because of different registered dose recommendations [12] and divergent national as well as local reimbursement strategies. Treatment with GH is still expensive and strategies to optimize treatment success as well as cost effectiveness are not well established.

Several observations from large international databases were published recently trying to compare national treatment outcomes and strategies of GH treatment [12–14] but without the comparison on treatment strategies comparing GH and treatment with biosimilar GH. Therefore, a national analysis with an underlying homogeneous prescribing and reimbursement background over the years can help to get detailed information on current treatment strategies with biosimilar GH.

Treatment guidelines suggest that for an optimal growth response, GH should be initiated as early as possible after diagnosis [1, 5, 15, 16]. Individual GH dosing should be based on the dose recommendation and the individual growth response [1, 5]. Higher doses may be advisable in some children born SGA who are very short at treatment start [17].

For the GH treatment of short children with GHD, SGA, and TS prediction models are available [16, 18–20]. These models indicate that optimizing validated key parameters can improve treatment success. An optimized treatment approach with respect to treatment start and ongoing dose optimization could help to improve cost effectiveness [21, 22]. Growth prediction models indicate that the first-year growth response is inversely correlated with chronological age at start of treatment. Furthermore, it could be shown that first-year growth response is positively correlated with weekly GH dose [15, 18]. Prediction models are used to calculate the Index of Responsiveness (IoR). By comparing the actually observed and the predicted growth response to GH, the IoR reflects the ability of an individual to respond to GH (responsiveness). The IoR may therefore be used to adapt GH treatment at an early stage of GH treatment. The aim of this analysis is to describe the development of biosimilar GH treatment use in children and adolescents over the last 12 years in Germany and to identify areas of potential improvement of efficacy.

Materials and Methods

PATRO Children is a PMS to monitor the long-term safety and efficacy of Omnitrope^® in infants, children, and adolescents. The study design was described elsewhere [8]. This multicenter, open, longitudinal, non-interventional study was conducted in children’s hospitals and specialized endocrinology clinics across various countries in which Omnitrope^® has been approved. The study started in 2007 in Germany and was closed in 2020 after reaching the relevant patient numbers according to the risk management plan.

Patient Population

Eligible patients were infants, children, and adolescents (male or female) who were receiving treatment with Omnitrope^®. Written informed consent was obtained from parents and – where appropriate – from patients prior to inclusion in the database. All diagnoses were made by investigators. The current analysis includes naïve children with GHD, SGA, and TS who were treated between 2007 and 2018 in Germany. All patients were prepubertal at treatment start. Patients treated for less than 1 year were excluded from analysis. For the analysis of changes of relevant treatment parameters over time patients were grouped in 4 groups of 3 years each according to the year of start of GH treatment: 2007–2009, 2010–2012, 2013–2015, and 2016–2018. A total of 1,144 patients with GHD, 459 patients with SGA, and 115 patients with TS were available for analysis. The following karyotypes for TS were included (naïve, prepubertal): complete absence of one X-chromosome (45,X; n = 30), mosaicism (45,X/46,XX; n = 32), partial absence of one X-chromosome (X, p, d; n = 6), structural aberrations (X,r; n = 4); other (n = 34), and missing (n = 9, karyotype not documented in database, diagnosis confirmed by treating physician). TS patients with karyotypes 45,X and 45,X/46,XX mosaicism were analyzed in detail.

Treatment and Visits

The patients were treated with approved formulations of Omnitrope^® in Germany. The frequency of visits was at the discretion of the treating physician; no additional or specific visits, tests, or assessments were required as part of the study.

Objectives

The primary objective of this PMS was to collect and analyze the long-term safety of Omnitrope^®, and the results were published elsewhere [9]. The current analysis focused on the secondary objective to investigate the efficacy of treatment. A statistical analysis plan specifically described analyses to investigate trends in age at start of therapy, in GH dose and dose adjustment, and in IoR in GHD, SGA, and TS patients and their influence on effectiveness.

Data Collection

Patient data were entered into an electronic case report form (CRF) at each routine visit. Electronic CRFs were reviewed and signed by the responsible physician or any of his/her authorized delegates. The CRFs were reviewed by data management and onsite monitoring was performed by a contract research organization to assure data quality. In addition, plausibility checks were carried out by the data management group [9].

Parameters

The height standard deviation score (HtSDS) was calculated using the lambda-mu-sigma method [23] according to recent German reference data for healthy children of the KiGGS study [24] as well as to Swiss reference data [25]. Target HtSDS was defined according to [26].

The IoR after 1 year is defined for GHD patients as (HV – HV_pred)/1.72 [27], for SGA patients as (HV – HV_pred)/1.3 [20], and for TS patients as (HV – HV_pred)/1.26 [19], considering HV at 1-year analysis visit and predicted height velocity (HV_pred). The IoR is the difference between observed and predicted HV divided by the SD of the predicted HV during the first year of GH treatment. A positive/satisfactory value of the IoR (>0) indicates a better/comparable growth responsiveness; a negative/nonsatisfactory value (<0) indicates a reduced growth responsiveness in comparison to the reference cohort that was used to develop the prediction model.

Predicted HV (HV_pred) in cm/year is defined for GHD patients according to Ranke et al. 1999 [27]: HV_pred = 12.41 + (−0.36 * age) + (0.28 * body weight standard deviation score [SDS]) + (1.54 * GH dose [ln IU/kg × week]) + (−0.6 * [HtSDS – MPH SDS]) + (0.47 * birth weight SDS). Predicted HV (HV_pred) in cm/yr is defined for SGA patients according to Ranke et al. 2003 [20]: HV_pred = 9.4 + (−0.31 * age) + (0.30 * body weight SDS) + 56.51 * (GH dose [mg/kg × day]) + (0.11 * MPH SDS), and for TS patients according to Ranke et al. 2000 [19]: HV_pred = 8.1 + (−0.3 * age) + (0.40 * body weight SDS) + (2.2 * GH dose [ln IU/kg × week]) + (−0.2 * [HtSDS – MPH SDS]) + (0.4 * number of injections per week) + (1.6 * [oxandrolone = 1; no oxandrolone = 0] (MPH, midparental height; HV, height velocity). Birth weight SDS was calculated according to reference standards of Niklasson et al. [28].

Statistics

Descriptive statistics was used to describe continuous parameters (e.g., age, height, weight) and categorical parameters. Data are provided separately for each of the three treatment indications. Continuous parameters will be compared, if appropriate, using the t-test (Welch’s test) according to [29].

Results

Demographic and Auxological Data

Demographic and auxological data for the three diagnostic groups are presented in Tables 1 and 2. There was a preponderance of male patients with 67.7% for GHD and 56.4% for SGA with no significant change over the years.

Table 1.

Demographic and auxological data of naïve prepubertal patients with GHD, SGA, and TS in PATRO children at baseline and after 1 year of treatment (GHD, SGA, TS all karyotypes)

	GHD (n = 1,144)	SGA (n = 459)	TS (n = 115)
Start of GH
Age, years	8.14±3.32	6.91±2.56	7.82±3.60
Male/female, %	67.7/32.3	56.4/43.6	0/100
Height (SDS) [P]	−2.76±0.88	−3.10±0.73	−3.07±0.86
Height (SDS) [K]	−2.96±0.92	−3.23±0.72	−3.03±0.79
Height velocity (SDS) [CS]	−2.49±1.67	−2.24±1.63	−2.62±1.86
Height velocity (SDS) [PC]	−3.14±1.98	−2.64±1.77	−3.03±2.09
Target height (SDS) [P]	−0.29±0.66	−0.40±0.61	0.17±0.71
Target height (SDS) [K]	−0.45±0.62	−0.56±0.57	−0.01±0.68
ΔHeight SDS to target HtSDS [P]	−2.47±0.97	−2.70±0.88	−3.18±0.78
ΔHeight SDS to target HtSDS [K]	−2.50±0.95	−2.68±0.84	−2.96±0.73
BMI (SDS) [P]	−0.07±1.18	−0.84±1.38	0.25±1.10
BMI (SDS) [K]	−0.51±1.15	−1.23±1.38	−0.09±0.98
GH dose, µg/kg/day	26.0±6.0	30.0±7.0	33.7±10.3
IGF-1, µg/L	89.5±67.7	101.8±57.2	127.6±97.3
1 year of GH
Height (SDS) [P]	−2.01±0.84	−2.37±0.77	−2.40±0.87
Height (SDS) [K]	−2.21±0.86	−2.53±0.76	−2.50±0.84
ΔHeight SDS to target HtSDS [P]	−1.71±0.89	−1.96±0.88	−2.52±0.81
ΔHeight SDS to target HtSDS [K]	−1.75±0.87	−1.97±0.84	−2.43±0.78
Height velocity (SDS) [CS]	3.14±2.13	2.95±1.81	2.10±1.45
Height velocity (SDS) [PC]	4.15±2.78	3.51±2.11	2.87±2.15
BMI (SDS) [P]	−0.04±1.10	−0.76±1.24	0.19±1.17
BMI (SDS) [K]	−0.53±1.04	−1.18±1.21	−0.32±0.73
GH dose, µg/kg/day	30.7±5,3	35.8±5.0	40.7±8.9
IoR	−0.21±1.17	0.04±1.08	0.07±1.11
IGF-1, µg/L	190.1±119.8	212.5±104.0	274.3±155.2
IGF-1 change from start, %	158.5±155.9	137.4±149.3	153.7±133.4

P = reference data according to Prader et al. 1989 [25]; K = reference data according to Neuhauser et al. 2013 [24], KiGGS; CS, cross-sectional; PC, peak centered.

Table 2.

Demographic and auxological data of naïve prepubertal TS patients in PATRO children at baseline and after 1 year of treatment (effectiveness population)

	TS (n = 115) – all karyotypes	TS (n = 30) – karyotype 45,X	TS (n = 32) – mosaicism 45,X/46,XX
Start of GH
Age, years	7.82±3.60	7.74±4.02	8.13±3. 45
Height (SDS) [P]	−3.07±0.86	−3.15±0.86	−3.42±1.04
Height (SDS) [K]	−3.03±0.79	−3.07±0.69	−3.41±1.01
Height velocity (SDS) [CS]	−2.62±1.86	−2.68±1.81	−2.52±2.33
Height velocity (SDS) [PC]	−3.03±2.09	−3.33±2.03	−2.83±2.43
Target height (SDS) [P]	0.17±0.71	0.30±0.70	−0.10±0.70
Target height (SDS) [K]	−0.01±0.68	0.1±0.70	−0.28±0.68
ΔHeight SDS to target HtSDS [P]	−3.18±0.78	−3.38±0.84	−3.15±0.91
ΔHeight SDS to target HtSDS [K]	−2.96±0.73	−3.11±0.79	−2.98±0.90
BMI (SDS) [P]	0.25±1.10	0.37±1.21	0.16±1.13
BMI (SDS) [K]	−0.09±0.98	0.05±1.02	−0.19±1.00
GH dose, µg/kg/day	33.7±10.3	32.4±9.7	34.4±10.1
IGF-1, µg/L	127.6±97.3	130.3±62.6	106.4±61.0
1 year of GH
Height (SDS) [P]	−2.40±0.87	−2.52±0.82	−2.71±1.00
Height (SDS) [K]	−2.50±0.84	−2.60±0.72	−2.82±1.04
ΔHeight SDS to target HtSDS [P]	−2.52±0.81	−2.77±0.86	−2.44±0.93
ΔHeight SDS to target HtSDS [K]	−2.43±0.78	−2.65±0.83	−2.39±0.95
Height velocity (SDS) [CS]	2.10±1.45	1.70±1.25	2.24±1.68
Height velocity (SDS) [PC]	2.87±2.15	2.70±2.38	2.81±1.81
BMI (SDS) [P]	0.19±1.17	0.25±1.11	−0.09±1.42
BMI (SDS) [K]	−0.32±0.73	−0.14±1.01	−0.47±1.30
GH dose, µg/kg/day	40.8±8.8	39.4±7.9	41.3±8.6
IoR	0.07±1.11	−0.11±1.06	0.27±1.09
IGF-1, µg/L	274.3±155.2	270.8±149.9	295.2±210.0
IGF-1 change from start, %	153.7±133.4	134.4±50.7	185.2±212.7

Data of the total TS group, of patients with 45,X karyotype, and of mosaic TS patients (45,X/46,XX) are shown. Other karyotypes are not presented because of low patient numbers.

P = reference data according to Prader et al. 1989 [25]; K = reference data according to Neuhauser et al. 2013 [24], KiGGS; CS, cross-sectional; PC, peak centered.

Age at Start of Treatment over the Recruitment Period 2007–2018

All naïve prepubertal patient groups started GH treatment at a relatively high chronological age with a mean around 8 years for GHD and TS and around 7 years for SGA (Table 3). There was a weak but not significant trend towards younger age at start of treatment up to the most recent time period of 2016–2018 (GHD: 8.04 ± 3.36, SGA: 6.67 ± 2.65, TS: 7.85 ± 3.380). Age at start of treatment was not significantly different between 45,X and mosaic TS patients (p = 0.683) (Table 2). The percentage of 45,X patients in the TS groups decreased from 50% in 2007–2009 to 22.7% in 2016–2018. In contrast, the percentage of mosaic Turner patients increased from 14.3 to 27.3% during the same time periods.

Table 3.

Age at start of GH treatment in GH naïve prepubertal children with GHD, SGA, and TS over 4 time periods within PATRO C (mean ± SD)

Time period (years)	Patient number (n)	Age (years)
GHD
2007–2009	161	8.33±3.19
2010–2012	273	7.95±3.25
2013–2015	289	8.36±3.39
2016–2018	421	8.04±3.36
Total	1,144	8.14±3.32
SGA
2007–2009	58	7.32±2.52
2010–2012	100	7.15±2.70
2013–2015	142	6.84±2.36
2016–2018	159	6.67±2.65
Total	459	6.91±2.56
TS (all karyotypes)
2007–2009	14	8.65±4.39
2010–2012	16	8.82±3.56
2013–2015	41	7.11±3.52
2016–2018	44	7.85±3.38
Total	115	7.82±3.60

GH Dosing

Naïve prepubertal patients with GHD started GH treatment with a low dose of 26.0 μg/kg/day at the lower end of the recommended dose range (25.0–35.0 μg/kg/day) (Table 1). The initial GH dose in SGA and TS patients (30.0 and 33.7 μg/kg/day, respectively) was below the recommendation of 35.0 μg/kg/day for SGA and 45.0–50.0 μg/kg/day for TS. After 1 year of treatment, the mean GH dose increased moderately to 30.7 for GHD, to 35.7 for SGA, and to 40.8 for TS patients (Tables 1, 4). The mean GH dose in GHD patients reached the middle of the recommended range after 0.5–1.0 years of treatment. The recommended dose of 35.0 μg/kg/day was achieved in SGA patients after 0.5–1 year of treatment. In contrast, the mean GH dose remained below the recommended range in TS patients throughout the first year of GH treatment (Table 4).

Table 4.

GH dosing (µg/kg/day) in naïve prepubertal children with GHD, SGA, and TS during first year of GH treatment over 4 time periods within PATRO C (mean ± SD)

Time period (years)	Treatment periods	GHD, µg/kg/day	SGA, µg/kg/day	TS, µg/kg/day
2007–2009	Baseline	27.4±6.1	31.4±5.7	35.5±9.9
	Baseline to 0.25 years	27.7±6.1	32.3±4.9	35.6±9.9
	0.25–0.5 years	28.5±7.2	32.8±4.4	36.5±10.6
	0.5–1 year	30.0±7.4	35.3±4.8	40.5±10.0
2010–2012	Baseline	26.1±6.2	31.9±7.0	35.1±9.3
	Baseline to 0.25 years	27.4±4.8	33.6±5.3	35.8±10.9
	0.25–0.5 years	29.0±4.7	35.1±5.0	36.5±13.0
	0.5–1 year	30.8±4.7	36.6±5.4	40.4±6.9
2013–2015	Baseline	25.6±5.5	29.9±6.8	33.2±10.2
	Baseline to 0.25 years	27.3±4.2	32.6±5.2	36.6±8.2
	0.25–0.5 years	29.3±4.8	34.8±5.0	38.7±7.6
	0.5–1 year	30.6±5.0	36.6±5.4	39.9±8.1
2016–2018	Baseline	25.5±6.0	28.4±7.1	33.3±11.1
	Baseline to 0.25 years	26.7±5.2	31.1±4.7	37.7±9.6
	0.25–0.5 years	28.8±5.2	32.8±4.6	40.0±9.6
	0.5–1 year	30.9±5.1	34.7±4.5	41.9±10.1
Recommended GH dose in Germany		25–35	35	45–50

Growth Results and Efficacy of Treatment

HtSDS was calculated at baseline and after 1 year of GH treatment according to Prader [25] and KiGGS [24]. There was a significant increase in HtSDS in all 3 patient groups (Figure 1, Fig. 2). The difference between the two height standards used was marginal. Delta HtSDS to target HtSDS increased in GHD patients from −2.47 ± 0.97 to −1.71 ± 0.89, in SGA patients from −2.70 ± 0.88 to −1.96 ± 0.88, and in TS patients from −3.18 ± 0.78 to −2.52 ± 0.81 after 1 year of treatment (Table 1). In TS patients with karyotype 45,X delta HtSDS to target HtSDS increased from −3.38 ± 0.84 to −2.77 ± 0.86; in 45,X/46,XX mosaic TS patients, the increase was from −3.15 ± 0.91 to −2.44 ± 0.93.

Fig. 1.

HtSDS at baseline and after 1 year of GH treatment calculated according to Prader et al. 1989 (P) [25] and KiGGS – Neuhauser et al. 2013 (K) [24]. The HtSDS according to Prader reference data was less negative compared to KiGGS reference data. There was a significant difference between HtSDS at start and after 1 year of GH treatment for all three diagnostic groups and for both reference populations (p < 0.001).

Fig. 2.

HtSDS at baseline and after 1 year of GH treatment calculated according to Prader (P) [25] and KiGGS (K) [24]; for all TS patients and for 45,X and 45,X/46,XX karyotypes separately. There was a significant difference between HtSDS at start and after 1 year of GH treatment for all three diagnostic groups and for both reference populations (p < 0.001 for the TS group [left panel], p < 0.02 for the 45,X group [middle panel], and p < 0.02 for the mosaic group [right panel]).

IoR after One Year of Treatment

In GHD patients, mean IoR was negative throughout the study period (Table 5). In the SGA patients, mean IoR was around zero in three of four time periods of the study. In SGA patients, mean IoR was negative in the first two time periods (2007–2009 and 2010–2012) and zero or near zero in the two more recent time periods. Mean IoR was negative in the first time period 2007–2009. In TS patients, mean IoR showed a trend to positive values. This can be attributed to a lower percentage of 45,X patients in the two more recent time periods from 2013 to 2015 and from 2016 to 2018 (23 and 23%, respectively) compared to the time periods from 2007 to 2009 and from 2010 to 2012 (43 and 46%, respectively).

Table 5.

IoR for all patients and for the diagnostic groups of GHD, SGA, and TS over 4 time periods within PATRO children (mean ± SD)

IoR	All indications	GHD	SGA	TS
Total	−0.14±1.14 (n = 1,126)	−0.21±1.17 (n = 704)	−0.04±1.08 (n = 336)	0.07±1.11 (n = 86)
2007–2009	−0.32±1.07 (n = 138)	−0.39±1.09 (n = 92)	−0.20±0.97 (n = 39)	−0.03±1.43 (n = 7)
2010–2012	−0.20±1.11 (n = 275)	−0.24±1.12 (n = 187)	−0.09±1.08 (n = 75)	−0.29±1.20 (n = 13)
2013–2015	−0.03±1.12 (n = 305)	−0.08±1.18 (n = 172)	−0.00±1.02 (n = 102)	0.20±1.09 (n = 31)
2016–2018	−0.11±1.19 (n = 408)	−0.20±1.22 (n = 253)	0.01±1.16 (n = 120)	0.10±1.03 (n = 35)

Discussion

The main findings of this study were that age at start of GH treatment is still high and may prevent children from achieving an optimal long-term growth result. In addition, GH dosing is suboptimal during the first year of treatment particularly in TS patients. The prospective use of a prediction model may help in optimizing treatment results for GHD, SGA, and TS patients.

The demographic data of our study showed a remarkably lower proportion of female than male patients in the GHD group. The preponderance of male patients was less pronounced in the SGA group. There was no relevant change over the years. This is in line with observations from the large KIGS observational study [14], which reported a male predominance in prepubertal children treated with GH. The male preponderance was found in idiopathic GHD, congenital GHD, and acquired GHD and did not change significantly from before 1992 to 2012 in Europe, the USA, and Japan. The male predominance was less marked in SGA patients as was the case in our study. The reason for the difference in the sex ratio between GHD and SGA patients may be found in the fact that the objective measure of birth weight and birth length for the diagnosis of SGA is available, whereas the diagnosis of GHD is somewhat arbitrary. Many GHD cohorts lack sufficient meticulousness to exclude patients with constitutional delay of growth and adolescence, which is predominantly seen in boys and contributes to male predominance in most GHD cohorts. However a higher incidence rate of GH deficiency in males than females of 1.58:1 was reported in a nationwide study from Denmark [30], but does not explain the male-to-female ratio in GH-treated children with GHD of about 2:1 [14]. Sociocultural reasons may play an important role in referral bias in favor of male patients among GH recipients [31]. Constitutional delay of puberty might be the underlying condition. For boys, psychosocial as well as peer pressure has a higher impact on the general condition and social acceptance. Therefore, boys are more likely to be diagnosed due to growth retardation than girls. Even in highly developed countries like Germany with an active public discussion on gender equality, an equal access to GH therapy seems not yet achieved. An appreciation of this gender bias is required for the proper care of short girls by German pediatricians and caregivers.

The aims of GH treatment in growth failure of children have been well defined [10]. However, there is a need for individualized treatment since GH responsiveness is variable.

Therefore, prediction models for GHD, TS, and SGA have been developed [18–20, 27] using simple variables that can be used in clinical practice to adjust the GH dose to achieve the desired growth response. Regarding first-year growth response, the IoR summarizes all these parameters, showing that an IoR between −1.0 and +1.0 can be regarded as a normal growth response to GH treatment [27]. Not only GHD and SGA but also TS patients are likely to benefit from treatment, as their IoR is the best (Table 1), and especially so in mosaic karyotypes (Table 2). Our data show that the mean IoR for GHD, SGA, and TS in the first treatment year was in the expected range (Table 1). Prepubertal children with GHD and SGA with a good first-year response to GH are likely to benefit from long-term treatment, even on low GH dosages [32].

GH dose is an important part of most prediction models of GH therapy and correlates positively with height gain during the first year and during subsequent years of treatment [18–20, 27, 33, 34]. Therefore, differences between predicted and observed first-year growth response (IoR) may have therapeutic consequences, including a modification of the GH dose at an early stage of therapy. The prediction model used here may be used to individualize GH dosing, i.e., to determine the GH dosage at the start of treatment to allow for the optimal first-year growth response. In case of a poor response to GH treatment after the first treatment year (i.e., IoR below −1.0), GH dosage could be increased in the second year to optimize the overall treatment response.

There might be potential for additional height gain with respect to an individualized GH treatment regimen based on first-year growth prediction, since the starting dose was below the recommended dosing range in the TS group and in part in the SGA group. The start of GH therapy in Germany is often made cautiously with a relatively low dose to avoid initial side effects and an elevated IGF-I.

In the GHD group, the starting GH dose remained low during the observational period from 2007 to 2018. The GH dose was increased slightly in all indications during the first year of treatment. The GH dose did not reach the recommended dosing range in TS. Children with GHD were treated with the mean recommended dose at the end of the first treatment year.

In patients with TS, the starting dose of GH and the dose after the first year of treatment were below the recommended and registered dosing range. Using these dosages, an optimal height outcome cannot be expected. The remarkably high IGF-I values after 1 year of treatment, however, point to the conclusion that probably only TS children with a good growth potential and a high responsiveness to GH should be treated with GH doses of <50 μg/kg/day if normal adult height is to be reached at the lowest costs and risks, as recommended earlier [21, 35].

All patient groups started GH treatment at a high chronological age with a slight but not significant trend towards younger therapy start up to 2018. The reasons for a late start of treatment may be a late diagnosis in TS patients and a late recognition of growth deceleration. Thus, action towards earlier diagnosis should be introduced in the German health system. In the case of SGA patients, the SGA status according to the licensing definition should be established before the age of 4 years, thus enabling a start of treatment immediately after the fourth birthday. For all indications, an early treatment start is correlated with a better short-term and long-term outcome [10, 36–40]. The late start of GH treatment and the low dosing at treatment start were comparable to other long-term observations for non-biosimilar GH products as listed in Table 6 except that by Hughes et al. [41] (Table 6, mean age at start of 4.88 years in boys).

Table 6.

Comparison of age at start of GH treatment, initial dose of GH, and HtSDS at start of treatment between different observational studies for GHD patients

Publication/study	Recruitment years	Patients (n)	Age at start, years	Initial dose of GH, µg/kg/day	HtSDS at start of GH
Hughes et al. [41] (2010) OZGROW	Before 2008	m 157, f 98	4.881, 2.901	n.a.	−2.092, −1.600
Ranke et al. [14] (2017) KIGS (IGHD)	1987–2012	m 18,017, f 7,686	9.1 (4.2/13.7)*, 8.2 (3.7/12.0)	30 (21.4–44.3), 30 (21.4–44.3)	−2.84 (−4.2/−1.7), −3.22 (−5.0/−1.9)
Polak et al. [39] (2017) NordiNet	2006–2015	1,457	9.0±3.9	27.8±6.1	n.a.
Blankenstein et al. [13] (2017) NordiNet (Germany)	2006–2016	2,603	8.9±3.8	28.9±8.7, mean dose: 30.7±6.4	−2.7±0.9
Pfäffle et al. [12] (2018) GeNeSIS (Germany)	1999–?	1,669	9.3±3.8	27.1±8.6	n.a.
Sävendahl et al. [42] (2019) NordiNet ANSWER	2006–2016, 2002–2016	7141, 8,580	9.12±4.12, 11.09±3.61	31.0±9.0, 44.0±11.0	−2.55±1.10, −1.98±0.98
PATRO Germany naïve patients	2007–2018	1,144	8.14±3.32	26.0±6.0	−2.69±0.89

n.a., not available.

*Data are given as median (10th and 90th centile).

¹Data are given as mean.

Conclusion

The results from our study using biosimilar GH show potential for treatment optimization in GHD, SGA, and TS patients. First, a younger age at treatment start is necessary for a better long-term height outcome. This can be achieved by earlier detection of growth failure in GHD and TS patients and by earlier documentation of the SGA status around the age of 4 years. Second, a more stringent dose optimization in short children with GHD, SGA, and TS during the first months of treatment taking into account the severity of the GHD in GHD patients is a prerequisite for optimal outcome. However, peak GH in stimulation tests was not included in the prediction model based on KIGS data because KIGS was multicentric and many different stimulation protocols, priming protocols (or no priming), and different assays were used in the participating centers. In addition, in many laboratories the SDS for IGF-I was not available at that time (before 1999). The use of prediction models may help to optimize GH dosing at an early stage of GH treatment. Thirdly, GH treatment may be restricted to TS patients with expected good responsiveness to treatment (calculated by validated growth prediction algorithms) and who are young enough to allow for satisfactory long-term growth outcome. The reasons for under-treatment of short statured female patients with GHD or SGA should be further investigated and eliminated with the aim of gender equality in GH treatment.

Statement of Ethics

This study protocol was reviewed and approved by the Freiburger Ethik-Kommission International (IRB/IEC), University of Freiburg, Germany (approval number EP00-501). Written informed consent was obtained from the participants’ parents/legal guardians to participate in the study. PATRO Children is a post-marketing surveillance (PMS) to monitor the long-term safety and efficacy of Omnitrope^® in infants, children, and adolescents. The study design was described elsewhere [8]. The PATRO Children study protocol was approved by the Ethics Review Committee of all participating centers in accordance with national laws and regulations. All procedures performed were in accordance with the ethical standards of these committees and with the 1964 Declaration of Helsinki and its later amendments. The list of participating centers and ethics committees is provided in the online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000539068).

Conflict of Interest Statement

C.J.P. has received travel grants, speaker fees, and consulting fees from Alexion, Pfizer, Novartis, Sandoz, Merck, Ferring, Kyowa Kirin, and Ipsen Pharma and serves on the German PATRO board. C.L. has received consultancy and speaker fees from Pfizer, Novo Nordisk, Ipsen, Merck Serono, and Sandoz and serves on the German PATRO board. R.P. has received consultancy and speaker fees from Ferring, Merck Serono, Novo Nordisk, and Sandoz and serves on the German PATRO board. K.O.S. serves on the German PATRO board and the PATRO Children Global Steering Committee and has received honoraria and grants from Alexion, Ipsen, Merck Serono, Novo Nordisk, Pfizer, Sandoz, and Vitaflo. H.S. is an employee of Sandoz Germany c/o Hexal AG, Holzkirchen, Germany.

Funding Sources

This study was funded by Sandoz Deutschland (Hexal AG).

Author Contributions

Carl-Joachim Partsch, Christof Land, Roland Pfäffle, Karl Otfried Schwab, and Heide Sommer developed the study plan and defined the data acquisition from the PATRO C data bank. Carl-Joachim Partsch and Christof Land drafted the manuscript and performed the statistical analyses. Roland Pfäffle, Karl Otfried Schwab, and Heide Sommer contributed to data analysis, data interpretation, and critical review of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding Statement

This study was funded by Sandoz Deutschland (Hexal AG).

Data Availability Statement

A subset of data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.