Safety and Effectiveness of Omnitrope® (Somatropin) in PATRO Children: A Multi-Center, Post-Marketing Surveillance Study Comparison of United States and Rest of World Data

PAtients TReated with Omnitrope ® (PATRO) Children is an international, non-interventional study with Omnitrope ® (somatropin, Sandoz Inc.), conducted across 14 different countries. Here we present a comparison of safety and effectiveness data from patients in the United States (US) and in other countries. All visits and assessments are carried out according to routine clinical practice, and doses of Omnitrope ® are given according to country-specic prescribing information. By September 2018, 294 patients had been enrolled in the US (53.1% recombinant human growth hormone [rhGH]-naïve) and 6206 patients had been enrolled across 13 other countries (international group; 86.2% rhGH-naïve). The most common indication in both groups was growth hormone deciency (GHD). Overall, 194 US patients (66.0%) and 2977 international patients (48.0%) experienced adverse events (AEs; 886 and 11,716 events, respectively), most of which were of mild or moderate intensity. The AEs were suspected to be treatment-related in ve US patients (1.7%) and 452 international patients (7.3%). All reported neoplasms were benign, non-serious, and considered unrelated to rhGH therapy. No cases of diabetes mellitus or hyperglycemia were reported. In rhGH-naïve GHD patients, after 3 years of rhGH therapy, the improvement in mean height SD score from baseline was +1.25 and +1.35 in US and international patients, respectively. Conclusion Omnitrope ® treatment appears to be well tolerated and effective in US patients and those from other countries. Across the pediatric indications included, there was no evidence of an increased risk of developing uncommon or unexpected AEs with rhGH.


Introduction
Omnitrope® is a recombinant human growth hormone (rhGH; somatropin) approved in the United States (US) and in Europe in 2006 [1][2][3]. In Europe, Omnitrope® was approved as a biosimilar on the basis that it matches the reference medicine (Genotropin®, P zer) in terms of safety, e cacy, and quality [4]. Approval of Omnitrope® in other countries has since followed [1,5]. The PAtients TReated with Omnitrope® (PATRO) Children study is a long-term, post-marketing surveillance program for Omnitrope®, initiated in 2006 [6,7].
Approved pediatric indications for rhGH include children with growth hormone de ciency (GHD), Turner syndrome, Prader-Willi syndrome (PWS), and short children born small for gestational age (SGA) [8,9]. A position statement supported by several endocrinology societies and published in 2016, concluded that rhGH has a good safety record when used to treat approved indications at recommended doses [10]. Nevertheless, the statement recognized the importance of continued monitoring of patients treated with rhGH [10], highlighting the value of post-approval surveillance studies such as PATRO Children.
The main objective of PATRO Children is to assess the safety of rhGH in pediatric patients, particularly in terms of diabetogenic potential and the risk of malignancies in all indications. The effectiveness of rhGH is analyzed as a secondary objective [6,7]. Here we present a descriptive comparison of safety and effectiveness data from patients enrolled in the US and patients enrolled in other countries, using data from an analysis conducted in September 2018.

Materials And Methods
PATRO Children is an international, longitudinal, non-interventional, observational study conducted in hospitals and specialized endocrinology clinics across 14 countries. The study methodology has previously been described [6,7]. In brief, infants, children, and adolescents who require rhGH treatment and receive at least one dose of Omnitrope® are enrolled. Patients previously treated with another rhGH medicine prior to starting the study are also eligible. Omnitrope® is administered per standard clinical practice and doses are given according to country-speci c prescribing information chosen by the physician.

Safety assessments
Adverse events (AEs) are monitored and recorded for the duration of Omnitrope® treatment. Emphasis is placed on long-term safety, recurrence or new onset of malignancies, and the development of glucose intolerance or diabetes. The relationship of AEs to study treatment is independently evaluated by investigator and sponsor assessment and classi ed according to worst-case scenario. Laboratory values, including glucose metabolism and anti-human growth hormone antibodies, are requested to be reported at least once a year, if obtained. Reasons for treatment discontinuation are also recorded.

Effectiveness assessments
Auxological data may be recorded at each visit and are requested to be documented at least once a year. Height velocity (HV, cm/year), height standard deviation (SD) score (HSDS), HV SD score (HVSDS), and body mass index (BMI) SD score (SDS) are derived from height and weight measurements and country-speci c reference tables.

Data collection and statistical analysis
Patient data are recorded in an electronic case report form (eCRF) at each visit. The eCRFs are reviewed and monitoring is performed by a contract research organization. Standard descriptive statistics are used to describe continuous parameters (e.g., age, height, weight) and categorical parameters (e.g., sex); as a non-interventional, observational study, statistical comparisons of safety and e cacy data was not possible.
The safety population includes all patients documented in the eCRF before the cut-off date (September 2018). The effectiveness population is a subset of the safety population and includes all patients with a documented height measurement at baseline (start of Omnitrope® treatment) and ≥ 1 measurement of height during study treatment (≥ 60 days after baseline). The 3-year analysis set includes patients who have completed at least 3 years of Omnitrope® treatment.
In the current analysis, data from patients enrolled in the US are compared with combined data from patients enrolled in the following countries: Austria, Canada, Czech Republic, France, Germany, Italy, Poland, Romania, Slovenia, Spain, Sweden, Taiwan, and the United Kingdom (the international group).

Patients and treatment (safety population)
As of September 2018, 294 patients had been enrolled from 14 centers in the US (US group) and 6206 patients had been enrolled from 299 centers across 13 other countries (international group). The most common indication in both was GHD; other indications are shown in Table 1.
The primary reasons for discontinuation are shown in Table 2. AEs were the primary reason for discontinuation for three US patients and 102 international patients (1.3% and 3.9% of discontinued patients, respectively).  and neoplasms benign, malignant, and unspeci ed (n = 4). Further details for treatment-related SAEs of interest are provided in Table 4. Among US patients who received a baseline rhGH dose of ≤ 50 µg/kg/day (n = 133), 54.1% reported at least one AE (n = 250 events) and 2.3% had a SAE (n = 3 events). Treatment-related AEs were reported in 0.8% of patients (n = 1 event). In US patients with a baseline dose > 50 µg/kg/day (n = 57), 77.2% reported an AE (n = 285 events) and 3.5% had a SAE (n = 3 events). Treatment-related AEs were reported in 3.5% of patients (n = 2 events). In patients from the international group who received a baseline rhGH dose of ≤ 35 µg/kg/day (n = 3515), 45.4% had at least one AE (n = 6146 events) and 11.5% had a SAE (n = 742 events). Treatment-related AEs were reported in 7.1% of patients (n = 364 events). In patients with a baseline dose > 35 µg/kg/day (n = 1332), 53.8% had an AE (n = 2895 events) and 12.8% had a SAE (n = 319 events). Treatment-related AEs were reported in 8.3% of patients (n = 147 events).

Effectiveness (3-year effectiveness population)
In total, 146 US patients completed at least 3 years of treatment and were included in the 3-year effectiveness population (including 54 rhGH-naïve GHD patients and 16 rhGH-naïve ISS patients). A total of 2753 international patients were included in the 3-year effectiveness population (including 1407 rhGH-naïve GHD patients and 56 rhGHnaïve ISS patients).
Improvements in HSDS and peak-centered HVSDS for rhGH-naïve GHD patients over 3 years of Omnitrope® treatment are shown in Fig. 1. In rhGH-naïve GHD patients, the improvement from baseline in mean HSDS at Year 1 was + 0.58 and + 0.69 in US and international patients, respectively. At Year 3, the improvement in mean HSDS from baseline was + 1.25 and + 1.35 in US and international patients, respectively. Similar improvements in HSDS were observed in prepubertal rhGH-naïve GHD patients; at Year 1 the mean improvement was + 0.68 (US patients) and + 0.71 (international patients) and at Year 3 the mean improvement was + 1.34 (US patients) and + 1.35 (international patients) (Fig. 1A).
At Year 3, the improvement from baseline in mean HVSDS was + 6.54 (US patients) and + 5.35 (international patients) in rhGH-naïve GHD patients. In prepubertal rhGH-naïve patients, the improvement in mean HVSDS at Year 3 was + 5.73 in US patients and + 4.82 in international patients (Fig. 1B).
In rhGH-naïve GHD patients from the US, BMI SDS increased from − 0.48 at baseline to − 0. 13

ISS patients
Improvements in HSDS and peak-centered HVSDS for rhGH-naïve ISS patients over 3 years of Omnitrope® treatment are shown in Fig. 2. In ISS patients who were rhGH-naïve at study entry, the improvement from baseline in mean HSDS at Year 1 was + 0.57 (US patients) and + 0.58 (international patients). At Year 3, the improvement in mean HSDS from baseline was + 1.14 (US patients) and + 1.17 (international patients). In prepubertal rhGH-naïve ISS patients, the mean improvement in HSDS at Year 1 was + 0.64 in both US and international groups. At Year 3 the mean improvement in HSDS was + 1.23 (US patients) and + 1.07 (international patients) ( Fig. 2A).
In rhGH-naïve ISS patients from the US, BMI SDS was 0.33 at baseline and 0.44 at Year 3 (an improvement of + 0.11). In international ISS patients, BMI SDS was − 0.58 at baseline and − 0.59 at Year 3.

Discussion
This analysis from the non-interventional, observational PATRO Children study indicates that treatment with Omnitrope® is well tolerated and effective in patients enrolled from the US and other countries. Some differences were apparent between US and international patients, which likely re ect variations in referral patterns, rhGH treatment practices, and approved indications across the countries in the study.
Overall, the effectiveness ndings from PATRO Children are consistent with other large observational studies of rhGH. In an analysis of data from the observational NordiNet® International Outcomes Study and the NovoNet®/American Norditropin® Studies, similar improvements in HSDS were observed following 1 year of rhGH therapy in patients with isolated GHD and ISS [11]. However, in contrast with the data from PATRO Children, slightly higher HSDS gains following 1 year of treatment were observed in prepubertal GHD and ISS patients compared with the overall group for each indication [11]. As participants in the PATRO Children study were, on average, older than those in the NordiNet®/ NovoNet® studies, this difference may be due to an effect of age and/or puberty in PATRO Children.
Across the pediatric indications examined in the current analysis, data show no evidence of an increased risk of developing uncommon or unexpected AEs, new or recurring malignancies, or diabetes during rhGH treatment. In both the US and international cohorts, less than 1% of reported SAEs were suspected to be treatment related. The safety ndings from this analysis are consistent with those from other post-approval registries of rhGH treatment [12][13][14][15][16][17][18][19].
rhGH doses were higher in patients from the US compared with the international group. This has been observed previously, including in a comparative analysis of children treated with growth hormone in the real-world US ANSWER study and the European NordiNet® study [20]. In this analysis, growth hormone dosing at baseline and during treatment was higher in the US cohort compared with the European cohort, which was attributed to cultural differences in prescribing practices [20].
The use of higher rhGH doses in the US group compared with the international group may, in part, also be due to differences in the recommended rhGH starting doses. For example, the recommended starting dose for patients born SGA is up to 68 µg/kg/day in the US [3] versus 35 µg/kg/day in Europe [2]. The recommended starting doses in other pediatric indications are similar in the US and Europe [2,3]. Less likely, is that geographical differences exist even within approved dose ranges.
Adverse event data and growth response at Year 1, strati ed by prescribed Omnitrope® dose at baseline, were assessed. Different cut-offs were chosen for the US (≤ 50 µg/kg/day, > 50 µg/kg/day) and international (≤ 35 µg/kg/day, > 35 µg/kg/day) groups, re ecting the different rhGH starting doses. In both cohorts, the proportion of AEs, SAEs, and treatment-related AEs was numerically higher in the high-dose than in the low-dose subgroup. Interestingly, for both cohorts there was little difference in the growth response between low and high baseline-dose groups.
Mean HSDS and HVSDS at baseline were higher in the US cohort compared with patients from the international group.
This may re ect the fact that a higher proportion of US patients received rhGH treatment before entering PATRO Children (46.9%) compared with the international cohort (13.8%). When starting rhGH treatment in the PATRO Children study, US patients were on average older than patients in the international group, which may also be due to the higher proportion of pre-treated patients in the US group. Other possible explanations include delayed diagnosis and subsequent initiation of rhGH therapy in a larger number of US patients, and the higher proportion of ISS patients in the US cohort.
Further differences between the US and international cohorts include a higher proportion of males in the US group compared with the international group. Similar ndings have been observed in other post-approval studies of rhGH [21].
A much larger percentage of US patients discontinued the study due to switching to another rhGH preparation; this is most likely explained by insurance-mandated changes. Insurance issues are known to be among the most common reasons for discontinuation of rhGH in the US [22]. Other issues include insurance denial of coverage, or medication costs exceeding the capability to pay despite insurance coverage [22]. These factors are likely to contribute to the high proportion of US patients in PATRO Children who discontinued due to miscellaneous reasons.
As with all observational studies, there are several limitations to be considered. First, there is a risk of bias due to missing or erroneous information, as data are collected according to routine clinical practice As patient visits are scheduled at the discretion of the treating physician and for patient convenience (rather than on a regular basis), there may be a long interval between visits for some, possibly causing AEs to be under-reported. The mean duration of observation on treatment in the study was relatively short (approximately 3 years) for both groups included in this analysis. This limits the interpretation of some data, for example, the occurrence of malignancies.
Another shortcoming is the difference in patient population between the two groups, with the US group comprising less than 5% of the international group. Furthermore, statistical comparisons between the groups were not pre-speci ed, hence it was not possible to reliably assess the statistical signi cance of differences.
Based on this analysis of data from the PATRO Children study, Omnitrope® treatment is well tolerated and effective in US patients and those from other countries. Across the pediatric indications included, available data show no evidence of an increased risk of developing uncommon or unexpected AEs, new or recurring malignancies, or diabetes during rhGH treatment. Some differences were observed between the US and international groups, which likely re ect variations in referral patterns, rhGH treatment practices, and approved indications. Availability of data and material The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

Code availability
Not applicable

Authors' contributions
All authors contributed to data interpretation, writing, and review of the manuscript, and approved the nal version of the manuscript for publication.