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 reflect variations in referral patterns, rhGH treatment practices, and approved indications across the countries in the study.
Overall, the effectiveness findings 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 findings from this analysis are consistent with those from other post-approval registries of rhGH treatment [12–19].
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, stratified 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, reflecting 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 reflect 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 findings 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-specified, hence it was not possible to reliably assess the statistical significance 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 reflect variations in referral patterns, rhGH treatment practices, and approved indications.