Efficacy and safety of two doses of Norditropin^® (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients

Abstract

Abstract. This randomized double-blind multicenter trial (NCT01927861) evaluated the growth-promoting effect and safety of Norditropin ® (NN220; somatropin) in Japanese children with short stature due to Noonan syndrome. Prepubertal children aged 3-<11 years (boys) or 3-<10 years (girls) with Noonan syndrome were randomized to receive GH 0.033 mg/kg/day (n = 25, mean age 6.57 years, 11 females) or 0.066 mg/kg/day (n = 26, mean age 6.06 years, eight females) for 104 weeks. Change in height standard deviation score (HSDS) from baseline was analyzed based on an ANCOVA model. Baseline HSDS was -3.24. Estimated change in HSDS [95% CI] after 104 weeks' treatment was 0.84 [0.66, 1.02] and 1.47 [1.29, 1.64] for the lower and higher doses, respectively; estimated mean difference 0.63 [0.38, 0.88], p < 0.0001. Rates and patterns of adverse events (AEs) were similar between groups. Most were mild and reported as unlikely to be related to Norditropin ® . There were no withdrawals due to AEs. Insulin-like growth factor-I SDS increased from -1.71 to -0.64 (0.033 mg/kg/day) and to 0.63 (0.066 mg/kg/day). HbA 1c increased slightly (0.033 mg/kg/day: +0.14%; 0.066 mg/kg/day: +0.13%); glucose profiles were almost unchanged; insulin profiles increased in both groups in the oral glucose tolerance test. There were no clinically significant abnormal electrocardiogram or echocardiography findings. We conclude that Norditropin ® at doses of 0.033 mg/kg/day or 0.066 mg/kg/day for 104 weeks increases height in Japanese children with short stature due to Noonan syndrome, with a favorable safety profile. The effect was greater with 0.066 mg/kg/day compared with 0.033 mg/kg/day.

A case of Noonan syndrome diagnosed using the facial recognition software (FACE2GENE)

“…The growth velocity of our patient improved after her GH replacement dose was increased. In a randomized double-blind trial on the efficacy and safety of 2 GH doses (0.033 mg/kg/day and 0.066 mg/kg/day) in patients with Noonan syndrome and short stature, greater efficacy was observed in the high dose group than in the low dose group [12].…”

Long-term efficacy and safety of two doses of Norditropin^® (somatropin) in Noonan syndrome: a 4-year randomized, double-blind, multicenter trial in Japanese patients

“…Inclusion criteria were as follows: Japanese children (boys three to <eleven years of age; girls three to <ten years of age) with short stature due to NS, clinically diagnosed according to van der Burgt score list [31], where epiphyseal fusion had not yet taken place. Further inclusion criteria were a HSDS of -2 or below according to the Japanese national reference data for children [32], the availability of height records for the period between 40-64 weeks prior to screening, and pre-pubertal status as described previously [27,33,34]. All included patients were naïve with respect to GH treatment.…”

“…Key exclusion criteria were known or suspected hypersensitivity to hGH or related products, diabetic type diagnosed with the Japanese Diabetes Society Classification [35], a history or presence of active malignancy, and prior GH treatment. Further exclusion criteria were as described by Ozono et al [27].…”

“…The primary endpoint was change in HSDS from baseline to 104 weeks of treatment based on Japanese national reference data for children as reported by Ozono et al [27]. Change in HSDS from baseline to 208 weeks of treatment based on Japanese national reference data for children or on reference data from Japanese NS patients, respectively, were secondary efficacy endpoints.…”

“…Based on results from the 104-week pivotal phase of the present trial (GHLIQUID-4020) in which treatment with 0.033 mg/kg/day and 0.066 mg/kg/day GH was shown to improve HSDS in children with short stature due to NS without any safety issues [27], Norditropin ® was approved in Japan in November 2017 for treatment of 'short stature due to NS'.…”