ESPE Abstracts (2019) 92 LB-1

A Trial Investigating the Long-Term Efficacy and Safety of Two Doses of Norditropin® (Somatropin; Recombinant Human Growth Hormone) in Japanese Children with Short Stature Due to Noonan Syndrome Over Four Years of Treatment

Reiko Horikawa1, Tsutomu Ogata2, Yoichi Matsubara3, Susumu Yokoya4, Yoshihisa Ogawa5, Keiji Nishijima5, Takaaki Endo5, Keiichi Ozono6

1Division of Endocrinology and Metabolism, National Centre for Child Health and Development, Tokyo, Japan. 2Department of Paediatrics, Hamamatsu University School of Medicine, Hamamatsu City, Japan. 3Research Institute, National Centre for Child Health and Development, Tokyo, Japan. 4Thyroid and Endocrine Centre, Fukushima Medical University, Fukushima, Japan. 5CMR Development Division, Novo Nordisk Pharma Ltd., Tokyo, Japan. 6Department of Paediatrics, Osaka University Graduate School of Medicine, Osaka, Japan

Objectives: This trial (NCT01927861) evaluated the growth-promoting effect and safety of Norditropin® (somatropin; recombinant human growth hormone) in Japanese children with short stature due to Noonan syndrome over four years of treatment.

Methods: Pre-pubertal children diagnosed with Noonan syndrome were randomized 1:1 to receive Norditropin® 0.033 mg/kg/day or 0.066 mg/kg/day. Change in height standard deviation score (SDS) from baseline to 208 weeks (four years) of treatment was analyzed using an ANCOVA model.

Results: Fifty-one children were randomized to Norditropin® 0.033 mg/kg/day (n=25, mean age [mean±SD] 6.57±2.42 years, 11 female) or 0.066 mg/kg/day (n=26, mean age 6.06±2.25 years, 8 female). Baseline height SDS was similar between groups, relative to a Japanese reference standard (0.033 mg/kg/day: –3.24±0.76; 0.066 mg/kg/day: –3.25±0.71] or a Japanese Noonan reference standard (0.033 mg/kg/day: –0.73±0.74; 0.066 mg/kg/day: –0.80±0.72). After 208 weeks of treatment, the estimated change (95% CI) in height SDS relative to the Japanese reference standard was 0.85 (0.59; 1.12) in the 0.033 mg/kg/day group and 1.84 (1.58; 2.10) in the 0.066 mg/kg/day group, with an estimated mean difference of 0.99 (95% CI:0.62; 1.36) (p<0.0001). Rates and patterns of adverse events (AEs) and the frequency of serious AEs were similar between groups. Mean insulin-like growth factor-I SDS increased from –1.71 at baseline to –0.75 (0.033 mg/kg/day) and to 0.57 (0.066 mg/kg/day). HbA1c increased slightly in both groups. Glucose profiles were almost unchanged and insulin profiles increased in both groups using an oral glucose tolerance test. Three patients in the 0.066 mg/kg/day group withdrew from the trial, two due to adverse events (polymyositis and scoliosis).

Conclusions: Japanese children with short stature due to Noonan syndrome treated with Norditropin® 0.033 or 0.066 mg/kg/day over 208 weeks showed significantly improved height SDS and a favorable safety profile. The increase in height SDS was statistically significant in the 0.066 mg/kg/day group compared with the 0.033 mg/kg/day group.