NCRELEX® was not clastogenic in the in vitro chromosome aberration assay and the in vivo mouse micronucleus assay.
Impairment of fertility: INCRELEX® had no effects on fertility in rats using intravenous doses 0.25, 1, and 4 mg/day (up to 4 times the clinical exposure with the MRHD based on AUC.)
14 CLINICAL STUDIES
14.1 Effects of INCRELEX® Treatment in Children with Severe Primary Insulin-like Growth Factor-1 Deficiency (Primary IGFD)Five clinical studies (four open-label and one double-blind, placebo-controlled), with subcutaneous doses of INCRELEX® generally ranging from 0.06 to 0.12 mg/kg (60 to 120 micrograms/kg) administered twice daily, were conducted in 71 pediatric subjects with severe Primary IGFD. Patients were enrolled in the trials on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations, and normal growth hormone secretion. Data from these 5 clinical studies were pooled for a global efficacy and safety analysis. Baseline characteristics for the patients eva luated in the primary and secondary efficacy analyses were (mean, SD): chronological age (years): 6.7 ± 3.8; height (cm): 84.8 ± 15.3 cm; height standard deviation score (SDS): -6.7 ± 1.8; height velocity (cm/yr): 2.8 ± 1.8; height velocity SDS: -3.3 ± 1.7; IGF-1 (ng/mL): 21.6 ± 20.6; IGF-1 SDS: -4.3 ± 1.6; and bone age (years): 4.2 ± 2.8. Sixty-one subjects had at least one year of treatment. Fifty-three (87%) had Laron Syndrome; 7 (11%) had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Thirty-seven (61%) of the subjects were male; forty-eight (79%) were Caucasian. Fifty-six (92%) of the subjects were pre-pubertal at baseline.
Annual results for height velocity, height velocity SDS, and height SDS are shown in Table 1. Pre-treatment height velocity data were available for 58 subjects. The height velocities at a given year of treatment were compared by paired t-tests to the pre-treatment height velocities of the same subjects completing that treatment year.
Table 1: Annual Height Results by Number of Years Treated with INCRELEX® Pre-Tx Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8
Pre-Tx = Pre-treatment; SD = Standard Deviation; SDS = Standard Deviation Score
* P-values for comparison versus pre-treatment values are computed using paired t-tests.
Height Velocity (cm/yr)
N 58 58 48 38 23 21 20 16 13
Mean (SD) 2.8 (1.8) 8.0 (2.2) 5.8 (1.5) 5.5 (1.8) 4.7 (1.6) 4.7 (1.6) 4.8 (1.5) 4.6 (1.5) 4.3 (1.1)
Mean (SD) for change from pre-treatment +5.2 (2.6) +2.9 (2.4) +2.3 (2.4) +1.5 (2.2) +1.5 (1.8) +1.5 (1.7) +1.0 (2.1) +0.7 (2.5)
P-value for change from pre-treatment * <0.0001 <0.0001 <0.0001 0.0045 0.0015 0.0009 0.0897 0.3059
Height Velocity SDS
N 58 58 47 37 22 19 18 15 11
Mean (SD) -3.3 (1.7) 1.9 (3.0) -0.2 (1.6) -0.2 (2.0) -0.7 (2.1) -0.6 (2.1) -0.4 (1.4) -0.4 (1.9) -0.4 (1.9)
Mean (SD) for change from pre-treatment +5.2 (3.1) +3.1 (2.3) +2.9 (2.3) +2.2 (2.2) +2.5 (2.2) +2.7 (1.7) +2.5 (2.1) +2.7 (2.8)
Height SDS
N 61 61 51 40 24 21 20 16 13
Mean (SD) -6.7 (1.8) -5.9 (1.8) -5.6 (1.8) -5.4 (1.8) -5.5 (1.9) -5.6 (1.8) -5.4 (1.8) -5.2 (2.0) -5.2 (2.0)
Mean (SD) for change from pre-treatment +0.8 (0.5) + |
