2017 Volume 65 Issue 2 Pages 159-174
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). HbA1c 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.
NOONAN SYNDROME (NS) (OMIM 163950) is an autosomal dominant disorder characterized by a number of clinical features including short stature, dysmorphic facial features with hypertelorism, and congenital heart defects [1-4]. The prevalence is estimated as 1 in 1,000 to 1 in 2,500 live births . It is a genetically heterogeneous condition caused by gain-of-function mutations of multiple genes, including PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2 and RIT1 [1-4]. Such mutations have been identified in 70–80% of patients , and the diagnosis of NS is still based on clinical findings in the remaining patients.
Short stature is a frequent clinical feature, observed in more than 50% of NS patients , although some patients do reach an adult height within the normal range without any growth-promoting treatment . NS patients typically exhibit normal length and weight at birth, progressive growth failure in infancy, sustained growth in childhood (below –2 standard deviation scores [SDS] of the growth curve of normal children), delayed growth spurt in puberty, and short stature in adulthood (just below –2 SDS) [1, 6-9].
The causes of the growth disturbances in Noonan syndrome are multifactorial. Growth hormone deficiency, GH insensitivity, and neurosecretory dysfunction have been reported in these patients [1, 10]. Children with Noonan syndrome are usually not GH deficient, but may be deficient in insulin-like growth factor-I (IGF-I), particularly those with PTPN11 mutations . Treatment with recombinant human GH (rhGH) has been shown to improve height velocity with no clinically significant adverse events (AEs) . The response to GH therapy in NS can be affected by a number of factors, such as dose of rhGH and type of genetic mutation involved. Moreover, results of long-term GH treatment of short stature due to Noonan syndrome demonstrate a significant improvement in adult height .
Currently, no specific drug is indicated in Japan for the treatment of short stature due to Noonan syndrome. Norditropin® (NN-220; somatropin; Novo Nordisk A/S, Denmark) is an rhGH licensed in Japan for use in treating short stature due to GH deficiency (GHD), Turner syndrome, achondroplasia, short children born small for gestational age (SGA), and adult GHD . Norditropin® was approved in the USA in 2007 for the treatment of children with short stature due to Noonan syndrome, at doses of up to 0.066 mg/kg/day [14, 15]. It is also licensed in Switzerland, South Korea, Israel, Brazil and the Philippines for this indication. The registration submission in these countries was based on two pivotal trials in Sweden: a 2-year, prospective, randomized, parallel-dose group trial (S/GHD/004/NOO) and a follow-up trial which lasted until adult height was attained and involved retrospective data collection (GHNOO-1658) . A number of studies, including clinical trials, case reports and observational studies, have also reported on the efficacy and safety of GH in Noonan syndrome (reviewed in ), all involving small numbers of patients. Reports on the use of GH in Japanese children with Noonan syndrome were published in 1995 (N = 39) , and 2004 (N = 15) .
The current trial examined the efficacy and safety of 104 weeks of treatment with two different doses of Norditropin® in Japanese children with short stature due to Noonan syndrome.
Japanese children with Noonan syndrome, clinically diagnosed according to the van der Burgt score  were eligible for the trial if they had a height SDS of –2 or below, according to the Japanese national reference data for children (subsequently referred to as the ‘Japanese national reference data’) . Further inclusion criteria were as follows: age range 3 to <11 years for boys, years, 3 to <10 years for girls; prepubertal status (i.e. girls breast and pubes Tanner stage I, and no menses; boys testicular volume <4 mL, and pubic hair and genitalia Tanner stage I) [21, 22]; and availability of height records for the period between 40–64 weeks prior to screening. As the target disease was ‘short stature due to Noonan syndrome’, a GH stimulation test was not a requirement. Informed consent was obtained from each subject’s parent or legally acceptable representative before any trial-related activities.
Exclusion criteria were as follows: known or suspected hypersensitivity against human GH or related products; diabetic type diagnosed with the Japanese Diabetes Society Classification ; a history or presence of active malignancy; prior GH treatment; severe cardiac disease, renal disease or hepatic disease (as judged by the investigator); previous screening for the trial; and receipt of any investigational medicinal product within 12 weeks prior to screening. Children who had received systemic administration of thyroid hormone (except replacement therapy), anti-thyroid hormone, androgen, estrogen, progesterone, anabolic steroid, adrenocortical steroid (treatment period ≥13 weeks), derivative of gonadotropin releasing hormone, and IGF-I within 2 years prior to screening, and children with any condition judged by the investigator as not appropriate for the trial, were also excluded.
This was a multicenter, randomized, parallel-group, double-blind trial investigating the long-term efficacy and safety of Norditropin® in Japanese children with short stature due to Noonan syndrome (ClinicalTrials.gov: NCT01927861; Japanese trial registration number JapicCTI-132336). It was conducted at 26 sites in Japan between August 2013 and June 2016. The trial was conducted in accordance with the Declaration of Helsinki (2008) , ICH Good Clinical Practice (GCP) (1996)  and the Ministry of Health and Welfare (MHW) Ordinance on GCP (1997) , and was reviewed and approved by local institutional review boards.
Children were randomized 1:1 to receive GH 0.033 mg/kg or 0.066 mg/kg once daily. Randomization codes were generated by the sponsor and administered centrally by an interactive voice/web response system. GH was administered subcutaneously using Norditropin® FlexPro® 5 mg or 10 mg pens that were indistinguishable for the two doses, with injection site alternating between the upper arm, thigh, abdominal wall or gluteal region.
This paper reports results from the pivotal phase of the trial, during which children were treated for 104 weeks. All children were offered the option of continuing treatment for a further 104 weeks in an extension trial (currently ongoing), giving a total of 208 weeks’ treatment if the full trial is completed.
The primary endpoint was change in height SDS from baseline to 104 weeks of treatment based on Japanese national reference data. Change in height SDS from baseline to 104 weeks of treatment, based on the reference data for Japanese individuals with Noonan syndrome , was a supportive secondary endpoint. Secondary efficacy endpoints were height velocity SDS and height velocity from baseline to 52 weeks of treatment and from 52 weeks to 104 weeks of treatment. Key safety secondary endpoints were the incidence of treatment-emergent AEs during 104 weeks of treatment, and change in IGF-I and change in HbA1c from baseline to 104 weeks of treatment. Changes in clinical laboratory tests, glucose tolerance (area under the curve [AUC] of glucose and AUC of insulin, based on the oral glucose tolerance test [OGTT]), bone age, bone age/chronological age ratio and vital signs from baseline to 104 weeks of treatment, and other laboratory measurements were also reported.
Clinical characteristics including height, height SDS, body weight, body mass index (BMI) and BMI SDS, and bone age were recorded at baseline and at specified visits. BMI and BMI SDS were derived using height and body weight, and BMI SDS was provided only for baseline. Height SDS values were derived using the Japanese national reference data and also the reference data for Japanese individuals with Noonan syndrome (subsequently referred to as the ‘Japanese Noonan syndrome reference data’) . All blood and urine samples were analyzed at a central laboratory. IGF-I SDS values were derived using reference data based on a normal Japanese population .
AEs were recorded at each visit. Any clinically significant worsening since baseline of a previous finding was reported as an AE. A serious AE (SAE) was defined as an experience that at any dose resulted in death, a life-threatening experience, in-patient hospitalization or prolongation of existing hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect. Important medical events that may not have resulted in death, been life-threatening or required hospitalization could be considered an SAE—when, based on appropriate medical judgement—they may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed above. Suspicion of transmission of infectious agents was always considered an SAE. The severity of AEs was classified as follows: mild, no or transient symptoms, no interference with the subject’s daily activities; moderate, marked symptoms, moderate interference with the subject’s daily activities; and severe, considerable interference with the subject’s daily activities, unacceptable.
In addition, all patients were monitored by electrocardiogram (ECG) and transthoracic echocardiography at baseline and every 26 weeks.
The sample size was calculated using a two-sided, two-sample t-test with a 5% significance level for H0: μ1 = μ2 vs. H1: μ1 ≠ μ2, where μi is the population mean, i = 1, 2 represents 0.033 mg/kg/day and 0.066 mg/kg/day, respectively. A total of 21 subjects per dose group gave a power of 80%, with a mean difference between the two dose groups of 0.45 and standard deviation (SD) = 0.5 in the primary endpoint. Based on a previous trial of GH in children born SGA , a 10% withdrawal rate was assumed and sample size was set at 24 subjects per dose group in order to ensure adequate power on the per protocol (PP) analysis set.
The full analysis set (FAS) included all randomized subjects. The PP analysis set included all randomized subjects in the FAS who had not violated any inclusion criteria and had not fulfilled any exclusion criteria, and with a non-missing height at baseline, at least 52 weeks of treatment, and at least one non-missing height after 52 weeks of treatment. All randomized patients fulfilled all inclusion criteria and the criteria for height measurements: completed 104 weeks of treatment; and none violated the criteria for exclusion; therefore, the FAS and PP sets were identical. The safety analysis set (SAS) included all subjects receiving at least one dose of GH. Analyses of all efficacy endpoints were performed based on the FAS. The primary analysis of the primary endpoint was repeated on the PP analysis set. Safety endpoints were summarized using the SAS. Missing values for endpoints other than OGTT, HbA1c and bone age were imputed using the last observation carried forward method.
Formal statistical tests were performed only at 104 weeks. Results at 104 weeks are presented as estimated mean treatment effects (LSMeans). Estimated mean treatment differences (or ratios) are presented together with two-sided 95% confidence intervals and p values for all endpoints analyzed statistically.
The primary analysis for the primary endpoint was performed based on an analysis of covariance (ANCOVA) model with treatment as a fixed effect and baseline height SDS as a covariate. In order to investigate possible effects of sex, age at start of treatment and height SDS at baseline on the primary endpoint, change in height SDS from baseline to 104 weeks of treatment was also analyzed in an exploratory analysis based on the ANCOVA model, with treatment and sex as fixed effects and age at start of treatment and baseline height SDS as covariates. In addition, as a post hoc analysis, change in height SDS from baseline was also analyzed to explore the treatment difference between the two dose groups after 52 weeks of treatment.
Patient flow is shown in Fig. 1. All 51 children completed the planned 104 weeks of treatment with GH. Total exposure to GH was similar in the two dose groups (0.033 mg/kg/day: 49.5 subject years; 0.066 mg/kg/day: 51.6 subject years).
Baseline characteristics are shown in Table 1. Mean age (SD) for all subjects was 6.31 (2.32) years; females accounted for 44.0% of the 0.033 mg/kg/day group and 30.8% of the 0.066 mg/kg/day group. Baseline values of height SDS were below –3 according to the Japanese national reference data; thus, these children were considerably below the national reference range for Japanese children.
The concomitant illnesses are classified according to the Medical Dictionary for Regulatory Activities (MedDRA) (edition 18.1) coding. Results are mean ± standard deviation unless otherwise stated.
*Only concomitant illnesses related to cardiac disorders are listed.
BMI, body mass index; IGF-I, insulin-like growth factor-I; SDS, standard deviation score
Genotyping of the following genes was performed in approximately 50% of the patients: PTPN11, KRAS, SOS1, RAF1, BRAF, SHOC2, and NRAS. The results are shown in Table 1.
No clinically relevant differences between the two dose groups were evident at baseline. Statistical analyses comparing dose groups at baseline were not performed in this randomized trial.
After 104 weeks of treatment, the estimated increase in height SDS according to Japanese national reference data was 0.84 (95% confidence interval [CI]: 0.66, 1.02) in the 0.033 mg/kg/day group and 1.47 (95% CI: 1.29, 1.64) in the 0.066 mg/kg/day group (FAS) (Fig. 2a). The increase in height SDS (Japanese national reference data) was statistically significantly greater in the 0.066 mg/kg/day group compared to the 0.033 mg/kg/day group, with an estimated mean difference of 0.63 (95% CI: 0.38, 0.88), p < 0.0001 (Fig. 2a). As the FAS and PP sets were identical, the results in the PP set were identical. After 104 weeks of treatment, nine patients (36.0%) in the 0.033 mg/kg/day group and 15 patients (57.7%) in the 0.066 mg/kg/day group had a height SDS above –2.0 (Japanese national reference data) compared to none at baseline.
Height SDS and change in height SDS at 104 weeks: a) Japanese national reference data; b) Japanese Noonan syndrome reference data
CI: confidence interval; ETD: Estimated treatment difference in height SDS for 0.066 mg/kg/day–0.033 mg/kg/day.
Values are mean + standard error. Mean estimates are from an ANCOVA method with treatment as a fixed effect and baseline response as a covariate in full analysis set. Missing data is imputed using last observation carried forward. Solid line is the total average value of height SDS at baseline.
After 52 weeks of treatment, the increase in height SDS (Japanese national reference data) was 0.61 (95% CI: 0.49, 0.73) in the 0.033 mg/kg/day group and 1.00 (95% CI: 0.88, 1.12) in the 0.066 mg/kg/day group (FAS, post hoc analysis). The increase was greater in the 0.066 mg/kg/day group compared to the 0.033 mg/kg/day group, with an estimated mean difference of 0.39 SDS (95% CI: 0.22, 0.55), p < 0.0001.
The results were similar when analyzed according to the Japanese Noonan syndrome reference data. After 104 weeks of treatment, the increase in height SDS was greater in the 0.066 mg/kg/day group compared to the 0.033 mg/kg/day group, with an estimated mean difference of 0.73 SDS (95% CI: 0.49, 0.96), p < 0.0001 (Fig. 2b).
Height SDS at each visit is shown in Fig. 3. After 104 weeks of treatment, height SDS had improved from –3.24 at baseline to –2.40 (0.033 mg/kg/day) and from –3.25 to –1.78 (0.066 mg/kg/day) according to the Japanese national reference data (Fig. 3a). When height SDS was calculated according to the Japanese Noonan syndrome reference data, it had improved from –0.73 to 0.02 (0.033 mg/kg/day) and from –0.80 to 0.68 (0.066 mg/kg/day) after 104 weeks of treatment (Fig. 3b).
Height SDS at each visit: a) Japanese national reference data; b) Japanese Noonan syndrome reference data
Full analysis set, last observation carried forward. Mean ± standard error.
Dashed line in Fig. 3a represents the lower end of the height SDS range for the Japanese national reference population (–2 SDS). Dashed line in Fig. 3b represents the middle of the height SDS range for the Noonan syndrome population.
Exploratory analysis showed that age at start of treatment had a statistically significant effect on the gain in height SDS achieved at 104 weeks (p = 0.0003): the younger the age at start of treatment, the greater the change in height SDS (Fig. 4). No statistically significant effects were seen for baseline height SDS or gender (data not shown).
Change in height SDS (Japanese national reference data) after 104 weeks of treatment with GH vs. age at start of treatment
Full analysis set, Last observation carried forward.
Fig. 5 shows the change in height SDS vs. change in IGF-I SDS, with Pearson correlation coefficients as follows: r = 0.5257, p < 0.0001.
Change in height SDS vs. change in IGF-I SDS
Full analysis set, last observation carried forward imputed data. Pearson correlation coefficients: r = 0.5257, p < 0.0001.
During treatment, the mean height velocity SDS in the 0.033 mg/kg/day group changed from a baseline value of –1.99 to 2.80 after 1 year of treatment and to 0.58 after 2 years of treatment. For the 0.066 mg/kg/day group, mean height velocity SDS was –1.70 at baseline, 5.01 at 1 year, and 2.65 at 2 years of treatment (Fig. 6a). A similar pattern was seen with mean height velocity, with values of 4.74, 7.88, and 6.20 cm/year (0.033 mg/kg/day group) and 5.08, 9.90 and 7.99 cm/year (0.066 mg/kg/day group) at baseline, 1 year and 2 years, respectively (Fig. 6b).
a) Height velocity SDS; b) height velocity (cm/year)
Full analysis set, last observation carried forward. Mean ± standard error.
Dashed line in Fig. 6a represents the middle of the height velocity SDS range for the Japanese national reference population.
Thus, observed increases in height velocity SDS and height velocity were greater with 0.066 mg/kg/day compared to 0.033 mg/kg/day in the first year of treatment (not analyzed statistically). In the second year of treatment, the height velocity SDS and height velocity decreased relative to the first year, but height velocity SDS was maintained above 0, and the height velocity was still greater than at baseline, in both dose groups.
After 104 weeks of treatment, 265 AEs were reported in 24 subjects (96.0%) in the 0.033 mg/kg/day group and 306 AEs were reported in 26 subjects (100%) in the 0.066 mg/kg/day group. Further details are provided in Table 2A.
E, number of events; N, number of subjects with events; Rate, event rate per 100 exposure years; %, percentage of subjects
The majority of AEs were of mild/moderate severity and reported as unlikely to be related to GH. In both dose groups, the most frequent AEs (with an incidence of ≥5%) were signs and symptoms commonly observed in children (i.e. general infections, respiratory tract infections, otitis media, eczema, fever). There were no apparent clinically relevant differences in the distribution of AEs between the two dose groups. There were no withdrawals due to AEs. Adverse drug reactions (ADRs; AEs possibly or probably related to GH) are listed in Table 2B. All ADRs were reported as mild and non-serious AEs.
E, number of events; N, number of subjects with events; Rate, event rate per 100 exposure years; %, percentage of subjects
Total number of subjects with events is less than the cumulative number of subjects with events because some patients experienced more than one event.
All serious AEs (SAEs) were single events. Seven SAEs were reported in seven children (0.033 mg/kg/day: 4 events; 0.066 mg/kg/day: 3 events). Six SAEs were general AEs commonly observed in children (gastroenteritis, pneumonia, mycoplasmal pneumonia, tonsillitis, dental caries, supernumerary teeth), and one SAE was reported as ‘head banging’. Two SAEs in the 0.033 mg/kg/day group were reported as severe, and none in the 0.066 mg/kg/day group. All seven SAEs were assessed as unlikely to be related to the trial products and all were reported as recovered.
No malignant tumors, central nervous system vascular disorders, hyperthyroidism or nephrotic syndrome were reported.
One AE of mild, impaired glucose tolerance was reported in a 9-year-old girl (0.066 mg/kg/day). The AE was considered probably related to the trial product. One AE of mild, non-serious febrile convulsion was reported in a 3-year old boy (0.033 mg/kg/day). The AE was considered unlikely to be related to the trial product.
Two cardiac disorders (0.033 mg/kg/day: tachycardia; 0.066 mg/kg/day: ventricular extra-systoles) were reported as AEs in a 5-year-old and a 4-year-old boy, respectively. Both AEs were reported as mild, non-serious and unlikely to be related to trial product. Tachycardia was observed for only 1 day (supraventricular tachycardia at screening), while ventricular extra-systoles were reported for 167 days (suspicion of right heart hypertrophy also at screening). Both subjects recovered from their AEs. With only two cardiac disorders reported, no trends could be observed with respect to demographics and baseline characteristics.
There were no abnormal, clinically significant ECG evaluations. Heart rate appeared to decrease, while the QRS and RR intervals tended to increase during the 104 weeks of treatment.
Echocardiography was performed at screening and weeks 26, 52, 78 and 104. There was no deterioration of any cardiac disorders observed at screening and there were no other clinically significant abnormal transthoracic echocardiography findings. Four patients with a normal echocardiograph at baseline had at least one abnormal, but not clinically significant, echocardiograph: one patient in the 0.033 mg/kg/day group (atrial septal defect at 104 weeks that had no effect on cardiac function) and three patients in the 0.066 mg/kg/day group (one with pulmonary stenosis, aortic stenosis of the bicuspid valve at week 78, resolved to normal at week 104; one with mild thickening of the left ventricle wall at week 26 and mild hypertrophic cardiomyopathy at weeks 52, 78 and 104; and one with mild mitral regurgitation at weeks 26, 52 and 78, resolved to normal at week 104).
IGF-I SDS increased steeply in the first 4 weeks, and then remained relatively stable until week 104 (Fig. 7). Mean IGF-I values remained below 0 SDS (0.033 mg/kg/day) and between 0 and 1 SDS (0.066 mg/kg/day) throughout 104 weeks’ treatment. The increases in IGF-I SDS from baseline to 104 weeks were statistically significantly greater with 0.066 mg/kg/day versus 0.033 mg/kg/day (p < 0.0001). The estimated IGF-I SDS after 104 weeks of treatment had increased from being just above the lower border of the reference range (i.e. –2 to +2) at baseline to mean values well within the normal range (0.033 mg/kg/day: from –1.71 to –0.64; 0.066 mg/kg/day: from –1.71 to 0.63). IGF-I SDS exceeded +2 (upper limit of normal) in small numbers of patients at some visits: at two visits for one patient each time (0.033 mg/kg/day) and at eight visits for one or more patients (0.066 mg/kg/day). At 104 weeks, five children in the 0.066 mg/kg/day group had an IGF-I SDS above +2, with values as follows: 2.2, 2.2, 2.3, 2.8 and 3.3.
IGF-I SDS over time
Safety analysis set, last observation carried forward. Mean ± standard error.
There were no major changes in HbA1c over the course of the trial and HbA1c levels were normal throughout the 104 weeks of treatment. At week 104, slight but similar increases in HbA1c were observed between dose groups (0.033 mg/kg/day: +0.14%; 0.066 mg/kg/day: +0.13%). At 104 weeks, glucose profiles as determined in the OGTT were almost unchanged from baseline (Fig. 8a). No statistically significant differences between dose groups were observed in the AUC of glucose. The estimated treatment ratio for AUC of glucose (0.066 mg/kg/day/0.033 mg/kg/day) at 104 weeks was 1.05 (95% CI: 0.97, 1.13), p = 0.2453. Insulin profiles according to the OGTT increased from baseline to 52 weeks, with further smaller increases from 52 to 104 weeks, in both groups (Fig. 8b). No statistically significant differences between dose groups were observed in the AUC of insulin. The estimated treatment ratio for AUC of insulin at 104 weeks was 1.29 (95% CI: 0.92, 1.79), p = 0.1336.
Blood glucose, week 52 and week 104, based on the OGTT
Safety analysis set. Mean ± standard error.
Insulin profiles at screening, week 52 and week 104, based on the OGTT
Safety analysis set. Mean ± standard error.
At baseline the mean bone age (SD) was 5.50 (2.15) and 5.03 (2.31) in the 0.033 mg/kg/day and 0.066 mg/kg/day groups, respectively. In each group, the patients’ mean bone age was about 1 year behind their chronological age (Table 1). After 104 weeks of treatment, the estimated mean bone age had approached chronological age in both dose groups, with a statistically significantly greater increase in the 0.066 mg/kg/day group (2.63 years) than in the 0.033 mg/kg/day group (2.08 years) during the 2-year period—an estimated mean difference of 0.55 (95% CI: 0.05, 1.04), p = 0.0321. The improved bone age was further reflected in bone age/chronological age ratios approaching 1.0 (0.033 mg/kg/day: 0.88; 0.066 mg/kg/day: 0.96) (Fig. 9). The differences between the two dose groups were statistically significant, with an estimated mean difference of 0.08 (95% CI: 0.02, 0.14), p = 0.0094.
Bone age/chronological age
Safety analysis set. Mean ± standard error. Dotted line indicates a ratio of 1.
There were no clinically relevant changes in lipids (total, low-density lipoprotein [LDL-] and high-density lipoprotein [HDL-] cholesterol) from baseline to 104 weeks, nor were there differences between dose groups. Observed mean BMI values appeared to be a little greater in the 0.066 mg/kg/day dose group than in the 0.033 mg/kg/day dose group throughout the trial, including baseline, but there were no differences in the change in BMI between the two dose groups over the 104 weeks. There were no clinically relevant differences between the two treatment groups in clinical laboratory tests, vital signs, urinalysis, or blood coagulation tests. By the end of the trial period, five children had entered puberty, as follows: in the 0.033 mg/kg/day group, two boys at age 10–11 years; in the 0.066 mg/kg/day group, one boy at age 10–11 years, one boy at 11–12 years, and one girl at 9–10 years. In addition, in each treatment group one boy at age 6–7 years was reported to have entered puberty based on testicular volume of 4 mL; no other signs of puberty were observed (all other Tanner parameters remained at stage 1 during 104 weeks of GH therapy) and precocious puberty was not reported. The remaining children did not enter puberty during the trial.
This study was conducted in order to examine the efficacy and safety of GH for the treatment of Japanese children with short stature due to Noonan syndrome. The results showed that treatment with GH increased height SDS in these patients, and that the effect was greater with 0.066 mg/kg/day compared with 0.033 mg/kg/day. No safety issues were identified during 104 weeks of treatment.
The study enrolled prepubertal Japanese children who had been clinically diagnosed as having Noonan syndrome and were of short stature. Of the patients who underwent genotyping (approximately 50%), approximately 33% had a PTPN11 mutation, and fewer than 5% each had mutations of SOS1, RAF1, or SHOC2. Thus, the frequency of genetic mutations in this subset of the trial population was broadly in line with that previously reported for patients with Noonan syndrome .
Both doses of GH resulted in increases in height SDS, but these were significantly greater with 0.066 mg/kg/day (1.47) than with 0.033 mg/kg/day (0.84) (Japanese national reference data). A similar pattern was seen using the Japanese Noonan syndrome reference data. Furthermore, a higher proportion of those treated with 0.066 mg/kg/day (57.7%), compared with those treated with 0.033 mg/kg/day (36.0%), attained a height SDS >–2 according to the Japanese national reference data after 104 weeks of treatment. At 104 weeks, estimated mean height SDS for patients receiving 0.033 mg/kg/day (–2.41) was still outside the normal range of –2 to +2 and IGF-I SDS was generally below 0 throughout the 104 week treatment period, although further increases can be expected with continuing treatment and, possibly, due to spontaneous growth. Doses of 0.033 mg/kg/day or 0.066 mg/kg/day can therefore both be recommended in the treatment of short stature due to Noonan syndrome, giving clinicians the possibility to use individualized dosing, and to increase the dose to 0.066 mg/kg/day if a patient does not respond well to the lower dose. Indeed, the increase in height SDS varies and may be dependent on several factors, such as age at start of treatment, duration of treatment, age at onset of puberty, and GH sensitivity [16, 29, 30].
Previous studies of GH in Noonan syndrome have consistently reported increases in mean height SDS values or mean height velocity using doses of 0.026–0.066 mg/kg/day (reviewed in . An earlier study in Japan in 15 children with Noonan syndrome were treated with a dose of 0.5 IU/kg/week (i.e. 0.025 mg/kg/day) for 2 years reported that mean (SD) height SDS increased from –2.8 (0.7) to –2.2 (0.5) . A study in Sweden used the same doses as in the current study—0.033 mg/kg/day or 0.066 mg/kg/day—to treat 25 prepubertal patients until they reached final height . In this study, for all patients overall, height SDS increased by a mean (SD) of 0.8 (0.4) SDS after 1 year and by a further 0.4 (0.7) SDS after 2 years. No significant difference was seen between doses when patients reached final height, but treatment periods varied and some patients changed dose during the study. The growth response during the prepubertal period was better if treatment was started at an earlier age . Enhancing prepubertal growth may be of benefit, as the main purpose of using GH in Noonan syndrome is to mitigate short stature as well as associated psychological issues (patients with Noonan syndrome may be at elevated risk of anxiety or depression [31, 32]).
As a whole, current data suggest that the overall increase in height SDS with GH therapy in Noonan syndrome ranges from 0.8 to 1.7 [12, 16, 30, 33], which represents a final height gain of 5 to 10 cm. At first sight, this may seem to be a small gain; however, an increase of 5 to 10 cm may allow a large subset of patients to reach normal adult height. This range of increase in adult height is similar to that seen with GH therapy in other non-GH deficient children, such as girls with Turner syndrome, who can usually gain a mean of 7 cm (range 5–17 cm) with GH therapy . Data suggest that early age at treatment start [16, 35] and GH dose both result in greater height gain.
In the current trial, IGF-I was monitored primarily as a safety endpoint, in order to ensure that IGF-I SDS levels did not routinely exceed 2. At 104 weeks, five children in the 0.066 mg/kg/day group had an IGF-I SDS above +2 SDS. Initial steep increases in IGF-I SDS were observed in the first 4 weeks of treatment. After 4 weeks and until 104 weeks, IGF-I SDS remained stable (Fig. 7) whereas height SDS increased throughout the treatment period (Fig. 3). There was a moderate correlation between change in height SDS and change in IGF-I SDS at 104 weeks (Fig. 5). Previous studies have shown a correlation between the increment in height SDS and the increment in IGF-I level during 1-year treatment with GH . Interestingly, the plot of change in height SDS vs. change in IGF-I SDS showed that some patients experienced large increases in height SDS with increases in IGF-I SDS that were <2 SDS, and that four patients experienced increases in height SDS even though changes in IGF-I SDS were <0 SDS. Together, these observations could suggest a possible direct effect of GH on bone that is not mediated via IGF-I .
No safety issues were identified with GH during 104 weeks of treatment. The proportion of subjects with AEs and event rates of AE were similar between the groups, and no clinically relevant differences between groups were seen on other clinical safety parameters. In order to monitor cardiac function, ECGs and echocardiography were performed at baseline and every 26 weeks. There was no evidence of a negative effect of GH on cardiac function or structure. The registration study by Osio et al. also reported an absence of cardiac side effects , and earlier studies which evaluated the effects of GH therapy on cardiac structure and function in Noonan syndrome have similarly reported that treatment did not affect ventricular wall thickness [10, 30, 37].
In the current trial, increases in HbA1c and in glucose AUC over 104 weeks were minimal and did not differ between the groups. Insulin AUC increased after 104 weeks of treatment. The concern for putative metabolic dysregulations caused by GH is due to the well-known effect of GH in promoting a mild form of insulin resistance. In this respect, although the Swedish study reported a slight temporary increase in fasting insulin levels in a small number of children with Noonan syndrome treated with GH, other markers of altered glucose metabolism were within the normal range .
The adult height of children receiving GH therapy might be compromised if premature epiphyseal arrest terminates their growth earlier than in untreated individuals . In the current study, the estimated bone age approached chronological age in both dose groups after 104 weeks of treatment, with a greater increase in the 0.066 mg/kg/day group than in the 0.033 mg/kg/day group, but mean bone age did not exceed chronological age at any time during the trial.
In individuals with Noonan syndrome, onset of puberty can be postponed by up to 2 years, and thus their growth may occur at an older age than normal subjects , which allows patients further time to increase their height. GH treatment allows bone age/chronological age ratio to normalise—i.e. to approach 1; if the bone age/chronological age ratio were to exceed 1, GH therapy could potentially decrease any advantage of delayed puberty. On the other hand, earlier initiation of GH treatment is thought to result in a better outcome, as longer duration of GH therapy during the prepubertal period and height SDS at onset of puberty were found to be associated with greater height gains in patients with Noonan syndrome . In 25 prepubertal children with Noonan syndrome treated with GH to adult height, Osio et al. reported a substantial increase in height SDS during the first prepubertal years of treatment that was maintained to onset of puberty; in male patients a further increase in height SDS was shown from onset of puberty to adult height . With respect to other indications, in patients with Turner syndrome enrolled in the National Cooperative Growth Study, height at onset of puberty was a significant positive predictive contributor of near adult height . In contrast, in children born small for gestational age (SGA), height SDS was found to decline during puberty resulting in a lower total height gain SDS at adult height than expected. In these patients, bone age for boys and girls was moderately advanced at onset of puberty . Thus, the benefits of GH therapy have to be balanced with its effect on bone age, and long-term observation is needed.
This study has several strengths: it was double-blind, included a comparison between two dose groups, and the number of patients was relatively large compared to previous studies of the use of GH in Noonan syndrome [11, 16-18]. A further strength is the use of reference values for height SDS for Japanese patients with Noonan syndrome, in addition to Japanese national reference data for children, to evaluate the growth promoting effect of GH. The study is limited in that it did not follow the children until they achieved adult height, and safety data after the 104 weeks of treatment have not yet been reported. However, further safety results will be available when the extension study (to 208 weeks) is completed.
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.
Medical writing assistance and editorial/submission support were provided by Grace Townshend and Beverly La Ferla of Watermeadow Medical, funded by Novo Nordisk A/S. We also thank the investigators and patients for their participation in this study.
Dr. Tsutomu Ogata, Dr. Yoichi Matsubara and Dr. Susumu Yokoya have nothing to declare.
Yoshihisa Ogawa and Keiji Nishijima are employees of Novo Nordisk Pharma Ltd.
Dr. Keiichi Ozono and Dr. Reiko Horikawa have received honoraria from Novo Nordisk Pharma Ltd.
Dr. Reiko Horikawa has received research funding from Novo Nordisk Pharma Ltd.
This study was funded by Novo Nordisk Pharma Ltd.