2026 年 73 巻 2 号 p. 229-241
Reports on long-term safety and effectiveness of daily GH replacement therapy in Japanese children with short stature due to Noonan syndrome (NS) are limited. This post-marketing, prospective, non-interventional study (ClinicalTrials.gov NCT03435627) evaluated the long‑term safety and effectiveness of daily GH therapy in this patient population. The study took place at 22 sites in Japan during November 2017–January 2022. Seventy participants were enrolled and received Norditropin® at least once during the study as per routine clinical practice: new patients (n = 35) received Norditropin® (somatropin) after study initiation and existing patients (n = 35) were previously enrolled in a 4-year trial of Norditropin® for NS (ClinicalTrials.gov NCT01927861). The main outcome measures were adverse drug reactions (ADRs) and serious adverse events (SAEs). Improvements in height were also measured. In total, four new patients experienced five ADRs and one new patient experienced one SAE. Five existing patients experienced one ADR each and three existing patients experienced one SAE each. One existing patient with pre-existing cardiomyopathy who experienced an SAE (arrhythmia) died during the study; Norditropin® causality was judged ‘unlikely.’ Change from baseline in mean (SD) height standard deviation score (SDS), according to Japanese and NS standards, was 1.01 (0.5) and 0.92 (0.3) for new patients and 1.01 (1.0) and 1.31 (0.8) for existing patients, respectively. Our results show that Norditropin® effectively improved height outcomes in Japanese children with NS and was well tolerated with no new safety issues identified. For patients with NS and cardiomyopathy receiving GH therapy, careful monitoring is advised.
Noonan syndrome (NS) is a genetic condition associated with short stature, facial dysmorphism, and neurocognitive and behavioral difficulties [1-5]. Additionally, cardiovascular disease and an increased risk of malignancy are common in children with NS [5, 6].
GH has been used as a treatment option for patients with short stature due to NS. Several studies have reported the safety and effectiveness of GH treatment for increasing height standard deviation score (SDS) in patients with short stature due to NS [1, 7-10]. Post-marketing studies of GH treatment for this patient population demonstrated growth-promoting effectiveness of GH, with no significant adverse effects [11].
Norditropin® (somatropin; Novo Nordisk A/S, Denmark), a human recombinant GH, is currently the only GH that is approved in 66 countries for the treatment of short stature due to NS, including the United States, the European Union, and Japan [12-16]. In Japan, Norditropin® is approved for children with short stature due to NS [14], at a recommended initial dose of 0.23 mg/kg/week, which can be increased to 0.47 mg/kg/week in case of lack of efficacy.
The approval of Norditropin® in Japan was based on the results of the 104-week pivotal phase 3 GHLIQUID-4020 trial (ClinicalTrials.gov NCT01927861), in which patients were randomized to 0.23 or 0.47 mg/kg/week of Norditropin® (equivalent to 0.033 or 0.066 mg/kg/day) and were found to have improved height SDS with no new safety concerns [16, 17]. After 208 weeks of the GHLIQUID-4020 trial, improvements in height outcomes remained consistent, with a significantly greater increase in height SDS in the group receiving 0.47 versus 0.23 mg/kg/week GH, and no new safety concerns were raised [16].
In Japan, post-marketing surveillance (PMS) is required by the Pharmaceutical and Medical Device Act and the Pharmaceutical and Medical Device Agency (PMDA) for post-approval marketing authorization of new products and indications. In this post-marketing study, long-term safety and effectiveness of Norditropin® in Japanese children with short stature due to NS were assessed in a real-world setting. The primary objective was to evaluate the long-term safety of GH treatment and the secondary objective was to evaluate the growth-promoting effect of daily GH treatment. Since cardiovascular disorders are a potential risk for patients with NS [5, 6], cardiovascular adverse events (AEs) were also evaluated.
GHLIQUID-4358 (ClinicalTrials.gov NCT03435627) was a post-marketing, prospective, non-interventional, Japanese study in a real-world setting in which children with short stature due to NS were treated with GH. The study took place at 22 sites in Japan starting from November 2017, with the first patient first visit in February 2018 and study completion in January 2022. The observation period in this study was between 2 and 4 years.
Patients were divided into two groups: an existing patient group and a new patient group. Existing patients were previously enrolled in the phase 3 GHLIQUID-4020 trial, thus their baseline was the start of that trial. New patients started GH treatment after the Japanese approval of GH for the indication of NS and the baseline for them was the start of this study (Fig. 1). Treatment period was up to 8.5 years for existing patients and up to 4 years for new patients.
For each patient, the decision to initiate GH treatment was made by the patient or their legally acceptable representative and the treating physician prior to, and independently from, the decision to include the patient in this study. Signed informed consent was obtained before each patient undertook any study-related activities. Additionally, investigators filled in paper case report forms (CRFs) for each patient enrolled at the study site after each study visit. The completed CRFs were collected by Novo Nordisk personnel upon study completion. Only data that were available as part of normal clinical practice were collected in the study.
This study was approved by an independent ethics committee, institutional review board, and other appropriate bodies (see Supplementary Material). The study was conducted in accordance with the Declaration of Helsinki [18], the Ministry of Health, Labour, and Welfare Ordinance on Good Post-marketing Study Practice, the Guidelines for Good Pharmacoepidemiology Practices, and the applicable relevant regulations [19].
PatientsPatients were Japanese children with height SDS ≤–2 below the reference, aged ≥3 years, females with bone age of <15 years and males with bone age of <17 years. Existing patients were previously assessed for short stature due to NS in GHLIQUID-4020 and new patients were clinically assessed and diagnosed with NS by the treating physician. Specific inclusion criteria for patients in the existing group from the GHLIQUID-4020 trial have been published previously [16, 17].
Patients were excluded if they had previously participated in GHLIQUID-4358 (defined as having given consent) and subsequently discontinued treatment, or if they had a known or suspected hypersensitivity to human GH or related products, including any component of the study products. In the new patient group only, patients were excluded if they had received GH products for the treatment of any indication other than short stature due to NS prior to the approval date of the NS indication.
EndpointsThe primary endpoint was the total number of adverse drug reactions (ADRs) reported during the 4-year study period. The secondary safety endpoints included the number of serious ADRs (SADRs), serious adverse events (SAEs), and cardiac AEs reported during the 4-year study period. ADRs, SADRs, AEs, and SAEs were defined according to the Good Clinical Practice (GCP) guidelines, which state that ADRs are all noxious or unintended responses to a medicinal product for which a causal relationship between the product and the event cannot be ruled out, whereas AEs are unfavorable or unintended events that occur regardless of whether they are related to the medicinal product [20]. Other observations related to safety included change in insulin-like growth factor-I (IGF-I) SDS and change in glycated hemoglobin (HbA1c), from start of treatment.
Secondary effectiveness endpoints included change from start of treatment in height SDS (according to Japanese and NS standards), height velocity (HV), and HV SDS. The number of patients who reached near-adult height was recorded. Attainment of near-adult height was classified when reaching HV <2 cm/year, or when males had reached a bone age of ≥17 years and females had reached a bone age of ≥15 years. The authors reviewed all the data points available for each patient and evaluated them based on these classifications to identify patients who had reached near-adult height.
Secondary safety and effectiveness results were not always reported at year 8.5 and at year 4 for the existing and new patients, respectively, due to the low number of patients with recorded results at those timepoints.
TreatmentGH treatment was administered daily by subcutaneous injection (Norditropin® FlexPro® 5 mg, 10 mg, or 15 mg, or Norditropin® S 10 mg).
Statistical methodsThe full analysis set (FAS) included all patients who received at least one dose of GH during the study period. The effectiveness analysis set (EAS) included all existing and new patients from the FAS who were treatment-naïve at GH initiation and had at least one height value at baseline and after starting the study. Data from existing and new patients were summarized separately. For the primary endpoint, number of ADRs was summarized by descriptive statistics and presented by patient group, Medical Dictionary for Regulatory Activities (MedDRA) system organ class, and MedDRA preferred term. Changes from baseline in height SDS, HV, and HV SDS were presented as 95% confidence intervals (CIs) for the means and p-values from a paired t-test.
A total of 70 patients with short stature due to NS were enrolled, exposed to GH treatment, and included in the FAS. There were 35 patients in the existing group (Fig. 2A) and 35 in the new group (Fig. 2B). All 70 patients in the FAS were included in the EAS. The treatment period for existing patients was up to 8.5 years, and up to 4 years for new patients.
CRF, case report form; IEC, independent ethics committee; IRB, institutional review board.
Baseline characteristics were largely similar between the existing and new patient groups (Table 1). In total, 35 (100%) patients in the existing patient group (17 and 18 patients in the low-dose and high-dose groups, respectively) and 27 (77.1%) patients in the new patient group had no signs of puberty. Five (14.3%) patients in the new patient group had signs of puberty. In terms of NS genotype, 18 (51.4%) patients in the existing patient group (10 [58.8%] patients in the low-dose group and 8 [44.4%] patients in the high-dose group) and 10 (28.6%) patients in the new patient group had the PTPN11 mutation. For 13 (37.1%) patients in the new patient group, genotype of NS was not examined.
| Variable | Existing patients —low dose (n = 17) |
Existing patients —high dose (n = 18) |
New patients (n = 35) |
|---|---|---|---|
| Male, n (%) | 9 (52.9) | 14 (77.8) | 21 (60.0) |
| Age at inclusion, years | 5.5 (2.0) | 5.0 (2.0) | 7.9 (3.8) |
| Height, cm | 97.40 (11.84) | 94.24 (11.41) | 111.25 (18.79) |
| Height SDS* | –3.280 (0.673) | –3.365 (0.665) | –2.928 (0.711) |
| Body weight, kg | 15.07 (4.59) | 14.08 (3.08) | 20.77 (8.93) |
| Bone age, years | 5.07 (2.24) | 4.17 (1.66) | 7.73 (3.58) |
| Signs of puberty, n (%) | |||
| No | 17 (100) | 18 (100) | 27 (77.1) |
| Yes | 0 (0) | 0 (0) | 5 (14.3) |
| Unknown | 0 (0) | 0 (0) | 3 (8.6) |
| GH dose (mg/kg/week) | 0.231 (—) | 0.462 (—) | 0.236 (0.037) |
| Clinical diagnostic criteria for NS, n (%) | |||
| Facial deformity | 17 (100) | 18 (100) | 35 (100.0) |
| Cardiac | 13 (76.5) | 13 (72.2) | 21 (60.0) |
| Short stature | 17 (100) | 18 (100) | 35 (100.0) |
| Chest wall | 11 (64.7) | 15 (83.3) | 30 (85.7) |
| Family history | 2 (11.8) | 4 (22.2) | 8 (22.9) |
| Other | 9 (52.9) | 12 (66.7) | 18 (51.4) |
| Genotype of NS, n (%) | |||
| PTPN11 | 10 (58.8) | 8 (44.4) | 10 (28.6) |
| KRAS | 0 (0) | 1 (5.6) | 1 (2.9) |
| SOS1 | 2 (11.8) | 0 (0) | 5 (14.3) |
| RAF1 | 0 (0) | 2 (11.1) | 3 (8.6) |
| BRAF | 0 (0) | 1 (5.6) | 0 (0) |
| SHOC2 | 0 (0) | 1 (5.6) | 0 (0) |
| NRAS | 0 (0) | 0 (0) | 0 (0) |
| RIT1 | 0 (0) | 0 (0) | 0 (0) |
| Not detected | 3 (17.6) | 5 (27.8) | 3 (8.6) |
| Not examined | 2 (11.8) | 0 (0) | 13 (37.1) |
* Calculated based on the Japanese national reference data for children (Japanese standard).
Data are mean (SD), unless otherwise stated. Baseline for the existing patient group was week 0 of the GHLIQUID-4020 trial, and for the new patient group was week 0 of this study.
FAS, full analysis set; n, number of patients; NS, Noonan syndrome; SDS, standard deviation score.
At baseline, summarized by periods of 6 months, the existing patient group received a mean GH dose of 0.35 mg/kg/week (0.23 and 0.46 mg/kg/week for the low-dose and high-dose groups, respectively), while the new patient group received a mean dose of 0.24 mg/kg/week. At the start of this study, which was between year 4 to 4.5 of treatment for the existing group, they received a mean dose of 0.28 mg/kg/week Norditropin®.
In total, 11 patients from the existing group discontinued the study. The most common reasons for discontinuation were withdrawal due to discontinuing Norditropin® and transfer to another hospital (n = 3 for each reason). In the new patient group, seven patients discontinued the study. The most common reasons for discontinuation were withdrawal due to discontinuing Norditropin®, missed visits, and transfer to another hospital (n = 2 for each reason).
SafetyIn the existing patient group, five patients (14.3%) each experienced an ADR (Table 2) and three patients (8.6%) each experienced an SAE: arrhythmia, odontoma, and ventricular tachycardia (Table 3). The arrhythmia and odontoma events were considered SADRs.
| ADR | Number (%) of patients | Number of events |
|---|---|---|
| Existing patients | ||
| Number of patients experiencing reactions | 5 (14.3) | 5 |
| Psychiatric disorders | ||
| Enuresis | 1 (2.9) | 1 |
| Cardiac disorders | ||
| Arrhythmia | 1 (2.9) | 1 |
| Respiratory, thoracic, and mediastinal disorders | ||
| Rhinitis allergic | 1 (2.9) | 1 |
| Congenital, familial, and genetic disorders | ||
| Odontoma | 1 (2.9) | 1 |
| General disorders and administration-site conditions | ||
| Injection-site pain | 1 (2.9) | 1 |
| New patients | ||
| Number of patients experiencing reactions | 4 (11.4) | 5 |
| Cardiac disorders | ||
| Ventricular extrasystoles | 1 (2.9) | 1 |
| Musculoskeletal and connective tissue disorders | ||
| Scoliosis | 2 (5.7) | 2 |
| Investigations | ||
| Increased brain natriuretic peptide | 1 (2.9) | 1 |
| Increased insulin-like growth factor | 1 (2.9) | 1 |
ADR, adverse drug reaction; FAS, full analysis set; MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term; SOC, system organ class.
| SAE | Number (%) of patients | Number of events |
|---|---|---|
| Existing patients | ||
| Number of patients experiencing events | 3 (8.6) | 3 |
| Cardiac disorders | ||
| Arrhythmia | 1 (2.9) | 1 |
| Ventricular tachycardia | 1 (2.9) | 1 |
| Congenital, familial, and genetic disorders | ||
| Odontoma | 1 (2.9) | 1 |
| New patients | ||
| Number of patients experiencing events | 1 (2.9) | 1 |
| Injury, poisoning, and procedural complications | ||
| Road traffic accident | 1 (2.9) | 1 |
FAS, full analysis set; MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term; SAE, serious adverse event; SOC, system organ class.
In the new patient group, four patients (11.4%) experienced five ADRs (Table 2). One patient (2.9%) experienced an SAE that was not considered an ADR (road traffic accident) (Table 3). AEs of cardiovascular disease occurred in two patients (5.7%).
There was one death due to fatal arrhythmia in the existing patient group during the study. The patient had concomitant illnesses at baseline prior to GH therapy initiation (week 0 of the GHLIQUID-4020 trial), including arrhythmia and hypertrophic obstructive cardiomyopathy, and received GH treatment for about 7 years. Although the patient’s pre-existing hypertrophic obstructive cardiomyopathy did not worsen for about 7 years, the lethal arrhythmia was judged to be associated with the condition, as it was present prior to initiation of GH treatment. The association of the lethal arrhythmia to GH treatment was deemed by the physician as ‘unlikely’ and judged by the sponsor as ‘impossible to assess.’
Secondary safety endpointsFor the low-dose existing patient group, mean (SD) IGF-I SDS was –1.7 (1.0) at baseline and –1.0 (0.9) after 8 years of treatment. For the high-dose existing patient group, mean (SD) IGF-I SDS was –1.5 (0.8) at baseline and 0.2 (0.8) after 8 years of treatment (Fig. 3). Across both dose groups, mean (SD) HbA1c (%) was 5.1 (0.2) at baseline and 5.2 (0.3) after 8 years of treatment. For the new patient group, mean (SD) IGF-I SDS was –1.6 (1.2) at baseline and –0.5 (1.7) after 3.5 years of treatment (Fig. 3). For the same group, mean (SD) HbA1c (%) was 5.1 (0.6) at baseline and 5.0 (0.4) after 3.5 years of treatment.
The dotted line at the 4.5-year timepoint indicates the start of this study for the existing patient group. Baseline for the existing patient group was week 0 of the GHLIQUID-4020 trial, and for the new patient group was week 0 of this study. For the existing patient group, year 4.5 marks the start of this study.
FAS, full analysis set; IGF-I, insulin-like growth factor; n, number of patients; SDS, standard deviation score.
Mean (SD) height SDS (Japanese standard) at baseline was –3.32 (0.66) and change from baseline after 8 years of treatment was 1.10 (0.99) (95% CI 0.63;1.58, p < 0.001, n = 19) (Fig. 4A). For the low-dose and high-dose groups, according to Japanese standard, change from baseline in mean (SD) height SDS after 8 years of treatment was 0.78 (0.81) and 1.47 (1.09), respectively. Mean (SD) height SDS (NS standard) at baseline was –0.85 (0.69) and change from baseline after 8 years of treatment was 1.31 (0.80) (95% CI 0.93;1.70, p < 0.001, n = 19) (Fig. 4B). Change from baseline in mean (SD) height SDS (NS standard) was 1.01 (0.60) and 1.65 (0.88) for the low-dose and high-dose groups, respectively. Mean (SD) HV at baseline was 4.89 cm/year (1.01) and change from baseline after 8 years of treatment was –0.33 cm/year (2.44) (95% CI –1.51;0.84, p = 0.56, n = 19) (Fig. 5). Mean (SD) HV SDS at baseline was –2.12 (1.27) and change from baseline after 8 years of treatment was 2.06 (3.61) (95% CI 0.32;3.80, p = 0.02, n = 19) (Fig. 6).
The dotted line at the 4.5-year timepoint indicates the start of this study for the existing patient group. Data shown are mean (SD). Height measurements were taken at the end of each follow-up year/half year. Baseline for the existing patient group was week 0 of the GHLIQUID-4020 trial, and for the new patient group was week 0 of this study. For the existing patient group, year 4.5 marks the start of this study. n shown in green represents number of patients in the existing patient group and n shown in blue represents number of patients in the new patient group.
EAS, effectiveness analysis set; n, number of patients; NS, Noonan syndrome; SDS, standard deviation score.
The dotted line at the 4.5-year timepoint indicates the start of this study for the existing patient group. Data shown are mean (SD). Measurements were taken at the end of each follow-up year. Baseline for the existing patient group was week 0 of the GHLIQUID-4020 trial, and for the new patient group was week 0 of this study. For the existing patient group, year 4.5 marks the start of this study. n shown in green represents number of patients in the existing patient group and n shown in blue represents number of patients in the new patient group.
EAS, effectiveness analysis set; n, number of patients.
The dotted line at the 4.5-year timepoint indicates the start of this study for the existing patient group. Data shown are mean (SD). Measurements were taken at the end of each follow-up year. Baseline for the existing patient group was week 0 of the GHLIQUID-4020 trial, and for the new patient group was week 0 of this study. For the existing patient group, year 4.5 marks the start of this study. n shown in green represents number of patients in the existing patient group and n shown in blue represents number of patients in the new patient group.
EAS, effectiveness analysis set; n, number of patients; SDS, standard deviation score.
A total of seven patients reached near-adult height in the existing patient group. The mean (SD) height SDS of these patients (Japanese standard) at baseline was –3.3 (0.7) and change from baseline at near-adult height was 0.9 (0.7). Mean (SD) height SDS (NS standard) at baseline was –0.7 (0.6) and change from baseline at near-adult height was 1.1 (0.6). The mean (SD) change from baseline in centimeters was 42.2 cm (4.2). Mean (SD) treatment duration was 7.7 (0.4) years and mean (SD) age was 15.7 (1.5) years.
New patientsMean (SD) height SDS (Japanese standard) at baseline was –2.93 (0.71) and change from baseline after 3.5 years of treatment was 1.01 (0.52) (95% CI 0.68;1.35, p < 0.001, n = 12) (Fig. 4A). Mean (SD) height SDS (NS standard) at baseline was –0.38 (0.64) and change from baseline after 3.5 years of treatment was 0.92 (0.31) (95% CI 0.72;1.11, p < 0.001, n = 12) (Fig. 4B). Mean (SD) HV at baseline was 4.69 (1.24) cm/year and change from baseline after 3 years of treatment was 1.02 (2.10) cm/year (95% CI –0.06;2.10, p = 0.06, n = 17) (Fig. 5). Mean (SD) HV SDS at baseline was –1.58 (2.38) and change from baseline after 3 years of treatment was 3.23 (2.36) (95% CI 2.02;4.44, p < 0.001, n = 17) (Fig. 6).
A total of four patients reached near-adult height in the new patient group. Their mean (SD) height SDS (Japanese standard) at baseline was –3.8 (0.7) and change from baseline at near-adult height was 1.0 (0.8). Mean (SD) height SDS (NS standard) at baseline was –0.7 (0.5) and change from baseline at near-adult height was 0.6 (0.2). The mean (SD) change from baseline in centimeters was 12.5 cm (3.5). Mean (SD) treatment duration was 2.7 (0.6) years and mean (SD) age was 17.1 (2.5) years.
SummaryA summary of the primary safety and effectiveness outcomes is presented in the Graphical Abstract.
In this study, the long-term safety and effectiveness of GH treatment were investigated in Japanese children with short stature due to NS. The effectiveness and the good safety profile seen in randomized controlled trials [16, 17] and clinical evaluations [8] of daily GH have been observed in this real-world study. GH treatment was found to have a consistently good safety profile and growth-promoting effect over the long term.
Two patients in total (2.9%) reported SADRs: arrhythmia and odontoma, with the former leading to death for which GH-related causality was deemed unlikely. The lethal arrhythmia was reported in the patient who had hypertrophic cardiomyopathy with severe left ventricle outflow tract obstruction and arrhythmia before the start of this study. The overall interpretation by the physician on electrocardiogram and transthoracic echocardiography (TTE) was ‘abnormal’ and ‘clinically not significant’ from the start of GHLIQUID-4020 trial and during this study. At the last TTE performed (2 years after the start of this study), hypertrophic obstructive cardiomyopathy was severe and the risk of lethal arrhythmia was high. Taken together, the lethal arrhythmia was likely related to the underlying cardiac condition of the patient and not Norditropin®.
It has previously been shown that patients with NS have an increased risk of developing several types of cancers, including leukemia and neuroblastoma [14, 21]. In one study, the increased risk of developing cancer in patients with the PTPN11 mutation was found to be 3.5-fold (95% CI 2.0;5.9%) compared with that in the general population [6]. In our study, the genotype of NS was not examined for a total of 15 patients, as initiating GH treatment in Japan does not require NS genotype to be examined. However, long-term surveillance is advised to monitor the increased risk of cancers in patients with NS.
Across height-based outcomes, improvements were observed for both groups from the start of treatment until the end of this study. The increase from baseline in height SDS was statistically significant up to year 3.5 for the new patient group and up to year 8 for the existing patient group. New patients had a total treatment duration of up to 4 years, in accordance with the primary endpoint’s defined period of observation. For the existing patient group, the start of this study corresponded to treatment year 4–4.5 as they were previously enrolled at the GHLIQUID-4020 trial for 4 years; hence, they had a total treatment duration that was longer than the primary observation period (≤8.5 years). At the start of this study, patients in the existing group received a lower mean dose of GH (0.28 mg/kg/week versus 0.35 mg/kg/week at baseline). During the same time period, a downward trend across height-based outcomes as well as IGF-I SDS can be observed. IGF-I SDS dropped to below 0 for the existing patients who received 0.47 mg/kg/week GH in the prior trial. These results suggest that dose optimization is important to achieve greater height outcomes and to increase the likelihood of final adult height attainment. In Japan, Norditropin® dose initiation is recommended at 0.23 mg/kg/week and can be increased up to 0.47 mg/kg/week. In the USA, a recommended initiation dose is not stated, but the maximum recommended dose is 0.46 mg/kg/week. In Europe, the dose recommended is 0.46 mg/kg/week, but it is also stated that, for some patients, a lower dose (0.23 mg/kg/week) may be sufficient [13, 22].
In addition to a higher mean starting dose of GH at baseline, patients in the existing patient group had a longer treatment duration than those in the new patient group (up to 8 years versus up to 4 years). This may explain why the mean age of patients who reached near-adult height was lower in the existing patient group than in the new patient group (15.7 years versus 17.1 years), as longer treatment duration and a higher initial GH dose could lead to a normalized age for completion of growth. Some children with NS continue to grow after 18 years of age [23], but the final height achieved by adulthood is often short, possibly due to delayed pubertal onset [1, 24, 25]. Although children with NS do not usually show the characteristic catch-up growth seen in children with GHD [26], a longer period of prepubertal GH treatment and a greater height SDS at pubertal onset have been shown to improve height SDS at near-adult height [1]. Further evidence is needed to confirm the effect of pubertal onset on final height in children with NS, and indeed the impact of delayed pubertal onset on reduced adult height. Nevertheless, the earlier growth termination in patients with NS at approximately 17 years following GH therapy as seen in this study could reflect growth patterns that are usually seen in the general population. The results pertaining to near-adult height attainment within the existing patient group suggest that longer treatment duration, facilitated by a younger age at treatment start, as well as a higher GH dose at treatment initiation, may aid in achieving near-adult height for patients with NS that is comparable to that observed in the general population.
The height-based outcomes and safety results from the current study are consistent with what has previously been published in the literature. The effectiveness and safety of GH in patients with NS were assessed in clinical practice using data from the NordiNet® IOS and the ANSWER Program registries [27]. Mean (SD) height SDS increase from baseline was 0.49 (0.37), 0.79 (0.58), and 1.01 (0.60), after first, second, and third years of treatment, respectively [27]. In a trial conducted in South Korea, 15 prepubertal children with short stature due to NS received daily GH for at least 3 years [28]. Mean (SD) height SDS increased significantly from –2.64 (0.64) to –1.54 (1.24) after 3 years of treatment, and no cardiac abnormalities occurred during treatment [28]. In an analysis of the effect of GH over 4 years in prepubertal patients with short stature due to NS and with a confirmed presence of PTPN11 mutation, long-term effectiveness was observed irrespective of the presence of the PTPN11 mutation [12]. The study included pooled data from the ANSWER Program and GHLIQUID-4020 trial [12]. Using the general population reference at baseline, mean (SD) height SDS was –3.0 (0.8) for PTPN11-positive patients and –3.1 (0.8) for PTPN11-negative patients. After 4 years of GH treatment, mean (SD) height SDS was –1.9 (1.1) and –1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference between the two groups (p = 0.3518) [12]. In another analysis that used data from the NordiNet® IOS and ANSWER Program registries, cardiovascular safety in children with NS receiving GH treatment was assessed [29]. The results showed that, out of 412 patients with NS included in the analysis, 22 (5.3%) experienced 34 events, none of which were related to cardiovascular events [29]. Lastly, in a multicenter study involving 23 children with short stature due to NS, mean (SD) height SDS increased from baseline –2.7 (0.4) to –1.9 (0.9) after 3 years of GH treatment [30]. Minor increases in the thickness of the left ventricular wall were observed in two patients after 3 years of treatment [30].
The results of this study align with previous investigations of the effectiveness and safety of GH therapy in children with NS. The low number of ADRs and AEs, including those deemed serious, provides reassurance about the long-term safety of GH treatment in this patient population. However, given the potential for altered intracellular (RAS/MAPK) signaling and the inherently elevated risk of adverse cardiovascular events in patients with NS [5, 31, 32], the potential influence of GH therapy on cardiac hypertrophy and arrhythmia in susceptible individuals remains to be determined. Thus, in patients with NS and pre-existing cardiac conditions, regular monitoring of myocardial hypertrophy during GH therapy is warranted.
Strengths and limitationsStrengths of this study are that it involved a population of 70 patients and a follow-up duration of 4 and 8.5 years. Additionally, this study was conducted in a real-life setting, enabling collection of impactful data that inform the outcomes of GH treatment in the real world. Dividing the patients into two groups allowed for a more comprehensive understanding of the long-term use of daily GH therapy in patients with NS, including the assessment of potential safety signals and growth patterns from different starting points of treatment (i.e., initiating treatment for the first time or continuing treatment over a longer duration). Separate analysis and reporting of outcomes for the two patient groups also allowed for the exploration of any potential influence of different treatment durations and dosing on effectiveness and safety, including the incidence of ADRs and SAEs.
A limitation of the study is that, for some analyses, data from all patients were not available. Final height data were not available from all patients, and the number of patients who reach near-adult height was small in both groups, thus no conclusions on effectiveness of GH treatment on final height can be determined, nor can the results be applied to the general population of patients with NS. As stated in the methodology, the criteria for near-adult height were based on the slowing of height velocity, bone age reaching a certain threshold or, alternatively, chronological age in the absence of bone age data, which does not necessarily equate to final adult height attainment. Although mean change from baseline in height SDS was significant in both groups, directly comparing the magnitude of these changes at different time points without final height data for all patients makes it difficult to ascertain superiority in final height. Additionally, the diagnosis of NS was given by the physician and was not a result of genetic diagnostic procedures.
The results from this PMS study reassuringly indicate that the outcomes of GH treatment in a controlled trial can be observed in real-world settings. Long-term GH treatment effectively promoted early catch-up growth in children with short stature due to NS and was well tolerated, with no new safety concerns found with GH treatment. Dose optimization is important to maintain improvements in height outcomes. For patients with NS and cardiomyopathy receiving GH therapy, careful monitoring by pediatric cardiologists is advised. Reports of long-term GH treatment for patients with NS are few, especially in Japan, making these real-world results very useful.
The authors thank the investigators and patients participating in this study. The authors would also like to thank Sujatha Gopal from Novo Nordisk for her contributions in improving the readability of the manuscript.
All authors fulfil the International Committee of Medical Journal Editors (ICMJE) criteria for authorship. All authors have had full access to the data and were involved in the analysis of the data and the development and critical review of each draft. All authors read and approved the final manuscript and agree to be accountable for aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
KM was designated as signatory physician for the study and responsible for reviewing and approving the study report. MK reports honoraria from Novo Nordisk and Pfizer. HY has received participation fees from Shindan to Chiryo Sha; lecture fees from AstraZeneca; and research funding/medical scholarship funding from Janssen Pharmaceutical and Mitsubishi Tanabe Pharma. TE is a shareholder and full-time employee at Novo Nordisk Pharma Ltd. AP is a shareholder and full-time employee at Novo Nordisk Health Care AG. J-MF serves as a consultant to Novo Nordisk Healthcare AG since August 2017, providing statistical support and advisory. RH reports advisory boards for Novo Nordisk; speaker fees from Novo Nordisk, Pfizer, JCR; and research funding from Sandoz.
This work was supported by Novo Nordisk. The funder was involved in the study design, collection, analysis, and interpretation of data, and reviewing of the report. Editorial support, under the direction of the authors, in the form of writing assistance, collating author comments, assembling tables/figures, grammatical editing, and referencing, was provided by Emra Baker, Malgorzata Urbacz, Beverly La Ferla, and Helen Marshall, of Ashfield MedComms, and was funded by Novo Nordisk. Patient enrollment, data management, and statistical analyses were carried out by CMIC Co., Ltd. Japan, funded by Novo Nordisk.
The approval committees and board were transparent in their functioning, independent of the researchers, sponsor and any other undue influence, and duly qualified.
Voluntary, signed, and dated informed consent forms were obtained from the patients and/or their legally acceptable representative prior to any study-related activity.
Datasets generated during and/or analyzed for the current study (ClinicalTrials.gov NCT03435627) are not publicly available, but may be shared by the corresponding author upon reasonable request.
