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Baystate Medical Center Children’s Hospital, Tufts University School of Medicine (E.O.R.), Springfield, Massachusetts 01199; Genentech, Inc. (K.M.A.), South San Francisco, California 94080; Children’s Hospital of Philadelphia (T.M.), Philadelphia, Pennsylvania 19104; Children’s Memorial Hospital (B.L.S.), Chicago, Illinois 60614; Arkansas Children’s Hospital (S.F.K.), Little Rock, Arkansas 72202; Alkermes, Inc. (R.B.N., K.M.F.), Cambridge, Massachusetts 02139; and Montefiore Medical Center (P.S.), Bronx, New York 10467
Address all correspondence and requests for reprints to: Edward O. Reiter, M.D., Department of Pediatrics, Baystate Medical Center Children’s Hospital, Tufts University School of Medicine, Springfield, Massachusetts 01199. E-mail: edward.reiter{at}bhs.org
Abstract
Treatment of naive children with GH deficiency has relied upon long-term replacement therapy with daily injections of GH. The daily schedule may be inconvenient for patients and their caregivers, possibly promoting nonadherence with the treatment regimen or premature termination of treatment. We studied a new sustained release GH formulation, administered once or twice monthly, to determine its efficacy and safety in this population.
Seventy-four prepubertal patients with documented GH deficiency were randomized to receive sustained release recombinant human GH at either 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly by sc injection in a 6-month open-label study. Efficacy was determined by growth data from 69 patients completing 6 months and 56 patients completing 12 months in an extension study.
Growth rates were significantly increased over baseline and were similar for the two dosage groups. The mean (±SD) annualized growth rate (pooled data) was 8.4 ± 2.1 cm/yr at 6 months, and the growth rate was 7.8 ± 1.8 at 12 months compared with 4.5 ± 2.3 at baseline. Standardized height, bone age, and predicted adult height assessments demonstrated catch-up growth without excessive skeletal maturation. Injection site-related events (including pain, erythema, and nodules) were the most commonly reported adverse events; no serious adverse events related to treatment were reported. Laboratory studies documented no accumulation of trough GH or IGF-I levels during treatment, nor did glucose intolerance or persistent hyperinsulinism develop.
Sustained release recombinant human GH is safe and effective for long-term GH replacement in children with GH deficiency. Patients achieved similar growth velocities when sustained release GH was given once or twice monthly. The enhanced convenience of this dosage form may result in greater long-term adherence to the treatment regimen.
THE INTRODUCTION OF recombinant human GH (rhGH) in 1985 revolutionized the treatment of GH deficiency (GHD) in the pediatric population. Before that time, replacement therapy doses and schedules were often defined by the availability of cadaveric hormone. With the greater availability of rhGH, the frequency of administration has increased from three to seven injections per wk to maximize growth. In addition, the average GH dosage in the United States has increased to approximately 0.3 mg/kg·wk (1, 2, 3). Administration was made more convenient with the evolution from im to sc injections. Development of liquid GH preparations and convenient pen injection devices has further simplified the administration process. These advancements still necessitated daily GH treatment, with attendant risk for dosing errors and noncompliance, as well as increased supply costs and number of caregivers. The development of a sustained release GH formulation [Nutropin Depot (somatropin, rDNA origin, for injectable suspension), Genentech, Inc., South San Francisco, CA] that is administered less frequently would reduce some of these concerns and inconveniences.
Nutropin Depot is a rhGH encapsulated in microspheres of biocompatable, biodegradable poly(lactide coglycolide) copolymer (ProLease, Alkermes, Inc., Cambridge, MA) (4, 5). Safe use of this copolymer in suture material and bone fixation devices has been previously described in children (6, 7), and similar microsphere systems are currently used in other commercially available sustained release products (8). After sc administration, GH is released from these microspheres in a biphasic manner. The initial release phase occurs by diffusion of rhGH from the microsphere surface into the sc tissue. During the sustained release phase, the copolymer slowly hydrolyzes, and rhGH is released and absorbed into the circulation over an extended period (5, 9, 10).
The objective of this study was to examine the efficacy and safety of two dose regimens of this sustained release GH formulation in children with growth failure due to GHD.
Materials and Methods
This randomized, open-label study was conducted at 27 medical centers. Eligible children were treated for 6 months, at which time they were invited to continue treatment in an extension study designed to gather information on long-term efficacy and safety. Efficacy was assessed using 6-month annualized and 12-month growth rates as well as changes in standardized height, bone age, and predicted adult height. The study protocol was reviewed and approved by the human research study committee at each participating site.
Subjects
Patients were eligible for study if they were prepubertal (Tanner stage 1) and had GHD documented by peak GH concentrations less than 10 µg/liter (at the investigators’ sites) in response to two pharmacological tests of GH secretory capacity (insulin-induced hypoglycemia, arginine, clonidine, or levodopa), bone age 9 yr or less (girls) or 10 yr or less (boys), and height at least 2 SD below the mean for age- and sex-matched controls. Children with multiple hormonal deficiencies were stabilized on other replacement therapies (e.g. hydrocortisone or levothyroxine) for at least 3 months before enrollment. Written informed consent from a parent or legal guardian was required, as was a willingness of patients to participate in all study assessments.
Patients were excluded if they had growth failure related to other causes, prior treatment of GHD, diabetes mellitus, panhypopituitarism with recently documented hypoglycemia, hypothalamic-pituitary tumors diagnosed or treated within the previous year, treatment with anabolic steroids for more than 30 d within 2 yr before study entry, or known allergy or sensitivity to any component of the sustained release GH product formulation.
Treatment
Randomization was conducted centrally (Alkermes, Inc.) using a random permuted blocks method, with a block size of four. Patients received one of two dose regimens of sustained release rhGH: 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly, administered sc, calculated according to each patient’s weight at baseline, which was adjusted as needed at each 3-month assessment. The dosages used in the study were selected based on previous efficacy, safety, and GH dose-response data (4, 11, 12). Prior pharmacokinetic studies indicated that these dose regimens would produce an adequate IGF-I increment and return of GH to sufficiently low levels before the next dose. All doses were administered sc at home by a parent or legal guardian on the same days of each month. Training regarding proper drug preparation, administration, and storage was provided before treatment initiation.
Clinical assessments
All patients underwent a pretreatment assessment at the
participating institution within 2 wk before initiating treatment to
confirm study eligibility and establish baseline measurements.
Assessment consisted of a complete physical examination, including
height, weight, and Tanner stage; medical history, including available
height measurements for the 18 months before study entry; bone age
x-ray within 3 months before the first dose of study drug; complete
blood count with differential and platelet counts; and routine
urinalysis with microscopic examination. Serum chemistries were
obtained, including sodium, potassium, chloride,
CO2, calcium, inorganic phosphorus, blood urea
nitrogen, creatinine, total protein, albumin, globulin,
albumin/globulin ratio, total bilirubin, alanine aminotransferase,
aspartate aminotransferase, alkaline phosphatase, 
-glutamyl
transferase, lactate dehydrogenase, and cholesterol. These
laboratory studies were repeated at 3, 6, and 12 months after
initiation of treatment. Thyroid function tests (total
T4, free T4, and TSH) were
performed at baseline and repeated at 6 months. Glucose metabolism (2-h
glucose tolerance testing and hemoglobin A1C);
serum concentrations of GH, IGF-I, and IGF-binding protein-3 (IGFBP-3);
and anti-GH antibodies were assessed at baseline and every 3 months.
More rigorous sampling studies had previously been undertaken (4, 11, 12) and are briefly reported in Results. Bone age
x-rays were obtained at baseline, 6 months, and 12 months.
Study end points/statistical analysis
The primary efficacy end point was the growth rate after 6 (annualized growth rate) and 12 months of treatment. All heights recorded were the average of three measurements, except for the prestudy heights, for which only one measurement was required. Pretreatment growth rates were calculated using the baseline height and the prestudy height measurement closest to 180 d before the start of the study. Outcomes were presented as the mean ± SD; 95% confidence intervals were included where appropriate. The changes in growth rate were compared using a paired t test.
Secondary efficacy end points included changes in standardized height and bone age at 6 and 12 months and predicted adult height calculated at 12 months using the Bayley-Pinneau method (13). The height SD score was calculated by the following formula: (actual height - mean height of normal subjects of same age and sex)/height SD score of normal subjects of same age and sex. Values for normal children were derived from data published by the National Center for Health Statistics (14). Growth rate SD scores were calculated similarly using data from Tanner and Davies (15). A paired t test was used to evaluate treatment-related changes in height SD scores. Bone age was determined by the Fels Institute method (16); changes were used to assess the effect of treatment on the rate of skeletal maturation. Predicted adult height (PAH) was calculated using the original Bayley-Pinneau tables for children with bone age greater than 6 yr and a revised Bayley-Pinneau predicted adult height method (Khamis, H. J., and A. F. Roche, personal communication) (16A ) for children with bone age of 3–6 yr. SD scores for PAH were based on normative data for adults.
The relationship between 12-month growth rates and selected baseline characteristics was evaluated using differences in the means for discrete variables and using correlation coefficients for continuous variables. A forward stepwise multiple regression analysis was used to investigate the relationship between 12-month growth rates and the variables sex, etiology of GHD (idiopathic vs. organic), maximum stimulated GH level, chronological age, bone age, standardized height, and bone age delay.
Safety
At each scheduled clinic visit, drug safety and tolerability were evaluated by physical examination, including vital sign measurement and injection site inspection, and clinical laboratory measurements, as previously described. Anti-GH antibody titers were determined using a radioimmunoprecipitation assay (Genentech, Inc.). Assays for antibody binding capacity were performed for all samples with a titer of 1.0 or more. Patients and their parents or guardians were instructed to report any adverse events occurring throughout the study period.
Results
Patient disposition
Seventy-four pediatric patients were randomized to receive sustained release rhGH [1.5 mg/kg once monthly (n = 36) or 0.75 mg/kg twice monthly (n = 38)]. Of these, 69 (93%) patients completed 6 months of treatment. Five patients were prematurely discontinued from the study for the following reasons: adverse event (2 patients, discussed below), protocol violation (1 patient ineligible for study), and withdrawn consent (1 patient with fear of needles, 1 patient who refused to take injections). Sixty-one of the 69 patients (88%) elected to continue treatment in an extension study. Of these, 56 (92%) completed 12 months of treatment. Five patients discontinued during the second 6 months for adverse event (2 patients, discussed below), loss to follow-up (1 patient), and inadequate growth (2 patients). Where appropriate, results are presented for data calculated after pooling of the 2 dose groups.
Baseline characteristics
The demographic and baseline characteristics of enrolled patients
are summarized in Table 1
. There
were no statistically significant differences between groups for any of
the characteristics. Mean maximum stimulated GH concentrations were
within a range consistent with moderate GHD. The generally normal
parental heights of the study participants support the premise that
short stature could not be explained by genetic factors alone.
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Growth rate. Growth rate measurements for both dose groups at
6 and 12 months are presented in Table 2. For 69 patients completing 6
months of treatment, the mean (±SD) growth rate at 6
months was 8.3 ± 1.7 cm/yr in the 1.5 mg/kg once-monthly and
8.4 ± 2.4 cm/yr in the 0.75 mg/kg twice-monthly dose groups. As
the results were not significantly different between dose groups,
results were pooled to yield an overall 6-month growth rate of 8.4
± 2.1 cm/yr (95% confidence interval, 7.9–8.9). For the 56 patients
who completed 12 months of treatment, growth rates at 12 months were
7.6 ± 1.7 and 7.9 ± 2.0 cm/yr for patients receiving 1.5
mg/kg once monthly and 0.75 mg/kg twice monthly, respectively. Pooling
dose groups, the overall mean 12-month growth rate was 7.8 ± 1.8
cm/yr (95% confidence interval, 7.3–8.3), significantly
(P < 0.0001) increased over prestudy growth rates. For
patients over 2 yr of age at baseline (n = 53), the growth rate
SD score improved from -1.8 ± 2.6 prestudy
to 1.9 ± 2.2 at month 12. The mean change in growth rate from
prestudy to 12 months on Nutropin Depot was 3.2 ±
2.8 cm/yr (n = 56). The change in growth rate was more pronounced
in patients with lower prestudy growth rate SD
scores (Fig. 1).
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and 3). Multiple
regression analysis confirmed these
findings, with higher growth rates associated with lower maximum
stimulated GH concentration of less than 5 µg/liter and younger
age.
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. At baseline, a pooled mean
height SD score of -3.0 indicates the presence of
significant growth failure, typical of the untreated prepubertal
GH-deficient population. Catch-up growth was observed in both dosage
groups, with mean height SD score increased to -2.6 at 6
months (pooled data, P < 0.0001). During the second 6
months of treatment, the mean height SD score
continued to improve to -2.4 (pooled data). In each dosage group (Fig. 4), the mean change in height SD score from
baseline to month 12 was significant (P < 0.0001).
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Predicted adult height. PAH can be used to evaluate height
change in the context of change in bone age and thus to estimate the
effects of GH therapy on ultimate height outcomes. A comparison of PAH
SD score at baseline, 6 months, and 12 months reveals
similar significant positive changes in both dosage groups (Fig. 5). The change in PAH
SD score at 12 months was 0.5 ± 0.6 (pooled data,
P < 0.0001).
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No deaths or serious adverse events related to study drug occurred during the 12-month study period. Four patients were prematurely discontinued from treatment, one each due to the following adverse events: pain during injection; periodic weakness and dizziness; nausea, vomiting, and diarrhea; and headache. Adverse events reported as possibly or probably related to treatment included headache (13% of patients), nausea (13%), leg pain (10%), and vomiting (8%).
Injection site-related events. Although sustained release rhGH injections were generally well tolerated, adverse events related to the injection site were commonly reported. For 1483 injections administered during the first 12 months of treatment, injection site reactions included nodules (60% of injections), erythema (54%), and postinjection pain (36%). Development of a nodule after injection was anticipated, and nodules were described as pea-sized and resolved spontaneously over time. Postinjection pain was described as soreness or tenderness, which resolved without intervention. Lipoatrophy, which was identified as a slight dimpling of the skin resulting from transient loss of sc fat, occurred in 11% of injections and resolved over time. No sterile abscesses were reported.
Parents or guardians were instructed to assess and record pain occurring during the injection at each dosing using the Wong-Baker FACES Rating Scale (17) during the first 6-month period. This scale uses a picture projection technique, where a pain score of 0 is represented by a happy face expressing "no hurt" and a score of 5 is represented by a sad face meaning "hurts the worst." Mean pain scores significantly (P < 0.05) decreased from 3.1± 1.9 (±SD) at month 1 to 2.3 ± 1.8 at month 6, indicating that patient tolerability of injections improved over this time period.
Clinical laboratory monitoring. Laboratory tests obtained at 3-month intervals revealed no clinically significant alterations in lipid metabolism, hepatic or renal function, or hematological parameters. Thyroid function tests remained within normal limits in all patients, except for one 11-yr-old boy who demonstrated an increased TSH level of 12.0 µU/ml and was subsequently diagnosed with Hashimoto’s thyroiditis. As anticipated in response to GH therapy, serum concentrations of inorganic phosphorus increased slightly, and alkaline phosphatase levels were increased at 6 and 12 months in both dosage groups.
No evidence of persistent hyperinsulinism, insulin resistance, or
altered hemoglobin A1C levels was found
throughout the 12-month period (Table 3). Among patients who completed
12 months of treatment, no evidence of glucose intolerance attributable
to treatment was observed. Fasting and postprandial glucose and insulin
trough levels were not different from baseline.
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GH, IGF-I, and IGFBP-3 (Table 4). Mean trough
(i.e. predose) concentrations of GH, IGF-I, and IGFBP-3 were
measured at 3-month intervals. In the 1.5 mg/kg once-monthly group,
trough levels of GH, IGF-I, and IGFBP-3 did not substantially differ
from baseline throughout the 6 months. In the 0.75 mg/kg twice-monthly
group, mean GH trough levels were increased compared with baseline at
months 3 and 6 (P < 0.05), but did not progressively
increase. Mean IGF-I trough levels were approximately 20–30 ng/ml
greater than baseline in the 0.75 mg/kg twice-monthly group at 3
months, but there was no further increase in subsequent trough samples.
Mean trough IGFBP-3 concentrations did not change significantly from
baseline in this dosing group. These data suggest that progressive
accumulation of GH or the GH-dependent peptides did not occur in either
dose group. Peak levels were not assessed in this particular study, as
these had been performed in prior dose-finding and pharmacokinetic
studies (4, 11, 12). The mean ±
SD GH Cmax values were
48 ± 26 and 90 ± 23 ng/ml, respectively, after 0.75 and 1.5
mg/kg doses at 12–13 h post-GH administration (see Fig. 1
in Ref.
4). The area under the curve between d 0 and 2 in these
pharmacokinetic studies accounted for approximately 50–60% of the
total d 0 to 28 area under the curve. IGF-I levels reached their
peak between 36 and 84 h after GH administration (see Fig. 2 in
Ref. 4).
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The availability of a sustained release preparation of rhGH allowed us to examine its efficacy and safety in prepubertal children with GHD. The data show a significant increment in growth rate with an increase in standardized height and predicted adult height in a setting of enhanced patient convenience and adequate safety. There was substantial patient and caregiver satisfaction, as demonstrated by the election of 88% of the patients to continue treatment in an extension study after the first 6 months and an overall 76% completing 1 yr of therapy.
Assessment of data at both 6 and 12 months documented a significant increase in mean growth rate over the pretreatment growth rate, with no differences found between the once-monthly or twice-monthly treatment regimens. During the first year of treatment with sustained release GH, the mean bone age advanced by 1.0 yr as well, indicating no undue advancement of skeletal maturation. The combination of increased growth rate and an appropriate rate of bone age advancement resulted in positive changes in the PAH SD score, supporting the potential for achievement of improved adult height in these patients.
The positive changes in predicted adult height occurred despite the finding that the mean growth rates were lower than those observed historically in studies using daily GH injections (1, 18, 19, 20, 21, 22, 23, 24, 25). These earlier studies showed average first year growth rates varying from 8.2–10.9 cm/yr. Such treatment results were generally achieved in patient groups with more profound GHD than that of the children in this report and who are therefore expected to demonstrate greater initial catch-up growth. The lesser severity of GHD in the present group is affirmed by the lower percentage of patients with an organic etiology of GHD (9%), higher mean peak GH levels during provocative testing, higher pretreatment growth rates, and lesser bone age delay. Growth rates correlated inversely with age and peak GH levels, as is usually seen in GH treatment studies. The younger and more GH-deficient patients had growth responses to sustained release GH that were more comparable to those in earlier studies of daily GH.
Another possible explanation for the efficacy data resides in the lower quantitative exposure to GH and IGF-I. In earlier GH pharmacokinetic studies for these two dosing regimens (4, 12), the area under the GH-time response curve was dose dependent, particularly for the initial release phase. In both of the current dosing regimens, GH levels returned to near-baseline concentrations by 14 d. Importantly, there was no progressive increase in either peak or trough levels of GH, indicating that there was no accumulation of GH on a month to month basis. Approximately 50–60% of the GH exposure occurred during the first 2 d, and the remainder occurred during the period preceding the next injection (4, 12). The aggregate GH exposure of these children was less than that from daily GH injections (4, 12) despite the fact that the monthly dose of sustained release GH was slightly greater than that of daily GH, indicating a lower overall bioavailability of the depot formulation.
The overall lower exposure to GH of the patients in this study may have relevance with regard to the development of insulin resistance and glucose intolerance (26, 27). Unlike most studies of daily GH, in which fasting and postprandial insulin concentrations remain elevated throughout treatment, trough values in this study were unchanged from baseline.
IGF-I and IGFBP-3 levels, biochemical markers of GH action, increased, but did not progressively accumulate. As shown by Kemp et al. (12), the mean peak IGF-I increments at 1.5–3.5 d after GH administration were in the 150–300 ng/ml range, similar to that seen with daily GH. However, IGF-I levels return toward baseline before the next dose, resulting in lower total IGF-I AUC compared with daily GH. Such data are reassuring in light of concerns of unconfirmed long-term consequences of exposure to supraphysiological concentrations of IGF-I (28, 29, 30).
During this study, injections were administered at home and were generally well tolerated. Injection-related pain was common, but rarely led to treatment discontinuation. Injection-related events were considered mild to moderate in severity. A topical anesthetic cream was used in some patients to attenuate pain during injection. Other adverse events possibly related to treatment included nausea, arthralgia, and headache, each of which has also been reported with short-acting GH formulations (31).
Current guidelines recommend initiation of GH replacement as soon as possible after the deficiency is diagnosed to maximize the therapeutic response and minimize behavioral and psychosocial issues that may be associated with short stature (16A, 32, 33, 34, 35) Long-term treatment is necessary, but can represent a clinical challenge in young patients, who may lack an understanding of the value of enduring a lengthy therapeutic regimen. Sustained release GH simplifies this long and repetitious regimen by reducing the frequency of injections and their consequent disruption of daily life. This sustained release formulation resulted in catch-up growth in children with GH deficiency, with an overall safety profile similar to that of daily GH. As such, it offers a viable alternative to daily injections for the chronic treatment of GHD.
Acknowledgments
Footnotes
This work was supported by Genentech, Inc.
Abbreviations: GHD, GH deficiency; IGFBP-3, IGF-binding protein-3; PAH, predicted adult height; rhGH, recombinant human GH.
Received February 15, 2001.
Accepted July 3, 2001.
References
This article has been cited by other articles:
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 A. R. Hoffman, B. M. K. Biller, D. Cook, J. Baptista, B. L. Silverman, L. Dao, K. M. Attie, P. Fielder, T. Maneatis, B. Lippe, et al. Efficacy of a Long-Acting Growth Hormone (GH) Preparation in Patients with Adult GH Deficiency J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6431 - 6440. [Abstract] [Full Text] [PDF]
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S. F. Kemp, P. J. Fielder, K. M. Attie, S. L. Blethen, E. O. Reiter, K. M. Ford, M. Marian, L. N. Dao, H. J. Lee, and P. Saenger Pharmacokinetic and Pharmacodynamic Characteristics of a Long-Acting Growth Hormone (GH) Preparation (Nutropin Depot) in GH-Deficient Children J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3234 - 3240. [Abstract] [Full Text] [PDF]
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D. M. Cook, B. M. K. Biller, M. L. Vance, A. R. Hoffman, L. S. Phillips, K. M. Ford, D. P. Benziger, A. Illeperuma, S. L. Blethen, K. M. Attie, et al. The Pharmacokinetic and Pharmacodynamic Characteristics of a Long-Acting Growth Hormone (GH) Preparation (Nutropin Depot) in GH-Deficient Adults J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4508 - 4514. [Abstract] [Full Text] [PDF]
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