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Department of Pediatrics (S.D.C., P.F.B.), University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229; Tercica, Inc. (J.K.), Brisbane, California 94005; Independant Consultant (J.F.), Santa Monica, California 90403; and Department of Pediatrics (L.E.U.), University of North Carolina, Chapel Hill, North Carolina 27599
Address all correspondence and requests for reprints to: Steven D. Chernausek, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229. E-mail: steven.chernausek{at}cchmc.org.
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Abstract |
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Objectives: The objective of the study was to examine the long-term efficacy and safety of recombinant human IGF-I (rhIGF-I) therapy for short children with severe IGF-I deficiency.
Design: Seventy-six children with IGF-I deficiency due to GH insensitivity were treated with rhIGF-I for up to 12 yr under a predominantly open-label design.
Setting: The study was conducted at general clinical research centers and with collaborating endocrinologists.
Subjects: Entry criteria included: age older than 2 yr, SD scores for height and circulating IGF-I concentration less than –2 for age and sex, and evidence of resistance to GH.
Intervention: rhIGF-I was administered sc in doses between 60 and 120 µg/kg twice daily.
Main Outcome Measures: Height velocity, skeletal maturation, and adverse events were measured.
Results: Height velocity increased from 2.8 cm/yr on average at baseline to 8.0 cm/yr during the first year of treatment (P < 0.0001) and was dependent on the dose administered. Height velocities were lower during subsequent years but remained above baseline for up to 8 yr. The most common adverse event was hypoglycemia, which was observed both before and during therapy. It was reported by 49% of treated subjects. The next most common adverse events were injection site lipohypertrophy (32%) and tonsillar/adenoidal hypertrophy (22%).
Conclusions: Treatment with rhIGF-I stimulates linear growth in children with severe IGF-I deficiency due to GH insensitivity. Adverse events are common but are rarely of sufficient severity to interrupt or modify treatment.
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Introduction |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Seventy-six children with severe IGF-I deficiency due to GH insensitivity were diagnosed by pediatric endocrinologists participating in the GH insensitivity syndrome (GHIS) collaborative group and referred to one of the principal investigators (S.D.C. or L.E.U.). Twenty-three subjects naive to rhIGF-I were studied primarily at either the University of North Carolina (UNC) or Cincinnati Children’s Hospital Medical Center. Ten other subjects had been treated previously with rhIGF-I (Pharmacia, Inc., Uppsala, Sweden). One had been treated for only 2 wk before enrolling in the current trial and therefore was included with the naive-to-treatment subjects for analysis. The remaining 43 were naive-to-treatment subjects enrolled after 1998 and treated by collaborating endocrinologists who provided data for this report. The study was conducted in accordance with national and international ethical and regulatory standards. The protocol and informed consent documents were reviewed and approved by the institutional review boards of the participating sites. Data from eight subjects have been reported previously (5).
The principal entry criteria were: age older than 2 yr, height SD score less than –2 for age and sex, IGF-I circulating concentration SD score less than –2 for age and sex, and evidence of GH resistance. The latter was generally defined as failure to increase serum IGF-I concentrations by more than 50 µg/liter after four daily sc GH injections of 0.1 mg/kg. Children who developed growth-attenuating antibodies during GH treatment (GH binding capacity > 10 µg/ml) also were enrolled. Children were excluded if they had prior or active malignancy, major organ dysfunction or treatment with medications that would diminish growth, or clinically significant abnormalities of cardiac function or rhythm.
For this analysis, subjects were categorized as follows: GHAB, subjects with neutralizing levels of GH antibody (n = 9); GHRD, subjects with an abnormality of the GH receptor documented either through molecular genetic analysis or by the absence of circulating GH binding protein (n = 28, 23 with defined abnormality of GHR gene); and GHIS phenotype, subjects with clinical features of GH receptor deficiency (e.g. markedly increased serum GH) but who lack direct confirmation of a GH receptor abnormality (n = 39). Most of the subjects in the latter group had neither GH receptor genetic studies performed nor measurement of GH binding protein.
Medication
Active drug (rhIGF-I, mecasermin) and placebo were provided by Genentech, Inc. (South San Francisco, CA). Vials of rhIGF-I and placebo were stored at 2–8 C.
Study procedures
For the subjects treated primarily at UNC and Cincinnati Children’s Hospital Medical Center, rhIGF-I therapy was begun at a low dose and titrated up to 120 µg/kg sc twice a day (BID) usually within 2 wk. At study inception some children received lower doses (40–80 µg/kg, BID) for the first few months. The first subjects enrolled were observed in the hospital to monitor for hypoglycemia. Monitoring of blood glucose concentrations using commercially available meters (ACCU-CHEK, Roche Diagnostics Corp., Indianapolis, IN) continued at home during the initial months of therapy for the first 23 enrollees. Caretakers were instructed in proper use of these meters by study personnel. Subjects were evaluated at regular intervals (typically twice yearly) until they completed the study. Scheduled study visits included review of interval medical history and a recording of adverse events, anthropometry, and physical examination. Laboratory assessments included the following: radiograph of hand and wrist for bone age [read centrally at the Fels Institute, Yellow Springs, OH, for subjects studied at UNC and Cincinnati using the FELS method (9)], hematological indices, serum chemistry panel, thyroid function, serum IGF-I concentration, and IGF-I antibodies. Additional safety assessments were performed in selected subjects (n = 23). These were chest x-ray, spleen and kidney ultrasound, audiometry and tympanometry, echocardiogram, whole-body dual-energy x-ray absorptiometry (DEXA) for body composition, 24-h urine creatinine, glomerular filtration rate by technetium scan, and cephalometric x-rays. Subjects enrolled after 1998 had dose titration and follow-up visits performed by their local pediatric endocrinologists; specialized laboratory assessments and study procedures were generally not available.
Subjects and their parents/guardians were instructed to administer rhIGF-I by sc injection, morning and evening, within 30 min of a meal. They were advised to withhold the injection when the child was unable to eat due to illness.
Fourteen subjects were treated with a GnRH superagonist in an attempt to achieve a greater adult height by delaying puberty to prolong their growth. No special adjustments have been made for these subjects in the analysis of height velocity or height SD scores.
Efficacy end points
Height velocity was the primary efficacy end point. Means, SDs, and ranges have been computed for naive-to-treatment subjects with at least a year of treatment data and for whom a pretreatment height velocity was available. Height measurements were obtained using wall-mounted stadiometers. Height SD scores were computed using the Centers for Disease Control and Prevention age- and gender-dependent means and SDs (10). Because heights were not always measured at close to 1-yr intervals, some annual heights were imputed by interpolation using the closest dates before and after the anniversary of treatment initiation. Near-adult height was evaluated in all subjects whose most recent bone age was at least 16 yr for males and 14 yr for females.
Laboratory methods
Subject sera were tested for the presence of antibodies to IGF-I using an ELISA developed by Genentech, Inc. Samples and control sera were incubated in rhIGF-I-coated microtiter plates for 2 h at room temperature. After washing, bound antibody was detected by the addition of Protein A-horseradish peroxidase conjugate for 2 h, followed by enzyme substrate, orthophenylenediamine, for 20–30 min. The reaction was stopped with sulfuric acid and the OD determined using a 490- to 492-nm filter for absorbance and 405 nm for reference. Positive controls were prepared by adding affinity-purified IGF-I rabbit antiserum to normal human serum. A serum sample was considered antibody positive when the OD of a 1:100 or greater dilution of the sample exceeded that of the negative control.
The IGF-I concentration in 2-h postdose blood samples was measured by immunoassay in selected subjects. Imaging studies, hematologic studies, and standard chemistry measures were performed at the respective study sites using standard methodologies.
Statistics
Height velocity during each year of treatment was compared with pretreatment height velocity using a two-sided, paired t test at a significance level of 0.05. An unbalanced mixed model ANOVA and covariance (PROC MIXED; SAS Institute, Cary, NC) was used for the analysis of percent body fat by DEXA.
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Results |
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The subjects were extremely growth retarded with severely delayed skeletal maturation (Table 1
). There were no baseline differences between those subjects in whom GH receptor abnormality had been documented (GHRD) and those with the GHIS phenotype with respect to age, sex, height SD score, body mass index (BMI) SD score, height velocity, or bone age (P > 0.1). Patients with GH-neutralizing antibodies (GHAB) were more growth retarded at baseline, compared with the others (mean height SD scores = –8.6 and –6.4, respectively, P < 0.001). The reason for this is unclear.
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Subjects were studied under five protocols, the last of which is currently intended to follow up subjects to adult height. Of the 76 original enrollees, 12 subjects withdrew or did not enroll in the current protocol. Of these 12, nine were noncompliant or lost to follow-up, one had poor growth, and two were parent-subject decisions. Six subjects completed the study by attaining near-adult height. Thus, 58 subjects remain in the study.
Circulating IGF-I concentrations during rhIGF-I therapy
Postdose concentrations were measured at least once in each of 28 subjects (124 measurements in total). The mean ± SD 2-h postdose serum IGF-I concentration at 80 µg/kg (n = 28) was 100 ± 106 ng/ml (median = 55), and for the 120 µg/kg dose (n = 83), the mean was 128 ± 111 ng/ml (median = 98). These concentrations were thus generally either below the normal range or in the low-normal ranges for the assays used but should be interpreted cautiously because of the inherent abnormalities of IGF binding protein (IGFBP) abundance expected in these subjects (11).
Growth promotion by rhIGF-I
Sixty-two subjects were naive to rhIGF-I treatment and had a least 1 yr of therapy. Fifty-nine of these had documented baseline height velocities that were used for assessment of response. Treatment with rhIGF-I stimulated linear growth independent of the degree of shortness (Fig. 1A) or diagnostic category (GHRD, GHIS, or GHAB, data not shown). The baseline height velocity (2.8 cm/yr on average) increased to 8.0 cm/yr during the first year of treatment (P < 0.0001). The median increment in first-year height velocity over baseline was 5.3 cm/yr (mean 5.2 cm/yr; range –2.8 to 10.4).
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). For subjects receiving an average dose of at least 100 µg/kg BID for 2 yr (n = 19), first- and second-year mean height velocities were 8.7 ± 1.7 and 6.1 ± 1.6 cm/yr, respectively, significantly greater (P < 0.0001) than the baseline height velocity (2.8 ± 1.3 cm/yr).
The treatment effect persisted over subsequent years, during which most subjects received 120 µg/kg BID (Fig. 1C). Although mean growth velocities were lower after the first year of treatment, they remained above baseline (although not greater than expected for normal children) for up to 8 yr. Most recent heights and bone ages of treated subjects are shown in Table 1. The putative effect of the therapy on adult height was assessed in the few subjects who attained near final adult height (Table 2). Their adult heights, in the absence of treatment, were predicted using the growth charts developed by Laron et al. (12), assuming that each subject would have grown at the average rate reported by Laron et al. if untreated. Accordingly, five of the six appeared to have gained more than 10 cm from rhIGF-I treatment.
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All subjects with bone ages determined at baseline and after at least 1 yr of treatment were analyzed, excluding any obtained after initiation of a GnRH superagonist. Skeletal maturation was delayed before rhIGF-I therapy (chronological age averaged 6.5 yr, bone age averaged 3.8 yr). The interval between the first and last bone age averaged 5.1 ± 3.0 yr within this group during which time bone age advanced 5.8 ± 2.9 yr. This modest difference (0.7 ± 1.8 yr), although statistically significant (P = 0.013; n = 47), indicates that skeletal maturation typically progresses in accord with advancing chronological age during treatment.
Kidney growth was estimated in 16 males and seven females, most of whom had ultrasonography at or near the time of initiation of rhIGF-I treatment. The initial examinations revealed renal lengths that were low for age, with a mean SD score of –3.2 ± 1.6. Kidney length SD scores for height (using the mean of the left and right renal lengths) were computed using norms from Han and Babcock (13). Mean baseline kidney length SD scores for height were –1.0 ± 0.8. The average kidney size increased significantly (P < 0.001) during rhIGF-I treatment and was 0.3 ± 1.7 SD above the mean after 4.2 ± 1.5 yr. Kidney length SD score height at last assessment exceeded +2 in five subjects (maximum +3.2).
Splenic length was measured on at least two occasions on each of 23 subjects. SD scores for height were computed using norms from Megremis et al. (14). Average spleen length SD score for height was –1.0 ± 1.2 at baseline. An increase in spleen size was detected by ultrasound in the majority of subjects during treatment (P < 0.05). Mean spleen length SD score for height was –0.1 ± 1.5 after an average of 4.1 yr of treatment. Two subjects had spleen length for height greater than 2 SD above the mean at last measure. Thymic enlargement was reported in eight of 23 subjects (35%) in whom chest radiographs were routinely obtained. Chest radiographs were not systematically performed in the remainder.
Metabolic measures
Finger stick blood glucose (FSBG) concentrations were measured four times daily in 23 subjects hospitalized during the initiation of rhIGF-I therapy. They received a regular diet and rhIGF-I injections as described. Episodes of both hyperglycemia [defined as premeal FSBG > 140 mg/dl (7.77 mmol/liter)] and hypoglycemia [FSBG < 50 mg/dl (2.78 mmol/liter)] were observed (Fig. 2). There were numerous occurrences of hypoglycemia before breakfast and lunch before initiation of IGF-I therapy. Instituting rhIGF-I therapy did not appear to influence the frequency of hypoglycemia at these times. However, the treatment may have lowered glucose concentrations later in the day because there were no occurrences of hypoglycemia before supper or at 2200 h until IGF-I therapy began. Despite this apparent trend, when we compared the fraction of blood glucose measures less than 50 mg/dl for each subject before and during rhIGF-I, no difference was found (P = 0.48, paired t test). Sporadic hyperglycemic episodes were observed in nine of the 23. There was no statistically significant difference between these nine and the others with respect to gender, age, baseline height and BMI SD scores, or first-year height velocities.
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Plasma cholesterol was in the normal range for the majority and appeared to increase modestly over time (Table 3). Triglyceride concentrations were normal during the first 4 yr of treatment but on average higher in the small number of subjects assessed at 8 yr. These changes occurred in the context of relatively small alterations in BMI and percent body fat, which was estimated by DEXA in 22 subjects. Body fat percentage averaged 26.2% at baseline. During the next 2 yr, there was a mean decrease of 2.5% (P < 0.05), but after 2 yr, the mean returned to the baseline level of 26.2%. Furthermore, there was no apparent effect of insulin sensitivity as estimated by homeostasis model assessment (15) during the first year of treatment, and glycated hemoglobin concentrations were normal and unchanged throughout.
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Adverse events of relevance to rhIGF-I therapy are listed in Table 4. Thirty-seven subjects (49%) had one or more hypoglycemic episodes reported during treatment with rhIGF-I. These occurred most often in the first month. Hypoglycemia was severe in seven; four had hypoglycemic convulsions. Of those reporting hypoglycemia, 12 (32%) had a history of hypoglycemia before beginning treatment. Using time-to-event analysis with censoring, younger subjects had a greater tendency for hypoglycemia (P = 0.004). Further analysis of 62 treatment-naive subjects treated at least 1 yr revealed that hypoglycemia occurred more commonly in younger, shorter subjects with a prior history of spontaneous hypoglycemia (data not shown).
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) may be an underestimate because certain adverse effects may require prolonged periods to manifest. For example, the incidence of snoring at the primary centers (at which the longest-treated subjects are monitored) was only one of 25 during the first year of treatment but 16 of 25 for the entire observation period. Concern about possible effects of tonsillar/adenoidal hypertrophy caused us to add hearing tests to the routine evaluation for 23 subjects studied at the primary centers. At their most recent examinations, 12 had completely normal hearing, nine had findings of mild conductive hearing loss, and two had moderately severe to profound hearing deficits. One of the more severely affected had hearing loss before rhIGF-I therapy documented by audiological measurement. The other had moderate sensorineural hearing loss that was identified early in the course of treatment and remained stable throughout. Because few had testing before initiation of rhIGF-I treatment, it cannot be determined whether a mild conductive deficit is feature of severe GHIS or an effect of therapy.
Lipohypertrophy at sites of rhIGF-I injections, as previously described (5), was reported in a third of the subjects, although the actual incidence may be higher. It could be minimized and reversed by attention to injection site dispersion, as with insulin.
Intracranial hypertension developed in three subjects early in the course of treatment. Two were twin siblings and had magnetic resonance imaging evidence of preexisting communicating hydrocephalus; their symptoms resolved without interruption of treatment. Resolution followed a temporary interruption of treatment and lumbar puncture to reduce cerebral spinal fluid pressure in the third subject. Treatment with rhIGF-I was resumed at a lower dose 6 months later without recurrence of symptoms.
Twenty-three subjects were monitored for the development of IGF-I antibodies. Of those, 14 tested positive during treatment (11 during the first year). Five of these tested consistently positive over the course of their treatment, whereas the remainder were intermittently positive. There was no significant difference between the mean height velocities during the first year (two-tailed P = 0.51) for subjects who were antibody positive at that time and those who were antibody negative.
Changes in facial appearance were noted in many subjects during therapy, particularly during puberty. These included an apparent coarsening of the face with enlargement of nose and brow as previously reported for subjects from this cohort (5). Figure 3 displays sequential facial photographs of three subjects.
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Discussion |
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The growth response is less than that observed when severely GH-deficient children are given GH replacement. Those children typically continue to grow at supranormal rates and usually achieve adult heights in the normal range (16). In contrast, our rhIGF-I-treated subjects grew at approximately normal rates after the first year of treatment and therefore seem unlikely to reach adult heights in the normal range. Compliance may have been a factor for some for which living conditions were especially challenging. However, more likely this reflects our inability to replicate physiological IGF-I distribution and action and/or to restore direct GH effects. The actions of IGF-I involve both endocrine and paracrine/autocrine mechanisms (17), but we have putatively restored the endocrine component only. If locally produced IGF-I is especially important for chondrocyte proliferation within the growth plate, then the effects of exogenous rhIGF-I may be limited. In addition, blood-borne IGF-I normally complexes with IGFBP-3 and acid labile subunit, all three of which depend on GH sufficiency. The sc administration of rhIGF-I does not correct the low concentrations of IGFBP-3 and acid labile subunit characteristic of GHIS (11). As a consequence the clearance of administered rhIGF-I (18) is accelerated and perhaps tissue distribution affected. Finally, lack of direct actions of GH may be involved as animal studies indicate GH has growth-promoting effects apart from the IGFs (1).
Before such long-term trials were conducted, there was concern that rhIGF-I therapy might produce unacceptable side effects. Disproportionate organ growth and hypoglycemia were among the principal worries. We did observe increased growth of the kidneys, spleen, and thymus, but the effect waned over time and had no clinical impact. Many subjects had events that could be related to increased growth of tonsillar and adenoidal tissue such as snoring. Some had persistent middle ear effusion requiring tympanostomy tubes. Eight subjects (11%) required tonsillectomy/adenoidectomy.
Early reports described isolated cases of soft tissue overgrowth and coarsening of facial features (19), which was attributed to hyperandrogenism in one case (20). We again observed the changes in facial features previously described during prolonged therapy (5). These have been difficult to quantify, vary in intensity among the subjects, and appear to regress partially after withdrawal of therapy. In a preliminary report involving eight subjects, cephalometric evaluation of craniofacial development during the first 2–4 yr of therapy indicated relatively rapid growth of the maxilla and mandible, compared with other facial structures (21). However, further analysis after 6 yr of therapy did not reveal further preferential growth of these structures (Backeljauw, P. F., personal communication).
Hypoglycemia occurred in almost half the subjects and with severe episodes in seven. Hypoglycemia was observed both before and during treatment; monitoring of subjects suggested that rhIGF-I had little effect on premeal blood glucose concentrations when adequate quantities of carbohydrates were consumed. This is in accord with prior reports describing blood glucose measures in GHIS patients given rhIGF-I (22, 23). Symptomatic hypoglycemic episodes, a definite hazard for subjects with low fasting blood glucose concentrations receiving rhIGF-I, were largely avoided by eating a meal at the time of each injection.
The appearance of benign intracranial hypertension has been reported previously during therapy with GH (24) and IGF-I (25, 26). The mechanisms involved are not known. Two of the cases reported here occurred in subjects with possible predispositions to the condition; all three resolved.
Metabolic abnormalities observed during the course of therapy (hypercholesterolemia, hypertriglyceridemia, hyperglycemia) are consistent with prior reports describing the metabolic status of patients with GH insensitivity (27). These may, in part, be a consequence of reduced IGF-I signaling on insulin sensitivity and pancreatic islet cell function (28, 29) but also may reflect other abnormalities because they did not resolve during IGF-I replacement. Indeed, rhIGF-I appears to be overall less effective than GH at reducing fat mass in deficiency states (30), even though short-term rhIGF-I has distinct lipolytic properties in GH insensitivity (31).
In summary, we report that rhIGF-I treatment has a prolonged effect on growth in children with severe IGF-I deficiency due to GH insensitivity. Although most subjects under study did not experience sufficient catch-up growth to bring their heights into the normal range, it appears that they may achieve adult heights significantly greater than expected in the absence of therapy. Whether the height outcome could be further improved by initiating treatment earlier, or by using different dosing regimens or products [such as IGF-I and IGFBP-3 combined (32)] remains unknown and reflects our inadequate understanding of IGF-I distribution and action.
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Acknowledgments |
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Footnotes |
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Disclosures: S.D.C. receives research support and lecture fees from Tercica, Inc., and Genentech, Inc., and serves as consultant to Tercica, Inc. P.F.B has received lecture fees from Tercica, Inc. J.F. has equity ownership and receives consulting fees from Tercica, Inc., and Genentech, Inc. J.F. has coauthored a patent with Tercica, Inc. J.K. is employed by Tercica, Inc. J.K. has received consultant fees and has equity ownership in Tercica, Inc., and Genentech, Inc. L.E.U. receives research support from Tercica, Inc., and serves on steering committee for Insmed, Inc.
First Published Online December 27, 2006
1 See Acknowledgments for members of the GH Insensitivity Syndrome Collaborative Group. 
Abbreviations: BID, Twice a day; BMI, body mass index; DEXA, dual-energy x-ray absorptiometry; FSBG, finger stick blood glucose; GHAB, GH-neutralizing antibodies; GHIS, GH insensitivity syndrome; GHRD, GH receptor deficiency; IGFBP, IGF binding protein; rh, recombinant human.
Received July 25, 2006.
Accepted December 14, 2006.
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