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Growth Hormone Treatment Improves Growth and Clinical Status in Prepubertal Children with Cystic Fibrosis: Results of a Multicenter Randomized Controlled Trial

Departments of Pediatrics (D.S.H., C.P., J.R.) and Biostatistics and Clinical Science (B.A.-H.), University of Texas Southwestern Medical School, Dallas, Texas 75390; University of South Carolina School of Medicine (D.B.), Columbia, South Carolina 29203; University of Utah (B.C.), Salt Lake City, Utah 84132; Cook Children’s Hospital (M.D.), Fort Worth, Texas 76104; Department of Pediatrics (T.F., R.S.), Washington University School of Medicine, St. Louis, Missouri 63110; Indiana University School of Medicine (M.H.), Indianapolis, Indiana 46202; Vanderbilt School of Medicine (J.S.), Nashville, Tennessee 37232; Dayton Children’s Hospital (F.R.), Dayton, Ohio 46404; Texas Children’s Hospital/Baylor College of Medicine (D.K.S.), Houston, Texas 77030

Address all correspondence and requests for reprints to: Dana S. Hardin, M.D., Chief of Pediatric Endocrinology, The Ohio State University, Columbus Children’s Hospital, 700 Children’s Drive, ED 543, Columbus, Ohio 43205-2696. E-mail: hardind{at}pediatrics.ohio-state.edu.

	Abstract

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Context: This multicenter, randomized, controlled, crossover trial of prepubertal children with cystic fibrosis (CF) tests the hypotheses that recombinant human GH (rhGH) treatment 1) improves height, weight, lean mass, and bone content irrespective of baseline measures; 2) improves clinical status and quality of life; and 3) has continued effect after cessation after 1 yr of treatment.

Methods: Sixty-one prepubertal subjects (25th percentile for height and weight) were randomized into two groups: daily rhGH treatment or no treatment groups for 1 yr. In yr 2, treatments were crossed over. Outcome measures included serial standardized height and weight, number of hospitalizations and antibiotic courses, random blood glucose levels, lean mass, bone mineral content, pulmonary function, nutritional intake, and CF quality of life questionnaires.

Results: Groups were similar at baseline and prepubertal during the entire study. After 1 yr, GH showed significantly greater gain in height, weight, lean mass, and bone mineral content. Gain in height was similar regardless of baseline. There were fewer hospitalizations in the rhGH-treated group and improvement in CF quality of life questionnaires measures of weight and body image. There was no difference in pulmonary function between groups. Results were similar in those treated with rhGH the second year. After cessation of rhGH treatment, there was sustained effect for increased height and weight velocity, as well as accrual of bone mineral.

Conclusion: rhGH therapy improves height and weight, decreases the number of hospitalizations, and improves quality of life in prepubertal children with CF. These effects are sustained after rhGH is discontinued.

	Introduction

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CYSTIC FIBROSIS (CF) is the most common lethal genetic disorder, currently affecting 30,000 people in the United States (1). It has long been recognized that the weights and heights of CF populations are skewed toward the lower percentile bands, and poor weight is associated with increased morbidity and mortality (2, 3). Height is an independent risk factor for worse pulmonary function (4, 5) and is of particular concern because even patients with good nutritional status do not achieve full target height (6, 7, 8).

Previous studies of the use of recombinant human GH (rhGH) in children with CF whose height and weight were in the 10th percentile or lower for age demonstrate improved growth (9, 10, 11, 12, 13, 14, 15), lean mass (14), and protein turnover (16). However, whether this effect can be extended to those less severely affected, but who may not be achieving their growth potential, is unknown. Moreover, if there is such an effect, the clinical relevance and sustainability of such treatment requires evaluation. Our current study examined the effect of rhGH on CF subjects with height and weight in the 25th percentile or lower, thus allowing comparison of growth response in children with a broad range of baseline height. We assessed other relevant end-points including weight, lean mass, clinical outcome, quality of life, and bone mineralization.

	Subjects and Methods

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Subjects

Sixty-one subjects were enrolled from 10 geographically dispersed CF centers in the United States with final analyses conducted on 57 subjects (see Appendix). Inclusion criteria included the following: age, 7–12 yr; height and weight in the 25th percentile or lower for age; Tanner I breast in females; and testicular development 3 cc or less in males. Exclusion criteria consisted of preexisting diabetes; systemic corticosteroid use within 6 months; colonization with Burkholderia cepacia; and/or addition of oral, enteral, or parenteral caloric supplements within the previous year.

The protocol was approved by the Institutional Review Boards at all participating centers. Parents gave written informed consent, and subjects, written assent. Each subject continued to receive pancreatic enzyme replacement, vitamin supplementation, inhaled bronchodilators, and mucolytics. Other therapies, including antibiotics, were prescribed as clinically indicated.

Subjects were randomized into one of two treatment arms for 1 yr: daily treatment with rhGH (GH) (Nutropin AQ, 0.3 mg/kg·wk; Genentech, San Francisco, CA) or no treatment (NT); subjects were then crossed over to the other arm and followed for a second year. The patients who had received rhGH the first year did not receive rhGH during the second year. We used their data to evaluate sustained effect after drug cessation (named the sustained effect group during the second year). Subjects treated with rhGH and their parents were instructed in the technique of injection, and compliance was assessed by return of rhGH vials. Placebo injection was not given to subjects in the NT group. GH stimulation testing was not performed before initiating therapy, and IGF-I levels were not followed. Assessment for development of puberty was conducted every 3 months.

Anthropometric measurements

Height and weight were measured every 3 months by experienced staff using wall-mounted stadiometers and a standardized scale and reported as the mean of three independent measurements. SD scores (SDS) were calculated using GenCalc (Genentech). Study visits were conducted when the subjects were clinically well (defined as no indication for antibiotic therapy or hospitalization).

Total body lean mass (LM) and bone mineral content (BMC) were measured every 6 months using dual energy x-ray absorptiometry. Each center used either a Hologic (Waltham, MA) or a Lunar (GE, Piscataway, NJ) device throughout the study. Thus, the same machine was used for individual subjects throughout the study. Quality analysis was measured twice per week using the phantom provided by each machine maker. Standardization of BMC into SDS was calculated using age-, gender-, and bone age-matched data from the Children’s Nutrition Research Center (17).

Clinical status

Hospitalizations and iv antibiotic courses related to pulmonary exacerbation were recorded and verified by the review of the medical record. Forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1) were measured by standard spirometry and established American Thoracic Society Guidelines. The mean of three efforts was expressed as absolute value and percent predicted (%) using Knudson standards (18).

Nutritional intake was measured using 24-h food history every 6 months. Data were analyzed using Diet Master Pro software (Lifestyle Technologies, Phoenix, AZ). Random blood glucose levels (DEX Meter; Bayer Health Care, New York, NY) measured at each visit were used to screen for glucose intolerance per National CF Foundation Guidelines (19). Bone age x-ray was obtained every 12 months (20).

Quality of life

Subjects and their parents filled out separate CF Health-Related Quality of Life questionnaires (HRQOL) (21) every 6 months. The parental questionnaires contained 84 questions, and the child’s contained 52. The following health components were assessed: physical functioning, vitality, life role, body image, eating disturbance, health perception, treatment burden, weight, respiratory system, and digestive system. Children were separated from parents during the questioning, and research coordinators recorded the children’s answers. Results were assembled by OVATION (Highland Park, IL).

Statistics

Data are reported as the mean ± SD. There was a carry-over effect of rhGH; therefore, the primary results were analyzed as a parallel study using only yr-1 data. The primary model for analysis of the first-year data was a two-factor repeated-measures ANOVA model with one repeated effect (baseline vs. month 12) and one group effect (GH vs. NT) and their interaction. The sustained effect of rhGH was determined by comparing the response of patients treated with rhGH during the first year to growth achieved during the second year after therapy was discontinued using a single-factor repeated-measures ANOVA model. The response to therapy was compared between subjects who had different baseline heights with a Student’s t test. SAS software version 9.1.3 (SAS Institute, Cary, NC) was used with significance determined at the level of 0.05.

	Results

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Subjects were similar at baseline (Table 1) and all remained prepubertal throughout the study. After the first year, the GH cohort demonstrated significantly greater height, weight (Fig. 1), height and weight velocity, and change in LM and BMC (Table 2). Both groups were osteopenic at baseline (22); however, BMC normalized in the GH group at 1 yr (BMC SDS: baseline: GH, –2.1 ± 0.6 and NT, –1.7 ± 0.9; 1 yr: GH, –1.4 ± 0.8 and NT, –1.7 ± 0.8, P = 0.04). Improvement was similar in the group obtaining rhGH the second year (–1.3 ± 0.7).

View larger version (25K): [in this window] [in a new window]   FIG. 1. Comparison of height and weight velocity at baseline and 1 yr. Depicted are the height (A) and weight (B) velocities at 1 yr between the children treated with rhGH the first year (GH) and those randomized to no treatment the first year (NT). The data are expressed as centimeters per year and kilograms per year and are summarized as mean ± SD. The GH cohort gained height and weight at a faster rate. These results are similar to our previous findings (14 ) from children with baseline height at the 10th percentile (SDS < –1.3).

View larger version (21K): [in this window] [in a new window]   FIG. 2. Hospitalizations for pulmonary exacerbation. Depicted is the comparison of the total number of hospitalizations per year for pulmonary exacerbation between the GH and NT groups at baseline and 1 yr. The change in total number of hospitalizations was significantly lower in GH.

Quality of life scores were similar between groups at baseline with the exception of lower perceived weight in GH (baseline: GH, 1.5 ± 0.8 and NT, 1.8 ± 0.9). The change in HRQOL scores for weight demonstrated greater perceived improvement in the GH group (change in HRQOL: GH, 0.4 ± 0.8 and NT, 0.3 ± 0.8, P = 0.04). The GH group also perceived better body image at 12 months (change in body image: GH, 0.3 ± 0.9 and NT, –0.2 ± 0.9, P = 0.03). There was no statistical difference between the groups for other HRQOL measures. Importantly, there was no difference in treatment burden despite institution of GH.

Caloric intake was similar at baseline and 1 yr in both groups (baseline kcal intake: GH, 2430 ± 710 kcal/d, or 101 kcal/kg, and NT, 2504 ± 946 kcal/d, or 109 kcal/kg; 1-yr kcal: GH, 2589 ± 856 and NT, 2610 ± 729 kcal/d) and was consistent with the stated guidelines set by the CF Foundation (23). Carbohydrate, fat, and protein intakes were similar at all time points in both groups (mean % of total calories: carbohydrate, 52; fat, 34; protein, 14). Casual blood glucose levels remained in the nondiabetic range (4) in all subjects, and there was no difference between the groups. Baseline bone age was similar in the GH and NT groups (9.1 ± 1.2 and 8.7 ± 1.2 yr, respectively) and advancement did not exceed 1 yr annually in any study group.

The sustained effect group was older (10.9 yr) and had higher baseline height, weight, LM, and BMC (data are presented as the 12-month data for the NT group; Table 2). Analysis at 6-month intervals reveals significantly greater rate of gain in weight and height than NT and is similar to GH (Table 2). There was continued increase in absolute FVC and FEV1 1 yr after GH was discontinued (FVC, +0.16 ± 0.1, P = 0.041, and FEV1, +0.13 ± 0.2, P = 0.048). Analysis of the nontreated group after crossing over to rhGH treatment during the second year reveals similar improvement in height gain (+ 9.0 ± 1.0 cm), weight gain (+5.1 ± 1.6 kg), LM (+5.6 ± 1.2 kg), and BMC (+184 ± 68 g).

We conducted a planned subgroup analysis of height response to rhGH by comparing those subjects severely stunted at baseline (height SDS < –2.2, n = 9, range –2.2 to –3.6) to those with greater baseline height (height SDS > –1.2, n = 9, range –0.01 to –1.2). The gain in height after rhGH therapy was similar in each group, with an increase of +0.42 ± 0.13 SDS and +0.47 ± 0.4 SDS, respectively (P = 0.3).

	Discussion

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The improvements in height, weight, and LM are consistent with those reported previously by our group and others (9, 10, 11, 12, 13, 14, 15, 24); however, this study reflects results from both a larger number of subjects and a wider range of baseline growth parameters, including patients in the normal percentile range, although possibly not achieving their full growth potential. The finding of equal improvement in height despite the degree of baseline stunting is new and reflects an important benefit of rhGH treatment given the findings by Konstan et al. (4) and Beker et al. (5) that children with lower height had poorer pulmonary function several years later. Improvement of body weight and LM are important anabolic effects of rhGH. Low weight and poor LM have been associated with greater morbidity (2, 25). Another important anabolic benefit of rhGH therapy is the increased accrual of bone mineral. Osteoporosis is a significant problem in CF (22, 25). These patients have many risks factors including poor growth and delayed puberty, at the time in which the majority of bone is accumulated (23). Greater accumulation of total BMC and its normalization in previously osteopenic children would allow a greater "bone bank" during adulthood, potentially limiting the incidence of osteoporosis in adults with CF.

One of the most important findings of this study is the decrease in hospitalizations with rhGH, which is consistent with our previous report (14). These results are likely representative of expected results nationally because subjects in this study were recruited from different U.S. centers with varying practices. Although the cost of hGH treatment is high, the cost is offset by reduction of even one hospitalization per year.

Our group has documented improved absolute FVC (14, 24) in patients with more severe growth failure. This was likely related to improved longitudinal growth. Although our current study did not find statistical difference between groups at any time point, FVC increased in the GH cohort and decreased in the NT cohort. There was continued improvement during the year after rhGH was discontinued, suggesting that change in pulmonary function may require more than 1 yr to be realized. Furthermore, there was no decline in percent predicted pulmonary function, despite the rapid increase in linear growth. These findings are clinically significant given the traditional yearly decline in CF patients (26).

Using validated questionnaires, our study documented improved perceived body weight, body image, eating, and role (activities relating to normal life, i.e. student, child) in the rhGH-treated group. We found no increase in treatment burden, which is remarkable because rhGH therapy requires daily sc injections. CF is associated with much physical and psychological stress. Improvement in quality of life reflects a no-cost, measurable benefit, which is particularly important as the lifespan continues to increase in these patients.

This is the first study to evaluate the potential for sustained effect of rhGH in CF. We observed continued improvement in the accrual of height, weight, and BMC. There did not appear to be sustained effect on accrual of LM, possibly secondary to the loss of anticatabolic effects (16) once rhGH treatment ceases. Studies of additional intervals will be required to determine how long rhGH actually results in greater accrual of LM.

Similar to our previous findings, rhGH treatment did not result in increased calorie consumption. Improved growth while maintaining similar caloric intake suggests improved efficiency of calorie use. Our group previously demonstrated improved protein catabolism in CF subjects treated with rhGH (16). This may be the mechanism of improved caloric efficiency. Despite the potential for rhGH to worsen insulin resistance (17), we did not find any evidence of glucose intolerance as measured by random blood glucose levels. Although an oral glucose tolerance test would have been a more rigorous method of assessment, it should be noted that the random blood glucose level is recommended by the North American Cystic Fibrosis Foundation as the first step in ruling out glucose intolerance. Thus, only a patient with elevated random blood glucose would undergo an oral glucose tolerance test, and none of our subjects would have received one based on these recommendations (19).

In summary, this clinical trial represents the first multicenter evaluation of the effects of rhGH therapy in CF children with varying growth patterns and is the largest study to date. We found similar improvement in growth as described in previous smaller single-center studies. Taking into account all studies of rhGH in prepubertal children with CF (11, 12, 13, 14, 15), more than 125 children have been studied. Significant improvement in height has been universally documented, and weight consistently improved in all studies but one, in which rhGH was given only three times per week (14). No study has shown deleterious effects of the drug. A criticism that has been made against rhGH use in CF is increased burden of medical care and cost, though our current study suggests that these concerns may be unwarranted. The collective data strongly suggest that rhGH therapy imparts considerable nutritional, growth, and clinical benefits to prepubertal CF children and should be considered important adjunctive treatment. These results are likely indicative of an anticatabolic benefit, which would be applicable to the justification for rhGH for treatment of children with other chronic illnesses affecting growth.

	Appendix: Total Number of Children Enrolled from CF Centers and Patient Dropouts

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Recruitment sites (and number of subjects from each)

University of Texas Southwestern/Children’s Medical Center (12 subjects), Texas Children’s Hospital/Baylor College of Medicine (4), Vanderbilt Medical School (6), University of South Carolina Medical School (4), Indiana University School of Medicine (8), University of Utah (8), Cook Children’s Hospital in Fort Worth (9), Dayton Children’s Hospital (1), and Washington University School of Medicine and St. Louis Children’s Hospital (9). Total enrolled: 61.

Dropouts and changes from enrollment

One subject randomized to treatment with hGH (male) quit during the first few weeks because of fear of injection. We excluded the data on a second male randomized to GH because he started enteral feedings during his treatment year. One subject randomized to NT did not return for follow-up, and we dropped the data on a second subject randomized to NT because she developed CF-related diabetes during the final 3 months of the first year. One subject (male) dropped out after completing the entire first year of hGH treatment at month 18 during the second year while not on treatment. We used his entire first-year data. During the trial, three subjects (all from the Dallas center) received single 5- or 6-d courses of systemic corticosteroids. Their data were included (two NT and one GH). Total number of subjects included in analysis: 57 children.

	Acknowledgments

 
The authors thank Dr. Mike Konstan and Dr. John Parks for critical review of the manuscript. D.S.H. thanks Dr. Sandra Blethen for her continued support and mentorship.

	Footnotes

 
This study was supported by a grant from The Genentech Center for Clinical Research in Endocrinology.

Disclosure Statement: D.S.H. was previously on the advisory board for Genentech; the remaining authors have nothing to disclose.

First Published Online October 3, 2006

Abbreviations: BMC, Bone mineral content; CF, cystic fibrosis; FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity; HRQOL, Health-Related Quality of Life questionnaires; LM, lean mass; rhGH, recombinant human growth hormone; SDS, SD score.

Received May 22, 2006.

Accepted September 27, 2006.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: 91/12/4925    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hardin, D. S. Articles by Shepherds, R. Search for Related Content PubMed PubMed Citation Articles by Hardin, D. S. Articles by Shepherds, R. Pubmed/NCBI databases OMIM Substance via MeSH Medline Plus Health Information Cystic Fibrosis Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology