Effectiveness of Recombinant Human Growth Hormone rh GH

Effectiveness of Recombinant Human Growth Hormone (rh. GH) in the Treatment of Patients With Cystic Fibrosis Prepared for: Agency for Healthcare Research and Quality (AHRQ) www. ahrq. gov

Outline of Material Introduction to cystic fibrosis (CF) and growth hormone Systematic review methods Results of studies of rh. GH use in patients with CF: Intermediate outcomes Health outcomes Correlation of intermediate and long-term outcomes Possible harms Future research Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Health Impact of Cystic Fibrosis in the United States An estimated 30, 000 people in the United States have CF. Approximately 1, 000 children each year are born with the disease. CF is the second most common life-shortening, childhood-onset genetic disease in the United States. Treatment advances now promote survival into adulthood; in 2006 the median age of survival was 37 years. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Characteristics of CF: Origin of the Disease CF is a genetic autosomal-recessive disorder. Caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Defects in CFTR alter the transport of sodium and chloride ions across epithelial membranes. Nearly all exocrine glands are affected. CFTR mutations result in the production of excessive, viscous mucus. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Clinical Features of Cystic Fibrosis Pulmonary: chronic sinopulmonary infection Progressive lung disease is responsible for most morbidity and mortality in patients with CF Complications: bronchiectasis, loss of lung tissue and function, respiratory insufficiency, and death Gastrointestinal: pancreatic insufficiency Gastrointestinal (GI) and endocrine complications: Steatorrhea, malnutrition, and growth retardation CF-related diabetes (CFRD) and osteoporosis Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Rationale for Use of Recombinant Human Growth Hormone (rh. GH) in Patients With CF Despite aggressive treatment of nutritional needs as part of standard care, as many as one-third of patients with CF in the United States are below the 10 th percentile for height and weight. Some studies have associated improved growth with better clinical outcomes in patients with CF. As an anabolic agent that promotes growth, rh. GH for treatment of patients with CF may lead to better intermediate and long-term health outcomes and improved quality of life. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Approved Therapeutic Uses of rh. GH has been approved by the U. S. Food and Drug Administration for treatment of: Growth-hormone deficiency Idiopathic short stature Turner syndrome Prader-Willi syndrome Chronic renal insufficiency Small for gestational age Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others. A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. The results of these reviews are summarized into Clinician Guides and Consumer Guides for use in decisionmaking and in discussions with patients. The Guides and the full report, with references for included and excluded studies, are available at www. effectivehealthcare. ahrq. gov. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Clinical Questions Addressed by the CER (1) Does treatment improve intermediate outcomes (pulmonary function, growth, body composition, bone mineralization, exercise tolerance)? Does treatment improve health outcomes (e. g. , intravenous antibiotic use, pulmonary exacerbations, hospitalization rate)? What is the strength of evidence that improvements in intermediate clinical outcomes lead to benefits in important health outcomes such as mortality risk and health-related quality of life (HRQo. L)? Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Clinical Questions Addressed by the CER (2) What is the risk of serious nonmalignant adverse events, such as development of CFRD, glucose intolerance, hyperglycemia, or liver disease? What is the risk of malignant adverse effects? What is the impact of therapy dose, duration, nutritional status, and concurrent medical therapies on effectiveness and safety? How do patient subgroup characteristics affect effectiveness and safety? Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Rating the Strength of Evidence From the CER: A Modification of the GRADE Methodology The strength of evidence pertaining to each key question of the CER is classified into four broad categories or grades: High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect. Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate. Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate. Insufficient Evidence is either unavailable or does not permit estimation of an effect. Guyatt GH, et al. BMJ 2008; 336: 924 -6; Owens DK, et al. J Clin Epidemiol 2010; 63: 513 -23; Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Outcomes of Interest in Studies of rh. GH Treatment of Patients With CF Intermediate Outcomes Health Outcomes Pulmonary function Anthropometrics Bone mineralization Exercise tolerance Frequency of Hospitalization Frequency of IV antibiotic use Quality of life Bone consequences: fractures, osteoporosis/osteopenia Mortality Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Adverse Events of Interest in Studies of rh. GH Treatment of Patients With CF Nonmalignant: Cystic fibrosis–related diabetes (CFRD) Glucose intolerance, hyperglycemia Malignant: Biomarkers of cancer risk Reports of cancer incidence Injection site reactions Liver function effects Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Controlled Trials of rh. GH Treatment for CF Summarized in the CER Study First Author, Year rh. GH Treated, N Untreated Controls, N Hardin et al. , 2001 10 9 Hutler et al. , 2002 6 4 Schibler et al. , 2003 10 9 Darmaun et al. , 2004 18 9 Hardin et al. , 2005 16 16 Hardin et al. , 2005 (b) 13 12 Hardin et al. , 2005 (c) 9 9 Hardin et al. , 2006 32 29 Schnabel et al. , 2007 42 21 Stalvey et al. , 2008 29 27 Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Characteristics of Trials of rh. GH Treatment for Patients With CF Nutritional needs were addressed for all patients before they entered the trials. Both pubertal and prepubertal patients were enrolled. Trials were conducted over 6 to 12 months. The most commonly used dosage schedule was 0. 3 mg/kg/week divided into equal daily doses. Doses ranged from 0. 27 to 0. 49 mg/kg/week. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

rh. GH Effects on Intermediate Outcomes in Controlled Trials: Pulmonary Function Control Summary Effect Mean Difference (95% CI) 48 0. 67 L 52 (0. 24, 1. 09)* 0. 23 L 60 (0. 01, 0. 46) * 9. 34% No. of Patients Outcome No. of Trials Treated Absolute FVC 3 Absolute FEV 1 6 Percent Predicted FVC 4 Percent Predicted FEV 1 5 52 58 84 71 48 (3. 41, 15. 27) * 2. 43% (-3. 99, 8. 85) Level of Evidence Moderate Low Moderate *Statistically significant. CI = confidence interval; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity. Phung OJ, Coleman CI, Baker EL , et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

rh. GH Effects on Intermediate Outcomes in Controlled Trials: Anthropometrics No. of Patients Outcome No. of Trials Height Velocity 4 82 57 Height Z-score 3 48 45 Weight 6 100 67 Weight Velocity 2 40 BMI 2 Lean Body Mass Treated Control Summary Effect Mean Difference (95% CI) Level of Evidence (2. 33, 4. 21)* Moderate (0. 35, 0. 66) * Moderate 1. 48 kg (0. 62, 2. 33) * Moderate 36 2. 15 kg/y (1. 52, 2. 78) * Moderate 22 18 2. 08 kg/m 2 (1. 2, 2. 96) * Moderate 9 170 131 1. 92 kg (1. 47, 2. 37) * Moderate Height 3 33 31 3. 13 cm (0. 88, 5. 38) * Low Weight Z-score 4 45 43 0. 49 Percent Ideal Body Weight 2 23 21 12. 57% Bone Mineral Content 4 68 64 192 g 3. 27 cm/y 0. 51 *Statistically significant. BMI = body mass index; CI = confidence interval. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm. (-0. 02, 1. 00) Low (7. 01, 18. 12) * Low (110, 273) * Low

rh. GH Effects on Health Outcomes Reported in Controlled Trials Outcome Hospitalizations per year No. of Patients No. of Trials Treated Control 4 64 59 Summary Effect Mean Difference (95% CI) -1. 62 per year (-1. 98, -1. 26) Level of Evidence Moderate CI = confidence interval. Hospitalization rate was reduced in treated patients during the course of the studies. Evidence about antibiotic use, pulmonary exacerbations, and HRQo. L was insufficient to formulate an estimate of effect. Bone consequences and mortality were not reported in any rh. GH trial. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Intermediate End Points and Health Outcomes in rh. GH-Treated Patients With CF (1) The studies of rh. GH therapy for patients with CF provide no evidence about the impact of treatment on long-term health and survival. How well do the intermediate end points measured in trials of rh. GH for CF patients (pulmonary function, anthropometrics) predict important health outcomes such as mortality and quality of life? To address this question, results were compiled from studies that used regression analysis to examine these linkages in patients with CF. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Intermediate End Points and Health Outcomes in rh. GH-Treated Patients With CF (2) § Included studies were conducted in children, adolescents, and adults with CF and reported on the correlation between intermediate outcomes and health outcomes. § Studies were not restricted to trials of rh. GH in patients with CF. Health Outcomes No. of Studies No. of Patients Mortality 34 56, 507 Health-Related Quality of Life 16 1416 Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Intermediate End Points and Health Outcomes in rh. GH-Treated Patients With CF (3) Review of the regression analysis studies found that: 1. Percent predicted FEV 1 is a consistent predictor of mortality, by multivariate regression analysis. Higher baseline scores or lesser rates of decline are linked to better survival rates in a majority of analyses. 2. Percent predicted FEV 1 is a multivariate predictor for several individual domains of HRQo. L questionnaires. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Intermediate End Points and Health Outcomes in rh. GH-Treated Patients With CF (4) 3. Other pulmonary function measures do not exhibit the predictive strength of percent predicted FEV 1. Other pulmonary function measures were linked to mortality and HRQo. L in about half of the univariate and multivariate analyses. 4. Among anthropometrics, only weight showed a consistent predictive relationship with mortality risk. 5. The connection between weight and HRQo. L is not clear. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Summary of Benefits (1) Hospitalizations per patient were reduced by 1. 6 per year on average. Level of Evidence = Moderate Increases in weight were observed for rh. GHtreated patients. Although weight is associated with mortality risk, there is no direct evidence about how the weight gains may modify disease outcomes. Level of Evidence = Moderate Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Summary of Benefits (2) Bone mineral content increased in rh. GH-treated patients, but it is not known if this change alters fracture risk. Level of Evidence = Low Percent predicted FEV 1 is a good predictor of mortality risk and influences HRQo. L, but rh. GH treatment did not improve this measure. Level of Evidence = Moderate Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Potential Harms of rh. GH Treatment to Patients With CF Glucose control and CFRD Cancer risk Injection-site reactions Liver-function effects Any adverse event Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Potential Harms of rh. GH Treatment to Patients With CF: Glucose Control and CFRD (1) CF can lead to CFRD through damage to pancreatic beta cells and loss of insulin sensitivity. Rh. GH influences glucose utilization and insulin sensitivity in ways that may increase the risk of developing CFRD. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Potential Harms of rh. GH Treatment to Patients With CF: Glucose Control and CFRD (2) No. of Patients Blood Glucose Measurement No. of Trials Treated Control Fasting 3 62 30 Summary Effect Mean Difference (95% CI) 5. 68 mg/d. L (0. 43, 10. 93) Strength of Evidence Moderate CI = confidence interval. Fasting blood glucose during treatment was elevated by 5. 7 mg/d. L on average. Hemoglobin A 1 c was unaffected by rh. GH treatment. (Level of Evidence = Low) Evidence about random, postprandial, and stimulated glucose levels is insufficient to estimate an effect. CFRD or glucose intolerance developed in 3 of 158 patients in studies where these events were monitored, but the evidence is insufficient to evaluate the role of rh. GH in these outcomes. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Potential Harms of rh. GH Treatment to Patients With CF: Cancer Risk (1) Patients with CF have an elevated risk of cancer of the digestive tract. Patients with CF are living longer, so it is important to evaluate the impact on cancer risk from rh. GH treatment. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Potential Harms of rh. GH Treatment to Patients With CF: Cancer Risk (2) Two investigational biomarkers of cancer risk are: IGF-I: insulin-like growth factor-I 100 ng/m. L increase over baseline or above control levels may indicate increased risk. IGFBP-3: insulin-like growth factor-binding protein-3 Elevations >1000 ng/m. L may indicate increased risk. No consensus exists regarding the value of these growth factors for estimating cancer risk. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Potential Harms of rh. GH Treatment to Patients With CF: Cancer Risk(3) Evidence about increases in IGF-I and IGFBP-3 during rh. GH treatment is insufficient to determine an effect. There is insufficient evidence from studies of rh. GH treatment of patients with growth hormone deficiency or idiopathic short stature to evaluate rh. GH-associated cancer risks. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Summary of Harms Study withdrawals were rare, suggesting that rh. GH treatment was well tolerated. Injection site reactions and liver transaminase effects were rare. rh. GH treatment elevated fasting blood glucose by 5. 7 mg/d. L. (Level of Evidence = Moderate) The evidence about effects on glucose control is insufficient to understand long-term risks. There is insufficient evidence to evaluate cancer risk by using either potential biomarkers or data from “on-label” rh. GH treatment regimens. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Conclusions About Benefits and Harms (1) Pubertal and prepubertal patients treated with rh. GH experienced a modest decrease in the annual rate of hospitalization during the treatment period. Modest increases in weight were observed, but while weight is associated with mortality risk, it is unclear if the weight change associated with rh. GH use modifies risk. Modest increases in bone mineral content were seen, but whether this increase alters the bone fracture risk is not known. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Conclusions About Benefits and Harms (2) There is no direct evidence about whether gains in pulmonary function and growth seen upon rh. GH treatment will lead to improved survival or other long-term health benefits. There is insufficient evidence to evaluate harms associated with rh. GH treatment, including the risk of CFRD and cancer. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Knowledge Gaps and Future Research Needs (1) The evidence is insufficient to determine how effectiveness, benefits, and harms are affected by: Dosage and duration of rh. GH treatment Age Sex Pubertal status Baseline clinical or nutritional status Prior or concurrent medical therapies Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Knowledge Gaps and Future Research Needs (2) A large, multicenter, randomized, placebocontrolled, double-blinded trial of rh. GH that includes prospective data collection for hospitalizations, mortality, bone fractures, and HRQo. L is needed to determine what role, if any, rh. GH has in the treatment of pediatric patients with CF. Prospective cohort studies should be developed to assess important long-term health outcomes in patients who have received rh. GH treatment to date. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

What To Discuss With Your Patients and Their Caregivers § The evidence about benefits and harms of rh. GH treatment for patients with CF is limited. § Whether the potential for reduced hospitalizations is applicable for the individual patient. § Whether the patient/caregiver has concerns about the long-term effects of rh. GH on diabetes and cancer risks in light of the insufficient evidence. § Patient/caregiver values and preferences concerning rh. GH administration (i. e. , by injection). Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http: //effectivehealthcare. ahrq. gov/hgh. cfm.

Additional Products Available Clinician Guide: Use of Recombinant Human Growth Hormone for Pediatric Patients With Cystic Fibrosis Consumer Guide: Human Growth Hormone for Children With Cystic Fibrosis: A Review of the Research for Parents and Caregivers