Prepared for: Agency for Healthcare Research and Quality (AHRQ) ahrq

1. Effectiveness of Recombinant Human Growth Hormone (rhGH) in the Treatment of PatientsWith Cystic Fibrosis Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

2. Outline of Material • Introduction to cystic fibrosis (CF) and growth hormone • Systematic review methods • Results of studies of rhGH 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.

3. Health Impact of Cystic Fibrosisin 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.

4. 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.

5. 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.

6. Rationale for Use of Recombinant Human Growth Hormone (rhGH) 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 10th 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, rhGH 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.

7. Approved Therapeutic Uses of rhGH • rhGH 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.

8. 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.

9. 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 (HRQoL)? Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http://effectivehealthcare.ahrq.gov/hgh.cfm.

10. 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.

11. 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: 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.

12. Outcomes of Interest in Studies of rhGH Treatment of Patients With CF • Intermediate Outcomes • Pulmonary function • Anthropometrics • Bone mineralization • Exercise tolerance • Health Outcomes • 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.

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

14. Controlled Trials of rhGH Treatment for CF Summarized in the CER Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http://effectivehealthcare.ahrq.gov/hgh.cfm.

15. Characteristics of Trials of rhGH 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.

16. rhGH Effects on Intermediate Outcomes in Controlled Trials: Pulmonary Function *Statistically significant. CI = confidence interval; FEV1 = 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.

17. rhGH Effects on Intermediate Outcomes in Controlled Trials: Anthropometrics *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.

18. rhGH Effects on Health OutcomesReported in Controlled Trials • Hospitalization rate was reduced in treated patients during the course of the studies. • Evidence about antibiotic use, pulmonary exacerbations, and HRQoL was insufficient to formulate an estimate of effect. • Bone consequences and mortality were not reported in any rhGH trial. 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.

19. Intermediate End Points and Health Outcomesin rhGH-Treated Patients With CF (1) • The studies of rhGH 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 rhGH 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.

20. Intermediate End Points and Health Outcomesin rhGH-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 rhGH 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.

21. Intermediate End Points and Health Outcomesin rhGH-Treated Patients With CF (3) Review of the regression analysis studies found that: • Percent predicted FEV1 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. • Percent predicted FEV1 is a multivariate predictor for several individual domains of HRQoL questionnaires. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http://effectivehealthcare.ahrq.gov/hgh.cfm.

22. Intermediate End Points and Health Outcomesin rhGH-Treated Patients With CF (4) • Other pulmonary function measures do not exhibit the predictive strength of percent predicted FEV1. • Other pulmonary function measures were linked to mortality and HRQoL in about half of the univariate and multivariate analyses. • Among anthropometrics, only weight showed a consistent predictive relationship with mortality risk. • The connection between weight and HRQoL 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.

23. 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 rhGH-treated 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.

24. Summary of Benefits (2) • Bone mineral content increased in rhGH-treated patients, but it is not known if this change alters fracture risk. • Level of Evidence = Low • Percent predicted FEV1 is a good predictor of mortality risk and influences HRQoL, but rhGH 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.

25. Potential Harms of rhGH Treatmentto 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.

26. Potential Harms of rhGH 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. • RhGH 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.

27. Potential Harms of rhGH Treatment to Patients With CF: Glucose Control and CFRD (2) • Fasting blood glucose during treatment was elevated by 5.7 mg/dL on average. • Hemoglobin A1c was unaffected by rhGH 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 rhGH in these outcomes. 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.

28. Potential Harms of rhGH 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 rhGH treatment. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http://effectivehealthcare.ahrq.gov/hgh.cfm.

29. Potential Harms of rhGH Treatment to Patients With CF: Cancer Risk (2) • Two investigational biomarkers of cancer risk are: • IGF-I: insulin-like growth factor-I • 100 ng/mL increase over baseline or above control levels may indicate increased risk. • IGFBP-3: insulin-like growth factor-binding protein-3 • Elevations >1000 ng/mL 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.

30. Potential Harms of rhGH Treatment to Patients With CF: Cancer Risk(3) • Evidence about increases in IGF-I and IGFBP-3 during rhGH treatment is insufficient to determine an effect. • There is insufficient evidence from studies of rhGH treatment of patients with growth hormone deficiency or idiopathic short stature to evaluate rhGH-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.

31. Summary of Harms • Study withdrawals were rare, suggesting that rhGH treatment was well tolerated. • Injection site reactions and liver transaminase effects were rare. • rhGH treatment elevated fasting blood glucose by 5.7 mg/dL. (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” rhGH treatment regimens. Phung OJ, Coleman CI, Baker EL, et al. AHRQ Comparative Effectiveness Review No. 23. Available at: http://effectivehealthcare.ahrq.gov/hgh.cfm.

32. Conclusions About Benefits and Harms (1) • Pubertal and prepubertal patients treated with rhGH 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 rhGH 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.

33. Conclusions About Benefits and Harms (2) • There is no direct evidence about whether gains in pulmonary function and growth seen upon rhGH treatment will lead to improved survival or other long-term health benefits. • There is insufficient evidence to evaluate harms associated with rhGH 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.

34. Knowledge Gaps andFuture Research Needs (1) • The evidence is insufficient to determine how effectiveness, benefits, and harms are affected by: • Dosage and duration of rhGH 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.

35. Knowledge Gaps andFuture Research Needs (2) • A large, multicenter, randomized, placebo-controlled, double-blinded trial of rhGH that includes prospective data collection for hospitalizations, mortality, bone fractures, and HRQoL is needed to determine what role, if any, rhGH 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 rhGH 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.

36. What To Discuss With Your Patientsand Their Caregivers • The evidence about benefits and harms of rhGH 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 rhGH on diabetes and cancer risks in light of the insufficient evidence. • Patient/caregiver values and preferences concerning rhGH 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.

37. 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