Effectiveness of Recombinant Human Growth Hormone (rhGH) in the Treatment of Patients With Cystic Fibrosis

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 CERA
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 High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
Moderate 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 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 2008336924-6 Owens DK,
et al. J Clin Epidemiol 201063513-23 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/osteope
  nia
• 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 fibrosisrelated 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
Study First Author, Year rhGH 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.
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
Outcome No. of Trials No. of Patients No. of Patients Summary Effect Mean Difference (95 CI) Level of Evidence
Outcome No. of Trials Treated Control Summary Effect Mean Difference (95 CI) Level of Evidence
Absolute FVC 3 52 48 0.67 L (0.24, 1.09) Moderate
Absolute FEV1 6 58 52 0.23 L (0.01, 0.46) Moderate
Percent Predicted FVC 4 84 60 9.34 (3.41, 15.27) Low
Percent Predicted FEV1 5 71 48 2.43 (-3.99, 8.85) Moderate
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
Outcome No. of Trials No. of Patients No. of Patients Summary Effect Mean Difference (95 CI) Level of Evidence
Outcome No. of Trials Treated Control Summary Effect Mean Difference (95 CI) Level of Evidence
Height Velocity 4 82 57 3.27 cm/y (2.33, 4.21) Moderate
Height Z-score 3 48 45 0.51 (0.35, 0.66) Moderate
Weight 6 100 67 1.48 kg (0.62, 2.33) Moderate
Weight Velocity 2 40 36 2.15 kg/y (1.52, 2.78) Moderate
BMI 2 22 18 2.08 kg/m2 (1.2, 2.96) Moderate
Lean Body Mass 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 (-0.02, 1.00) Low
Percent Ideal Body Weight 2 23 21 12.57 (7.01, 18.12) Low
Bone Mineral Content 4 68 64 192 g (110, 273) Low
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
Outcome No. of Trials No. of Patients No. of Patients Summary Effect Mean Difference (95 CI) Level of Evidence
Outcome No. of Trials Treated Control Summary Effect Mean Difference (95 CI) Level of Evidence
Hospitalizations per year 4 64 59 -1.62 per year (-1.98, -1.26) Moderate
CI confidence interval.

• 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.

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.

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.
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)
Blood Glucose Measurement No. of Trials No. of Patients No. of Patients Summary Effect Mean Difference (95 CI) Strength of Evidence
Blood Glucose Measurement No. of Trials Treated Control Summary Effect Mean Difference (95 CI) Strength of Evidence
Fasting 3 62 30 5.68 mg/dL (0.43, 10.93) Moderate
CI confidence interval.

• 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.

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 gt1000 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