- Email: [email protected]
Recombinant growth hormone therapy for cystic fibrosis in children and young adults
Paediatric Respiratory Reviews 14 (2013) 232–233
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Cochrane Corner
Recombinant growth hormone therapy for cystic fibrosis in children and young adults V. Thaker 1,*, B. Carter 2 1 2
Division of Pediatric Endocrinology, Boston Children’s Hospital, Boston MA 02115 Institute of Primary Care & Public Health, Cardiff University School of Heath Park, Cardiff, CF14 4YS
WHY DO WE NEED THIS REVIEW? Malnutrition and progressive lung disease are hallmarks of cystic fibrosis (CF).1 Improvement in nutrition with aggressive nutritional therapy has shown to improve clinical outcome.2 It has been proposed that linear growth may independently improve lung function and a role for anabolic agents like recombinant growth hormone (rhGH) in the treatment of patients with CF has been suggested.3 However, this therapy is expensive and invasive.4 Small individual studies have shown variable results with regard to the benefits of rhGH. Hence, our systematic review was undertaken to provide a guide for the use of rhGH in children and young adults with CF.
below the 25th percentile for their age and gender. Two review authors independently extracted data from each trial and additional information was requested from trial investigators. The following comparisons from the included trials were presented:
low-dose rhGH versus placebo; low-dose rhGH versus no treatment; high-dose rhGH versus placebo; high-dose versus low-dose rhGH.
WHAT COMPARISONS DID WE MAKE IN THE REVIEW? The aim of the review was to evaluate the effectiveness and safety of rhGH therapy in improving lung function, quality of life (QoL) and the clinical status of children and young adults with CF.5 Typically, rhGH is self-administered as a subcutaneous injection, generally delivered six to seven times per week in the dose of 0.1 to 0.4 mg/kg/week. We considered a low dose as 0.1 mg/kg/ week and a high dose as 0.5 mg/kg/wk. We identified 22 potentially eligible studies of all preparations or doses of rhGH by any route in CF patients aged up to 25 years. We included four trials (three randomised controlled trials (RCT) and one quasi-RCT).6–9 Two additional ongoing studies were identified and will be assessed for inclusion as soon as they are published. From the four studies, 161 patients participated with an age range of 7 to 23 years. Most of these patients had a Tanner Stage 1 of sexual maturity staging and both height and weight
* Corresponding author. E-mail address: [email protected] (V. Thaker). 1526-0542/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2013.08.003
Figure 1. Standard rhGH versus no treatment. Outcome: Change in FVC from baseline.
Figure 2. Standard rhGH versus no treatment. Outcome: Change in height from baseline (cm).
V. Thaker, B. Carter / Paediatric Respiratory Reviews 14 (2013) 232–233
233
limited evidence of change in fasting blood glucose levels and exercise capacity; however, there was insufficient evidence to conclude any changes in hospitalisations, antibiotic use or adverse event rates. WHAT DO THE GUIDELINES SAY?
Figure 3. Standard rhGH versus no treatment. Outcome: Lean tissue mass (kg).
Figure 4. Standard rhGH versus no treatment. Outcome: Body weight (kg).
At present there is no clinical recommendation on the use of rhGH in children and young adults with CF. Patients with CF are at risk of malnutrition and growth failure and therapy with rhGH has been proposed to boost growth and improve pulmonary function. We found only modest improvement in some outcomes in children and young people after rhGH therapy, namely nutritional and pulmonary function outcomes. This limited improvement needs to be weighed against the cost and burden of treatment. Therefore, we recommend that long-term, well-designed RCTs of rhGH are required using outcomes that are patient focused including QoL.5 Completion of such trials will enable these interventions to be better evaluated and allow the development of guidance by patient organisations and professional societies. References
WHAT DID WE FIND? Four trials that recruited 161 patients were included in the review. Each study was judged as having an overall ’unclear’ risk of bias, largely due to inadequate reporting of the risk of bias domains. These domains consisted of: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; and other bias.10 The trials were evaluated at 6 to 12 months after initiation of treatment. From the primary outcomes we found limited evidence of an effect due to rhGH. The pulmonary function test outcome suggested that vital capacity was improved following rhGH (Figure 1). The nutritional parameter outcome showed consistent evidence of an improvement in height (Figure 2) and lean tissue mass (Figure 3) but the evidence of any improvement in weight was mixed (Figure 4). There was no evidence found for improvement in QoL. The secondary outcomes included: blood glucose abnormality; muscular strength and exercise capacity; serum insulin-like growth factor and protein binding; disease exacerbation; adverse events; and cost. Evaluation of the secondary outcomes found
1. Ratjen F, Do¨ring G. Cystic fibrosis. Lancet 2003;361:681–9. 2. Konstan MW, et al. Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. Journal of Pediatrics 2003;142:624–30. 3. Colombo C, Battezzati A. Growth failure in cystic fibrosis: a true need for anabolic agents? Journal of Pediatrics 2005;146:303–5. 4. Takeda A, et al. Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation. Health Technology Assessment (Winchester England) 2010;14:1–209. iii–iv. 5. Thaker V, Haagensen AL, Carter B, Fedorowicz Z, Houston BW. Recombinant growth hormone therapy for cystic fibrosis in children and young adults. Cochrane Database of Systematic Reviews 2013. http://dx.doi.org/10.1002/ 14651858.CD008901.pub2. Art. No.: CD008901. 6. Hu¨tler M, Schnabel D. Effect of growth hormone on exercise tolerance in children with cystic fibrosis. Sports Medicine 2002;34:567–72. 7. Schibler A, Heiden R. Von Der. Prospective randomised treatment with recombinant human growth hormone in cystic fibrosis. Archives of Disease in Childhood 2003;88:1078–81. 8. Schnabel D, Grasemann C, Staab D, Wollmann H, Ratjen F. A multicenter, randomized, double-blind, placebo-controlled trial to evaluate the metabolic and respiratory effects of growth hormone in children with cystic fibrosis. Pediatrics 2007;119:e1230–8. 9. Stalvey MS, Anbar RD, Konstan MW, Jacobs JR, Bakker B, Lippe B, Geller DE. A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis. Pediatric Pulmonology 2012;47:252–63. 10. Higgins JPT, Altman DG (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
In collaboration with the Cochrane CF and Genetic Disorders Group’ http://cfgd.cochrane.org/.
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Cochrane Corner
Recombinant growth hormone therapy for cystic fibrosis in children and young adults V. Thaker 1,*, B. Carter 2 1 2
Division of Pediatric Endocrinology, Boston Children’s Hospital, Boston MA 02115 Institute of Primary Care & Public Health, Cardiff University School of Heath Park, Cardiff, CF14 4YS
WHY DO WE NEED THIS REVIEW? Malnutrition and progressive lung disease are hallmarks of cystic fibrosis (CF).1 Improvement in nutrition with aggressive nutritional therapy has shown to improve clinical outcome.2 It has been proposed that linear growth may independently improve lung function and a role for anabolic agents like recombinant growth hormone (rhGH) in the treatment of patients with CF has been suggested.3 However, this therapy is expensive and invasive.4 Small individual studies have shown variable results with regard to the benefits of rhGH. Hence, our systematic review was undertaken to provide a guide for the use of rhGH in children and young adults with CF.
below the 25th percentile for their age and gender. Two review authors independently extracted data from each trial and additional information was requested from trial investigators. The following comparisons from the included trials were presented:
low-dose rhGH versus placebo; low-dose rhGH versus no treatment; high-dose rhGH versus placebo; high-dose versus low-dose rhGH.
WHAT COMPARISONS DID WE MAKE IN THE REVIEW? The aim of the review was to evaluate the effectiveness and safety of rhGH therapy in improving lung function, quality of life (QoL) and the clinical status of children and young adults with CF.5 Typically, rhGH is self-administered as a subcutaneous injection, generally delivered six to seven times per week in the dose of 0.1 to 0.4 mg/kg/week. We considered a low dose as 0.1 mg/kg/ week and a high dose as 0.5 mg/kg/wk. We identified 22 potentially eligible studies of all preparations or doses of rhGH by any route in CF patients aged up to 25 years. We included four trials (three randomised controlled trials (RCT) and one quasi-RCT).6–9 Two additional ongoing studies were identified and will be assessed for inclusion as soon as they are published. From the four studies, 161 patients participated with an age range of 7 to 23 years. Most of these patients had a Tanner Stage 1 of sexual maturity staging and both height and weight
* Corresponding author. E-mail address: [email protected] (V. Thaker). 1526-0542/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2013.08.003
Figure 1. Standard rhGH versus no treatment. Outcome: Change in FVC from baseline.
Figure 2. Standard rhGH versus no treatment. Outcome: Change in height from baseline (cm).
V. Thaker, B. Carter / Paediatric Respiratory Reviews 14 (2013) 232–233
233
limited evidence of change in fasting blood glucose levels and exercise capacity; however, there was insufficient evidence to conclude any changes in hospitalisations, antibiotic use or adverse event rates. WHAT DO THE GUIDELINES SAY?
Figure 3. Standard rhGH versus no treatment. Outcome: Lean tissue mass (kg).
Figure 4. Standard rhGH versus no treatment. Outcome: Body weight (kg).
At present there is no clinical recommendation on the use of rhGH in children and young adults with CF. Patients with CF are at risk of malnutrition and growth failure and therapy with rhGH has been proposed to boost growth and improve pulmonary function. We found only modest improvement in some outcomes in children and young people after rhGH therapy, namely nutritional and pulmonary function outcomes. This limited improvement needs to be weighed against the cost and burden of treatment. Therefore, we recommend that long-term, well-designed RCTs of rhGH are required using outcomes that are patient focused including QoL.5 Completion of such trials will enable these interventions to be better evaluated and allow the development of guidance by patient organisations and professional societies. References
WHAT DID WE FIND? Four trials that recruited 161 patients were included in the review. Each study was judged as having an overall ’unclear’ risk of bias, largely due to inadequate reporting of the risk of bias domains. These domains consisted of: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; and other bias.10 The trials were evaluated at 6 to 12 months after initiation of treatment. From the primary outcomes we found limited evidence of an effect due to rhGH. The pulmonary function test outcome suggested that vital capacity was improved following rhGH (Figure 1). The nutritional parameter outcome showed consistent evidence of an improvement in height (Figure 2) and lean tissue mass (Figure 3) but the evidence of any improvement in weight was mixed (Figure 4). There was no evidence found for improvement in QoL. The secondary outcomes included: blood glucose abnormality; muscular strength and exercise capacity; serum insulin-like growth factor and protein binding; disease exacerbation; adverse events; and cost. Evaluation of the secondary outcomes found
1. Ratjen F, Do¨ring G. Cystic fibrosis. Lancet 2003;361:681–9. 2. Konstan MW, et al. Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. Journal of Pediatrics 2003;142:624–30. 3. Colombo C, Battezzati A. Growth failure in cystic fibrosis: a true need for anabolic agents? Journal of Pediatrics 2005;146:303–5. 4. Takeda A, et al. Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation. Health Technology Assessment (Winchester England) 2010;14:1–209. iii–iv. 5. Thaker V, Haagensen AL, Carter B, Fedorowicz Z, Houston BW. Recombinant growth hormone therapy for cystic fibrosis in children and young adults. Cochrane Database of Systematic Reviews 2013. http://dx.doi.org/10.1002/ 14651858.CD008901.pub2. Art. No.: CD008901. 6. Hu¨tler M, Schnabel D. Effect of growth hormone on exercise tolerance in children with cystic fibrosis. Sports Medicine 2002;34:567–72. 7. Schibler A, Heiden R. Von Der. Prospective randomised treatment with recombinant human growth hormone in cystic fibrosis. Archives of Disease in Childhood 2003;88:1078–81. 8. Schnabel D, Grasemann C, Staab D, Wollmann H, Ratjen F. A multicenter, randomized, double-blind, placebo-controlled trial to evaluate the metabolic and respiratory effects of growth hormone in children with cystic fibrosis. Pediatrics 2007;119:e1230–8. 9. Stalvey MS, Anbar RD, Konstan MW, Jacobs JR, Bakker B, Lippe B, Geller DE. A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis. Pediatric Pulmonology 2012;47:252–63. 10. Higgins JPT, Altman DG (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
In collaboration with the Cochrane CF and Genetic Disorders Group’ http://cfgd.cochrane.org/.