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Cochrane Database of Systematic Reviews Protocol - Intervention

Recombinant growth hormone therapy for cystic fibrosis in children and young adults

Authors' declarations of interest

Version published: 08 December 2010 Version history

https://doi.org/10.1002/14651858.CD008901

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the effectiveness and safety of recombinant human growth hormone therapy in improving lung function, quality of life and clinical status of children and young adults with CF.

Background

Description of the condition

Cystic fibrosis (CF) is the most common autosomal recessive genetic disease of the Caucasian population which affects approximately 1 in 2500 live births (Ratjen 2003). A genetic defect results in thickened secretions across cells and a number of clinical symptoms predominantly chronic lung disease and exocrine pancreatic insufficiency.

Inadequate gastrointestinal function results in the malabsorption of fat, essential vitamins and fatty acids. Long‐standing lung disease increases caloric requirements which is compounded by a loss of appetite due to the disease, to medications and to the psychological stress of chronic disease (Kawchak 1996; O'Rawe 1992; Patel 2003; Reilly 1997). Malnutrition and growth failure are commonly seen in CF; 20.2% of individuals with CF under 25 years of age are below the 10th percentile for weight and 23.1% are below the 10th percentile for height (CFF 2008).

In the past, failure to thrive was one of the presenting features of CF. Approximately 40% of infants were below the 5th percentile for weight and length at diagnosis with some catch‐up growth after diagnosis (Barkhouse 1989; Karlberg 1991; Lai 1998; Morison 1997). With the introduction of newborn screening in the USA, failure to thrive is less likely to be seen, but poor growth is still a problem (Assael 2009).

After infancy, the rate of growth of children with CF follows a normal pattern until nine years of age, albeit at lower centiles (Farrell 2001; Karlberg 1991); adolescent years show more severe growth impairment associated with: a delay in skeletal maturation; the delayed onset of puberty and pubertal growth spurt; and in attaining adult height (Haeusler 1994; Lucidi 2009; Morison 1997). Despite comprehensive care at specialized centres, studies show growth in individuals with CF below that of controls (Stettler 2000; Wiedemann 2007); consequently, the height of adults with CF is reduced (Byard 1994; CFF 2008; Lucidi 2009).

Malnutrition and short stature have been shown to contribute to a poor clinical outcome (Corey 1988). While the nutritional care of people with CF has improved significantly, data from the CFF Registry indicate that growth retardation by four years of age is a significant independent prognostic indicator of survival (Beker 2001). This suggests that improved growth may allow more lung mass and better lung function, which could be important, independent of the issue of improving weight gain. Furthermore, prospective studies have suggested that aggressive nutritional intervention may positively affect pulmonary function (Konstan 2003; Sharma 2001). Despite adherence to updated nutritional guidelines (Borowitz 2002; Sinaasappel 2002), there are still individuals with CF who cannot meet their energy needs or maintain the benefits of nutritional interventions (Dalzell 1992; Stettler 2000) and who are at risk of nutritional failure and deterioration of pulmonary function. 

Individuals with CF show normal spontaneous and stimulated growth hormone (GH) levels, but low levels of GH effector proteins (insulin like growth factor ‐1 (IGF‐1)) and binding proteins (IGFBP‐3) which correlate with height and BMI. Thus, growth failure in CF may be due to relative GH insensitivity (Laursen 1999; Taylor 1997). In addition, the chronic inflammation in CF results in production of inflammatory chemicals like body interleukins (IL‐1, IL‐6) and tumour necrosis factor (TNF‐alpha), which have also been shown to reduce levels of IGF‐1 (De Benedetti 1997). There is strong evidence that low IGF‐1 levels result in loss of lean body mass and respiratory muscle wasting which ultimately results in the deterioration of lung function and increasing morbidity (Sermet‐Gaudelus 2003).

Description of the intervention

Growth hormone is the most important substance produced by the human body for growth. It is released from the pituitary gland in a pulsatile manner throughout the day. At night GH release peaks and stimulates the production of IGF‐1 in the liver, which is its major effector protein and also serves to control its secretion.

Recombinant human GH (rhGH) (somatotropin) has been available since 1985 and is self‐administered (or given by a parent) at home, usually as a subcutaneous injection. The frequency of dose is generally six to seven times per week, preferably at night to mimic the body's natural rhythm.

Treatment with rhGH is expensive. According to a NHS Health Technology Assessment Programme, the costs for treating children with the four licensed conditions (growth hormone deficiency, Prader Willi Syndrome, idiopathic short stature and Turners syndrome) in England and Wales would be approximately £180 million (Bryant 2002). For growth hormone deficiency, the cost of therapy for a nine‐year old child for eight years would average more than £50,000 and that of a 12‐year old child for five years over £40,000. This raises the question of cost‐benefit analysis for the use of therapy, especially if anticipated costs are higher as in CF.

Adverse effects of the therapy

Besides the discomfort and local reactions caused by daily injections, mild adverse effects like headache, nausea, fever, vomiting have been noted. Overall, the incidence of adverse effects in children treated with rhGH therapy is under three per cent. Adverse effects associated with rhGH therapy are intracranial hypertension (pseudotumor cerebri), moderate and severe edema, slipped capital femoral epiphysis, worsening of scoliosis, gynaecomastia and hyperglycaemia (Wilson 2003). There have been some recent concerns that rhGH therapy may increase the tendency towards new tumour formation (Giovannucci 2002; Verhelst 2002), although there are no current documented results with short and long‐term follow‐up in children and adults.

In trials assessing the results of rhGH therapy on glucose metabolism, a slight increase in fasting and post‐prandial insulin and blood glucose levels has been demonstrated (Cutfield 2000; Jeffcoate 2002). In pre‐pubertal children with CF at a high risk for CF‐related diabetes, the long‐term safety of rhGH therapy should be an important consideration.

How the intervention might work

Although people with CF demonstrate normal GH levels, low levels of IGF‐1 have been found indicating a relative GH resistance (Laursen 1999). Treatment with GH can accelerate linear growth in pre‐pubertal children with growth failure including those with CF (Hardin 2004). It also modifies body composition, promoting fat‐free mass in the body. In the long term, GH treatment increases bone mass and bone mineral density which can be detected by dual energy X‐ray absorptiometry (DEXA) scan.

Recombinant human growth hormone increases IGF‐1 levels and improves growth velocity, lean tissue mass and bone density in children with CF (Hardin 1997; Huseman 1996). Improved linear growth can improve pulmonary function, exercise capacity, reduce infection rates and provide a better quality of life (Beker 2001; Corey 1988). It was also noted that GH reduced TNF‐alpha in people with CF and reduces protein degradation (Hardin 2001).

Why it is important to do this review

Recombinant growth hormone therapy is expensive and has potential side effects such as impairment in glucose metabolism. Presently there is no uniform consensus on the use of GH therapy in individuals with CF. A systematic review of the use of rhGH in people with CF is needed to confirm the benefits before justifying this expensive treatment. If a systematic review of the studies reveals a benefit in the quality of life, pulmonary function and morbidity (including hospitalisations) for people with CF, it will serve as an important adjunct to the current therapy. It may cause a significant impact in the management and life of children and young adults with CF who have a better prognosis today with modern therapies.            

Objectives

To evaluate the effectiveness and safety of recombinant human growth hormone therapy in improving lung function, quality of life and clinical status of children and young adults with CF.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled  trials and quasi‐randomized trials

Types of participants

Participants of either sex up to the age of 25 years with confirmed diagnosis of CF (e.g. by sweat test or molecular diagnosis) who have not received growth hormone therapy in the previous six months.

Types of interventions

Recombinant human growth hormone therapy of any dose compared to placebo, no treatment or a different dose regimen.

Types of outcome measures

Primary outcomes

  1. Pulmonary function tests

    1. forced expiratory volume at one second (FEV1) (% predicted or liters)

    2. forced vital capacity (FVC) (% predicted or liters)

    3. maximal inspiratory pressure (PImax)

    4. maximal expiratory pressure (PEmax)

  2. Nutritional parameters

    1. height (cm) and height standard deviation score (SDS)

    2. weight (kg) and weight SDS

    3. height velocity

    4. weight velocity

    5. lean body mass measured by dual x‐ray absorptiometry (DEXA) scan

  3. Quality of life (QoL) (measured by a validated tool such as Cystic Fibrosis Questionnaire‐Revised version (CFQ‐R (Quittner 2009)) and Cystic Fibrosis Quality of Life Questionnaire (CFQoL (Gee 2000))

Secondary outcomes

  1. Impact of GH therapy on blood glucose abnormality

    1. impact on fasting insulin levels in non‐diabetic participants (by measuring insulin levels)

    2. fasting and post‐prandial blood glucose levels (hemoglobin A1c levels and oral glucose tolerance tests)

    3. change in exogenous insulin requirements and blood sugar control in diabetic participants

  2. Muscular strength and exercise capacity

    1. changes in overall muscle strength (as measured by hand grip)

    2. six‐minute walk

  3. Serum insulin‐like growth factor‐1(IGF‐1) levels and insulin‐like growth factor binding protein 3 (IGFBP‐3) levels

  4. Change in disease exacerbation

    1. hospitalisation

      1. frequency

      2. duration

    2. need for antibiotics

      1. oral

      2. intravenous

  5. Any adverse effects reported

    1. mild, requiring no treatment. (e.g. transient glucosuria, transient splenomegaly and muscular prominence)

    2. moderate, requiring treatment (e.g. benign intracranial hypertension, effects on glucose metabolism)

    3. life‐threatening or severe (requiring hospitalisation) (e.g. slipped capital epiphyses, incidence of malignant disease )

  6. Cost

Search methods for identification of studies

Electronic searches

We will identify relevant studies from the Group's Cystic Fibrosis Trials Register. The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (Clinical Trials) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE, a search of EMBASE to 1995 and the prospective handsearching of two journals ‐ Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work is identified by searching the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cochrane Cystic Fibrosis and Genetic Disorders Group Module.

Searching other resources

We will search the bibliographic references of identified studies for references to additional studies. We will search relevant endocrine journals and proceedings of Endocrinology Society meetings. Also, we will contact leading researchers in the field for relevant information.

Data collection and analysis

Selection of studies

Two authors (VT and BH) will independently assess the abstracts of studies resulting from the searches. We will obtain full copies of all relevant and potentially relevant studies (those appearing to meet the inclusion criteria, and for which there were insufficient data in the title and abstract to make a clear decision). The two review authors (VT and BH) will then independently assess the full text papers and resolve any disagreement on the eligibility of included studies through discussion and consensus or if necessary through a third author (VJ). We will then exclude those records that do not meet the inclusion criteria and we will note the reasons for their exclusion in the 'Characteristics of excluded studies' table in the review.

Data extraction and management

We will enter study details into the 'Characteristics of included studies' table in the review and will collect outcome data using a pre‐determined form designed for this purpose. Two authors (VT and BH) will independently extract data and only include data for which there is a consensus. We plan to resolve any disagreements by consulting with a third review author (VJ).

The following details will be extracted:

  1. Trial methods:

    1. method of allocation;

    2. allocation concealment;

    3. masking of participants, trialists and outcome assessors;

    4. exclusion of participants after randomisation and proportion and reasons for losses at follow‐up.

  2. Participants:

    1. country of origin and study setting;

    2. sample size;

    3. age;

    4. gender;

    5. inclusion and exclusion criteria.

  3. Intervention:

    1. study duration;

    2. type;

    3. concentration, dose and frequency;

    4. duration of intervention in follow‐up.

  4. Control:

    1. type;

    2. concentration, dose and frequency;

    3. duration of intervention in follow‐up.

  5. Outcomes:

    1. primary and secondary outcomes mentioned in the Types of outcome measures section of this review.

If stated, the sources of funding of any of the included studies will be recorded.

The review authors will use this information to help them assess heterogeneity and the external validity of any included trials.

We will use the Review Manager software developed by the Cochrane Collaboration for data organising and analysis (Revman 2008).

Assessment of risk of bias in included studies

Each review author will grade the selected trial using a simple contingency form and follow the domain‐based evaluation described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions 5.0 (Higgins 2008a). The authors will compare the evaluations and discuss and resolve any inconsistencies in these evaluations.

The authors will assess the following domains as 'Yes' (i.e. low risk of bias), 'Unclear' (i.e. uncertain risk of bias) or 'No' (i.e. high risk of bias):

  1. adequate sequence generation;

  2. adequate allocation concealment;

  3. adequate blinding (of participants, personnel and outcome assessors); 

  4. incomplete outcome data addressed;

  5. free of selective outcome reporting;

  6. free of other bias.

They will categorize the risk of bias in any included study according to the following:

  • low risk of bias (plausible bias unlikely to seriously alter the results) if all criteria were met;

  • unclear risk of bias (plausible bias that raises some doubt about the results) if one or more criteria were assessed as unclear; or 

  • high risk of bias (plausible bias that seriously weakens confidence in the results) if one or more criteria were not met.

The authors plan to report these assessments in the table 'Risk of bias in included studies' in the review.

Measures of treatment effect

The authors will include the results from studies that meet the inclusion criteria in the review and data for any of the outcomes of interest in a subsequent meta‐analysis.

The authors will process data according to intention‐to‐treat principle, using in the denominator the number of randomised participants. They will assume missing values for outcome measures to represent a poor outcome.

For dichotomous outcomes, the authors will express the results as relative risk (RR) with 95% confidence intervals (CI). For continuous outcomes, the authors will use mean differences (MD) (when measures are in the same unit) or standardised mean differences (SMD) (when different scales are used to evaluate the same outcome) and their 95% CIs.

For continuous outcomes, we will record the mean relative change from baseline for each group or mean post‐treatment or post‐intervention values and their standard deviations (SD). If standard errors are reported, we will calculate the standard deviation. We will then calculate a pooled estimate of treatment effect by the MD and 95% CI again using RevMan (RevMan 2008)

For time‐to‐event outcomes, we will calculate the OR or hazards ratio (HR) using RevMan. The OR is derived using Peto's method applied to dichotomous data (RevMan 2008); the HR is derived either using the log rank approach or log HRs using the generic inverse variance method depending on whether we extract data from the primary studies, or obtain the data from re‐analysis of individual patient data.

The authors will summarise adverse events reports for each trial.

Unit of analysis issues

We will compare and analyse any unit of analysis errors that might arise as result of repeated observations on the participants as data collected at identical time points for specific outcomes across the included studies. We will follow the advice provided in Section 16.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions version 5.0 (Higgins 2008b).

We will not include cross‐over studies as the duration of treatment effect and the disease effect are more likely to develop over different time periods and the appropriate wash‐out period cannot be clearly defined. However, if data from the first half of the cross‐over trial are suitable, we will include them.

Dealing with missing data

We will attempt to retrieve missing data from the investigators of any of the included trials; if unsuccessful or if the discrepancies are significant, we will provide a narrative synthesis of the data as reported.

Assessment of heterogeneity

We will assess clinical heterogeneity by examining the characteristics of the studies, the similarity between the types of participants, the interventions and the outcomes as specified in the criteria for included studies. We will assess heterogeneity using the I‐squared (I2) statistic. If moderate levels of heterogeneity are detected for the primary outcomes (I2 > 50%), reasons for heterogeneity will be explored using subgroup analysis. We will consider heterogeneity to be significant when the P value is less than 0.10 (Higgins 2003).

Assessment of reporting biases

If we identify sufficient trials for inclusion in this review, we will assess publication bias according to the recommendations on testing for funnel plot asymmetry (Egger 1997) and as described in section 10.4.3.1 of the Cochrane Handbook for Systematic Reviews of Interventions 5.0 (Higgins 2008b). If we then identify asymmetry, we will try to assess other possible causes and explore these in the discussion if appropriate.

Data synthesis

For the synthesis and meta‐analysis of any quantitative data we plan to use the random‐effects model.

We will seek statistical support from the Cystic Fibrosis and Genetic Disorders Group. Two review authors (VT, VJ) will analyse any data reported in the included studies and relevant to the primary and secondary outcomes of this review using RevMan 5.0 (RevMan 2008). They will report results as suggested in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions 5.0 (Higgins 2008c).

Subgroup analysis and investigation of heterogeneity

If we identify heterogeneity we will investigate this with the following subgroup analyses:

  1. Tanner stage of puberty (Tanner 1962);

  2. sex;

  3. baseline nutritional or anthropometric status;

  4. lung function (FEV1 < 50%, 50% to 80% and > 80%).

Sensitivity analysis

If we are able to include more than one study, we plan to conduct sensitivity analyses to assess the robustness of our review results by repeating the analysis with the following adjustments: exclusion of studies with unclear or inadequate allocation concealment; unclear or inadequate blinding of outcomes assessment; and completeness of follow‐up.