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

Vidhu Thaker; Ben Carter; Melissa Putman

doi:10.1002/14651858.CD008901.pub4

. 2018 Dec 17;2018(12):CD008901. doi: 10.1002/14651858.CD008901.pub4

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

Vidhu Thaker ^1,^✉, Ben Carter ², Melissa Putman ³

Editor: Cochrane Cystic Fibrosis and Genetic Disorders Group

PMCID: PMC6517261 PMID: 30557452

Abstract

Background

Cystic fibrosis (CF) is an inherited condition causing disease most noticeably in the lungs, digestive tract and pancreas. People with CF often have malnutrition and growth delay. Adequate nutritional supplementation does not improve growth optimally and hence an anabolic agent, recombinant human growth hormone (rhGH), has been proposed as a potential intervention. This is an update of a previously published review.

Objectives

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

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 22 October 2018.

We also searched ongoing trials registers in clinicaltrials.gov from the United States and WHO International Clinical Trials Registry Platform (ICTRP). Date of latest search: 05 March 2018.

We conducted a search of relevant endocrine journals and proceedings of the Endocrinology Society meetings using Web of Science, Scopus and Proceedings First. Date of latest search: 04 March 2018.

Selection criteria

Randomised and quasi‐randomised controlled trials of all preparations of rhGH compared to either no treatment, or placebo, or each other at any dose (high‐dose and low‐dose) or route and for any duration, in children or young adults (aged up to 25 years) diagnosed with CF (by sweat test or genetic testing).

Data collection and analysis

Two authors independently screened papers, extracted trial details and assessed their risk of bias. We assessed the quality of the evidence using the GRADE system.

Main results

We included eight trials (291 participants, aged between five and 23 years) in this revision of the review. Seven trials compared standard‐dose rhGH (approximately 0.3 mg/kg/week) to no treatment and one three‐arm trial (63 participants) compared placebo, standard‐dose rhGH (0.3 mg/kg/week) and high‐dose rhGH (0.5 mg/kg/week). Six trials lasted for one year and two trials for six months. We found that rhGH treatment may improve some of the pulmonary function outcomes but there was no difference between standard and high‐dose levels (low‐quality evidence, limited by inconsistency across the trials, small number of participants and short duration of therapy). The trials show evidence of improvement in the anthropometric parameters (height, weight and lean body mass) with rhGH therapy, again no differences between dose levels. We found improvement in height for all comparisons (very low‐ to low quality evidence), but improvements in weight and lean body mass were only reported for standard‐dose rhGH versus no treatment (very low‐quality evidence). There is some evidence indicating a change in the level of fasting blood glucose with rhGH therapy, however, it did not cross the clinical threshold for diagnosis of diabetes in the trials of short duration (low‐quality evidence). There is low‐ to very low‐quality evidence for improvement of pulmonary exacerbations with no further significant adverse effects, but this is limited by the short duration of trials and the small number of participants. One small trial provided inconsistent evidence on improvement in quality of life (very low‐quality evidence). There is limited evidence from three trials in improvements in exercise capacity (low‐quality evidence). None of the trials have systematically compared the expense of therapy on overall healthcare costs.

Authors' conclusions

When compared with no treatment, rhGH therapy is effective in improving the intermediate outcomes in height, weight and lean body mass. Some measures of pulmonary function showed moderate improvement, but no consistent benefit was seen across all trials. The significant change in blood glucose levels, although not causing diabetes, emphasizes the need for careful monitoring of this adverse effect with therapy in a population predisposed to CF‐related diabetes. No significant changes in quality of life, clinical status or side‐effects were observed in this review due to the small number of participants. Long‐term, well‐designed randomised controlled trials of rhGH in individuals with CF are required prior to routine clinical use of rhGH in CF.

Plain language summary

The use of recombinant growth hormone to improve growth and health in children and young adults with cystic fibrosis

Review question

We reviewed the evidence about the effects of recombinant human growth hormone (rhGH) on the health of people with cystic fibrosis (CF).

Background

CF is an inherited condition causing disease in the lungs, digestive system and pancreas. People with CF are often underweight and have delayed growth, that may impact their lung function. Nutritional supplements may not be enough and it has been suggested that treatment with rhGH, which improves the rate of growth and bone density, might help. Treatment with rhGH is usually given once a day via a needle under the skin. It is expensive and may affect glucose metabolism that has implications for children at risk of CF‐related diabetes. Hence, we need to critically review the risks and benefits of this treatment. This is an update of an earlier review.

Search date

The evidence is current to: 22 October 2018.

Study characteristics

This review looked at using of rhGH to improve lung function, growth and quality of life for children and young adults with CF. It includes eight trials with 291 individuals with CF being selected for one treatment or the other randomly. The individuals in the trials were five to 23 years old, but most had not yet reached puberty. Six trials lasted for one year and two trials for six months. Treatment with rhGH was compared to no treatment in seven trials and to a placebo (a liquid that did not contain any growth hormone) in one trial. The trial that used a placebo compared it to two different doses of rhGH treatment.

Key results

Results showed a modest improvement in height, weight and lean body mass between six and 12 months. However, there was no consistent evidence that rhGH treatment improves lung function, muscle strength, or quality of life. The trials were small and we did not find any evidence on changes in glucose metabolism or the long‐term risk of diabetes due to the treatment. Given these results, we are not able to identify any clear benefit of therapy and believe that more research from well‐designed, adequately powered clinical trials is needed.

Quality of the evidence

We did not have enough information to decide if overall the trials were biased in a way that might affect the results. All the measured outcomes were clearly reported in the trials, but the trials were small, and did not have enough participants to show a difference that may not have been due to chance. We also had concerns that outcomes which were based on personal judgement, such as quality of life scores, might be affected because those taking part in seven of the trials were able to tell which group they were in.

Summary of findings

Background

Description of the condition

Cystic fibrosis (CF) is the most common autosomal recessive genetic disease in individuals of European ancestry, and affects approximately 1 in 2500 live births (Ratjen 2003). A genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in thickened secretions across cells causing a spectrum of clinical symptoms dominated by 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 compounded by a loss of appetite due to the disease, medications and the psychological stress of chronic disease (Kawchak 1996; O'Rawe 1992; Patel 2003; Reilly 1997). Malnutrition and growth failure are commonly seen in CF; 11.5% of individuals with CF under 19 years of age are below the 10th percentile for weight and 9.8% are below the fifth percentile for height (CFF 2016).

In the past, failure to thrive was one of the presenting features of CF. Approximately 40% of infants were below the fifth percentile for weight and length at diagnosis with some catch‐up growth after diagnosis (Barkhouse 1989; Karlberg 1991; Lai 1998; Morison 1997). In the USA, since the introduction of newborn screening for CF, failure to thrive is less likely to be seen, but poor growth is still a problem (Coffey 2017; Leung 2017).

Height and weight influences pulmonary function in people with CF (Mauch 2016; Zemel 2000). Diagnosis by newborn screening has significantly improved the long‐term height and weight outcomes in children and adolescents with CF, but benefits on lung function are yet to be identified (Assael 2009; Leung 2017).

After infancy, the rate of growth of children with CF follows a nearly normal pattern in the pre‐pubertal age, albeit at lower centiles (Farrell 2001; Karlberg 1991). The adolescent years show more severe growth impairment associated with a delay in skeletal maturation, a delayed pubertal growth spurt, and the attainment of adult height (Haeusler 1994; Lucidi 2009; Morison 1997). Despite comprehensive care at specialised 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 2016; 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 body mass index (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

GH acts to mediate growth and metabolic functions in the body. 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 (Williams 2011).

Recombinant human GH (rhGH) (somatotropin) has been available since 1985 and is self‐administered 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.The dose of the therapy generally varies between 0.1 mg to 0.4 mg/kg/week depending on the clinical condition.

Treatment with rhGH is expensive. According to an NHS Health Technology Assessment Programme, the costs for treating children with four of the licensed conditions (growth hormone deficiency, Prader Willi Syndrome, idiopathic short stature and Turners syndrome) in England and Wales with rhGH would be approximately GBP 180 million (Bryant 2002). For GH deficiency, the cost of therapy (in 2000) for a nine‐year old child for eight years would average more than GBP 50,000 and that for a 12‐year old child for five years over GBP 40,000 (Bryant 2002). This raises the question of consideration 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 and vomiting have been noted. Overall, the incidence of adverse effects in children treated with rhGH therapy is under 3%. Adverse effects associated with rhGH therapy are intracranial hypertension (pseudotumour 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 rhGH 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, rhGH treatment increases bone mass and bone mineral density which can be detected by dual energy X‐ray absorptiometry (DEXA) scan.

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

Why it is important to do this review

Therapy with rhGH has potential side effects such as impairment in glucose metabolism. Presently there is no agreement on the use of rhGH therapy in individuals with CF. A systematic review of the use of rhGH in people with CF is needed to evaluate the treatment outcomes before justifying treatment. If a systematic review of the studies reveals a benefit in pulmonary function, the QoL, and morbidity (including hospitalisations) for people with CF, this will serve as an important adjunct to their current therapy.

This is an update of a previously published review (Thaker 2013; Thaker 2015).

Objectives

To evaluate the effectiveness and safety of rhGH therapy in improving lung function, QoL and clinical status of children and young adults with CF.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi‐RCTs.

Types of participants

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

Types of interventions

Therapy with rhGH at any dose compared to placebo, no treatment or a different dose regimen.

Types of outcome measures

Primary outcomes

Pulmonary function tests
1. forced expiratory volume at one second (FEV₁) (% predicted or litres)
2. forced vital capacity (FVC) (% predicted or litres)
3. maximal inspiratory pressure (PImax)
4. maximal expiratory pressure (PEmax)
Anthropometric parameters
1. height (cm) and height z score or standard deviation score (SDS)
2. height velocity
3. weight (kg) and weight z score or SDS
4. weight velocity
5. lean body mass (LBM) measured by DEXA scan
QoL (measured by a validated tool such as the Cystic Fibrosis Questionnaire‐Revised version (CFQ‐R (Quittner 2009)) and the Cystic Fibrosis Quality of Life Questionnaire (CFQoL (Gee 2000))

Secondary outcomes

Impact of rhGH therapy on blood glucose abnormality
1. impact on fasting insulin levels in non‐diabetic participants (by measuring insulin levels)
2. fasting blood glucose (FBG) and post‐prandial blood glucose (PPBG) levels (haemoglobin A1c levels and oral glucose tolerance tests)
3. change in exogenous insulin requirements and blood sugar control in diabetic participants
Muscular strength and exercise capacity
1. changes in overall muscle strength (as measured by hand grip or bicycle ergometry (post hoc change))
2. six‐minute walk
Serum insulin‐like growth factor‐1 (IGF‐1) levels and insulin‐like growth factor binding protein 3 (IGFBP‐3) levels
Change in disease exacerbation
1. hospitalisation
  1. frequency
  2. duration
2. need for antibiotics
  1. oral
  2. intravenous
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)
Cost

Search methods for identification of studies

Searches were not limited by language or publication status.

Electronic searches

We identified relevant studies from the Group's Cystic Fibrosis Trials Register using the terms: treatment of growth failure AND (rhGH OR not stated).

The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library), weekly 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's website.

Date of the latest search: 22 October 2018.

We conducted a search of relevant endocrine journals and proceedings of the Endocrinology and Pulmonary Society meetings. We used Web of Science, Scopus and Proceedings First to conduct this search.

Date of the latest search: 04 March 2018.

We searched the online trial registries at www.clinicaltrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) at www.who.int/trialsearch for ongoing clinical trials.

Date of latest search: 05 March 2018.

The search strategies for these additional electronic searches are detailed in the appendices (Appendix 2).

Searching other resources

The bibliographic references of identified trials were reviewed for references to additional trials.

Data collection and analysis

Selection of studies

Two authors (VT and BH, and from 2018, MP) independently assessed the abstracts of trials identified from the searches. We obtained full copies of all relevant and potentially relevant trials (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, BH and from 2018 MP) then independently assessed the full text papers and resolved any disagreement on the eligibility of included trials through discussion and consensus or, if necessary, through a third author (BC). We then excluded those records that did not meet the inclusion criteria and we noted the reasons for their exclusion in the 'Characteristics of excluded studies' table in the review.

Data extraction and management

We entered trial details into the 'Characteristics of included studies' table in the review and collected outcome data using a pre‐determined form designed for this purpose. Two authors (VT, BH and subsequently MP) independently extracted data and only included data for which there was a consensus. We resolved any disagreements by consulting with a third review author (BC).

We extracted the following details.

Trial methods
1. method of allocation
2. allocation concealment
3. masking of participants, clinicians and outcome assessors
4. exclusion of participants after randomisation and proportion and reasons for losses at follow‐up
Participants
1. country of origin and study setting
2. sample size
3. age
4. gender
5. inclusion and exclusion criteria
Intervention
1. trial duration
2. type
3. concentration, dose and frequency
4. duration of intervention in follow‐up
Control
1. type
2. concentration, dose and frequency
3. duration of intervention in follow‐up
Outcomes:
1. primary and secondary outcomes mentioned in the Types of outcome measures section of this review

If stated, we recorded the sources of funding of any of the included trials.

We used this information to help assess heterogeneity and the external validity of any included trials. We used Cochrane's Review Manager software for data organisation and analysis (RevMan 2014).

Assessment of risk of bias in included studies

Each review author graded the selected trials using a simple contingency form and followed the domain‐based evaluation described in Chapter 8 of theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). The authors compared the evaluations and discussed and resolved any inconsistencies in these evaluations.

We assessed the following domains as having either a low, unclear or high risk of bias:

sequence generation;
allocation concealment;
blinding (of participants, personnel and outcome assessors);
incomplete outcome data;
selective outcome reporting;
other bias.

We categorised the risk of bias in any included trial 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.

We report these assessments in the table 'Risk of bias in included studies' in the review.

Measures of treatment effect

For dichotomous outcomes (need for antibiotics, number of people with pulmonary exacerbations and adverse effects), we reported the results as the risk ratio (RR) with 95% confidence intervals (CI). For continuous outcomes (pulmonary function tests, nutritional parameters, QoL, blood glucose levels, muscular strength and exercise capacity, measures of serum IGF‐1 levels, cost of therapy and hospitalisation), we reported the mean relative change from baseline for each group or mean post‐intervention values and their standard deviations (SD). We used Review Manager software to analyse the data (RevMan 2014). We reported data as the mean difference (MD) or standardised mean difference (SMD) if different units are used with 95% CIs.

We processed data according to the intention‐to‐treat principle, using in the denominator the number of randomised participants. We assumed missing values for outcome measures to represent a poor outcome for both groups.

Unit of analysis issues

We did not include any cluster‐RCTs, and we reported repeated measures studies that collected multiple time points for outcomes at clinically relevant time points as discussed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

We have included data from the first period of cross‐over trials (Hardin 2005a; Hardin 2006). We have excluded data from later periods of 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 washout period cannot be clearly defined.

Dealing with missing data

We contacted primary research investigators about missing data from included and ongoing trials. We have provided a narrative synthesis of information where data were not provided.

Assessment of heterogeneity

We assessed clinical heterogeneity by examining the characteristics of the trials, the similarity between the types of participants, the interventions and the outcomes as specified in the criteria for included trials. We used the I² statistic to assess heterogeneity. If we found moderate levels of heterogeneity for the primary outcomes (I² greater than 50%), we would have explored reasons for heterogeneity using subgroup analysis. We considered heterogeneity to be significant when the P value was less than 0.10 (Higgins 2003).

Assessment of reporting biases

We planned to assess publication bias according to the recommendations on testing for funnel plot asymmetry (Egger 1997) and as described in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2011); however, we were unable to do so due to a lack of data available for analysis.

Data synthesis

For the synthesis and meta‐analysis of any quantitative data we used the random‐effects model. We did not consider it appropriate to combine data for any outcome due to the differences in participant characteristics where trial data were reported at the same time points.

We sought statistical support from the Cochrane Cystic Fibrosis and Genetic Disorders Group. Two review authors (VT, BC) analysed data reported in the included studies and relevant to the primary and secondary outcomes of this review using the Review Manager software (RevMan 2014). We report results as suggested in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011).

Subgroup analysis and investigation of heterogeneity

We have not performed any subgroup analyses to date due to the small amount of data, the inability to obtain raw data and the absence of heterogeneity. In future updates, if further trials are identified, we will undertake subgroup analyses for the following groups:

Tanner stage of puberty (Tanner 1962);
gender;
baseline nutritional or anthropometric status;
lung function (FEV₁ < 50%, 50% to 80% and > 80%).

Sensitivity analysis

We planned to perform sensitivity analyses if we were able to combine a sufficient number of trials and if we noted a high degree of statistical heterogeneity (I² over 50%) that could not be reasonably explained. We performed meta‐analyses where multiple trials were available for the same outcome. We also performed sensitivity analyses to assess the robustness of our review results by repeating the analysis with the following adjustments: exclusion of trials with unclear or inadequate allocation concealment; unclear or inadequate blinding of outcomes assessment; and completeness of follow‐up.

Summary of findings tables

At the 2018 update, we included a summary of findings table for each comparison in the review. The four main comparisons are as follows

standard‐dose rhGH compared to placebo for children and young adults with CF;
standard‐dose rhGH compared to no treatment for children and young adults with CF;
high‐dose rhGH compared to placebo for children and young adults with CF;
high‐dose rhGH compared to standard‐dose rhGH for children and young adults with CF.

We have selected the following seven outcomes, which we consider to be the most important, to include in the tables.

FEV₁ % predicted (change from baseline)
FVC % predicted (change from baseline)
Height velocity (cm/year) (at the end of the trial)
Weight (kg) (change from the baseline)
QoL (measured during the trial)
FBG (mg/dL) (at the end of the trial)
Number of pulmonary exacerbations or hospitalisations (during the trial period)

We used the GRADE approach to assess the quality of the evidence for each outcome based on the risk of bias within the trials, relevance to our population of interest (indirectness), unexplained heterogeneity or inconsistency, imprecision of the results or high risk of publication bias. We downgraded the evidence once if the risk was serious and twice if the risk was deemed to be very serious.

We have reported at the longest available time point (final) in the tables.

Results

Description of studies

Results of the search

The electronic searches retrieved 40 references. After examination of the titles and abstracts of these references, we eliminated from the review any trials that did not match our inclusion criteria and were clearly ineligible. We obtained full‐text copies of the 24 potentially eligible trials and subjected these to further evaluation. The review authors discussed the eligibility of these trials, resolved any remaining uncertainties by consensus and found eight trials to be eligible. Four trials were included in the initial review (Hütler 2002; Schibler 2003; Schnabel 2007; Stalvey 2012), four additional trials previously listed as 'Awaiting classification', were added in the 2018 update of the review after contact with the lead investigator who confirmed that each trial had independent participants (Hardin 2001; Hardin 2005a; Hardin 2005b; Hardin 2006).

We excluded 13 trials from the results of the search of the Cochrane Cystic Fibrosis Trials Register (Alemzadeh 1998; Bucuvalas 2001; Darmaun 2004; Eubanks 2002; Hardin 1997; Hardin 1998; Hardin 2005c; Huseman 1996; Kissner 2000; Marchand 2000; Sackey 1995; Safai‐Kutti 1991; Vanderwel 2006). Our additional online searches identified one new trial from Iranian Registry of Clinical Trials (Ghergherechi 2017) and one trial from the National Institutes of Health clinical trials database (www.clinicaltrials.gov) (NCT00803179); both of these were excluded.

This process is shown in a PRISMA diagram (Figure 1).

Included studies

Methods

Eight published trials are included in this review (Hardin 2001; Hardin 2005a; Hardin 2005b; Hardin 2006; Hütler 2002; Schibler 2003; Schnabel 2007; Stalvey 2012). One was a quasi‐RCT, where sex‐ and age‐matched pairs were recruited and randomly assigned to treatment (Schibler 2003).

Five were RCTs of parallel design (Hardin 2001; Hardin 2005b; Schibler 2003; Schnabel 2007; Stalvey 2012) and three trials were cross‐over in design (Hardin 2005a; Hardin 2006; Hütler 2002). In two trials, participants were randomised to treatment or no treatment for one year followed by continued treatment for another year; only results from the first year of these trial are included in this review (Hardin 2005a; Hardin 2006). In the third cross‐over trial participants received rhGH or no treatment for six months and then crossed over to the alternative treatment for a further six months without any washout period in between (Hütler 2002).

One of the double‐blinded parallel trials used three treatment arms; low‐dose, high‐dose, and placebo (Schnabel 2007). The double‐blind phase in the treatment arms lasted for 24 weeks, following which the controls were randomly assigned to one of the two doses of the rhGH for an additional 24 weeks.

The minimum duration of treatment in six trials was one year (Hardin 2001; Hardin 2005a; Hardin 2005b; Hardin 2006; Schibler 2003; Stalvey 2012), while two trials lasted for six months (Hütler 2002; Schnabel 2007).

Participants and settings

A total of 291 participants provided data for the eight included trials. All trials included diagnosed cases of CF, either by sweat testing or presence of the CFTR gene. The age range of participants was from five years (Stalvey 2012) to 23 years (Schibler 2003), although most of the trials recruited younger participants in Tanner Stage 1 of sexual maturity staging. The height and weight percentile of the participants ranged from below the 10th to below the 25th percentile for age and gender. Most of the participants were in a stable disease state with no colonisation with Burkholderia cepacia and no recent use of systemic or oral steroids. Most of the trials excluded participants with evidence of glucose intolerance or active CF‐related diabetes (CFRD). All of the trials were carried out at tertiary care CF centres in outpatient settings. Three of the trials were single centre (Hütler 2002; Schibler 2003; Hardin 2005b); five were conducted at more than one site (Hardin 2001; Hardin 2005a; Hardin 2006; Schnabel 2007; Stalvey 2012). Only one of the trials included children receiving enteral nutrition (Hardin 2005a).

Interventions

The intervention was daily subcutaneous injections of rhGH. Five trials used the brand Nutropin AQ® (Genentech Inc.) at a dose of 0.3 mg/kg/week (Hardin 2001; Hardin 2005a; Hardin 2005b; Hardin 2006; Stalvey 2012). One trial used rhGH (Saizen®, Merck Serono S.A.) at a dose of 1 IU/kg/week (Schibler 2003). In a further trial, doses of 0.77 to 0.98 IU/kg/week of rhGH (Genotropin®, Pharmacia GmbH, Stockholm, Sweden) were used (Hütler 2002). In the remaining trial, two doses of rhGH (somatotropin) were used ‐ low dose, 0.039 mg/kg/day (0.273 mg/kg/week) and high dose, 0.070 mg/kg/day (0.49 mg/kg/week) (Schnabel 2007). Only one trial used a placebo as a control (Schnabel 2007); the remaining trials compared the active intervention to no treatment (Hardin 2001; Hardin 2005a; Hardin 2005b; Hardin 2006; Hütler 2002; Schibler 2003; Stalvey 2012).

Outcomes measured

All the trials measured at least one of the two of the primary outcomes included in the review ‐ pulmonary function tests and anthropometric parameters. Two trials used validated QoL questionnaires (Hardin 2006; Schnabel 2007). Most of the trials addressed blood glucose abnormality, either in quantitative values or information in the text. Four trials measured changes in serum markers, either IGF‐1 or IGFBP3 (Hardin 2001; Hardin 2005a; Hardin 2005b; Schnabel 2007). Two trials measured changes in disease exacerbation or use of antibiotics, or both (Hardin 2006; Schnabel 2007). Three trials measured exercise capacity ‐ albeit using different parameters (Hütler 2002; Schibler 2003; Schnabel 2007). None of the trials evaluated the cost of the therapy, although one trial mentions information on cost‐benefit analysis in the text (Hardin 2006).

Excluded studies

We excluded 15 trials in total from the review; nine since they were not randomised (Alemzadeh 1998; Ghergherechi 2017; Hardin 1997; Hardin 1998; Hardin 2005c; Huseman 1996; NCT00803179; Sackey 1995; Vanderwel 2006). In six trials the intervention was not appropriate: one used glutamine in conjunction with rhGH (Darmaun 2004); two used an appetite stimulant (megestrol acetate) (Eubanks 2002; Marchand 2000); one used progestational agents (Kissner 2000); one used oral zinc supplementation (Safai‐Kutti 1991); and one used IGF‐1 (Bucuvalas 2001).

Further information on these trials is available in the Characteristics of excluded studies.

Risk of bias in included studies

We classified the risk of bias for the eight included trials in this review as previously described (Assessment of risk of bias in included studies).    We judged all of the included trials as having an 'unclear' overall risk of bias. We based these assessments to a large extent on the inadequate reporting of several of the criteria that are considered to be important in the evaluation of methodological rigour in terms of study design and conduct. For further details, please see the risk of bias tables in Characteristics of included studies, the risk of bias graph (Figure 2) and the risk of bias summary (Figure 3).

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Generation of allocation sequence

We judged two trials to have a low risk of bias for the generation of allocation sequence (Hardin 2005a; Stalvey 2012). Hardin reported use of a computer‐generated random assignment in the 2005a trial (Hardin 2005a). Stalvey reported the use of a permuted block randomisation scheme developed by an interactive voice response development system at each site (Stalvey 2012).

The remaining trials do not describe details of the generation of allocation sequence and hence we classified these as having an unclear risk of bias (Hardin 2001; Hardin 2005b; Hardin 2006; Hütler 2002; Schibler 2003; Schnabel 2007).

Concealment of allocation

One trial included a statement "For this open‐label trial, there was no allocation concealment" (Stalvey 2012). However, based on the context, it is possible that the authors are referring to blinding rather than concealment of the allocation sequence, and hence we have judged this as unclear risk. None of the remaining trials described how the allocation sequence was concealed, which did not allow us to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment. We therefore judged all eight trials to have an unclear risk of bias for this domain.

Blinding

Perfomance bias

In one of the trials, participants were grouped into low‐dose, high‐dose and placebo; it is noted in the manuscript that participants and healthcare providers were blinded and hence the overall judgement is low risk of bias (Schnabel 2007).

The remaining seven trials are judged to have a high risk of bias (Hütler 2002; Hardin 2001; Schibler 2003; Hardin 2005a; Hardin 2005b; Hardin 2006; Stalvey 2012). In five of these trials the participants and personnel were able to differentiate between treatment groups (e.g. subcutaneous injection versus no treatment) (Hardin 2001; Hardin 2005a; Hardin 2005b; Hütler 2002; Schibler 2003), in two trials no blinding of participants was stated (Hardin 2006; Stalvey 2012).

Detection bias

None of the eight included trials described any methods to blind outcome assessors and we therefore judge them to have an unclear risk of bias (Hardin 2001; Hardin 2005a; Hardin 2005b; Hardin 2006; Hütler 2002; Schibler 2003; Schnabel 2007; Stalvey 2012).

Incomplete outcome data

We judged five trials as having a low risk of bias (Hardin 2005a; Hardin 2005b; Hardin 2006; Hütler 2002; Schibler 2003). There were no reports of dropouts or incomplete data in either Hardin trial from 2005 (Hardin 2005a; Hardin 2005b). In the latest Hardin trial, 61 participants were enrolled and 57 were included in the analyses; the dropouts, two from each group, are accounted for in the paper (Hardin 2006). In one cross‐over trial there were no withdrawals and no missing or incomplete data (Hütler 2002). The Schibler trial describes the withdrawal of one control evaluated for lung transplantation, likely due to worsening of the disease and also has a low risk of bias (Schibler 2003).

We judged the remaining trials to have an unclear risk of bias (Hardin 2001; Schnabel 2007; Stalvey 2012). In the earliest Hardin trial, 21 participants were enrolled and two participants dropped out within six weeks of starting the trial (Hardin 2001). The Schnabel trial reports the analysis of 63 out of the 67 participants enrolled, but no details are provided on the withdrawals (Schnabel 2007). The Stalvey trial enrolled 68 participants and reported results on efficacy in 53 participants only (loss of 22% participants); several reasons including loss to follow‐up, death of one participant and improper study practices at one centre were reported for this discrepancy (Stalvey 2012).

Selective reporting

Although no trial protocols were available, based on information presented in the methods sections of each of the reports, the investigators appear to have reported on all of their stated objectives and expected outcomes, a number of which were pre‐specified inclusion criteria for this systematic review. We therefore judge there to be a low risk of bias from selective reporting for the included trials.

Other potential sources of bias

All of the included trials were supported in some part by pharmaceutical companies, Pharmacia GmbH (Hütler 2002); Merck Serono SA (Schibler 2003); Pharmacia GmbH (Schnabel 2007) and Genetech Inc. (Hardin 2001; Hardin 2005a; Hardin 2005b; Hardin 2006; Stalvey 2012). The effect, if any, of this support on the results is unclear.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4

Summary of findings for the main comparison. Standard rhGH compared to placebo for cystic fibrosis in children and young adults.

Standard rhGH compared with placebo for children and young adults with CF
Patient or population: children and young adults with CF Settings: outpatient Intervention: standard rhGH Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Standard rhGH
FEV₁ (% predicted) change since baseline Follow‐up: 6 months	The mean (SD) change in FEV₁ % predicted since baseline in the control group was 1% (23%).	The mean change in FEV₁ % predicted in the standard rhGH group was 2.50% higher (8.60 lower to 13.60 higher).	‐	43 participants  (1 study)	⊕⊕⊝⊝  low^1,2	No significant differences were found between treatment groups.
FVC (% predicted) change since baseline Follow‐up: 6 months	The mean (SD) change in FVC % predicted from baseline in the control group was ‐0.70% (15.1%).	The mean change in FVC (% predicted) in the standard rhGH group was 3.80% higher  (4.67 lower to 12.27 higher).	‐	43 participants  (1 study)	⊕⊕⊝⊝  low^1,2	No significant differences were found between treatment groups.
Height velocity (cm/year) Follow‐up: 6 months	The mean (SD) height velocity in the control group was 3.5 (2.3) cm/year.	The mean height velocity in the standard rhGH group was 2.1 cm/year higher (0.54 lower to 3.66 higher).	‐	43 participants  (1 study)	⊕⊕⊝⊝  low^1,2	Height velocity (change in height measured in cm/year) showed significant improvement in those receiving standard rhGH; however, there was no statistically significant difference in the height z score between treatment groups.
Weight (kg) Change from baseline Follow‐up: 6 months	The mean (SD) change from baseline in weight in the control group was 1.4 (1.7) kg.	The mean change in weight in the standard rhGH group was 1.00 kg higher (‐0.08 lower to 2.08 higher).	‐	43 participants  (1 study)	⊕⊕⊝⊝ low^1,2	No significant differences were found between the two treatment groups.
QoL Follow‐up: 6 months	See comments.				⊕⊝⊝⊝ very low^1,2,3	Schnabel used standardised CF HRQoL questionnaires and reported no major differences among the treatment groups (no data available for analysis).
Fasting blood glucose (mg/dL) Follow‐up: 6 months	The mean (SD) fasting blood glucose level in the control group was 88.8 (13.7) mg/dL.	The mean fasting blood glucose level in the standard rhGH group was 12.40 mg/dL higher (3.76 higher to 21.04 higher).	‐	43 participants  (1 study)	⊕⊕⊝⊝  low^1,2	Statistically significant difference found in favour of the standard rhGH group.
Number of pulmonary exacerbations or hospitalisations Follow‐up: 6 months	182 pulmonary exacerbations per 1000 participants.	273 pulmonary exacerbations per 1000 participants (89 to 835).	RR 1.50  (0.49 to 4.59)	44 participants  (1 study)	⊕⊕⊝⊝  low^1,2	RR greater than 1 indicates an advantage for placebo.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) in the standard rhGH group is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CF: cystic fibrosis;CI: confidence interval; FEV₁: forced expiratory volume at one second; FVC: forced vital capacity; HRQoL: health‐related quality of life; N/A: not applicable; QoL: quality of life; rhGH: recombinant growth hormone; RR: risk ratio; SD: standard deviation.
GRADE Working Group grades of evidence  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

Standard rhGH compared with no treatment for children and young adults with CF
Patient or population: children and young adults with CF Settings: outpatient Intervention: standard rhGH Comparison: no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	No treatment	Standard rhGH
FEV₁(% predicted) Follow‐up: 12 months	The mean change in FEV₁ % predicted in the control group was ‐0.4 (4.1).	The mean change in FEV₁ % predicted) in the intervention group was 0.29 higher (0.62 lower to 1.19 higher).	‐	19 participants (1 study)	⊕⊝⊝⊝  very low^1,2,3	No statistically significant difference between treatment groups. The change in FEV₁`(L) was reported by 2 trials (n = 75) and showed a significantly greater increase in the standard rhGH group, SMD 0.74 (95% CI 0.26 to 1.22).
FVC (% predicted) Follow‐up: 12 months	The mean (SD) change in FVC % predicted in the control group was 0.4 (2.5) (‐0.1 to 0.4).	The mean change in FVC % predicted in the intervention group was 1.00 higher (0.03 higher to 1.96 higher).	‐	19 participants (1 study)	⊕⊝⊝⊝very low^1,2,3	Statistically significant difference found in favour of the standard rhGH group. The change in FVC (L) was reported by 2 trials (n = 75) and showed a significantly greater increase in the standard rhGH group, SMD 1.61 (95% CI 0.17 to 3.06).
Height velocity (cm/year) Follow‐up: 12 months	The mean (range) height velocity in the control group was 4.47 (3.71 to 5.3) cm/year.	The mean height in the intervention group was 3.53 cm/year higher (2.77 higher to 4.30 higher).	‐	156 participants (4 studies)	⊕⊝⊝⊝  very low^1,2,3	Statistically significant difference found in favour of the standard rhGH group. There was a similar result in favour of the rhGH treatment group in height z score measured at the end of the trial, MD 0.58 (95% CI 0.36 to 0.80).
Weight (kg) Change from baseline Follow‐up: 12 months	The mean (range) change in weight from baseline in the control group was 1.75 kg (0.7 to 2.8).	The mean change in weight in the intervention group was 1.00 kg higher (0.32 lower to 1.68 higher).	‐	62 participants (1 study)	⊕⊝⊝⊝ very low^1,2,3	A separate study found no statistically significant difference between the two groups in change from baseline (kg) at six months. In relation to weight velocity, results were consistently significantly higher in the rhGH group at 12 months.
QoL Change from baseline Follow‐up: 12 months	The mean (SD) change from baseline in HRQoL score in the control group was 0.3 (0.8).	The mean change from baseline in HRQoL score in the intervention group was 0.10 higher (0.32 lower to 0.52 higher).	‐	57 participants  (1 study)	⊕⊝⊝⊝  very low^1,2,3	No statistically significant difference found between treatment groups; however, the same trial reported a significant difference in Body Image Score favouring rhGH.
Fasting blood glucose (mg/dL) Follow‐up: 12 months	The mean (range) fasting blood glucose in the control group was 93.33 mg/dL (88.90 mg/dL to 101.00 mg/dL).	The mean fasting blood glucose in the intervention group was 3.2 mg/dL higher (6.09 mg/dL lower to 12.49 mg/dL higher).	‐	92 participants (3 studies)	⊕⊝⊝⊝  very low^1,2,3	No statistically significant difference found between the two groups.
Number of pulmonary exacerbations or hospitalisations	The mean (range) number of hospitalisations in the control group was 2.70 (2.2 to 3.0).	The mean number of hospitalisations in the intervention group was 1.34 lower (1.75 lower to 0.93 lower).	‐	94 participants (3 studies)	⊕⊝⊝⊝  very low^1,2,3	Statistically significant difference found in favour of the standard rhGH group. The episodes of hospitalisations were reported as mean and SD between the 2 groups in these studies. The total number of hospitalisations in each group are not available to calculate RR.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CF: cystic fibrosis;CI: confidence interval; FEV₁: forced expiratory volume at 1 second; FVC: forced vital capacity; HRQoL: health‐related quality of life; N/A: not applicable; QoL: quality of life; rhGH: recombinant growth hormone; RR: risk ratio; SD: standard deviation.
GRADE Working Group grades of evidence  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

High‐dose rhGH compared to placebo for children and young adults with CF
Patient or population: children and young adults with CF  Setting: outpatient  Intervention: high‐dose rhGH  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	High‐dose rhGH
FEV₁ (% predicted) Change from baseline Follow‐up: 6 months	The mean (SD) change from baseline in FEV₁ % predicted in the control group was 1.0 (23.0)% predicted.	The mean change from baseline in FEV₁ % predicted in the intervention group was 3.30% higher (8.16% lower to 14.76% higher).	‐	41 participants  (1 study)	⊕⊕⊝⊝  low^1,2	No statistically significant difference found between treatment groups.
FVC (% predicted) Change from baseline Follow‐up: 6 months	The mean (SD) change from baseline in FVC % predicted in the control group was ‐0.70 (15.10) % predicted.	The mean change from baseline in FVC % predicted in the intervention group was 6.70% higher (1.41% lower to 14.81% higher).	‐	41 participants  (1 study)	⊕⊕⊝⊝  low^1,2	No statistically significant difference found between treatment groups.
Height velocity (cm/year) Follow‐up: 6 months	The mean (SD) height velocity in the control group was 3.5 (2.3) cm/year.	The mean height velocity in the intervention group was 3.30 cm/year higher (1.17 higher to 5.43 higher).	‐	41 participants  (1 study)	⊕⊕⊝⊝  low^1,2	Statistically significant difference found in favour of the standard rhGH group. A similarly significant result was also seen in the height z score at the end of the study.
Weight (kg) Change from baseline Follow‐up: 6 months	The mean (SD) change in weight from baseline in the control group was 1.4 (1.7) kg.	The mean change in weight in the intervention group was 0.80 kg higher (0.44 lower to 2.04 higher).		41 participants  (1 study)	⊕⊕⊝⊝  low^1,2	No statistically significant difference found between treatment groups.
QoL Follow‐up: 6 months	See comments			41 participants  (1 study)	⊕⊝⊝⊝  very low^1,2,3	Schnabel reported QoL using standardised CF HRQoL questionnaires, but did not provide data we could enter into the analysis; the published paper reported no major differences between the treatment groups.
Fasting blood glucose (mg/dL) Follow‐up: 6 months	The mean (SD) fasting blood glucose in the control group was 88.8 (13.7) mg/dL.	The mean fasting blood glucose in the intervention group was 8.00 mg/dL higher (0.30 mg/dL lower to 16.3 mg/dL higher).	‐	41 participants  (1 study)	⊕⊕⊝⊝  low^1,2	No statistically significant difference found between treatment groups
Number of pulmonary exacerbations or hospitalisations Follow‐up: 6 months	182 pulmonary exacerbations per 1,000 participants.	350 pulmonary exacerbations per 1,000 participants (120 to 1021).	RR 1.92 (0.66 to 5.61)	42 participants  (1 study)	⊕⊕⊝⊝  low^1,2	RR over 1 indicates an advantage for placebo.
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CF: cystic fibrosis; CI: confidence interval; FEV₁: forced expiratory volume at 1 second; FVC: forced vital capacity; HRQoL: health‐related quality of life; N/A: not applicable; QoL: quality of life; rhGH: recombinant growth hormone; RR: risk ratio; SD: standard deviation.
GRADE Working Group grades of evidence  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

High‐dose rhGH compared to standard dose rhGH for children and young adults with CF
Patient or population: children and young adults with CF  Setting: outpatient  Intervention: high‐dose rhGH  Comparison: standard‐dose rhGH
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Standard‐dose rhGH	High‐dose rhGH
FEV₁ (% predicted) Change from baseline Follow‐up: 6 months	The mean (SD) absolute change from baseline in FEV₁ % predicted in the standard‐dose group was 5.60 (2.90)% predicted.	The mean absolute change from baseline in FEV₁ % predicted in the high‐dose group was 1.20% higher (1.04% lower to 3.44% higher).	‐	42 participants  (1 study)	⊕⊕⊝⊝  low^1,2	No statistically significant difference found between treatment groups. This was also true for FEV₁ z score.
FVC (% predicted) Change from baseline Follow‐up: 6 months	The mean (SD) absolute change from baseline in FVC % predicted in the standard‐dose group was ‐0.70 (15.1) % predicted.	The mean absolute change from baseline in FVC % predicted in the high‐dose group was 6.70% higher (1.29% lower to 14.69% higher).	‐	42 participants  (1 study)	⊕⊕⊝⊝  low^1,2	No statistically significant difference found between treatment groups.
Height velocity (cm/year) Follow‐up: 6 months	The mean (SD) change from baseline in height velocity in the standard‐dose group was 5.6 (2.9) cm/year.	The mean change from baseline in height velocity in the high‐dose group was 1.20 cm/year higher (1.04 lower to 3.44 higher).	‐	42 participants  (1 study)	⊕⊕⊝⊝  low^1,2	No statistically significant difference found between treatment groups. Also no difference between groups in height velocity z score.
Weight (kg) Change from baseline Follow‐up: 6 months	The mean (SD) change from baseline in weight in the standard‐dose group was 2.4 (1.9) kg.	The mean change from baseline in weight in the high‐dose group was 0.2 kg lower (1.48 kg lower to 1.08 kg higher).		42 participants  (1 study)	⊕⊕⊝⊝  low^1,2	No statistically significant difference found between treatment groups.
QoL	Not reported.				N/A
Fasting blood glucose (mg/dL) Follow‐up: 6 months	The mean (SD) fasting blood glucose level in the standard‐dose group was 101.20 (15.2) mg/dL.	The mean fasting blood glucose level in the high‐dose group was 4.40 mg/dL lower (13.05 mg/dL lower to 4.25 mg/dL higher).	‐	42 participants  (1 study)	⊕⊕⊝⊝  low^1,2	No statistically significant difference found between treatment groups.
Number of pulmonary exacerbations or hospitalisations Follow‐up: 6 months	273 pulmonary exacerbations per 1000 participants.	350 pulmonary exacerbations per 1000 participants (142 to 868).	RR 1.28  (0.52 to 3.18)	42 participants  (1 study)	⊕⊕⊝⊝  low^1,2	RR greater than 1 indicates an advantage for standard rhGH.
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CF: cystic fibrosis; CI: confidence interval; FEV₁: forced expiratory volume at 1 second; FVC: forced vital capacity; HRQoL: health‐related quality of life; N/A: not applicable; QoL: quality of life; rhGH: recombinant growth hormone; RR: risk ratio; SD: standard deviation.
GRADE Working Group grades of evidence  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

Date	Event	Description
20 November 2018	New citation required but conclusions have not changed	Despite the inclusion of new trials, our conclusions remain the same.
20 November 2018	New search has been performed	A search of the Cystic Fibrosis and Genetic Disorders Review Group's Cystic Fibrosis Trials Register identified four references which were potentially eligible for inclusion in the review, all of which were additional references to trials already listed in the review either as included or awaiting classification. We were able to include four additional trials, previously listed as 'Awaiting classification', in the review after communication with the primary author (Hardin 2001; Hardin 2005a; Hardin 2005b; Hardin 2006). We excluded one trial previously listed as 'Awaiting classification' (Bucuvalas 2001). The search of online trials registries identified two new trials that were deemed ineligible for inclusion in the review (Ghergherechi 2017; NCT00803179). Summary of findings tables (one for each comparison presented) have been added to the review.

Date	Event	Description
12 May 2015	New citation required but conclusions have not changed	We have not been able to incorporate any new evidence into this review and so our conclusions remain the same.
12 May 2015	New search has been performed	A new search of the Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register did not identify any new references potentially eligible for inclusion in this review.
11 February 2014	Feedback has been incorporated	Feedback received via Wiley's online feedback system has been addressed and the response included in this version of the review.

Term	Explanation
benign	of mild type or character that does not threaten health or life
electrolytes	any of the ions (as of sodium or calcium) that in biological fluid regulate or affect most metabolic processes
endothelial	of, relating to, or produced from the endothelium (the layer of flat cells lining the closed spaces of the body such as the inside of blood vessels, lymphatic vessels, the heart, and body cavities)
epithelium	a membranous cellular outside layer of tissue that covers a free surface or lines a tube or cavity of an animal body and serves especially to enclose and protect the other parts of the body, to produce secretions and excretions, and to function in assimilation
exocrine glands	a gland (as a sweat gland, a salivary gland, or a kidney) that releases a secretion external to or at the surface of an organ by means of a canal or duct
exogenous	growing from or on the outside
glucosuria	presence of glucose in the urine
hyperglycaemia	abnormally high blood sugar levels
intracranial hypertension	increase in the pressure in the brain fluid, called cerebrospinal fluid, above normal
longitudinal growth	increase in length
mammalian cell line	cells derived from a mammal
malignant	tending to deteriorate, infiltrate, metastasize and terminate fatally
percentile	(or centile) is the value of a variable below which a certain percent of observations fall
polypeptide hormone	hormone made up of several amino acids
post‐prandial	after a meal
prognostic indicator	of, relating to, or serving as ground for a prognosis
scoliosis	a lateral curvature of the spine
slipped capital epiphyses	orthopedic condition in which the growth center of the hip (the capital femoral epiphysis) slips backwards on the top of the femur (the thighbone)
splenomegaly	enlargement of spleen
transient	temporary

Resource	Date searched	Search strategy
Scopus	1995 to March 2018	1. Recombinant growth hormone/ Title‐Abs‐Key 2. rhGH/Title‐Abs‐Key 3. Growth hormone/Title‐Abs‐Key 4. Human Growth hormone/Title‐Abs‐Key 5. Somatropin/Title‐Abs‐Key 6. Somatotropin/Title‐Abs‐Key 7. Somatotrophin/Title‐Abs‐Key 8. Nutropin/Title‐Abs‐Key 9. Genotropin/Title‐Abs‐Key 10. Humatropin/Title‐Abs‐Key 11. Norditropin/Title‐Abs‐Key 12. OR/1‐11 13. cystic fibrosis/Title‐Abs‐Key 14. 12 AND 13 15. Child/Title‐Abs‐Key 16. Adolescen/Title‐Abs‐Key 17. 14 AND 15 OR 16
Clinicaltrials.gov (clinicaltrials.gov)	05 March 2018	1. Growth hormone 2. Recombinant growth hormone 3. somatotropin 4. rhGH 5. OR/1‐5 6. cystic fibrosis 7. 5 AND 6
WHO ICTRP (http://apps.who.int/trialsearch/)	05 March 2018	1. Growth hormone 2. Recombinant growth hormone 3. somatotropin 4. rhGH 5. OR/ 1‐5 6. cystic fibrosis 7. 5 AND 6
Web of Science	1995 to March 2018	1. Recombinant growth hormone/ Topic‐Title‐Key 2. rhGH/Topic‐Title‐Key 3. Growth hormone/Topic‐Title‐Key 4. Human Growth hormone/Topic‐Title‐Key 5. Somatropin/Topic‐Title‐Key 6. Somatotropin/Topic‐Title‐Key 7. Somatotrophin/Topic‐Title‐Key 8. Nutropin/Topic‐Title‐Key 9. Genotropin/Topic‐Title‐Key 10. Humatropin/Topic‐Title‐Key 11. Norditropin/Topic‐Title‐Key 12. OR/1‐11 13. cystic fibrosis/Topic‐Title‐Key 14. 12 AND 13 15. Child/Topic‐Title‐Key 16. Adolescen/Topic‐Title‐Key 17. 14 AND 15 OR 16

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FEV₁ (% predicted) change from baseline	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	2.5 [‐8.60, 13.60]
2 FEV₁ (Z‐score) change from baseline	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.23, 0.23]
3 FVC (% predicted) change from baseline	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	3.8 [‐4.67, 12.27]
4 Height (z score)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	2.5 [‐0.77, 5.77]
5 Height velocity (cm/year)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
5.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	2.10 [0.54, 3.66]
6 Weight change from baseline (kg)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	1.0 [‐0.08, 2.08]
7 Lean body mass (kg) ‐ change from baseline	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	1.0 [‐0.40, 2.40]
8 Fasting blood glucose (mg/dL)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
8.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	12.40 [3.76, 21.04]
9 Postprandial blood glucose (mg/dL)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
9.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	12.10 [‐7.18, 31.38]
10 Exercise capacity (watts)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
10.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	9.8 [‐0.90, 20.50]
11 VO2 max (mL/min)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
11.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	10.1 [‐3.85, 24.05]
12 Insulin like growth factor (IGF‐1) (Z‐score)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
12.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	1.37 [0.68, 2.06]
13 IGFBP‐3 (z score)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
13.1 At 6 months	1	43	Mean Difference (IV, Random, 95% CI)	0.65 [‐0.10, 1.40]
14 Number of pulmonary exacerbations	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
14.1 At 6 months	1	44	Risk Ratio (M‐H, Random, 95% CI)	1.5 [0.49, 4.59]
15 Adverse effects	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
15.1 Any adverse effects	1	44	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.67, 1.72]
15.2 Severe adverse effects	1	44	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.39, 4.05]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FEV₁ (% predicted)	3		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
1.1 At 12 months	3	93	Std. Mean Difference (IV, Random, 95% CI)	‐0.22 [‐0.65, 0.21]
2 FEV₁ change from baseline	4		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1 At 6 months	2	29	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.31 [‐1.06, 0.44]
2.2 At 12 months	3	94	Std. Mean Difference (IV, Fixed, 95% CI)	0.64 [0.21, 1.06]
3 FVC (% predicted)	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.1 At 12 months	3	93	Mean Difference (IV, Random, 95% CI)	3.05 [‐9.50, 15.60]
4 FVC change from baseline	3		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
4.1 At 6 months	1	19	Std. Mean Difference (IV, Random, 95% CI)	0.43 [‐0.48, 1.34]
4.2 At 12 months	3	94	Std. Mean Difference (IV, Random, 95% CI)	1.32 [0.55, 2.10]
5 Peak inspiratory pressure (PIP), mm Hg	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
5.1 At 12 months	1	19	Mean Difference (IV, Random, 95% CI)	‐21.0 [‐28.69, ‐13.31]
6 Peak expiratory pressure (mm Hg)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.1 At 12 months	1	28	Mean Difference (IV, Random, 95% CI)	23.0 [16.89, 29.11]
7 Height (z score)	4		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.1 At 12 months	4	131	Mean Difference (IV, Random, 95% CI)	0.58 [0.36, 0.80]
8 Height (cm) change from baseline	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
8.1 At 6 months	1	10	Mean Difference (IV, Random, 95% CI)	1.40 [‐0.07, 2.87]
9 Height velocity (cm/year)	4		Mean Difference (IV, Random, 95% CI)	Subtotals only
9.1 At 6 months	2	76	Mean Difference (IV, Random, 95% CI)	4.51 [2.21, 6.81]
9.2 At 12 months	4	156	Mean Difference (IV, Random, 95% CI)	3.53 [2.77, 4.30]
10 Height percentile rank	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
10.1 At 12 months	1	19	Mean Difference (IV, Random, 95% CI)	12.2 [10.84, 13.56]
11 Weight (z score)	4		Mean Difference (IV, Random, 95% CI)	Subtotals only
11.1 At 6 months	1	19	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.21, ‐0.00]
11.2 At 12 months	4	88	Mean Difference (IV, Random, 95% CI)	0.48 [‐0.07, 1.03]
12 Weight (kg) change from baseline	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
12.1 At 6 months	1	10	Mean Difference (IV, Random, 95% CI)	1.0 [‐0.22, 2.22]
12.2 At 12 months	1	62	Mean Difference (IV, Random, 95% CI)	1.0 [0.18, 1.82]
13 Weight velocity (kg/year)	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
13.1 At 6 months	2	76	Mean Difference (IV, Random, 95% CI)	3.12 [1.27, 4.97]
13.2 At 12 months	3	94	Mean Difference (IV, Random, 95% CI)	2.82 [1.53, 4.10]
14 Weight percentile rank	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
14.1 At 12 months	1	19	Mean Difference (IV, Random, 95% CI)	5.50 [4.02, 6.98]
15 Lean body mass change (kg)	7		Mean Difference (IV, Random, 95% CI)	Subtotals only
15.1 At 6 months	3	90	Mean Difference (IV, Random, 95% CI)	2.57 [2.01, 3.12]
15.2 At 12 months (age population pre‐puberty at entry of study)	5	191	Mean Difference (IV, Random, 95% CI)	2.12 [1.13, 3.10]
15.3 At 12 months (age populations spans pubertal age range)	1	19	Mean Difference (IV, Random, 95% CI)	2.50 [1.85, 3.15]
16 Quality of life	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
16.1 Health Care Quality of Life (HRQOL) score change	1	57	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.32, 0.52]
16.2 Body Image Score change	1	57	Mean Difference (IV, Random, 95% CI)	0.5 [0.03, 0.97]
17 Plasma insulin level (μU/mL)	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
17.1 At 6 months	1	19	Mean Difference (IV, Random, 95% CI)	3.10 [2.40, 3.80]
17.2 At 12 months	2	73	Mean Difference (IV, Random, 95% CI)	1.55 [‐0.60, 3.70]
18 Fasting blood glucose (mg/dL)	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
18.1 At 6 months	1	19	Mean Difference (IV, Random, 95% CI)	4.0 [‐12.57, 20.57]
18.2 At 12 months	3	92	Mean Difference (IV, Random, 95% CI)	3.20 [‐6.09, 12.49]
19 Postprandial blood glucose (mg/dL)	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
19.1 At 6 months	1	19	Mean Difference (IV, Random, 95% CI)	5.0 [‐2.20, 12.20]
19.2 At 12 months	2	38	Mean Difference (IV, Random, 95% CI)	‐10.75 [‐32.74, 11.25]
20 Hemoglobin A1c (%)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
20.1 At 6 months	1	19	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.44, 0.64]
20.2 At 12 months	1	19	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐0.66, 0.06]
21 Change in haemoglobin A1c from baseline (%)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
21.1 At 12 months	1	19	Mean Difference (IV, Random, 95% CI)	0.14 [‐0.30, 0.58]
22 Exercise capacity (watts)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
22.1 At 6 months	1	19	Mean Difference (IV, Random, 95% CI)	23.10 [15.58, 30.62]
22.2 At 12 months	1	19	Mean Difference (IV, Random, 95% CI)	31.90 [22.68, 41.12]
23 VO2 max	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
23.1 At 6 months (mL/min)	1	10	Mean Difference (IV, Random, 95% CI)	3.65 [0.60, 6.70]
23.2 At 12 months (mL/kg/min)	1	19	Mean Difference (IV, Random, 95% CI)	6.1 [4.29, 7.91]
24 Six‐minute walk test (m) change from baseline	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
24.1 At 12 months	1	56	Mean Difference (IV, Random, 95% CI)	25.9 [‐43.57, 95.37]
25 IGF‐1 level (ng/dL)	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
25.1 At 6 months	1	19	Mean Difference (IV, Random, 95% CI)	152.0 [62.89, 241.11]
25.2 At 12 months	3	69	Mean Difference (IV, Random, 95% CI)	198.17 [135.59, 260.74]
26 Hospitalisation	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
26.1 At 12 months	3	94	Mean Difference (IV, Random, 95% CI)	‐1.34 [‐1.75, ‐0.93]
27 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
27.1 Drug‐related adverse effect	1	68	Risk Ratio (M‐H, Random, 95% CI)	18.73 [1.14, 307.37]
27.2 Injection‐site bruising	1	68	Risk Ratio (M‐H, Random, 95% CI)	13.38 [0.79, 225.34]
27.3 Hyperglycaemia	1	68	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.22, 1.80]
27.4 Papilledema	1	68	Risk Ratio (M‐H, Random, 95% CI)	2.68 [0.11, 63.45]
27.5 Headache	1	68	Risk Ratio (M‐H, Random, 95% CI)	2.68 [0.11, 63.45]
27.6 Death	1	68	Risk Ratio (M‐H, Random, 95% CI)	2.68 [0.11, 63.45]

Methods	RCT. Duration: 1 year. Design: parallel design. Multicentre: CF centres in the USA (Texas Children's Hospital, Houston and Cook's Children's Hospital, Forth Worth).
Participants	Randomised: N = 19 (10 males, 9 females), age 8 ‐ 13 years. Inclusion criteria diagnosed cases of CF height and weight < 10th percentile Tanner Stage 1 adequate caloric intake Exclusion criteria glucose intolerance or cystic fibrosis‐related diabetes infection with B cepacia weight loss > 3% in the 3 months prior to the trial treatment with systemic or oral steroids in the prior 6 weeks poor adherence to nutritional feeding Withdrawals/losses to follow‐up: n = 2, group assignment unknown.
Interventions	Intervention: daily SC injection of rhGH (Nutropin AQ®) 0.3 mg/kg/week, adjusted every 3 months for weight gain. Control: no therapy. Concomitant therapy: standard CF care, antibiotics and hospitalised as needed.
Outcomes	Primary outcomes pulmonary function tests Anthropometric measures ‐ height, weight, height velocity, weight velocity, lean body mass Secondary outcomes blood glucose abnormality ‐ haemoglobin A1c, fasting and postprandial blood glucose, insulin level IGF‐1 levels disease exacerbation ‐ hospitalisation frequency and intravenous antibiotics
Notes	"Supported by a grants from Genentech Foundation and from NIH grant MO1‐RR‐02558 (University of Texas Clinical Research Center)".
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method for random assignment not reported.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment has not been described in the paper.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Unlikely as the comparative group was no treatment.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No blinding of the outcome assessors reported.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	The results report 19 participants who completed the trial per protocol. No details of group assignment of the 2 participants or the reasons for drop out are provided.
Selective reporting (reporting bias)	Low risk	The results of outcomes measured in the Methods section are all reported in the paper. The clinical trial protocol is not available for review.
Other bias	High risk	Partially supported by a grant from Genentech Foundation, the manufacturer of rhGH used in the trial.

Roles and responsibilities
Task	Author
Protocol stage: draft the protocol	VT, VJ, AH, BH
Review stage: select which trials to include (2 + 1 arbiter)	VT, VJ, BH
Review stage: extract data from trials (2 people)	VT, BH, BC
Review stage: enter data into RevMan	VT, BC
Review stage: carry out the analysis	VT, BC
Review stage: interpret the analysis	VT, ZF, BC
Review stage: draft the final review	VT, AH, ZF, BC
Update stage: update the review	VT, AH, VJ, BH, ZF, BC
1st revision of the review	VT, AH, VJ, BH, ZF, BC
2nd revision of the review	VT, BC, MP
2nd revision: selection of trials	VT, MP
2nd revision: extract data from trials	VT, MP
2nd revision: interpret the analysis	VT, BC, MP
2nd revision: draft the final review	VT, BC, MP

Methods	RCT. Duration: 2 years. Design: cross‐over trial. Multicentre: CF centres in the USA (Children's Medical Center, Dallas, TX; Texas Children's Hospital, Houston, TX; Indiana University, Indianapolis, IN; Washington University, St. Louis, MO).
Participants	Randomised: N = 18, age 9.2 ‐ 13.8 years, gender distribution not available. Inclusion criteria diagnosed cases of CF enteral nutrition for at least 2 years prior to enrolment Tanner Stage 1 pubertal status Height/Weight < 10th percentile adequate caloric intake Exclusion criteria treatment with systemic corticosteroid therapy within 6 weeks of study infection with B cepacia poor adherence to nutritional feeding
Interventions	Intervention: daily SC injection of rhGH (Nutropin AQ®) 0.3 mg/kg/week, adjusted every 3 months for weight gain. Control: no therapy. Concomitant therapy: standard CF care including pancreatic enzyme therapy, enteral nutrition, antibiotics and hospitalised as needed. Year 1: 9 participants received rhGH treatment and 9 received no treatment. Year 2: All participants received treatment with rhGH.
Outcomes	Primary outcomes pulmonary function tests ‐ FVC and FEV₁ every 3 months anthropometric measures ‐ height, weight, height velocity, weight velocity every 3 months lean body mass and bone mineral content by DEXA every 6 months Secondary outcomes blood glucose abnormality ‐ casual blood glucose every 3 months, fasting blood glucose as well as night‐time glucose levels during enteral feeding in 12 participants IGF‐1 levels at baseline and yearly disease exacerbation ‐ hospitalisation frequency and intravenous antibiotics nutritional status‐ 3‐day food record every 6 months compliance with enteral feedings ‐ response to the physician, annual clinic dietary assessment, and by food journal. Levels of vitamin A, D and E, as well as electrolytes and calcium were obtained from medical records where available
Notes	"Supported in part by the Genentech Center for Clinical Research". In the 2nd year of the trial, all participants received rhGH treatment. Only data at the end of 1st year included.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random assignment performed by computer‐generated assignment.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment has not been described in the paper.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Unlikely as the comparative group was no treatment.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No blinding of the outcome assessors reported.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All the participants completed the treatment and are included in the analysis.
Selective reporting (reporting bias)	Low risk	The results of outcomes measured in the Methods section are all reported in the paper. The clinical trial protocol is not available for review.
Other bias	Unclear risk	Partial funding support information provided (Genentech Center for Clinical Research). Unclear on the additional support.

Methods	RCT. Duration: 2 years (1st year randomised for rhGH treatment or no treatment, 2nd year all participants received rhGH). Single center: USA (University of Texas at Baylor College of Medicine, Houston, TX).
Participants	Randomised: N = 32, (17 males, 15 females) age 9.1 ‐ 13.1 years. Inclusion criteria diagnosed cases of CF Tanner Stage 1 pubertal status Height/Weight < 10th percentile Exclusion criteria treatment with systemic corticosteroid therapy within 6 weeks of study infection with B cepacia severe acute illness
Interventions	Intervention: daily SC injection of rhGH (Nutropin AQ®) 0.3 mg/kg/week, adjusted every 3 months for weight gain. Control: no therapy. Concomitant therapy: standard CF care including pancreatic enzyme therapy, enteral nutrition, antibiotics and hospitalised as needed.
Outcomes	Primary outcomes anthropometric measures ‐ height, weight, height velocity, weight velocity every 3 months bone mineral content and lean body mass by DEXA every 6 months Secondary outcomes IGF‐1 levels at baseline and yearly sex‐steroids measurement, estradiol or testosterone disease exacerbation ‐ hospitalisation frequency and intravenous antibiotics bone age x‐rays.
Notes	The trial was supported by grants from the National Institutes of Health, National Cystic Fibrosis Foundation, Genentech Center for Research and United States Department of Agriculture. Data from the 1st year of treatment used. Bone mineral content is additional outcome of interest reported in this trial but not included as an outcome in the review.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method for random assignment not reported.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment has not been described in the paper.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Unlikely as the comparative group was no treatment.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No blinding of the outcome assessors reported.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All the participants completed the treatment and are included in the analysis.
Selective reporting (reporting bias)	Unclear risk	The results of outcomes measured in the Methods section are all reported in the paper. The clinical trial protocol is not available for review.
Other bias	Unclear risk	Partial funding support information provided (National Institutes of Health, National Cystic Fibrosis Foundation, Genentech Center for Research and United States Department of Agriculture). Unclear on the additional support.

Methods	RCT. Duration: 2 years, cross‐over of the participants in the treatment arms at the end of year 1. Design: cross‐over trial. Multicenter study in USA (University of Texas Southwestern/Children’s Medical Center (n = 12), Texas Children’s Hospital/Baylor College of Medicine (n = 4), Vanderbilt Medical School (n = 6), University of South Carolina Medical School (n = 4), Indiana University School of Medicine (n = 8), University of Utah (n = 8), Cook Children’s Hospital in Fort Worth (n = 9), Dayton Children’s Hospital (n = 1), and Washington University School of Medicine and St. Louis Children’s Hospital (n = 9)).
Participants	Randomised N = 61 (29 females, 32 males), age 8 to 12.5 years, 57 participants included in the final analyses. Inclusion criteria diagnosed cases of CF height and weight < 25th percentile Tanner Stage 1 Exclusion criteria pre‐existing diabetes treatment with systemic corticosteroid therapy within 6 months colonisation with B cepacia addition of oral, enteral, or parenteral caloric supplements within the previous year
Interventions	Intervention: daily SC injection of rhGH (Nutropin AQ®) 0.3 mg/kg/week; dose adjusted every 3 months for weight gain. Control: no treatment. Concomitant treatment: pancreatic enzyme treatment, vitamin supplementation, inhaled bronchodilators, and mucolytics. Other therapies, including antibiotics, prescribed as indicated.
Outcomes	Primary outcomes pulmonary function tests (FEV₁, FVC) anthropometric parameters ‐ height, weight, height velocity, weight velocity, lean body mass Health‐Related Quality of Life questionnaire Secondary outcomes blood glucose abnormality ‐ random blood glucose levels IGF‐1 levels changes in disease exacerbation ‐ hospitalisation, intravenous antibiotic use
Notes	The Year 2 data for participants who received rhGH in Year 1 year was used to evaluate the sustained effect of therapy after cessation. "The study was supported by a grant from the Genetech Center for Clinical Research in Endocrinology." The first author previously served on the advisory board for Genentech.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method for random assignment not reported.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment has not been described in the paper.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	There was no blinding of the participants and personnel.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No blinding of outcome assessors is reported.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Details of the four out of 61 participants not included in the analyses are reported. There was equal drop‐out from treatment and no‐treatment group.
Selective reporting (reporting bias)	Low risk	The results of outcomes measured in the Methods section are all reported in the paper. The clinical trial protocol is not available for review.
Other bias	Unclear risk	Partial funding support information provided (Genetech Center for Clinical Research in Endocrinology). The first author previously served on the advisory board for Genentech. Unclear on the additional support.

Methods	RCT. Duration: 2 periods of 6 months each with no wash‐out period in between. Design: cross‐over design. Single centre in Germany (Children's Hospital, Humboldt University and Children's Hospital Clinic, Buch).
Participants	Randomised, N = 10 Inclusion criteria diagnosed with CF relative underweight and short stature with delayed skeletal maturation pre‐pubertal no active glucocorticosteroid treatment no growth hormone deficiency no CF‐specific sports rehabilitation program
Interventions	Intervention: daily SC injections of rhGH (Genotropin®, Pharmacia GmbH, Stockholm) in the dose of 0.11 ‐ 0.14 IU/kg/d. Control: no treatment.
Outcomes	Primary outcomes pulmonary function tests ‐ FEV₁, FVC, MEF nutritional parameters ‐ height, lean body mass Secondary outcomes muscular strength and exercise capacity
Notes	Only published data from the first half of the trial used. The study was supported by a grant from the Mukoviszidose e.V Foundation. Pharmacia GmbH provided the Genotropin®. The trial authors disclose professional relationships with companies or manufacturers who will benefit from the results of the present trial.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote "Patients were randomly assigned to either the GH treatment or control period" (page 568). No details on the process of randomisation provided.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment has not been described in the paper.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Unlikely as the comparative group was no treatment.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Outcome assessors and data analysts: no information on blinding.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants included in the trial completed it. No loss to follow‐up.
Selective reporting (reporting bias)	Low risk	The results of outcomes measured in the Methods section are all reported in the paper. The clinical trial protocol is not available for review.
Other bias	Unclear risk	The trial authors disclose professional relationships with companies or manufacturers who will benefit from the results of the present trial.

Methods	Double‐blind, placebo‐controlled RCT. Duration : 24 weeks double‐blind followed by 24 weeks open‐label treatment period. Design: parallel design.  Multicentre: 12 German CF centres.
Participants	Randomised: N = 63, age 9 ‐ 20 years. Inclusion criteria established diagnosis of CF bone age of 8 ‐ 18 years BMI < 10th or body weight < 3rd percentile despite a high caloric intake Exclusion criteria acute pulmonary exacerbation 4 weeks prior to study entry systemic disease like diabetes, liver cirrhosis, renal failure, malignancy inability to perform exercise or pulmonary function test treatment with rhGH or steroids in the year prior to study Withdrawals or loss to follow‐up: 4 (details not described, analysis by ITT).
Interventions	Intervention: daily SC injections of somatotropin in 1 of the 2 treatment arms ‐ 0.070 mg/kg/day (0.21 IU/kg/day) or 0.039 mg/kg/day ( ~0.11IU/kg/day) using a Genotropin® pen. Control: placebo injection with Genotropin® pen. At the end of 24 weeks, in the open‐label phase, the 2 intervention groups were continued on their daily dose. The control group was randomly assigned to a dose group for another 24 weeks.
Outcomes	Primary outcomes pulmonary function tests ‐ FEV₁, FVC nutritional parameters ‐ height, weight, height velocity, weight velocity, lean body mass QoL questionnaires Secondary outcomes blood glucose abnormality ‐ fasting and postprandial blood glucose levels exercise capacity ‐ measured using Borg scale at the end of an exercise test IGF‐1 and IGFBP‐3 levels change in disease exacerbation ‐ hospitalisation report on adverse events
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The trial was designed as a multicenter, randomised, double‐blind, placebo‐controlled, parallel‐groups study to compare the efficacy and the safety of 2 fixed dosages of rhGH or placebo in patients with CF" (page e1231). Comment: insufficient detail reported about the method used to generate the allocation sequence to allow a clear assessment of whether it would produce comparable groups.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment has not been described in the paper.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Participants: blinded as all participants received injections. Healthcare providers: no details provided, but reported as a double‐blind trial and all participants received injection. Comment: overall judgement low risk.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Outcome assessors and data analyst blinding ‐ unclear.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	63 out of the 67 participants (94%) randomised were included in the analysis of efficacy and safety per intention to treat. Withdrawals have not been described.
Selective reporting (reporting bias)	Low risk	The results of outcomes measured in the Methods section are all reported in the paper. The clinical trial protocol is not available for review.
Other bias	Unclear risk	No other disclosures by authors in the manuscript.

Methods	RCT open‐label. Duration: 12 months of intervention; 18 months follow‐up. Design: parallel study design. Multicentre in USA (24 centres).
Participants	Randomised, N= 68 (36 in treatment arm and 32 in control). Aged 5 ‐ 13 years. Inclusion criteria diagnosed cases of CF height < 10th percentile bone age < 11 years Tanner 1 sexual maturity stage adequate nutrition per CF Foundation guidelines
Interventions	Intervention: daily SC injections of rhGH 0.3 mg/kg/week. Control: no treatment.
Outcomes	Analysis was divided into efficacy analysis and safety analysis. Efficacy analysis: 33 participants in the treatment arm and 29 controls were included. Primary outcomes pulmonary function tests ‐ FEV₁, FVC, FEV₁/FVC nutritional parameters ‐ height, weight, lean body mass Secondary outcomes change in glucose parameters, fasting and postprandial glucose, glucose tolerance test
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Permuted block randomisation scheme was developed by an interactive voice response development system for group assignment at each site" (page 2).
Allocation concealment (selection bias)	Unclear risk	Paper states "For this open‐label trial, there was no allocation concealment." However, it is not clear if this refers to allocation concealment as defined by Cochrane or to blinding. No details are provided on allocation concealment as defined by Cochrane, and hence we have judged it as unclear risk.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐labelled trial.  Participants: no.  Control: no treatment. Healthcare providers: not possible (control: no treatment).
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Outcome assessors and data analysts: unclear if blinded.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	ITT method of analysis used. 68 participants randomised, 62 included in the efficacy analysis. Details of the participants excluded from the analysis described in the trial.
Selective reporting (reporting bias)	Low risk	Although the protocol is not available, all details appear to have been covered.
Other bias	Unclear risk	4 of the 5 authors have received consultancy fees from Genentech Inc., 2 authors are current or former employees of Genetech Inc. and own stock in the company.

Study	Reason for exclusion
Alemzadeh 1998	Not an RCT.
Bucuvalas 2001	The intervention is IGF‐1 not rhGH.
Darmaun 2004	Each participant was given randomised treatments of glutamine, rhGH or both with 2‐week wash‐out periods in between. Although the order of treatments was randomised, use of glutamine with rhGH excludes the trial.
Eubanks 2002	Study of appetite stimulant megestrol acetate and not rhGH.
Ghergherechi 2017	Not an RCT; enrolled 34 children under the age of 12 years. For the first 6 months they were observed without treatment followed by treatment with rhGH.
Hardin 1997	Retrospective chart review, not an RCT.
Hardin 1998	Not an RCT.
Hardin 2005c	Retrospective study, not an RCT.
Huseman 1996	Case series, not an RCT.
Kissner 2000	Intervention not rhGH.
Marchand 2000	Comparison of appetite stimulant megestrol acetate and not rhGH.
NCT00803179	Not an RCT; enrolled 5 adults, terminated due to poor enrolment with loss to follow‐up.
Sackey 1995	Not an RCT.
Safai‐Kutti 1991	Intervention zinc supplementation and not rhGH.
Vanderwel 2006	Retrospective trial, not an RCT.

PERMALINK

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

Vidhu Thaker

Ben Carter

Melissa Putman

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

Adverse effects of the therapy

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings tables

Results

Description of studies

Results of the search

1.

Included studies

Methods

Participants and settings

Interventions

Outcomes measured

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Generation of allocation sequence

Concealment of allocation

Blinding

Perfomance bias

Detection bias

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Standard rhGH compared to placebo for cystic fibrosis in children and young adults.

Summary of findings 2. Standard rhGH compared to no treatment for cystic fibrosis in children and young adults.

Summary of findings 3. High‐dose rhGH compared to placebo for children and young adults with cystic fibrosis.

Summary of findings 4. High‐dose rhGH compared to standard‐dose rhGH for children and young adults with cystic fibrosis.

Recombinant growth hormone (standard dose) versus placebo

Primary outcomes

1. Pulmonary function tests

a. FEV1

1.1. Analysis.

1.2. Analysis.

b. FVC

a. FEV₁

a. FEV₁

c. PI_max

d. PE_max