Intervention Review

You have free access to this content

Appetite stimulants for people with cystic fibrosis

  1. Ruth Chinuck1,*,
  2. Jane Dewar2,
  3. David R Baldwin3,
  4. Elizabeth Hendron4

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 27 JUL 2014

Assessed as up-to-date: 14 JUL 2014

DOI: 10.1002/14651858.CD008190.pub2


How to Cite

Chinuck R, Dewar J, Baldwin DR, Hendron E. Appetite stimulants for people with cystic fibrosis. Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD008190. DOI: 10.1002/14651858.CD008190.pub2.

Author Information

  1. 1

    Nottingham University Hospitals, City Campus, Adult CF Unit, Department of Dietetics and Nutrition, Therapy Services, Nottingham, UK

  2. 2

    Nottingham University Hospitals, City Campus, Adult Cystic Fibrosis Unit, Nottingham, UK

  3. 3

    Nottingham University Hospitals, City Campus, Respiratory Medicine Unit, Nottingham, UK

  4. 4

    Nottingham City Hospital Campus, PGEC Library, Nottingham, UK

*Ruth Chinuck, Adult CF Unit, Department of Dietetics and Nutrition, Therapy Services, Nottingham University Hospitals, City Campus, Hucknall Road, Nottingham, NG5 1PB, UK. ruth.chinuck@nuh.nhs.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 27 JUL 2014

SEARCH

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 
Summary of findings for the main comparison. Appetite stimulants versus placebo for people with cystic fibrosis

Appetite stimulants versus placebo for people with cystic fibrosis

Patient or population: people with cystic fibrosis
Settings:
Intervention: Appetite stimulants versus placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlAppetite stimulants versus placebo

Change in weight (kg) - at 3 months
Follow up: mean 3 months
The mean change in weight (kg) - at 3 months in the intervention groups was
3.0 higher
(0.92 to 5.08 higher)
17
(1 study)
⊕⊕⊕⊝
moderate1

Change in weight (kg) - at 6 months
Follow up: mean 6 months
The mean change in weight (kg) - at 6 months in the intervention groups was
3.8 higher
(1.27 to 6.33 higher)
17
(1 study)
⊕⊕⊕⊝
moderate1

Change in weight z score - at 3 months
Follow up: mean 3 months
The mean change in weight z score - at 3 months in the intervention groups was
0.61 higher
(0.29 to 0.93 higher)
40
(3 studies)
⊕⊕⊕⊝
moderate2

Change in weight z score - at 6 months
Follow up: mean 6 months
The mean change in weight z score - at 6 months in the intervention groups was
0.74 higher
(0.26 to 1.22 higher)
17
(1 study)
⊕⊕⊕⊝
moderate1

Change in FEV1 (% predicted) - at 3 months
Follow up: mean 3 months
The mean change in FEV1 (% predicted) - at 3 months in the intervention groups was
13.55 higher
(1.88 lower to 28.98 higher)
17
(1 study)
⊕⊕⊕⊝
moderate1

Change in FEV1 (% predicted) - at 6 months
Follow up: mean 6 months
The mean change in FEV1 (% predicted) - at 6 months in the intervention groups was
5.64 higher
(4.43 lower to 15.71 higher)
17
(1 study)
⊕⊕⊕⊝
moderate1

Increase in appetite (subjective reporting)
Follow up: mean 6 months
Study populationOR 45.25
(3.57 to 573.33)
23
(2 studies)
⊕⊕⊕⊝
moderate2

154 per 1000892 per 1000
(394 to 990)

Moderate

143 per 1000883 per 1000
(373 to 990)

*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% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;

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.

 FEV1: forced expiratory volume at one second
1 Dropout due to outcome (no effect)
2 Attrition bias

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Description of the condition

Treating and managing loss of weight, inadequate weight gain and failure to thrive can be a challenging problem in cystic fibrosis (CF). Weight loss is a complex problem contributed to, in part, by anorexia (leading to reduced energy intake resulting in reduced nutrient absorption) and also by intestinal malabsorption. An increased resting energy expenditure, as a result of deteriorating pulmonary function and chronic sepsis, also contributes to weight loss (Elborn 1996). This results in a recurring cycle of weight loss and malnutrition, contributing to reduced lung function, a lower quality of life (QoL) and increased morbidity and mortality (Hardin 2002; Sharma 2001; Sinaasappel 2002). Furthermore, pulmonary exacerbations have important adverse effects on body protein metabolism (Shepherd 1998). Symptoms of anorexia, weight loss and tissue wasting, combined with a decrease in muscle mass and adipose tissue, are together known as anorexia-cachexia syndrome (Lopez 2004).

The importance of maintaining optimal nutrition in people with CF is well-recognised. However, the exact mechanism of anorexia in CF remains uncertain (Berenstein 2005) and there is as yet no objective method of assessing appetite in CF. Inadequate appetite tends to be diagnosed through elimination of all other contributory factors (Nasr 2008). The aetiology of anorexia is likely to be multifactorial; it may be caused in part by chronic infection due to factors such as increased mucus production and the anorectic effects of elevated serum inflammatory cytokines (Elborn 1996). Tumour necrosis factor (TNF)-α in particular may be implicated (Suter 1989). In addition, anorexia may be related to the presence of severe sinusitis, gastroesophageal reflux, and protein or energy malnutrition or both (Eubanks 2002).

Currently, little is known about the incidence and aetiology of anorexia and poor appetite in CF and to date, there is no consensus on the management of these symptoms (Chinuck 2007; O'Brien 2013).

 

Description of the intervention

Whilst appetite stimulants are prescribed, they are not currently licensed for use in CF in either adults or children. They are used as part of an array of treatment for anorexia and weight loss, but their use is controversial because of doubts about efficacy and concerns about toxicity. Research to date has consisted of small, sometimes poorly controlled studies. Multiple agents have been studied in the CF population which may have a secondary effect on appetite stimulation. These agents have a range of primary characteristics and include hormones (ghrelin, growth hormone, insulin), antihistamines (cyproheptadine (CH), pizotifen, steroids (megesterol acetate (MA), oxandrolone, prednisone), cannabinoids (dronabinol), antidepressants (mirtazapine) and antipsychotics (olanzapine). In addition to the agents which have already been studied in CF, there are potential interventions which may have implications for patients with CF since similar effects could well occur. Given this wide range of agents, a definition of an appetite stimulant for consideration in this review will be: "an agent with a biologically plausible mechanism by which it may stimulate appetite and where it is prescribed specifically for that indication". Thus we will restrict the interventions considered to be appetite stimulants for the purpose of this review to: CH; MA; oxandrolone; dronabinol; mirtazapine; pizotifen; risperidone; and olanzapine. All agents are administered orally.

 

Cyproheptadine

This agent is used as an antihistamine and clinical recommended dosages differ in children and adults (Auden Mckenzie 2014; BNF 2014). It has been investigated for use as an appetite stimulant in CF (Homnick 2004).

 

Dronabinol

Capsules of synthetic tetrahydrocannabinol (THC) (dronabinol) have been available for restricted medical use in the USA since 1985. Nabilone, a synthetic THC analogue taken orally, is the only cannabinoid licensed for prescription in the UK for the treatment of nausea and vomiting caused by chemotherapy; its use in other indications is only possible on a ‘named patient’ basis if the drug is supplied by a hospital pharmacy (EMC 2014a). Dronabinol has been shown to be effective as an oral appetite stimulant in HIV and cancer patients using doses of 2.5 mg to a maximum of 5 mg twice daily (Anstead 2003).

 

Megestrol acetate

The progestogen steroid MA (also known as Megace®) is mainly used as a treatment for breast cancer in women; in addition, MA is sometimes used to treat cancer of the uterus and occasionally to treat prostate cancer (EMC 2014b). One of its adjunctive effects is weight gain and it has been used for appetite stimulation and weight gain in areas such as advanced cancer, AIDS,and the elderly (Lopez 2004); renal failure (Chung 2006; Hobbs 2012); chronic heart failure (von Haehling 2009); chronic obstructive pulmonary disease (Weisberg 2002); and CF (Eubanks 2002; Marchand 2000).

It is not very water-soluble and thus its bio-availability is low; but bio-availability is improved if MA is taken with food. Several formulations have been developed in an attempt to improve bio-availability, e.g. a micronized tablet form and a concentrated oral suspension. The most recent is an oral suspension form using nanocrystal technology, which is licensed for anorexia-cachexia in patients with AIDS.

 

Mirtazapine

Mirtazapine (Remeron®) is typically used as an anti-depressant in tablet form and the dosage differs between initial and maintenance treatment (EMC 2014c). In two trials evaluating its role as an appetite stimulant in people with CF, mirtazapine was given at a doses ranging from 15 mg to 45 mg per day (Sykes 2006; Young 2000).

 

Olanzipine

Olanzipine is an atypical anti-psychotic drug (EMC 2014d). Whilst limited data is available, olanzapine has been used to stimulate appetite, improve BMI and improve other disease-related symptoms (e.g., eating attitudes, anxiety) in anorexia patients aged nine years and older. The dose used to stimulate appetite has been higher than in psychiatric practice (Nasr 2008).

 

Oxandrolone

Therapy with the anabolic steroid oxandrolone (Oxandrin®) should be intermittent and the duration should depend on patient response and adverse reactions. Two to four week blocks of therapy are usually adequate and dosage differs depending on the age of the patient (MedLibrary 2014; Upsher-Smith 2014). Oxandrolone has been used principally in anorexia in cancer patients, but it has also been investigated in CF (Tongudai 1971; Varness 2009).

 

Pizotifen

Pizotifen is an antihistamine and serotonin antagonist used to treat migraine at differing age-dependent doses (EMC 2014e).

 

Risperidone

Risperidone is indicated in the treatment of acute and chronic psychoses, and in the management of aggression in moderate to severe Alzheimer’s dementia. Recommended doses vary depending on the condition being treated and the age and weight of the patient (EMC 2014f). It is not recommended for use in children, except for conduct disorder and then only for children over five years of age.

 

How the intervention might work

Given that the agents are of the varying types, the mechanisms of action are varied and mostly unclear in CF patients.

 

Cyproheptadine

Cyproheptadine hydrochloride is a serotonin and histamine antagonist approved by the Food and Drug Administration (FDA) in the USA for use in children for allergic rhinitis, allergic conjunctivitis, urticaria, dermatographism and mild angioedema. Unexplained weight gain has been observed in patients with CF who have taken CH.

 

Dronabinol

Dronabinol is the principal psychoactive substance present in marijuana (Nasr 2008). However, the mechanism of action in CF is unreported (Anstead 2003).

 

Megesterol acetate

It has been elucidated that MA may cause appetite stimulation and weight gain in individuals with anorexia or cachexia or both (Loprinzi 1993). The mechanism by which it does this has not been established, but, it has been shown to have the secondary effect of appetite stimulation (Homnick 2004). Increased levels of cytokines are known to be associated with anorexia and cachexia in people with cancer (Eubanks 2002). It has been reported that MA inhibits cytokines and so may be a treatment option for cachexia (Taylor 2007). Additionally, it has been hypothesized that cytokines inhibit the action of TNF on fatty tissue and its products (Marchand 2000); and that cytokines released during inflammation and malignancy act on the central nervous system to alter the release and function of a number of neurotransmitters, thereby altering both appetite and metabolic rate (Grossberg 2010). However, this has not been elucidated in CF.

 

Mirtazapine

Mirtazapine has noradrenergic and serotonergic enhancing properties as well antihistamine effects and a common side effect observed is appetite stimulation (Young 2000).

 

Olanzipine

Olanzipine, an antipsychotic, is associated with clearly documented weight gain and adverse metabolic effects. Although increased appetite or caloric intake and various receptors, hormones and peptides, have been implicated, the biological mechanisms contributing to the increase in weight and glucose and lipid abnormalities with antipsychotics are largely unknown (Nasr 2008; Nasrallah 2003).

 

Oxandralone

Oxandralone is weak oral androgen which has anabolic properties with minimal androgenic effects (Varness 2009).

 

Pizotifen

Pizotifen is a sedating antihistamine which is reported to have an orexigenic effect in patients with pulmonary tuberculosis (Ohnhaus 1974). However, like CH its mechanism of action as an appetite enhancer is unclear.

 

Risperidone

Risperidone may cause weight gain due to the blockade of certain receptors, for example, 5-HT2c, that modulate appetite and body weight and associated with modest weight changes that are not dose-related. However, the mechanisms involved in drug-related weight gain for both risperidone and olanzapine are as yet uncertain (Nasr 2008; Nasrallah 2003).

 

Why it is important to do this review

Nutrition and weight are corner-stones of CF management. A lack of appetite has not only been reported as a common indicator of pulmonary exacerbation in CF patients (Abbott 2011), but also plays a key role in weight loss. The use of appetite stimulants in CF is controversial because of doubts concerning efficacy and also because of possible side effects. Hence the aim of the review is to establish whether appetite stimulants should be recommended in people with CF.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

The aim of this review is to systematically search for and evaluate evidence on the beneficial effects of appetite stimulants in the management of CF-related anorexia and synthesize reports of any side-effects.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials (RCTs) and quasi-RCTs (with no language restraints).

 

Types of participants

People with CF (diagnosed clinically and confirmed with sweat test or genetic testing or both) of any age, irrespective of pancreatic insufficiency or sufficiency and of any disease severity.

 

Types of interventions

We considered an appetite stimulant to be an agent with a biologically plausible mechanism by which it may stimulate appetite and where it is prescribed specifically for that indication (addition of this definition is a post hoc change). In light of this definition, we considered trials eligible for inclusion if they compared appetite stimulants or any agent used as an appetite stimulant to placebo, control or no treatment; different appetite stimulants and the same appetite stimulants at different doses or regimens of at least one month duration.

 

Types of outcome measures

 

Primary outcomes

  1. Change in body weight (kg)
  2. Change in body composition
    1. lean body mass (LBM)
    2. fat mass
    3. body mass index (BMI)
  3. Change in pulmonary function
    1. forced expiratory volume in one second (FEV1) (absolute values)
    2. FEV1 (% predicted)

 

Secondary outcomes

  1. Subjective report of anorexia or change in appetite or both
  2. QoL (subjective report or measured by a validated questionnaire)
  3. Dietary intake
    1. energy intake (measured in kcal per day)
    2. protein intake (measured in grams of protein per day)
  4. Any adverse events directly related to the intervention
  5. Change in the number of pulmonary exacerbations

 

Search methods for identification of studies

 

Electronic searches

Relevant trials were identified from the Group's Cystic Fibrosis Trials Register using the terms: appetite stimulant OR treatment of growth failure OR depression OR psychosis OR insulin OR anabolic steroid OR headache.

The Cystic Fibrosis Trials Register was compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE, a search of Embase to 1980 and the prospective handsearching of two journals - Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work was 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 Cystic Fibrosis and Genetic Disorders Group Module.

Date of the last search of the Cystic Fibrosis Trials Register: 08 April 2014.

We used Healthcare Databases Advanced Search (HDAS) via www.library.nhs.uk to search MEDLINE (1950 to 01 April 2014), CINAHL (1981 to 01 May 2012) and Embase (1980 to 01 April 2014). Details of the search strategies can be found in the appendices (Appendix 1; Appendix 2; Appendix 3).

These searches were completed: 01 April 2014.

 

Searching other resources

We contacted the authors of conference abstracts to determine if further publications were in press, hand searched and reviewed citations and references located in articles we identified.

We also requested additional material such as unpublished further trials and negative trials from personal contacts with experts and the suppliers of appetite stimulants (Bristol-Myers Squibb Company and Actavis Mid Atlantic LLC).

 

Data collection and analysis

 

Selection of studies

Authors (RC and JD) independently screened titles and abstracts of trials identified through the searches and selected those that met selection criteria. They extracted and entered trial details in the generic study selection and data extraction form developed by the Cochrane Cystic Fibrosis and Genetic Disorders Review Group. This process encouraged adherence to the criteria for trials to be included in the review in order to avoid including those trials which were not exclusively researching agents prescribed for appetite or which may not work on appetite stimulation.

In the event of uncertainty or disagreement on study selection, the authors resolved this through discussion and consultation with a third author (DRB).

 

Data extraction and management

Authors independently extracted, cross-checked data reported for the outcomes listed above, discussed any differences and reached a consensus on the extracted data. If authors were unable to extract data, they reported the outcome results narratively.

The authors planned to assess outcome measures at the time-points over one and up to six months and at six-monthly intervals thereafter. In the review, the authors actually present data at three and six months, leading to a difference between the protocol and the review. However, it was not considered clinically relevant to combine the time-points at three and six months.

 

Assessment of risk of bias in included studies

Authors independently assessed the risk of bias for each included trial (without blinding to authorship or journal publication) following the domain-based assessment tool described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 (Higgins 2011). This comprised of a description and a judgement for each entry in a ‘Risk of bias’ table, where each entry addresses a specific feature of the trial. The judgement for each entry involved answering a question, with answers of low risk of bias, high risk of bias, and unclear risk of bias (indicating either lack of information or uncertainty over the potential for bias). The authors assessed the following risk of bias items: randomisation procedure; allocation concealment; blinding of investigators, participants or outcome assessors; intention-to-treat analysis, completeness of follow-up and incomplete outcome data; and selective reporting. The authors also noted details of statistical assessment such as differences in means, overall treatment effects, heterogeneity, subgroup and sensitivity analyses. The information was presented in the 'Risk of Bias' tables (Characteristics of included studies). They resolved any discrepancies by consensus and when necessary by discussion with a third author (DRB). Further details regarding the risk of bias tool are set out in the additional tables ( Table 1).

 

Measures of treatment effect

The authors conducted the primary analysis using the Cochrane Collaboration's software (RevMan 2011). They measured any treatment effects for dichotomous data using the odds ratio (OR) and 95% confidence intervals (CIs). They measured any treatment effects for continuous data by analysing the mean changes from baseline measures and their standard deviations (SDs) to calculate the difference in means (MD) and their 95% CIs.

Originally, if studies measured data longitudinally, the authors planned to base the analysis on the final time-point results, since methods are not yet available to carry out a meta-analysis of aggregate longitudinal data, unless individual patient data (IPD) (Jones 2005). However, when completing the data analysis, the authors decided to present all available data at selected time-points separately. Trial investigators measured data longitudinally in one included trial of MA (Eubanks 2002); the review authors reported data at each time-point independently and did not combine these.

 

Unit of analysis issues

When conducting the meta-analysis combining results from cross-over trials, the authors used the methods recommended by Elbourne (Elbourne 2002). Where the individual data are available, the within-participant changes and variation can be calculated directly and authors were able to include data from both arms of the trial. If the authors needed to combine data from cross-over trials with data from parallel trials in a meta-analysis, they used the weighted mean difference method discussed by Curtin (Curtin 2002a; Curtin 2002b; Curtin 2002c), where the SDs entered into the meta-analysis are adjusted to allow for within-person correlations and produce the correct standard errors.

 

Dealing with missing data

The review authors described the drop outs and reasons given for these in the primary papers. They contacted the original investigators if there were any missing data.

 

Assessment of heterogeneity

Authors considered the extent to which results of trials were consistent by considering the chi2 test produced in the RevMan forest plots which assesses whether observed differences in results were compatible with chance alone. Authors also used the I² statistic; thresholds for the interpretation of I2 were used as follows:

  •  0% to 40%: might not be important;
  • 30% to 60%: may represent evidence of moderate heterogeneity;
  • 50% to 90%: may represent evidence of substantial heterogeneity;
  • 75% to 100%:may represent evidence of considerable heterogeneity (Higgins 2003)

 

Assessment of reporting biases

The review authors assessed publication bias by contacting authors for the trials listed as 'Awaiting classification' to seek clarification for the details of these (Epifanio 2012; Kissner 2000). Although, the authors originally planned to assess the existence of publication bias from the meta-analyses by a funnel plot, there were not sufficient numbers of trials combined (minimum of 10) to allow this. Furthermore, the authors also acknowledge that the reasons for funnel plot asymmetry extend beyond reporting bias alone, for example methodological differences or pure chance.

The review authors assessed outcome reporting bias by obtaining data from the clinical trial registry, or by comparing the 'Methods' section to the 'Results' section of the full publications and using knowledge of the clinical area. If the authors suspected outcome reporting bias, they contacted the trial investigators to firstly ascertain if they had measured and analysed the outcome and secondly to obtain the data.

 

Data synthesis

The authors used a fixed-effect model in the analyses. They had planned to use a random-effects model if they had identified at least moderate heterogeneity (e.g. I2 value at least between 30% and 60%) (Higgins 2003). They considered and presented different interventions separately to identify their individual effects.

 

Subgroup analysis and investigation of heterogeneity

If the authors had identified clinical and statistical heterogeneity and they had included a sufficient number of trials (at least 10 trials) with enough published or reported details to allow the authors to extract data about separate participant types, they planned to undertake subgroup analyses to investigate the following further:

  • level of disease severity (assessed by FEV1 % predicted (Pellegrino 2005) and BMI classification (CF Trust 2002);
  • different appetite stimulants;
  • dosage of appetite stimulants

The authors were able to include several trials in the review; however, no single meta-analysis combined a sufficient number of data sets to allow the authors to undertake a subgroup analysis to investigate heterogeneity.

 

Sensitivity analysis

There were insufficient trials combined within any single meta-analysis to justify the use of a sensitivity analysis. If there are sufficient trials combined in future updates of this review, the authors plan to analyse data combining and splitting cross-over and parallel trials in order to test if the current findings are robust.

 

Summary of findings table

In a post hoc change to the protocol, a summary of findings (GRADE) table was generated to rate the quality of evidence for change in body weight (Balshem 2011).

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Description of studies

 

Results of the search

The combined searches identified 108 titles and abstracts in total. Of the 108 references, 99 references (to 68 individual trials) were excluded from the review. There are two references (to two individual trials) listed as 'Awaiting classification' until we are able to obtain further information to allow us to categorically include or exclude these trials (we have contacted the authors of these trials for clarification); no trials are currently in progress. Therefore, nine references to three trials are included in the review.

 

Included studies

We included three RCTs which addressed the use of potential appetite stimulants in children and adults with CF (Eubanks 2002; Homnick 2004; Marchand 2000).

 

Trial design

All trials were conducted in the USA (Eubanks 2002; Homnick 2004; Marchand 2000). One was of cross-over design (Marchand 2000) and the remaining two were of parallel design (Eubanks 2002; Homnick 2004). Data from parallel and cross-over trials were combined, so adjusted SDs were used (Curtin 2002a; Curtin 2002b; Curtin 2002c). The duration of trials varied in duration from three months (Homnick 2004) to six months (Eubanks 2002).

 

Participants

One trial recruited only children, including pre-pubertal children (Marchand 2000), with the remaining two trials including both adults and children (Eubanks 2002; Homnick 2004). All three trials reported the gender split between females and males (Eubanks 2002; Homnick 2004; Marchand 2000). Male to female ratios were different across all trials; the male to female ratio being eight males to nine females in the Eubanks trial (Eubanks 2002), six males to 10 females in the Homnick trial (Homnick 2004) and three males to nine females in the Marchand trial (Marchand 2000).

 

Interventions

Two of the trials looked at MA (Eubanks 2002; Marchand 2000) and one studied CH (Homnick 2004). The dosage of oral appetite stimulants varied from trial to trial; in two trials, MA was administered at a dose of 10 mg/kg/day (Eubanks 2002; Marchand 2000); and in the third study CH was administered at a dose of 4 mg four times daily (Homnick 2004). All trials used placebo treatments as comparators (Eubanks 2002; Homnick 2004; Marchand 2000).

 

Outcomes

All three trials reported on the change in body weight, change in pulmonary function and adverse events (Eubanks 2002; Homnick 2004; Marchand 2000). Two trials reported on change in body composition (Eubanks 2002; Homnick 2004); two trials reported change in appetite (Homnick 2004; Marchand 2000); and one trial reported on the change of dietary intake (Marchand 2000). One trial reported on the change in the number of pulmonary exacerbations (Eubanks 2002); and two trials reported on change in QoL (Homnick 2004; Marchand 2000) - one of these reported on QoL in the Results section even though this was not stated as planned in the Methods section of the paper (Marchand 2000).

 

Excluded studies

In total 99 references to 68 individual trials were excluded from the review. Of these, in three trials participants were not diagnosed with CF or were not human (Loprinzi 1993; Rogan 2010; Weisberg 2002). A total of 26 trials did not use the researching agent primarily as an appetite stimulant, instead the agent was given for the following reasons: growth hormone therapy (Bucuvalas 2001; Darmaun 2004; Hardin 2001; Hardin 2005a; Hardin 2005b; Hardin 2006; Hutler 2002; Schibler 2003; Schnabel 2007; Stalvey 2011); insulin therapy (Ballmann 2013;Grover 2008; Minicucci 2012; Moran 2009; Moran 2001; Teeter 2004); zinc supplementation (Safai 1991); prednisone therapy (Auerbach 1985; Cohen-Cymberknoh 2008; Dovey 2007; Greally 1992; Linnane 2001; Nyamugunduru 1998; Pantin 1986; Rosenstein 1991); and treatment with ghrelin (Cohen 2008; Cohen 2010). A total of 19 trials were not RCTs or quasi-RCTs (Alemzadeh 1998; Anstead 2003; Canfield 1998; Dowsett 1999; Eubanks 2000; Guillot 2011; Nasrallah 2003; Newkirk 2000; Ohnhaus 1974; Parsons 2009; Paterson 2010; Phung 2010; Ross 2005; Sackey 1995; Stylianou 2007; Taylor 1997; Tongudai 1971; von Haehling 2009; Young 2000). Six papers were review articles (Berenstein 2005; Chinuck 2007; Chung 2006; Hardin 2007; Lopez 2004; Nasr 2008), seven were case studies or case series (Crawley 2003; Durant 1998; Hardin 1997; Hardin 2004; Nasr 1999; Stalvey 2008; Varness 2009), three were retrospective analyses of medical records (Hardin 2005c; Switzer 2009; Sykes 2006), one was a consensus document (CF Trust 2002) and one was an overview of appetite regulation (Dhillo 2007).

 

Risk of bias in included studies

The risk of bias in included trials is summarised in the risk of bias summary (Figure 1).

 FigureFigure 1. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

 

Randomisation procedure

All the included trials referred to random allocation, ranging from a brief comment of fact that the patients were randomised to a detailed description of the sequence generation. We judged the single trial that was described as randomised, but which gave no details, as having an unclear risk of bias (Marchand 2000). The remaining two trials stated the use of a computer-generated randomisation procedure (Eubanks 2002) or more specifically SAS small block randomisation (Homnick 2004) and we judged them both as having a low risk of bias.

 

Allocation concealment

None of the included trials discussed the method of allocation concealment and the risk of bias for all was unclear (Eubanks 2002; Homnick 2004; Marchand 2000).

 

Blinding

Two of the trials were referred to as double-blind (Eubanks 2002; Marchand 2000) and one stated that only the pharmacist investigator and trial coordinator remained unblinded (Homnick 2004). We judged all these trials as having a low risk of bias.

 

Incomplete outcome data

One trial had minimal drop-outs or drop-outs which were unrelated to the intervention and we classified this as having a low risk of bias (Homnick 2004). The remaining trials were judged to have a high risk of bias (Eubanks 2002; Marchand 2000). One trial had a drop-out explicitly linked to the intervention (no effect in the placebo group) and no evidence of a treatment of the missing data to reduce the bias (Eubanks 2002) and the second trial had a 50% drop-out rate (6 from 12 participants) with the missing data being excluded and no clear evidence that bias was not introduced (Marchand 2000).

 

Selective reporting

The risk of reporting bias in the three included trials was judged by comparing the published methods with the reported results (Eubanks 2002; Homnick 2004; Marchand 2000). None of these trials appeared to be free from selective reporting as the outcomes stated in the Methods sections were not reported in the Results sections: dietary intake (Eubanks 2002); dietary intake and pulmonary function (Homnick 2004; Marchand 2000). In contrast, outcomes not stated in the Methods section were subsequently reported in the Results section as follows: dietary energy intake and spirometry (Homnick 2004); QoL (Marchand 2000). In addition, outcomes stated in the Methods section of the Eubanks paper, were reported using unexpected measures i.e. weight for age z-score only, instead of being additional to weight as a mean (SD) (Eubanks 2002). Furthermore, Eubanks reported LBM and fat mass for the MA group but not for the placebo group (Eubanks 2002).

 

Other potential sources of bias

Homnick reported significant differences in FEV1 % predicted between the placebo and CH groups at baseline; mean (SD) 42.3 (17.6) in the placebo group and 68.9 (28.1) in the CH group (P = 0.0392) (Homnick 2004). Allowing for an adjustment of the P value for testing multiple outcomes, the difference is not significant and hence is not evidence for a risk of bias.

No other potential sources of bias were identified in the other trials (Eubanks 2002; Marchand 2000).

 

Effects of interventions

See:  Summary of findings for the main comparison Appetite stimulants versus placebo for people with cystic fibrosis

All three trials reported data for appetite stimulants versus control (Eubanks 2002; Homnick 2004; Marchand 2000).

 

Primary outcomes

 

1. Change in body weight (kg)

The effect of MA compared with placebo on change in body weight was reported in one paediatric trial (Marchand 2000) and one trial of children and adults (Eubanks 2002). The effect of CH compared with placebo on change in body weight was reported in one trial of both children and adults (Homnick 2004).

Eubanks reported a significant change in weight in favour of the treatment group at both three and six months (Eubanks 2002), MD 3.00 kg (95% CI 0.92 to 5.08) and MD 3.80 kg (95% CI 1.27 to 6.33) respectively ( Analysis 1.1).

All three trials reported change in weight z score (WAZ) at three months and results were statistically significant when combined, MD 0.61 (95% CI 0.29 to 0.93) (P <0.001) ( Analysis 1.2). The quality was assessed as moderate using the GRADE approach and the heterogeneity was low (I² statistic = 0%) ( Analysis 1.2). In one cross-over trial the individual patient data for WAZ score were available from a graph (Marchand 2000). Therefore the within-subject variation could be calculated and the meta-analysis carried out using the methodology of Elbourne with the paired subject intervention and control periods used as the unit of analysis (Elbourne 2002). Only Eubanks reported WAZ at six months, MD 0.74 (95% CI 0.26 to 1.22), which is presented separately from the three-month data ( Analysis 1.2). This trial also presented results for one and two months on a graph, but not in the text or tables, with the WAZ effect size and standard error similar to the three-month value (Eubanks 2002).

The subgroup analysis of three-month data for WAZ by appetite stimulant type did not give any evidence for different effects of MA and CH on weight gain (test for subgroup difference Chi² = 0.22, df = 1, P = 0.64; I² = 0%) with both subgroups showing a significant weight gain; MA 0.68 (95% CI 0.24 to 1.13) (P = 0.003) and CH 0.53 (95% CI 0.07 to 0.99) (P = 0.02) ( Analysis 1.3).

In the nine-month paediatric trial, Marchand reported the "average" change in weight with ranges, so data could not be entered into the analysis (Marchand 2000). Marchand reported an "average" weight gain of 3.05 kg in the MA group (range 0.1 kg to 7.0 kg) versus 0.3 kg (range -0.3 kg to 0.8 kg) in the placebo group; this was significant (P = 0.04).

 

2. Change in body composition

 
a. LBM

None of the trials reported the change in LBM in sufficient detail to be included into a meta-analysis; and no further data were obtained when the trialists were contacted.

Eubanks reported significant increases in triceps skin-fold measurements and mid-arm circumference in the treatment group at three and six months (P < 0.01) (Eubanks 2002). Marchand also reported an improvement in LBM in the group receiving MA (Marchand 2000).

 
b. fat mass

Likewise, none of the trials reported the change in fat mass in sufficient detail to be included into a meta-analysis.

Eubanks reported an increase in fat mass and fat-free mass in the MA group, assessed by DEXA (P < 0.02, at three and six months) (Eubanks 2002). Marchand also reported an improvement in body fat in the MA group (Marchand 2000). In the 2004 trial, Homnick showed a significant increase fat and fat-free mass in the CH group over 12 weeks (Homnick 2004).

 
c. BMI

None of the trials reported the change in BMI in sufficient detail to be included into a meta-analysis.

In the 2004 study, Homnick showed a significant increase in BMI in the group receiving CH and no significant change in BMI for the placebo group (Homnick 2004); however, variation of the change in BMI was not given and no direct comparison between groups was carried out.

 

3. Change in pulmonary function

Whilst change in lung function is a primary outcome measure of appetite stimulant use, it is important to highlight that the included trials were not performed to directly affect pulmonary function; the use of appetite stimulants may take longer than any of the trials reviewed to show improvement in respiratory muscle function.

The effect of MA (Eubanks 2002; Marchand 2000) and CH (Homnick 2004) compared with placebo on change in pulmonary function was reported in children and adults.

 
a. FEV1 (absolute values)

None of the trials reported any change in absolute values of FEV1.

 
b. FEV1 (% predicted)

Eubanks reported an improvement in FEV1 (% predicted) graphically at two, three, and six months in the MA treatment group (P < 0.04) and also graphically at one month with no significant difference. The variation of the change in FEV1 (% predicted) was not reported, but could be read from a graph (Eubanks 2002). Using these data, the difference between intervention and control groups of the change in FEV1 (% predicted) at three months was not significant, MD 13.55 (95% CI -1.88 to 28.98) (P = 0.09) and the change at six months was also not significant, MD 5.64 (95% CI -4.43 to 15.71) (P = 0.27) ( Analysis 1.4).

In the 2004 paper, Homnick did not report means or SDs for the difference between baseline and follow up. The trial reported there were no significant differences in spirometric measures, but no FEV1 (% predicted) values at 12 weeks were stipulated (Homnick 2004).

Marchand reported FEV1 (% predicted) increased by 15.3% on average in the MA group (this was not significant) and by 3.8% in the placebo group (Marchand 2000). Insufficient detail was given to extract the variation in the change in FEV1 (% predicted) for the groups.

 

Secondary outcomes

 

1. Subjective report of anorexia or loss of appetite or both

The effect of MA and CH compared to placebo on the change in anorexia and appetite was reported for both children and adults (Homnick 2004; Marchand 2000).

Homnick reported that at three months five participants in the CH treatment group demonstrated increased appetite versus two participants in the placebo group; this was after assessment using part of a brief five-question questionnaire (Homnick 2004). After assessment on interview, Marchand reported that all patients demonstrated an increase in appetite whilst receiving MA (Marchand 2000).The meta-analysis for the two trials shows a statistically significant result, OR 45.25 (95% CI 3.57 to 573.33) (P = 0.003) ( Analysis 1.5).

 

2. QoL (subjective report or measured by a validated questionnaire)

The effect of MA compared with placebo on change in QoL was either not measured or reported (Eubanks 2002; Marchand 2000). Only the Homnick paper reported on the effect of CH versus placebo on the change in QoL. In this paper, Homnick reported less fatigue in two patients in the treatment group (Homnick 2004).

 

3. Dietary intake

 
a. energy intake (measured in kcal/day)

The effect of MA versus placebo on change in dietary energy and protein intake was reported in one paediatric trial (Marchand 2000). Marchand reported calorific intake was calculated from three-day food records, but did not differ between the treatment and placebo groups (Marchand 2000). The effect of CH versus placebo on energy intake was reported in one trial where mean caloric intake was determined by three-day food records prior to visits at 4 weeks and 12 weeks; no significant differences between groups was demonstrated (Homnick 2004).

There was insufficient detail for the data to be included in a meta-analysis.

 
b. protein intake (measured in grams of protein/day)

None of the trials reported protein intake results.

 

4. Any adverse events directly related to the intervention

Both objective and subjective adverse events were reported for both MA and CH. However, trials reported adverse effects subjectively without specifying which groups (treatment or placebo) the participants belonged to. Reported adverse effects included effects on glucose tolerance, decreased cortisol levels, increased insulin levels, insomnia, pulmonary exacerbations, blocked port-a-cath, constipation, haemoptysis and mild transient sedation; these are shown in the additional tables ( Table 2).

Eubanks reported MA to significantly decrease morning cortisol levels compared to placebo. Furthermore, bone mineral density was stated to remain stable in the MA-treated participants over the entire six-month treatment period; however, the data were not reported (Eubanks 2002). Homnick reported no significant side effects except for increased general fatigue in the CH group (Homnick 2004).

 

5. Change in the number of pulmonary exacerbations

Two trials reported on this outcome (Eubanks 2002; Homnick 2004). Eubanks reported that in the MA group six patients required intravenous (IV) antibiotics and four required aerosolised antibiotics (Eubanks 2002). Homnick did not report any significant differences from baseline to week 12 in oral or IV antibiotic use with CH (Homnick 2004).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Whilst intuitively an increase in appetite should result in an increase in weight, the precise relationship between the two has not been studied, and is difficult to ascertain for the following reasons. Firstly, there are no good measures of appetite per se; also, the relationship between appetite and weight gain is likely to differ significantly between individuals, and any impact of appetite on weight will be modulated by each individuals eating habits, exercise levels, and metabolic demands. That given, it seems sensible to assume that an increase in appetite should result in weight gain, but further trials are required to delineate this relationship more carefully.

We know that lung function is closely associated with nutritional status in CF and this is an independent predictor of survival (Bell 2008; Borowitz 1996; Corey 1998). However, due to the condition, most CF patients are on a high-calorie diet to help achieve normal growth and development and maintain good lung function (Nasr 2008). Achieving this energy intake from food can be difficult, and is usually not successful (Poustie 2006), but the consequences of inadequate calorie intake, i.e. anorexia, can lead to malnutrition (Nasr 2008).

Appetite stimulation and increasing food intake may be one way to try and address the anorexia. The aim of the review was to ascertain the side effects and effect of appetite stimulants on CF- anorexia, and hence explore their clinical usefulness.

 

Summary of main results

 

Response to treatment

Both MA and CH are effective in improving weight and WAZ in children and adults with CF; statistically significant increases in both weight and WAZ were seen in the appetite stimulant group compared to the placebo group at three and six months ( Analysis 1.1;  Analysis 1.2). While data showed significant increases in WAZ for both MA and CH separately, there was no significant difference between the two stimulants, so it cannot be concluded that one stimulant is more effective than the other ( Analysis 1.3). However, what constitutes a clinically significant weight gain for children and adults with CF has yet to be directly investigated. Recommendations from the USA aim for a BMI of 22 and 23 in females and males respectively (Stallings 2008). In the UK, it is recommended that weight loss of more than 5% body weight for more than two months duration should be prevented and an adult BMI of less than 19 should be avoided (CF Trust 2002). In children, USA recommendations have reported weight for length should be at least the 50th percentile from birth up to two years and in children from 2 to 20 years BMI should be at least equal to the 50th percentile (Stallings 2008). Thus, the definition of significant weight gain is not clearly agreed.

The quality of weight gain is also clinically significant as correlations have been found between FEV1 and LBM, which influence skeletal muscle, suggesting an influence of muscle wasting on pulmonary function (Steinkamp 2002). Thus, improving fat-free mass compared with fat mass may well be preferable, in order to optimise lung function and body image. However, there was no evidence found of a larger increase in FEV1 (% predicted) in the appetite stimulant group compared to the placebo group at three or six months, with differences being not significant ( Analysis 1.4).

It is important to highlight that owing to the lack of objective markers for appetite change, the assumption has been made that improved dietary intake and body composition are indicative of an improved appetite. No RCTs have been published assessing appetite using a validated tool. Published trial data did provide some subjective support that MA and CH may improve appetite in children and adults, but the evidence was scant (Homnick 2004). In one trial, during the three months of MA treatment, there was evidence that all children reported increase in appetite whilst receiving MA; however, there was no evidence that MA acted to increase calorific intake (Marchand 2000). In a trial of CH, there was limited evidence in children and adults to support an increase in appetite (Homnick 2004). The pooled data from the two trials, which reported an increase in appetite, showed a larger proportion of patients with increased appetite in the appetite stimulant group compared to the control group, OR 45.25 (95% CI 3.57 to 573.33) (P = 0.003) ( Analysis 1.5). Whilst this was statistically significant, the change also appeared to represent a clinically significant improvement in appetite which was sustained over six months. Although the large CIs and subjective reporting of appetite change do indicate a low level of precision, they also endorse the need for further rigorous trials, particularly since the change in appetite is clinically meaningful. For clinicians to judge which appetite stimulant to use with individual patients and make an informed decision, they require information on: significant gains in appetite and weight; type; age of use; starting and maximum dosages; and the effect of ceasing stimulants.

There was no evidence that CH improved calorific intake (Homnick 2004), and so although MA and CH were both reported to improve appetite, this outcome was not reported consistently.

 

Adverse effects of stimulants

The adverse effects of both MA and CH were not fully determined; the only significant effect reported in the papers was transient mild sedation (Eubanks 2002). However unlike MA, which seems to display a propensity to induce glucose dysregulation, CH does not appear to affect glucose tolerance ( Table 2).

 

Dosage, duration and timing of appetite stimulants

Although, the data suggested weight gain may be optimised by treating patients with 10 mg/kg/day of MA (Eubanks 2002; Marchand 2000) or 4 mg four times daily of CH for three months (Homnick 2004); the available data from RCTs do not present conclusive evidence for the dose and duration of anorexia in adults and children with appetite stimulants. Long duration of treatment or the time-dependency could not be formally assessed due to insufficient data points from the RCTs and hence also the meta-analyses.

 

Overall completeness and applicability of evidence

All of the trials included in the analysis directly investigated the impact of the appetite stimulants MA and CH on relevant outcome measures in patients with CF. All relevant types of participants, interventions and outcomes have been investigated. However, currently there are no validated measures of appetite per se available for research purposes in CF, and therefore, any effects of these appetite stimulants seen in the reported outcome measures are at best surrogate markers of appetite. More research is required to delineate valid measures of appetite in CF, which could then be applied to the outcome measures included in this review, and to the study of appetite stimulants.

Hence, within the constraints of the current literature and research tools available, the objectives of this review have been satisfied. The effects of appetite stimulants in CF-related anorexia and any side effects reported have been rigorously evaluated.

Three other appetite stimulants, oxandrolone, dronabilol and mirtazapine, have been studied in CF. However, these trials were not included within the review because they did not meet eligibility criteria. The role of these agents in appetite stimulation in CF deserves further stringent study.

Whilst more research is required to delineate the role of appetite stimulants in CF and so inform clinical practice, at present the evidence presented within this review suggests that there is a rationale for the short-term use of MA and CH (six months). Clinicians need to be aware of potential side effects of these agents and monitor patients accordingly. The clinical benefits need to be balanced, not only against the risks of potential adverse events, but on a case-by case basis. However, there is insufficient evidence at present to recommend the use of these agents on a long-term basis (over six months).

 

Quality of the evidence

Trial quality was frequently sub-optimal, which may bias any observed treatment effects, on average, in the direction of over-estimating the true treatment effect.

There were areas of the reporting within the included trials that would have been greatly improved if the authors had followed the CONSORT reporting guidelines for RCTs, specifically in reporting the details of the random sequence generation, allocation concealment and blinding (Moher 2001; Moher 2003; Moher 2004). We suspect that many of the trials were correctly randomised, but the evidence was not presented in the published papers and so the risk of bias was marked as unclear.

The risk of bias of the included trials was graded as moderate ( Summary of findings for the main comparison). All three trials reported sufficient detail for a selection of outcomes to be included in the meta-analyses. All the trials used oral appetite stimulants compared to a placebo. All of the meta-analyses were of moderate quality, due to attrition bias caused by either a proportionately large drop-out rate or drop outs due to the intervention which was not corrected for in the analysis (Figure 1). Thus, whilst the data may suggest MA and CH have a potential use as appetite stimulants in children and adults due to the improvements in weight, WAZ score and appetite; this is based upon moderate quality data from a small number of trials and so cannot be conclusively recommended based upon the findings in the review.

 

Potential biases in the review process

The number of trials included in the review did not allow for an analysis of publication bias and so we are not able to comment on this aspect of potential bias.

In several trials it was not possible to obtain the effect size and SDs. The outcomes and SDs at baseline and follow up were reported accurately, but often the SD of the difference in outcome measure between baseline and follow up was not reported and could not be calculated from reported data. The difference can be calculated from baseline and follow-up measurements, but the SD of the difference cannot be simply calculated due to within-subject correlations. It is strongly recommended that outcome differences and SDs of differences are reported in future trials.

Trial quality was frequently sub-optimal, which may bias any observed treatment effects on average in the direction of over-estimating the true effect.

Strengths of the review were the methods used for searching, trial selection and analysis, which in our opinion did not introduce any bias.

 

Agreements and disagreements with other studies or reviews

The review concurs with the findings of two other reviews of appetite stimulants (Chinuck 2007; Nasr 2008); although the evidence was only reviewed systematically by Chinuck, whose review served to illuminate the potential role of appetite stimulants in the management of anorexia associated with CF (Chinuck 2007). This review concluded that larger RCTs were necessary to confirm the safety and validate the efficacy of their use in CF and also highlighted the impossibility of drawing firm long-term conclusions for the other agents or stimulants given the low numbers of patients in the trials (Chinuck 2007).

The side effects of adrenal insufficiency, testicular failure (McKone 2002) and bone metabolism (Wermers 2004) have been elucidated in the literature and we would have reported these outcomes under adverse effects in the review if the included trials had measured and documented these accordingly.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 

Implications for practice

The data included in this review suggest that MA and CH may be useful for short-term (i.e. six months) treatment of anorexia in adults and children with CF. However, it cannot be concluded that any one stimulant is more effective than another. The included RCTs and the meta-analyses were unable to suggest an optimal dosage, duration or timing of appetite stimulant therapy. Furthermore, if cost and availability of the agents are compared, MA prescribed at 160 mg once per day costs GBP17.83 for 30 tablets, but the most cost competitive agent is CH, 4 mg tablets prescribed once per day at a cost of GBP0.77 for 30 tablets (Chinuck 2013 [pers comm]). Although all trials of appetite stimulants reported adverse events, data were difficult to interpret because trials were underpowered to detect clinically important differences. Furthermore, the reporting of adverse events was not consistent and there were no reports on the frequency in adverse events per patient years. Despite these important limitations, the results suggested a positive effect of appetite stimulants on both weight gain and appetite.

Hence, at present, the dose of appetite stimulants and duration of therapy should fall within the short-term range (e.g. six months) as used in the trials reviewed. Clinicians need to be aware of the potential adverse effects of these medications and actively monitor patients accordingly. The clinical benefits of appetite stimulants in CF need to be balanced, not only against the risks of potential adverse events, but also considered on a case-by-case basis.

 
Implications for research

In order to further our understanding of the role of appetite stimulants in CF, it is first necessary to determine meaningful surrogate measures for appetite and also define what constitutes quality weight gain. This will then allow much more precise and meaningful research to be conducted into appetite stimulants. Trials should evaluate the effectiveness of MA and CH on poor appetite in CF. Further research must define the best direct method of documenting the presence of poor appetite amongst patients. Trials should use a validated measure of symptoms, and should include a disease-specific instrument for measuring poor appetite. There are, as yet, no validated scoring systems for grading appetite and the best objective measure of evaluating appetite is yet to be defined.

Since there is insufficient evidence based on RCTs to recommend any more than short-term use of appetite stimulants in CF, this review highlights the need for multicentred, adequately powered and well-designed trials to prove or disprove their potential to increase appetite safely in CF, and establish the optimal mode of treatment.

Research is further complicated by the fact that the aetiology of poor appetite may be multifactorial and not fully understood. There are also uncertainties not only about the effective duration and appropriate dose, but also the side effects of appetite stimulants in both adults and children with CF.

Gaps in the current knowledge and issues for future trials are:

  • do appetite stimulants actually improve appetite and what is the magnitude of this effect?
  • do appetite stimulants result in sustained weight gain?
  • what quality of weight gain is considered clinically significant?
  • what quality of weight gain can be expected from appetite stimulants?
  • which side effects should be monitored and what is their clinical significance?
  • when should appetite stimulant administration begin and end; alongside the duration and clinical indications?
  • which appetite stimulants work best for toddlers, children, prepubertal children, teenagers, young adults and adults?
  • should treatment vary according to whether the patient is awaiting transplantation?
  • should some steroid-based appetite stimulants be a contra-indication for listed lung-transplant patients because of potential bone loss whilst on steroids (Tschopp 2002)?
  • which are the important patient-related outcomes when taking appetite stimulants?

These questions remain unanswered because currently available trials lack important clinical outcomes and are underpowered to detect differences in treatment effects across subgroups of patients, resulting in overall poor quality data. Future trials need to improve the quality of conducting RCTs and reporting clinically significant outcomes so they are unbiased and clear by following the CONSORT statement (Ioannidis 2004; Moher 2001; Moher 2003; Moher 2004).

We recommend that future trials:

  • are adequately powered and robust, designed to elucidate the magnitude in effect for both clinical and patient-related relevant outcomes i.e. appetite change, lung function, cost per quality adjusted life year (QALY), QoL (e.g. sick leave from employment, functional ability and psychological impact);
  • define clinically significant weight gain in both children and adults;
  • establish valid surrogate markers of appetite change (both objective and subjective);
  • report changes in nutritional and dietary intake along with changes in pre-defined surrogate markers for appetite change;
  • report on a pre-defined list of adverse effects as well as monitoring any unexpected adverse effects for all age groups;
  • ensure complete data sets are reported for all outcomes (including mean change data and their SDs); and
  • report outcome differences and SDs of differences to allow for meaningful meta-analyses.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

The authors would like to acknowledge the input from the statistician Dr Graham Warren for his help in drafting the protocol and his great assistance in appropriately analysing the data presented within this review.

The authors would also like to thank Nikki Jahnke and Professor Alan Smyth for their support and also the patients who have inspired this review. We hope it will lead to more meaningful trials and make a small difference in the lives of those who suffer with CF-related anorexia.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
Comparison 1. Appetite stimulants versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Change in weight (kg)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    1.1 at 3 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 at 6 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Change in weight z score3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 at 3 months
340Mean Difference (IV, Fixed, 95% CI)0.61 [0.29, 0.93]

    2.2 at 6 months
117Mean Difference (IV, Fixed, 95% CI)0.74 [0.26, 1.22]

 3 Change in weight z score (at 3 months)3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 Megasterol acetate
228Mean Difference (IV, Fixed, 95% CI)0.68 [0.24, 1.13]

    3.2 Cyproheptadine hydrochloride
112Mean Difference (IV, Fixed, 95% CI)0.53 [0.07, 0.99]

 4 Change in FEV1 %1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 at 3 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 at 6 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Increase in appetite (subjective reporting)2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 At 3 months
223Odds Ratio (M-H, Fixed, 95% CI)45.25 [3.57, 573.33]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Appendix 1. MEDLINE (HDAS) search strategy (1950 to 01 April 2014)


Date last run: 01 April 2014

1. Cystic fibrosis (ti, ab)

2. Cystic Fibrosis (sh)

3. CF (ti, ab)

4. Mucovicidosis (ti,ab)

5. 1 or 2 or 3 or 4

6. Appetite stimulants (ti,ab)

7. Appetite stimulants (sh)

8. Cyproheptadine (sh)

9. Cyproheptadine (ti,ab)

10. Appetite (sh)

11. Prednisolone (sh)

12. Progestational agents (ti, ab)

13. Progestins (sh)

14. Anabolic agents (ti,ab)

15. Megesterol (ti,ab)

16. Megesterol (sh)

17. Megesterol acetate (sh)

18. Megace (ti, ab)

19. Mirtazapine (ti,ab)

20. Antidepressive agents (sh)

21. Antidepressants (ti,ab)

22. Cannaboids (ti,ab)

23. Tetrahydrocannabinol (sh)

24. Antihistamines (ti,ab)

25. Histamine antagonists (sh)

26. Corticosteroids (ti,ab)

27. Prednisone (sh)

28. Steroids (sh)

29. Hormone therapy (ti,ab)

30. Growth Hormone (sh)

31. Hormones (sh)

32. Dronabinol (ti,ab)

33. Pizotyline (sh)

34. pizotifen ti,ab

35. risperidone ti,ab

36. Risperidone (sh)

37. olanzapine ti,ab

38. 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37

39. anorexia (ti,ab)

40. anorexia( sh)

41. weight (ti,ab)

42. 34 or 35 or 36

43. 5 and 38 and 42



 

Appendix 2. CINAHL (HDAS) search strategy (1981 to 01 May 2012)


Date last run: 01 May 2012

1.Cystic fibrosis (ti, ab)

2. Cystic fibrosis (sh)

3. 1 or 2

4. Appetite stimulants (ti, ab)

5. Appetite stimulating agents (sh)

6. Appetite (sh)

7. Progestational agents (ti,ab)

8. Progestational hormones (sh)

9. Progestational hormones synthetics (sh)

10. Antidepressive agents, second generation (sh)

11. Antidepressive agents, tricyclic(sh)

12. Anabolic agents (ti,ab)

13. Anabolic steroids(sh)

14. Megesterol acetate (ti,ab)

15. Mirtazapine (sh)

16. Antidepressants (ti,ab)

17. Antihistamines (ti,ab)

18. Histamine H1 antagonists (sh)

19. Histamine H2 antagonists (sh)

20. Corticosteroids (ti, ab)

21. Steroids (sh)

22. Hormone therapy (sh)

23. Hormones, synthetic (sh)

24. growth hormone (ti, ab)

25. Hormones (ti, ab)

26. Tetrahydrocannabinol (sh)

27. 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26

28. Anorexia (ti, ab)

29. Anorexia (sh)

30. weight (ti,ab)

31. 28 or 29 or 30

32. 3 and 28 and 31



 

Appendix 3. EMBASE (HDAS) search strategy (1980 to 01 April 2014)


Date last run: 01 May 2012

1. Cystic fibrosis (ti, ab)
2. Cystic fibrosis (sh)
3. CF (ti, ab)
4. Mucovicidosis (ti,ab)
5. 1 or 2 or 3 or 4
6. Appetite stimulants (ti, ab)
7. Appetite stimulant (sh)
8. Progestational agents (ti, ab)
9. Gestagen (sh)
10. Anabolic agents (ti, ab)
11. Anabolic agent (sh)
12. Megesterol (ti, ab)
13. Megesterol acetate (ti, ab)
14. Megace (ti, ab)
15. Megestrol acetate (sh)
16. Mirtazapine (ti, ab)
17. Mirtazapine (sh)
18. Antidepressants (ti, ab)
19. Antidepressant agent (sh)
20. Cannaboids (ti, ab)
21. Cannabinoid derivative (sh)
22. Antihistamines (ti, ab)
23. Antihistaminic agent (sh)
24. Corticosteroids (ti, ab)
25. Corticosteroid (sh)
26. Steroids (ti, ab)
27. Steroid (sh)
28. Hormone therapy (ti, ab)
29. Hormones (ti, ab)
30. Hormone (sh)
31. Cyproheptadine (ti, ab)
32. Cyproheptadine (sh)
33. Dronabinol (ti, ab)
34. Dronabinol (sh)

35. Pizotyline (sh)

36. Pizotifen (sh)

37. risperidone ti,ab

38. Risperidone (sh)

39. olanzapine ti,ab

40. 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39
41. Anorexia (ti, ab)
42. Anorexia (sh)
43. weight (ti,ab)
44. 36 or 37 or 38
45. 5 and 40 and 44



 

Appendix 4. Glossary


TermDefinition

adipose tissuefat

aetiologycause

anorexialoss of appetite

chronic sepsispresence in the blood or other tissues of disease causing micro-organisms

cytokinesproteins which generate an immune response

energy expenditureenergy used up

gastroesophageal reflux (GOR)return flow of the stomach contents into to the oesophagus

inflammatoryimmune response characterised by inflammation

intestinal malabsorptionreduced absorption of nutrients by the small intestine

meta-analysisa statistical approach to combine the results of multiple studies

morbiditydiseased condition or state

mortalitydeath

pulmonary exacerbationslung infections

quasi-randomised controlled triala trial which uses systematic methods, such as alternation, assignment based on date of birth, case record number and date of presentation to assign participants to treatment or control groups -an important weakness with these methods is that concealing the allocation schedule is usually impossible, which allows foreknowledge of intervention assignment among those recruiting participants to the study, and biased allocations

risk of biaschance of systematic error or prejudice towards something

serumclear portion of any body fluid

sinusitisinflammation of a sinus or cavity

tumour necrosis factor (TNF)proteins produced by the white blood cells which mediate inflammation

weight for age z-score (WAZ)the number of standard deviations of the actual weight of a child from the median weight of children of his or her age as determined from the standard sample



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Ruth Chinuck, Dr David Baldwin and Dr Jane Dewar assessed all trials for inclusion and completed the final version of the review. Elizabeth Hendron completed the literature search.

Ruth Chinuck will act as the guarantor for the review.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Ruth Chinuck declares no potential conflict of interest.

Jane Dewar declares no potential conflict of interest.

David Baldwin declares no potential conflict of interest.

Elizabeth Hendron declares no potential conflict of interest.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Internal sources

  • Nottingham University Hospitals, City Campus, UK.

 

External sources

  • Nottingham University, UK.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

There were four post hoc changes to the Methods section of the review regarding data analysis.

1. We introduced a definition of an appetite stimulant to make the eligibility criteria clearer.

2. Originally, if trials had measured data longitudinally, the authors planned to base the analysis on the final time-point results (Jones 2005). However, when completing the data analysis, the authors decided to present all available data at selected time-points separately.

3. The authors originally planned to present data at over one and up to six months and at six-monthly intervals thereafter; however, it was not considered clinically relevant to combine the time-points at three and six months, hence data are presented at three, six and twelve months.

4. Although GRADE Tables were not planned as per protocol, they were generated for change in body weight by a statistician.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Eubanks 2002 {published data only}
  • Eubanks V, Atchison J, Arani R, Clancy JP, Sorscher EJ, Wooldridge N, et al. Effects of megestrol acetate on energy intake, weight gain, body composition and resting energy expenditure in cystic fibrosis patients [abstract]. Pediatric Pulmonology 2000;30 (Suppl 20):322-3.
  • Eubanks V, Koppersmith N, Wooldridge N, Clancy JP, Lyrene R, Arani RB, et al. Effects of megestrol acetate on weight gain, body composition, and pulmonary function in patients with cystic fibrosis. Journal of Pediatrics 2002;140(4):439-44.
Homnick 2004 {published data only}
  • Homnick D, Marks JH, Hare KL, Bonnema SK. Long-term trial of cyproheptadine as an appetite stimulant in cystic fibrosis. Pediatric Pulmonology 2005;40(3):251-6.
  • Homnick DN, Homnick BD, Brooks CD, Reeves AJ, Hare KL, Marks JH, et al. The use of cyproheptadine as an appetite stimulant in cystic fibrosis patients [abstract]. Pediatric Pulmonology 2003;36 (Suppl 25):343.
  • Homnick DN, Homnick BD, Reeves AJ, Marks JH, Pimentel RS, Bonnema SK. Cyproheptadine is an effective appetite stimulant in cystic fibrosis. Pediatric Pulmonology 2004;38(2):129-34.
  • Homnick DN, Marks JH, Hare KL, Pimentel RS, Bonnema SK. Long-term trial of cyproheptadine as an appetite stimulant in cystic fibrosis [abstract]. Pediatric Pulmonology 2004;38 (Suppl 27):330.
  • Homnick DN, Marks JH, Rubin BK. The effect of a first-generation antihistamine on sputum viscoelasticity in cystic fibrosis. Journal of Aerosol Medicine 2007;20(1):45-9.
Marchand 2000 {published data only}
  • Marchand V, Baker SS, Baker RD. Leptin level in children with cystic fibrosis, effect megestrol acetate treatment [abstract]. Journal of Pediatric Gastroenterology and Nutrition 1999;29:512.
  • Marchand V, Baker SS, Stark TJ, Baker RD. Randomized, double-blind, placebo-controlled pilot trial of megestrol acetate in malnourished children with cystic fibrosis. Journal of Pediatric Gastroenterology and Nutrition 2000;31(3):264-9.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Alemzadeh 1998 {published data only}
Anstead 2003 {published data only}
  • Anstead MI, Kuhn RJ, Martyn D, Craigmyle L, Kanga JF. Dronabinol, an effective and safe appetite stimulant in cystic fibrosis [abstract]. Pediatric Pulmonology 2003;36 (Suppl 25):343.
Auerbach 1985 {published data only}
  • Auerbach HS, Williams M, Kirkpatrick JA, Colten HR. Alternate-day prednisone reduces morbidity and improves pulmonary function in cystic fibrosis. Lancet 1985;2(8457):686-8.
  • Donati MA, Haver K, Gerson W, Klein M, McLaughlin FJ, Wohl MEB. Long-term alternate day prednisone therapy in cystic fibrosis [abstract]. Pediatric Pulmonology 1990;9 (Suppl 5):322.
Ballmann 2013 {published data only}
  • Ballmann M, Hubert D, Assael BM, Mosnier-Pudar H, Barao Ocampo M, Scheunig N, et al. Repaglinide versus insulin in the treatment of CFRD diagnosed by screening: an open prospective randomized study [abstract]. Pediatric Pulmonology 2013;48 Suppl 26:421, Abstract no: 582. [CENTRAL: 962122; CFGD Register: CO53b; CRS: 5500125000000394]
Ballmann 2013a {published data only}
  • Ballmann M, Hubert D, Assael BM, Mosnier-Pudar H, Smaczny C, Kessler L, et al. Treatment of early diagnosed CFRD with oral drugs verus insulin: An open prospective randomized study [abstract]. Journal of Cystic Fibrosis 2013;12 Suppl 1:S32, Abstract no: WS16.1. [CENTRAL: 962115; CFGD Register: CO53a; CRS: 5500100000011659]
Berenstein 2005 {published data only}
Bucuvalas 2001 {published data only}
  • Bucuvalas JC, Chernausek SD, Alfaro MP, Krug S, Ritschel W, Wilmott RW. Insulin-like growth factor-1 enhances linear growth in undernourished prepubertal children with cystic fibrosis [abstract]. Pediatric Pulmonology 1998;26(Suppl 17):355.
  • Bucuvalas JC, Chernausek SD, Alfaro MP, Krug SK, Ritschel W, Wilmott RW. Effect of insulin-like growth factor-1 treatment in children with cystic fibrosis. Journal of Pediatric Gastroenterology and Nutrition 2001;33(5):576-81.
Canfield 1998 {published data only}
  • Canfield TM. The effect of megestrol on nutritional status in patients with cystic fibrosis [abstract]. Pediatric Pulmonology 1998;26 (Suppl 17):359.
CF Trust 2002 {published data only}
  • CF Trust Nutrition Working Group. Nutritional Management of Cystic Fibrosis: A consensus report. UK CF Trust 2002:13. [: ISBN 0-9540536-5-6]
Chinuck 2007 {published data only}
Chung 2006 {published data only}
  • Chung SH, Stenvinkel P, Lindholm B, Avesani CM. Identifying and managing malnutrition stemming from different causes. Peritoneal Dialysis International 2006;27(Suppl 2):S239-44.
Cohen 2008 {published data only}
Cohen 2010 {published data only}
Cohen-Cymberknoh 2008 {published data only}
  • Cohen-Cymberknoh M, Shoseyov D, Efrati O, Armoni S, Kerem E. Intravenous methylprednisolone pulse therapy vs.oral prednisone for allergic bronchopulmonary aspergillosis (ABPA) in CF [abstract]. Journal of Cystic Fibrosis 2008;7 (Suppl 2):S58.
Crawley 2003 {published data only}
  • Crawley J, Pandya S, Ledson MJ, Walshaw MJ. Use of megestrol acetate to improve body weight in malnourished adult cystic fibrosis patients [abstract]. Journal of Cystic Fibrosis 2003;2 (Suppl 1):S86, Abstract 336.
Darmaun 2004 {published data only}
  • Darmaun D, Hayes V, Schaeffer D, Welch S, Mauras N. Effects of glutamine and recombinant human growth hormone on protein metabolism in prepubertal children with cystic fibrosis. The Journal of Clinical Endocrinology and Metabolism 2004;89(3):1146-52.
  • Schaeffer D, Darmaun D, Punati J, Mauras N, Hayes VY. Use of glutamine and recombinant human growth hormone in children with cystic fibrosis [abstract]. Pediatric Pulmonology 2000;30 (Suppl 20):323.
Dhillo 2007 {published data only}
Dovey 2007 {published data only}
  • Dovey M, Aiken ML, Emerson J, McNamara S, Waltz DA, Gibson RL. Oral corticosteroids therapy in cystic fibrosis patients hospitalized for pulmonary exacerbation: a pilot study. Chest 2007;132(4):1212-8.
  • Dovey M, Aitken ML, Emerson J, McNamara S, Dorman D, Gibson RL. A randomised, double-blind, placebo-controlled trial of oral corticosteroid therapy in cystic fibrosis patients hospitalized for pulmonary exacerbations [abstract]. Pediatric Pulmonology 2004;38 (Suppl 27):301.
Dowsett 1999 {published data only}
  • Dowsett J. The use of megestrol acetate in the treatment of cachexia associated with cystic fibrosis [abstract]. Netherlands Journal of Medicine 1999;54(Suppl):S83-84.
Durant 1998 {published data only}
  • Durant M, Farmer G. Megesterol acetate: treatment of growth failure in children with cystic fibrosis [abstract]. Pediatric Pulmonlogy 1998;26 (Suppl 17):360.
Eubanks 2000 {published data only}
  • Eubanks V, Wooldridge N, Clancy JP, Sorscher E, Lyrene R, Makris C. Megesterol acetate effects on weight in CF subject exhibiting growth failure: a case controlled study [abstract]. Pediatric Pulmonology 1998;26 (Suppl 17):360.
Greally 1992 {published data only}
  • Greally P, Hussain MJ, Vergani D, Price JF. Interleukin-1 alpha, soluble interleukin-2 receptor, and IgG concentrations in cystic fibrosis treated with prednisolone. Archives of Disease in Childhood 1994;71(1):35-9.
  • Greally P, Sampson AJ, Piper PJ, Price JF. Effect of prednisolone on airways obstruction in patients with cystic fibrosis [abstract]. The European Respiratory Journal 1992;5(Suppl 15):259s.
  • Greally P, Sampson AP, Piper PJ, Price JF. Prednisolone reduces airways obstruction in children with cystic fibrosis. Proceedings of the 11th International Cystic Fibrosis Congress, Dublin, Ireland. 1992:TS12.
Grover 2008 {published data only}
Guillot 2011 {published data only}
  • Guillot MV, Desforges AS, Voisin-Chiret AS, Schumann P, Launay A, Lecomte C. Evaluating the use of megesterol acetate in Caen and Lisieux CF Centers. Journal of Cystic Fibrosis 2011;10(1):7.
Hardin 1997 {published data only}
Hardin 2001 {published data only}
  • Hardin DS, Ellis K, McConnell RA, Seilheimer DK. Growth hormone improves lean body mass in prepubertal CF children [abstract]. Pediatric Pulmonology 1998;26 (Suppl 17):357. [CFGD Register: GN122a]
  • Hardin DS, Ellis KJ, Dyson M, Rice J, McConnell R, Seilheimer DK. Growth hormone decreases protein catabolism in children with cystic fibrosis. Journal of Clinical Endocrinology and Metabolism 2001;86(9):4424-8. [CFGD Register: GN122d]
  • Hardin DS, Ellis KJ, Dyson M, Rice J, McConnell R, Seilheimer DK. Growth hormone improves clinical status in prepubertal children with cystic fibrosis: results of a randomized controlled trial. Journal of Pediatrics 2001;139(5):636-42. [CFGD Register: GN122e]
  • Hardin DS, Ellis KJ, McConnel R, Seilheimer DK. Growth hormone improves clinical status in cystic fibrosis children [abstract]. Pediatric Pulmonology 1999;28 (Suppl 19):297. [CFGD Register: GN122b]
  • Hardin DS, Stratton R, Kramer JC, Reyes de la Rocha S, Govaerts K, Wilson DP. Growth hormone improves weight velocity and height velocity in prepubertal children with cystic fibrosis. Hormone and Metabolic Research 1998a;30(10):636-641.
Hardin 2004 {published data only}
  • Hardin DS, Rice J, Rosenblatt R. Use of growth hormone in adults with CF [abstract]. Pediatric Pulmonology 2004;38 (S27):343.
Hardin 2005a {published data only}
  • Hardin DS, Ahn C, Prestige C, Seilheimer DK, Ellis KJ. Growth hormone improves bone mineral content in children with cystic fibrosis. Journal of Pediatric Endocrinology and Metabolism 2005;18(6):589-95.
Hardin 2005b {published data only}
  • Hardin DS, Rice J, Ahn C, Ferkol T, Howenstine M, Spears S, et al. Growth hormone treatment enhances nutrition and growth in children with cystic fibrosis receiving enteral nutrition. The Journal of Pediatrics 2005;146(3):324-8. [CFGD Register: GN122h]
Hardin 2005c {published data only}
Hardin 2006 {published data only}
  • Hardin D, Rice J, Ahn C, Brown D, Chatfield B, Dyson M, et al. Growth hormone improves bone mineralization in prepubertal children with CF - results of a multicenter study [abstract]. Pediatric Pulmonology 2004;38 (Suppl 27):343. [CFGD Register: GN122g]
  • Hardin DS, Adams-Huet B, Brown D, Chatfield B, Dyson M, Ferkol T, et al. Growth hormone treatment improves growth and clinical status in prepubertal children with cystic fibrosis: results of a multicenter randomized controlled trial. Journal of Clinical Endocrinology and Metabolism 2006;91(12):4925-9. [CFGD Register: GN122i]
  • Hardin DS, Chatfield B, Dyson M, Hicks D, Howenstine M, Lee P, et al. Multicentre trial of growth hormone in children with CF [abstract]. Pediatric Pulmonology 2001;32 (Suppl 22):338. [CFGD Register: GN122c]
  • Hardin DS, Rice J, Ahn C, Chatfield B, Dyson M, Howenstein M, et al. Growth hormone improves pulmonary function, weight, and height - results from a multicenter study [abstract]. Pediatric Pulmonology 2002;34 (Suppl 24):337. [CFGD Register: GN122f]
Hardin 2007 {published data only}
  • Hardin DS. A review of the management of two common clinical problems found in patients with cystic fibrosis: cystic fibrosis-related diabetes and poor growth. Hormone Research 2007;68(Suppl 5):113-6.
Hutler 2002 {published data only}
  • Hutler M, Schnabel D, Staab D, Tacke A, Wahn U, Boning D, et al. Effect of growth hormone on exercise tolerance in children with cystic fibrosis. Medicine and Science in Sports and Exercise 2002;34(4):567-72.
Linnane 2001 {published data only}
  • Linnane SJ, Thin AG, Keatings VM, Moynihan JB, Mc Loughlin P, Fitzgerald MX. Glucocorticoid treatment reduces exhaled nitric oxide in cystic fibrosis patients. European Respiratory Journal 2001;17(6):1267-70.
Lopez 2004 {published data only}
  • López AP, Figuls RM, Cuchi GU, Berenstein EG, Pasies BA, Alegre MB, et al. Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome. Journal of Pain and Symptom Management 2004;27(4):360-9.
Loprinzi 1993 {published data only}
  • Loprinzi CL, Schaid DJ, Dose AM, Burnham NL, Jensen MD. Body-composition changes in patients who gain weight while receiving megestrol acetate. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 1993;11(1):152-4.
Minicucci 2012 {published data only}
  • Minicucci L. New diagnostic and therapeutic approaches in cystic fibrosis related diabetes (CFRD) [abstract]. Journal of Cystic Fibrosis 2008;7 Suppl 3:S6, Abstract no: R25. [CFGD Register: CO42a]
  • Minicucci L, Casciaro R, De Alessandri A, Haupt M, Caso M, Lucidi V, et al. Efficacy of slow release insulin in patients with cystic fibrosis and glucide intolerance [abstract]. Journal of Cystic Fibrosis 2009;8 Suppl 2:S82, Abstract no: 331. [CFGD Register: CO42b]
  • Minicucci L, Haupt M, Casciaro R, De Alessandri A, Bagnasco F, Lucidi V, et al. Slow-release insulin in cystic fibrosis patients with glucose intolerance: a randomized clinical trial. Pediatric Diabetes 2012;13(2):197-202. [CFGD Register: CO42c]
Moran 2001 {published data only}
  • Milla CE, Phillips J, Moran A. Insulin and glucose excursion following pre-meal insulin lispro or repaglinide in CFRD [abstract]. Pediatric Pulmonology 2001;32(Suppl 22):335.
  • Moran A, Phillips J, Milla C. Insulin and glucose excursion following premeal insulin lispo or repaglinide in cystic fibrosis-related diabetes. Diabetes Care 2001;24(10):1706-10.
Moran 2009 {published data only}
  • Moran A, Pekow P, Grover P, Zorn M, Slovis B, Pilewski J, et al. Insulin therapy to improve BMI in cystic fibrosis related diabetes without fasting hyperglycemia: Results of the CFRDT Trial. Diabetes Care 2009;32(10):1783-8. [CFGD Register: CO43]
Nasr 1999 {published data only}
Nasr 2008 {published data only}
Nasrallah 2003 {published data only}
Newkirk 2000 {published data only}
  • Newkirk M, Martine JC, Ewig J, Kriseman T, Gondor M, Fariello A. Adrenal suppression in children with cystic fibrosis treated with megesterol acetate [abstract]. Pediatric Pulmonology 2000;30 (Suppl 20):323.
Nyamugunduru 1998 {published data only}
  • Nyamugunduru G, Desai M, Rayner RJ, Simmonds E, Weller PH, Spencer DA. A CFRD double-blind parallel placebo controlled randomised study of oral prednisolone in acute respiratory exacerbations in children with cystic fibrosis [abstract]. Thorax 1998;53(Suppl 4):A61.
  • Nyamugunduru G, Desai M, Spencer D, Clarke J, Weller P. A double-blind parallel placebo-controlled randomised study of the addition of short-course oral prednisolone in treatment of acute respiratory exacerbations in children with cystic fibrosis [abstract]. Proceedings of the 22nd European Cystic Fibrosis Conference; 1998 June 13-19; Berlin, Germany. 1998:79.
  • Nyamugunduru G, Desai M, Weller PH, Spencer DA. The effect of oral prednisolone on serum interleukin-8 concentrations in acute respiratory exacerbations in children with cystic fibrosis [abstract]. Proceedings of the 13th International Cystic Fibrosis Congress; 2000 June 4-8; Stockholm, Sweden. 2000:183.
Ohnhaus 1974 {published data only}
Pantin 1986 {published data only}
  • Pantin F, Stead RJ, Hodson M, Batten J. Prednisolone in the treatment of airflow obstruction in adults with cystic fibrosis. Thorax 1986;41(1):34-8.
  • Stead RJ, Pantin CFA, Hodson ME, Batten JC. Prednisolone in the treatment of airflow obstruction in adults with cystic fibrosis [abstract]. Proceedings of the 13th Annual Meeting of the European Working Group for Cystic Fibrosis; 1985 Nov 3-8; Jerusalem, Israel. 1985:112.
Parsons 2009 {published data only}
  • Parson, B Allison, DB Loebel, A Williams, K Giller, E Romano, S Siu, C. Weight effetcs associated with antipsychotics:A comprehensive database analysis. Schizophrenia Research 2009;110:103-110.
Paterson 2010 {published data only}
  • Paterson I, Taylor M, Ross E, Bicknell S, MacGregor G. Promoting weight gain with olanzapine in underweight adults with cystic fibrosis [abstract]. Journal of Cystic Fibrosis 2010;9 Suppl 1:S90, Abstract no.: 349.
Phung 2010 {published data only}
  • Phung OJ, Coleman CI, Baker EL, Scholle JM, Girotto JE, Makanji SS, et al. Recombinant human growth hormone in the treatment of patients with cystic fibrosis. Pediatrics 2010;125(5):e1211-e1226.
Rogan 2010 {published data only}
  • Rogan MP, Reznikov LR, Pezzulo AA, Gansemer ND, Samuel M, Prather RS, et al. Pigs and humans with cystic fibrosis have reduced insulin-like growth factor (IGF1) levels at birth. Proceedings of the National Academy of Sciences of the United States of America 2010;107(47):20571-5.
Rosenstein 1991 {published data only}
  • Eigen H, Rosenstein BJ, FitzSimmons S, Schidlow DV. A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. Cystic Fibrosis Foundation Prednisone Trial Group. Journal of Pediatrics 1995;126(4):515-23.
  • Hsu J, Kuhns LR. Longitudinal study in bone absorptiometry in children with cystic fibrosis enrolled in steroid therapy [abstract]. Pediatric Pulmonology 1991;10 (Suppl 6):313.
  • Lai HC, FitzSimmons SC, Allen DB, Kosorok MR, Rosenstein BJ, Campbell PW, et al. Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis. New England Journal of Medicine 2000;342(12):851-9.
  • Lai HC, Kosorok MR, Allen DB, FitzSimmons SC, Rosenstein BJ, Campbell PW, et al. Long-term growth evaluation in children with cystic fibrosis with history of regular use of alternate-day prednisone therapy [abstract]. Pediatric Pulmonology 1999;28 (Suppl 19):297.
  • Rosenstein BJ, Eigen H. Risks of alternate-day prednisone in patients with cystic fibrosis. Pediatrics 1991;87(2):245-6.
Ross 2005 {published data only}
  • Ross E, Davidson S, Sriram S, Hempsey S, Jane Y, Margaret K, Bicknell S. Weight gain associated with low dose olanzapine therapy in severely underweight adults with cystic fibrosis. Pediatric Pulmonology 2005;40:350.
Sackey 1995 {published data only}
Safai 1991 {published data only}
  • Safai KS, Selin E, Larsson S, Jagenburg R, Denfors I, Sten G, et al. Zinc therapy in children with cystic fibrosis. Beitrage zur Infusiontherapie 1991;27:104-14.
Schibler 2003 {published data only}
  • Schibler A, von der Heiden R, Birrer P, Mullis PE. Moderate improved exercise capacity in patients with cystic fibrosis after treatment with recombinant human growth hormone [abstract]. Proceedings of 12th European Respiratory Society Annual Congress; 2002 Sept 14-18; Stockholm. 2002:P3287.
  • Schibler A, von der Heiden R, Birrer P, Mullis PE. Prospective randomised treatment with recombinant human growth hormone in cystic fibrosis. Archives of Disease in Childhood 2003;88(12):1078-81.
  • von der Heiden R, Kraemer R, Birrer P, Waldegg G, Mullis PE. Effect of growth hormone (r-hGH) treatment on working capacity, body composition, lung function and immunological parameters in patients with cystic fibrosis (CF) [abstract]. Proceedings of 21st European Cystic Fibrosis Conference; 1997 June 1-6; Davos, Switzerland. 1997:132.
Schnabel 2007 {published data only}
  • Grasemann C, Ratjen F, Schnabel D, Reutershahn E, Vester U, Grasemann H. Effect of growth hormone therapy on nitric oxide formation in cystic fibrosis patients. European Respiratory Journal 2008;4:815-21.
  • Grasemann H, Grasemann C, Schnabel D, Ratjen F. Growth hormone therapy results in increased L-arginine and nitrate concentrations in serum but decreased exhaled nitric oxide in patients with cystic fibrosis [abstract]. Pediatric Pulmonology 2006;41 (S29):335.
  • Grasemann H, Grasemann C, Schnabel F, Ratjen F. Recombinant human growth hormone therapy results in increased systemic nitric oxide (NO) formation but decreased exhaled NO in patients with cystic fibrosis [abstract]. American Thoracic Society International Conference, San Diego, CA 2006;Poster:A408p.
  • Schnabel D, Graseman C, Staab D, Wollman H, Ratjen F, and for the German Cystic Fibrosis Growth Hormone Study Group. A multicenter, randomized, double-blind, placebo-controlled trial to evaluate the metabolic and respiratory effects of growth hormone in children with cystic fibrosis. Paediatrics 2007;119(6):e1230-8.
  • Schnabel D, Grasemann C, Staab D, Wollmann H, Ratjen F. A multicenter, randomized, double-blind placebo-controlled trial evaluating the metabolic and respiratory effects of growth hormone in children with cystic fibrosis [abstract]. Pediatric Pulmonology 2006;41 (Suppl 29):393.
Stalvey 2008 {published data only}
  • Stalvey MS, Torrez DM, Hillan J, Gonzalez-Peralta, Haafiz A, Rosenbloom AL. Growth hormone therapy improves growth in children with cystic fibrosis-related liver disease. Journal of Pediatric Endocrinology and Metabolism 2008;21(8):793-7.
Stalvey 2011 {published data only}
  • Geller DE, Anbar RD, Konstan MW, Stalvey MS, Jacobs JR, Bakker B. Growth hormone effects on pulmonary function in prepubertal children with cystic fibrosis [abstract]. Pediatric Pulmonology 2008;43 (Suppl 31):368. [CFGD Register: GN128b]
  • Stalvey MS, Anbar RD, Konstan MW, Jacobs JR, Bakker B, Lippe B, et al. A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis. Pediatric Pulmonology 2012;47(3):252-63. [CFGD Register: GN128c]
  • Stalvey MS, Geller DE, Anbar RD, Konstan MW, Jacobs JR, Bakker B. Growth hormone (GH) increases height, weight and lean body mass (LBM) in prepubertal children with cystic fibrosis (CF): results of a multicenter randomized control trial [abstract]. Pediatric Pulmonology 2007;42 (Suppl 30):393. [CFGD Register: GN128a]
Stylianou 2007 {published data only}
  • Stylianou C, Galli-Tsinopoulou A, Koliakos G, Fotoulaki M, Nousia-Arvanitakis S. Ghrelin and leptin levels in young adults with cystic fibrosis: relationship with body fat. Journal of Cystic Fibrosis 2007;6(4):293-6.
Switzer 2009 {published data only}
  • Switzer M, Rice J, Rice M, Hardin DS. Insulin-like growth factor-1 levels predict weight, height and protein catabolism in children and adolescents with cystic fibrosis. Journal of Pediatric Endocrinology and Metabolism 2009;22(5):417-24.
Sykes 2006 {published data only}
  • Sykes R, Kittell F, Marcus M, Tarter E, Schroth M. Mirtazapine for appetite stimulation in children with cystic fibrosis [abstract]. Pediatric Pulmonology 2006;41 (Suppl 29):389.
Taylor 1997 {published data only}
  • Taylor AM,  Bush A,  Thomson A,  Oades PJ,  Marchant JL,  Bruce-Morgan C, et al. Relation between insulin-like growth factor-I, body mass index and clinical status in cystic fibrosis. Archives of Disease in Childhood 1997;76(4):304-9.
Teeter 2004 {published data only}
  • Teeter JG, The Exubera Phase 3 study Group, Pfizer Global Research and Development GCU. One-year pulmonary safety and efficacy of inhaled insulin as adjunctive therapy in type 2 diabetes patients poorly controlled on oral agent monotherapy [abstract]. European Respiratory Journal 2004;24(Suppl 48):P3773.
Tongudai 1971 {published data only}
  • Tongudai S, Braverman S, Kirkpatrick JA, Huang NN. Evaluation of oxandrolone in patients with cystic fibrosis. Proceedings of the 12th Annual Meeting-Cystic Fibrosis Club Abstracts; April 28; Atlantic City, New Jersey. 1971:54.
Varness 2009 {published data only}
  • Varness T, Seffrood EE, Connor EL, Rock MJ, Allen DB. Oxandrolone improves height velocity and BMI in patients with cystic fibrosis. International Journal of Pediatric Endocrinology 2010 Jan 24 [Epub ahead of print]. [DOI: 10.1155/2009/826895]
von Haehling 2009 {published data only}
Weisberg 2002 {published data only}
Young 2000 {published data only}
  • Young J, Danduran MJ, McColley SA, Boar SR. The role of mirtazapine as an appetite stimulant in malnourished individuals with CF [abstract]. Pediatric Pulmonology 2000;30 (Suppl 20):326.

References to studies awaiting assessment

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Epifanio 2012 {published data only}
  • Epifanio M, Marostica P, Mattiello R, Feix L, Nejedlo R, Fischer G, et al. A randomized, double-blind, placebo-controlled trial of cyproheptadine for appetite stimulation in cystic fibrosis. Journal of Pediatrics (Rio J) 2012;88(2):155-60.
Kissner 2000 {published data only}

Additional references

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Abbott 2011
  • Abbott J, Holt A, Morton AM, Hart A, Milne G, Wolfe SP, et al. Patient indicators of a pulmonary exacerbation: Preliminary reports from school aged children map onto those of adults. Journal of Cystic Fibrosis 2012;11(3):180-6.
Auden Mckenzie 2014
  • Auden McKenzie (Pharma Division) Ltd. PERIACTIN® Tablets. www.audenmckenzie.com/Periactin4mgTabletsSmPC020211.pdf (accessed 05 June 2014).
Balshem 2011
  • Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, Guyatt GH. GRADE Guidelines:3. Rating the Quality of Evidence. Journal of Clinical Epidemiology 2011;64(4):401-6.
Bell 2008
BNF 2014
  • British National Fomulary. Periactin. www.medicinescomplete.com/mc/bnf/current/PHP1940-periactin.htm#PHP1940-periactin (accessed 05 June 2014).
Borowitz 1996
  • Borowitz D. The interrelationship of nutrition and pulmonary function in patients with cystic fibrosis. Current Opinion in Pulmonary Medicine 1996;2(6):457-61.
Chinuck 2013 [pers comm]
  • Chinuck RS. Reference costs for Megace, cyproheptadine and somatropin [personal communication]. Email to: C Horton-Smith 23 April 2013.
Corey 1998
  • Corey M, Mc Laughlan FJ, Williams M, Levison H. A comparison of survival, growth and pulmonary function in patients with CF in Boston and Toronto. Journal of Clinical Epidemiology 1998;41(6):583-91.
Curtin 2002a
Curtin 2002b
Curtin 2002c
Elborn 1996
Elbourne 2002
  • Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140-9.
EMC 2014a
  • Electronic Medicines Compendium. Nabilone tablets 1 mg. www.medicines.org.uk/emc/medicine/20515/SPC/Nabilone+1mg+Capsules (accessed 25 March 2014).
EMC 2014b
  • Electronic Medicines Compendium. Megace 160 mg tablets. www.medicines.org.uk/emc/medicine/346/SPC/Megace+160+mg+Tablets (accessed 26 March 2014).
EMC 2014c
  • Electronic Medicines Compendium. Mirtazapine 15 mg tablets. www.medicines.org.uk/emc/medicine/24969/SPC/Mirtazapine+15+mg+orodispersible+tablets (accessed 25 March 2014).
EMC 2014d
  • Electronic Medicines Compendium. Olanzapine Sandoz 20 mg film-coated tablets. www.medicines.org.uk/emc/medicine/25455/SPC/Olanzapine+Sandoz+20+mg+Film-coated+Tablets (accessed 26 March 2014).
EMC 2014e
  • Electronic Medicines Compendium. Pizotifen tablets 0.5 mg. www.medicines.org.uk/emc/medicine/24179/SPC/Pizotifen+Tablets+0.5mg/ (accessed 25 March 2014).
EMC 2014f
  • Electronic Medicines Compendium. Risperdal Tablets, Liquid & Quicklet. www.medicines.org.uk/emc/medicine/12818/SPC (accessed 26 March 2014).
Grossberg 2010
Hardin 2002
  • Hardin DS. Growth problems and growth hormone treatment in children with cystic fibrosis. Journal of Pediatric Endocrinology & Metabolism 2002;15(Suppl 2):731-5.
Higgins 2003
Higgins 2011
  • Higgins JPT, Altman DG, Sterne JAC on behalf of the Cochrane Statistical Methods Group and the Cochrane Bias Methods Group (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Hobbs 2012
  • Hobbs DJ, Bunchman TE, Weismantel DP, Cole MR, Ferguson KB, Gast TR, et al. Megestrol acetate improves weight gain in pediatric patients with chronic kidney disease. Journal of Renal Nutrition 2012;20(6):408-13.
Ioannidis 2004
  • Ioannidis JP, Evans SJ, Gøtzsche PC, O’Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Annals of Internal Medicine 2004;141(10):781-8.
Jones 2005
  • Jones AP, Riley R, Williamson PR, Whitehead A. Meta-analysis of longitudinal data. Proceedings of the Royal Statistical Society Annual Conference. 2005.
McKone 2002
MedLibrary 2014
  • MedLibrary (Food & Drug Agency). Oxandrolone. www.medlibrary.org/lib/info/google-search/?cx=partner-pub-3862246084592963%3A1mitg9hzsad&cof=FORID%3A10&ie=UTF-8&q=oxandrolone&sa=Search&siteurl=medlibrary.org%2F&ref=&ss=4143j3496931j13 (accessed 18 June 2014).
Moher 2001
Moher 2003
  • Moher D Schulz KF Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Clinical Oral Investigations 2003;7(1):2-7.
Moher 2004
O'Brien 2013
Pellegrino 2005
Poustie 2006
  • Poustie VJ, Russell JE, Watling RM, Ashby D, Smyth RL, CALICO Trial Collaborative Group. Oral protein energy supplements for children with cystic fibrosis: CALICO multicentre randomised controlled trial. BMJ 2006;332(7542):632-6.
RevMan 2011
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
Sharma 2001
Shepherd 1998
  • Shepherd RW, Holt TL, Cleghorn G, Ward LC, Isles A, Francis P. Short-term nutritional supplementation during management of pulmonary exacerbations in cystic fibrosis: a controlled study, including effects of protein turnover. American Journal of Clinical Nutrition 1998;48(2):235-9.
Sinaasappel 2002
  • Sinaasappel M, Stern M, Littlewood J, Wolfe S, Steinkamp G, Heijerman HG, et al. Nutrition in patients with cystic fibrosis: a European Consensus. Journal of Cystic Fibrosis 2002;1(2):51-75.
Stallings 2008
  • Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. Journal American Dietetic Association 2008;108(5):832-9.
Steinkamp 2002
  • Steinkamp G, Wiedemann B. Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project. Thorax 2002;57:596-601.
Suter 1989
  • Suter S, Schaad UB, Roux-Lombard P, Girardin E, Grau G, Dayer JM. Relation between tumor necrosis factor-alpha and granulocyte elastase-alpha 1-proteinase inhibitor complexes in the plasma of patients with cystic fibrosis. American Review of Respiratory Disease 1989;140(6):1640-4.
Taylor 2007
  • Tayor C. The regulation of appetite in cystic fibrosis symposium. Proceedings of 30th European Cystic Fibrosis Conference, Belek, Turkey. 2007.
Tschopp 2002
  • Tschopp O, Boehler A, Speich R, Weder W, Seifert B, Russi EW, et al. Osteoporosis before lung transplantation: association with low body mass index, but not with underlying disease. American Journal of Transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2002;2(2):167-72.
Upsher-Smith 2014
  • Upsher-Smith Laboratories, Inc. Oxandrolone tablets. www.upsher-smith.com/wp-content/uploads/Oxandrolone_PI.pdf (accessed 18 June 2014).
von Haehling 2009
Wermers 2004