Appetite stimulants for people with cystic fibrosis

Abstract

Background

Chronic loss of appetite in cystic fibrosis concerns both individuals and families. Appetite stimulants have been used to help cystic fibrosis patients with chronic anorexia attain optimal body mass index (BMI) and nutritional status. However, these may have adverse effects on clinical status. This is an updated version of the original review.

Objectives

To systematically search for and evaluate the evidence on the beneficial effects of appetite stimulants in the management of cystic fibrosis‐related anorexia and synthesise reports of any side effects.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register and online trials registries; handsearched reference lists; and contacted local and international experts to identify relevant trials.

Last search of the Cystic Fibrosis Trials Register: 23 May 2022.

Last search of online trial registries: 10 May 2022.

Selection criteria

Randomised and quasi‐randomised controlled trials of appetite stimulants compared to placebo, control, no treatment or different appetite stimulants, or to the same appetite stimulants at different doses or regimens for at least one month in adults and children with cystic fibrosis.

Data collection and analysis

Review authors independently extracted data and assessed risk of bias of the included trials. We used the GRADE approach to assess the certainty of the evidence and performed meta‐analyses.

Main results

We included four trials (70 participants) comparing appetite stimulants (cyproheptadine hydrochloride and megestrol acetate) to placebo; the numbers of adults or children within each trial were not always reported. We assessed the certainty of evidence as low due to the small number of participants, incomplete or selective outcome reporting, and unclear risk of selection bias. 

Regarding our primary outcomes, a meta‐analysis of two trials (42 participants) showed that appetite stimulants may produce a larger increase in weight (kg) at three months (mean difference (MD) 1.25 kg, 95% confidence interval (Cl) 0.45 to 2.05), and one trial (17 participants) showed a similar result at six months (MD 3.80 kg, 95% CI 1.27 to 6.33) (both low‐certainty evidence). Results also showed that weight z score may increase with appetite stimulants compared to placebo at three months (MD 0.61, 95% CI 0.29 to 0.93; 3 studies; 40 participants; P < 0.001) and at six months (MD 0.74, 95% CI 0.26 to 1.22; 1 trial; 17 participants). There was no evidence of a difference in effect between cyproheptadine hydrochloride and megestrol acetate for either outcome.  

Only one trial (25 participants) reported analysable data for body composition (BMI), with results favouring cyproheptadine hydrochloride compared to placebo; a further trial (16 participants) narratively agreed with this result.

All four trials reported on lung function at durations ranging from two to nine months. Considering analysable data, two trials (42 participants) found that appetite stimulants may make little or no difference in forced expiratory volume at one second (FEV₁) % predicted at three months, and one trial (17 participants) found similar results at six months. Two further three‐month trials narratively agreed with these results.

Limited information was reported for secondary outcomes. Two trials (23 participants) reported results showing that appetite stimulants may increase appetite compared to placebo at three months (odds ratio 45.25, 95% CI 3.57 to 573.33; low‐certainty evidence). 

Only one study reported on quality of life, finding that cyproheptadine reduced fatigue in two participants compared with none with placebo. One study (25 participants) found no difference in energy intake between appetite stimulant or placebo at three months. Insufficient reporting of adverse effects prevented a full determination of their impact. Two studies (33 participants) narratively reported similar requirements for additional antibiotics between appetite stimulants and placebo at three months. 

Authors' conclusions

At six months in adults and children, appetite stimulants improved only two of the outcomes of this review: weight (or weight z score) and subjectively reported appetite. Insufficient reporting of side effects prevented a full determination of their impact. Whilst the data may suggest the potential use of appetite stimulants in treating anorexia in adults and children with cystic fibrosis, this is based upon low‐certainty evidence from a small number of trials, therefore firm conclusions cannot be drawn. Clinicians need to be aware of the potential adverse effects of appetite stimulants and actively monitor any individuals prescribed these medications accordingly.

Research is required to determine meaningful surrogate measures for appetite and to define what constitutes quality weight gain. Future trials of appetite stimulants should use a validated measure of symptoms including a disease‐specific instrument for measuring poor appetite. This review highlights the need for multicentred, adequately powered, and well‐designed trials to evaluate agents to safely increase appetite in people with cystic fibrosis and to establish the optimal mode of treatment.

Plain language summary

Appetite stimulants for people with cystic fibrosis

Review question

We looked for evidence on both beneficial and adverse effects of using appetite stimulants in people with anorexia linked to cystic fibrosis.

Background

Loss of appetite in people with cystic fibrosis concerns both those with the disease and their families. Appetite stimulants have been used to help people with cystic fibrosis who have a poor appetite to increase the amounts they eat so they gain weight and improve their overall health. However, there are concerns that appetite stimulants can cause side effects. This is an updated version of the original review.

Search date

We last looked for evidence on 23 May 2022.

Study characteristics

We included four trials (70 participants), two of which were performed in children and two in both children and adults. The trials looked at the effects of drugs (megestrol acetate and cyproheptadine hydrochloride) compared to a placebo (a tablet that contained no medicine) to stimulate appetite. The trials lasted between three and six months.

Key results

We found that these drugs may improve weight and appetite in the short term (up to six months). No effect was seen on lung function. All stimulants can have adverse effects which can worsen cystic fibrosis, such as effects on blood sugar control, fatigue, mood, fluid retention, the liver, and shortness of breath, but unfortunately insufficient reporting of side effects prevented a full understanding of their effects. The included trials were too small to show if megestrol acetate and cyproheptadine hydrochloride can improve weight and appetite safely.

Whilst there is evidence to suggest that appetite stimulants may improve weight and poor appetite in adults and children with cystic fibrosis, we believe more research is needed to identify appropriate ways of measuring appetite, and then to collect sound data from enough patients to find out if appetite stimulants can improve appetite safely in cystic fibrosis.

Certainty of the evidence

We have low confidence in the results being able to show the true effectiveness of appetite stimulants. We came to this conclusion because although we think that most of the people taking part had the same chance of being in the appetite stimulant or placebo group, and no one could not tell the difference between the appetite stimulant or the placebo, there may be some bias due to the small numbers of participants in the studies, and because in two studies some participants withdrew without clear reasons being given. Another possible source of bias is that three studies did not report on all of their pre‐planned outcomes. 

Summary of findings

Summary of findings 1. 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 Setting: outpatients Intervention: appetite stimulants Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Appetite stimulants
Change in weight (kg) Follow‐up: 3 months	The mean change in weight ranged from 0.67 kg to 1.3 kg.	The mean change in weight (kg) in the intervention group was 1.25 kghigher (0.45 higher to 2.05 higher).	‐	42 (2 studies)	⊕⊕⊝⊝ Lowa,b
Change in weight (kg) Follow‐up: 6 months	The mean change in weight was 1.5 kg.	The mean change in weight (kg) in the intervention group was 3.8 kg higher (1.27 to 6.33 higher).	‐	17 (1 study)	⊕⊕⊝⊝ Lowa,b
Change in weight z score Follow‐up: 3 months	The mean change in weight z score ranged from −0.05 to 0.07.	The mean change in weight z score in the intervention group was 0.61 higher (0.29 higher to 0.93 higher).	‐	40 (3 studies)	⊕⊕⊝⊝ Lowb,c
Change in weight z score Follow‐up: 6 months	The mean change in weight z score was 0.02.	The mean change in weight z score in the intervention group was 0.74 higher (0.26 to 1.22 higher).	‐	17 (1 study)	⊕⊕⊝⊝ Lowa,b
Change in FEV1 % predicted Follow‐up: 3 months	The mean change in FEV1 % predicted ranged from −3.7% to −1.81%.	The mean change in FEV1 % predicted in the intervention group was 4.26% higher (5.45 lower to 13.97 higher).	‐	42 (2 studies)	⊕⊕⊝⊝ Lowa,b
Change in FEV1 % predicted Follow‐up: 6 months	The mean change in FEV1 % predicted was 0.83.	The mean change in FEV1 % predicted in the intervention group was 5.64 higher (4.43 lower to 15.71 higher).	‐	17 (1 study)	⊕⊕⊝⊝ Lowa,b
Increase in appetite (subjective reporting) Follow‐up: 3 months	Of the 23 participants responding to the questionnaires, all 10 participants who took appetite stimulants reported a subjective increase in appetite, compared to only 2 out of 13 participants in the placebo group.		OR 45.25 (3.57 to 573.33)	23 (2 studies)	⊕⊕⊝⊝ Lowd,e	The numbers  were too small to calculate the corresponding risk, therefore results have been reported narratively.
*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; FEV1: forced expiratory volume at one second; OR: odds ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aDowngraded once due to risk of attrition and reporting bias.
^bDowngraded once for imprecision due to small number of participants.
^cDowngraded once due to risk of attrition and reporting bias as well as unclear risk of selection bias.
^dDowngraded once due to risk of bias within the included trials as follows: one study was at unclear risk of bias for the randomisation process, and both studies were at unclear risk for allocation concealment; one study was at high risk of attrition bias; and both studies were at high risk of reporting bias.
^eDowngraded once for imprecision due to very low participant numbers and low event rates.

Background

For an explanation of terms used in this review, please see the glossary (Appendix 1).

Description of the condition

Treating and managing loss of weight, inadequate weight gain, and failure to thrive can be challenging 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). Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have shown some improvements in anthropometry dependent on genetic mutation and the modulator used (Bailey 2021). 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, gastro‐oesophageal 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 there is no consensus on the management of these symptoms to date (Chinuck 2007; O'Brien 2013).

Description of the intervention

Whilst appetite stimulants are prescribed to people with CF, 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 conducted 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 (megestrol acetate (MA), oxandrolone, prednisone), cannabinoids (dronabinol), antidepressants (mirtazapine), and antipsychotics (olanzapine). In addition to agents that have already been studied in CF, there are other interventions with possible similar effects that could have implications for people with CF. 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. We will thus 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

CH is used as an antihistamine, and clinical recommended dosages differ in children and adults (BNF 2014). It has been investigated for use as an appetite stimulant in CF (Epifanio 2012; 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 people with HIV or cancer at doses of 2.5 mg to a maximum of 5 mg twice daily (Anstead 2003).

Megestrol acetate

The progestogen steroid MA (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 prostate cancer (EMC 2014b). One of its adjunctive effects is weight gain, and it has been used for appetite stimulation and weight gain for such indications 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).

MA is not very water‐soluble, thus its bio‐availability is low, although bio‐availability is improved if it is taken with food. Several formulations have been developed in an attempt to improve bio‐availability (e.g. a micronised tablet form and a concentrated oral suspension). The most recent of these is an oral suspension form using nanocrystal technology, which is licensed for anorexia‐cachexia in people with AIDS.

Mirtazapine

Mirtazapine (Remeron) is typically used as an antidepressant 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 antipsychotic drug (EMC 2014d). Whilst limited data are available, olanzapine has been used to stimulate appetite and improve body mass index (BMI) and other disease‐related symptoms (e.g. eating attitudes, anxiety) in people with anorexia aged nine years and older. The dose used to stimulate appetite has been higher than that used in psychiatric practice (Nasr 2008).

Oxandrolone

Therapy with the anabolic steroid oxandrolone (Oxandrin) should be intermittent, and the duration should depend on an individual's response and adverse reactions. Two‐ to four‐week blocks of therapy are usually adequate, and dosage differs depending on the age of the individual (MedLibrary 2014; Upsher‐Smith 2022). Oxandrolone has been used principally in anorexia in people with cancer, 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 individual (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 vary in type, the mechanisms of action are varied and mostly unclear in people with CF.

Cyproheptadine

CH is a serotonin and histamine antagonist approved by the US Food and Drug Administration (FDA) for use in children for allergic rhinitis, allergic conjunctivitis, urticaria, dermatographism, and mild angio‐oedema. Unexplained weight gain has been observed in people 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).

Megestrol acetate

It has been elucidated that MA may cause appetite stimulation and weight gain in people with anorexia or cachexia, or both (Loprinzi 1993). The mechanism by which this occurs 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 hypothesised 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 people with pulmonary tuberculosis (Ohnhaus 1974). However, as with 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 is 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 cornerstones of CF management. A lack of appetite has not only been reported as a common indicator of pulmonary exacerbation in people with CF (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 due to possible side effects. Hence the aim of this review was to establish whether appetite stimulants should be recommended in people with CF. This is an updated version of the original review (Chinuck 2014).

Objectives

To systematically search for and evaluate the evidence on the beneficial effects of appetite stimulants in the management of CF‐related anorexia and synthesise reports of any side effects.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi‐RCTs (with no language restrictions).

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; or the same appetite stimulants at different doses or regimens of at least one month duration.

Types of outcome measures

We have reported on the following outcomes.

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) (L)

   2. FEV₁ % predicted

Secondary outcomes

1. Subjective report of anorexia or change in appetite, or both

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

3. Dietary intake:

   1. energy intake (measured in kilocalories (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

We searched for all relevant published and unpublished trials without any language restrictions (we did not exclude trials reported in a language other than English), year, or publication status.

Electronic searches

We identified relevant trials from the Cochrane Cystic Fibrosis and Genetic Disorders 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 Journal of Cystic Fibrosis. We identified unpublished work 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's website.

Date of the last search of the Cystic Fibrosis Trials Register: 23 May 2022.

We also searched the following databases and trial registries:

1. US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 10 May 2022);

2. World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch; searched 10 May 2022).

The previous author team also searched these additional resources for a previous version of this review, but this has not been updated as the current author team do not have access to this resource:

1. MEDLINE HDAS (1946 to 1 April 2014);

2. Embase HDAS (1974 to 1 April 2014);

3. CINAHL HDAS (Cumulative Index to Nursing and Allied Health Literature; 1982 to 1 May 2012).

Details of the search strategies can be found in Appendix 2.  

Searching other resources

We checked the bibliographies of included trials and any relevant systematic reviews identified for further references to relevant trials. We also contacted the authors of conference abstracts to determine if further publications were in press.

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 and Actavis Mid Atlantic LLC).

Data collection and analysis

Selection of studies

Two review authors (RC and JD for the original review and DM and JT for the subsequent updates) independently screened the titles and abstracts of trials identified by the searches and selected those that potentially met the selection criteria. We obtained the full‐text articles of potentially relevant trials and the review authors assessed these for inclusion in the review. The review authors extracted and entered details onto the generic trial selection and data extraction form developed by the Cochrane Cystic Fibrosis and Genetic Disorders Review Group. This process encouraged adherence to our inclusion criteria in order to avoid including trials that were not exclusively researching agents prescribed for appetite or that may not work on appetite stimulation.

In the event of uncertainty or disagreement on trial selection, this was resolved through discussion or by consultation with a member of the editorial base. 

Data extraction and management

Review authors independently extracted data from the included trials, cross‐checked data reported for the outcomes listed in Types of outcome measures, discussed any differences, and reached a consensus on the extracted data. If review authors were unable to extract data, they reported the outcome results narratively.

We planned to assess outcome measures at the time points of over one and up to six months and at six‐monthly intervals thereafter. In the current version of the review, we presented data from the included trials 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

Review 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 (Higgins 2011). This comprised 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 an answer of low risk of bias, high risk of bias, or unclear risk of bias (indicating either lack of information or uncertainty over the potential for bias). The review authors assessed the following risk of bias domains: randomisation procedure; allocation concealment; blinding of investigators, participants, and outcome assessors; intention‐to‐treat analysis, completeness of follow‐up, and incomplete outcome data; selective reporting; and other potential sources of bias. We also noted details of statistical assessment such as differences in means, overall treatment effects, heterogeneity, and subgroup and sensitivity analyses. We presented this information in risk of bias tables (see Characteristics of included studies). Any discrepancies were resolved by consensus or by discussion with a member of the editorial base when necessary. Further details regarding the risk of bias tool are provided in Table 2.

1. Cochrane risk of bias tool.

Domain	Description	Review authors’ judgement
Sequence generation (selection bias)	Description of the method used to generate the allocation sequence in sufficient detail to permit an assessment of whether it should produce comparable groups	Was the allocation sequence adequately generated?
Allocation concealment (selection bias)	Description of the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment	Was allocation adequately concealed?
Blinding of participants, personnel, and outcome assessors (performance bias and detection bias)	Description of measures used, if any, to blind study participants, personnel, and outcome assessors from knowledge of which intervention a participant received. Any information relating to whether the intended blinding was effective	Was knowledge of the allocated intervention adequately prevented during the study?
Incomplete outcome data (attrition bias)	Description of the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. Details of whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomised participants), reasons for attrition/exclusions where reported, and any re‐inclusions in analyses performed by the review authors	Were incomplete outcome data adequately addressed?
Selective outcome reporting (reporting bias)	Details of how the possibility of selective outcome reporting was examined by the review authors, and what was found	Are reports of the study free of the suggestion of selective outcome reporting?
Other potential sources of bias	Any important concerns about bias not addressed in the other risk of bias domains. If particular questions or entries were prespecified in the protocol of the review, responses should be provided for each question or entry.	Did the study appear to be free of other problems that could put it at high risk of bias?

Measures of treatment effect

We conducted the primary analysis using the Cochrane software Review Manager Web (RevMan Web 2022). We measured any treatment effects for dichotomous data using the odds ratio (OR) and 95% confidence intervals (CIs). We 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, we planned that if studies measured data longitudinally, we would 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) are available (Jones 2005). However, when completing the data analysis, we decided to present all available data at selected time points separately. Trial investigators measured data longitudinally in one included trial of MA (Eubanks 2002); we 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, we used the methods recommended by Elbourne (Elbourne 2002). Where individual data are available, the within‐participant changes and variation can be calculated directly, and we were able to include data from both arms of the trial. If we needed to combine data from cross‐over trials with data from parallel trials in a meta‐analysis, we 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

We described dropouts and the reasons given for them as provided in the primary papers. We contacted the original investigators if there were any missing data.

Assessment of heterogeneity

We considered the extent to which results of trials were consistent using the Chi² test produced in the Review Manager Web forest plots, which assesses whether observed differences in results are compatible with chance alone. We also used the I² statistic; thresholds for the interpretation of I² were as follows:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%:may represent considerable heterogeneity (Higgins 2003)

Assessment of reporting biases

We assessed publication bias by contacting the authors of trials assessed as awaiting classification to seek clarification on details of these studies (Epifanio 2012; Kissner 2000). Whilst we originally planned to assess the existence of publication bias from the meta‐analyses by a funnel plot, an insufficient number of trials combined (minimum of 10 required) precluded this. Furthermore, we acknowledge that the reasons for funnel plot asymmetry extend beyond reporting bias alone, for example methodological differences or pure chance.

We assessed outcome reporting bias by obtaining data from the clinical trial registry, or by comparing the methods and results sections of the full publications and using knowledge of the clinical area. If we suspected outcome reporting bias, we contacted the trial investigators firstly to ascertain if they had measured and analysed the outcome, and secondly to obtain the data.

Data synthesis

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

Subgroup analysis and investigation of heterogeneity

We planned that if we identified clinical and statistical heterogeneity, and there were enough trials (at least 10) with sufficient published or reported details to permit the extraction of data for separate participant types, we would undertake subgroup analyses to investigate the following:

1. level of disease severity (assessed by FEV₁ % predicted, Pellegrino 2005, and BMI classification, CF Trust 2002);

2. different appetite stimulants;

3. dosage of appetite stimulants.

Whilst we were able to include several trials in the review, no single meta‐analysis combined a sufficient number of data sets to permit 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, we will analyse data combining and splitting cross‐over and parallel trials to test if the current findings are robust.

Summary of findings and assessment of the certainty of the evidence

In a post hoc change to the protocol, we generated a summary of findings (GRADE) table to rate the certainty of evidence for change in body weight (Balshem 2011). We assessed the following outcomes in the table:

1. change in weight (kg) at three months;

2. change in weight (kg) at six months;

3. change in weight (z score) at three months;

4. change in weight (z score) at six months;

5. change in FEV₁ % predicted at six months;

6. change in appetite at three months.

Results

Description of studies

Results of the search

The combined searches identified a total of 179 titles and abstracts. Of these, 167 references (109 individual trials) were excluded from the review. There are no trials awaiting classification, and one trial is currently in progress. We included 11 references to four trials in the review. Please see the figures for a PRISMA diagram relating to the 2022 update only (Figure 1).

1.

Study flow diagram (2022 update).

Included studies

We included four RCTs, with a total of 70 participants, that addressed the use of potential appetite stimulants in children and adults with CF (Epifanio 2012; Eubanks 2002; Homnick 2004; Marchand 2000).

Trial design

Three trials were conducted in the USA (Eubanks 2002; Homnick 2004; Marchand 2000), and one in Brazil (Epifanio 2012). One trial had a cross‐over design (Marchand 2000), whilst the remaining three trials had a parallel design (Epifanio 2012; Eubanks 2002; Homnick 2004). We combined data from parallel and cross‐over trials using adjusted SDs (Curtin 2002a; Curtin 2002b; Curtin 2002c). 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); one trial recruited children and adolescents (Epifanio 2012); and the remaining two trials included both children and adults (Eubanks 2002; Homnick 2004). All trials reported the gender split between females and males (Epifanio 2012; Eubanks 2002; Homnick 2004; Marchand 2000). Male‐to‐female ratios differed across trials: 14 males to 11 females in Epifanio 2012; 8 males to 9 females in Eubanks 2002; 6 males to 10 females in Homnick 2004; and 3 males to 9 females in Marchand 2000.

Interventions

Two trials evaluated MA (Eubanks 2002; Marchand 2000), and two trials evaluated CH (Epifanio 2012; Homnick 2004). The dosage of oral appetite stimulants varied across trials; in two trials, MA was administered at a dose of 10 mg/kg/day (Eubanks 2002; Marchand 2000); in one trial, CH was administered at a dose of 4 mg four times daily (Homnick 2004); and in the final study, CH was administered as 2 mg three times a day for one week, then 4 mg three times a day for 11 weeks (Epifanio 2012). All trials used a placebo as the comparator (Epifanio 2012; Eubanks 2002; Homnick 2004; Marchand 2000).

Outcomes

All four trials reported on change in body weight, change in pulmonary function, and adverse events (Epifanio 2012; Eubanks 2002; Homnick 2004; Marchand 2000). Three trials reported on change in body composition (Epifanio 2012; Eubanks 2002; Homnick 2004); two trials reported on change in appetite (Homnick 2004; Marchand 2000); and two trials reported on change of dietary intake (Epifanio 2012; Marchand 2000). One trial reported on change in the number of pulmonary exacerbations (Eubanks 2002), and two trials reported on change in QoL (Homnick 2004; Marchand 2000); one of these studies reported on QoL in the results section of the paper even though this was not stated in the methods section of the paper (Marchand 2000).

Excluded studies

We excluded a total of 109 studies (168 references) from the review. Forty‐eight studies were not RCTs or quasi‐RCTs (Alemzadeh 1998; Amorim 2011; Anstead 2003; Battersby 2017; Canfield 1998; Chung 2006; Claes 2020; Cohen 2008; Cohen 2010; Crawley 2003; Darmaun 2004; Dhillo 2007; Dowsett 1999; Durant 1998; Eubanks 2000; Green 2015; Grunert 2020; Guillot 2011a; Guillot 2011b; Hardin 1997; Hardin 2004; Hardin 2007; Kissner 2000; Le 2019; Leung 2019; McLearn‐Montz 2018; Nasr 1999; Nasr 2008; Nasrallah 2003; Newkirk 2000; Ohnhaus 1974; Parsons 2009; Paterson 2010; Phung 2010; Price 2016; Ross 2005; Sackey 1995; Stalvey 2008; Stylianou 2007; Sullivan 2017; Switzer 2009; Sykes 2006; Taylor 1997; Tongudai 1971; Van Meerbeeck 2021; Varness 2009; von Haehling 2009; Young 2000); one study was a retrospective analysis of medical records (Hardin 2005c); and one study was a consensus document (CF Trust 2002). One study, identified at ClinicalTrials.gov, was terminated early after recruitment of only five participants, and no data were available (NCT00803179). Three papers were review articles (Berenstein 2005; Chinuck 2007; Lopez 2004). In three studies participants were not diagnosed with CF or were not human (Loprinzi 1993; Rogan 2010; Weisberg 2002).

A total of 52 studies did not use the researching agent primarily as an appetite stimulant; they assessed the following:

• growth hormone therapy (14 studies) (Bucuvalas 2001; Hardin 2001; Hardin 2005a; Hardin 2005b; Hardin 2006; Huseman 1996; Hutler 2002; NCT00005112; NCT00016445; Schibler 2003; Schnabel 2007; Stalvey 2011; Thaker 2013; Vanderwel 2006);

• insulin therapy (10 studies) (Ballmann 2013; de Lind van Wijngaarden‐van den Berg 2014; Grover 2008; Minicucci 2012; Moran 2001; Moran 2009; NCT01149005; Seggelke 2011; Teeter 2004; Verge 2015);

• zinc supplementation (1 study) (Safai 1991);

• prednisone therapy (8 studies) (Auerbach 1985; Cohen‐Cymberknoh 2008; Dovey 2007; Greally 1992; Linnane 2001; Nyamugunduru 1998; Pantin 1986; Rosenstein 1991);

• carbohydrate counting (1 study) (Grancini 2019);

• L‐glutathione (1 study) (Visca 2013);

• gene therapy (2 studies) (King 2018; Sawicki 2014);

• mental health or quality of life treatments such as behavioural therapy (14 studies) (ACTRN12619000572167; Bathgate 2019; Branch‐Smith 2018; DRKS00010979; Geirhos 2022; Goetz 2016; Hider 2020; Hilliard 2015; Lunkenheimer 2020; McLean 2014; NCT03139266; NCT03800459; O'Hayer 2017; O'Hayer 2019);

• insomnia (1 study) (Hjelm 2020). 

Ongoing studies

One trial had no results published, and the trial registry entry has not been updated since 2010 (NCT00763477). The principal investigator reports that they aim to publish results in the future. 

Risk of bias in included studies

Risk of bias in the included trials is summarised in a risk of bias graph and risk of bias summary (Figure 2; Figure 3).

2.

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

3.

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

Allocation

Randomisation procedure

All included trials referred to random allocation, from briefly commenting that participants were randomised to providing 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 three trials reported using a computer‐generated randomisation procedure (Epifanio 2012; Eubanks 2002), or more specifically SAS small block randomisation (Homnick 2004), and were judged as having a low risk of bias.

Allocation concealment

One trial reported storing the intervention in opaque envelopes (Epifanio 2012). None of the other included trials discussed the method of allocation concealment; we assessed these trials as at unclear risk of bias (Eubanks 2002; Homnick 2004; Marchand 2000).

Blinding

Three trials were described as double‐blind (Epifanio 2012; Eubanks 2002; Marchand 2000), whilst the remaining trial stated that only the pharmacist investigator and trial co‐ordinator remained unblinded (Homnick 2004). We judged all included trials as having a low risk of bias.

Incomplete outcome data

We judged two trials to have a low risk of bias (Epifanio 2012; Homnick 2004). In one of these trials, four out of 25 participants did not complete the trial (16% dropout rate), but there were equal numbers across groups, and the reasons for dropout were similar: one participant from each group withdrew due to non‐adherence; one participant withdrew from the intervention group because of an intolerance to CH; and one participant withdrew from the placebo group because of an allergy to the placebo (Epifanio 2012). A further trial had minimal dropouts, or dropouts that were unrelated to the intervention (Homnick 2004). 

We judged the two remaining trials to have a high risk of bias (Eubanks 2002; Marchand 2000). One trial had a dropout explicitly linked to the intervention (no effect in the placebo group), and there was no evidence of a treatment of the missing data to reduce the bias (Eubanks 2002). The second trial had a 50% dropout rate (six out of 12 participants), with the missing data being excluded and no clear evidence that bias was not introduced (Marchand 2000).

Selective reporting

In one trial, whilst there were no apparent differences between the methods and results sections, we could not be certain of this as the original paper was written in Portuguese, and we had no access to the trial protocol. We therefore judged this study to be at unclear risk of reporting bias (Epifanio 2012). 

We assessed the risk of reporting bias in the other three included trials 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, and were therefore judged to have a high risk of bias. The following outcomes were stated in the methods sections of the papers but not reported on in the results sections: dietary intake (Eubanks 2002), and dietary intake and pulmonary function (Homnick 2004; Marchand 2000). In contrast, the following outcomes not stated in the methods sections were subsequently reported on in the results sections: dietary energy intake and spirometry (Homnick 2004), and QoL (Marchand 2000). In addition, outcomes stated in the methods section of Eubanks 2002 were reported using unexpected measures (i.e. weight for age z score only, instead of being additional to weight as a mean (SD)). Furthermore, Eubanks and colleagues reported LBM and fat mass for the MA group but not for the placebo group (Eubanks 2002).

Other potential sources of bias

Homnick 2004 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 = 0.039). Allowing for an adjustment of the P value for testing multiple outcomes, the difference was not significant, and hence was not evidence for risk of bias.

We identified no other potential sources of bias in the remaining trials (Epifanio 2012; Eubanks 2002; Marchand 2000).

Effects of interventions

See: Table 1

All four trials (70 participants) reported data for appetite stimulants versus control (Epifanio 2012; Eubanks 2002; Homnick 2004; Marchand 2000). Two trials compared the effect of MA with placebo (Eubanks 2002; Marchand 2000), and two trials compared the effect of CH with placebo (Epifanio 2012; Homnick 2004). Explanations for our assessment of the certainty of the evidence are provided in Table 1. 

Primary outcomes

1. Change in body weight (kg)

All four trials (70 participants) reported data for change in body weight (Epifanio 2012; Eubanks 2002; Homnick 2004; Marchand 2000). 

Two trials (42 participants), one of MA and one of CH, reported a change in weight at three months (Epifanio 2012; Eubanks 2002). Combined data showed that the appetite stimulant may lead to a greater weight gain compared with placebo (mean difference (MD) 1.25 kg, 95% confidence interval (Cl) 0.45 to 2.05) (Analysis 1.1) (low‐certainty evidence). Only one trial of MA (17 participants) reported on change in weight at six months (Eubanks 2002); similar to the earlier time point, the intervention may lead to a greater weight gain than the placebo (MD 3.80 kg, 95% CI 1.27 to 6.33) (Analysis 1.1) (low‐certainty evidence).

1.1. Analysis.

Comparison 1: Appetite stimulants versus placebo, Outcome 1: Change in weight (kg)

Three trials (45 participants) reported that appetite stimulants may lead to a greater change in weight z score (WAZ) at three months (Eubanks 2002; Homnick 2004; Marchand 2000); combined results were statistically significant (MD 0.61, 95% CI 0.29 to 0.93) (P < 0.001) (Analysis 1.2). We assessed the certainty of the evidence as low, and heterogeneity was low (I² = 0%) (Analysis 1.2). In one cross‐over trial (12 participants), individual patient data for WAZ score were available from a graph (Marchand 2000), therefore the within‐participant variation could be calculated, and the meta‐analysis carried out using the methodology of Elbourne with the paired participant intervention and control periods used as the unit of analysis (Elbourne 2002). Only Eubanks 2002 (17 participants) reported WAZ at six months, with similar results to the three‐month data (MD 0.74, 95% CI 0.26 to 1.22) (Analysis 1.2) (low‐certainty evidence); the same 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).

1.2. Analysis.

Comparison 1: Appetite stimulants versus placebo, Outcome 2: Change in weight z score

The subgroup analysis of three‐month data for WAZ by appetite stimulant did not provide any evidence for different effects of MA and CH on weight gain (test for subgroup difference Chi² = 0.04, df = 1, P = 0.84; 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 0.62 (95% CI 0.21 to 1.03) (P = 0.003) (Analysis 1.3).

1.3. Analysis.

Comparison 1: Appetite stimulants versus placebo, Outcome 3: Change in weight z score at 3 months (subgroup analysis by appetite stimulant)

In the nine‐month paediatric trial (12 participants), Marchand 2000 reported the "average" change in weight with ranges, therefore data could not be entered into the analysis; investigators observed an "average" weight gain of 3.05 kg in the MA group (range 0.1 kg to 7.0 kg) versus 0.3 kg in the placebo group (range −0.3 kg to 0.8 kg); this was significant (P = 0.04) (Marchand 2000).

2. Change in body composition

a. Lean body mass (LBM)

None of the trials reported change in LBM in sufficient detail to permit inclusion in a meta‐analysis, and no further data were obtained from the investigators when contacted.

In the original paper, Eubanks 2002 (17 participants) reported significant increases in triceps skin‐fold measurements and mid‐arm circumference in the treatment group at three and six months (P < 0.01); further data were not available for analysis in this review. Marchand 2000 (12 participants) also reported an improvement in LBM in the group receiving MA.

b. Fat mass

Likewise, none of the trials reported change in fat mass in sufficient detail to permit inclusion in a meta‐analysis.

In the original paper, Eubanks 2002 (17 participants) reported an increase in both fat mass and fat‐free mass in the MA group, assessed by dual‐energy X‐ray absorptiometry (DEXA) (P < 0.02, at three and six months); further data were not available for analysis in this review. Marchand 2000 (12 participants) also reported an improvement in body fat in the MA group. In the 2004 trial, Homnick (16 participants) reported a significant increase in fat and fat‐free mass in the CH group over 12 weeks (Homnick 2004).

c. Body mass index (BMI)

Homnick (16 participants) also reported 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.

Epifanio 2012 (25 participants) reported an increase in BMI in the intervention group and a decrease in the control group; when analysed the data favoured appetite stimulants (MD 0.53, 95% CI 0.07 to 0.99) (Analysis 1.4).

1.4. Analysis.

Comparison 1: Appetite stimulants versus placebo, Outcome 4: Change in body composition (BMI)

3. Change in pulmonary function

Whilst a 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 to show an improvement in respiratory muscle function than any of the trials reviewed and included. The effect of MA, Eubanks 2002; Marchand 2000, and CH, Epifanio 2012; Homnick 2004, compared with placebo on change in pulmonary function was reported in children and adults.

a. Forced expiratory volume in one second (FEV₁) (L)

None of the trials reported any change in FEV₁ (L).

b. FEV₁ % predicted

Eubanks 2002 (17 participants) 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 between groups; further data were not available for analysis in this review. The variation of the change in FEV₁ % predicted was not reported, but could be read from a graph (Eubanks 2002). Epifanio 2012 (25 participants) also reported change in FEV₁ % predicted at three months.

Combined three‐month data showed little or no difference between groups in change in FEV₁ % predicted (MD 4.26, 95% CI −5.45 to 13.97; P = 0.39; 2 trials; 42 participants; low‐certainty evidence; Analysis 1.5). Data at six months from the Eubanks 2002 trial alone (17 participants) also showed little or no difference between groups in FEV₁ % predicted (MD 5.64, 95% CI −4.43 to 15.71; P = 0.27; low‐certainty evidence; Analysis 1.5).

1.5. Analysis.

Comparison 1: Appetite stimulants versus placebo, Outcome 5: Change in FEV₁ %

Homnick 2004 (16 participants) 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 2000 (12 participants) reported that FEV₁ % predicted increased by 15.3% on average in the MA group (this was not significant) and by 3.8% in the placebo group. 

Secondary outcomes

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

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

Homnick 2004 (16 participants in total, 12 participants assessed for this outcome) reported that at three months, five out of five participants in the CH treatment group answering the questionnaire demonstrated increased appetite versus two participants out of seven in the placebo group; this was assessed using part of a brief five‐question questionnaire. After assessment on interview, Marchand 2000 (12 participants in total, 11 participants assessed for this outcome) reported that all participants demonstrated an increase in appetite whilst receiving MA. When analysed, the data showed that appetite stimulants may increase appetite (odds ratio 45.25, 95% CI 3.57 to 573.33; 2 trials; 23 participants; low‐certainty evidence; Analysis 1.6).

1.6. Analysis.

Comparison 1: Appetite stimulants versus placebo, Outcome 6: Increase in appetite (subjective reporting)

2. Quality of life (QoL)

Only Homnick 2004 (16 participants) reported on the effect of CH versus placebo on change in QoL, with less fatigue reported in two participants in the treatment group only. The remaining trials (54 participants) either did not measure or did not report the effect of appetite stimulants compared with placebo on change in QoL (Epifanio 2012; Eubanks 2002; Marchand 2000).

3. Dietary intake

a. Energy intake (kcal/day)

Two trials (41 participants) reported the effect of CH versus placebo on energy intake (Epifanio 2012; Homnick 2004). Only Epifanio 2012 (25 participants) provided analysable data, but did not demonstrate a difference in energy intake between appetite stimulant or placebo (MD 372.12 kcal, 95% CI −630.80 to 1375.04; Analysis 1.7). Mean caloric intake in Homnick 2004 (16 participants) was determined by three‐day food records prior to visits at four weeks and 12 weeks; the investigators reported no differences between groups (Homnick 2004). One paediatric trial (12 participants) reported the effect of MA versus placebo on change in dietary energy and protein intake; investigators calculated the calorific intake from three‐day food records, but intake did not differ between the treatment and placebo groups (Marchand 2000).

1.7. Analysis.

Comparison 1: Appetite stimulants versus placebo, Outcome 7: Dietary intake

b. Protein intake (grams of protein/day)

None of the trials reported protein intake results.

4. Any adverse events directly related to the intervention

Objective and subjective adverse events were reported for both MA and CH. Epifanio 2012 reported that 2 out of 25 participants experienced fatigue and sleepiness, but it was unclear to which groups these participants belonged. The remaining trials (45 participants) reported adverse effects subjectively, and again without specifying which groups (treatment or placebo) the participants were in. 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; see Table 3.

2. Adverse events of appetite stimulants.

Study ID	Appetite stimulant	Adverse event reported	Change in adverse event observed for the treatment group	Change in adverse event observed for the control group	Treatment group: frequency of adverse events	Control group: frequency of adverse events
Marchand 2000	Megestrol acetate (Megace)	1. Diabetes	‐	‐	2/6	Not reported
		2. Glucosuria	‐	‐	2/6	Not reported
		3. Increased fasting insulin levels	‐	‐	6/6	0/6
		4. Hyperactivity	‐	‐	2/6	Not reported
		5. Irritability	‐	‐	1/6	Not reported
		6. Decreased morning cortisol levels	‐	‐	4/6	Not reported
		7. Increased fasting c‐peptide levels	‐	‐	6/6	No changes reported
		8. Increased insulin‐like growth factor‐1	‐	‐	6/6	6/6
		9. Glucose intolerance	‐	‐	Not reported	1/6
		10. Insomnia	‐	‐	2/6	Not reported
		11. Change in the number of pulmonary exacerbations	‐	‐	5/6	3/6
Eubanks 2002	Megestrol acetate (Megace)	1. Insomnia	‐	‐	4/10	1/7
		2. Elevated mean insulin levels	‐	‐	10/10	Data not reported
		3. Elevated liver enzymes	‐	‐	1/10	0/7
		4. Pulmonary exacerbation requiring IV ABs	‐	‐	6/10	6/7
		5. Pulmonary exacerbation requiring aerosolised ABs	‐	‐	4/10	4/7
		6. Transient hyperglycaemia	‐	‐	2/10	Data not reported
		7. Moodiness	‐	‐	3/10	0/7
		8. Depression	‐	‐	1/10	0/7
		9. Vomiting	‐	‐	0/10	1/7
		10. Nausea	‐	‐	0/10	1/7
		11. Elevated haemoglobin A1C levels	‐	‐	1/10	0/7
		12. Skin rash	‐	‐	1/10	2/7
		13. Constipation	‐	‐	1/10	0/7
		14. Decrease in morning cortisol levels	Significant but reversible decrease	‐	7/10	0/7
		15. Menstrual irregularities	‐	‐	1/10	1/7
		16. Night sweats	‐	‐	2/10	2/7
Homnick 2004	Cyproheptadine	1. Poorly controlled diabetes	‐	‐	1/8	Not reported
		2. Increased general fatigue	‐	‐
		a. At baseline	‐	‐	2/8	2/8
		b. At 4 weeks	‐	‐	3/8	1/8
		2. Reduced fatigue	‐	‐
		a. At 4 weeks	‐	‐	2/8	Not reported
		3. Days of oral antibiotic use	‐	‐	No difference reported	No difference reported
		4. Days of IV antibiotic use	‐	‐	No difference reported	No difference reported
		5. Transient increase in liver function tests	‐	‐	No difference reported	1/8

AB: antibiotic
IV: intravenous

Eubanks 2002 (17 participants) reported that MA significantly decreased morning cortisol levels compared to placebo. Furthermore, bone mineral density was reported to have remained stable in the MA‐treated participants over the entire six‐month treatment period, although data were not reported (Eubanks 2002). Homnick 2004 (16 participants) reported no significant side effects except for increased general fatigue in the CH group.

5. Change in the number of pulmonary exacerbations

Two trials (33 participants) reported on this outcome (Eubanks 2002; Homnick 2004). Eubanks 2002 (25 participants) reported that in the MA group, six participants required intravenous (IV) antibiotics and four required aerosolised antibiotics (Eubanks 2002). Homnick 2004 (16 participants) did not report any significant differences from baseline to week 12 in oral or IV antibiotic use with CH.

Discussion

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 individual's 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 people with CF 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 attempt to address the anorexia. The aim of this 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 may slightly improve weight and WAZ in children and adults with CF; increases in both weight and WAZ were seen in the appetite stimulant group compared with the placebo group at three and six months (Analysis 1.1; Analysis 1.2) (low‐certainty evidence). Whilst data showed significant increases in WAZ for both MA and CH separately, there was no 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 be prevented, and an adult BMI of less than 19 be avoided (CF Trust 2002). In children, USA recommendations state that 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). The definition of significant weight gain is thus not clearly agreed upon.

The composition 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). Improving fat‐free mass compared with fat mass may thus well be preferable in order to optimise lung function and body image. However, we found no evidence of a larger increase in FEV₁ (% predicted) in the appetite stimulant group compared with the placebo group at three or six months (Analysis 1.5) (low‐certainty evidence).

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 increased 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). Pooled data from the two trials, which reported an increase in appetite, showed a larger proportion of participants with increased appetite in the appetite stimulant group compared with the control group (Analysis 1.6). However, the certainty of the evidence was low, as only small numbers of participants were included in these trials, and risk of bias due to subjective reporting of appetite change.  

Calorific intake was not consistently reported. Only one trial reported analysable data for the change in calorific intake (Analysis 1.7) (Epifanio 2012); neither this trial nor the narrative reports from the other trials for this outcome reported a difference between appetite stimulants and placebo (Homnick 2004; Marchand 2000).

Adverse effects of stimulants

The adverse effects of both MA and CH are not fully determined; the only significant effect reported in the papers was transient mild sedation (Eubanks 2002). However unlike MA, which seems to show a propensity to induce glucose dysregulation, CH does not appear to affect glucose tolerance (Table 3).

Dosage, duration, and timing of appetite stimulants

The data suggest that weight gain may be optimised by treating individuals with 10 mg/kg/day of MA (Eubanks 2002; Marchand 2000). However, the dosage for CH varied between the other two studies, with one trial administering 4 mg four times daily of CH for three months (Homnick 2004), and the second trial initially administering 2 mg/mL three times a day for one week, followed by 4 mg/mL three times a day for the remaining 11 weeks (Epifanio 2012). The available data from RCTs do not present conclusive evidence for the dose and duration of appetite stimulants in adults and children with anorexia. Longer 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 included trials directly investigated the impact of the appetite stimulants MA or CH on relevant outcome measures in people with CF. All trials used oral appetite stimulants compared with a placebo. All relevant types of participants, interventions, and outcomes have been investigated. However, there are currently no validated measures of appetite per se available for research purposes in CF, 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, dronabinol, and mirtazapine, have been studied in CF. However, trials of these therapies were not included in the review because they did not meet our 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 to inform clinical practice, 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 individuals 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 justify the use of these agents on a longer‐term basis (over six months).

Quality of the evidence

Trial quality was frequently suboptimal, which could have biased any observed treatment effects, on average, in the direction of overestimating 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 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.

Although there were sufficient data to undertake meta‐analyses for some outcomes, all four included trials reported sufficient detail for a selection of outcomes to be included in the meta‐analyses. A major concern was incomplete reporting of data or selective outcome reporting, or both, with all trials listing outcomes in the methods section of the paper that were not reported on in the results.

We assessed the certainty of the evidence supporting the outcomes as low using the GRADE approach (Table 1). We downgraded the certainty of the evidence due to risk of bias (incomplete and selective reporting of outcome data as mentioned above, attrition bias caused by either a proportionately large dropout rate or dropouts due to the intervention and not corrected for in the analyses and the randomisation procedures). In addition, numbers of participants were small and event rates were low, increasing concerns about imprecision.

Potential biases in the review process

The number of trials included in the review precluded an analysis of publication bias, therefore we are unable 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 the 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‐participant correlations. It is strongly recommended that outcome differences and SDs of differences be reported in future trials.

Trial quality was frequently suboptimal, which could have biased any observed treatment effects on average in the direction of overestimating the true effect.

The 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

This 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 and colleagues, whose review served to illuminate the potential role of appetite stimulants in the management of anorexia associated with CF (Chinuck 2007). That review concluded that larger RCTs were needed to confirm the safety and validate the efficacy of the use of appetite stimulants in CF, and also highlighted the impossibility of drawing firm long‐term conclusions for the other agents or stimulants given the low numbers of participants 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 included these outcomes in our reporting of adverse effects if the included trials had measured and documented these accordingly.

Authors' conclusions

Implications for practice.

The data included in this review suggest that megestrol acetate (MA) and cyproheptadine hydrochloride (CH) may be useful for short‐term (i.e. six months) treatment of anorexia in adults and children with cystic fibrosis (CF). However, we cannot conclude whether any one stimulant is more effective than another. Based on the included randomised controlled trials (RCTs) and the meta‐analyses, we are 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 GBP 19.52 for 30 tablets (BNF 2021), but the most cost‐competitive agent is CH: 4 mg tablets prescribed once per day at a cost of GBP 5.99 for 30 tablets (BNF 2021). Although all trials of appetite stimulants reported some 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 suggest a potential positive effect of appetite stimulants on both weight gain and appetite. In order to judge which appetite stimulant to use with individuals and to make an informed decision, clinicians require information on: significant gains in appetite and weight; type; age of use; starting and maximum dosages; and the effect of ceasing stimulants. 

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 against the risks of potential adverse events and 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, as well as 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. Trials should use a validated measure of symptoms, and should include a disease‐specific instrument for measuring poor appetite. There are currently no validated scoring systems for grading appetite, and the best objective measure of evaluating appetite has yet to be defined.

Given that based on RCTs, there is insufficient evidence for 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 the potential of these agents to increase appetite safely in CF, and to establish the optimal mode of treatment.

Research is further complicated by the fact that the aetiology of poor appetite may be multifactorial and is 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 as follows.

• 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 individual is awaiting transplantation?

• Should some steroid‐based appetite stimulants be contraindicated 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 participants, resulting in overall poor‐quality data. The conduct of future RCTs needs to be improved with unbiased and clear reporting of clinically significant outcomes in accordance with the CONSORT statement (Ioannidis 2004; Moher 2001; Moher 2003; Moher 2004).

We recommend that future RCTs:

• 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), quality of life (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 predefined surrogate markers for appetite change;

• report on a predefined 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 standard deviations); and

• report outcome differences and standard deviations of differences to allow for meaningful meta‐analyses.

What's new

Date	Event	Description
30 May 2022	New citation required but conclusions have not changed	A new review team has updated this review and included a single new study assessing cyproheptadine as an appetite stimulant in children and adolescents with cystic fibrosis (Epifanio 2012). This evidence has been assessed as of low certainty, and our findings agree with the previously reported evidence, therefore our conclusions remain the same.
30 May 2022	New search has been performed	A search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register identified 54 new references potentially eligible for inclusion in this updated review; three of these were duplicates, leaving 51 to be evaluated. A search of ClinicalTrials.gov identified a further two studies. One new reference was added to a study previously listed as awaiting classification, and was included in this update (Epifanio 2012). We excluded 42 references to 24 new studies (ACTRN12619000572167; Bathgate 2019; Branch‐Smith 2018; de Lind van Wijngaarden‐van den Berg 2014; DRKS00010979; Geirhos 2022; Grancini 2019; Hilliard 2015; Hjelm 2020; Lunkenheimer 2020; McLean 2014; NCT00005112; NCT00016445; NCT00803179; NCT01149005; NCT03139266; NCT03800459; O'Hayer 2017; O'Hayer 2019; Schnabel 2007; Seggelke 2011; Tongudai 1971; Vanderwel 2006; Verge 2015). Eight new references were added to five already excluded studies (Ballmann 2013; Hardin 2006; Hutler 2002; Moran 2009; Stalvey 2011). One excluded study was previously listed as two separate studies, which have now been combined (Ballmann 2013). One study previously listed as awaiting classification has been excluded (Kissner 2000). A previously excluded study has been listed as an ongoing study following contact with the lead investigator, who reported that results had been gathered with a view to publish in the future (NCT00763477).

History

Protocol first published: Issue 1, 2010
Review first published: Issue 7, 2014

Appendices

Appendix 1. Glossary

Term	Definition
Adipose tissue	Fat
Aetiology	Cause
Anorexia	Loss of appetite
Chronic sepsis	Presence in the blood or other tissues of disease‐causing micro‐organisms
Cytokines	Proteins that generate an immune response
Energy expenditure	Energy used up
Gastro‐oesophageal reflux	Return flow of the stomach contents into the oesophagus
Inflammatory	Immune response characterised by inflammation
Intestinal malabsorption	Reduced absorption of nutrients by the small intestine
Meta‐analysis	A statistical approach to combine the results of multiple studies
Morbidity	Diseased condition or state
Mortality	Death
Pulmonary exacerbations	Lung infections
Quasi‐randomised controlled trial	A trial that uses systematic methods, such as alternation, assignment based on date of birth, case record number, or date of presentation, to assign participants to treatment or control groups. An important weakness of such methods is that concealing the allocation schedule is usually impossible, which allows foreknowledge of intervention assignment amongst those recruiting participants to the study as well as biased allocations.
Risk of bias	Chance of systematic error or prejudice towards something
Serum	Clear portion of any body fluid
Sinusitis	Inflammation of a sinus or cavity
Tumour necrosis factor (TNF)	Proteins produced by the white blood cells that 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

Appendix 2. Electronic search strategies

Database	Search strategy	Date last searched
MEDLINE (via HDAS)  (1950 onwards)	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	01 April 2014
EMBASE (via HDAS) (1980 onwards)	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) 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	01 April 2014
CINAHL (via HDAS) (1981 onwards)	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	01 May 2012
ClinicalTrials.gov (clinicaltrials.gov)	[Advanced Search]   CONDITION/ DISEASE: cystic fibrosis OTHER TERMS: appetite stimulants OR cyproheptadine OR appetite OR prednisolone OR progestational agents OR progestins OR anabolic agents OR megesterol OR megesterol acetate OR megace OR mirtazapine OR antidepressive agents OR antidepressants OR cannaboids OR cannabinoid derivative OR tetrahydrocannabinol OR antihistamines OR histamine antagonists OR corticosteroids OR prednisone OR steroids OR hormone therapy OR growth hormone OR hormones OR dronabinol OR pizotyline OR pizotifen OR risperidone OR olanzapine OR anorexia OR weight STUDY TYPE: Interventional Studies	10 May 2022
WHO ICTRP (apps.who.int/trialsearch/)	[Advanced Search]   Title: Cystic fibrosis OR Cystic Fibrosis OR CF OR Mucovicidosis AND  Intervention: Appetite stimulants OR Cyproheptadine OR Prednisolone OR Progestational agents OR Progestins OR Anabolic agents OR Megesterol OR Megesterol acetate OR Megace OR Mirtazapine OR Antidepressive agents OR Antidepressants OR Cannaboids OR Tetrahydrocannabinol OR Antihistamines OR Histamine antagonists OR Corticosteroids OR Prednisone OR Steroids OR Hormone therapy OR Growth Hormone OR Hormones OR Dronabinol OR Pizotyline OR pizotifen OR risperidone OR Risperidone OR olanzapine OR anorexia OR weight	10 May 2022

 

Data and analyses

Comparison 1. Appetite stimulants versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Change in weight (kg)	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1.1 At 3 months	2	42	Mean Difference (IV, Fixed, 95% CI)	1.25 [0.45, 2.05]
1.1.2 At 6 months	1	17	Mean Difference (IV, Fixed, 95% CI)	3.80 [1.27, 6.33]
1.2 Change in weight z score	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.2.1 At 3 months	3	40	Mean Difference (IV, Fixed, 95% CI)	0.61 [0.29, 0.93]
1.2.2 At 6 months	1	17	Mean Difference (IV, Fixed, 95% CI)	0.74 [0.26, 1.22]
1.3 Change in weight z score at 3 months (subgroup analysis by appetite stimulant)	4		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.3.1 Megestrol acetate	2	28	Mean Difference (IV, Fixed, 95% CI)	0.68 [0.24, 1.13]
1.3.2 Cyproheptadine	2	37	Mean Difference (IV, Fixed, 95% CI)	0.62 [0.21, 1.03]
1.4 Change in body composition (BMI)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.5 Change in FEV1 %	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.5.1 At 3 months	2	42	Mean Difference (IV, Fixed, 95% CI)	4.26 [‐5.45, 13.97]
1.5.2 At 6 months	1	17	Mean Difference (IV, Fixed, 95% CI)	5.64 [‐4.43, 15.71]
1.6 Increase in appetite (subjective reporting)	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.6.1 At 3 months	2	23	Odds Ratio (M‐H, Fixed, 95% CI)	45.25 [3.57, 573.33]
1.7 Dietary intake	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.7.1 At 3 months	1	25	Mean Difference (IV, Fixed, 95% CI)	372.12 [‐630.80, 1375.04]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Epifanio 2012.

Study characteristics
Methods	Double‐blind, parallel, placebo‐controlled RCT Duration: 12 weeks Location: 2 centres in Brazil
Participants	25 participants with CF, aged 5 to 18 years. Weight‐age ratio under 85% Age, mean (SD): CH 11 (3) years, placebo 9 (3) years Gender split (males): CH 7 (64%), placebo 7 (50%)
Interventions	Treatment: CH 2 mg/mL 3x daily for 1 week, then 4 mg/mL 3x daily for the remaining 11 weeks Control: placebo 3x daily for 12 weeks Each participant received a kit containing 2 vials and metred syringes. The first vial contained 60 mL of either CH or placebo to be used during Week 1, and the second vial contained 240 mL of the same treatment for the rest of the intervention period. Appearance, smell, and taste of the syrups were identical in both groups. Concentration varied in the 2 bottles delivered to participants in the CH group; the first vial contained 2 mg in 1 mL of the syrup to evaluate possible undesirable side effects, such as sedation and somnolence, that might be present up to 3 or 4 days after starting the treatment. The second vial contained placebo or 4 mg in 1 mL of CH. Both groups were thus instructed to always take 1 mL of syrup for the 12 weeks of treatment.
Outcomes	Weight, height, BMI, and spirometry
Notes	Short‐term use. Adverse events (fatigue and sleepiness) identified in 2 of the 25 participants (unclear whether from control or treatment group). 2 participants in the CH group did not complete the study (1 because of intolerance to the study drug and 1 because of non‐adherence). 2 participants in the placebo group did not complete the study (1 because of allergy to the study drug and 1 because of non‐adherence).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised into 2 groups, divided into blocks of 10 using PEPI statistical and StatCalc suite.
Allocation concealment (selection bias)	Low risk	Bottles containing CH or placebo were kept in opaque envelopes. The envelopes were handed to the investigator according to each participant's scheduled visit.
Blinding (performance bias and detection bias) Participants	Low risk	Participants were blinded.
Blinding (performance bias and detection bias) Clinicians	Low risk	Person responsible for participant care was blinded.
Blinding (performance bias and detection bias) Outcome assessors	Unclear risk	Not reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	4 participants did not complete the study, 2 from each group and for similar reasons.  CH group: 1 participant withdrew because of intolerance to the study drug and 1 because of non‐adherence. Placebo: 1 participant withdrew because of allergy to the placebo and 1 because of non‐adherence.
Selective reporting (reporting bias)	Unclear risk	Unable to access the trial protocol; no apparent differences between methods and results sections based on translated data extraction form
Other bias	Low risk	None identified.

Eubanks 2002.

Study characteristics
Methods	Double‐blinded, placebo‐controlled RCT Parallel design Duration: 6 months Country: USA
Participants	17 participants Age: > 6 years Gender split: 8 females, 9 males Treatment: n = 10; placebo: n = 7 Inclusion criteria: pancreatic insufficiency, FEV1 > 40%, growth failure defined as no weight gain in the preceding 6 months
Interventions	Treatment: MA 10 mg/kg/day (adjusted at subsequent visits) Control: placebo
Outcomes	Weight, weight for age, triceps skinfold measurements, mid‐arm circumference, FEV1, FVC, morning cortisol levels, insulin levels, bone mineral density Measured at Days 0 to 90, and Days 0 to 180
Notes	Main component of weight gain was in body fat stores. After completion of the 6‐month trial, the placebo group was offered MA for a further 6 months.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Participants allocated by computer‐generated randomisation schedule."
Allocation concealment (selection bias)	Unclear risk	Method of concealment not described.
Blinding (performance bias and detection bias) Participants	Low risk	Double‐blind
Blinding (performance bias and detection bias) Clinicians	Low risk	Double‐blind
Blinding (performance bias and detection bias) Outcome assessors	Low risk	Participants, treating physician, and ancillary staff were blinded.
Incomplete outcome data (attrition bias) All outcomes	High risk	3 participants in the placebo group withdrew when they failed to observe a treatment effect, which is a potential source of bias.
Selective reporting (reporting bias)	High risk	Dietary intake stated as an outcome in the methods but not reported on in the results. Unexpected measures used to report outcomes (i.e. weight for age z score only, instead of being additional to weight as a mean (SD)). Furthermore, the study authors reported lean body and fat mass for the MA group but not for the placebo group.
Other bias	Low risk	No evident risk of other bias

Homnick 2004.

Study characteristics
Methods	Double‐blinded, placebo‐controlled RCT Parallel design Duration: 12 weeks Country: USA
Participants	18 participants enrolled, 16 completed study Age: adults and children Gender split: 6 males, 10 females Treatment: n = 8; placebo: n = 8
Interventions	Treatment: CH 4 mg 4x daily Control: placebo
Outcomes	Weight, height, BMI percentiles, ideal body weight/height, weight for age z scores, fat, fat‐free mass, appetite, spirometry
Notes	No significant side effects except transient mild sedation in CH group
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	SAS small block randomisation.
Allocation concealment (selection bias)	Unclear risk	Not discussed.
Blinding (performance bias and detection bias) Participants	Low risk	Only the pharmacist investigator and study co‐ordinator remained unblinded; participants were blinded.
Blinding (performance bias and detection bias) Clinicians	Low risk	Only the pharmacist investigator and study co‐ordinator remained unblinded; clinicians were blinded.
Blinding (performance bias and detection bias) Outcome assessors	Low risk	Only the pharmacist investigator and study co‐ordinator remained unblinded; outcome assessors were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No outcome‐related dropouts.
Selective reporting (reporting bias)	High risk	Outcomes stated in the methods section (dietary intake, pulmonary function) were not reported. Furthermore, outcomes not stated in the methods section (dietary energy intake and spirometry) were subsequently reported in the results section.
Other bias	Low risk	Significant differences reported 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 = 0.039); however, allowing for an adjustment of the P value for testing multiple outcomes, the difference is not significant and is not evidence for risk of bias.

Marchand 2000.

Study characteristics
Methods	Double‐blinded, placebo‐controlled RCT Cross‐over design Duration: 12 weeks treatment followed by 12‐week washout period, and then 12 weeks alternate treatment Country: USA
Participants	12 participants Age: mean age 7.4 years Gender split: 3 males, 9 females
Interventions	Treatment: MA 10 mg/kg/day Control: placebo Clinical assessment at week 0, 6, 12, 24, and 36
Outcomes	Weight, appetite, calorific intake, FEV1 % predicted and FVC % predicted, adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "... patients were randomized"; no detailed information provided
Allocation concealment (selection bias)	Unclear risk	Not discussed
Blinding (performance bias and detection bias) Participants	Low risk	Double‐blind
Blinding (performance bias and detection bias) Clinicians	Low risk	Double‐blind
Blinding (performance bias and detection bias) Outcome assessors	Low risk	No specific information provided, but weight measurement unlikely to be affected by lack of blinding of outcome assessor.
Incomplete outcome data (attrition bias) All outcomes	High risk	6 of 12 participants dropped out. No reasons given for 3 participants; 2 participants developed diabetes following MA; and 1 participant left trial due to glucose intolerance on placebo. Not clear if these dropouts were on first or second period of cross‐over trial. No data used from dropouts.
Selective reporting (reporting bias)	High risk	Outcomes stated in the methods section (dietary intake, pulmonary function) were not reported. Furthermore, QoL was not stated in the methods section but was reported on in the results.
Other bias	Low risk	No evident risk of other bias

BMI: body mass index
CF: cystic fibrosis
CH: cyproheptadine hydrochloride
FEV₁: forced expiratory volume at one second
FVC: forced vital capacity
MA: megestrol acetate
QoL: quality of life
RCT: randomised controlled trial
SD: standard deviation

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
ACTRN12619000572167	Not an appetite stimulant; study evaluated mental health/quality of life
Alemzadeh 1998	Not a randomised controlled trial
Amorim 2011	Not an appetite stimulant, not randomised controlled trial
Anstead 2003	Not a randomised controlled trial
Auerbach 1985	Intervention not relevant (i.e. prednisone was not given to stimulate appetite)
Ballmann 2013	Intervention not relevant (i.e. insulin was not given to stimulate appetite)
Bathgate 2019	Not an appetite stimulant
Battersby 2017	Not a randomised controlled trial
Berenstein 2005	Not a randomised controlled trial; review article
Branch‐Smith 2018	Not an appetite stimulant
Bucuvalas 2001	Intervention not relevant (i.e. growth hormone therapy was not given to stimulate appetite)
Canfield 1998	Not a randomised controlled trial
CF Trust 2002	Consensus document, not a randomised controlled trial
Chinuck 2007	Systematic review of appetite stimulants
Chung 2006	Not a randomised controlled trial
Claes 2020	Not a randomised controlled trial
Cohen 2008	Not a randomised controlled trial
Cohen 2010	Not a randomised controlled trial
Cohen‐Cymberknoh 2008	Intervention not relevant (i.e. prednisone was not given to stimulate appetite)
Crawley 2003	Not a randomised controlled trial
Darmaun 2004	Comparison of 2 active treatments; not a comparison of active treatment to placebo or no treatment
de Lind van Wijngaarden‐van den Berg 2014	Intervention not relevant. Insulin therapy and metformin not used as appetite stimulant.
Dhillo 2007	Not a randomised controlled trial
Dovey 2007	Intervention not relevant (i.e. prednisone was not given to stimulate appetite)
Dowsett 1999	Not a randomised controlled trial
DRKS00010979	Not an appetite stimulant; study evaluated mental health/quality of life
Durant 1998	Not a randomised controlled trial
Eubanks 2000	Not a randomised controlled trial
Geirhos 2022	Not an appetite stimulant; study evaluated mental health/quality of life
Goetz 2016	Intervention not relevant (i.e. did not use an intervention to stimulate appetite)
Grancini 2019	Not an appetite stimulant
Greally 1992	Intervention not relevant (i.e. prednisone was not given to stimulate appetite)
Green 2015	Not a randomised controlled trial
Grover 2008	Intervention not relevant (i.e. insulin was not given to stimulate appetite)
Grunert 2020	Not a randomised controlled trial
Guillot 2011a	Not randomised controlled trial
Guillot 2011b	Not a randomised controlled trial
Hardin 1997	Not a randomised controlled trial
Hardin 2001	Intervention not relevant (i.e. growth hormone therapy was not given to stimulate appetite)
Hardin 2004	Not a randomised controlled trial
Hardin 2005a	Intervention not relevant (i.e. growth hormone therapy was not given to stimulate appetite)
Hardin 2005b	Intervention not relevant (i.e. growth hormone therapy was not given to stimulate appetite)
Hardin 2005c	Not a randomised controlled trial; retrospective evaluation of medical records
Hardin 2006	Intervention not relevant (i.e. growth hormone therapy was not given to stimulate appetite)
Hardin 2007	Not a randomised controlled trial
Hider 2020	Not an appetite stimulant, not a randomised controlled trial
Hilliard 2015	Intervention not relevant (i.e. assessing medication adherence and depressive symptoms)
Hjelm 2020	Not an appetite stimulant; study evaluated insomnia
Huseman 1996	Not an appetite stimulant
Hutler 2002	Intervention not relevant (i.e. growth hormone therapy was not given to stimulate appetite)
King 2018	Not an appetite stimulant
Kissner 2000	Not a randomised controlled trial
Le 2019	Not a randomised controlled trial
Leung 2019	Not an appetite stimulant, not a randomised controlled trial
Linnane 2001	Intervention not relevant (i.e. prednisone was not given to stimulate appetite)
Lopez 2004	Not a randomised controlled trial; review article
Loprinzi 1993	Participants not relevant (i.e. people with advanced cancer)
Lunkenheimer 2020	Not an appetite stimulant
McLean 2014	Intervention not relevant (i.e. did not use appetite stimulant)
McLearn‐Montz 2018	Not an appetite stimulant, not a randomised controlled trial
Minicucci 2012	Intervention not relevant; insulin would not be prescribed primarily to improve appetite; its primary effect is not appetite stimulation
Moran 2001	Intervention not relevant (i.e. insulin was not given to stimulate appetite)
Moran 2009	Intervention not relevant; insulin would not be prescribed primarily to improve appetite; its primary effect is not appetite stimulation
Nasr 1999	Not a randomised controlled trial (case study)
Nasr 2008	Not a randomised controlled trial
Nasrallah 2003	Not a randomised controlled trial
NCT00005112	Not an appetite stimulant
NCT00016445	Not an appetite stimulant; study evaluated growth hormone treatment
NCT00803179	Terminated early due to poor enrolment and participants being lost to follow‐up, no data available
NCT01149005	Not an appetite stimulant; study evaluated insulin treatment
NCT03139266	Not an appetite stimulant; study evaluated mental health/quality of life
NCT03800459	Not an appetite stimulant; study evaluated mental health/quality of life
Newkirk 2000	Not a randomised controlled trial
Nyamugunduru 1998	Intervention not relevant (i.e. prednisone was not given to stimulate appetite)
O'Hayer 2017	Not an appetite stimulant
O'Hayer 2019	Not an appetite stimulant
Ohnhaus 1974	Not a randomised controlled trial
Pantin 1986	Intervention not relevant (i.e. prednisone was not given to stimulate appetite)
Parsons 2009	Not a randomised controlled trial
Paterson 2010	Not a randomised controlled trial
Phung 2010	Not a randomised controlled trial
Price 2016	Not a randomised controlled trial
Rogan 2010	Participants not relevant (i.e. pigs)
Rosenstein 1991	Intervention not relevant (i.e. prednisone was not given to stimulate appetite)
Ross 2005	Not a randomised controlled trial
Sackey 1995	Not a randomised controlled trial
Safai 1991	Intervention not relevant; zinc supplementation would not be prescribed primarily to improve appetite; its primary effect is not appetite stimulation
Sawicki 2014	Not an appetite stimulant
Schibler 2003	Intervention not relevant (i.e. growth hormone therapy was not given to stimulate appetite)
Schnabel 2007	Intervention not relevant (i.e. growth hormone therapy was not given to stimulate appetite)
Seggelke 2011	Not an appetite stimulant; study evaluated insulin treatment
Stalvey 2008	Not a randomised controlled trial
Stalvey 2011	Intervention not relevant (i.e. growth hormone therapy was not given to stimulate appetite)
Stylianou 2007	Not a randomised controlled trial
Sullivan 2017	Not a randomised controlled trial
Switzer 2009	Not a randomised controlled trial
Sykes 2006	Not a randomised controlled trial
Taylor 1997	Not a randomised controlled trial
Teeter 2004	Intervention not relevant (i.e. insulin was not given to stimulate appetite)
Thaker 2013	Not an appetite stimulant
Tongudai 1971	Not a randomised controlled trial or a quasi‐randomised trial
Vanderwel 2006	Not an appetite stimulant
Van Meerbeeck 2021	Not a randomised controlled trial
Varness 2009	Not a randomised controlled trial
Verge 2015	Not an appetite stimulant; study evaluated insulin treatment
Visca 2013	Not an appetite stimulant
von Haehling 2009	Not a randomised controlled trial
Weisberg 2002	Participants not relevant
Young 2000	Not a randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

NCT00763477.

Study name	The effect of ghrelin on appetite and immune function in patients with cystic fibrosis
Methods	Cross‐over randomised controlled trial, triple‐blind (participant, care provider, investigator) Duration: 4 weeks
Participants	Target of 20 participants with cystic fibrosis, 18 to 80 years, BMI ≤ 19 kg/m²
Interventions	Ghrelin subcutaneous injection, placebo (saline injections)
Outcomes	Primary outcome: appetite Secondary outcome: weight
Starting date	April 2010, estimated completion date April 2011
Contact information	andres.floto@papworth.nhs.uk
Notes	The study has 3 sections: a cross‐sectional study of the levels of blood metabolic signals in participants with cystic fibrosis and healthy controls; a laboratory study of the effect of ghrelin on immune cells extracted from the blood of participants with cystic fibrosis and healthy controls; a cross‐over interventional study of repeated ghrelin administration in malnourished cystic fibrosis patients. We contacted Dr Floto in June 2021, who reported that they have not yet published results, but that they hope to do so in the future.

BMI: body mass index

Differences between protocol and review

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

3. We 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 12 months.

4. Although GRADE tables were not planned as per protocol, they were generated for this update by a statistician.

Contributions of authors

Protocol and original review (2014)

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.

Updates

Diane McTavish and Judith Thornton, with support from Diogenes S Ferreira for one trial, assessed all new trials for inclusion and updated the final version of the review.  

Sources of support

Internal sources

• No sources of support provided

External sources

• National Institute for Health Research, UK

  This systematic review was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group.

Declarations of interest

Original review

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.

Updates

Diane McTavish declares no potential conflict of interest.

Judith Thornton declares no potential conflict of interest.

New search for studies and content updated (no change to conclusions)