Appetite stimulants for people with cystic fibrosis

  • Review
  • Intervention

Authors


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 and nutritional status. However, these may have adverse effects on clinical status.

Objectives

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

Search methods

Trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, MEDLINE, Embase, CINAHL, handsearching reference lists and contacting local and international experts.

Last search of online databases: 01 April 2014.

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

Selection criteria

Randomised and quasi-randomised controlled trials of appetite stimulants, compared to placebo or no treatment for at least one month in adults and children with cystic fibrosis.

Data collection and analysis

Authors independently extracted data and assessed the risk of bias within eligible trials. Meta-analyses were performed.

Main results

Three trials (total of 47 recruited patients) comparing appetite stimulants (cyproheptadine hydrochloride and megesterol acetate) to placebo were included; the numbers of adults or children within each trial were not always reported. The risk of bias of the included trials was graded as moderate.

A meta-analysis of all three trials showed appetite stimulants produced a larger increase in weight z score at three months compared to placebo, mean difference 0.61 (95% confidence interval 0.29 to 0.93) (P < 0.001) (n = 40) with no evidence of a difference in effect between two different appetite stimulants. One of these trials also reported a significant weight increase with megesterol acetate compared to placebo at six months (n = 17). The three trials reported no significant differences in forced expiratory volume at one second (per cent predicted) between the appetite stimulant groups and placebo at follow up, with durations ranging from two to nine months. A meta-analysis of two trials showed a significantly higher proportion of patients reporting increased appetite, odds ratio 45.25 (95% confidence interval 3.57 to 573.33) (P = 0.003) (n = 23), but the frequency of reported side effects was undetermined.

Authors' conclusions

In the short term (six months) in adults and children, appetite stimulants improved only two of the outcomes in this review - weight (or weight z score) and appetite; and side effects were insufficiently reported to determine the full extent 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 moderate quality data from a small number of trials and so this therapy cannot be conclusively recommended based upon the findings in the review. Clinicians need to be aware of the potential adverse effects of appetite stimulants and actively monitor any patients prescribed these medications accordingly.

Research is needed to determine meaningful surrogate measures for appetite and 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.

Résumé scientifique

Stimulants de l'appétit pour les personnes atteintes de mucoviscidose

Contexte

La perte d'appétit chronique chez les personnes atteintes de mucoviscidose est une source de préoccupation pour les individus ainsi que leurs familles. Des stimulants de l'appétit ont été utilisés pour aider les patients atteints de mucoviscidose souffrant d'anorexie chronique à atteindre un indice de masse corporelle et un état nutritionnel optimaux. Ceux-ci peuvent toutefois avoir des effets néfastes sur l'état clinique.

Objectifs

L'objectif de cette revue est de rechercher et évaluer systématiquement les preuves sur les effets bénéfiques des stimulants de l'appétit dans la gestion de l'anorexie associée à la mucoviscidose et d'effectuer une synthèse des effets secondaires rapportés.

Stratégie de recherche documentaire

Des essais ont été identifiés à travers des recherches dans le registre des essais sur la mucoviscidose du groupe Cochrane sur la mucoviscidose et les autres maladies génétiques, MEDLINE, Embase et CINAHL, ainsi qu'une recherche manuelle de listes bibliographiques et des contacts avec des experts locaux et internationaux.

Dernière recherche dans les bases de données en ligne : 1er avril 2014.

Dernières recherches effectuées dans le registre des essais cliniques sur la mucoviscidose : 8 avril 2014.

Critères de sélection

Essais contrôlés randomisés et quasi randomisés de stimulants de l'appétit, comparés à un placebo ou à l'absence de traitement pendant au moins un mois chez des adultes et des enfants atteints de mucoviscidose.

Recueil et analyse des données

Les auteurs de la revue ont indépendamment extrait les données et évalué le risque de biais dans les essais éligibles. Des méta-analyses ont été effectuées.

Résultats principaux

Trois essais (total de 47 patients recrutés) comparant des stimulants de l'appétit (chlorhydrate de cyproheptadine et acétate mégestrol) à un placebo ont été inclus ; le nombre d'adultes ou d'enfants au sein de chaque essai n'était pas toujours signalé. Le risque de biais des essais inclus a été estimé comme étant modéré.

Une méta-analyse de ces trois essais a montré que les stimulants de l'appétit produisaient une plus grande augmentation du score z de poids à trois mois par rapport au placebo, différence moyenne de 0,61 (intervalle de confiance à 95 % de 0,29 à 0,93) (P < 0,001) (n = 40), sans preuve d'une différence d'effet entre deux stimulants de l'appétit différents. Un de ces essais a également signalé une augmentation significative du poids avec l'acétate mégestrol par rapport au placebo à six mois (n = 17). Les trois essais n'ont rapporté aucune différence significative dans le volume expiratoire forcé à une seconde (en pourcentage de la valeur prédite) entre les groupes sous stimulants de l'appétit et placebo lors du suivi, dont la durée allait de deux à neuf mois. Une méta-analyse de deux essais a mis en évidence une proportion significativement plus élevée de patients signalant une augmentation de l'appétit, rapport des cotes 45,25 (intervalle de confiance à 95 % de 3,57 à 573,33) (P = 0,003) (n = 23), mais la fréquence des effets indésirables rapportés était indéterminée.

Conclusions des auteurs

À court terme (six mois), chez l'adulte et l'enfant, les stimulants de l'appétit ont amélioré seulement deux des critères de jugement de cette revue - le poids (ou le score z du poids) et l'appétit ; et les effets secondaires ont été insuffisamment consignés pour déterminer l'ampleur totale de leur impact. Bien que les données puissent suggérer une utilisation potentielle pour des stimulants de l'appétit dans le traitement de l'anorexie chez l'adulte et l'enfant atteint de mucoviscidose, ce résultat est fondé sur des données de qualité modérée issues d'un petit nombre d'essais ; ainsi, les résultats de cette revue ne permettent pas de recommander de façon conclusive ce traitement. Les cliniciens doivent être conscients des effets indésirables potentiels des stimulants de l'appétit et, par conséquent, surveiller activement les patients recevant ces médicaments.

Des recherches sont nécessaires pour déterminer des mesures de substitution significatives pour l'appétit et définir ce qui constitue un gain de poids de qualité. Les futurs essais de stimulants de l'appétit doivent utiliser une mesure validée de symptômes, y compris un instrument spécifique de la maladie pour mesurer le manque d'appétit. Cette revue met en évidence le besoin d'essais multicentriques bien conçus et d'une puissance statistique suffisante pour évaluer des agents permettant d'augmenter en toute sécurité l'appétit chez les personnes atteintes de mucoviscidose et déterminer le mode de traitement optimal.

Notes de traduction

Traduction réalisée par le Centre Cochrane Français

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 the patients themselves 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 overall health. However, there are concerns that appetite stimulants have the potential to cause side effects.

Search date

We last looked for evidence on 8th April 2014.

Study characteristics

We included three trials, with a total of 47 patients, one of these was in young children and there were both children and adults in other two. These trials looked at the effects of drugs (megesterol 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, in the short term (up to six months), these drugs may improve weight and appetite. There was no effect seen on lung function. All stimulants may have adverse effects which can worsen cystic fibrosis, such as the effects on blood sugar control, fatigue, mood, fluid retention, the liver and shortness of breath, but unfortunately accurate evidence for how often these symptoms occurred was not always reported in the same way. The trials we found were too small to show if megesterol acetate and cyproheptadine hydrochloride can improve weigh and appetite safely.

While there is evidence to suggest that appetite stimulants can 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.

Quality of the evidence

We are happy that in two of the three trials, volunteers had equal chances of receiving appetite stimulants or placebo, but we are not sure if this is true for the third trial. It was not clear to us whether volunteers or their clinicians would be able to work out which group they were going to be put into. We believe that none of the volunteers or their clinicians could tell if they were receiving appetite stimulants or a placebo. Volunteers withdrew from two studies and we have some concerns about the reasons for this. We also have some concerns that some of the outcomes that the trial was going to measure were not reported in the published results.

Résumé simplifié

Stimulants de l'appétit pour les personnes atteintes de mucoviscidose

Question de la revue

Nous avons cherché des preuves sur les effets bénéfiques et néfastes de l'utilisation de stimulants de l'appétit chez les personnes souffrant d'anorexie associée à la mucoviscidose.

Contexte

La perte d'appétit chez les personnes atteintes de mucoviscidose est une source de préoccupation pour les patients ainsi que leurs familles. Des stimulants de l'appétit ont été utilisés pour aider les personnes atteintes de mucoviscidose, souffrant d'un manque d'appétit, à augmenter les quantités qu'elles consomment afin de prendre du poids et améliorer leur santé globale. Cependant, des inquiétudes existent sur les potentiels effets secondaires des stimulants de l'appétit.

Date de recherche

Nous avons effectué la dernière recherche de preuves le 8 avril 2014.

Caractéristiques des études

Nous avons inclus trois essais, avec un total de 47 patients, dont un essai portant sur de jeunes enfants et deux autres portant sur des enfants et des adultes. Ces essais examinaient les effets de médicaments (acétate mégestrol et chlorhydrate de cyproheptadine) par rapport à un placebo (un comprimé qui ne contient pas de médicament) pour stimuler l'appétit. La durée de ces essais allait de trois à six mois.

Principaux résultats

Nous avons constaté que, à court terme (jusqu'à six mois), ces médicaments peuvent améliorer le poids et l'appétit. Aucun effet n'était observé sur la fonction pulmonaire. Tous les stimulants peuvent avoir des effets indésirables pouvant aggraver la mucoviscidose, tels que des effets sur le contrôle de la glycémie, la fatigue, l'humeur, la rétention d'eau, le foie et l'essoufflement, mais les données précises sur la fréquence d'occurrence de ces symptômes n'étaient malheureusement pas toujours consignées de la même manière. Les essais que nous avons trouvés étaient trop petits pour montrer si l'acétate mégestrol et le chlorhydrate de cyproheptadine peuvent améliorer le poids et l'appétit en toute sécurité.

Bien qu'il existe des preuves suggérant que les stimulants de l'appétit puissent améliorer le poids et le manque d'appétit chez les adultes et les enfants atteints de mucoviscidose, nous pensons que plus de recherches sont nécessaires pour identifier d'abord des moyens appropriés de mesurer l'appétit et recueillir ensuite des données fiables de suffisamment de patients permettant de savoir si les stimulants de l'appétit peuvent effectivement améliorer l'appétit en toute sécurité dans la mucoviscidose.

Qualité des preuves

Nous sommes contents que, dans deux des trois essais, les volontaires aient eu des chances égales de recevoir des stimulants de l'appétit ou un placebo, mais nous ne savons pas si cela était vrai pour le troisième essai. Il n'était pas clair pour nous si les volontaires ou leurs médecins pouvaient arriver à savoir dans quel groupe ils allaient être assignés. Nous pensons qu'aucun des volontaires ou de leurs médecins ne pouvait dire s'ils recevaient des stimulants de l'appétit ou un placebo. Des volontaires sont sortis de deux études et nous avons quelques préoccupations concernant les raisons de leur retrait. Nous craignons également que certains des résultats que l'essai devait mesurer n'aient pas été consignés dans les résultats publiés.

Notes de traduction

Traduction réalisée par le Centre Cochrane Français

Summary of findings(Explanation)

Summary of findings for the main comparison. Appetite stimulants versus placebo for people with cystic fibrosis
  1. FEV1: forced expiratory volume at one second

    1 Dropout due to outcome (no effect)
    2 Attrition bias

Appetite stimulants versus placebo for people with cystic fibrosis
Patient or population: people with cystic fibrosis
Settings:
Intervention: Appetite stimulants versus placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Appetite stimulants versus placebo
Change in weight (kg) - at 3 months
Follow up: mean 3 months
 The mean change in weight (kg) - at 3 months in the intervention groups was
3.0 higher
(0.92 to 5.08 higher)
 17
(1 study)
⊕⊕⊕⊝
moderate 1
 
Change in weight (kg) - at 6 months
Follow up: mean 6 months
 The mean change in weight (kg) - at 6 months in the intervention groups was
3.8 higher
(1.27 to 6.33 higher)
 17
(1 study)
⊕⊕⊕⊝
moderate 1
 
Change in weight z score - at 3 months
Follow up: mean 3 months
 The mean change in weight z score - at 3 months in the intervention groups was
0.61 higher
(0.29 to 0.93 higher)
 40
(3 studies)
⊕⊕⊕⊝
moderate 2
 
Change in weight z score - at 6 months
Follow up: mean 6 months
 The mean change in weight z score - at 6 months in the intervention groups was
0.74 higher
(0.26 to 1.22 higher)
 17
(1 study)
⊕⊕⊕⊝
moderate 1
 
Change in FEV1 (% predicted) - at 3 months
Follow up: mean 3 months
 The mean change in FEV1 (% predicted) - at 3 months in the intervention groups was
13.55 higher
(1.88 lower to 28.98 higher)
 17
(1 study)
⊕⊕⊕⊝
moderate 1
 
Change in FEV1 (% predicted) - at 6 months
Follow up: mean 6 months
 The mean change in FEV1 (% predicted) - at 6 months in the intervention groups was
5.64 higher
(4.43 lower to 15.71 higher)
 17
(1 study)
⊕⊕⊕⊝
moderate 1
 
Increase in appetite (subjective reporting)
Follow up: mean 6 months
Study population OR 45.25
(3.57 to 573.33)
23
(2 studies)
⊕⊕⊕⊝
moderate 2
 
154 per 1000 892 per 1000
(394 to 990)
Moderate
143 per 1000 883 per 1000
(373 to 990)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

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

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

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

Description of the intervention

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

Cyproheptadine

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

Dronabinol

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

Megestrol acetate

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

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

Mirtazapine

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

Olanzipine

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

Oxandrolone

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

Pizotifen

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

Risperidone

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

How the intervention might work

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

Cyproheptadine

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

Dronabinol

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

Megesterol acetate

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

Mirtazapine

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

Olanzipine

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

Oxandralone

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

Pizotifen

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

Risperidone

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

Why it is important to do this review

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

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

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

Types of participants

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

Types of interventions

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

Types of outcome measures

Primary outcomes
  1. Change in body weight (kg)

  2. Change in body composition

    1. lean body mass (LBM)

    2. fat mass

    3. body mass index (BMI)

  3. Change in pulmonary function

    1. forced expiratory volume in one second (FEV1) (absolute values)

    2. FEV1 (% predicted)

Secondary outcomes
  1. Subjective report of anorexia or change in appetite or both

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

  3. Dietary intake

    1. energy intake (measured in kcal per day)

    2. protein intake (measured in grams of protein per day)

  4. Any adverse events directly related to the intervention

  5. Change in the number of pulmonary exacerbations

Search methods for identification of studies

Electronic searches

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

The Cystic Fibrosis Trials Register was compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE, a search of Embase to 1980 and the prospective handsearching of two journals - Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work was identified by searching the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cystic Fibrosis and Genetic Disorders Group Module.

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

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

These searches were completed: 01 April 2014.

Searching other resources

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

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

Data collection and analysis

Selection of studies

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

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

Data extraction and management

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

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

Assessment of risk of bias in included studies

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

Table 1. The Cochrane Collaboration's tool for assessing risk of bias
Domain Description Review authors’ judgement
Sequence generationDescription of the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.Was the allocation sequence adequately generated?
Allocation concealmentDescription 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 assessorsDescription of all measures used, if any, to blind study participants and personnel 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 dataDescription 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 randomized 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 reportingDetails 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 suggestion of selective outcome reporting?
Other sources of bias

Any important concerns about bias not addressed in the other domains in the tool.

If particular questions or entries were pre-specified in the review’s protocol, responses should be provided for each question or entry.

Was the study apparently free of other problems that could put it at a high risk of bias?

Measures of treatment effect

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

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

Unit of analysis issues

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

Dealing with missing data

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

Assessment of heterogeneity

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

  •  0% to 40%: might not be important;

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

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

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

Assessment of reporting biases

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

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

Data synthesis

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

Subgroup analysis and investigation of heterogeneity

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

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

  • different appetite stimulants;

  • dosage of appetite stimulants

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

Sensitivity analysis

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

Summary of findings table

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

Results

Description of studies

Results of the search

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

Included studies

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

Trial design

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

Participants

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

Interventions

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

Outcomes

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

Excluded studies

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

Risk of bias in included studies

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

Figure 1.

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

Allocation

Randomisation procedure

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

Allocation concealment

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

Blinding

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

Incomplete outcome data

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

Selective reporting

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

Other potential sources of bias

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

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

Effects of interventions

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

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

Primary outcomes

1. Change in body weight (kg)

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

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

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

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

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

2. Change in body composition
a. LBM

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

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

b. fat mass

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

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

c. BMI

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

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

3. Change in pulmonary function

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

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

a. FEV1 (absolute values)

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

b. FEV1 (% predicted)

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

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

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

Secondary outcomes

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

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

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

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

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

3. Dietary intake
a. energy intake (measured in kcal/day)

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

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

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

None of the trials reported protein intake results.

4. Any adverse events directly related to the intervention

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

Table 2. Adverse events of appetite stimulants
  1. AB: antibiotic
    IV: intravenous

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 2000Megesterol acetate (Megace®)1. Diabetes  2/6not reported
2. Glucosuria  2/6not reported
3. Increased fasting insulin levels  6/60/6
4. Hyperactivity  2/6not reported
5. Irritability  1/6not reported
6. Decreased morning cortisol levels  4/6not reported
7. Increased fasting c-peptide levels  6/6no changes reported
8. Increased insulin-like growth factor-1  6/66/6
9. Glucose intolerance  not reported1/6
10. Insomnia  2/6not reported
11. Change in the number of pulmonary exacerbations  5/63/6
Eubanks 2002Megesterol acetate (Megace®)1. Insomnia  4/101/7
2. Elevated mean insulin levels           10/10Data not reported
3. Elevated liver enzymes                   1/100/7
4. Pulmonary exacerbation requiring IV ABs    6/106/7
5. Pulmonary exacerbation requiring aerosolised ABs   4/104/7
6. Transient hyperglycaemia   2/10Data not reported
7. Moodiness  3/100/7
8. Depression  1/100/7
9. Vomiting   0/101/7
10. Nausea  0/101/7
11. Elevated haemoglobin A1C levels  1/100/7
12. Skin rash  1/102/7
13. Constipation  1/100/7
14. Decrease in morning cortisol levelsSignificant but reversible decrease 7/100/7
15. Menstrual irregularities  1/101/7
16. Night sweats  2/102/7
Homnick 2004Cyproheptadine1. Poorly-controlled diabetes   1/8not reported
2. Increased general fatigue     
a. At baseline  2/82/8
b. At 4 weeks  3/81/8
2. Reduced fatigue    
a. At 4 weeks   2/8Not reported
3. Days of oral antibiotic use   No difference reportedNo difference reported
4. Days of IV antibiotic use   No difference reportedNo difference reported
5. Transient increase in liver function tests   no reported1/8

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

5. Change in the number of pulmonary exacerbations

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

Discussion

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

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

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

Summary of main results

Response to treatment

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

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

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

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

Adverse effects of stimulants

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

Dosage, duration and timing of appetite stimulants

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

Overall completeness and applicability of evidence

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

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

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

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

Quality of the evidence

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

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

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

Potential biases in the review process

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

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

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

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

Agreements and disagreements with other studies or reviews

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

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

Authors' conclusions

Implications for practice

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

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

Implications for research

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

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

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

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

  • do appetite stimulants actually improve appetite and what is the magnitude of this effect?

  • do appetite stimulants result in sustained weight gain?

  • what quality of weight gain is considered clinically significant?

  • what quality of weight gain can be expected from appetite stimulants?

  • which side effects should be monitored and what is their clinical significance?

  • when should appetite stimulant administration begin and end; alongside the duration and clinical indications?

  • which appetite stimulants work best for toddlers, children, prepubertal children, teenagers, young adults and adults?

  • should treatment vary according to whether the patient is awaiting transplantation?

  • should some steroid-based appetite stimulants be a contra-indication for listed lung-transplant patients because of potential bone loss whilst on steroids (Tschopp 2002)?

  • which are the important patient-related outcomes when taking appetite stimulants?

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

We recommend that future trials:

  • are adequately powered and robust, designed to elucidate the magnitude in effect for both clinical and patient-related relevant outcomes i.e. appetite change, lung function, cost per quality adjusted life year (QALY), QoL (e.g. sick leave from employment, functional ability and psychological impact);

  • define clinically significant weight gain in both children and adults;

  • establish valid surrogate markers of appetite change (both objective and subjective);

  • report changes in nutritional and dietary intake along with changes in pre-defined surrogate markers for appetite change;

  • report on a pre-defined list of adverse effects as well as monitoring any unexpected adverse effects for all age groups;

  • ensure complete data sets are reported for all outcomes (including mean change data and their SDs); and

  • report outcome differences and SDs of differences to allow for meaningful meta-analyses.

Acknowledgements

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

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

Data and analyses

Download statistical data

Comparison 1. Appetite stimulants versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Change in weight (kg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 at 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 at 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Change in weight z score3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 at 3 months340Mean Difference (IV, Fixed, 95% CI)0.61 [0.29, 0.93]
2.2 at 6 months117Mean Difference (IV, Fixed, 95% CI)0.74 [0.26, 1.22]
3 Change in weight z score (at 3 months)3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 Megasterol acetate228Mean Difference (IV, Fixed, 95% CI)0.68 [0.24, 1.13]
3.2 Cyproheptadine hydrochloride112Mean Difference (IV, Fixed, 95% CI)0.53 [0.07, 0.99]
4 Change in FEV1 %1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 at 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 at 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Increase in appetite (subjective reporting)2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 At 3 months223Odds Ratio (M-H, Fixed, 95% CI)45.25 [3.57, 573.33]
Analysis 1.1.

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

Analysis 1.2.

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

Analysis 1.3.

Comparison 1 Appetite stimulants versus placebo, Outcome 3 Change in weight z score (at 3 months).

Analysis 1.4.

Comparison 1 Appetite stimulants versus placebo, Outcome 4 Change in FEV1 %.

Analysis 1.5.

Comparison 1 Appetite stimulants versus placebo, Outcome 5 Increase in appetite (subjective reporting).

Appendices

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

Date last run: 01 April 2014

1. Cystic fibrosis (ti, ab)

2. Cystic Fibrosis (sh)

3. CF (ti, ab)

4. Mucovicidosis (ti,ab)

5. 1 or 2 or 3 or 4

6. Appetite stimulants (ti,ab)

7. Appetite stimulants (sh)

8. Cyproheptadine (sh)

9. Cyproheptadine (ti,ab)

10. Appetite (sh)

11. Prednisolone (sh)

12. Progestational agents (ti, ab)

13. Progestins (sh)

14. Anabolic agents (ti,ab)

15. Megesterol (ti,ab)

16. Megesterol (sh)

17. Megesterol acetate (sh)

18. Megace (ti, ab)

19. Mirtazapine (ti,ab)

20. Antidepressive agents (sh)

21. Antidepressants (ti,ab)

22. Cannaboids (ti,ab)

23. Tetrahydrocannabinol (sh)

24. Antihistamines (ti,ab)

25. Histamine antagonists (sh)

26. Corticosteroids (ti,ab)

27. Prednisone (sh)

28. Steroids (sh)

29. Hormone therapy (ti,ab)

30. Growth Hormone (sh)

31. Hormones (sh)

32. Dronabinol (ti,ab)

33. Pizotyline (sh)

34. pizotifen ti,ab

35. risperidone ti,ab

36. Risperidone (sh)

37. olanzapine ti,ab

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

39. anorexia (ti,ab)

40. anorexia( sh)

41. weight (ti,ab)

42. 34 or 35 or 36

43. 5 and 38 and 42

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

Date last run: 01 May 2012

1.Cystic fibrosis (ti, ab)

2. Cystic fibrosis (sh)

3. 1 or 2

4. Appetite stimulants (ti, ab)

5. Appetite stimulating agents (sh)

6. Appetite (sh)

7. Progestational agents (ti,ab)

8. Progestational hormones (sh)

9. Progestational hormones synthetics (sh)

10. Antidepressive agents, second generation (sh)

11. Antidepressive agents, tricyclic(sh)

12. Anabolic agents (ti,ab)

13. Anabolic steroids(sh)

14. Megesterol acetate (ti,ab)

15. Mirtazapine (sh)

16. Antidepressants (ti,ab)

17. Antihistamines (ti,ab)

18. Histamine H1 antagonists (sh)

19. Histamine H2 antagonists (sh)

20. Corticosteroids (ti, ab)

21. Steroids (sh)

22. Hormone therapy (sh)

23. Hormones, synthetic (sh)

24. growth hormone (ti, ab)

25. Hormones (ti, ab)

26. Tetrahydrocannabinol (sh)

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

28. Anorexia (ti, ab)

29. Anorexia (sh)

30. weight (ti,ab)

31. 28 or 29 or 30

32. 3 and 28 and 31

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

Date last run: 01 May 2012

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

35. Pizotyline (sh)

36. Pizotifen (sh)

37. risperidone ti,ab

38. Risperidone (sh)

39. olanzapine ti,ab

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

Appendix 4. Glossary

Term Definition
adipose tissuefat
aetiologycause
anorexialoss of appetite
chronic sepsispresence in the blood or other tissues of disease causing micro-organisms
cytokinesproteins which generate an immune response
energy expenditureenergy used up
gastroesophageal reflux (GOR)return flow of the stomach contents into to the oesophagus
inflammatoryimmune response characterised by inflammation
intestinal malabsorptionreduced absorption of nutrients by the small intestine
meta-analysisa statistical approach to combine the results of multiple studies
morbiditydiseased condition or state
mortalitydeath
pulmonary exacerbationslung infections
quasi-randomised controlled triala trial which uses systematic methods, such as alternation, assignment based on date of birth, case record number and date of presentation to assign participants to treatment or control groups -an important weakness with these methods is that concealing the allocation schedule is usually impossible, which allows foreknowledge of intervention assignment among those recruiting participants to the study, and biased allocations
risk of biaschance of systematic error or prejudice towards something
serumclear portion of any body fluid
sinusitisinflammation of a sinus or cavity
tumour necrosis factor (TNF)proteins produced by the white blood cells which mediate inflammation
weight for age z-score (WAZ)the number of standard deviations of the actual weight of a child from the median weight of children of his or her age as determined from the standard sample

Contributions of authors

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

Ruth Chinuck will act as the guarantor for the review.

Declarations of interest

Ruth Chinuck declares no potential conflict of interest.

Jane Dewar declares no potential conflict of interest.

David Baldwin declares no potential conflict of interest.

Elizabeth Hendron declares no potential conflict of interest.

Sources of support

Internal sources

  • Nottingham University Hospitals, City Campus, UK.

External sources

  • Nottingham University, UK.

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

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

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

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Eubanks 2002

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 Day 0 - 90, and Day 0 - 180.

Notes

Main component of weight gain was in body fat stores.

After completion of the 6-month trial, the placebo group were offered MA for a further 6 months.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Participants allocated by computer-generated randomisation schedule."
Allocation concealment (selection bias)Unclear riskMethod of concealment not described.
Blinding (performance bias and detection bias)
Participants
Low riskDouble-blind.
Blinding (performance bias and detection bias)
Clinicians
Low riskDouble-blind.
Blinding (performance bias and detection bias)
Outcome assessors
Low riskParticipants, treating physician and ancillary staff blinded.
Incomplete outcome data (attrition bias)
All outcomes
High risk3 patients 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 riskDietary intake stated as an outcome in the 'Methods' section, but not reported in '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, Eubanks reported lean body and fat mass for the megesterol acetate group but not for the placebo group.
Other biasLow riskNo other evident risk of additional bias.

Homnick 2004

Methods

Double-blinded, placebo-controlled RCT.

Parallel design.

Duration: 12 weeks.

Country: USA.

Participants

18 patients 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.

OutcomesWeight , height, BMI percentiles, ideal body weight/height, weight for age Z scores, fat, fat-free mass, appetite, spirometry.
NotesNo significant side effects except transient mild sedation in CH group.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSAS small block randomisation.
Allocation concealment (selection bias)Unclear riskNot discussed.
Blinding (performance bias and detection bias)
Participants
Low riskOnly the pharmacist investigator and study coordinator remained unblinded, participants were blinded.
Blinding (performance bias and detection bias)
Clinicians
Low riskOnly the pharmacist investigator and study coordinator remained unblinded, clinicians were blinded.
Blinding (performance bias and detection bias)
Outcome assessors
Low riskOnly the pharmacist investigator and study coordinator remained unblinded, outcome assessors were blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo outcome related drop-out.
Selective reporting (reporting bias)High riskOutcomes stated in the 'Methods' section (dietary intake, pulmonary function) were not reported. Plus, outcomes not stated in the 'Methods' section (dietary energy intake and spirometry) were subsequently reported in the 'Results' section.
Other biasLow riskSignificant 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 = 0.0392), but allowing for an adjustment of the P value for testing multiple outcomes the difference is not significant and is not evidence for a risk of bias.

Marchand 2000

  1. a

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

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.

OutcomesWeight, appetite, calorific intake, FEV1 (% predicted) and FVC (% predicted), adverse events.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "... patients were randomized.", no detailed information.
Allocation concealment (selection bias)Unclear riskNot discussed.
Blinding (performance bias and detection bias)
Participants
Low riskDouble-blind.
Blinding (performance bias and detection bias)
Clinicians
Low riskDouble-blind.
Blinding (performance bias and detection bias)
Outcome assessors
Low riskNo specific information, but weight measurement unlikely to be affected by not blinding assessor.
Incomplete outcome data (attrition bias)
All outcomes
High risk6 out of 12 patients dropped out. No reason given for 3 patients, 2 for developed diabetes following MA, 1 for glucose intolerance on placebo. Not clear if these drop-outs were on first or second period of cross-over trial. No data used from dropouts.
Selective reporting (reporting bias)High riskOutcomes stated in the 'Methods' section (dietary intake, pulmonary function) were not reported. Plus QoL not stated in the 'Methods' section, but reported in the 'Results'.
Other biasLow riskNo other evident risk of additional bias.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Alemzadeh 1998Not a randomised controlled trial.
Anstead 2003Not randomised controlled trial.
Auerbach 1985Not relevant intervention i.e. prednisone was not given to stimulate appetite.
Ballmann 2013Not relevant intervention i.e. insulin was not given to stimulate appetite
Ballmann 2013aNot relevant intervention i.e. insulin was not given to stimulate appetite.
Berenstein 2005Not a randomised controlled trial - review article.
Bucuvalas 2001Not relevant intervention i.e. growth hormone therapy was not given to stimulate appetite.
Canfield 1998Not randomised controlled trial.
CF Trust 2002A consensus document, not randomised controlled trial.
Chinuck 2007A systematic review of appetite stimulants.
Chung 2006Not randomised controlled trial.
Cohen 2008Not randomised controlled trial.
Cohen 2010Not randomised controlled trial.
Cohen-Cymberknoh 2008Not relevant intervention i.e. prednisone was not given to stimulate appetite.
Crawley 2003Not randomised controlled trial.
Darmaun 2004Comparison of two active treatments; not a comparison of active treatment to placebo or no treatment.
Dhillo 2007Not a randomised controlled trial.
Dovey 2007Not relevant intervention i.e. prednisone was not given to stimulate appetite.
Dowsett 1999Not randomised controlled trial.
Durant 1998Not randomised controlled trial.
Eubanks 2000Not randomised controlled trial.
Greally 1992Not relevant intervention i.e. prednisone was not given to stimulate appetite
Grover 2008Not relevant intervention i.e. insulin was not given to stimulate appetite.
Guillot 2011Not randomised controlled trial.
Hardin 1997Not randomised controlled trial.
Hardin 2001Not relevant intervention i.e. growth hormone therapy was not given to stimulate appetite.
Hardin 2004Not a randomised controlled trial.
Hardin 2005aNot relevant intervention i.e. growth hormone therapy was not given to stimulate appetite.
Hardin 2005bNot relevant intervention i.e. growth hormone therapy was not given to stimulate appetite.
Hardin 2005cNot a randomised controlled trial - retrospective evaluation of medical records.
Hardin 2006Not relevant intervention i.e. growth hormone therapy was not given to stimulate appetite.
Hardin 2007Not randomised controlled trial.
Hutler 2002Not relevant intervention i.e. growth hormone therapy was not given to stimulate appetite.
Linnane 2001Not relevant intervention i.e. prednisone was not given to stimulate appetite.
Lopez 2004Not a randomised controlled trial - review article.
Loprinzi 1993Not relevant participants - patients with advanced cancer.
Minicucci 2012Not relevant intervention - insulin would not be prescribed to primarily improve appetite. It’s primary effect is not appetite stimulation.
Moran 2001Not relevant intervention i.e. insulin was not given to stimulate appetite.
Moran 2009Not relevant intervention - insulin would not be prescribed to primarily improve appetite. It’s primary effect is not appetite stimulation.
Nasr 1999Not a randomised controlled trial (case study).
Nasr 2008Not a randomised controlled trial.
Nasrallah 2003Not a randomised controlled trial.
Newkirk 2000Not randomised controlled trial.
Nyamugunduru 1998Not relevant intervention i.e. prednisone was not given to stimulate appetite.
Ohnhaus 1974Not a randomised controlled trial
Pantin 1986Not relevant intervention i.e. prednisone was not given to stimulate appetite.
Parsons 2009Not a randomised controlled trial.
Paterson 2010Not randomised controlled trial.
Phung 2010Not a randomised controlled trial.
Rogan 2010Not relevant participants i.e. pigs.
Rosenstein 1991Not relevant intervention i.e. prednisone was not given to stimulate appetite.
Ross 2005Not randomised controlled trial.
Sackey 1995Not a randomised controlled trial.
Safai 1991Not relevant intervention. Zinc supplementation would not be prescribed to primarily improve appetite. It’s primary effect is not appetite stimulation, therefore excluded.
Schibler 2003Not relevant intervention i.e. growth hormone therapy was not given to stimulate appetite.
Schnabel 2007Not relevant intervention i.e. growth hormone therapy was not given to stimulate appetite.
Stalvey 2008Not a randomised controlled trial.
Stalvey 2011Not relevant intervention i.e. growth hormone therapy was not given to stimulate appetite.
Stylianou 2007Not randomised controlled trial.
Switzer 2009Not a randomised controlled trial.
Sykes 2006Not a randomised controlled trial.
Taylor 1997Not a randomised controlled trial.
Teeter 2004Not relevant intervention i.e. insulin was not given to stimulate appetite.
Tongudai 1971Not a randomised controlled trial or a quasi-randomised trial.
Varness 2009Not a randomised controlled trial.
von Haehling 2009Not a randomised controlled trial.
Weisberg 2002Not relevant participants.
Young 2000Not a randomised controlled trial.

Characteristics of studies awaiting assessment [ordered by study ID]

Epifanio 2012

Methods

Double-blind, parallel, placebo-controlled trial.

Duration: 12 weeks.

Two centres in Brazil.

Participants

25 patients with CF, aged 5 - 18 years.

Gender split unreported from the abstract.

Interventions

Treatment: cyproheptadine 4 mg 3x daily.

Control: placebo.

OutcomesWeight, height, BMI and spirometry.
NotesShort-term use. No adverse events identified or reported. Abstract published. Written to the authors on the 10/5/12 for results on this review's outcome measures and full published paper before inclusion in the review.

Kissner 2000

  1. a

    BMI: body mass index
    CF: cystic fibrosis
    GH: growth hormone
    MA: megesterol acetate
    RCT: randomised controlled trial

MethodsThe initiation of a double-blind, placebo-controlled, RCT of MA.
Participants

10 participants with CF.

Age: 18-27 years.

Interventions

Treatment: 800 mg of MA suspension per day until weight gain was adequate, and then reduced to 400mg per day as needed.

Control: placebo.

OutcomesMean weight gain, change in appetite, adverse events.
Notes

Prospective, double-blind, placebo-controlled randomised trial was initiated as a result of the preliminary data from Kissner 2000.

Kissner DG. Role of progestational agents in the treatment of undernourished patients with cystic fibrosis. Pediatric Pulmonology 2000;29(3):244. Letter. RC contacted the authors  24/8/12; awaiting further details before inclusion in the review. 

Ancillary