Abstract: 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. 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.

Plain-language summary: 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. 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. 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.