Abstract: One parallel trial and 12 cross-over trials of children and adults with cystic fibrosis were included in the review. The number of participants in each trial varied between 14 and 129 with a total of 512 participants included in the review. All the included trials were for a duration of four weeks. The included trials had mostly an unclear risk of bias from the randomisation process as the details of this were not given; they also mostly had a high risk of attrition bias and reporting bias. We could not combine data from all the trials as they compared different formulations. Findings from individual studies provided insufficient evidence to determine the size and precision of the effects of different formulations. Ten studies reported information on the review's primary outcome (nutritional status); however, we were only able to combine data from two small cross-over studies (n = 41). The estimated gain in body weight was imprecise, 0.32 kg (95% confidence interval -0.03 to 0.67; P = 0.07). Combined data from the same studies gave statistically significant results favouring enteric-coated microspheres over enteric-coated tablets for our secondary outcomes stool frequency, mean difference -0.58 (95% confidence interval -0.85 to -0.30; P < 0.0001); proportion of days with abdominal pain, mean difference -7.96% (95% confidence interval -12.97 to -2.94; P = 0.002); and fecal fat excretion, mean difference -11.79 g (95% confidence interval -17.42 to -6.15; P < 0.0001). Data from another single small cross-over study also favoured enteric-coated microspheres over non-enteric-coated tablets with adjuvant cimetidine in terms of stool frequency, mean difference -0.70 (95% confidence interval -0.90 to -0.50; P < 0.00001). There is limited evidence of benefit from enteric-coated microspheres when compared to non-enteric coated pancreatic enzyme preparations up to one month. In the only comparison where we could combine any data, the fact that these were cross-over studies is likely to underestimate the level of inconsistency between the results of the studies due to over-inflation of confidence intervals from the individual studies.There is no evidence on the long-term effectiveness and risks associated with pancreatic enzyme replacement therapy. There is also no evidence on the relative dosages of enzymes needed for people with different levels of severity of pancreatic insufficiency, optimum time to start treatment and variations based on differences in meals and meal sizes. There is a need for a properly designed study that can answer these questions.

Plain-language summary: The review included 13 studies with 512 adults and children with cystic fibrosis; in all of them treatment lasted for four weeks. Studies compared different formulations of pancreatic enzyme supplements, so we could not combine many of the results. Also the design of 12 of the studies meant that those taking part received both types of supplement for four weeks each, although the order in which they received them was chosen at random. This also made it difficult to analyse the results. Most of the studies were old; the most recent was from 2015, but the oldest was from 1986. We could only combine data from two small studies where individuals took miniature drug capsules (microspheres), which were treated so that the release of the medication is delayed until they have passed from the stomach into the intestine, and normal size tablets which were treated in the same way. The results did not clearly favour one or the other treatment for any of our most important outcomes (weight, height or body mass index). However, those taking the delayed-release microspheres had less fat in their feces than those taking delayed release tablets (normal size) as well as having less abdominal pain and not needing to go to the toilet as often. In a different study, those people taking the delayed-release microspheres also had less fat in their feces than those taking supplements that weren't treated so the release of medication was delayed. We didn't find any evidence that one type of these enteric-coated microspheres was better than another; or that enteric-coated microspheres were better than enteric-coated mini-microspheres (which are smaller). We didn't find any evidence on different doses of enzymes needed for people who produce different levels of pancreatic enzymes, on the best time for individuals to start treatment and different amounts of supplements based on differences in type of food eaten and meal sizes. A properly designed sudy is needed to answer these questions. We could not be sure that the people in the included studies had equal chances of being put into the different treatment groups as no details were published about how the decisions were made. Several studies also had large numbers of individuals who dropped out and often reasons for this were not given. In most studies, people took one treatment and then after a while swapped to the alternative treatment; we could only combine results from two studies which were designed in this way, and that design means that the results may seem to be more consistent than they really are when we analyse them. Finally, several studies did not completely report their findings in a way we could analyse in this review. We are not sure how these factors affect our confidence in the results we found.