Pancreatic enzyme replacement therapy timings in cystic fibrosis

Review question

We reviewed the evidence about the different timings of pancreatic enzyme replacement therapy (PERT) in people (of any age) with cystic fibrosis (CF).


CF is an inherited condition affecting over 70,000 individuals worldwide. Between 80% and 90% of people with CF are not able to produce enough pancreatic enzymes to breakdown and absorb fat, protein and fat-soluble vitamins from food. This can lead to fatty stools (poo) and weight loss. It is thought that if fat is not digested properly, it could contribute to a higher risk of developing constipation or other serious gut complications such as distal intestinal obstruction syndrome.

PERT provides the enzymes required to breakdown fat and the dosage is based upon the fat content of a meal or the person's body weight. PERT has been shown to improve weight and is associated with improved lung function. Despite current dose guidance, there are differences in PERT doses and there is no set guidance for when the therapy should be taken in relation to a meal (i.e. before, during or after eating).

Search date

The evidence is current to: 24 June 2021.

Study characteristics

We did not find any studies where PERT was given to people with CF who were pancreatic insufficient at different timings relative to their meals. We excluded nine studies. Four of these assessed the timing of PERT administration, but they had a cross-over design where participants had one intervention and then swapped to the second intervention. We excluded these studies because they did not leave enough time between the different interventions to be sure that the effects of the first intervention were not affecting the results from the second intervention. Four studies did not look at the timing of PERT and one study evaluated a new educational program for PERT. One study was terminated early and we will assess this again at the first update of this review if we are able to obtain more information from the investigators.

Key results

No studies met the eligibility criteria. Further research is needed to work out the best time to take PERT in relation to a meal.

Authors' conclusions: 

We were unable to determine whether one dosing schedule for PERT is better than another since we identified no eligible RCTs. While the introduction of PERT to people with CF can improve their nutritional status, there are a limited number of studies which address this review question, and none met our eligibility criteria. Since malnutrition and adverse gastrointestinal symptoms remain a common feature in CF, the assessment of the relative performance of dosing schedules may provide evidence to improve outcomes in people with CF who are pancreatic insufficient.

Further research is needed to fully evaluate the role of dosing schedules for PERT in fat absorption. Research should also establish reliable outcome measures and minimal clinically important differences. While RCTs with a cross-over design may have advantages over a parallel group design, an adequate washout period between intervention periods is essential.

Read the full abstract...

Cystic fibrosis (CF) is an autosomal recessive, life-limiting, multisystem disease affecting over 70,000 individuals worldwide. Between 80% and 90% of people with CF suffer with pancreatic exocrine insufficiency, which if left untreated, leads to a poor nutritional status. Pancreatic enzyme replacement therapy (PERT) has been shown to be effective in improving nutritional status and subsequently associated with improved lung function. However, the timings of PERT administration in relation to a meal are subjective and not standardised, meaning that variations in the timing of PERT dosing persist.


The primary objective of the review is to compare the efficacy (fat absorption) and effectiveness (nutritional status, lung function and quality of life) of different PERT dosing strategies in terms of timing of administration for treating dietary malabsorption in all individuals with CF.

Search strategy: 

We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.

Date of last search: 24 June 2021.

We also searched ongoing trials registers on 09 July 2021.

Selection criteria: 

Randomised controlled trials (RCTs), including cross-over RCTs with a minimum washout period of two weeks, and quasi-RCTs of PERT dosing regimens in people (of any age) with CF.

Data collection and analysis: 

Two authors independently assessed and screened the studies identified from the searches. We planned to use GRADE to assess the certainty of evidence for our pre-specified critical outcomes, but we did not identify any eligible studies.

Main results: 

No studies met the eligibility criteria and therefore we did not include any in this review. The excluded studies were either cross-over in design (but lacking a sufficient washout period between treatments) or did not assess the timing of PERT. One study which was terminated early is awaiting assessment pending further information.