Dosing regimens for pancreatic enzyme replacement therapy (PERT) in cystic fibrosis (2024)

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The primary objective of the review is to compare the efficacy (fat absorption) and effectiveness (nutritional status, lung function and QoL) of different PERT dosing strategies (both dose and administration timings) on dietary malabsorption in all individuals with CF. It will not address co‐administration of proton pump inhibitors as this has been addressed elsewhere.

Background

Description of the condition

Cystic fibrosis (CF) is an autosomal recessive, life‐limiting, multisystem disease affecting over 70,000 individuals worldwide and has an incidence of 1 in 2500 live births (CF Foundation 2018). In CF, there is an absent or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein caused by a gene mutation, which can lead to dysfunctional secretion in epithelial cells present in organs such as the airways, pancreatic and biliary ducts and gastrointestinal system. In Northern Europe, the most common mutation is Phe508del (Farrell 2018). Between 80% and 90% of people with CF suffer pancreatic exocrine insufficiency (PI), resulting in inadequate digestion and consequently inadequate absorption of fat and protein (Fieker 2011; Ooi 2011). This can lead to steatorrhoea and a loss of body weight (Elborn 2016; Haupt 2014; Somaraju 2016). It is thought that pancreatic damage is a consequence of secretions building up in the pancreatic duct and thus the loss of pancreatic tissue is progressive (Singh 2017).

PI causes inadequate digestion, and thus inadequate absorption of fat, protein and fat‐soluble vitamins. Fat malabsorption is thought to contribute to a higher risk of developing constipation and a more serious gastrointestinal complication, distal intestinal obstruction syndrome (DIOS). Abnormal digestion of proteins and carbohydrates can also affect nutritional status (Kuhn 2010). PI can also be a predictor of CF‐related diabetes, another consequence of pancreatic damage (Singh 2017; Soave 2014).

Whilst there are some classical signs of PI, clinical presentation can be non‐specific with poor weight gain in childhood or unexplained weight loss in adults being the only sign. Low levels of faecal elastase‐1 in stools have been validated as a sensitive and specific marker of PI (Vanga 2018). A faecal elastase‐1 level less than 100 μg/g stool is considered a result of PI; a faecal elastase‐1 level above 200 μg/g stool is considered pancreatic sufficient (Beharry 2002). In adults,a 72‐hour faecal fat estimation above 7 g of fat over a 24‐hour period is the gold standard test of fat malabsorption caused by PI (Vanga 2018).

Pancreatic enzyme replacement therapy (PERT) has been shown to be safe and effective for improving the nutritional status in people with CF (Somaraju 2016). Individuals treated with PERT have also seen improvements in their lung function. Current European, American and Australasian guidelines recommend PERT dosage should be dependent on fat content in meals or snacks eaten, with a daily maximum of 4000 lipase units per gram of fat eaten or 10,000 lipase units per kg body weight (CF Trust 2016; Saxby 2017; Stallings 2008; Turck 2016). Upper limits of treatment dose were introduced because of concerns over the risk of of fibrosing colonopathy (Borowitz 2013; NICE 2017; Smyth 1995; Somaraju 2016). Guidelines also suggest that doses can be titrated dependent on clinical symptoms (NICE 2017; Somaraju 2016). However, variations in PERT dosage still persist between different centres and countries (Calvo‐Lerma 2017).

Description of the intervention

PERT is usually a pancrelipase, derived from porcine sources and containing multiple enzyme classes. It is most commonly taken in the form of capsules, where the enteric coating of the capsule will begin to dissolve in the stomach at pH 5 to 6. This enables the pancreatic enzymes to be released in the duodenum and to have maximal activity (Gelfond 2013; Kuhn 2010). At present, the most common methods to calculate dose levels of PERT are by body weight (500 to 2500 units per kg per meal) or meal fat content (500 to 4000 units of lipase per gram of fat per day) (Singh 2017; Turck 2016). For infants, there are limited primary data on the optimal PERT dosage. In spite of this, consensus documents recommend up to 5000 units lipase per breastfeed or 100 mL to 120 mL of infant formula (Borowitz 2013; CF Trust 2016; Smith 2016). It is important for the pancreatic enzymes to reach the duodenum at a similar time to partially digested food in order for the enzymes to be most effective (Kuhn 2010). In vitro studies have shown that the breakdown of triglycerides to free fatty acids improves in the presence of PERT in a CF intestine model and there may be optimal doses of enzymes dependant on food type (Asensio‐Grau 2018; Calvo‐Lerma 2019). Similarly, clinical trials have shown that the introduction of PERT leads to a significant improvement in the co‐efficient of fat absorption (CFA) and stool characteristics compared to placebo (Graff 2010). Abdominal symptoms were also reported to improve with pancrelipase supplementation (Graff 2010).

There are several brands, strengths and preparations of PERT available; with different products available in different jurisdictions. In the UK these include (BNF 2018; NICE 2018):

granules (Creon Micro^® , Pancrex^® V Powder);
capsules (Pancrease HL^®, Creon^® 40000, Creon^® 25000, Creon^® 10000, Nutrizym^® 22, Pancrex^®);
tablets (Pancrex^® V tablets forte, Pancrex^® V tablets, Pancrex^®).

PERT should not be mixed with food for more than one hour before the meal. The Pancrex^® V powder is the only medication that can be given via nasogastric or gastrostomy tube (NICE 2017).

How the intervention might work

The aim of PERT is to compensate for the inadequate enzyme production present in people with PI. The optimum environment for PERT, after its enteric coating has been dissolved, is thought to be between pH 7 to pH 8. This should be achieved in the duodenum in combination with food to mimic normal digestion (pancreatic bicarbonate neutralises stomach acid in order to ensure optimal enzyme function) (Kuhn 2010; Singh 2017). As a result, PERT has been shown to improve the CFA, a marker of fat malabsorption, to over 85% in some people. However, one trial showed that 24% of people with PI failed to see this improvement, despite the addition of a proton‐pump inhibitor (Woestenenk 2015).

This review will focus on the different dosing regimens of PERT and how it affects the clinical outcome of people with CF.

Why it is important to do this review

PI affects the majority of the population who have CF and is partly responsible for their poor nutritional status. Although PERT has a significant impact on steatorrhoea, body mass index (BMI) and lung function, the question still remains whether there is an optimal approach to dosing which could increase the CFA closer to 100%. It is also not clear whether measurable improvements in fat absorption lead to improvements in measures of overall nutrition and quality of life (QoL) in people with CF.

At present, there have been no reviews for fixed or variable dosing recommendations per g of fat or per kg of body weight, nor have there been any recommendations on drug administration. This is therefore an important topic to address.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs), including cross‐over RCTs with a minimum washout period of two weeks. The review authors will also consider quasi‐RCTs if baseline characteristics of intervention groups are similar (Higgins 2011b) and we will use the Cochrane risk of bias tool to highlight any issues. They will exclude non‐RCTs and any trials using historical controls.

Types of participants

Individuals of all ages, with a confirmed diagnosis of CF by genotype or sweat chloride testing, with and without PI.

Types of interventions

The review authors will consider regimens pre‐specifying different administration timings (e.g. before, during or after a meal) in any dosage (dose/kg body weight or dose/g ingested fat or any other strategy) or formulation of PERT in people, of any age, with CF. Where 'standard of care' or 'dietitian advice' is used as a comparator, a specific regimen will need to be defined to allow comparisons of the regimen rather than clinical supervision. Studies should specify whether clinical supervision was standardised as part of the regimen.

Types of outcome measures

Primary outcomes

The review authors will assess the following outcomes at two and four weeks of the treatment period. If the study period is longer than four weeks, we will assess outcomes at monthly intervals if data are available.

Fat malabsorption (absolute CFA based on 72‐hour stool collection)
Nutritional status (change from baseline)
1. weight in kg, % of predicted weight or z score
2. height in cm, % of predicted height or z score
3. BMI, % of predicted BMI or z score
Adverse events
See Also
Pancrex V 125 mg hard capsules - Summary of Product Characteristics (SmPC)Pancreatic enzyme replacement therapy (PERT) for pancreatic insufficiency Pancrex V Powder - Summary of Product Characteristics (SmPC)PANCREX V POWDER | Drugs.com
1. relating to gastrointestinal system
2. relating to other systems

Secondary outcomes

Lung function (change from baseline)
1. forced expiratory volume (FEV₁) in L or % predicted
2. forced vital capacity (FVC) in L or % predicted
3. lung clearance index (LCI)
Change in participant‐reported QoL score assessed using a validated tool (e.g. CF QoL (Gee 2000), CFQ‐R (Quittner 2009) or equivalent)
Change in participant‐reported symptom score, assessed using a validated tool (e.g. CFQ‐R (Quittner 2009), CFAbd‐Score (Jaudszus 2019) or equivalent)

Search methods for identification of studies

The review authors will search for all relevant published and unpublished trials without restrictions on language, year or publication status.

Electronic searches

The Cochrane Cystic Fibrosis and Genetic Disorders Group's Information Specialist will conduct a systematic search of the Group's Cystic Fibrosis Trials Register for relevant trials using the following term: pancreatic enzymes. The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library), weekly searches of MEDLINE, a search of Embase to 1995 and the prospective handsearching of two journals ‐ Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work is 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 section of the Cochrane Cystic Fibrosis and Genetic Disorders Group's website.

The review authors will search the following trials registries (for search strategies, please see Appendix 1):

International Standard Randomised Controlled Trial Number Registry www.isrctn.com;
The World Health Organization International Clinical Trials Registry Platform www.who.int/trialsearch;
ClinicalTrials.gov www.clinicaltrials.gov.

Searching other resources

The review authors will check the bibliographies of included studies and any relevant systematic reviews identified to identify further references to relevant studies. They will also contact experts and organisations in the field to obtain additional information on relevant studies.

Data collection and analysis

Selection of studies

The review authors will follow Cochrane guidance (Higgins 2011a). One author (CN) will check for and remove any duplicates identified from the searches. Two authors (GM and CN) will independently review all titles and abstracts and discard references which clearly do not meet the inclusion criteria. They will then further independently review the full texts of references for inclusion in the review. They will resolve any disagreement through discussion and, if necessary, ask a third author (AS) to review and discuss to make a final decision.

The review authors will use Covidence for selecting and managing included studies (Covidence 2019).

Data extraction and management

Two review authors (GM and CN) will independently review the included studies and extract data using a standardised electronic data collection form as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). They will review each data collection form for any discrepancies and resolve these by discussion. If necessary, a third author (AS) will mediate discussions. If needed, the review authors may contact the study investigators for further information.

The authors will extract data on the number of participants, their characteristics, trial design, dose (i.e. dose per g fat or dose per kg body weight) and timings of administration (i.e. before, during or after a meal). They will document the treatment effect at two and four weeks then monthly thereafter. There will be a minimum treatment period of two weeks (for cross‐over studies this will be two weeks for each arm) to enable the clinical impact to be measurable (e.g. fat malabsorption and nutritional status). The authors will compare the intervention with 'usual care' (standard regimen or dietitian direction) (CF Trust 2016; Turck 2016).

Assessment of risk of bias in included studies

The data extraction forms will include a section for assessment using the Cochrane risk of bias tool (Higgins 2011b). This will allow review authors to record risk of bias judgements under the six domains outlined: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias.

If review authors require further information regarding the studies they will contact the study investigators. Two review authors (GM and CN) will compare their assessments of bias to decide whether any bias will impact the results or conclusions of the study.

Measures of treatment effect

Measures of treatment effect will follow guidelines set out by the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011).

The review authors will assess continuous data (weight, height, BMI, CFA and lung function) by calculating the mean difference (MD) and 95% confidence intervals (CIs) between groups. For data where studies report multiple measures for the same outcome, the authors will calculate a standardised mean difference (SMD). For dichotomous data (adverse effects of PERT), they will analyse the treatment effect using the risk ratios (RR) with 95% CIs.

Unit of analysis issues

For cluster‐RCTs, the review authors will analyse data using a summary measurement from each cluster to reduce the risk of false‐positive conclusions. They will estimate the intra‐cluster correlation co‐efficient from the cluster‐RCT or other trials with similar design or population. If they obtain the intra‐cluster correlation co‐efficient from an external study, they will perform a sensitivity analysis to evaluate the effect of variation. They will then apply the design effect calculation to reduce the trials to an effective sample size and so use the CIs to compare with other RCTs (Higgins 2011c).

For cross‐over RCTs, there may be a 'carry‐over' effect where the effects of the first intervention may carry‐over into the second period. Some studies reduce this risk by having a washout period. The minimum washout period for an included study will be two weeks. Although it is possible to test for carry‐over effects and report the results from each treatment period separately, it can increase the risk of reporting bias and therefore is not recommended. Where paired data are available from the cross‐over RCTs and the authors do not consider carry‐over effects to be a problem, they will extract the MD and standard errors to perform a paired t‐test and estimate the effects of measurements on interventions compared with controls. The meta‐analysis may include the effect estimate using the generic inverse‐variance method in the Review Manager software (RevMan 2014). For a cross‐over RCT, where the design is inappropriate, the review authors will only analyse data from the first period (Elbourne 2002; Higgins 2011c).

For studies with multiple treatment groups, any common intervention groups will not be independent of each other and therefore a unit of analysis issue will occur. Therefore, if these studies meet the inclusion criteria, the review authors will undertake a fixed‐effect meta‐analysis across comparisons. The authors will identify, select and combine the treatment and placebo groups relevant to the systematic review and meta‐analysis to avoid double‐counting and multiple comparisons (Higgins 2011c).

Dealing with missing data

If data are missing from the included studies, the review authors will attempt to contact the original study authors and request the data. They will also make an assessment to determine whether the data are missing at random. Where possible, the review authors will perform an intention‐to‐treat analysis where all randomised participants are analysed in the treatment arm to which they were originally assigned (Higgins 2011c).

Data 'not missing at random' exposes the study to publication bias and could affect subgroup analysis. In this situation, if the original study authors have made any assumptions regarding the missing data, such as poor outcome, the review authors will perform a sensitivity analysis. They will also address the potential impacts in the 'Discussion' section of the review (Higgins 2011c).

If studies do not report baseline data or confirm stratification for baseline CFA in their randomisation, then the review authors will attempt to contact the original study authors and request the baseline data to enable an assessment for mismatch between groups.

Assessment of heterogeneity

If the review authors are able to combine studies in a meta‐analysis, they will use the I² test to assess for heterogeneity. The authors will use the guidance on I² test results in the Cochrane Handbook for Systematic Reviews of Interventions:

0% to 40% ‐ might not be important;
30% to 60% ‐ moderate heterogeneity;
50% to 90% ‐ substantial heterogeneity; and
75% to 100% ‐ considerable heterogeneity.

This is a rough guide as the Cochrane Handbook for Systematic Reviews of Interventions states the importance of inconsistency depends on the magnitude and direction of effects and the strength of evidence (Deeks 2011),

Assessment of reporting biases

The review authors will assess different types of reporting biases: publication bias, time lag bias, multiple publication bias, location bias, citation bias, language bias and outcome reporting bias. The authors will use funnel plots to measure the level of publication biases between studies by measuring the study size against intervention effects, if there are a minimum of 10 studies (Sterne 2011).

As the review authors may not be able to detect publication biases via asymmetrical funnel plots, they will use multiple search strategies to identify relevant studies and attempt to contact authors who have only published abstract data for their studies to identify any publication biases. To test for asymmetry, the review authors will perform a linear regression of the effect estimates and standard errors (Sterne 2011).

Data synthesis

The authors will use a fixed‐effect meta‐analysis model to summarise the effects of outcomes in the included studies (Deeks 2011; Higgins 2003).

Subgroup analysis and investigation of heterogeneity

If the authors identify and combine a sufficient number of studies, then they will undertake the following subgroup analyses:

age of participants
- 1. infants not yet weaned (under three years old);
  2. pre‐school age children (three to five years old);
  3. school‐age children (five to 16 years old);
  4. adults (over 16 years old).
PERT administration methods:
- 1. granules;
  2. capsules;
  3. tablets of different strength.

Sensitivity analysis

If the authors identify and combine a sufficient number of studies for inclusion, they will perform a sensitivity analysis to determine how robust the findings are. If there is little difference between the original analysis and repeated sensitivity analysis, a higher degree of certainty can be placed on the original results and conclusions. If the results are widely different, the original conclusions from the study need to be viewed cautiously (Deeks 2011).

If there are any missing data, the review authors will make every effort to contact the study author(s). If the original findings are arbitrary or unclear, the review authors will perform a sensitivity analysis to assess the impact of the assumptions made with these values. A small difference following the sensitivity analysis will strengthen the initial conclusions. The results will be presented in a summary table (Deeks 2011; Higgins 2011c).

If the review authors use an intra‐cluster correlation co‐efficient from an external study, the review authors will perform a sensitivity analysis to evaluate the effect of variation.

Summary of findings table

The review authors will present the following outcome measures in a summary of findings table:

CFA at two weeks;
CFA at four weeks;
weight at four weeks;
adverse events in the gastrointestinal system at four weeks;
participant‐reported symptom score at four weeks.

The authors will report the magnitude of effect (MD and 95% CI) and number of participants and studies for each outcome. They will assess the quality of evidence from very low to high using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach (Schünemann 2011). The grade is dependent upon confidence in the estimate of the effect of the intervention. The quality of evidence may be downgraded if there are limitations in the design, indirect evidence, inconsistent or imprecision of results, or a high probability of publication bias.

If there are sufficient data for subgroup analyses (age and administration methods), this will be reported as other comments in the summary of findings table.

Acknowledgements

This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

We would like to acknowledge Nikki Jahnke (Managing Editor at the Cochrane Cystic Fibrosis and Genetic Disorders Group) for her ongoing support throughout the review process.

Appendices

Appendix 1. Additional electronic search strategies

Database	Search terms
International Standard Randomised Controlled Trial Number Registry (www.isrctn.com)	[Basic Search] (Cystic fibrosis OR mucoviscidosis) AND ("pancreatic enzyme" OR “pancreatic exocrine” OR pert OR creon OR pancrex OR pancrease OR Nutrizym OR forte OR ultrase OR pancrelipase OR pancrecarb OR liprotamase OR Sollpura)
The World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch)	[Advanced Search] CONDITION: cystic fibrosis OR mucoviscidosis INTERVENTION: pancreatic enzyme OR pancreatic exocrine OR pert OR creon OR pancrex OR pancrease OR Nutrizym OR forte OR ultrase OR pancrelipase OR pancrecarb OR liprotamase OR Sollpura RECRUITMENT STATUS: All
ClinicalTrials.gov (www.clinicaltrials.gov)	[Advanced Search] CONDITION/ DISEASE: cystic fibrosis OR mucoviscidosis STUDY TYPE: Interventional Studies INTERVENTION/ TREATMENT: “pancreatic enzyme” OR “pancreatic exocrine” OR pert OR creon OR pancrex OR pancrease OR Nutrizym OR forte OR ultrase OR pancrelipase OR pancrecarb OR liprotamase OR Sollpura

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What's new

Date	Event	Description
21 November 2019	Amended	CoI declarations updated.

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Contributions of authors

Task	Who will undertake the task
Conceiving the review	CN + GM + ARS
Designing the review	CN + GM + ARS
Coordinating the review	CN
Draft the protocol	CN + GM

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Sources of support

Internal sources

No sources of support supplied

External sources

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

Declarations of interest

CN has spoken at a symposium sponsored by Vertex.

GM has spoken at symposia sponsored by Vertex and Astellas.

ARS declares relevant activities of consultancy for Vertex and a research grant from Vertex to his institution. He has spoken at symposia sponsored by Vertex, Teva and Novartis. He has taken part in trials sponsored by Vertex.

Please note that Vertex produce and market CFTR modulators and not drugs used in PERT.

New

References

Additional references

Asensio‐Grau A, Peinado I, Heredia A, Andres A. Effect of cooking methods and intestinal conditions on lipolysis, proteolysis and xanthophylls bioaccessibility of eggs. Journal of Functional Foods 2018;46:579‐86. [Google Scholar]
Beharry S, Ellis L, Corey M, Marcon M, Durie P. How useful is fecal pancreatic elastase 1 as a marker of exocrine pancreatic disease?. Journal of Paediatrics 2002;141(1):84‐90. [DOI] [PubMed] [Google Scholar]
BMJ Group and Pharmaceutical Press. Exocrine pancreatic insufficiency. bnf.nice.org.uk/treatment‐summary/exocrine‐pancreatic‐insufficiency.html (accessed 03 Jan 2019).
Borowitz D, Gelfond D, Maguiness K, Heubi JE, Ramsey B. Maximal daily dose of pancreatic enzyme replacement therapy in infants with cystic fibrosis: a reconsideration. Journal of Cystic Fibrosis 2013;12(6):784‐5. [DOI] [PubMed] [Google Scholar]
Calvo‐Lerma J, Hulst JM, Asseiceira I, Claes I, Garriga M, Colombo C, et al. Nutritional status, nutrient intake and use of enzyme supplements in paediatric patients with Cystic Fibrosis; a European multicentre study with reference to current guidelines. Journal of Cystic Fibrosis 2017;16(4):510‐8. [DOI] [PubMed] [Google Scholar]
Calvo‐Lerma J, Fornes‐Ferrer V, Peinado I, Heredia A, Ribes‐Koninckx C, Andres A. A first approach for an evidence‐based in vitro digestion method to adjust pancreatic enzyme replacement therapy in cystic fibrosis. PLoS ONE 2019;14(2):e0212459. [DOI] [PMC free article] [PubMed] [Google Scholar]
CF Foundation. About cystic fibrosis. www.cff.org/What‐is‐CF/About‐Cystic‐Fibrosis/ (accessed 22 Nov 2018).
UK Cystic Fibrosis Trust Nutrition Consensus Working Group. Nutritional Management of Cystic Fibrosis. 2nd Edition; May 2016. Available at www.cysticfibrosis.org.uk/the‐work‐we‐do/clinical‐care/consensus‐documents.
Veritas Health Innovation. Covidence systematic review software. Melbourne, Australia: Veritas Health Innovation, 2019.
Deeks JJ, Higgins JP, Altman DG on behalf of the Cochrane Statistical Methods Group, editor(s). Chapter 9: Analysing data and undertaking meta‐analysis. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Elborn JS. Cystic fibrosis. Lancet 2016;388(10059):2519‐31. [DOI] [PubMed] [Google Scholar]
Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta‐analyses involving cross‐over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140‐9. [DOI] [PubMed] [Google Scholar]
Farrell P, Férec C, Macek M, Frischer T, Renner S, Riss K, et al. Estimating the age of p.(Phe508del) with family studies of geographically distinct European populations and the early spread of cystic fibrosis. European Journal of Human Genetics 2018;26(12):1832‐9. [DOI: 10.1038/s41431-018-0234-z] [DOI] [PMC free article] [PubMed] [Google Scholar]
Fieker A, Philpott J, Armand M. Enzyme replacement therapy for pancreatic insufficiency: present and future. Clinical and Experimental Gastroenterology 2011;4:55‐73. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gee L, Abbott J, Conway SP, Etherington C, Webb AK. Development of a disease specific health related quality of life measure for adults and adolescents with cystic fibrosis. Thorax 2000;55(11):946–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gelfond D, Ma C, Semler J, Borowitz D. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Digestive Diseases and Science 2013;58(8):2275‐81. [DOI] [PubMed] [Google Scholar]
Graff GR, Maguiness K, McNamara J, Morton R, Boyd D, Beckmann K, et al. Efficacy and tolerability of a new formulation of pancrelipase delayed‐release capsules in children aged 7 to 11 years with exocrine pancreatic insufficiency and cystic fibrosis: a multicenter, randomized, double‐blind, placebo‐controlled, two‐period crossover, superiority study. Clinical Therapeutics 2010;32(1):89‐103. [DOI] [PubMed] [Google Scholar]
Haupt ME, Kwasny MJ, Schechter MS, McColley SA. Pancreatic enzyme replacement therapy dosing and nutritional outcomes in children with cystic fibrosis. Journal of Pediatrics 2014;164(5):1110‐5 e1. [DOI] [PubMed] [Google Scholar]
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327(7414):557‐60. [DOI] [PMC free article] [PubMed] [Google Scholar]
Higgins JP, Deeks JJ, editor(s). Chapter 7: Selecting studies and collecting data. In: Higgins JP, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Higgins JP, Altman DG, Sterne JA on behalf of the Cochrane Statistical Methods Group and the Cochrane Bias Methods Group, editor(s). Chapter 8: Assessing risk of bias in included studies. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Higgins JP, Deeks JJ, Altman DG on behalf of the Cochrane Statistical Methods Group, editor(s). Chapter 16: Special topics in statistics. In: Higgins JP, Green S, editor(s). Cochrane Handbook of Systematic Reviews of Interventions. Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Jaudszus A, Zeman E, Jans T, Pfeifer E, Tabori H, Arnold C, et al. Validity and reliability of a novel multimodal questionnaire for the assessment of abdominal symptoms in people with cystic fibrosis (CFAbd‐Score). Patient 2019;12(4):419‐28. [DOI] [PubMed] [Google Scholar]
Kuhn Rj, Gelrud A, Munck A, Caras S. CREON (pancrelipase delayed‐release capsules) for the treatment of exocrine pancreatic insufficiency. Advances in Therapy 2010;27(12):895‐916. [DOI] [PubMed] [Google Scholar]
National Institute for Health and Care Excellance. Cystic fibrosis: diagnosis and management; October 2017. Available from www.nice.org.uk/guidance/ng78. [PubMed]
National Institute of Health and Care Excellence. Pancreatin: indications and doses. bnf.nice.org.uk/drug/pancreatin.html#indicationsAndDoses (accessed 04 December 2018).
Ooi CY, Dorfman R, Cipolli M, Gonska T, Castellani C, Keenan K, et al. Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology 2011;140(1):153‐61. [DOI] [PubMed] [Google Scholar]
Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire‐Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest 2009;135(6):1610‐8. [DOI: 10.1378/chest.08-1190] [DOI] [PMC free article] [PubMed] [Google Scholar]
The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Saxby N, Painter C, Kench A, King S, Crowder T, Haak N. Nutrition guidelines for cystic fibrosis in Australia and New Zealand; August 2017. Available from www.thoracic.org.au/journal‐publishing/area?command=record&id=46. [DOI] [PubMed]
Schünemann HJ, Oxman AD, Vist GE, Higgins JP, Deeks JJ, Glasziou P, et al on behalf of the Cochrane Applicability and Recommendations Methods Group and the Cochrane Statistical Methods Group. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Singth VK, Schwarzenberg SJ. Pancreatic insufficiency in cystic fibrosis. Journal of Cystic Fibrosis 2017;16(Suppl 2):S70‐S78. [DOI] [PubMed] [Google Scholar]
Smith RC, Smith SF, Wilson J, Pearce C, Wray N, Vo R, et al. Summary and recommendations from the Australasian guidelines for the management of pancreatic exocrine insufficiency. Pancreatology 2016;16(2):164‐80. [DOI] [PubMed] [Google Scholar]
Smyth RL, Ashby D, O'Hea U, Burrows E, Lewis P, Velzen D, et al. Fibrosing colonpathy in cystic fibrosis: results of a case control study. Lancet 1995;346(8985):1247‐51. [DOI] [PubMed] [Google Scholar]
Soave D, Miller MR, Keenan K, Li W, Gong J, Ip W, et al. Evidence for a causal relationship between early exocrine pancreatic disease and cystic fibrosis‐related diabetes: a Mendelian randomization study. Diabetes 2014;63(6):2114‐9. [DOI] [PMC free article] [PubMed] [Google Scholar]
Somaraju UR, Solis‐Moya A. Pancreatic enzyme replacement therapy for people with cystic fibrosis. Cochrane Database of Systematic Reviews 2016, Issue 11. [DOI: 10.1002/14651858.CD008227.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H, Clinical Practice Guidelines on Growth and Nutrition Subcommittee, Ad Hoc Working Group. Evidence‐based practice recommendations for nutrition‐related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. Journal of the American Dietetic Association 2008;108(5):832‐9. [PUBMED: 18442507] [DOI] [PubMed] [Google Scholar]
Sterne JA, Egger M, Moher D on behalf of the Cochrane Bias Methods Group, editor(s). Chapter 10: Addressing reporting biases. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Turck D, Braegger CP, Colombo C, Declercq D, Morton A, Pancheva R, et al. ESPEN‐ESPGHAN‐ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis. Clinical Nutrition 2016;35(3):557‐77. [DOI] [PubMed] [Google Scholar]
Vanga RR, Tansel A, Sidiq S, El‐Serag HB, Othman MO. Diagnostic performance of measurement of fecal elastase‐1 in detection of exocrine pancreatic insufficiency: systematic review and meta‐analysis. Clinical Gastroenterology and Hepatology 2018;16(8):1220‐8. [DOI] [PMC free article] [PubMed] [Google Scholar]
Woestenenk JW, Ent CK, Houwen R. Pancreatic enzyme replacement therapy and coefficient of fat absorption in children and adolescents with cystic fibrosis. Journal of Pediatric Gastroenterology and Nutrition 2015;61(3):355‐60. [DOI] [PubMed] [Google Scholar]