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Meta-Analysis
. 2020 Aug 5;8(8):CD008227.
doi: 10.1002/14651858.CD008227.pub4.

Pancreatic enzyme replacement therapy for people with cystic fibrosis

Usha Rani R Somaraju  1 , Arturo Solis-Moya  2
Affiliations
Meta-Analysis

Pancreatic enzyme replacement therapy for people with cystic fibrosis

Usha Rani R Somaraju et al. Cochrane Database Syst Rev. .

Abstract

Background: Most people with cystic fibrosis (CF) (80% to 90%) need pancreatic enzyme replacement therapy (PERT) to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed. A systematic review on the efficacy and safety of PERT is needed to guide clinical practice, as there is variability between centres with respect to assessment of pancreatic function, time of commencing treatment, dose and choice of supplements. This is an updated version of a published review.

Objectives: To evaluate the efficacy and safety of PERT in children and adults with CF and to compare the efficacy and safety of different formulations of PERT and their appropriateness in different age groups. Also, to compare the effects of PERT in CF according to different diagnostic subgroups (e.g. different ages at introduction of therapy and different categories of pancreatic function).

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 07 November 2019. We also searched an ongoing trials website and the websites of the pharmaceutical companies who manufacture pancreatic enzyme replacements for any additional trials. Most recent search: 26 December 2019.

Selection criteria: Randomised and quasi-randomised controlled trials in people of any age, with CF and receiving PERT, at any dosage and in any formulation, for a period of not less than four weeks, compared to placebo or other PERT preparations.

Data collection and analysis: Two authors independently assessed trials and extracted outcome data. They also assessed the risk of bias and quality of the evidence (GRADE) of the trials included in the review.

Main results: 14 trials were included in the review (641 children and adults with CF), two of these were parallel trials and 12 were cross-over trials. Interventions included different enteric and non-enteric-coated preparations of varying formulations in comparison to each other. The number of participants in each trial varied between 14 and 129. 13 trials were for a duration of four weeks and one trial lasted seven weeks. The majority of the trials had an unclear risk of bias from the randomisation process as the details of this were not given; they also had a high risk of attrition bias and reporting bias. The quality of the evidence ranged from moderate to very low. We mostly could not combine data from the trials as they compared different formulations and the findings from individual trials provided insufficient evidence to determine the size and precision of the effects of different formulations.

Authors' conclusions: 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 trials is likely to underestimate the level of inconsistency between the results of the trials due to over-inflation of CIs from the individual trials.There is no evidence on the long-term effectiveness and risks associated with PERT. 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 trial that can answer these questions.

Trial registration: ClinicalTrials.gov NCT02279498 NCT01641393 NCT00449878 NCT01710644 NCT02137382.

PubMed Disclaimer

Conflict of interest statement

Neither author has any interests to declare.

Figures

1
1
Forest plot of comparison: 2 ECM versus ECT, outcome: 2.2 Stool frequency [number/day].
2
2
Forest plot of comparison: 2 ECM versus ECT, outcome: 2.3 Abdominal pain [% days].
3
3
Forest plot of comparison: 2 ECM versus ECT, outcome: 2.4 FFE [g/day].
4
4
Forest plot of comparison: 4 ECM (Creon®) versus another ECM, outcome: 4.5 Coefficient of fat absorption [%].
1.1
1.1. Analysis
Comparison 1: ECM versus NECT + adjuvant cimetidine, Outcome 1: Change in weight
1.2
1.2. Analysis
Comparison 1: ECM versus NECT + adjuvant cimetidine, Outcome 2: Stool frequency
1.3
1.3. Analysis
Comparison 1: ECM versus NECT + adjuvant cimetidine, Outcome 3: Abdominal pain
1.4
1.4. Analysis
Comparison 1: ECM versus NECT + adjuvant cimetidine, Outcome 4: FFE
2.1
2.1. Analysis
Comparison 2: ECM versus ECT, Outcome 1: Change in weight
2.2
2.2. Analysis
Comparison 2: ECM versus ECT, Outcome 2: Stool frequency
2.3
2.3. Analysis
Comparison 2: ECM versus ECT, Outcome 3: Abdominal pain
2.4
2.4. Analysis
Comparison 2: ECM versus ECT, Outcome 4: FFE
3.1
3.1. Analysis
Comparison 3: ECM versus ECMM, Outcome 1: FFE
4.1
4.1. Analysis
Comparison 4: ECM (Creon®) versus another ECM, Outcome 1: Change in body weight [kg]
4.2
4.2. Analysis
Comparison 4: ECM (Creon®) versus another ECM, Outcome 2: Stool frequency (number/day)
4.3
4.3. Analysis
Comparison 4: ECM (Creon®) versus another ECM, Outcome 3: Proportion of days with abdominal pain
4.4
4.4. Analysis
Comparison 4: ECM (Creon®) versus another ECM, Outcome 4: Proportion of days with flatulence
4.5
4.5. Analysis
Comparison 4: ECM (Creon®) versus another ECM, Outcome 5: Coefficient of fat absorption [%]
5.1
5.1. Analysis
Comparison 5: ECM versus TPE, Outcome 1: FFE
6.1
6.1. Analysis
Comparison 6: Liprotamase versus porcine PERT, Outcome 1: Pulmonary exacerbation
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References

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Gow 1981 {published data only}
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    1. Shepherd RW, Gow R. Comparative trial of measures to prevent acid-peptic inactivation of pancreatic enzyme supplements in pancreatic insufficiency due to cystic fibrosis. Australian and New Zealand Journal of Medicine 1982;12:106. [CFGD REGISTER: GN134b]
Graff 2010 {published data only}
    1. Boydd D, Caras SD, Zipfel L, Sander-Struckmeier S. Evaluation of sparse stool collections compared to 72-hour collections as an efficacy measure of pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency. Pediatric Pulmonology 2010;45 Suppl 33:420. [ABSTRACT NO.: 554] [CENTRAL: 793676] [CFGD REGISTER: GN218b]
    1. Caras S, Boyd D, Zipfel L, Sander-Struckmeier S. Evaluation of stool collections to measure efficacy of PERT in subjects with exocrine pancreatic insufficiency. Journal of Pediatric Gastroenterology and Nutrition 2011;53(6):634-40. [CENTRAL: 892801] [CFGD REGISTER: GN218d] [EMBASE: 2011653202] - PubMed
    1. 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. [CENTRAL: 743659] [CFGD REGISTER: GN218a] [PMID: ] - PubMed
    1. Maguiness KM, Graff G, Boyd D, Caras D. Efficacy of pancrealipase delayed-release capsules (CREON®) in correcting nitrogen malabsorption in subjects with CF in randomized, controlled trials. Pediatric Pulmonology 2010;45 Suppl 33:417. [ABSTRACT NO.: 547] [CENTRAL: 793539] [CFGD REGISTER: GN218c // GN214c]
Heubi 2007 {published data only}
    1. Heubi J, Boas SR, Blake K, Nasr SZ, Woo MS, Graff GR, et al. EUR-1008, a PEP, is safe and effective in cystic fibrosis (CF) patients with exocrine pancreatic insufficiency (EPI). Pediatric Pulmonology 2007;42 Suppl 30:392. [CFGD REGISTER: GN207b]
    1. Heubi J, Wooldridge J, Anelli M. Clinical response to pancreatic enzyme therapy correlates with diseases severity of exocrine pancreatic insufficiency ((EPI). In: Proceedings of the American Thoracic Society International Conference, May 16-21, 2008, Toronto, Canada. 2008:A863. [ABSTRACT NO.: #E16] [CFGD REGISTER: GN207i]
    1. Heubi JE, Boad SR, Blake K, Nasr SZ, Woo MS, Graff GR, et al. Zentase TM, a new PEP safe and effective treatment for EPI. In: Proceedings of the American Thoracic Society International Conference; 2008 May 16-21; Toronto, Canada. 2008:A863. [ABSTRACT NO.: #E17] [CFGD REGISTER: GN207j]
    1. Heubi JE, Boas SR, Blake K, Nasr SZ, Woo MS, Graff GR, et al. EUR-1008 (a new pancreatic enzyme product, PEP) was shown to be safe and effective in cystic fibrosis (CF) patients with exocrine pancreatic insufficiency (EPI). Journal of Cystic Fibrosis 2007;6 Suppl 1:S61. [CFGD REGISTER: GN207a] - PubMed
    1. Heubi JE, Straforini C, Thieroff-Ekerdt R. Switching CF patients from previous pancreatic enzyme replacement therapy to ZENPEP™ (pancrelipase delayed-release capsules) improves symptom control of exocrine pancreatic insufficieny. Journal of Cystic Fibrosis 2010;9 Suppl 1:S77. [ABSTRACT NO.: 299] [CFGD REGISTER: GN207g]
Heubi 2016 {published data only}
    1. Heubi J, Schaeffer D, Ahrens R, Sollo N, Strausbaugh S, Graff G, et al. A randomized, controlled clinical trial of a novel microbial lipase (NM-BL) in patients with exocrine pancreatic insufficiency due to cystic fibrosis. Pancreatology 2016;16(3 Suppl 1):S108. [CENTRAL: CN-01179133] [CFGD REGISTER: GN252d] [EMBASE: 72346107] - PubMed
    1. Heubi JE, Schaeffer D, Ahrens R, Sollo N, Strausbaugh S, Graff G, et al. Safety and efficacy of a novel microbial lipase (NM-BL) in patients with exocrine pancreatic insufficiency due to cystic fibrosis. Pediatric Pulmonology 2015;50 Suppl 41:402. [ABSTRACT NO.: 555] [CENTRAL: 1092206] [CFGD REGISTER: GN252a] - PubMed
    1. Heubi JE, Schaeffer D, Ahrens RC, Sollo N, Strausbaugh S, Graff G, et al. A randomized, controlled clinical trial of a liquid microbial lipase (NM-BL) in patients with exocrine pancreatic insufficiency due to cystic fibrosis. Journal of Cystic Fibrosis 2016;15 Suppl 1:S29. [ABSTRACT NO.: WS17.6] [CENTRAL: 1157595] [CFGD REGISTER: GN252b] - PubMed
    1. Heubi JE, Schaeffer D, Ahrens RC, Sollo N, Strausbaugh S, Graff G, et al. Safety and efficacy of a novel microbial lipase in patients with exocrine pancreatic insufficiency due to cystic fibrosis: a randomized controlled clinical trial. Journal of Pediatrics 2016;176:156-61. [CENTRAL: 1157596] [CFGD REGISTER: GN252c] [DOI: 10.1016/j.jpeds.2016.05.049] [PMID: ] - DOI - PubMed
Hill 1993 {published data only}
    1. Hill CM, Rolles CJ, Keegan P, Chand RA. Pancreatic enzyme supplementation in cystic fibrosis [letter]. Archives of Disease in Childhood 1993;68(1):150. [CFGD REGISTER: GN171] [MEDLINE: ] - PMC - PubMed
Hilman 1982 {published data only}
    1. Hilman B, LeBlanc M, Hawley S, Dufton-Gross N, Gines D, Tolman N, et al. Cross-over bioequivalence study of two pH sensitive enteric coated pancreatic enzymes in patients with cystic fibrosis. In: Proceedings of the 23rd Annual Meeting Cystic Fibrosis Club Abstracts; 1982 May 14; Washington D.C. 1982:122. [CFGD REGISTER: GN174]
Holsclaw 1979 {published data only}
    1. Holsclaw DS, Fahl JC, Keith HH. Enhancement of enzyme replacement therapy in cystic fibrosis (CF). In: Proceedings of the 20th Annual Meeting Cystic Fibrosis Club Abstracts; 1979 May 1; Atlanta, Georgia. 1979:19. [CFGD REGISTER: GN177]
Hubbard 1984 {published data only}
    1. Hubbard VS, Wolf RO, Lester LA, Egge AC. Diagnostic and therapeutic applications of bentiromide screening test for exocrine pancreatic insufficiency in patients with cystic fibrosis. Comparison with other tests of exocrine pancreatic disease. Digestive Diseases and Sciences 1984;29(10):881-9. [CFGD REGISTER: GN198] - PubMed
Kalnins 2005 {published data only}
    1. Kalnins D, Corey M, Ellis L, Durie PR, Pencharz PB. Combining unprotected pancreatic enzymes with pH-sensitive enteric-coated microspheres does not improve nutrient digestion in patients with cystic fibrosis. Journal of Pediatrics 2005;146(4):489-93. [CFGD REGISTER: GN202] - PubMed
Kalnins 2006 {published data only}
    1. Kalnins D, Ellis L, Corey M, Pencharz PB, Stewart C, Tullis E, et al. Enteric-coated pancreatic enzyme with bicarbonate is equal to standard enteric-coated enzyme in treating malabsorption in cystic fibrosis. Journal of Pediatric Gastroenterology and Nutrition 2006;42(3):256-61. [CFGD REGISTER: GN188b] - PubMed
    1. Kalnins D, Stewart C, Ellis L, Corey M, Tullis E, Pencharz PB, et al. Does the addition of bicarbonate to an enzyme microsphere preparation improve efficacy? Pediatric Pulmonology 1998;26 Suppl 17:355. [CFGD REGISTER: GN188a] [MEDLINE: ]
Katona 2000 {published data only}
    1. Katona DR, Nakamura CT, Bowman CM, Margetis M, Keens TG, Woo MS. Does pancreacarb improve the treatment of pancreatic insufficiency in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine 2000;161(3):A72. [CFGD REGISTER: GN197] [MEDLINE: ]
Khaw 1977 {published data only}
    1. Khaw KT, Adeniyi-Jones S, Gordon D, Palombo J, Coryer R, Schlaman C, et al. Comparative effectiveness of viokase, cotazym and pancrease in children with cystic fibrosis. In: 18th Cystic Fibrosis Club Abstracts; 1977. 1977:57. [CFGD REGISTER: GN160]
Konstan 2004 {published data only}
    1. Konstan M, Stern R, Trout R, Sherman J, Eigen H, Wagener J, et al. Ultrase MT12® and Ultrase MT20® in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy. Pediatric Pulmonology 2004;38 Suppl 27:339. [CENTRAL: 797027] [CFGD REGISTER: GN201a] - PubMed
    1. Konstan MW, Stern RC, Trout JR, Sherman JM, Eigen H, Wagener JS, et al. Ultrase MT12 and Ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy. Alimentary Pharmacology & Therapeutics 2004;20(11-12):1365-71. [CENTRAL: 514057] [CFGD REGISTER: GN201b] [PMID: ] - PubMed
Konstan 2008 {published data only}
    1. Coleman CI. Pancrelipase DR caps approved for EPI. Drug Topics 2012;156(8):www.drugtopics.com/treatment-areas/pancrelipase-dr-caps-approved-epi. [CENTRAL: CN-00902156] [CFGD REGISTER: GN209c] [EMBASE: 365719275] [www.drugtopics.com/treatment-areas/pancrelipase-dr-caps-approved-epi]
    1. Konstan MW, Accurso FJ, Nasr SZ, Ahrens RC, Graff GR. Efficacy and safety of a unique enteric-coated bicarbonate-buffered pancreatic enzyme replacement therapy in children and adults with cystic fibrosis. Clinical Investigation 2013;3(8):723-9. [CENTRAL: 918902] [CFGD REGISTER: GN209b] [EMBASE: 2013513339] - PMC - PubMed
    1. Konstan MW, Strausbaugh SD, Ahrens RC, Accurso FJ, Graff GR, Nasr SZ. A randomized, double-blind, placebo-controlled, multicenter, cross-over study to evaluate the effectiveness and safety of a novel pancrelipase (Pancrecarb® MS-16) in reducing steatorrhea in children and adults with cystic fibrosis. Pediatric Pulmonology 2008;43 Suppl 31:425. [CFGD REGISTER: GN209a]
Konstan 2010 {published data only}
    1. Konstan MW, Liou TG, Strausbaugh SD, Ahrens R, Kanga JF, Graff GR, et al. Efficacy and safety of a new formulation of pancrelipase (Ultrase MT20) in the treatment of malabsorption in exocrine pancreatic insufficiency in cystic fibrosis. Gastroenterology Research and Practice 2010. [CENTRAL: 889209] [CFGD REGISTER: GN239] [EMBASE: 2011059347] - PMC - PubMed
Kraisinger 1993 {published data only}
    1. Kraisinger M, Hendeles L, Stecenko A, Neiberger R. Hyperuricosuria associated with microencapsulated pancreated enzymes. Pediatric Pulmonology 1993;16 Suppl 9:269. [CFGD REGISTER: GN166]
Lancellotti 1996 {published data only}
    1. Lancellotti L, Cabrini G, Zanolla L, Mastella G. High- versus low-lipase acid-resistant enzyme preparations in cystic fibrosis: a crossover randomized clinical trial. Journal of Pediatric Gastroenterology and Nutrition 1996;22(1):73-8. [CFGD REGISTER: GN172] [MEDLINE: ] - PubMed
Lazaro 1990 {published data only}
    1. Lazaro A, Olivan G, Ros MI, Nebreda JR, Bueno M. Comparative trial between two pancreatine in enteric coated microspheres preparations in children with cystic fibrosis and steatorrhoea [Estudio comparativo cruzado de dos preparados de pancreatina en microesferas en una serie de ni±os con fibrosis quÝstica y esteatorrea.]. BoletÝn de la Sociedad de PediatrÝa de Arag¾n, La Rioja y Soria 1990;20:170-6. [CFGD REGISTER: GN193]
Leitz 2009 {published data only}
    1. Leitz GJ, Trapnell B, Strausbaugh S, Woo M, Shin-Yir T, Silber S, et al. A randomised double-blind (withdrawal) phase 3 study to evaluate the efficacy and tolerability of pancrease-mt capsules compared with placebo in the treatment of subjects with cystic fibrosis-dependent exocrine pancreatic insufficiency. Pediatric Pulmonology 2009;44 Suppl 32:407. [ABSTRACT NO.: 544] [CFGD REGISTER: GN213a]
    1. Trapnell BC, Strausbaugh SD, Woo MS, Tong S-Y, Silber SA, Mulberg AE, et al. Efficacy and safety of PANCREAZE for treatment of exocrine pancreatic insufficiency due to cystic fibrosis. Journal of Cystic Fibrosis 2011;10(5):350-6. [CENTRAL: 887395] [CFGD REGISTER: GN213b ] [EMBASE: 2011499244] - PubMed
Lubin 1979 {published data only}
    1. Lubin AH, Scott DH, Bonner JL. Failure of antacids to improve the effectiveness and/or utilization of pancreatic extracts in children with cystic fibrosis. In: Proceedings of the 20th Annual Meeting Cystic Fibrosis Club Abstracts; 1979 May 1; Atlanta, Georgia. 1979:57. [CFGD REGISTER: GN190]
Mack 1991 {published data only}
    1. Mack G, Cooper PJ, Buchanan N. Effects of enzyme supplementation on oral absorption of ciprofloxacin in patients with cystic fibrosis. Antimicrobial Agents and Chemotherapy 1991;35:1484-5. [CFGD REGISTER: PI135] - PMC - PubMed
Mischler 1980 {published data only}
    1. Mischler EH, Parrel SJ, Odell GB, Farrell PM. A controlled study of enteric coated pancreatic enzyme microspheres in patients with cystic fibrosis. In: Proceedings of the 21st Annual Meeting Cystic Fibrosis Club Abstracts; 1980 April 29; San Antonio, Texas. 1980:80. [CFGD REGISTER: GN161]
Mischler 1982 {published data only}
    1. Mischler EH, Parrell S, Farrell PM, Odell GB. Comparison of effectiveness of pancreatic enzyme preparations in cystic fibrosis. American Journal of Diseases of Children 1982;136(12):1060-3. [CFGD REGISTER: GN136] - PubMed
Morrison 1992 {published data only}
    1. Morrison G, Morrison J, Redmond A, Byers C, McCracken K, Dodge JA. Pancreatic enzyme supplements in cystic fibrosis [letter]. Lancet 1991;338:1596-7. [CFGD REGISTER: GN154b] [MEDLINE: ] - PubMed
    1. Morrison G, Morrison JM, Redmond AO, Byers CA, McCracken KJ, Dodge JA, et al. Comparison between a standard pancreatic supplement and a high enzyme preparation in cystic fibrosis. Alimentary Pharmacology & Therapeutics 1992;6(5):549-55. [CFGD REGISTER: GN154a] - PubMed
Munck 2009 {published data only}
    1. Munck A, Duhamel JF, Lamireau T, Le Luyer B, Le Tallec C, Bellon G, et al. Pancreatic enzyme replacement therapy for young cystic fibrosis patients. Journal of Cystic Fibrosis 2009;8(1):14-8. [CFGD REGISTER: GN204b] - PubMed
    1. Munck A. Creon® for children is preferred by parents of CF patients to Creon® 10000 MMS [abstract]. Journal of Cystic Fibrosis 2006;5 Suppl 1:S57. [CFGD REGISTER: GN204a]
Munoz 1987 {published data only}
    1. Munoz Conde J, Perez Perez M, Dapena Fernandes J. Cross-over comparison of creonR and pankreon granulateR in cystic fibrosis with steatorrhoea. In: Proceedings of the 15th Annual Meeting of the European Working Group for Cystic Fibrosis; 1987; Oslo, Norway. 1987. [CFGD REGISTER: GN163]
NCT00217204 {unpublished data only}
    1. NCT00217204. A phase II, randomized, investigator-blinded, parallel-group, pilot study evaluating the safety, palatability and effectiveness of four doses of pancrelipase microtablets in the treatment of infants and toddlers with cystic fibrosis-related pancreatic insufficiency and fat malabsorption [A phase II, randomized, investigator-blinded, parallel-group, pilot study evaluating the safety, palatability and effectiveness of four doses of pancrelipase microtablets in the treatment of infants and toddlers with cystic fibrosis-related pancreatic insufficiency and fat malabsorption]. clinicaltrials.gov/ct2/show/NCT00217204 (first posted 22 September 2005).
NCT00449904 {unpublished data only}
    1. NCT00449904. Open-label phase III long-term safety trial of liprotamase (DIGEST) [An open-label clinical study evaluating the long-term safety of ALTU-135 for the treatment of patients with cystic fibrosis-related exocrine pancreatic insufficiency]. clinicaltrials.gov/ct2/show/NCT00449904 (first posted 21 March 2007).
NCT01327703 {unpublished data only}
    1. NCT01327703. Control of steatorrhea in participants with cystic fibrosis and exocrine pancreatic nsufficiency [An open-label, multicenter, randomized, cross-over study to compare the safety and efficacy of PANZYTRAT® 25,000 to KREON® 25,000 in the control of steatorrhea in subjects aged 7 years and older with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI)]. clinicaltrials.gov/ct2/show/NCT01327703 (first posted 04 April 2011). [EUDRACT: 2010-019267-11]
NCT01652157 {unpublished data only}
    1. NCT01652157. Long-term study in US cystic fibrosis patients receiving digestive enzyme supplements to assess narrowing of the large intestine causing adverse intestinal symptoms (fibrosing colonopathy) [A long-term prospective observational safety study of the incidence of and risk factors for fibrosing colonopathy in US patients with cystic fibrosis treated with pancreatic enzyme replacement therapy: a harmonized protocol across sponsors (The CF-FC Study)]. clinicaltrials.gov/ct2/show/NCT01652157 (first posted 27 July 2012).
NCT01851694 {unpublished data only}
    1. NCT01851694. Beta-cell response to incretin hormones in cystic fibrosis [Determination of beta-cell responsiveness to the incretin hormones GLP-1 and GIP in cystic fibrosis]. clinicaltrials.gov/ct2/show/NCT01851694 (first posted 10 May 2013).
NCT01858519 {unpublished data only}
    1. NCT01858519. Prevalence of antibodies to selected porcine viruses in patients with cystic fibrosis receiving porcine-derived pancreatic enzyme replacement therapy [A point prevalence study to evaluate the prevalence of antibodies to selected porcine viruses in patients with cystic fibrosis who are receiving porcine-derived pancreatic enzyme replacement therapy: a harmonized protocol across sponsors]. clinicaltrials.gov/ct2/show/NCT01858519 (first posted 21 May 2013).
NCT02137382 {unpublished data only}
    1. NCT02137382. A double-blind, randomized, multicenter, cross-over study to compare the effect of Creon N and Creon® on fat digestion in subjects ≥ 12 years of age with pancreatic exocrine insufficiency due to cystic fibrosis. clinicaltrials.gov/ct2/show/NCT02137382 (first received 12 February 2014).
NCT03746483 {unpublished data only}
    1. NCT03746483. OPTION: a trial to assess the safety & efficacy of MS1819 in patients with exocrine pancreatic insufficiency due to cystic fibrosis (OPTION) [A phase 2, open-label, multicenter, 2x2 crossover trial to assess the safety and efficacy of MS1819-SD in patients with exocrine pancreatic insufficiency ued to cystic fibrosis]. clinicaltrials.gov/ct2/show/NCT03746483 (first posted 19 November 2018).
Neijens 1982 {published data only}
    1. Neijens HJ, Bouquet J, Sinaasappel M, Kerrebijn KF, Grose WFA. Comparison of the effects of pancreatic enzyme as acid-resistant microspheres to granules and of the addition of N-acetyl-cysteine on the malabsorption in CF. In: Proceedings of the 11th European Cystic Fibrosis Conference; 1982; Brussels. 1982:197. [CFGD REGISTER: GN179]
Perano 2014 {published data only}
    1. Kuo P, Stevens JE, Russo A, Maddox A, Wishart JM, Jones KL, et al. Gastric emptying, incretin hormone secretion, and postprandial glycemia in cystic fibrosis--effects of pancreatic enzyme supplementation. Journal of Clinical Endocrinolgy and Metabolism 2011;96(5):E851-5. [CFGD REGISTER: GN224a] - PubMed
    1. Perano SJ, Couper JJ, Horowitz M, Martin AJ, Kritas S, Sullivan T, et al. Pancreatic enzyme supplementation improves the incretin hormone response and attenuates postprandial glycemia in adolescents with cystic fibrosis: a randomized crossover trial. Journal of Clinical Endocrinology and Metabolism 2014;99(7):2486-93. [CFGD REGISTER: GN224b] - PubMed
Ritz 2004 {published data only}
    1. Ritz MA, Fraser RJ, Di Matteo AC, Greville H, Butler R, Cmielewski P, et al. Evaluation of the 13C-triolein breath test for fat malabsorption in adult patients with cystic fibrosis. Journal of Gastroenterology and Hepatology 2004;19(4):448-53. [CFGD REGISTER: GN200] - PubMed
Robinson 1989 {published data only}
    1. Robinson PJ, Olinsky A, Smith AL, Chitravanshi SB. High compared with standard dose lipase pancreatic supplement. Archives of Disease in Childhood 1989;64(1):143-5. [CFGD REGISTER: GN147b] - PMC - PubMed
    1. Robinson PJ, Olinsky A. Evaluation of a new enteric coated pancreatic enzyme. Excerpta Medica, Asia Pacific Congress Series 1988;74:G.I.(b)6. [CFGD REGISTER: GN147a]
Robinson 1998 {published data only}
    1. Robinson PJ, Natoli G. Comparison of high-dose and standard-dose pancreatic enzyme capsules in children with cystic fibrosis. Australian Journal of Hospital Pharmacy 1998;28(3):160-4. [CFGD REGISTER: GN191]
Santini 2000 {published data only}
    1. Santini B, Antonelli M, Battistini A, Bertasi S, Collura M, Esposito I, et al. Comparison of two enteric coated microsphere preparations in the treatment of pancreatic exocrine insufficiency caused by cystic fibrosis. Digestive Liver Disease 2000;32(5):406-11. [CFGD REGISTER: GN178b] - PubMed
    1. Santini B, Bertasi S, Collura M, Di Febbaro L, Ferrari R, Ferrero L, et al. Open label multicenter cross over study on two enteric coated microspheres in the treatment of CF pancreatic insufficiency. In: Proceedings of the 21st European Cystic Fibrosis Conference; 1997 June 1-6; Davos, Switzerland. 1997:170. [CFGD REGISTER: GN178a]
Shah 1993 {published data only}
    1. Shah A, Dinwiddie R, Madge S, Prescott P, Hudson G. High dose Nutrizym 22 in cystic fibrosis. European Journal of Pediatrics 1993;152(9):763-4. [CFGD REGISTER: GN156b] - PubMed
    1. Shah A, Hudson G, Madge S, Dinwiddie R. High dose Nutrizym 22 in cystic fibrosis. In: Proceedings of the 11th International Cystic Fibrosis Congress; 1992; Dublin, Ireland. 1992:TP78. [CFGD REGISTER: GN156a]
Sinaasappel 1998 {published data only}
    1. Sinaasappel M, Swart GR, Hoekstra JH, Houwen RH, Laag J, Gijsbers CF, et al. Double-blind, cross-over, study to prove the equivalence of creon 10000 minimicrospheres (MMS) versus creon 8000 microspheres (MS) in patients with cystic fibrosis (CF). Pediatric Pulmonology 1998;26 Suppl 17:358. [CFGD REGISTER: GN186]
Stapleton 2001 {published data only}
    1. Stapleton DR, Gurrin LC, Zubrick SR, Silburn SR, Sherriff JL, Sly PD. The effect of 'Go and Grow with CF' on nutrition and pancreatic enzyme knowledge of children with cystic fibrosis. Australian Journal of Nutrition and Dietetics 2001;58(3):164-8. [CFGD REGISTER: GN199]
Stern 2000 {published data only}
    1. Stern RC, Eisenberg JD, Wagener JS, Ahrens R, Rock M, doPico G, et al. A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency. American Journal of Gastroenterology 2000;95(8):1932-8. [CFGD REGISTER: GN192] - PubMed
Thomson 1993 {published data only}
    1. Thomson M, Clague A, Cleghorn GJ, Shepherd RW. Comparative in vitro and in vivo studies of enteric-coated pancrelipase preparations for pancreatic insufficiency. Journal of Pediatric Gastroenterology and Nutrition 1993;17(4):407-13. [CFGD REGISTER: GN157] - PubMed
Trapnell 2009 {published data only}
    1. Maguiness K, Graff G, Boyd D, Caras S, Beckmann K. Efficacy of Pacrealipase delayed-release capsules (CREON®) in correcting nitrogen malabsorption in subjects with CF in randomized controlled trials. Pediatric Pulmonology 2010;45 Suppl 33:417. [ABSTRACT NO.: 547] [CFGD REGISTER: GN214c // GN218c]
    1. Pollack P, Sander-Struckmeier S, Beckmann K, Janssen-Van Solingen G. No effect of drugs reducing gastric acid production on the efficacy of pancrelipase delayed-release capsules (CREON) in randomized trials of patients with exocrine pancreatic insufficiency. American Journal of Gastroenterology 2011;106:S53. [CFGD REGISTER: GN214e]
    1. Trapnell B, Maguiness K, Graff G, Boyd D, Caras S, Beckmann K. Pancrelipase delayed-release capsules (Creon®) in patients with pancreatic insufficiency due to CF: age and severity analyses. Pediatric Pulmonology 2009;44 Suppl 32:402. [ABSTRACT NO.: 531] [CFGD REGISTER: GN214a]
    1. Trapnell BC, Maguiness K, Graff G, Boyd D, Beckmann K, Caras S. Efficacy and safety of Creon® 24,000 in subjects with exocrine pancreatic insufficiency due to cystic fibrosis. Journal of Cystic Fibrosis 2009;8(6):370-7. [CFGD REGISTER: GN214d] - PubMed
    1. Trapnell BC, Maguiness K, Graff GR, Boyd D, Caras SD. Efficacy and safety of a new formulation of CREON® in patients with exocrine pancreatic insufficiency due to CF. Journal of Cystic Fibrosis 2009;8 Suppl 2:S80. [ABSTRACT NO.: 323] [CFGD REGISTER: GN214b] - PubMed
van der Haak 2016 {published data only}
    1. Haak N, Boase J, Davidson G, Butler R, Miller M, Kaambwa B, et al. Preliminary report of the (13)C-mixed triglyceride breath test to assess timing of pancreatic enzyme replacement therapy in children with cystic fibrosis. Journal of Cystic Fibrosis 2016;15(5):669-74. [CENTRAL: 1157597] [CFGD REGISTER: GN258] [DOI: 10.1016/j.jcf.2016.03.008] [PMID: ] - DOI - PubMed
Van de Vijver 2011 {published data only}
    1. Van de Vijver E, Desager K, Mulberg AE, Staelens S, Verkade HJ, Bodewes FA, et al. Treatment of infants and toddlers with cystic fibrosis-related pancreatic insufficiency and fat malabsorption with pancrelipase MT. Journal of Pediatric Gastroenterology and Nutrition 2011;53(1):61-4. [CENTRAL: 799167] [CFGD REGISTER: GN240] [PMID: ] - PubMed
Vitti 1975 {published data only}
    1. Vitti TG, Berg TJ, Pagtakhan RD. The effect of pancreatic enzyme supplement on the intestinal absorption of ampicillin and cloxacillin in children with cystic fibrosis. In: Proceedings of the 16th Cystic Fibrosis Club Abstracts; 1975. 1975:56. [CFGD REGISTER: PI81]
Warwick 1982 {published data only}
    1. Warwick WJ, Budd JR. Comparison of cotayme-S and pancrease. In: Proceedings of the 23rd Annual Meeting Cystic Fibrosis Club Abstracts; 1982 May 14; Washington D.C.. 1982:145. [CFGD REGISTER: GN175]
Weber 1979 {published data only}
    1. Weber AM, Gheldere B, Roy CC, Fontaine A, Dufour OL, Morin CL, et al. Effectiveness of enteric coated pancrease in cystic fibrosis (CF) children under 4 years old. In: Proceedings of the 20th Annual Meeting Cystic Fibrosis Club Abstracts; 1979 May 1; Atlanta, Georgia. 1979:18. [CFGD REGISTER: GN176]
Wooldridge 2009 {published data only}
    1. Wooldridge JL, Heubi JE, Amaro-Galvez R, Boas SR, Blake KV, Nasr SZ, et al. EUR-1008 pancreatic enzyme replacement is safe and effective in patients with cystic fibrosis and pancreatic insufficiency. Journal of Cystic Fibrosis 2009;8(6):405-17. [CFGD REGISTER: GN212b] - PubMed
    1. Wooldridge JL, Heubi JE, Thieroff-Ekerdt R. Exploratory analysis of the effect of dosing options on the efficacy of EUR-1008 (Zenpep) in young children with CF and exocrine pancreatic insufficiency. Pediatric Pulmonology 2009;44 Suppl 32:411. [ABSTRACT NO.: 554] [CFGD REGISTER: GN212a]
    1. Wooldridge JL, Schaeffer D, Jacobs D, Thieroff-Ekerdt R. Long-term safety assessment of Zenpep® (pancrelipase delayed-release capsules) in infants aged 1-12 months with exocrine pancreatic insufficiency associated with cystic fibrosis. Pediatric Pulmonology 2012;47(S35):418. [ABSTRACT NO.: 531] [CFGD REGISTER: GN225]
Zentler 1992 {published data only}
    1. Assoufi BA, Zentler-Munro P, Cornell S, Northfield TC, Hodson ME. Efficacy of acid resistant fungal lipase in the treatment of steatorrhoea due to adult cystic fibrosis. Pediatric Pulmonology 1988;5(Suppl 2):145. [CFGD REGISTER: GN151a] - PubMed
    1. Zentler Munro PL, Assoufi BA, Balasubramanian K, Cornell S, Benoliel D, Northfield TC, et al. Therapeutic potential and clinical efficacy of acid-resistant fungal lipase in the treatment of pancreatic steatorrhoea due to cystic fibrosis. Pancreas 1992;7(3):311-9. [CFGD REGISTER: GN151b] - PubMed

References to studies awaiting assessment

Brekke 2019 {published data only}
    1. Brekke G, Terp Raun AM, Molgaard C, Pressler T, Skov M. Impact of administration mode of Pancreatic Enzyme Replacement Therapy (PERT) on abdominal pain, bowel habits and quality of life (QoL) in children and adolescents with cystic fibrosis - a randomised cross-over intervention study: preliminary data. Journal of Cystic Fibrosis 2019;18 Suppl:S137. [ABSTRACT NO.: P283] [CENTRAL: CN-01990654] [CFGD REGISTER: GN287] [EMBASE: 2001976059]
Holsclaw 1980 {published data only}
    1. Holsclaw DS, Keith H. Long-term benefits of pH-sensitive enteric-coated enzymes in CF. In: Proceedings of the 8th International Cystic Fibrosis Congress; 1980; Toronto, Canada. 1980:19a. [CFGD REGISTER: GN137]
Knill 1973 {published data only}
    1. Knill Jones RP, Pearce H, Batten PJ, Williams R. Comparative double-blind experience of a polyenzymatic preparation in chronic pancreatic insufficiency (author's transl) [Essai comparatif en double insu d'une preparation polyenzymatique dans l'insuffisance pancreatique chronique.]. Acta Gastroenterologica Belgica 1973;36(9):489-504. [CFGD REGISTER: GN132] - PubMed
Konstan 2018b {published data only}
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Lenoir 2008 {published data only}
    1. Lenoir G, Dubray C, Hubert D, Chiron R, Philippe P, Sarles J. Phase 2 study in young CF adults with the recombinant acid lipase MERISPASE®. Journal of Cystic Fibrosis 2008;7 Suppl 2:S29. [CFGD REGISTER: GN208]
Regele 1996 {published data only}
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Stern 1988 {published data only}
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References to ongoing studies

NCT03924947 {unpublished data only}
    1. NCT03924947. A study to compare US marketed pancrelipase drug product with drug product manufactured with a modernized process at an alternate manufacturing site, in participants with exocrine pancreatic insufficiency due to cystic fibrosis [A phase 4 study to compare US marketed Creon drug product with drug product manufactured with a modernized process at an alternate manufacturing site, in participants with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis]. clinicaltrials.gov/ct2/show/NCT03924947 (first posted 23 April 2019).

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References to other published versions of this review

Somaraju 2014
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Associated data