Pancreatic enzyme replacement therapy for people with cystic fibrosis

Usha Rani Somaraju; Arturo Solis‐Moya

doi:10.1002/14651858.CD008227.pub2

Traitement substitutif par enzymes pancréatiques pour les personnes atteintes de mucoviscidose

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Referencias

References to studies included in this review

Ir a:

estudios excluidos
estudios a la espera de valoración
otras referencias

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References to studies excluded from this review

Ir a:

estudios incluidos
estudios a la espera de valoración
otras referencias

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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]

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References to studies awaiting assessment

Ir a:

estudios incluidos
estudios excluidos
otras referencias

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos
estudios a la espera de clasificación

Assoufi 1994

Methods	Randomised, double‐blind cross‐over trial. Duration: there was a run‐in period (duration not specified) followed by randomisation to 1 of 2 arms. 28 days in each arm. UK based. Home setting.
Participants	17 patients diagnosed with CF. Age: 18 to 42 years.
Interventions	Group 1: Nutrizyme GR (10000 BP units of lipase). Group 2: Nutrizyme 22 (22000 BP units of lipase). Lipase intake was equivalent to previous intake of patients and was kept constant during the trial.
Outcomes	Weight gain, appetite, stool consistency, stool frequency and FFE.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information not given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	Low risk	When on Nutrizyme 22, patients took an equal number of placebo capsules and high‐dose enzyme capsules to make the total number of capsules the same as when taking Nutrizyme GR.
Blinding of participants and personnel (performance bias) Clinicians	Unclear risk	Information not given.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Information not given.
Incomplete outcome data (attrition bias) All outcomes	High risk	1 patient withdrew after the run‐in period; reason was not given.
Selective reporting (reporting bias)	High risk	SDs were not presented for the outcome faecal fat excretion; other outcomes were reported in a way, that could not be included in analysis.
Other bias	Unclear risk	Information not given.

Borowitz 2005

Methods	Randomised, double‐blind, 3‐arm parallel, dose‐ranging, multicentre trial. Duration: 29 days. Participants recruited from 26 CF Foundation‐accredited centres in the USA. Home setting.
Participants	139 patients with previously diagnosed CF and undergoing treatment were screened and 129 enrolled as intention‐to‐treat population. Age: mean (SD) 21.5 (8.5) years. Gender split: 71% were males.
Interventions	Group 1: Altu‐135 5000 units of lipase. Group 2: Altu‐135 25,000 units of lipase. Group 3: Altu‐135 100,000 units of lipase. Doses were not adjusted on basis of weight or food ingested, but were fixed per meal or snack. Lipase, protease & amylase were in a ratio of 1:1:0.15
Outcomes	CFA, CNA, adverse events, QoL using the CFQ‐R.
Notes	The CFA and CNA were measured at baseline and at 14 days after randomisation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised, but further information not given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	Low risk	All participants received equal number of unlabelled capsules.
Blinding of participants and personnel (performance bias) Clinicians	Unclear risk	Information not given.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Information not given.
Incomplete outcome data (attrition bias) All outcomes	Low risk	129 participants were enrolled as intention‐to‐treat population, of whom 12 withdrew (4 due to gastrointestinal adverse events); 117 patients who received at least 1 dose were included in a modified intention‐to‐treat analysis.
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported.
Other bias	High risk	Trial sponsored and actively supported by Altus Pharmaceuticals.

Elliott 1992

Methods	Randomised, double‐blind, cross‐over trial. Duration: 4 weeks for each treatment arm with a 2 week run‐in period. Single‐centre trial in New Zealand. Home setting.
Participants	30 children previously diagnosed with CF using clinical and laboratory data. Age: median 10.1 years. Gender split: 17 girls, 13 boys.
Interventions	Group 1: Creon® (lipase 8000 BP, amylase 9000 BP, protease 210 BP). Group 2: Pancrease® (lipase 5000 BP, amylase 3000 BP, protease 350 BP). Participants were started on doses of lipase slightly lower or equivalent to pretrial period. Later they were allowed to adjust according to their requirement.
Outcomes	Mean weight gain, adequate daily intake of energy, fat and nitrogen, stool weight, FFE and nitrogen excretion.
Notes	For the outcomes of interest to the review, the results were given in a descriptive method; means and SDs not given.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information not given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	Low risk	Both formulations were prepared in identical opaque capsules from commercial stock.
Blinding of participants and personnel (performance bias) Clinicians	Unclear risk	Information not given.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Information not given.
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 patients withdrew consent and 1 patient was hospitalised due to respiratory exacerbations during the run‐in period.
Selective reporting (reporting bias)	High risk	Results were reported in a narrative method and could not be included in analysis
Other bias	High risk	Boehringer Ingelheim (NZ) Limited Kali Chemie provided funding and trial materials.

Henker 1987

Methods	Randomised, open‐label, cross‐over trial. Duration: each arm was for 4 weeks. No run‐in period specified. Single centre in the former East Germany.
Participants	45 patients with CF. Age: mean 11.8 years. Gender split: 24 boys and 21 girls.
Interventions	Group 1: Pancreon forte (conventional). Group 2: Creon® (acid protected microspheres).
Outcomes	Weight gain, height, stool frequency, FFE.
Notes	Outcomes were given in a descriptive method.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information not given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	High risk	No blinding.
Blinding of participants and personnel (performance bias) Clinicians	High risk	No blinding.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Information not given.
Selective reporting (reporting bias)	High risk	Narrative results only ‐ could not be included in analysis.
Other bias	Unclear risk	Information not given.

Lacy 1992

Methods	Randomised, double‐blind, 3‐arm cross‐over trial of 3 different ECMs. Duration: each treatment arm lasted 4 weeks after an initial 2 week run‐in period. Single‐centre trial based in the UK.
Participants	22 children with CF. Age: 5 ‐ 16 years. Gender split not given.
Interventions	Group 1: Nutrizyme GR. Group 2: Nutrizyme MP. Group 3: Creon®. The preparations were compared in a capsule for capsule basis, even though there was a difference in enzyme content.
Outcomes	Symptom scores, weight gain and CFA.
Notes	Results were given descriptively.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information not given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Clinicians	Unclear risk	Information not given.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Information not given.
Incomplete outcome data (attrition bias) All outcomes	High risk	4 patients withdrew from study, reasons were not given.
Selective reporting (reporting bias)	High risk	Outcomes were reported in a way that could not be included in analysis.
Other bias	Unclear risk	Information not given.

Patchell 1999

Methods	Prospective, randomised, open‐label, cross‐over trial. Duration: treatment was for a period of 10 weeks; 2 weeks run in, followed by randomisation to 1 of the 2 arms for 4 weeks, and then cross over to alternative treatment for the next 4 weeks. Multicentre trial at 3 hospitals in the UK.
Participants	59 children with CF, diagnosed by 2 sweat tests or genotype, had proven pancreatic insufficiency. Age : mean (SD) age of 10 (3.5) years. Gender split: not given.
Interventions	Group 1: ECM (Creon 8000 MS). Group 2: ECMM (Creon 10000 MMS). Dose was lipase for lipase. The median intake of lipase/kg body weight/day was 6689 for Creon 8000 and 8527 for Creon 10000.
Outcomes	FFE, CFA, stool frequency, abdominal pain, patient preference.
Notes	The stool collection for CFA was done only in 1 centre, with 22 patients.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised, further information not given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	High risk	No blinding.
Blinding of participants and personnel (performance bias) Clinicians	High risk	No blinding.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Stool collection data were from 1 hospital only with 22 patients in an intent‐to‐treat analysis. 54 patients completed the trial, 2 dropped out in run‐in period due to abdominal pain and loose stools; a further 2 dropped out during the ECMM phase (1 due to abdominal pain and loose stools and 1 due to meconium ileus equivalent). The 5th patient dropped out during the ECMM phase due to an appendix abscess considered to be unrelated to treatment.
Selective reporting (reporting bias)	High risk	Data on stool frequency and abdominal pain reported in a way that could not be included in the analysis.
Other bias	Low risk	Trial appears to be free of other sources of bias.

Petersen 1984

Methods	Randomised, double‐blind, cross‐over trial. Duration: each treatment arm lasted 4 weeks; no run‐in period. Not clear if a single or multicentre trial based in Denmark.
Participants	11 children with documented CF. Age: 2 ‐ 11 years of age. Gender split: 2 males and 9 females.
Interventions	Group 1: pH sensitive ECM Pancrease (1 ‐ 2 capsules containing 330 FIP‐u protease, 6200 FIP‐u lipase, 3600 FIP‐u amylase/capsule). Group 2: conventional ECM Pancreatin (10 ‐ 35 ml containing 525 FIP‐u trypsin, 12000 FIP‐u lipase, 12750 FIP‐u amylase). Patients were allowed to change doses depending on individual requirements
Outcomes	Symptom scores for stool frequency, consistency, colour, odour and abdominal cramps; weight gain; fat absorption.
Notes	Results reported as medians.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information not given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	Low risk	During both periods placebo preparations were given in the form of capsules or granules.
Blinding of participants and personnel (performance bias) Clinicians	Unclear risk	Information not given.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Information not given.
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were no withdrawals, with all 11 patients completing the study.
Selective reporting (reporting bias)	High risk	The results were reported in medians due to which the data could not be included in the analysis.
Other bias	Low risk	No other sources of bias were found.

Stead 1986

Methods	Open‐label randomised cross‐over trial. Duration: 2 consecutive 28‐day treatment periods. Single centre in the UK (Brompton Hospital Adolescent and Adult Cystic Fibrosis Clinic, London).
Participants	23 patients with CF diagnosed by sweat chloride concentration > 70 mmol/L, evidence of pancreatic insufficiency and symptomatic steatorrhoea. Age: mean (SD) 24.8 (4.2) years. Gender split: 11 males and 12 females.
Interventions	Group 1: ECM (Creon capsules). Group 2: ECT (Pancrex V Forte). Patients received either their usual regimen of ECT or ECM in a ratio of 0.7 capsules for each ECT. Declared lipase of Pancrex V forte to Creon capsules is 0.7:1, protease is 1.6 : 1.
Outcomes	Change in weight, frequency of stools, abdominal pain, FFE and CFA.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised but no further information given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	High risk	No blinding.
Blinding of participants and personnel (performance bias) Clinicians	High risk	No blinding.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 patients withdrew from study and reasons were given. 1 patient was unable to swallow microsphere capsules and another took more lipase during 1 month than the other.
Selective reporting (reporting bias)	Low risk	Expected outcomes are reported.
Other bias	Unclear risk	Trial supported by Duphar Laboratories.

Stead 1987

Methods	Open‐label, randomised, cross‐over trial. Duration: 2 consecutive 28‐day treatment periods. Single centre in the UK.
Participants	14 patients with CF, diagnosed by sweat chloride > 70 mmol/L and typical pulmonary disease. Age: mean 21.4 years. Gender split: 8 males and 6 females.
Interventions	Group 1: ECM (Creon) with food. Group 2: NECT (Pancrex V) with food and adjuvant cimetidine 40 min before meals. Both contain 8000 BP units of lipase, number of capsules for each individual was same during both treatment periods.
Outcomes	Change in weight, stool frequency, abdominal pain, FFE and CFA.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised, but further information not given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	High risk	No blinding.
Blinding of participants and personnel (performance bias) Clinicians	High risk	No blinding.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	1 patient withdrew due to inability to control frequency of stools. The treatment arm was not specified.
Selective reporting (reporting bias)	Low risk	Expected outcomes are reported.
Other bias	Unclear risk	Creon® was supplied by Duphar Laboratories.

Vidailhet 1987

Methods	Randomised, 2‐arm cross‐over trial. Duration: after an 8‐day initial washout each treatment given for a period of 30 days. Single‐centre trial in France. Home setting.
Participants	17 children with documented CF. Age: 1 ‐ 12.5 years. Gender split was not given.
Interventions	Group 1: ECM (Creon®) (1.2 ‐ 2.4 g/day). Group 2: lyophilised TPE (4 ‐ 8 g/day).
Outcomes	Body weight, FFE, nutritional indicators (body weight to length index, subscapular skin fold, plasma cholesterol, pre‐albumin, retinol, retinol binding protein, zinc and total essential fatty acids), therapeutic tolerance (drug acceptance, alanine amino transferase, prothrombin time, serum bilirubin and uric acid, urinary uric acid excretion).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised, but further information not given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Clinicians	Unclear risk	Information not given.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Information not given.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Information not given.
Selective reporting (reporting bias)	High risk	Change in body weight was incompletely reported and cannot be included in the review.
Other bias	Unclear risk	Information not given.

Vyas 1990

Methods	Randomised, double‐blind, double‐placebo cross‐over trial. Duration: 4 weeks for each treatment arm. Single‐centre trial in the UK (London).
Participants	20 children with CF diagnosed by sweat test sodium greater than 70 mmol/L Age: mean 9.9 years; range 4.1 ‐ 15.3 years. All had steatorrhoea and weight and height above 3rd percentile. The mean weight was 26.0 kg (range 14.2 kg ‐ 50.7 kg) and the mean height was 1.32 metres (range 1.1 metres ‐ 1.63 metres). Gender split not given.
Interventions	Group 1: active ECM plus placebo ECT. Group 2: placebo ECM plus active ECT. Dosage of ECM was calculated to provide equivalent dosage of lipase to ECT. The day‐to‐day dosage of active drug and placebo varied slightly depending on the patients diet.
Outcomes	Change in weight, stool frequency, abdominal pain, FFE.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised, but further information not given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	Low risk	While taking ECM, patients received a placebo of ECT and while taking ECT, they took a placebo preparation of ECM.
Blinding of participants and personnel (performance bias) Clinicians	Unclear risk	Information not given.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Information not given.
Incomplete outcome data (attrition bias) All outcomes	High risk	Only 12 paired samples were analysed for FFE.
Selective reporting (reporting bias)	Low risk	Expected outcomes are reported.
Other bias	High risk	Duphar Ltd, UK supplied pancreatic enzyme supplements and supported the trial.

Williams 1990

Methods	Randomised, single blind cross‐over trial. Duration: 10 weeks in total, 2‐week run‐in period followed by 4 weeks for each treatment arm. Not clear if multi‐ or single‐centre trial based in the UK. Home setting.
Participants	39 children with symptoms of CF, at least 2 abnormal sweat chloride results and pancreatic insufficiency. Age: median (range) 9.7 (5 ‐ 17) years. Clinical state, as measured by the Shwachman score (100 = normal) ranged from 37 to 91 with a median value of 79. 12 patients were unsuitable for analysis, the remaining 27 children (15 boys and 12 girls) completed the trial.
Interventions	Group 1: ECM Creon® (lipase 8000 BP units, amylase 9000 BP units, protease 210 BP units). Group 2: ECM Pancrease® (lipase 5000 BP units, amylase 2900 BP units, protease 330 BP units). Participants took same number of capsules per day during both treatment periods.
Outcomes	CFA, patient preference, nitrogen excretion, weight change, symptom score for appetite, number, colour and consistency of stools, abdominal pain and general condition.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised, but further information not given.
Allocation concealment (selection bias)	Unclear risk	Information not given.
Blinding of participants and personnel (performance bias) Participants	High risk	Blinding not done.
Blinding of participants and personnel (performance bias) Clinicians	Low risk	Trial medication was issued by pharmacist and order of treatment was not known to the doctor.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding not done.
Incomplete outcome data (attrition bias) All outcomes	High risk	12 patients (31%) were withdrawn from trial for various reasons and not included in analysis: 7 withdrew because of respiratory exacerbations or infective illnesses that interfered with dietary intake such that their standard individualised menu could not be followed; 1 failed to attend for follow up; 1 withdrew because of intolerable symptoms of steatorrhoea on Pancrease®, further assessment on Creon® (her usual treatment) showed poor control of fat malabsorption with a CFA of 77%; 3 patients inadvertently took unequal numbers of capsules during the 2 treatment periods and were therefore excluded from the analysis.
Selective reporting (reporting bias)	High risk	Change in weight and symptom scores for abdominal pain, stool frequency were measured but were reported incompletely, so cannot be entered in a meta‐analysis.
Other bias	High risk	Corresponding author was financially supported by Cilag Limited (Pancrease).

CF: cystic fibrosis
CFA: co‐efficient of fat absorption
CFQ‐R: Cystic Fibrosis Questionnaire‐Revised
CNA: co‐efficient of nitrogen absorption
ECM: enteric‐coated microspheres
ECMM; enteric‐coated mini‐microspheres
ECT: enteric‐coated tablets
FFE: faecal fat excretion
NECT: non enteric‐coated tablets
QoL: quality of life
SD: standard deviation
TPE: total pancreatic extracts

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos
estudios a la espera de clasificación

Study	Reason for exclusion
Ansaldi 1988	Cross‐over study with PERT for 5 days in each arm.
Araujo 2011	Doesn't appear to have a control group, PERT dosage increased according to fecal fat levels.
Beker 1994	Cross‐over study with PERT for 3 days in each arm.
Beverley 1987	Cross‐over study with 3 arms of 15 days each.
Borowitz 2008	The study drugs were given for a period of 6 days only after randomisation.
Bouquet 1988	Cross‐over study with each treatment period only 2 weeks.
Bowler 1993	Crossover study with 2 arms of 2 weeks each.
Brady 1991	Crossover study with 2 arms of 7 days each.
Brady 1992	Cross‐over study of enzymes given before and during meals; 2 periods of 1 week each.
Brady 2006	Cross‐over study with 2 treatment periods of 1 week each.
Breuel 1996	Study assesses pancreatic enzyme activity.
Butt 2001	Study assesses breath tests.
Chazalette 1988	Open label cross‐over study with periods of 1 week each.
Chazalette 1993	Parallel group study for a period of 8 days.
Colombo 2001	Study compares different methods for assessing exocrine pancreatic function.
De Boeck 1998	Single dose intervention.
Desager 2006	Parallel study period of 10 days.
Duhamel 1988	Cross‐over study with 2 periods of 8 days each.
Duhamel 1998	Cross‐over study with 2 periods of 14 days each. Study assessed patient preference, but also assessed clinical symptoms.
Durie 1980	Cross‐over study with 4 preparations given for 1 week each.
Dutta 1988	Crossover study with each intervention given only on a single day.
Easley 1998	Cross‐over study with each intervention given only on a single day.
Ellis 1994	Cross‐over study (assessing coating of PERT) with 2 weeks in each arm.
Foucaud 1989	Placebo‐controlled, parallel study but treatment period for 1 week.
Gan 1994	Cross‐over study with 2 arms of 14 days each.
Goodchild 1974	Cross‐over study with 2 weeks in each arm.
Gow 1981	Cross‐over study of 4 periods of 14 days each.
Graff 2010	Intervention only give for 5 days.
Heubi 2007	Cross‐over placebo‐controlled trial with 2 periods of 1 week each.
Hill 1993	Letter reports cross‐over trial to compare patient preference of different formulations; no other outcomes stated.
Hilman 1982	Cross‐over study with a total 2‐week study period.
Holsclaw 1979	Cross‐over study of 6 treatment (Viokase vs Cotazyme vs Pancrelipase with and without bicarbonate) periods of 3 weeks each.
Hubbard 1984	Study assesses use of bentiromide screening test.
Kalnins 2005	Cross‐over study with 2 treatment periods of 2 weeks each.
Kalnins 2006	Cross‐over study with 2 treatment periods of 14 days each.
Katona 2000	Not an RCT or a quasi‐RCT.
Khaw 1977	Cross‐over study with two treatment periods of 12 days each.
Konstan 2004	Intervention given only for 6 days.
Konstan 2008	Cross‐over trial with 2 treatment periods of 5 days each.
Konstan 2010	Treatment only 6 to 7 days in each arm of the 2‐phase cross‐over trial.
Kraisinger 1993	Cross‐over trial with 2 treatment periods of 4 days each.
Kuo 2011	Cross‐over trial with 2 single interventions on separate days.
Lancellotti 1996	Open‐label, cross‐over study with 2 treatment periods of 5 days each.
Lazaro 1990	Cross‐over trial with 2 periods of 6 days each.
Leitz 2009	Placebo‐controlled trial with a treatment period of 1 day.
Lubin 1979	Study assesses use of antacids in conjunction with PERT intervention not relevant.
Mack 1991	Cross‐over study assessing antibiotic absorption with PERT compared to without in a single intervention.
Mischler 1980	Cross‐over study with 2 arms of 5 days each.
Mischler 1982	Cross‐over trial 2 periods of 5 days each.
Morrison 1992	Not an RCT or quasi‐RCT.
Munck 2009	Cross‐over study with 2 treatment periods of 2 weeks each.
Munoz 1987	Cross‐over study with 2 treatment periods of 1 week each.
Neijens 1982	Cross‐over study with treatment periods of 2 weeks each.
Ritz 2004	Study evaluated a breath test used to assess fat malabsorption and not PERT.
Robinson 1989	Cross‐over study with 2 treatment periods of 2 weeks each.
Robinson 1998	Cross‐over study with 2 periods of 2 weeks each.
Santini 2000	Cross‐over study with 2 treatment periods of 1 week each.
Shah 1993	PERT taken for 2‐week period only.
Sinaasappel 1998	Cross‐over trial with 2 periods of 14 days each.
Stapleton 2001	Study assessing knowledge and education of PERT.
Stern 2000	Parallel RCT but duration only 5 ‐ 7 days.
Thomson 1993	Cross‐over trial with 3 periods of 7 days each.
Trapnell 2009	Cross‐over RCT with 5‐day course of PERT and same for placebo.
Van de Vijver 2011	Treatment period only 5 days.
Vitti 1975	Study assesses antibiotic absorption when given with PERT.
Warwick 1982	Cross‐over study with 2 treatment periods of 1 week each.
Weber 1979	Cross‐over study with 2 periods of 8 days each.
Wooldridge 2009	Cross‐over study with 2 periods of 7 days each.
Wooldridge 2012	Not an RCT or quasi RCT.
Zentler 1992	RCT with 3 interventions for 2 weeks each.

PERT: pancreatic enzyme replacement therapy
RCT: randomized controlled trial
vs: versus

Characteristics of studies awaiting assessment [ordered by study ID]

Ir a:

estudios incluidos
estudios excluidos

Dalzell 1992

Methods	Randomized, double‐blind, cross‐over trial. Duration: 12 months. UK‐based trial.
Participants	20 patients with CF and chronic distal intestinal obstruction. Mean age: 13.1 years. Gender split: 4 males and 16 females.
Interventions	Group 1: low‐dose PERT. Group 2: high‐dose PERT.
Outcomes	Weight gain, CFA, episodes of acute distal intestinal obstruction syndrome, abdominal mass, abdominal pain.
Notes	Results given in ranges. Await further details from authors.

Holsclaw 1980

Methods	Possibly randomised, not clear. Duration: 14 months for intervention, control not clear. USA‐based trial.
Participants	20 patients with CF.
Interventions	Pancrease (enteric‐coated) ‐ dose 9 to 11 per day ‐ compared with usual supplement (Viokase or Cotazyme) for a period of 14 months in pancrease arm, duration of other usual supplement not given.
Outcomes	Body weight, urine uric acid, serum albumin, abdominal symptoms.
Notes	Not stated whether patients were randomised or not. Possible extension of excluded study Holsclaw 1979.

Knill 1973

Methods	Randomised double‐blind cross‐over trial with 3 arms. Duration: 3 months in total, each arm lasted 1 month, not clear if washout period was used.
Participants	11 patients with CF and 1 patient with chronic pancreatitis. All adults.
Interventions	Pancrex V Forte: 3 tablets equivalent to 3 g pancreatine BP. Nutrizym: 2 tablets equivalent to 3.2 g pancreatine BP. Nutrizym plus bromelin: 2 tablets equivalent to 3.2 g pancreatine BP also containing 50g bromelin. Nutrizym tablets looked the same whether containing bromelin or not, but not identical to Pancrex V Forte. Patients not allowed to tell outcome assessors how many tablets they were taking.
Outcomes	Self‐reported bowel habits, general health and respiratory symptoms (daily diary), FFE.
Notes	Combined data given for all patients (CF data not split out). Full trial in French ‐ needs translation. 2 patients who had been on high doses of Pancrex V Forte (9 ‐ 12 per meal) took double the normal preparations in the trial.

Lenoir 2008

Methods	Single blind cross‐over and parallel design. Single‐centre trial.
Participants	24 adult CF patients.
Interventions	Recombinant acid lipase marketed as MERISPASE® Session 1: all patients received low‐dose pancreatic extract. Session 2: 3 different doses of lipase (MERISPASE®) compared with 84,000 units of pancreatic extract. Session 3: all patients received low doses of CREON®, 3 groups receiving MERISPASE® continued.
Outcomes	Safety, tolerance, CFA.
Notes	Meristem Therapeutics went out of business in September 2008; clinical trials blocked in phase II. No one appears to be producing or using this agent.

Regele 1996

Methods	Randomised, double‐blind cross‐over study without placebo. Duration : 28 days in each arm. Not clear if single centre or multicentre, based in Germany.
Participants	16 patients (9 females, 7 males) diagnosed with CF by at least 2 sweat chloride values of ≽ 70 mM and pancreatic insufficient. Age: mean 9.9, range 3 ‐ 27.
Interventions	Treatment A: Kreon 25000 (per capsule: 25000 U of lipase, 18000 U of amylase and 1000 U of protease). Treatment B: Panzyrtat (per capsule: 20000 U of lipase, 18000 U of amylase and 1000 U of protease). Both groups received the same number of capsules in each arm.
Outcomes	FFE, faecal chymotrypsin, faecal immunoreactive human lipase and serum immunoreactive trypsin.
Notes	Mean FFE for both the arms together was given. FFE for individual treatment periods not given.

Taylor 1993

Methods	Open prospective trial; not clear if randomised. Cross‐over trial, each arm 3 months. Consecutive so implies no washout.
Participants	23 patients with CF. Age: range 1.3 ‐ 16.8 years.
Interventions	Creon 25000 compared with conventional microsphere preparations.
Outcomes	FFE, BMI, height SD score, lean body mass, clinical symptoms (diary), dietary intake, spirometry, Schwachman and Crispin Norman scores, stool frequency.
Notes

BMI: body mass index
CF: cystic fibrosis
CFA: co‐efficient of fat absorption
ECM: enteric‐coated microspheres
FFE: faecal fat excretion
PERT: pancreatic enzyme replacement therapy
SD: standard deviation

Data and analyses

Open in table viewer

Comparison 1. ECM versus NECT + adjuvant cimetidine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in weight Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.1 Comparison 1 ECM versus NECT + adjuvant cimetidine, Outcome 1 Change in weight.
1.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Stool frequency Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.2 Comparison 1 ECM versus NECT + adjuvant cimetidine, Outcome 2 Stool frequency.
2.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Abdominal pain Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.3 Comparison 1 ECM versus NECT + adjuvant cimetidine, Outcome 3 Abdominal pain.
3.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 FFE Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.4 Comparison 1 ECM versus NECT + adjuvant cimetidine, Outcome 4 FFE.
4.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Open in table viewer

Comparison 2. ECM versus ECT

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in weight Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.1 Comparison 2 ECM versus ECT, Outcome 1 Change in weight.
1.1 At 1 month	2	82	Mean Difference (IV, Fixed, 95% CI)	0.32 [‐0.03, 0.67]
2 Stool frequency Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.2 Comparison 2 ECM versus ECT, Outcome 2 Stool frequency.
2.1 At 1 month	2	82	Mean Difference (IV, Fixed, 95% CI)	‐0.58 [‐0.85, ‐0.30]
3 Abdominal pain Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.3 Comparison 2 ECM versus ECT, Outcome 3 Abdominal pain.
3.1 At 1 month	2	82	Mean Difference (IV, Fixed, 95% CI)	‐7.96 [‐12.97, ‐2.94]
4 FFE Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.4 Comparison 2 ECM versus ECT, Outcome 4 FFE.
4.1 At 1 month	2	66	Mean Difference (IV, Fixed, 95% CI)	‐11.79 [‐17.42, ‐6.15]

Open in table viewer

Comparison 3. ECM versus ECMM

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FFE Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 3.1 Comparison 3 ECM versus ECMM, Outcome 1 FFE.
1.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Open in table viewer

Comparison 4. Creon® versus Pancrease®

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Co‐efficient of fat absorption Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 4.1 Comparison 4 Creon® versus Pancrease®, Outcome 1 Co‐efficient of fat absorption.
1.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Open in table viewer

Comparison 5. ECM versus TPE

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FFE Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 5.1 Comparison 5 ECM versus TPE, Outcome 1 FFE.
1.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Figure 1

Forest plot of comparison: 2 ECM versus ECT, outcome: 2.2 Stool frequency [number/day].

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Figure 2

Forest plot of comparison: 2 ECM versus ECT, outcome: 2.3 Abdominal pain [% days].

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Figure 3

Forest plot of comparison: 2 ECM versus ECT, outcome: 2.4 FFE [g/day].

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Analysis 1.1

Comparison 1 ECM versus NECT + adjuvant cimetidine, Outcome 1 Change in weight.

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Analysis 1.2

Comparison 1 ECM versus NECT + adjuvant cimetidine, Outcome 2 Stool frequency.

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Analysis 1.3

Comparison 1 ECM versus NECT + adjuvant cimetidine, Outcome 3 Abdominal pain.

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Analysis 1.4

Comparison 1 ECM versus NECT + adjuvant cimetidine, Outcome 4 FFE.

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Analysis 2.1

Comparison 2 ECM versus ECT, Outcome 1 Change in weight.

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Analysis 2.2

Comparison 2 ECM versus ECT, Outcome 2 Stool frequency.

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Analysis 2.3

Comparison 2 ECM versus ECT, Outcome 3 Abdominal pain.

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Analysis 2.4

Comparison 2 ECM versus ECT, Outcome 4 FFE.

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Analysis 3.1

Comparison 3 ECM versus ECMM, Outcome 1 FFE.

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Analysis 4.1

Comparison 4 Creon® versus Pancrease®, Outcome 1 Co‐efficient of fat absorption.

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Analysis 5.1

Comparison 5 ECM versus TPE, Outcome 1 FFE.

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Table 1. Glossary of terms

Term/abbreviation	Definition
BMI	body mass index
CF	cystic fibrosis
CFA	coefficient of fat absorption
chyme	the semi‐fluid mass of partly digested food expelled by the stomach into the duodenum
DIOS	distal intestinal obstruction syndrome
ECM	enteric coated microspheres
FFE	faecal fat excretion
hyperuricaemia	an excess of uric acid in the blood
hyperuricosuria	the presence of excessive amounts of uric acid in the urine
Ileocecum	the combined ileum (end of the small intestine) and cecum (start of the large intestine)
NECM	non‐enteric coated microspheres
PERT	pancreatic enzyme replacement therapy
PI	pancreatic insufficiency
porcine	relating to or suggesting swine (pigs)
RCT	randomised controlled trial
steatorrhoea	loss of fat in the stools

Table 1. Glossary of terms

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Comparison 1. ECM versus NECT + adjuvant cimetidine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in weight Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Stool frequency Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Abdominal pain Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 FFE Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. ECM versus NECT + adjuvant cimetidine

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Comparison 2. ECM versus ECT

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in weight Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 At 1 month	2	82	Mean Difference (IV, Fixed, 95% CI)	0.32 [‐0.03, 0.67]
2 Stool frequency Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 At 1 month	2	82	Mean Difference (IV, Fixed, 95% CI)	‐0.58 [‐0.85, ‐0.30]
3 Abdominal pain Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

3.1 At 1 month	2	82	Mean Difference (IV, Fixed, 95% CI)	‐7.96 [‐12.97, ‐2.94]
4 FFE Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.1 At 1 month	2	66	Mean Difference (IV, Fixed, 95% CI)	‐11.79 [‐17.42, ‐6.15]

Comparison 2. ECM versus ECT

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Comparison 3. ECM versus ECMM

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FFE Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. ECM versus ECMM

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Comparison 4. Creon® versus Pancrease®

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Co‐efficient of fat absorption Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 4. Creon® versus Pancrease®

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Comparison 5. ECM versus TPE

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FFE Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 5. ECM versus TPE

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Referencias

References to studies included in this review

Assoufi 1994 {published data only}

Borowitz 2005 {published data only}

Elliott 1992 {published data only}

Henker 1987 {published data only}

Lacy 1992 {published data only}

Patchell 1999 {published data only}

Petersen 1984 {published data only}

Stead 1986 {published data only}

Stead 1987 {published data only}

Vidailhet 1987 {published data only}

Vyas 1990 {published data only}

Williams 1990 {published data only}

References to studies excluded from this review

Ansaldi 1988 {published data only}

Araujo 2011 {published data only}

Beker 1994 {published data only}

Beverley 1987 {published data only}

Borowitz 2008 {published data only}

Bouquet 1988 {published data only}

Bowler 1993 {published data only}

Brady 1991 {published data only}

Brady 1992 {published data only}

Brady 2006 {published data only}

Breuel 1996 {published data only}

Butt 2001 {published data only}

Chazalette 1988 {published data only}

Chazalette 1993 {published data only}

Colombo 2001 {published data only}

De Boeck 1998 {published data only}

Desager 2006 {published data only}

Duhamel 1988 {published data only}

Duhamel 1998 {published data only}

Durie 1980 {published data only}

Dutta 1988 {published data only}

Easley 1998 {published data only}

Ellis 1994 {published data only}

Foucaud 1989 {published data only}

Gan 1994 {published data only}

Goodchild 1974 {published data only}

Gow 1981 {published data only}

Graff 2010 {published data only}

Heubi 2007 {published data only}

Hill 1993 {published data only}

Hilman 1982 {published data only}

Holsclaw 1979 {published data only}

Hubbard 1984 {published data only}

Kalnins 2005 {published data only}

Kalnins 2006 {published data only}

Katona 2000 {published data only}

Khaw 1977 {published data only}

Konstan 2004 {published data only}

Konstan 2008 {published data only}

Konstan 2010 {published data only}

Kraisinger 1993 {published data only}

Kuo 2011 {published data only}

Lancellotti 1996 {published data only}

Lazaro 1990 {published data only}

Leitz 2009 {published data only}

Lubin 1979 {published data only}

Mack 1991 {published data only}

Mischler 1980 {published data only}

Mischler 1982 {published data only}

Morrison 1992 {published data only}

Munck 2009 {published data only}

Munoz 1987 {published data only}

Neijens 1982 {published data only}

Ritz 2004 {published data only}

Robinson 1989 {published data only}

Robinson 1998 {published data only}

Santini 2000 {published data only}

Shah 1993 {published data only}

Sinaasappel 1998 {published data only}

Stapleton 2001 {published data only}

Stern 2000 {published data only}

Thomson 1993 {published data only}

Trapnell 2009 {published data only}