Creon Minimicrospheres vs. Creon 8000 microspheres an open randomised crossover preference study

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1 Journal of Cystic Fibrosis 1 (2002) Creon Minimicrospheres vs. Creon 8000 microspheres an open randomised crossover preference study a, a a a b c d C.J. Patchell *, M. Desai, P.H. Weller, A. MacDonald, R.L. Smyth, A. Bush, J.S. Gilbody, S.A. Duff d a Birmingham Children s Hospital NHS Trust, Birmingham B4 6NH, UK b Alder Hey Children s Hospital, Liverpool L12 2AP, UK c Royal Brompton Hospital, London SW3 6NP, UK d Solvay Healthcare Ltd, Southampton SO18 3JD, UK Abstract Creon Minimicrospheres (Creon MMS) is a pancreatic enzyme formulation that contains smaller spheres of pancreatin in a 50% smaller capsule than conventional microspheres (Creon 8000). This three-centre study investigated the preference of cystic fibrosis (CF) patients for these products. In one centre, 72 h stool fat excretion and coefficient of fat absorption (CFA) were also compared. Fifty-nine patients with a mean age 10 years (range 3 17) took Creon 8000 ms for 14 days and were then randomised to 28 days of Creon 8000 ms followed by 28 days of Creon MMS, or vice versa. Dosing was lipase for lipase according to the labelled declaration. At the end of the second treatment period, 51 of 54 patients who completed the study expressed a preference, with a statistically significant preference in favour of Creon MMS (47y51; 87%) vs. Creon 8000 ms (4y51; 7.4%; P ). Stool fat (gyday) and CFA (%) were measured in 24 patients at the end of each treatment period: the products were therapeutically equivalent (Creon : 8.4 gyday, 91.3% CFA; Creon 8000: 6.7 gy day, 93.5% CFA). Both products were well tolerated. In conclusion, in CF children we found a clear preference for Creon MMS compared with Creon 8000 ms with no difference in fat absorption between the two products. Creon s smaller capsules are easier to take and should aid patient compliance European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. Keywords: Cystic fibrosis; Pancreatic enzymes; Paediatrics 1. Introduction Pancreatic enzyme replacement therapy is given to manage pancreatic exocrine insufficiency (PEI) in cystic fibrosis (CF) and following pancreatectomy, total gastrectomy or chronic pancreatitis. Modern enzyme preparations consist of ph sensitive enteric-coated microspheres, contained in capsules. Following ingestion, the capsules break down to release the microspheres in the stomach. On entering the duodenum, the ph sensitive coating breaks down to release the pancreatic enzymes. In 1998 a new formulation of the enteric coated pancreatin preparation Creon MMS replaced the *Corresponding author. address: carolyn.patchell@bhamchildrens.wmids.nhs.uk (C.J. Patchell). established 8000 ms. It contains smaller spheres of pancreatin (range mm diameter) than the normal microspheres (range mm), and is delivered in a 50% smaller capsule than Creon 8000 ms. The smaller size of minimicrospheres should facilitate the distribution of pancreatin particles in the chyme of the stomach and their passage through the pylorus w1,2x. This study investigated the relative patient preference for Creon MMS vs. Creon 8000 ms in pancreatic insufficient CF children in three hospital centres. In one centre, 72 h stool fat excretion, stool weight and coefficient of fat absorption (CFA) were also compared (Fig. 1). Previous studies have compared these products with respect to preference or CFA w3 5x in CF and chronic pancreatitis patients over a 2 week treatment period. This study, however, is the first to compare Creon 8000 ms and Creon MMS over a longer treatment period of 4 weeks /02/$ - see front matter 2002 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. PII: S Ž

2 288 C.J. Patchell et al. / Journal of Cystic Fibrosis 1 (2002) Methods and materials This was a prospective, randomised, open, crossover study conducted in three hospital centres. All children were diagnosed with CF by two sweat tests or genotype, had proven PEI, were capable of swallowing capsules whole, and had taken two enzyme capsules or more per meal with satisfactory symptom control for at least 6 months prior to study entry. Children were excluded from taking part in the study if they were: 1. unable to swallow capsules whole or took less than two capsules per meal; 2. if they had gastrointestinal disease or significant disease unrelated to CF; and 3. if they had recently taken drugs that influence gastric or duodenal ph. Written informed consent was obtained from the patient andyor their parentyguardian. The study was conducted according to the principles of Good Clinical Practice and was approved by appropriate Ethics Committees. Prior to inclusion, all patients underwent a medical history and examination, and information was collected regarding demographic data (Table 1), concomitant medication and symptoms. Patients received Creon 8000 ms for 14 days (run-in period) at the same lipase dose as pre-study, during which time diary cards were used to record frequency and severity of loose stools, bloating and flatulence. On day 14, patients returned to the clinic and following a repeat assessment of symptoms, adverse events and concomitant medication, were randomised to receive 28 days of Creon 8000 ms followed by 28 days of Creon MMS, or vice versa. Dosing was lipase for lipase. Patients were asked to keep a daily symptom diary card recording stool frequency consistency, presence and severity of flatulence and abdominal pain. At the end of the study patients were asked to express a preference for one of the two products with reference Table 1 Summary of patient demographic data (all patients, Ns59) Mean S.D. Range Age (years) Weight (kg) Height (cm) BMI (kgym ) to ease of swallowing the capsule, presence or absence of an aftertaste and feeling of fullness after swallowing the capsules Diet and stool fat data In one centre (24 patients), a complete stool collection was carried out during the last 72 h of each treatment period. The method of van der Kamer w8x was used to determine stool fat. In addition, patients completed a diet diary during the last 5 days of each treatment period, weighed all food intake and were asked to follow an individualised menu during each treatment period as far as possible (recording variations in the diary). Food was coded according to food type by the dietitian, and analysed by computer using Microdiet 9, a dietary analysis programme based on McCance and Widdowson s The Composition of Foods w7x to give a total fat intake in gyday and gykg. Patients were asked to keep packaging from processed, pre-packed and frozen foods so that accurate nutritional compositions could be obtained. Some families chose to freeze certain meals so that they could be precisely replicated. CFA was calculated using the formula: Fat intake (g)yfat excretion (g)=100% Fat intake (g) and mean daily stool weight was derived from the net weight of the 72-h stool collection. Fig. 1. CFA (%).

3 C.J. Patchell et al. / Journal of Cystic Fibrosis 1 (2002) Table 2 Capsule number and lipase intake Variable Run-in Creon 8000 ms Creon Ns59 Ns55 MMS Ns57 Mean number of capsules per day Mean Range N a Duration of treatment (days) Mean Range N a Lipase intake IUyday Mean Range a Data available from (No) Statistical methods Sample size calculations The sample size estimation was based on the primary efficacy parameter of patient preference. To achieve a power of at least 80% at level 5% for a two-sided binomial test and assuming a dropout rate of 20%, 86 patients were required to be randomised Analysis The data were analysed for all patients who were treated with at least one dose of study drug in each of the two crossover periods (intent-to-treat sample), and for all patients in a per-protocol patient sample. Product preference was compared using a two-sided sign test at a 5% significance level. The aim of stool collection and a constant fat intake was to prove therapeutic equivalence of the two pancreatic enzyme supplements. Equivalence was defined as a difference not exceeding 15 g fatyday for stool fat and 15% of CFA. Differences in stool fat and CFA were analysed using analysis of variance and 90% confidence intervals were calculated to show equivalence of the two products. An analysis of covariance (ANCOVA) was also performed including number of lipase units consumed as a covariate in order to adjust for potential differences associated with varying amounts of lipase consumed with the two pancreatic enzyme supplements. 3. Results An interim analysis was performed after 31 patients had completed the study. The results of this revealed a highly significant preference for Creon MMS, and so the study was halted prematurely after 59 patients had been randomised. Of the 59 patients randomised, 54 completed the study; demographic data are presented in Table 1. Two patients withdrew during the run-in period due to abdominal pain and loose stools, and a further two during the Creon phase: one due to abdominal pain and loose stools, and one due to meconium ileus equivalent. One patient withdrew due to an appendix abscess during the Creon phase, which was considered to be unrelated to the treatment Creon intake Patients took an average of 26 capsules daily of Creon 8000 ( IU lipaseyday) and 23.4 capsules daily of Creon ( IU lipaseyday) (Table 2). The median intake of lipaseykg body weight was 6689 IUykgyday for Creon 8000, 8527 IUykgyday for Creon Patient preference Fifty-one of 54 patients expressed a preference for one or other product. There was a highly significant preference for Creon MMS, with 47y51 (87%) preferring Creon MMS vs. 4y51 (7.4%) preferring Creon 8000 ms (P ) (Table 3) Stool collection and dietary data Twenty-two patients were included in the intent-totreat sample for stool collection data. ANCOVA of CFA Table 3 Patient preference Cr 8000y Cr y Total Cr Cr 8000 Creon Creon Both equal 0 3 3

4 290 C.J. Patchell et al. / Journal of Cystic Fibrosis 1 (2002) Table 4 Stool fat (gyday) CFA (%) Dietary fat intake (gyday) Stool weight (gyday) Creon 8000 Creon Creon 8000 Creon Creon 8000 Creon Creon 8000 Creon Mean S.D Median Range % CI contrast 0.718; ; ; ;1.473 and fat excretion to test for differences between products using alternative covariates of total lipase, lipase per gram of fat and lipase per kilogram weight and allowing for between subject variation showed no significant differences between the products (P)0.1). Equivalence of the two products was thus observed with respect to CFA; the median CFA for both being 94.4% (range ), Creon 8000 median 94.4, mean 93.5, (range ), Creon median 94.4, mean 91.3, (range ). Equivalence was also shown for stool fat, stool weight and dietary fat intake. Details are given in Table 4 and Fig Clinical symptomatology No treatment differences in stool frequency, stool consistency, flatulence and abdominal pain were observed. The median stool frequency was two stools per day for both Creon MMS and Creon 8000 ms and in the majority of these patients stools were described as being formed in consistency. Flatulence and abdominal pain were mainly absent or mild throughout the study Acceptability and compliance Problems with compliance were infrequent (92.4% compliance with Creon MMS and 80.2% with Creon 8000). No patient reported difficulty with taking Creon MMS and only three reported problems of swallowing Creon 8000 ms. 4. Discussion In this study we have demonstrated a highly significant preference for Creon MMS over Creon 8000 ms by children with CF. The preference is likely to have been due to the smaller capsule size which was more acceptable, even though all patients studied had already been satisfactorily swallowing the larger Creon 8000 ms capsules for a period of time. The preference for Creon MMS should have a beneficial effect on compliance. The smaller capsule size should also enable patients to swallow the capsules whole at a younger age, which would improve fat absorption in this group of patients w3x. These results of this study are consistent with results seen in a previous study of Creon MMS with Creon MS w4x. Patients on both Creon preparations showed equivalent fat absorption with a CFA of 90% in all, but 5 out of 45 patients, demonstrating the high efficiency of both products. Of the 5 patients with % CFA-90%, none described abdominal pain, flatulence or loose stools indicating that stool descriptions may not always be a good indication of adequacy of enzyme treatment. One of the patients had an equivalent high fat excretion on both products Fig. 2. Mean stool fat (gyday).

5 C.J. Patchell et al. / Journal of Cystic Fibrosis 1 (2002) indicating an insufficient lipase intake for both products. Two of the remaining subjects with poor % CFA results were from one family with difficult social circumstances in whom record keeping and stool collection may have been inaccurate. The results in this study are comparable with a German study comparing Creon MMS with Creon 8000 ms in patients with CF w5,6x. It has long been recognised that good nutrition is of paramount importance in the management of CF and has been shown to be associated with improved pulmonary function w9x. Optimum control of steatorrhoea is vital if good nutritional status is to be achieved. In any study evaluating children with a chronic disease such as CF, compliance to treatment is an important consideration. In this study, no children were excluded due to poor compliance with enzyme therapy (as determined by capsule counts at the end of each treatment period), although all patients had a less than 20% difference between prescribed and achieved enzyme dosage. Symptom diaries and dietary records were usually kept to a high standard. The completeness of the faecal fat collections could not be guaranteed, but can be assumed to have been good because compliance with study medication, symptom diaries and adherence to a controlled fat diet were good. The use of a controlled fat diet is difficult but is important when fat absorption is being assessed as in this study. There are potentially certain disadvantages in the use of a slightly higher lipase preparation, the most significant disadvantage being the slightly reduced flexibility in adjusting lipase dosage, particularly in children who have low lipase requirements. However, children requiring small enzyme dosages were not studied in this trial and so it has not been possible to explore this further. The use of high strength pancreatic enzymes has been linked to the development of fibrosing colonopathy w10x. Following reports of the development of colonic strictures, in patients using high strength enzymes, the Committee on Safety in Medicines recommended that dosages of any pancreatic enzyme should be kept below IU lipaseykg body weightyday w11x. Although no Creon preparation has been linked with the development of fibrosing colonopathy, dosages should be monitored carefully to avoid high dosages. In conclusion, Creon MMS has been shown to be popular, easy to swallow and efficacious in the management of pancreatic insufficiency associated with CF. Acknowledgments The authors acknowledge the contribution made to the study by Anita MacDonald and Jackie Francis. The statistical analysis was performed by Wilhelm Sauermann, Statistician, DATAMAP, Germany and Paul Davis, Statistician, Institute of Child Health, Birmingham Children s Hospital. The laboratory processes were co-ordinated by Elisabeth Caldwell, Haverfern Laboratories, UK. This work was supported by a grant from Solvay Healthcare Ltd, Southampton, UK. References w1x Meyer JH, Elashoff J, Porter-Fink V, et al. Human postprandial gastric emptying of 1 3-millimeter spheres. Gastroenterology 1988;94: w2x Kuhnelt P, Mundlos S, Adler G. Einfluß der Pelletgroße eines Pankreasenzympraparates auf die duodenale lipolytische Aktivitat. (The size of enteric coated microspheres influences the intraduodenal lipolytic activity). Zeit Gastroenterol. 1991;29: w3x Littlewood JM, Woolfe SP. Control of malabsorption in cystic fibrosis. Paediatric Drugs 2000;3: w4x Hosansky F, Patris A. Open label multicentre, randomised crossover study to investigate patients preference of Creon minimicrospheres over Creon ms in patients with pancreatic exocrine insufficiency caused by cystic fibrosis. Solvay Pharma (France) Integrated Clinical and Statistical Report No. K , w5x Sander S, Sauermann W. Double-blind, multicentre, randomised, crossover study to prove equivalent efficacy of Creon minimicrospheres and Creon microspheres in patients with pancreatic exocrine insufficiency caused by chronic pancreatitis. Solvay Pharmaceutical Integrated Clinical and Statistical Report No. K , w6x Sander S, Sauermann W. Double-blind, multicentre, randomised, crossover study to prove equivalent efficacy of Creon mms and Creon 8000 ms in patients with pancreatic exocrine insufficiency caused by cystic fibrosis. Solvay Pharmaceuticals Integrated Clinical and Statistical Report No. K , w7x McCance, Widdowsons. The Composition of Foods and supplements. Fifth ed., Royal Society of Chemistry, Ministry of Agriculture, Fisheries and Food, w8x van der Kamer JH, ten Bokkel H, Weyers HA. Rapid method for the determination of fat in faeces. J. Biol. Chem. 1949;177: w9x Shepherd R, Cooksley WGE, Domville Cooke WD. Improved growth and clinical, nutritional and respiratory changes in response to nutritional therapy in cystic fibrosis. J. Pediatr. 1980;97: w10x Smyth RL, Van Veltzen D, Smyth AR, et al. Strictures of the ascending colon in cystic fibrosis and high strength enzymes. Lancet 1994;343:85 6. w11x Committee on Safety of Medicines. Report of the pancreatic enzymes working party; London: Committee on Safety of Medicines; 1995