Pancreatology xxx (2013) 1e7. Contents lists available at SciVerse ScienceDirect. Pancreatology. journal homepage:

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1 Pancreatology xxx (2013) 1e7 Contents lists available at SciVerse ScienceDirect Pancreatology journal homepage: Original article A 51-week, open-label clinical trial in India to assess the efficacy and safety of pancreatin enteric-coated minimicrospheres in patients with pancreatic exocrine insufficiency due to chronic pancreatitis Hariharan Ramesh a, *, Nageshwar Reddy b, Shobna Bhatia c, J.S. Rajkumar d, Amol Bapaye e, Dinesh Kini f, Mukesh Kalla g, Vinay Thorat h a Department of Surgical Gastroenterology and Liver Transplantation, Lakeshore Hospital & Research Centre, NH 47 Bypass, Maradu, Nettoor P.O., Kochi , Kerala, India b Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India c Department of Gastroenterology, Seth G. S. Medical College and KEM Hospital, Mumbai, India d Division of Gastroenterology, Lifeline Multispeciality Hospital, Chennai, India e Department of Gastroenterology, Deenanath Mangeshkar Hospital & Research Centre, Pune, India f Manipal AcuNova MHB Clinical Research Centre, Manipal Hospital, Bangalore, India g Department of Gastroenterology, S. R. Kalla Memorial Hospital, Jaipur, India h Department of Medical Gastroenterology, Poona Hospital & Research Centre, Pune, India article info abstract Article history: Received 7 September 2012 Received in revised form 25 January 2013 Accepted 26 January 2013 Keywords: Chronic pancreatitis Creon Pancreatic exocrine insufficiency Pancreatin Pancrelipase Background/objectives: To assess the efficacy and safety of pancreatin (pancrelipase) enteric-coated minimicrospheres (MMS) over a one-year period in patients with pancreatic exocrine insufficiency (PEI) due to chronic pancreatitis (CP). Methods: This was a 51-week, open-label extension (OLE) of a one-week, multicenter, double-blind, randomized, placebo-controlled trial in India that enrolled patients 18 years of age with confirmed PEI due to CP. Patients received pancreatin (Creon Ò MMSÔ) at a dose of 80,000 Ph. Eur. lipase units with each of three main meals/day and 40,000 with each of up to three snacks/day. Results: Of 61 patients entering the OLE, 48 completed treatment (nine were lost to follow up, two withdrew consent, one discontinued due to adverse event [acute exacerbation of CP], one protocol violation). There were significant improvements from baseline to end of OLE in mean SD coefficient of fat absorption (CFA: %), coefficient of nitrogen absorption (CNA: %), body weight ( kg), BMI ( kg/m 2 ), and most nutritional laboratory parameters tested (p 0.001). Mean daily stool frequency was reduced from 2.8 to 1.6 (p < 0.001). Improvements in clinical symptoms, clinical global impression of disease symptoms, and quality of life were also observed. Treatmentemergent adverse events (TEAEs) were observed in 64% of patients overall. Only 13% of patients experienced TEAEs judged treatment related. Conclusions: In patients with PEI due to CP, treatment with pancreatin for one year was associated with significant improvements in fat absorption, nitrogen absorption, and nutritional parameters, improvements in clinical symptoms, and a favorable safety and tolerability profile. Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. 1. Introduction Chronic pancreatitis (CP) is a progressive, inflammatory disorder that results in fibrosis and irreversible damage to pancreatic tissue [1,2]. Most cases are thought to result from the complex interactions of various environmental and genetic factors, although some appear to be idiopathic, with no clear risk factors, and there * Corresponding author. Tel.: þ ; fax: þ address: hrameshoffice@gmail.com (H. Ramesh). are also hereditary, autoimmune, and obstructive forms [1,2]. Along with abdominal pain, one of the main symptoms of CP is pancreatic exocrine insufficiency (PEI) [1], described as a lack of adequate pancreatic enzyme activity in the small intestine. PEI results in the maldigestion of food, leading to the symptoms of malnutrition, weight loss, abdominal pain, and steatorrhea [3]. Quality of life is adversely affected in patients with CP, and along with abdominal pain, the digestive symptoms associated with PEI are a contributing factor [4e7]. Management of CP should include assessment of nutritional status, which can be performed by monitoring body /$ e see front matter Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

2 2 H. Ramesh et al. / Pancreatology xxx (2013) 1e7 weight and body mass index (BMI) [8]. Assessment of nutritional laboratory parameters such as serum albumin, retinol-binding protein, and cholesterol may also be useful. Even in patients who do not overtly display clinical symptoms of PEI, and in those who appear to have their symptoms adequately controlled with treatment, nutritional parameters may be abnormally low [9,10]. This finding highlights the importance of normalizing nutritional parameters in conjunction with symptom control when treating PEI [9,10]. Pancreatic enzyme replacement therapy (PERT) is the standard of care for PEI whatever its etiology, and has been shown to be effective in improving maldigestion and the clinical symptoms associated with PEI. Pancreatin enteric-coated minimicrospheres (MMS) has been assessed in a number of clinical trials and through extensive clinical experience. Clinical studies support the efficacy and safety of different pancreatin (pancrelipase) formulations in patients with CP [11e14], pancreatic surgery (PS) [12,13], and cystic fibrosis [15e20]. In addition, the longer-term efficacy and safety of pancreatin in patients with PEI due to CP or PS is supported by a 6-month, open-label extension of a double-blind study [13]. The pancreatin MMS formulation was shown to be effective in treating PEI due to CP, with a good safety profile, in a one-week, double-blind, randomized, placebo-controlled study carried out in India [14]. Significantly greater improvements in fat and nitrogen absorption from baseline to the end of the doubleblind phase were seen with pancreatin vs. placebo, along with greater reductions in mean stool frequency, stool weight, stool fat, and stool nitrogen, and greater improvements in the clinical global impression (CGI) of disease symptoms. Here we report the outcomes from the 51-week, open-label extension (OLE) period of this trial, which was carried out to assess the longer-term efficacy, safety, and tolerability of pancreatin in this patient population. 2. Methods This was a 51-week OLE of a one-week, multicenter, doubleblind, randomized, placebo-controlled trial (clinicaltrials.gov number NCT ). The design and outcomes of the doubleblind phase are reported in detail elsewhere [14]. Patients were enrolled at nine centers in India between June 2008 and May The study was conducted in compliance with EU Clinical Trial Directive 2001/20/EC, the International Conference on Harmonisation (ICH) guideline for Good Clinical Practice, and the ethical principles of the Declaration of Helsinki, and was approved by an independent ethics committee that complied with local regulatory requirements Study participants Details of the full inclusion/exclusion criteria are published elsewhere [14]. Briefly, patients with a confirmed diagnosis of CP were eligible if they had provided written informed consent, were 18 years of age, and had PEI confirmed by a coefficient of fat absorption (CFA) 80% during the run-in period. Patients were prohibited from consuming additional PERT preparations concomitantly, but medications affecting duodenal ph, gastric emptying, or bile secretion were permissible at stable doses. All patients completing the doubleblind phase were eligible to enter the OLE Treatment During the OLE, all patients received pancreatin (Creon Ò MMSÔ; Abbott, Hannover, Germany) and were to consume two capsules orally with each main meal (three meals per day) and one capsule with each snack (up to three snacks per day). The dose in Ph. Eur. lipase units was therefore 80,000 per meal and 40,000 per snack. Medication was provided in aluminumealuminum blister packs as required at each study visit Efficacy assessments Stool fat and stool nitrogen were assessed by analysis of stool samples collected over 72 h. Subjects were hospitalized for five days to allow stool collection. Dietary diaries were also completed for 96 h, starting 24 h before stool collection. Patients were advised by a dietician how to ingest at least 100 g dietary fat/day during this period. CFA, coefficient of nitrogen absorption (CNA), stool weight, stool fat, stool nitrogen, and fat and nitrogen intake were assessed during the run-in period (baseline value; subjects were without PERT during run-in), at the end of the double-blind period, and at the end of the study (week 52 or early termination). Stool weight, stool fat, and stool nitrogen were determined from the 72-h stool collections. Fat and nitrogen intake was determined by a dietician from study participants 96-h dietary diaries recorded during the stool collections, using suitable software. Stool analysis was performed at St John s Laboratory, Bangalore. Stool fat content was determined by the method of van de Kamer [21]. CFA was determined by the equation CFA ¼ 100*[(mean fat intake mean stool fat)/mean fat intake]. CNA was determined by the equation CNA ¼ 100*[(mean nitrogen intake mean stool nitrogen)/mean nitrogen intake]. Body weight and BMI were measured at screening, baseline, end of the double-blind phase, and at weeks 5, 13, 26, 39, and 52. Nutritional laboratory parameters (triglycerides, total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, retinol-binding protein, transferrin, total protein, prealbumin, albumin, and vitamin E) were assessed from blood sampled at baseline, end of double-blind phase, and weeks 5, 13, 26, 39, and 52. Although planned, no measurements were made for total serum protein and albumin at baseline, week 26, or end of OLE due to laboratory error. Therefore, change from baseline analysis and treatment comparisons were not possible for these parameters. Instead, the change from the end of the double-blind period to weeks 5, 13, and 39 was analyzed for subjects receiving placebo during the double-blind period to estimate the effect of longerterm pancreatin treatment. Clinical symptoms of PEI were assessed by investigators at baseline, at the end of the double-blind phase, and at weeks 5,13, 26, 39, and 52. Subjects provided information on the number of stools per day and their consistency (hard, formed/normal, soft, watery); flatulence (none, mild, moderate, or severe); and abdominal pain (none, mild, moderate, or severe). The CGI of disease symptoms was determined by investigators at baseline, at the end of the doubleblind phase, and at weeks 5, 13, 26, 39, and 52. Patients rated symptoms as none (absent), mild (present but not bothersome), moderate (bothersome), severe (interfered with normal activity), or incapacitating (prevented normal activity). Quality of life was assessed using the SF-36 Ò Health Survey questionnaire at baseline, end of double-blind phase, and at study end. The SF-36 comprises eight component scores and two summary scores, with higher scores indicating better quality of life Safety evaluation Recorded adverse events (AEs) were coded according to the Medical Dictionary for Regulatory Activities version Other safety assessments included vital signs (all time points), physical examination (all time points), and laboratory safety tests (baseline, week 26, and end of OLE). Laboratory safety tests comprised hematological analyses (fasting hemoglobin, hematocrit, red blood cell count, white

3 H. Ramesh et al. / Pancreatology xxx (2013) 1e7 3 blood cell count, and platelet count) and biochemical analyses (fasting glucose, creatinine, alkaline phosphatase, total bilirubin, alanine aminotransferase, aspartate aminotransferase, gammaglutamyl transferase, uric acid, calcium, phosphate, potassium, and serum pancreatic lipase). Blood samples were analyzed at Quintiles Research (India) Pvt. Ltd., Bangalore, India Statistical analysis Data were analyzed using SAS Ò Release 9.1. Safety analyses were performed on the OLE safety sample (all subjects who had been allocated to treatment in the double-blind phase and took at least one dose of pancreatin or placebo, and who received at least one dose of pancreatin in the open-label phase). Efficacy analyses were performed using the OLE full analysis (FA) sample, defined as all subjects in the OLE safety sample who had at least one postbaseline assessment of any efficacy measurement. Efficacy outcomes were described by standard summary statistics. Missing values at baseline were not imputed. Post-hoc exploratory statistical analysis to investigate change from baseline in efficacy outcomes was carried out using the Wilcoxon signed rank test. A post-hoc exploratory completer analysis was also carried out for the efficacy outcomes, which included subjects in the OLE FA sample who completed the study and had values recorded for the respective parameters at all visits. 3. Results Patient disposition for the entire study is shown in Fig. 1.Ofthe61 patients entering the OLE, 48 completed the study. Subject demographic characteristics are shown in Table 1. Comorbid conditions were present in 85.2% of patients entering the OLE, and the most common were diabetes mellitus (47.5%), pancreaticojejunostomy (23.0%), and abdominal pain (13.1%). Overall, 85.2% subjects took concomitant medications at any time during the entire study. Commonly taken medications (>20% patients) included those for peptic ulcer or gastro-esophageal reflux disease (44.3%), insulins and analogs (42.6%), and oral hypoglycemic/anti-diabetic agents (26.2%). One participant took another PERT concomitant with pancreatin during the OLE (from day 185 to 226) Efficacy Statistically significant improvements from baseline to end of the OLE in CFA, CNA, stool fat, stool nitrogen, and stool weight were observed, as shown in Table 2. Mean fat and nitrogen intake were Pancreatin (n = 34) Pancreatin (n = 34) Completed (n = 48) Randomized N = 62 (safety sample) Completed (FA sample) Pancreatin OLE (n = 61) Placebo (n = 28) Placebo (n = 27) (OLE FA sample) Discontinued (n = 13) Lost to follow-up (n = 9) Withdrew consent (n = 2) Adverse event (n = 1) Protocol violation a (n = 1) Fig. 1. Patient disposition. a CFA at baseline >80%. Discontinued (n = 1) Withdrew consent (n = 1) Table 1 Subject characteristics at baseline (OLE safety sample). Parameter Pancreatin (N ¼ 61) Age, years Mean SD Median (min/max) 44 (18/62) Gender, n (%) Male 46 (75.4) Female 15 (24.6) Race, n (%) Asian 61 (100) Weight, kg, mean SD BMI, kg/m 2, mean SD similar at baseline and at the end of the OLE (fat: vs g/day; nitrogen: 11.1 vs g/day). The exploratory completer analysis, which included only subjects who completed the study and had values recorded at all visits, showed identical mean SD changes from baseline to the end of the OLE for the CFA ( %) and CNA ( %). At the end of the OLE, the CFA had normalized (93%) in 12 patients (26%). The decrease in mean daily stool frequency throughout the study is shown in Fig. 2a. Significant improvements in both mean SD body weight ( kg; p ¼ 0.001) and BMI ( kg/m 2 ; p ¼ 0.001) were observed from baseline to the end of the OLE (Fig. 2b and c). At baseline the median BMI was <20 (19.2) and at the end of the OLE the median BMI was >20 (20.9). An increase in body weight of 7% occurred in 37 (61.7%) subjects by the end of the OLE. Significant improvements were observed in most nutritional laboratory parameters from baseline to end of study (Table 3). Improvements in clinical symptoms (stool consistency, flatulence, and abdominal pain) are summarized in Fig. 3aec. The proportion of patients reporting formed/normal stool consistency improved from 59.0% at baseline to 77.1% at the end of the OLE period. The proportion of patients with no flatulence improved from 23.0% at baseline to 60.4% at OLE end. The proportion of patients with no abdominal pain increased from 49.2% to 81.3% at OLE end. Improvements in the CGI of disease symptoms from baseline until the end of the OLE are shown in Fig. 3d. At the end of the OLE, improvements were seen compared with baseline in seven of the eight SF-36 component scores and the two summary scores, with significant improvements seen for bodily pain, general health, vitality, role-emotional, mental health, and the mental component summary (Fig. 4). A subanalysis to assess the impact of proton-pump inhibitors (PPIs) indicated that there were no differences in end-of-treatment CFA values in patients taking PPIs ( %; n ¼ 22) and those not taking PPIs ( %; n ¼ 25). Baseline CFAs were % in the PPI group and % in the non-ppi group. The mean SD change in CFA from baseline to end of treatment was % among subjects taking PPIs and % in subjects not taking PPIs (significance not tested) Safety The median overall duration of exposure to pancreatin was 362 days (range, 8e416 days). Treatment-emergent adverse events (TEAEs) are summarized in Table 4. During the entire study period, 139 AEs were reported, with 39 subjects (63.9%) reporting at least one TEAE. Nine TEAEs that were judged probably or possibly related to treatment were reported in eight patients: constipation (n ¼ 7), abdominal discomfort (n ¼ 1), and frequent bowel movements (n ¼ 1). Treatment-emergent serious AEs (TESAEs) were experienced by five patients (8.2%); none were considered treatmentrelated as assessed by the investigator. Overall, 13 severe TEAEs

4 4 H. Ramesh et al. / Pancreatology xxx (2013) 1e7 Table 2 Changes from baseline to end of the OLE in CFA, CNA and stool characteristics (OLE FA sample). Baseline End of OLE Change from baseline p Value a n Mean SD n Mean SD n Mean SD CFA, % CNA, % Stool fat content, g/day Stool nitrogen content, g/day Stool weight, g/day a p Value for change from baseline to end of OLE (Wilcoxon signed rank test). were reported in seven subjects (11.5%): gastritis, constipation, fatigue, pain, alcoholic liver disease, urinary tract infection, head injury, diabetes mellitus, cerebral infarction, hemiplegia, convulsion (all in one subject each), and acute pancreatitis (reported twice in one subject); none were considered related to treatment by the investigator. One patient discontinued treatment during the OLE due to the TESAE of acute exacerbation of CP. No deaths occurred during the study. There were no relevant changes in vital signs. Changes to abnormal quantitative laboratory parameter values that occurred in >8% of subjects at risk were: hematocrit 9% subjects, monocytes 11%, uric acid 13% (all abnormally low), eosinophils 20%, fasting glucose 39%, AST 9% (all abnormally high). Markedly abnormal values were most frequent for fasting glucose (high), hematocrit (low), GGT (high), hemoglobin (low), and calcium (low). 4. Discussion In this 51-week OLE of a one-week, randomized, double-blind, placebo-controlled study in India enrolling patients with PEI due to CP, significant improvements from baseline to study end were observed in CFA, CNA, stool characteristics, and stool frequency. To our knowledge, the present study is the first to assess the longterm efficacy of PERT using direct testing of stool fat and stool nitrogen. Body weight and BMI continued to improve throughout the study, with statistically significant improvements from baseline to OLE end in these accepted markers of nutritional status. Together with the significant improvements in most of the nutritional laboratory parameters tested, these observations suggest that nutritional status was improved with long-term pancreatin therapy. Clinical symptoms showed modest improvement and the CGI of disease symptoms also improved throughout the study. The improvement in abdominal pain observed in this study most likely reflects an improvement in lower abdominal pain associated with PEI-related maldigestion rather than the characteristic severe pancreatic pain (in the epigastric region) often experienced by patients with CP. However, this cannot be verified as no distinction regarding abdominal pain type or location was made in this study. Quality of life improved from baseline to OLE end, with statistically significant changes in bodily pain, general health, vitality, role-emotional, mental health, and the mental component summary. a b c Fig. 2. (a) Stool frequency, (b) body weight, and (c) BMI throughout the study (OLE FA sample).

5 H. Ramesh et al. / Pancreatology xxx (2013) 1e7 5 Table 3 Nutritional laboratory parameters (OLE FA sample). Parameter Baseline End of OLE Change from baseline p Value n Mean SD n Mean SD n Mean SD Triglycerides, mmol/l Total cholesterol, mmol/l LDL cholesterol, mmol/l HDL cholesterol, mmol/l Retinol binding protein, mg/l Transferrin, mg/dl Prealbumin, g/l Vitamin E, mg/l Total protein, g/l a n/a Albumin, g/l a n/a Reference ranges: triglycerides 0.5e2.8 mmol/l; total cholesterol 3.4e5.2 mmol/l; LDL cholesterol 0.0e3.4 mmol/l; HDL cholesterol 1.0e2.1 mmol/l; retinol binding protein 30.0e60.0 mg/l; transferrin 200e360 mg/dl; prealbumin 0.2e0.3/0.4 g/l (women/men); vitamin E 4.3e13.3 mg/l; total protein 60.0e84.0 g/l; albumin 35.0e53.0 g/l. a No readings were taken for these parameters at baseline, week 26, or end of OLE. The values reported are the changes from the end of the double-blind period to week 39 in subjects receiving placebo during the double-blind period (n ¼ 22). A subanalysis of CFA according to concomitant PPI use indicated no difference in CFA values in subjects receiving PPIs vs. those not taking concomitant PPIs. As this was an exploratory analysis, no firm conclusions can be drawn regarding the effects of PPI use. However, a retrospective analysis of pancreatin clinical trial data (1142 subjects) also found no effect of acid-suppressing medication on the efficacy of pancreatin [22]. These findings support the treatment guidelines recommendation that acid-suppressing medications are not needed routinely when PERT is initiated. However, these medications may be useful in patients who are treatment-compliant but continue to experience symptoms of PEI on high-dose PERT or patients with confirmed gastric or duodenal hyperacidity [23e27]. Pancreatin treatment for up to one year was well tolerated, with a favorable safety profile at the strength and dose administered. The overall rate of TEAEs observed was acceptable given the long duration of the trial and the general health of study participants. The number of TEAEs judged by investigators to be possibly or probably related to treatment observed throughout the entire study period was low, and comparable with other studies assessing PERT given continuously for more than 2 weeks [13,19,20,28]. The TEAEs that were considered related to treatment are all adverse drug reactions known to be associated with pancreatin treatment (constipation, abdominal discomfort, and frequent bowel movements). The outcomes reported here for the end of the 51-week OLE do not consider the treatment that subjects received in the one-week, double-blind phase, as the effect of this on patient status after one year is considered negligible. During the double-blind period, in the 34 patients receiving pancreatin, the mean CFA improved from 66.5% at baseline to 86.1%, and the mean CNA from 78.8% at baseline to 83.8% [14], indicating that in these patients, significant improvement occurred during the first week of pancreatin treatment. These improvements were then maintained to the end of the OLE in this patient group (further changes from end of double-blind phase were CFA þ3.0% and CNA þ1.9%). In the double-blind phase, in patients receiving placebo, the changes in the CFA and CNA were þ3.2% and þ0.6%, respectively. In these patients, the improvements observed at the end of the OLE occurred with openlabel pancreatin treatment. The findings of this study compare well with those of studies assessing other pancreatin formulations in patients with PEI due to a b c d Fig. 3. Clinical symptoms: (a) stool consistency, (b) flatulence, (c) abdominal pain, (d) clinical global impression of disease symptoms (OLE FA sample).

6 6 H. Ramesh et al. / Pancreatology xxx (2013) 1e7 Fig. 4. Quality of life according to the SF-36 questionnaire (OLE FA sample). CP, with similar on-treatment CFA and CNA values compared with short-term clinical trials [11,12]. The double-blind, randomized, placebo-controlled trial reported by Whitcomb et al. [12], which enrolled patients in the United States and Eastern Europe with PEI due to CP or PS, had a 6-month OLE [13]. In that trial, fat and nitrogen absorption were not measured in the OLE. However, there were improvements over 6 months in mean body weight (2.7 kg; p < ), mean BMI (0.9 kg/m 2 ), stool frequency, clinical symptoms, and the CGI of disease symptoms. No clinically meaningful changes in quality of life were observed. Small (non-significant) increases in nutritional laboratory parameters were seen, with greater increases in patients who were malnourished at baseline (BMI < 18.5). The authors suggested that the lack of significant improvement in these parameters was because most subjects were not underweight/malnourished at baseline, and that larger changes would be expected in underweight/malnourished patients. In comparison, patients in our study had lower baseline mean body weight (50 kg vs. 67 kg) and BMI (18.8 kg/m 2 vs kg/m 2 ), suggesting a patient population that was less well nourished at study start. In this population, significant Table 4 Summary of TEAEs occurring in 5% patients at any time during the study (OLE safety sample). All patients (N ¼ 61) At least one TEAE, n (%) 39 (63.9) At least one TESAE, n (%) 5 (8.2) TEAEs possibly/probably related to treatment, n (%) 8 (13.1) TEAEs leading to discontinuation, n (%) 1 (1.6) Gastrointestinal disorders, n (%) 24 (39.3) Abdominal discomfort 3 (4.9) Abdominal pain 10 (16.4) Constipation 10 (16.4) Gastritis 3 (4.9) Hyperchlorhydria 3 (4.9) General disorders/administration site conditions, n (%) 9 (14.8) Pain 3 (4.9) Pyrexia 5 (8.2) Investigations, n (%) 12 (19.7) Blood glucose increase 6 (9.8) HDL decreased 4 (6.6) Liver function test abnormal 3 (4.9) Musculoskeletal and connective tissue disorders, n (%) 9 (14.8) Arthralgia 5 (8.2) Musculoskeletal pain 3 (4.9) Nervous system disorders, n (%) 6 (9.8) Headache 3 (4.9) improvements were seen in most nutritional parameters assessed. In an observational study of 20 patients with PEI due to CP, body weight increased from 67.5 kg to 71.8 kg (p < 0.001), serum RBP from 2.4 to 3.1 mg/dl (p < 0.001) and serum prealbumin from 20.7 to 25.2 mg/dl (p < 0.001) after one year of pancreatin treatment [9]. It cannot be explained why serum prealbumin levels did not improve in the present study, despite improvements in protein absorption (as shown by CNA improvement from baseline). Whether this may be due to dietary differences in this patient population is not clear. Furthermore, the mean baseline prealbumin level was within the normal reference range, although this was also true of other nutritional parameters that did show statistically significant improvements. Unfortunately, the change from baseline in total protein and albumin was not assessable in this study, as previously noted. A recent retrospective analysis of CP patients with PEI who were PERT-naïve indicated that albumin, prealbumin and retinol binding protein levels below the lower limit of normal and magnesium levels <2.05 mg/dl increases the risk of PEI [29]. In a randomized, double-blind, doseeresponse, crossover study assessing a different PERT ([pancrelipase] Delayed-Release Capsules; Zenpep, Eurand S.p.A., Milan, Italy) in which patients with PEI due to CP received PERT for 18e22 days, on-treatment CFA and CNA values were comparable with those in our study [28]. PERT was associated with significant increases in body weight, BMI, and HDL-C levels but no change in LDL-C levels or fat-soluble vitamins A, E, and K, although treatment time was shorter than in the two pancreatin studies noted above. In clinical practice, PERT dose should be tailored to the individual patient s needs based on factors such as PEI severity, diet, and nutritional status, and the intake of a balanced diet is also important in order to achieve normal nutritional status with PERT [10]. The dosing schedule of 80,000 Ph. Eur. lipase units per main meal and 40,000 per snack used throughout this study was selected in order to ensure an adequate dose for this patient population with a baseline CFA <80% (suggesting moderate-to-severe PEI) who were receiving a high-fat diet during stool collection periods. This dose is comparable to that used in the double-blind phase of the Whitcomb et al. study (72,000 USP lipase units per main meal and 36,000 per snack), although in that study, dosing during the openlabel phase was directed by the investigators, resulting in a lower mean dose of 186,960 lipase units/day [13]. As noted above, the patients enrolled in this study most likely had moderate-to-severe PEI (baseline CFA <80%). It is likely that patients with mild-to-moderate PEI would also benefit from PERT treatment to some degree, although our findings cannot be

7 H. Ramesh et al. / Pancreatology xxx (2013) 1e7 7 extrapolated to milder PEI, as such patients were not enrolled. In the study discussed above that assessed a different PERT formulation, post-hoc analysis indicated modest CFA improvements from baseline in patients with a placebo CFA of 75% to <85%, whereas no change was observed in those with a placebo CFA 85% [28]. The patients in the present study were younger than those enrolled in other studies of PERT efficacy for the treatment of PEI due to CP in Europe and the United States. This may be due to the differing CP etiology in this patient population, with a potentially higher incidence of tropical calcifying pancreatitis compared with Western populations, which tends to have an earlier onset [2,30,31]. These findings are applicable to other pancreatin MMS formulations, which have the same composition and characteristics and differ only in the number of lipase units contained in each capsule. Together, the data support the efficacy of pancreatin (Creon MMS) in patients with PEI due to CP, with a favorable tolerability profile. Efficacy was sustained over a one-year period, with significant improvements in fat and nitrogen absorption, nutritional status, stool frequency and characteristics, and quality of life. Conflict of interest statement Hariharan Ramesh has participated in an advisory board for Pfizer Medical and Research Division on improving outcomes in Candida infections in liver transplant patients, has participated as a speaker in a symposium on pancreatic exocrine insufficiency for Abbott, and has had travel/accommodation expenses covered or reimbursed by Abbott and Dr Reddy s Laboratories Ltd. Shobna Bhatia has received research funding (paid to institution) from Pfizer. Nageshwar Reddy, JS Rajkumar, Amol Bapaye, Dinesh Kini, Mukesh Kalla, and Vinay Thorat have no relevant conflicts of interest to disclose. Acknowledgments The authors thank the following for their assistance: Dr Anita Bijoor, Department of Biochemistry and Biophysics, St John s Medical College, Bangalore, India for analysis of stool samples; personnel at Quintiles India; the study team at Lakeshore hospital: Manish Gandhi, Mahesh Subramaniaiyer, and Asha S Nair; the clinical research coordinators at Deenanath Mangeshkar Hospital and Research Center: Shivangi Dorwat and Pooja Shrivastava. This study was funded by Abbott, Hannover, Germany. Medical writing assistance was provided by Helen Varley, PhD, Envision Scientific Solutions, Horsham, UK and funded by Abbott. References [1] Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120:682e707. [2] Braganza JM, Lee SH, McCloy RF, McMahon MJ. Chronic pancreatitis. Lancet 2011;377:1184e97. [3] Domínguez-Muñoz JE. Pancreatic exocrine insufficiency: diagnosis and treatment. 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