- Email: [email protected]
Safety and Efficacy of a Novel Microbial Lipase in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis: A Randomized Controlled Clinical Trial
Safety and Efficacy of a Novel Microbial Lipase in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis: A Randomized Controlled Clinical Trial James E. Heubi, MD1, David Schaeffer, MD2, Richard C. Ahrens, MD3, Natalie Sollo, MD4, Steven Strausbaugh, MD5, Gavin Graff, MD6, Raksha Jain, MD7, Stephan Witte, PhD8, and Kristin Forssmann, MD8 Objective To evaluate the safety and efficacy of a novel microbial lipase (NM-BL) in a liquid formulation for the treatment of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF) in a phase IIa proofof-concept study. Study design We conducted a double-blind, randomized, placebo controlled crossover study in patients with cystic fibrosis and exocrine pancreatic insufficiency. Adolescent and adult patients with CF were randomized to receive NM-BL or placebo for 1 week as replacement for their usual pancreatic enzyme formulation. They were subsequently crossed-over to the alternate study treatment. The coefficient of fat absorption was evaluated as the primary endpoint. Symptoms and adverse events were evaluated as secondary endpoints. Results A total of 35 patients were randomized into the study and 22 patients completed both treatment periods. During treatment with NM-BL, the coefficient of fat absorption was significantly greater (72.7%) compared with placebo (53.8%) with a difference between groups of 18.8% (P < .001). Subjective assessment of stool fat and stool consistency also improved under treatment with NM-BL. Adverse events were mostly gastrointestinal in nature and were more common in the group receiving NM-BL. Conclusions Currently available pancreatic enzyme products are limited because of the lack of liquid formulations and being largely porcine based. The novel microbial lipase NM-BL was safe and effective in this short term trial. The trial provided clinical proof-of-concept for this novel microbial lipase as a treatment for EPI in CF. A larger phase 2 dose ranging trial is warranted. (J Pediatr 2016;-:---). Trial Registration ClinicalTrials.gov: NCT01710644.
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xocrine pancreatic insufficiency (EPI) affects up to 90% of patients with cystic fibrosis (CF). In these patients, the pancreas fails to produce adequate amounts of digestive enzymes, leading to fat malabsorption and potential malnutrition. Untreated EPI results in steatorrhea, gastrointestinal symptoms (including abdominal pain, flatulence, diarrhea, and weight loss), and poor growth in infants and children.1 Current standard therapy for the treatment of EPI is pancreatic enzyme replacement therapy (PERT), which uses products that contain porcine pancreatin (pancrelipase in the US). These porcine pancreatic preparations, however, have several shortcomings. Most of the commercially available products are enteric coated to protect the lipase from irreversible inactivation by gastric acid and proteases. This protective coating requires the near-neutral pH in the duodenum for timely dissolution. Patients with CF often have more acidic duodenal contents as the result of impaired bicarbonate secretion, which has been shown to delay the release of the administered enzymes. In addition, because of their low specific activity, these animal-derived products require ingestion of relatively large number of capsules per meal. Finally, no existing porcine PERTs are available in a liquid form.2 The novel microbial lipase (NM-BL) contains only lipase (ie, no proteases), which may limit its use as the sole PERT used to treat patients with CF or other From the Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Nemours Children’s Clinic, Jacksonville, causes of pancreatic insufficiency. The main clinical consequence of EPI is fat FL; Roy J and Lucille A Carver College of Medicine, 1
2
3
BMI CF CFA CNA EPI NM-BL PERT SAE TEAE
Body mass index Cystic fibrosis Coefficient of fat absorption Coefficient of nitrogen absorption Exocrine pancreatic insufficiency Novel microbial lipase Pancreatic enzyme-replacement therapy Serious adverse event Treatment-emergent adverse event
University of Iowa, Iowa City, IA; 4University of Kansas School of Medicine-Wichita/Via Christi Research, Wichita, KS; 5Rainbow Babies and Children’s Hospital, Cleveland, OH; 6Penn State Milton S. Hershey Medical Center, Hershey, PA; 7The University of Texas Southwestern Medical Center, Dallas, TX; and 8 Nordmark Arzneimittel GmbH & Co. KG, Uetersen, Germany All phases of this study were funded by Nordmark Arzneimittel GmbH & Co. KG, Uetersen Germany. K.F. is an employee of Nordmark. All other authors received investigator and/or consulting fees from Nordmark. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2016.05.049
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maldigestion and steatorrhea. Lipase is the most unstable pancreatic enzyme, probably because of its high sensitivity to degradation by proteases and inactivation by acidic pH. Although reduced secretion of pancreatic amylase and protease can be compensated for by salivary amylase, intestinal glycosidase, colonic flora, gastric pepsin, and intestinal peptidases, the digestive action of pancreatic lipase is only minimally supplemented by extrapancreatic sources.3,4 Consequently, steatorrhea occurs earlier and is more pronounced than azotorrhea in most cases and may even be the only clinical feature of malabsorption.5,6 NM-BL is a novel bacterial lipase (INN: burlulipase) produced by a fermentative process that uses Burkholderia plantarii, a gram-negative bacterium that is not pathogenic to humans. NM-BL could overcome some of the shortcomings of porcine pancreatin formulations. In contrast to commercially available PERTs, NM-BL is a liquid formulation that is administered in a cup of water with a meal. In vitro experiments have shown that NM-BL is more resistant to inactivation by gastric acid and proteases than conventional pancreatin products. In dogs with experimentally induced pancreatic insufficiency, the efficacy of NM-BL was comparable with conventional porcine products in reducing steatorrhea.7 To further investigate use of NMBL for pancreatic enzyme replacement, we conducted a placebo controlled phase IIa clinical study to investigate its safety and efficacy in patients with CF and EPI.
Methods We conducted a multicenter, randomized, placebo controlled, double-blind, crossover study of the safety and efficacy of NM-BL in patients with CF and EPI $12 years of age (ClinicalTrials.gov: NCT01710644). The study protocol and informed consent forms were approved by the institutional review boards at each study institution. After verbal explanation of the study, all subjects/guardians signed an informed consent form. In the case of patients aged <18 years, assent was given. The design of the study followed published expert recommendations.8 Male and female subjects with CF followed at 1 of 9 CF Foundation-accredited centers were selected for this study. Subjects were eligible if they were $12 years of age, had a diagnosis of CF based on standard criteria,9 and had documented EPI with a fecal elastase less than 50 mg/g. Subjects were required to be on treatment with PERT, had to be clinically and nutritionally stable with an acceptable body mass index (BMI; BMI percentile >10% for patients #20 years of age or a BMI >19.8 for male patients aged >20 years or a BMI >18.5 for female patients aged >20 years), and to be on stable treatment with acid-suppression therapy. Subjects were excluded if they had a history of fibrosing colonopathy, significant bowel resection, solid-organ transplant, being refractory to PERT, cirrhosis and portal hypertension, a history of distal intestinal obstruction syndrome or a current diagnosis of intestinal bacterial overgrowth, ileus or acute abdomen, or a requirement for tube feeding during the study. All subjects continued their other 2
Volume medications for treatment of CF, including proton pump inhibitors or H2 antagonists. If patients met the criteria at the initial screening visit, eligible subjects continued on their usual PERT for up to 4 weeks and were randomized to 1 of 2 treatment arms: NM-BL then placebo or placebo then NM-BL. For each treatment period, patients were hospitalized at the site and the subject’s prescribed PERT was discontinued. Patients were put on an individualized high-calorie and high-fat diet as recommended in CF Foundation nutrition guidelines,10 consisting of 100 g of fat and at least 2 g of fat per kg body weight provided in 3 meals and 2 snacks. Fat and protein intake was recorded on the basis of the amount of food consumed. Patients received 90 mg of NM-BL protein per main meal and 45 mg of NM-BL protein per snack dissolved in approximately 50 mL of water to be consumed along with the respective meal. On the evenings of days 2 and 5, the subjects received 400500 mg of a blue stool marker (FD&C blue no. 2) to mark the start and end of the 72-hour stool collection period required for the coefficient of fat absorption (CFA) assessment. After the appearance of the second blue stool, the study drug and high-fat diet were discontinued, and patients were discharged and resumed their normal PERT for 1-4 weeks before they returned for the second treatment period (Figure 1; available at www.jpeds.com). The procedure used in the second period was identical to the first period. A follow-up visit occurred 4-10 days after the discharge from the second treatment period. An independent data monitoring committee of the CF Foundation was set up before trial commencement. The board reviewed the trial design and an interim analysis of blinded safety data after 50% of the planned number of patients had completed the study. Outcomes The primary objective of the study was to evaluate the efficacy of NM-BL compared with placebo in improving fat absorption as determined by the CFA. The stool collection was performed from the first appearance of dyed stool to the second appearance of the dyed stool (day 6 or 7 of each treatment period depending on the subject’s intestinal motility). The fat content of the stool was measured by a gravimetric method.11 The CFA is considered the gold standard measure for the evaluation of fat absorption and is accepted by regulatory authorities as surrogate endpoint for EPI. The CFA was calculated from the fat intake and excretion according to the following formula: CFAð%Þ ¼ 100 ½fat intake fat excretion=fat intake: Secondary efficacy outcomes included the coefficient of nitrogen absorption (CNA), representing the protein absorption and clinical symptoms (stool frequency, consistency, flatulence, and abdominal pain). The CNA was calculated similar to the CFA. Clinical symptomatology was determined from data recorded daily by subjects regarding the stool Heubi et al
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Table I. Demographics of randomized patients Characteristic Age, y <18 $18 Sex, male Ethnic origin Not Hispanic or Latino Hispanic or Latino Race White Black or African American Height, cm Weight, kg BMI, kg/m2 BMI percentile
19.9 (5.8) 39% (12) 61% (19) 65% (20) 97% (30) 3% (1) 94% (29) 6% (2) 165 (8) 60.5 (10.8) 22.1 (2.6) 48% (22.6)
Data are presented as mean (SD) for continuous variables, and as percentage for categorical data.
frequency (number per day), stool consistency (hard, formed/normal, soft, watery), flatulence (none, mild, moderate, severe), and abdominal pain (none, mild, moderate, severe) as described previously.12 Safety outcomes included adverse events, physical examination, vital signs including body weight, and clinical laboratory variables. Sample Size Calculation, Randomization, and Statistical Analyses For the primary variable, CFA, an SD of 20% was assumed. To be able to detect a 15% difference between placebo and NM-BL with 90% power and a significance level of 5%, we calculated that a sample size of 21 patients was needed. For a 1:1 treatment sequence allocation, 22 patients with both treatment periods complete were required. Patients who dropped out prematurely were replaced. The assumptions for the sample size calculation were reassessed and confirmed once during the course of the study based on blinded study data. The randomization code was generated by an independent statistician before the study by use of
the PROC PLAN procedure in SAS. Patients were allocated to 1 of the treatment arms by an interactive computer system. Investigators and study team were blinded to the treatments until the database was locked. Analysis of the clinical data was performed on an intention-to-treat basis and were performed with SAS, version 9.2 (SAS Institute Inc, Cary, North Carolina). The primary endpoint CFA was analyzed with an ANOVA model with treatment, treatment period, and sequence as fixed effects and patient within sequence as a random effect.
Results From June 2013 to June 2014, a total 35 subjects consented to participate in this study and were subsequently randomized. Overall, 22 patients completed both treatment periods and 28 patients completed at least the placebo period and 29 patients completed at least the NM-BL period (Figure 2; available at www.jpeds.com). Demographic characteristics of the randomized study population can be seen in Table I. After 11 patients completed the study, we conducted a blinded interim analysis to assess the safety of the study drug and the Data Monitoring Committee convened and recommended the study to continue. CFA (least squares mean) was significantly greater with NM-BL compared with placebo (Table II). The mean (SD) total fat intake between days 3 and 5 of the 2 treatment periods was similar in both treatment groups: 489 128 g during placebo and 421 140 g during treatment with NM-BL. There was no meaningful difference in CFA observed in subjects aged 12-18 years and those aged >18 years. In 4 subjects with more severe EPI, as determined by a placebo CFA of <40%, there was a trend for a greater effect from NM-BL treatment compared with subjects whose placebo CFA was $40% (P = .07). Although the actual difference is large, it did not reach statistical significance, most likely because of a
Table II. CFA results Placebo Overall (N = 27) LS mean (95% CI) P value By disease severity Placebo CFA <40% (n = 4) LS mean (95% CI) P value Placebo CFA $40% (n = 18) LS mean (95% CI) P value By age group Age <8 y (n = 10) LS mean (95% CI) P value Age $18 y (n = 17) LS mean (95% CI) P value
NM-BL
Difference
53.8 (45.0-62.7)
72.7 (63.3-82.0)
18.8 (9.7-28.0) <.001
23.8 (15.4 to 62.9)
68.6 (29.4-107.8)
44.9 (10.6 to 100.3) .073
61.7 (53.3-70.2)
74.1 (65.7-82.6)
12.4 (4.7-20.1) .004
54.5 (40.4-68.7)
75.4 (60.8-90.1)
20.9 (5.3-36.6) .016
53.1 (39.9-66.3)
72.2 (58.0-86.3)
19.1 (6.6-31.6) .006
LS, least squares.
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A NM-BL
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100 80 60 40 20
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80 60 40 20
0
0 1
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Percent of subjects
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80 60 40 20
20
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80 60 40 20
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D NM-BL
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Percent of subjects
Percent of subjects
100 80 60 40 20
no yes
80 60 40 20
0
0 1
2
3 4 5 Treatment day
6
1
2
3 4 5 Treatment day
6
Figure 3. Effect of NM-BL on A, abdominal pain, B, stool consistency, C, flatulence, and D, subjective stool fat.
type 2 error. The mean CFA on NM-BL was similar in these 2 subject groups (68.6% and 71.1%, respectively). There was no clinically meaningful or statistically significant 4
difference in the CNA, which was 58.1% (95% CI 50.166.1) with placebo and 58.3% (95% CI 50.0-66.5) with NM-BL. Heubi et al
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The time course of clinical symptoms is presented in Figure 3. Abdominal pain was worse during treatment with NM-BL, whereas flatulence was comparable during both treatments. Stool consistency and subjective stool fat were improved during treatment with NM-BL. Treatment-emergent adverse events (TEAEs) were mostly gastrointestinal in nature as expected in the population with CF. A greater incidence of TEAEs was observed during treatment with NM-BL compared with placebo (Table III). The most common TEAEs were related to the gastrointestinal system. In total, 7 patients experienced a serious adverse event (SAE). Four patients experienced SAEs of pulmonary exacerbations of CF outside the treatment periods (1 before randomization, 2 during the stabilization period, and 1 in the follow-up period). Three patients experienced SAEs during treatment with NM-BL. Two of these patients experienced SAEs (enteritis and small bowel obstruction) were considered related to the study medication by the investigator and the patients were withdrawn from the study. One SAE observed during NM-BL treatment (Clostridium difficile infection) was considered unrelated to study medication. No deaths occurred during the study.
Discussion We evaluated NM-BL, a novel bacterial lipase only product in a liquid formulation in patients with CF with EPI. In this randomized, double-blind, multicenter, 2-period crossover study proof-of-concept for the treatment of EPI with this lipase was shown to be safe and efficacious for the first time. Overall, NM-BL was safe and well tolerated at the dose level studied. During NM-BL treatment, patients had a statistically Table III. Treatment-emergent adverse events
Any TEAE Serious TEAE Discontinuation due to TEAE Severe TEAE Most common TEAE* Gastrointestinal disorder Abdominal pain Constipation Abdominal discomfort Vomiting Nausea Flatulence Abdominal tenderness Diarrhea Abdominal distension Steatorrhea General disorders Product taste abnormal Pyrexia Metabolism/nutrition Decreased appetite Nervous system disorders Headache
Placebo, n = 28 (100%)
NM-BL, n = 29 (100%)
13 (46.4) 0 0 0
19 (65.5) 3 (10.3) 4 (13.8) 8 (27.6)
12 (42.9) 5 (17.9) 0 0 2 (7.1) 2 (7.1) 3 (10.7) 0 1 (3.6) 2 (7.1) 2 (7.1) 0 0 0 1 (3.6) 0 1 (3.6) 1 (3.6)
17 (58.6) 8 (27.6) 5 (17.2) 4 (13.8) 4 (13.8) 3 (10.3) 3 (10.3) 2 (6.9) 2 (6.9) 0 0 5 (17.2) 3 (10.3) 2 (6.9) 2 (6.9) 2 (6.9) 2 (6.9) 2 (6.9)
*Occurring in $5% of subjects in either treatment group.
significant improvement of fat absorption as measured by the CFA. The greatest improvements were seen in patients with more severe disease (placebo CFA <40%). Improved stool consistency and reduced steatorrhea were also observed during NM-BL treatment. The CNA, a surrogate representing digestion of proteins, did not change under treatment with NM-BL. This finding was expected, because the product tested did not contain proteases. It is still not known whether protease supplementation is required for the treatment of EPI. It has been suggested that endogenous gut proteases can compensate for the lack of proteolytic activity from pancreatic secretion and that only lipase substitution may be needed for the clinical treatment of EPI.3,6 Because excessive azotorrhea may have adverse effects on growth in infants and children, long-term outcome studies with weight gain and lean muscle mass as outcome variables may therefore be required to prove the long-term safety of a lipase-only product in children. Alternatively, this product may be used as a supplement to enteric feedings and formulae used for this indication may contain hydrolyzed protein and sources of carbohydrate that are less dependent upon pancreatic amylase for digestion and absorption. Adverse events observed in the study were mostly gastrointestinal in nature and were largely those expected for the underlying CF disease. A greater number of adverse events and withdrawals due to adverse events were observed when patients received NM-BL compared with placebo. The greater number of adverse events during NM-BL treatment may result from the high dose of NM-BL (360 mg/day), which was at the upper end of the expected dose range for NMBL. This dose was intentionally chosen to enable the study to show clinical proof of concept for the efficacy of NMBL, because little was known on the minimally effective dose at the time of the design of the study. The observed adverse events have been mostly gastrointestinal in nature and may be the result of the underlying disease, the study drug and its mode of action, or a combination of both. Therefore, the safety and efficacy profile of the compound will need to be investigated further in a dose ranging study. Comparison of the efficacy of NM-BL with that of currently marketed porcine-based PERTs presents several challenges. When we compared the results of this study with those of other PERT trials, consideration needs to be given to the concept that the method used for the determination of lipase activity in pancrelipase products (US Pharmacopeia) is not suitable for lipases of microbial origin. The US Pharmacopeia method requires the use of a substrate, which results in artificially low lipase activities for microbial lipases. Therefore, the resulting lipase units would not be comparable with animal-sourced lipases. To avoid confusion with the dosing of NM-BL, the Food and Drug Administration recommended a dosing of NM-BL according to the mass of protein dosed. This is possible, because NM-BL is a pure protein with a defined activity per mg. In addition, study designs, analytical methods with regard to stool fat determination, nutritional intake, as well as dosing schemes differed in recently conducted PERT studies have been different and might influence efficacy. This should be taken into account
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when comparing CFA values of different studies as surrogate directly. Our findings with NM-BL appear comparable with those observed with porcine-based PERTs. In study populations in which approximately 50% of subjects had severe EPI (untreated CFA <40%), improvement in CFA observed with available porcine pancrelipase products ranged from 26% to 39%.12-14 The CFA improvements observed with NM-BL in this study were 19% in the overall population and 45% in the population with severe EPI. Our findings may be potentially better than the other product containing a microbial lipase, liprotamase, that has been studied. Liprotamase is in advanced clinical development and improved the CFA by 11% in a large phase 3 study in the overall population and by 17% in those with untreated CFA <40%.15 As a liquid formulation, NM-BL may become a valuable alternative for younger children, who cannot easily swallow capsules16 and for use with formula administered through gastrostomies or jejunostomies as caloric supplements for patients with CF and EPI who grow poorly and cannot be supplemented adequately by mouth to support normal growth. This study provides clinical proof-of-concept for the treatment of EPI in CF with the novel microbial lipase NM-BL. As a liquid formulation, NM-BL may be more convenient to administer than conventional porcine derived PERTs that requires patients to swallow large numbers of capsules. Similarly, NM-BL may become a valuable alternative for younger children who cannot easily swallow capsules. It also may be useful for patients requiring tube feeding because lipase replacement for these patients is not optimal with currently available products.16 Thus, NM-BL may become a valuable addition to the currently available treatments of EPI, particularly in pediatric patients. n We are grateful to all study participants who devoted their time for participation in the study. We also acknowledge the important contributions of the study nurses, dieticians, and involved study personnel. The members of the data safety monitoring board, chaired by Lynne Quittell, MD, critically reviewed the study design and monitored blinded safety data. At Nordmark, the entire project team played a critical role and we thank them for their contributions to this clinical study. Submitted for publication Feb 16, 2016; last revision received Apr 12, 2016; accepted May 12, 2016. Reprint requests: James E. Heubi, MD, Children’s Hospital Medical Center, 241 Albert Sabin Way, S10.313, Cincinnati, OH 45229. E-mail: James.Heubi@ cchmc.org
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1. Baker SS, Borowitz D, Baker RD. Pancreatic exocrine function in patients with cystic fibrosis. Curr Gastroenterol Rep 2005;7: 227-33. 2. Trang T, Chan J, Graham DY. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21(st) century. World J Gastroenterol 2014;20:114671-85. 3. Domınguez-Mu~ noz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Curr Gastroenterol Rep 2007;9:116-22. 4. Hammer HF. Pancreatic exocrine insufficiency: diagnostic evaluation and replacement therapy with pancreatic enzymes. Dig Dis 2010;28: 339-43. 5. DiMagno EP, Clain JE, Layer P. Chronic pancreatitis. In: Go VL, ed. The Pancreas: biology, pathophysiology and disease. 2nd ed. New York: Raven Press; 1993. p. 665-706. 6. Ferrone M, Raimondo M, Scolapio JS. Pancreatic enzyme pharmacotherapy. Pharmacotherapy 2007;27:910-20. 7. Suzuki A, Mizumoto A, Rerknimitr R, Sarr MG, DiMango EP. Effect of bacterial or porcine lipase with low- or high-fat diets on nutrient absorption in pancreatic-insufficient dogs. Gastroenterology 1999; 116:431-7. 8. Konstan MW, Borowitz D, Mayer-Hamblett N, Milla C, Hendeles L, Murray S, et al. Study design considerations for evaluating the efficacy and safety of pancreatic enzyme replacement therapy in patients with cystic fibrosis. Clin Investig (Lond) 2013;3:731-41. 9. Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr 2008;153:S4-14. 10. Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 2002;35:246-59. 11. van de Kamer JH, ten Bokkel Huinink H, Weyers HA. Rapid method for the determination of fat in feces. J Biol Chem 1949;177:347-55. 12. Trapnell BC, Maguiness K, Graff GR, Boyd D, Beckmann K, Caras S. Efficacy and safety of Creon 24,000 in subjects with exocrine pancreatic insufficiency due to cystic fibrosis. J Cyst Fibros 2009;8:370-7. 13. Trapnell BC, Strausbaugh SD, Woo MS, Tong S-Y, Silber SA, Mulberg AE, et al. Efficacy and safety of PANCREAZE for treatment of exocrine pancreatic insufficiency due to cystic fibrosis. J Cyst Fibros 2011;10:350-6. 14. Wooldridge JL, Heubi JE, Amaro-Galvez R, Boas SR, Blake KV, Nasr SZ, et al. EUR-1008 pancreatic enzyme replacement is safe and effective in patients with cystic fibrosis and pancreatic insufficiency. J Cyst Fibros 2009;8:405-17. 15. Borowitz D, Stevens C, Brettman LR, Campion M, Chatfield B, Cipolli M. International phase III trial of liprotamase efficacy and safety in pancreatic-insufficient cystic fibrosis patients. J Cyst Fibros 2011;10: 443-52. 16. Nicolo M, Stratton KW, Rooney W, Boullata J. Pancreatic enzyme replacement therapy for enterally fed patients with cystic fibrosis. Nutr Clin Pract 2013;28:485-9.
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Screening ≤ 35 days before first Treatment Period Randomization
Placebo 72 hour CFA Assessment
NM-BL 360 mg/day 72 hour CFA Assessment
NM-BL 360 mg/day 72 hour CFA Assessment
EoS Visit 7EoS (±3) days Visitafter discharge 7last (±3) days from study center
Placebo 72 hour CFA Assessment
Pre-study PERT
Pre-study PERT Stabilization on pre study PERT 1-4 weeks
Treatment Period 1
Treatment Period 2 (6 – 7 days, inpatient)
(6 – 7 days, inpatient)
Double-blind Part
Figure 1. CONSORT diagram. EoS, end-of-study.
Screened (n=35) Randomized (n=35)
withdrawn (n=3) • adverse event (n=2) • withdrew consent (n=1)
withdrawn (n=4) • withdrew consent (n=2) • non-compliant (n=1) • adverse event (n=1)
Dosed with NM-BL (n=15)
Dosed with placebo (n=16)
Stabilization period (n=12)
Stabilization period (n=15)
withdrawn (n=1) • pregnancy (n=1)
Dosed with placebo (n=12)
Dosed with NM-BL (n=14)
withdrawn (n=4) • adverse event (n=2) • withdrew consent (n=1) • other (n=1)
Completed (n=12)
completed (n=10)
withdrawn (n=1) • withdrew consent (n=1)
Analyzed for efficacy (n=22) Analyzed for safety (n=31)
Figure 2. Study participant flow. Safety and Efficacy of a Novel Microbial Lipase in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis: A Randomized Controlled Clinical Trial
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xocrine pancreatic insufficiency (EPI) affects up to 90% of patients with cystic fibrosis (CF). In these patients, the pancreas fails to produce adequate amounts of digestive enzymes, leading to fat malabsorption and potential malnutrition. Untreated EPI results in steatorrhea, gastrointestinal symptoms (including abdominal pain, flatulence, diarrhea, and weight loss), and poor growth in infants and children.1 Current standard therapy for the treatment of EPI is pancreatic enzyme replacement therapy (PERT), which uses products that contain porcine pancreatin (pancrelipase in the US). These porcine pancreatic preparations, however, have several shortcomings. Most of the commercially available products are enteric coated to protect the lipase from irreversible inactivation by gastric acid and proteases. This protective coating requires the near-neutral pH in the duodenum for timely dissolution. Patients with CF often have more acidic duodenal contents as the result of impaired bicarbonate secretion, which has been shown to delay the release of the administered enzymes. In addition, because of their low specific activity, these animal-derived products require ingestion of relatively large number of capsules per meal. Finally, no existing porcine PERTs are available in a liquid form.2 The novel microbial lipase (NM-BL) contains only lipase (ie, no proteases), which may limit its use as the sole PERT used to treat patients with CF or other From the Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Nemours Children’s Clinic, Jacksonville, causes of pancreatic insufficiency. The main clinical consequence of EPI is fat FL; Roy J and Lucille A Carver College of Medicine, 1
2
3
BMI CF CFA CNA EPI NM-BL PERT SAE TEAE
Body mass index Cystic fibrosis Coefficient of fat absorption Coefficient of nitrogen absorption Exocrine pancreatic insufficiency Novel microbial lipase Pancreatic enzyme-replacement therapy Serious adverse event Treatment-emergent adverse event
University of Iowa, Iowa City, IA; 4University of Kansas School of Medicine-Wichita/Via Christi Research, Wichita, KS; 5Rainbow Babies and Children’s Hospital, Cleveland, OH; 6Penn State Milton S. Hershey Medical Center, Hershey, PA; 7The University of Texas Southwestern Medical Center, Dallas, TX; and 8 Nordmark Arzneimittel GmbH & Co. KG, Uetersen, Germany All phases of this study were funded by Nordmark Arzneimittel GmbH & Co. KG, Uetersen Germany. K.F. is an employee of Nordmark. All other authors received investigator and/or consulting fees from Nordmark. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2016.05.049
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maldigestion and steatorrhea. Lipase is the most unstable pancreatic enzyme, probably because of its high sensitivity to degradation by proteases and inactivation by acidic pH. Although reduced secretion of pancreatic amylase and protease can be compensated for by salivary amylase, intestinal glycosidase, colonic flora, gastric pepsin, and intestinal peptidases, the digestive action of pancreatic lipase is only minimally supplemented by extrapancreatic sources.3,4 Consequently, steatorrhea occurs earlier and is more pronounced than azotorrhea in most cases and may even be the only clinical feature of malabsorption.5,6 NM-BL is a novel bacterial lipase (INN: burlulipase) produced by a fermentative process that uses Burkholderia plantarii, a gram-negative bacterium that is not pathogenic to humans. NM-BL could overcome some of the shortcomings of porcine pancreatin formulations. In contrast to commercially available PERTs, NM-BL is a liquid formulation that is administered in a cup of water with a meal. In vitro experiments have shown that NM-BL is more resistant to inactivation by gastric acid and proteases than conventional pancreatin products. In dogs with experimentally induced pancreatic insufficiency, the efficacy of NM-BL was comparable with conventional porcine products in reducing steatorrhea.7 To further investigate use of NMBL for pancreatic enzyme replacement, we conducted a placebo controlled phase IIa clinical study to investigate its safety and efficacy in patients with CF and EPI.
Methods We conducted a multicenter, randomized, placebo controlled, double-blind, crossover study of the safety and efficacy of NM-BL in patients with CF and EPI $12 years of age (ClinicalTrials.gov: NCT01710644). The study protocol and informed consent forms were approved by the institutional review boards at each study institution. After verbal explanation of the study, all subjects/guardians signed an informed consent form. In the case of patients aged <18 years, assent was given. The design of the study followed published expert recommendations.8 Male and female subjects with CF followed at 1 of 9 CF Foundation-accredited centers were selected for this study. Subjects were eligible if they were $12 years of age, had a diagnosis of CF based on standard criteria,9 and had documented EPI with a fecal elastase less than 50 mg/g. Subjects were required to be on treatment with PERT, had to be clinically and nutritionally stable with an acceptable body mass index (BMI; BMI percentile >10% for patients #20 years of age or a BMI >19.8 for male patients aged >20 years or a BMI >18.5 for female patients aged >20 years), and to be on stable treatment with acid-suppression therapy. Subjects were excluded if they had a history of fibrosing colonopathy, significant bowel resection, solid-organ transplant, being refractory to PERT, cirrhosis and portal hypertension, a history of distal intestinal obstruction syndrome or a current diagnosis of intestinal bacterial overgrowth, ileus or acute abdomen, or a requirement for tube feeding during the study. All subjects continued their other 2
Volume medications for treatment of CF, including proton pump inhibitors or H2 antagonists. If patients met the criteria at the initial screening visit, eligible subjects continued on their usual PERT for up to 4 weeks and were randomized to 1 of 2 treatment arms: NM-BL then placebo or placebo then NM-BL. For each treatment period, patients were hospitalized at the site and the subject’s prescribed PERT was discontinued. Patients were put on an individualized high-calorie and high-fat diet as recommended in CF Foundation nutrition guidelines,10 consisting of 100 g of fat and at least 2 g of fat per kg body weight provided in 3 meals and 2 snacks. Fat and protein intake was recorded on the basis of the amount of food consumed. Patients received 90 mg of NM-BL protein per main meal and 45 mg of NM-BL protein per snack dissolved in approximately 50 mL of water to be consumed along with the respective meal. On the evenings of days 2 and 5, the subjects received 400500 mg of a blue stool marker (FD&C blue no. 2) to mark the start and end of the 72-hour stool collection period required for the coefficient of fat absorption (CFA) assessment. After the appearance of the second blue stool, the study drug and high-fat diet were discontinued, and patients were discharged and resumed their normal PERT for 1-4 weeks before they returned for the second treatment period (Figure 1; available at www.jpeds.com). The procedure used in the second period was identical to the first period. A follow-up visit occurred 4-10 days after the discharge from the second treatment period. An independent data monitoring committee of the CF Foundation was set up before trial commencement. The board reviewed the trial design and an interim analysis of blinded safety data after 50% of the planned number of patients had completed the study. Outcomes The primary objective of the study was to evaluate the efficacy of NM-BL compared with placebo in improving fat absorption as determined by the CFA. The stool collection was performed from the first appearance of dyed stool to the second appearance of the dyed stool (day 6 or 7 of each treatment period depending on the subject’s intestinal motility). The fat content of the stool was measured by a gravimetric method.11 The CFA is considered the gold standard measure for the evaluation of fat absorption and is accepted by regulatory authorities as surrogate endpoint for EPI. The CFA was calculated from the fat intake and excretion according to the following formula: CFAð%Þ ¼ 100 ½fat intake fat excretion=fat intake: Secondary efficacy outcomes included the coefficient of nitrogen absorption (CNA), representing the protein absorption and clinical symptoms (stool frequency, consistency, flatulence, and abdominal pain). The CNA was calculated similar to the CFA. Clinical symptomatology was determined from data recorded daily by subjects regarding the stool Heubi et al
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Table I. Demographics of randomized patients Characteristic Age, y <18 $18 Sex, male Ethnic origin Not Hispanic or Latino Hispanic or Latino Race White Black or African American Height, cm Weight, kg BMI, kg/m2 BMI percentile
19.9 (5.8) 39% (12) 61% (19) 65% (20) 97% (30) 3% (1) 94% (29) 6% (2) 165 (8) 60.5 (10.8) 22.1 (2.6) 48% (22.6)
Data are presented as mean (SD) for continuous variables, and as percentage for categorical data.
frequency (number per day), stool consistency (hard, formed/normal, soft, watery), flatulence (none, mild, moderate, severe), and abdominal pain (none, mild, moderate, severe) as described previously.12 Safety outcomes included adverse events, physical examination, vital signs including body weight, and clinical laboratory variables. Sample Size Calculation, Randomization, and Statistical Analyses For the primary variable, CFA, an SD of 20% was assumed. To be able to detect a 15% difference between placebo and NM-BL with 90% power and a significance level of 5%, we calculated that a sample size of 21 patients was needed. For a 1:1 treatment sequence allocation, 22 patients with both treatment periods complete were required. Patients who dropped out prematurely were replaced. The assumptions for the sample size calculation were reassessed and confirmed once during the course of the study based on blinded study data. The randomization code was generated by an independent statistician before the study by use of
the PROC PLAN procedure in SAS. Patients were allocated to 1 of the treatment arms by an interactive computer system. Investigators and study team were blinded to the treatments until the database was locked. Analysis of the clinical data was performed on an intention-to-treat basis and were performed with SAS, version 9.2 (SAS Institute Inc, Cary, North Carolina). The primary endpoint CFA was analyzed with an ANOVA model with treatment, treatment period, and sequence as fixed effects and patient within sequence as a random effect.
Results From June 2013 to June 2014, a total 35 subjects consented to participate in this study and were subsequently randomized. Overall, 22 patients completed both treatment periods and 28 patients completed at least the placebo period and 29 patients completed at least the NM-BL period (Figure 2; available at www.jpeds.com). Demographic characteristics of the randomized study population can be seen in Table I. After 11 patients completed the study, we conducted a blinded interim analysis to assess the safety of the study drug and the Data Monitoring Committee convened and recommended the study to continue. CFA (least squares mean) was significantly greater with NM-BL compared with placebo (Table II). The mean (SD) total fat intake between days 3 and 5 of the 2 treatment periods was similar in both treatment groups: 489 128 g during placebo and 421 140 g during treatment with NM-BL. There was no meaningful difference in CFA observed in subjects aged 12-18 years and those aged >18 years. In 4 subjects with more severe EPI, as determined by a placebo CFA of <40%, there was a trend for a greater effect from NM-BL treatment compared with subjects whose placebo CFA was $40% (P = .07). Although the actual difference is large, it did not reach statistical significance, most likely because of a
Table II. CFA results Placebo Overall (N = 27) LS mean (95% CI) P value By disease severity Placebo CFA <40% (n = 4) LS mean (95% CI) P value Placebo CFA $40% (n = 18) LS mean (95% CI) P value By age group Age <8 y (n = 10) LS mean (95% CI) P value Age $18 y (n = 17) LS mean (95% CI) P value
NM-BL
Difference
53.8 (45.0-62.7)
72.7 (63.3-82.0)
18.8 (9.7-28.0) <.001
23.8 (15.4 to 62.9)
68.6 (29.4-107.8)
44.9 (10.6 to 100.3) .073
61.7 (53.3-70.2)
74.1 (65.7-82.6)
12.4 (4.7-20.1) .004
54.5 (40.4-68.7)
75.4 (60.8-90.1)
20.9 (5.3-36.6) .016
53.1 (39.9-66.3)
72.2 (58.0-86.3)
19.1 (6.6-31.6) .006
LS, least squares.
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www.jpeds.com Abdominal Pain
A NM-BL
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100
Percent of subjects
Percent of subjects
100 80 60 40 20
none mild moderate severe
80 60 40 20
0
0 1
2
3 4 5 Treatment day
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1
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B NM-BL
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Percent of subjects
Percent of subjects
100 80 60 40
Hard Formed/ Normal Soft Watery
80 60 40 20
20
0
0 1
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6
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C NM-BL
Placebo
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Percent of subjects
Percent of subjects
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none mild moderate severe
80 60 40 20
0
0 1
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Subjective Stool Fat
D NM-BL
Placebo
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Percent of subjects
Percent of subjects
100 80 60 40 20
no yes
80 60 40 20
0
0 1
2
3 4 5 Treatment day
6
1
2
3 4 5 Treatment day
6
Figure 3. Effect of NM-BL on A, abdominal pain, B, stool consistency, C, flatulence, and D, subjective stool fat.
type 2 error. The mean CFA on NM-BL was similar in these 2 subject groups (68.6% and 71.1%, respectively). There was no clinically meaningful or statistically significant 4
difference in the CNA, which was 58.1% (95% CI 50.166.1) with placebo and 58.3% (95% CI 50.0-66.5) with NM-BL. Heubi et al
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The time course of clinical symptoms is presented in Figure 3. Abdominal pain was worse during treatment with NM-BL, whereas flatulence was comparable during both treatments. Stool consistency and subjective stool fat were improved during treatment with NM-BL. Treatment-emergent adverse events (TEAEs) were mostly gastrointestinal in nature as expected in the population with CF. A greater incidence of TEAEs was observed during treatment with NM-BL compared with placebo (Table III). The most common TEAEs were related to the gastrointestinal system. In total, 7 patients experienced a serious adverse event (SAE). Four patients experienced SAEs of pulmonary exacerbations of CF outside the treatment periods (1 before randomization, 2 during the stabilization period, and 1 in the follow-up period). Three patients experienced SAEs during treatment with NM-BL. Two of these patients experienced SAEs (enteritis and small bowel obstruction) were considered related to the study medication by the investigator and the patients were withdrawn from the study. One SAE observed during NM-BL treatment (Clostridium difficile infection) was considered unrelated to study medication. No deaths occurred during the study.
Discussion We evaluated NM-BL, a novel bacterial lipase only product in a liquid formulation in patients with CF with EPI. In this randomized, double-blind, multicenter, 2-period crossover study proof-of-concept for the treatment of EPI with this lipase was shown to be safe and efficacious for the first time. Overall, NM-BL was safe and well tolerated at the dose level studied. During NM-BL treatment, patients had a statistically Table III. Treatment-emergent adverse events
Any TEAE Serious TEAE Discontinuation due to TEAE Severe TEAE Most common TEAE* Gastrointestinal disorder Abdominal pain Constipation Abdominal discomfort Vomiting Nausea Flatulence Abdominal tenderness Diarrhea Abdominal distension Steatorrhea General disorders Product taste abnormal Pyrexia Metabolism/nutrition Decreased appetite Nervous system disorders Headache
Placebo, n = 28 (100%)
NM-BL, n = 29 (100%)
13 (46.4) 0 0 0
19 (65.5) 3 (10.3) 4 (13.8) 8 (27.6)
12 (42.9) 5 (17.9) 0 0 2 (7.1) 2 (7.1) 3 (10.7) 0 1 (3.6) 2 (7.1) 2 (7.1) 0 0 0 1 (3.6) 0 1 (3.6) 1 (3.6)
17 (58.6) 8 (27.6) 5 (17.2) 4 (13.8) 4 (13.8) 3 (10.3) 3 (10.3) 2 (6.9) 2 (6.9) 0 0 5 (17.2) 3 (10.3) 2 (6.9) 2 (6.9) 2 (6.9) 2 (6.9) 2 (6.9)
*Occurring in $5% of subjects in either treatment group.
significant improvement of fat absorption as measured by the CFA. The greatest improvements were seen in patients with more severe disease (placebo CFA <40%). Improved stool consistency and reduced steatorrhea were also observed during NM-BL treatment. The CNA, a surrogate representing digestion of proteins, did not change under treatment with NM-BL. This finding was expected, because the product tested did not contain proteases. It is still not known whether protease supplementation is required for the treatment of EPI. It has been suggested that endogenous gut proteases can compensate for the lack of proteolytic activity from pancreatic secretion and that only lipase substitution may be needed for the clinical treatment of EPI.3,6 Because excessive azotorrhea may have adverse effects on growth in infants and children, long-term outcome studies with weight gain and lean muscle mass as outcome variables may therefore be required to prove the long-term safety of a lipase-only product in children. Alternatively, this product may be used as a supplement to enteric feedings and formulae used for this indication may contain hydrolyzed protein and sources of carbohydrate that are less dependent upon pancreatic amylase for digestion and absorption. Adverse events observed in the study were mostly gastrointestinal in nature and were largely those expected for the underlying CF disease. A greater number of adverse events and withdrawals due to adverse events were observed when patients received NM-BL compared with placebo. The greater number of adverse events during NM-BL treatment may result from the high dose of NM-BL (360 mg/day), which was at the upper end of the expected dose range for NMBL. This dose was intentionally chosen to enable the study to show clinical proof of concept for the efficacy of NMBL, because little was known on the minimally effective dose at the time of the design of the study. The observed adverse events have been mostly gastrointestinal in nature and may be the result of the underlying disease, the study drug and its mode of action, or a combination of both. Therefore, the safety and efficacy profile of the compound will need to be investigated further in a dose ranging study. Comparison of the efficacy of NM-BL with that of currently marketed porcine-based PERTs presents several challenges. When we compared the results of this study with those of other PERT trials, consideration needs to be given to the concept that the method used for the determination of lipase activity in pancrelipase products (US Pharmacopeia) is not suitable for lipases of microbial origin. The US Pharmacopeia method requires the use of a substrate, which results in artificially low lipase activities for microbial lipases. Therefore, the resulting lipase units would not be comparable with animal-sourced lipases. To avoid confusion with the dosing of NM-BL, the Food and Drug Administration recommended a dosing of NM-BL according to the mass of protein dosed. This is possible, because NM-BL is a pure protein with a defined activity per mg. In addition, study designs, analytical methods with regard to stool fat determination, nutritional intake, as well as dosing schemes differed in recently conducted PERT studies have been different and might influence efficacy. This should be taken into account
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when comparing CFA values of different studies as surrogate directly. Our findings with NM-BL appear comparable with those observed with porcine-based PERTs. In study populations in which approximately 50% of subjects had severe EPI (untreated CFA <40%), improvement in CFA observed with available porcine pancrelipase products ranged from 26% to 39%.12-14 The CFA improvements observed with NM-BL in this study were 19% in the overall population and 45% in the population with severe EPI. Our findings may be potentially better than the other product containing a microbial lipase, liprotamase, that has been studied. Liprotamase is in advanced clinical development and improved the CFA by 11% in a large phase 3 study in the overall population and by 17% in those with untreated CFA <40%.15 As a liquid formulation, NM-BL may become a valuable alternative for younger children, who cannot easily swallow capsules16 and for use with formula administered through gastrostomies or jejunostomies as caloric supplements for patients with CF and EPI who grow poorly and cannot be supplemented adequately by mouth to support normal growth. This study provides clinical proof-of-concept for the treatment of EPI in CF with the novel microbial lipase NM-BL. As a liquid formulation, NM-BL may be more convenient to administer than conventional porcine derived PERTs that requires patients to swallow large numbers of capsules. Similarly, NM-BL may become a valuable alternative for younger children who cannot easily swallow capsules. It also may be useful for patients requiring tube feeding because lipase replacement for these patients is not optimal with currently available products.16 Thus, NM-BL may become a valuable addition to the currently available treatments of EPI, particularly in pediatric patients. n We are grateful to all study participants who devoted their time for participation in the study. We also acknowledge the important contributions of the study nurses, dieticians, and involved study personnel. The members of the data safety monitoring board, chaired by Lynne Quittell, MD, critically reviewed the study design and monitored blinded safety data. At Nordmark, the entire project team played a critical role and we thank them for their contributions to this clinical study. Submitted for publication Feb 16, 2016; last revision received Apr 12, 2016; accepted May 12, 2016. Reprint requests: James E. Heubi, MD, Children’s Hospital Medical Center, 241 Albert Sabin Way, S10.313, Cincinnati, OH 45229. E-mail: James.Heubi@ cchmc.org
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www.jpeds.com References
1. Baker SS, Borowitz D, Baker RD. Pancreatic exocrine function in patients with cystic fibrosis. Curr Gastroenterol Rep 2005;7: 227-33. 2. Trang T, Chan J, Graham DY. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21(st) century. World J Gastroenterol 2014;20:114671-85. 3. Domınguez-Mu~ noz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Curr Gastroenterol Rep 2007;9:116-22. 4. Hammer HF. Pancreatic exocrine insufficiency: diagnostic evaluation and replacement therapy with pancreatic enzymes. Dig Dis 2010;28: 339-43. 5. DiMagno EP, Clain JE, Layer P. Chronic pancreatitis. In: Go VL, ed. The Pancreas: biology, pathophysiology and disease. 2nd ed. New York: Raven Press; 1993. p. 665-706. 6. Ferrone M, Raimondo M, Scolapio JS. Pancreatic enzyme pharmacotherapy. Pharmacotherapy 2007;27:910-20. 7. Suzuki A, Mizumoto A, Rerknimitr R, Sarr MG, DiMango EP. Effect of bacterial or porcine lipase with low- or high-fat diets on nutrient absorption in pancreatic-insufficient dogs. Gastroenterology 1999; 116:431-7. 8. Konstan MW, Borowitz D, Mayer-Hamblett N, Milla C, Hendeles L, Murray S, et al. Study design considerations for evaluating the efficacy and safety of pancreatic enzyme replacement therapy in patients with cystic fibrosis. Clin Investig (Lond) 2013;3:731-41. 9. Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr 2008;153:S4-14. 10. Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 2002;35:246-59. 11. van de Kamer JH, ten Bokkel Huinink H, Weyers HA. Rapid method for the determination of fat in feces. J Biol Chem 1949;177:347-55. 12. Trapnell BC, Maguiness K, Graff GR, Boyd D, Beckmann K, Caras S. Efficacy and safety of Creon 24,000 in subjects with exocrine pancreatic insufficiency due to cystic fibrosis. J Cyst Fibros 2009;8:370-7. 13. Trapnell BC, Strausbaugh SD, Woo MS, Tong S-Y, Silber SA, Mulberg AE, et al. Efficacy and safety of PANCREAZE for treatment of exocrine pancreatic insufficiency due to cystic fibrosis. J Cyst Fibros 2011;10:350-6. 14. Wooldridge JL, Heubi JE, Amaro-Galvez R, Boas SR, Blake KV, Nasr SZ, et al. EUR-1008 pancreatic enzyme replacement is safe and effective in patients with cystic fibrosis and pancreatic insufficiency. J Cyst Fibros 2009;8:405-17. 15. Borowitz D, Stevens C, Brettman LR, Campion M, Chatfield B, Cipolli M. International phase III trial of liprotamase efficacy and safety in pancreatic-insufficient cystic fibrosis patients. J Cyst Fibros 2011;10: 443-52. 16. Nicolo M, Stratton KW, Rooney W, Boullata J. Pancreatic enzyme replacement therapy for enterally fed patients with cystic fibrosis. Nutr Clin Pract 2013;28:485-9.
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Screening ≤ 35 days before first Treatment Period Randomization
Placebo 72 hour CFA Assessment
NM-BL 360 mg/day 72 hour CFA Assessment
NM-BL 360 mg/day 72 hour CFA Assessment
EoS Visit 7EoS (±3) days Visitafter discharge 7last (±3) days from study center
Placebo 72 hour CFA Assessment
Pre-study PERT
Pre-study PERT Stabilization on pre study PERT 1-4 weeks
Treatment Period 1
Treatment Period 2 (6 – 7 days, inpatient)
(6 – 7 days, inpatient)
Double-blind Part
Figure 1. CONSORT diagram. EoS, end-of-study.
Screened (n=35) Randomized (n=35)
withdrawn (n=3) • adverse event (n=2) • withdrew consent (n=1)
withdrawn (n=4) • withdrew consent (n=2) • non-compliant (n=1) • adverse event (n=1)
Dosed with NM-BL (n=15)
Dosed with placebo (n=16)
Stabilization period (n=12)
Stabilization period (n=15)
withdrawn (n=1) • pregnancy (n=1)
Dosed with placebo (n=12)
Dosed with NM-BL (n=14)
withdrawn (n=4) • adverse event (n=2) • withdrew consent (n=1) • other (n=1)
Completed (n=12)
completed (n=10)
withdrawn (n=1) • withdrew consent (n=1)
Analyzed for efficacy (n=22) Analyzed for safety (n=31)
Figure 2. Study participant flow. Safety and Efficacy of a Novel Microbial Lipase in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis: A Randomized Controlled Clinical Trial
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