What Is Known
- Approximately 10% to 15% of children with cystic fibrosis who are not meeting nutritional goals with dietary intake alone receive enteral nutrition overnight.
- No recommendations can be made regarding the use of pancreatic enzyme replacement therapy with enteral nutrition due to the absence of well-controlled randomized clinical trials.
What Is New
- Despite receiving enteral nutrition for an average of 6.6 years, body mass index percentiles are <50% in children with cystic fibrosis.
- Administering enteral nutrition through a digestive cartridge resulted in a >2-fold increase in plasma concentration of omega-3 fatty acids used as markers of fat absorption in patients with cystic fibrosis.
In patients with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI), fat malabsorption can lead to decreased caloric intake and deficiencies of fatty acids (FAs), such as docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), which are important for growth and development (1,2). In addition, gastrointestinal (GI) symptoms of fat malabsorption can result in decreased appetite. Patients with CF use pancreatic enzyme replacement therapy (PERT) in conjunction with meals to increase the absorption of fat and other nutrients (3).
Approximately 3600 patients with CF in the United States use enteral nutrition (EN) because they are otherwise unable to meet growth and weight goals (3). Although enteral formulas are available with stable hydrolyzed protein, formulas containing hydrolyzed fat are unavailable due to the poor stability of hydrolyzed fats. Also, published guidelines for EN in patients with CF concluded that no recommendations can be made regarding PERT use with EN due to the absence of well-controlled randomized clinical trials (4). Therefore, patients with CF who receive EN are at risk for suboptimal fat absorption and increased GI symptoms due to malabsorption of fat in enteral formula.
Relizorb (digestive cartridge; Alcresta Therapeutics, Inc, Newton, MA) is a single-use digestive enzyme cartridge that connects in-line with the enteral feeding set. The cartridge (Supplemental Digital Content 1, http://links.lww.com/MPG/A989) is cylindrical clear plastic with single inlet and outlet connection ports. Lipase is covalently bound to small white beads retained within the cartridge. The fat in enteral formula is hydrolyzed as it comes in contact with the lipase while passing through the beads in the cartridge. The digestive cartridge is designed to hydrolyze triglycerides in EN and achieves >90% hydrolysis of triglycerides in most formulas tested in vitro (5).
The objective of this study was to evaluate safety, tolerability, and fat absorption with digestive cartridge use in patients with CF and EPI receiving EN.
Patients with CF and EPI were recruited from 11 CF centers in the United States. Patients were eligible for inclusion if they had a confirmed diagnosis of CF and documented history of EPI, were of age 4 to 45 years, receiving EN at least 4 times a week via a feeding tube, using PERT, and stable with no significant changes in health status within 14 days before baseline evaluation. Exclusion criteria included uncontrolled diabetes mellitus (defined as unstable blood glucose requiring variable insulin doses), significant liver disease, lung or liver transplant, active cancer, intestinal inflammatory diseases, pregnancy or lactation, substance abuse, history of fibrosing colonopathy, or recurring distal intestinal obstructive syndrome. The study was conducted in compliance with its clinical study protocol and in accordance with International Standard ISO 14155, Good Clinical Practice, and the Declaration of Helsinki (6). The protocol, amendments, and informed consent were approved by central or local institutional review boards. Written informed consent (and assent when applicable) was obtained from each patient (or patient's legal representative) before study entry.
This study was comprised of 3 periods: a 7-day run-in period (Period A), a randomized, double-blind, placebo-controlled, crossover period (Period B), and a 7-day open-label safety period (Period C) (Supplemental Digital Content 2, http://links.lww.com/MPG/A990). The study was designed with input from the CF Foundation Therapeutics Development Network.
At study entry, a medical history and physical examination were performed, and blood samples were collected for screening laboratory analysis. Body mass index (BMI) and BMI percentile in children were calculated.
Period A was a run-in observation period. During this 7-day period, participants adapted to 500 to 1000 mL of a standardized enteral formula (Peptamen 1.5; Nestle Health Science Inc., Florham Park, NJ) in place of their usual formula. Peptamen 1.5, which contains 9.8 g of fat per 250 mL (70% medium-chain triglycerides [MCTs] and 30% long-chain triglycerides [LCTs) (7), was chosen because it is a commonly used semi-elemental formula in patients with CF and, except for fat content, is similar to formula with a higher fat and LCT content used later in the study. Peptamen 1.5 is not supplemented with DHA or EPA. Study participants otherwise maintained their treatment regimens, including usual doses of PERT products in conjunction with EN. Baseline GI symptoms were also recorded during Period A.
Randomization occurred on the first day of Period B, a double-blind, randomized crossover period to evaluate fat absorption from enteral formula with and without digestive cartridge. Participants received in-clinic feedings of 500 mL of Impact® Peptide 1.5 (Nestle Health Science Inc) via feeding tube over 4 hours after an overnight fast. Impact Peptide 1.5 contains 15.9 g of fat per 250 mL (50% MCTs and 50% LCTs), as well as 4.9 g/L of DHA and EPA (8), and was chosen because it would increase the sensitivity of the evaluation of fat absorption. Participants were randomized to first receive EN through either digestive cartridge or placebo cartridge. Placebo cartridges were identical to the blinded digestive cartridges in appearance and handling. After a 7-day washout period when participants received Peptamen 1.5 with their usual dose of PERT products but without digestive cartridge, participants crossed over and received EN through the opposite cartridge (placebo or digestive cartridge). For 3 days before each in-clinic feeding, participants were asked to discontinue any motility agents and were counseled to avoid dietary intake of foods containing omega-3 fats. Participants did not receive EN the night before the in-clinic EN, and did not use PERT products in association with the in-clinic feeding.
During Period C, the 7-day open-label safety period, participants received 500 to 1000 mL of Impact Peptide 1.5 as their overnight EN delivered through a single digestive cartridge. Impact Peptide 1.5 was used during this period to assess the tolerability of digestive cartridge with a formula containing a relatively high fat and LCT content. Participants were instructed to maintain their usual treatment regimen, including their usual dose of PERT products, in conjunction with EN.
The efficacy endpoint was change in plasma FA concentrations of DHA and EPA, as markers of fat absorption, for 24 hours. For in-clinic feedings, blood samples were obtained for plasma FA analysis just before the feeding and at 1, 3, 7, 9, 12, and 24 hours after initiation. Plasma DHA and EPA were measured using a validated ultra-high performance liquid chromatography method (PPD Laboratories, Richmond, VA).
Safety and tolerability endpoints were recorded throughout the study, including GI events associated with fat malabsorption (eg, abdominal pain, bloating, and steatorrhea). Non-GI adverse events (AEs) and unanticipated adverse device effects were also recorded.
Participants completed a study-specific questionnaire at study entry and exit. This questionnaire was used to capture information about EN and PERT use and the effect of EN, with and without cartridge use, on appetite and breakfast consumption.
Statistical analysis was performed using SAS version 9.2 (SAS Institute Inc, Cary, NC). Efficacy data were analyzed using differences in the plasma FA concentrations for 24 hours after a single EN feeding administered through either digestive cartridge or placebo cartridge. The sum of total DHA and EPA (DHA + EPA) plasma concentrations at each time point were used to determine the peak concentration for 24 hours (Cmax), absorption kinetics, and bioavailability as measured by the area under the curve for plasma concentrations over 24 hours (AUC0–24). Cmax was compared between digestive cartridge and placebo using a Student t test. AUC0–24 was calculated using time-weighted averages for each participant and compared using a mixed-model analysis of variance. Given intersubject variability in baseline FA plasma concentrations, values for DHA + EPA were baseline adjusted before analysis, consistent with other studies (9,10).
Thirty-four screened patients were enrolled as participants in the study: 1 withdrew after hospitalization for pulmonary exacerbation, 1 withdrew after initially receiving the incorrect formula but re-enrolled; 33 were randomized and completed the study (Supplemental Digital Content 3, http://links.lww.com/MPG/A991). Both participants who withdrew did so before randomization. An independent safety monitoring board approved study continuation after reviewing safety data from the first 8 participants.
Of the 33 study participants, the mean (SD) age was 14.5 (6.2) years and 20 (60.6%) were male (Table 1). At study entry, participants reported receiving EN through a feeding tube for a mean of 6.6 years, starting at a mean age of 8.2 years. Participants reported receiving a mean volume of approximately 800 mL of EN per feeding, and using a mean of 8 to 9 (range 2–21) PERT capsules in conjunction with each EN feeding.
The mean (SD) baseline plasma concentration for total DHA + EPA in this study cohort was 49.0 (25.7) μg/mL, approximately 60% of the mean plasma level observed in normal healthy humans (11). Compared with placebo use, AUC0–24 (SD) for total DHA + EPA was significantly higher with digestive cartridge use by a factor of 2.8 (537.0 [400.5] μg × h/mL vs 192.2 [198.7] μg × h/mL, respectively; P < 0.001) (Fig. 1). Similarly, compared with placebo use, the Cmax (SD) of total DHA + EPA was significantly higher with digestive cartridge use, by a factor of 2.2 (42.8 [22.9] μg/mL vs 20.1 [13.5] μg/mL; P < 0.001). With digestive cartridge use, plasma concentrations of total DHA + EPA from 7 through 24 hours were consistent with concentrations found in healthy humans. DHA and EPA absorption results were consistent across age groups.
Digestive cartridge use was generally safe and well tolerated. There were no unanticipated adverse device effects. Three, 11, and 4 non-GI AEs occurred in Periods A, B, and C, respectively, and most non-GI AEs were mild in severity and related to respiratory events commonly experienced by patients with CF; no non-GI AE was considered to be treatment related. There were no GI AEs reported that were temporally associated with digestive or placebo cartridge use in Period B. Despite receiving a formula with a higher fat content and a higher percentage of LCTs in Period C, the overall number of reported GI events, as well as several individual events such as abdominal pain, bloating, constipation, and diarrhea, was lower with digestive cartridge use during Period C compared with Period A (Table 2), although the number of reported gas events were higher in Period C compared with Period A. In addition, >50% of participants reported a decrease in severity of most GI events with digestive cartridge use in Period C compared with Period A. A standardized response mean distribution-based method was used post hoc to test for clinically important differences. This analysis suggested that observed decreases in severity observed with digestive cartridge use in 6 GI events were of mild (bloating, nausea, indigestion/heartburn), moderate (steatorrhea), or large (diarrhea, constipation) clinical importance.
During digestive cartridge use in Period C, 14 (42.4%) of the 33 participants reported not self-administering PERT products with EN, despite protocol instructions to maintain their usual treatment practice. Consistent with findings for the overall study group, these 14 participants reported fewer and less severe GI events during digestive cartridge use without PERT in the open-label safety period, compared with during PERT use in Period A. Of the 19 participants who self-administered PERT with EN in both Periods A and C, there were no differences in the number of GI events reported between the 2 study periods.
More participants reported preservation of appetite and ability to eat breakfast while using digestive cartridge during Period C compared with PERT alone pre-study. At study entry, 50.0% of study participants reported missing breakfast while using PERT alone pre-study, while 33.3% of study participants reported missing breakfast using digestive cartridge during Period C. In addition, 46.9% of participants reported a reduction in appetite after EN use pre-study while using PERT alone, compared with only 30.3% of participants using digestive cartridge in Period C.
The results of this randomized trial demonstrate EN administered through digestive cartridge resulted in a nearly 3-fold increase in plasma concentration of DHA and EPA, suggesting an increase in overall fat absorption. There was also a decrease in the frequency and severity of some symptoms of malabsorption and an increase in reported appetite preservation and breakfast consumption observed during digestive cartridge use. These findings may have important implications for the management of patients with CF and EPI who require EN. Before participating in this study, patients had been receiving up to 1.5 L of enteral formula nightly for a mean of 6.6 years, and yet, still had plasma concentrations of omega-3 FAs that were well below concentrations found in healthy humans, and BMI or BMI percentiles that were below target for patients with CF. These suboptimal nutrition measurements occurred despite use of a mean of 8 to 9 PERT capsules in conjunction with EN. Interestingly, recently published Cystic Fibrosis Foundation Evidence-Informed Guidelines state “In the absence of clinical trials, no specific recommendations can be made regarding the use of pancreatic enzyme therapy with enteral feeding.” (4)
In this study, omega-3 FAs DHA and EPA were used as markers of fat absorption. Traditionally, the coefficient of fat absorption (CFA) has been used to measure fat absorption, and using alternative measures of fat absorption could be considered a limitation of this study. CFA is, however, an indirect measurement of fat absorption with a relatively high coefficient of variation and is cumbersome to perform (12). Moreover, CFA assessments include all ingested fats, not just fat in EN, and since EN represents only 25% to 30% of daily caloric intake, CFA may not be sensitive or specific enough to detect differences in absorption of fat from EN alone. In contrast, measurement of plasma DHA and EPA with the sensitive ultra-high performance liquid chromatography method is a direct measurement of fat absorption that only requires 25 μL of plasma, an important consideration in pediatric patients (13).
The relationship between plasma FA concentrations and fat intake and absorption has been previously established (14,15). Moreover, conversion of essential FAs to DHA and EPA is limited, accounting for <1% of DHA and EPA in the body (16–18), and plasma concentrations of DHA and EPA remain stable for 2 to 3 days. Because the primary source of plasma DHA and EPA is through intake rather than conversion, and given the relative stability of plasma concentrations, plasma DHA and EPA concentrations serve as appropriate markers of absorption of fat from EN.
DHA and EPA also have important clinical relevance in CF. In this study, DHA and EPA plasma concentrations were approximately 60% of values observed in normal subjects, and the risk of DHA and EPA deficiencies in patients with fat malabsorption has been noted in other studies (19–21). Several reports on patients with CF have described blood and tissue FA imbalances or deficiencies characterized by low levels of omega-3 FAs and increased release and turnover of arachidonic acid (20–23). Fatty acid imbalances can potentially play a critical role in the production of eicosanoid inflammatory mediators and may contribute to lung and GI symptoms associated with CF (19–21,24). Studies evaluating FA supplementation have demonstrated a decrease in pulmonary exacerbations and antibiotic use when DHA and EPA levels have increased by 1.7-fold (20,25).
In this study, the use of digestive cartridge was demonstrated to be safe and well tolerated. Importantly, there was an observed decrease in the frequency and severity of several GI events reported during the open-label safety period (Period C) compared with the baseline run-in period (Period A), despite using a formula with increased fat content and a higher percentage of LCTs. This is not surprising, because increased absorption of fat in the enteral formula should result in a decrease in symptoms of fat malabsorption. Furthermore, more participants reported preservation of appetite and breakfast consumption with digestive cartridge use compared with their pre-study regimen, presumably due to an increase in absorption of fat from EN and resultant decreases in the frequency and severity of symptoms of fat malabsorption. The ability to eat breakfast in these patients could potentially account for an incremental increase in caloric intake of 700 to 1200 kcal/day.
The use of different formulas in Periods A and C is a potential confounder in comparing the frequency and severity of symptoms in the 2 periods. The purpose of using Impact Peptide 1.5 in Period C was to test the tolerability of digestive cartridge use with a formula that has a relatively high amount of fat with at least an equal ratio of MCTs to LCTs, thus increasing the sensitivity to detect issues arising from fat malabsorption that may be undetected if using a formula like Peptamen 1.5. The use of Impact Peptide 1.5 in Period A without digestive cartridge use may, however, have caused an increase in symptoms of fat malabsorption. Therefore, to avoid the potential for artificially increasing symptoms of fat malabsorption in Period A, the formula was standardized to Peptamen 1.5, a formula that is commonly used and well tolerated in patients with CF that is similar to Impact Peptide except for fat content.
The major limitation in this study is that the study sample size is small. Despite the relatively small sample size, the study, however, included approximately 1% of the population of patients with CF who receive EN (3). In addition, the age range of the study population is representative of the population of patients with CF in the United States (3). Thus, these study results should be generalizable to the larger population of patients with CF and EPI who receive supplemental EN. Only 1 feeding through digestive cartridge was, however, used to measure its effect on fat absorption, and only 7 days of digestive cartridge use were used to measure its safety. A longer-term study is currently ongoing to assess the effects of sustained digestive cartridge use, particularly without concomitant PERT use.
In conclusion, despite long-term use of EN in conjunction with PERT products, patients with CF exhibit low baseline levels of omega-3 FAs DHA and EPA, as well as BMI or BMI percentiles that are below target. This study demonstrated that digestive cartridge use was safe, well tolerated, and resulted in an almost 3-fold increase in absorption of omega-3 FAs DHA and EPA, a marker of fat absorption, in adults and children with CF and EPI requiring EN. Furthermore, a decrease in the occurrence and severity of reported GI symptoms and an increase in reported preservation of appetite and ability to consume breakfast was observed with digestive cartridge use.
The authors would like to acknowledge Yeni Nieves of Premier Research Group for the statistical analysis of the study data, and Chantal Caviness, MD, PhD, of Eubio Medical Communications for her support with manuscript preparation.
The authors would also like to thank the patients and their families for their participation in the study. Finally, the authors express their gratitude to the staff at the sites participating in the study, and acknowledge the following investigators and study coordinators for their contributions to the study: Thomas Keens, MD, Cathy Salata, RN, Children's Hospital of Los Angeles, Los Angeles, CA; Perry Brown, MD, Dixie Durham, MHS, CCRC, St. Luke's Regional Medical Center, Boise, ID; Colby Wyatt, MD, PhD, Harmony Renna, CCRC, Maine Medical Center, Portland, ME; David Orenstein, MD, Erinn Kasubinski, BSN, RN, Children's Hospital of Pittsburgh, Pittsburgh, PA; Rebekah F. Brown, MD, Stephanie D. Steen, RN, Vanderbilt University Medical Center, Nashville, TN; James Chmiel, MD, Cindy Schaefer, RN, Rainbow Babies and Children's Hospital, Cleveland, OH; Karen S. McCoy, MD, Terri Johnson, RN, Nationwide Children's Hospital, Columbus, OH; Phillip Black, MD, Kristen Williams, RN, CCRC, Children's Mercy Hospital, Kansas City, MO; John Stevens, MD, Lori Shively, RN, Riley Hospital for Children, Indianapolis, IN; Julie Noe, MD, Patricia Hastings, Children's Hospital of Wisconsin, Milwaukee, WI; Jamie Wooldridge, MD, Freda Branch, Cardinal Glennon Children's Hospital, St. Louis, MO.
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