Abstract
Background & Aims: Exclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn's disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier. Methods: We performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestlé) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7 to 12 (stage 2) (n = 40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7 to 12 (n = 38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed; 16S ribosomal RNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 (pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week 12. Results: Four patients withdrew from the study because of intolerance by 48 hours, 74 patients (mean age 14.2 ± 2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (P = .002; odds ratio for tolerance of CDED and PEN, 13.92; 95% confidence interval [CI] 1.68–115.14). At week 6, 30 (75%) of 40 children given CDED plus PEN were in corticosteroid-free remission vs 20 (59%) of 34 children given EEN (P = .38). At week 12, 28 (75.6%) of 37 children given CDED plus PEN were in corticosteroid-free remission compared with 14 (45.1%) of 31 children given EEN and then PEN (P = .01; odds ratio for remission in children given CDED and PEN, 3.77; CI 1.34–10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria. Conclusion: CDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD. Clinicaltrials.gov no: NCT01728870.
| Original language | English |
|---|---|
| Pages (from-to) | 440-450.e8 |
| Journal | Gastroenterology |
| Volume | 157 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Aug 2019 |
Bibliographical note
Funding Information:Funding Initial funding for the study in Israel was provided by unrestricted grants from the Azrieli Foundation and Nestlé Health Science to AL. Nestlé Health Science also kindly provided Modulen to all participating sites to ensure uniformity of the formula used among participants and provide the formula to enrolled patients for the duration of the study. The conduct of the study in Canada (Halifax, Edmonton) was supported by local divisional funds, a Women and Children's Health Research Institute (WCHRI) Research Capacity Building Award (EW) and a Canadian Institutes of Health Research (CIHR) New Investigator award (JVL). The funders of the study had no role in the design of the study, data collection or analysis, interpretation of data, writing of the report, or in the decision to submit the paper for publication. None of the funders or participating physicians had access to the data. All data were held confidentially by a single research coordinator and data manager who validated the data and performed an extensive query process (RSB).
Funding Information:
Funding Initial funding for the study in Israel was provided by unrestricted grants from the Azrieli Foundation and Nestl? Health Science to AL. Nestl? Health Science also kindly provided Modulen to all participating sites to ensure uniformity of the formula used among participants and provide the formula to enrolled patients for the duration of the study. The conduct of the study in Canada (Halifax, Edmonton) was supported by local divisional funds, a Women and Children's Health Research Institute (WCHRI) Research Capacity Building Award (EW) and a Canadian Institutes of Health Research (CIHR) New Investigator award (JVL). The funders of the study had no role in the design of the study, data collection or analysis, interpretation of data, writing of the report, or in the decision to submit the paper for publication. None of the funders or participating physicians had access to the data. All data were held confidentially by a single research coordinator and data manager who validated the data and performed an extensive query process (RSB). Conflicts of interest These authors disclose the following: AL reports grants, from Nestl? Health Science, and grants from Janssen unrelated to this field; advisory boards, travel, speaker fees or DSMBs from Celgene, Takeda and AbbVie, and a licensing and consulting agreement with IP with Nestl? health to develop new products based on diet. EW reports personal fees from Janssen, personal fees from AbbVie, outside the submitted work. RSB reports personal fees from Consulting to Nestl? Health Science, during the conduct of the study; personal fees from Invited speaker by Nestl? Health Science, personal fees from Invited speaker by Takeda, outside the submitted work. RS reports personal fees from Janssen, AbbVie, Mead Johnson, Lapidot and Abbott, outside the submitted work. JVL reports consulting, travel and/or speaker fees and research support from AbbVie, Janssen, Nestl? Health Science, Merck, P&G, GSK, Illumina, Otsuka. The remaining authors disclose no conflicts. Funding Initial funding for the study in Israel was provided by unrestricted grants from the Azrieli Foundation and Nestl? Health Science to AL. Nestl? Health Science also kindly provided Modulen to all participating sites to ensure uniformity of the formula used among participants and provide the formula to enrolled patients for the duration of the study. The conduct of the study in Canada (Halifax, Edmonton) was supported by local divisional funds, a Women and Children's Health Research Institute (WCHRI) Research Capacity Building Award (EW) and a Canadian Institutes of Health Research (CIHR) New Investigator award (JVL). The funders of the study had no role in the design of the study, data collection or analysis, interpretation of data, writing of the report, or in the decision to submit the paper for publication. None of the funders or participating physicians had access to the data. All data were held confidentially by a single research coordinator and data manager who validated the data and performed an extensive query process (RSB). The authors thank all participating children and their families, as well as the many colleagues in pediatric gastroenterology and pediatric nutrition at all participating sites who made this study possible: in Tel Aviv (Tamar Pfeffer-Gik who initially coordinated the study), Halifax (Anthony Otley, Mohsin Rashid, Angela Noble, Jessica Connors, Jennifer Haskett, Lisa Parkinson-McGraw, Brad MacIntyre), Edmonton (Hien Huynh, Matthew Carroll, Alexandra Petrova, Min Chen, Jessica Wu). Antonia Harvey, Registered Dietitian, and Marin Whebby, Research Assistant, modified the CDED-recipes for use in Canada and maintained the Canadian CDED-study Web site, supervised by S. Grant, Department of Applied Human Nutrition, Mount Saint Vincent University, and partially funded by the Mount Saint Vincent University New Scholar's Research Grant. AL was supported by grants from the Azrieli Foundation and Nestl? Health Science. JVL was supported by a Canadian Institutes of Health Research (CIHR)-Canadian Association of Gastroenterology-Crohn's Colitis Canada New Investigator Award (2015?2019), a Canada Research Chair Tier 2 in Translational Microbiomics (2018?2019), and a Canadian Foundation of Innovation John R. Evans Leadership Fund (awards #35235 and #36764), a Nova Scotia Health Research Foundation (NSHRF) establishment award (2015?2017), an IWK Health Centre Research Associateship, a Future Leaders in IBD project grant, a donation from the MacLeod family, and by a CIHR-SPOR-Chronic Diseases grant (Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects: the IMAGINE-SPOR chronic disease network). EW was supported by grants from the Crohn's and Colitis Foundation and Crohn's Colitis Canada as well as a WCHRI Research Capacity Award. Author Contributions: AL: design of CDED diet, funding for clinical study, patient enrollment, and review of manuscript. EW: patient enrollment, data analysis, writing of manuscript. RSB: design of support system, design of case report form, coordination of study, data management and analysis, article figures and tables. AA, RS, MK, SC, SP, AO, HS, PM: patient enrollment. TBZ, GA: data analysis. LA: dietary data management. SG: design of dietary support system. JVL was Principal Investigator for the Canadian arm, design of patient support system, funding of study, patient enrollment, data analysis and writing of manuscript, and performed the microbiome translational aspects of the study along with KAD and JPB. Conflicts of interest These authors disclose the following: AL reports grants, from Nestl? Health Science, and grants from Janssen unrelated to this field; advisory boards, travel, speaker fees or DSMBs from Celgene, Takeda and AbbVie, and a licensing and consulting agreement with IP with Nestl? health to develop new products based on diet. EW reports personal fees from Janssen, personal fees from AbbVie, outside the submitted work. RSB reports personal fees from Consulting to Nestl? Health Science, during the conduct of the study; personal fees from Invited speaker by Nestl? Health Science, personal fees from Invited speaker by Takeda, outside the submitted work. RS reports personal fees from Janssen, AbbVie, Mead Johnson, Lapidot and Abbott, outside the submitted work. JVL reports consulting, travel and/or speaker fees and research support from AbbVie, Janssen, Nestl? Health Science, Merck, P&G, GSK, Illumina, Otsuka. The remaining authors disclose no conflicts. Funding Initial funding for the study in Israel was provided by unrestricted grants from the Azrieli Foundation and Nestl? Health Science to AL. Nestl? Health Science also kindly provided Modulen to all participating sites to ensure uniformity of the formula used among participants and provide the formula to enrolled patients for the duration of the study. The conduct of the study in Canada (Halifax, Edmonton) was supported by local divisional funds, a Women and Children's Health Research Institute (WCHRI) Research Capacity Building Award (EW) and a Canadian Institutes of Health Research (CIHR) New Investigator award (JVL). The funders of the study had no role in the design of the study, data collection or analysis, interpretation of data, writing of the report, or in the decision to submit the paper for publication. None of the funders or participating physicians had access to the data. All data were held confidentially by a single research coordinator and data manager who validated the data and performed an extensive query process (RSB).
Funding Information:
Antonia Harvey, Registered Dietitian, and Marin Whebby, Research Assistant, modified the CDED-recipes for use in Canada and maintained the Canadian CDED-study Web site, supervised by S. Grant, Department of Applied Human Nutrition, Mount Saint Vincent University, and partially funded by the Mount Saint Vincent University New Scholar’s Research Grant. AL was supported by grants from the Azrieli Foundation and Nestlé Health Science. JVL was supported by a Canadian Institutes of Health Research (CIHR)-Canadian Association of Gastroenterology-Crohn’s Colitis Canada New Investigator Award (2015–2019), a Canada Research Chair Tier 2 in Translational Microbiomics (2018–2019), and a Canadian Foundation of Innovation John R. Evans Leadership Fund (awards #35235 and #36764), a Nova Scotia Health Research Foundation (NSHRF) establishment award (2015–2017), an IWK Health Centre Research Associateship, a Future Leaders in IBD project grant, a donation from the MacLeod family, and by a CIHR-SPOR-Chronic Diseases grant (Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects: the IMAGINE-SPOR chronic disease network). EW was supported by grants from the Crohn’s and Colitis Foundation and Crohn’s Colitis Canada as well as a WCHRI Research Capacity Award.
Publisher Copyright:
© 2019 AGA Institute
ASJC Scopus Subject Areas
- Hepatology
- Gastroenterology