A Dietary Intervention Study on the Microbiome in Crohn's Disease Patients

Study Purpose

This protocol is designed to compare the effectiveness of a dietary intervention for 7 days, given to patients with Crohn's disease (CD) in remission: a soy-based diet, which has been demonstrated to have numerous health benefits. The diet will be compared to participant 'baseline' (pre-diet) in terms of its ability to change the composition of gut bacteria and their production of butyrate, an important short chain fatty acid (SCFA) that limits bowel inflammation, a characteristic of this debilitating disease.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years - 55 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

  • - Documented diagnosis of Crohn's disease - Harvey Bradshaw Index (HBI) score <4 (indicating quiescent disease, remission) - Short Crohn's Disease Activity Index score (sCDAI) <150 (indicating quiescent disease, remission) - Signed written informed consent.
  • - Able to receive food shipments delivered to a work or home environment.
  • - Negative pregnancy test at screening visit in females of childbearing potential - Use of appropriate contraceptive methods for females of childbearing potential and males with procreative capacity during treatment - Stable medication use for ≥2 months at time of study enrolment, including but not limited to: steroids/corticosteroids, biologic therapy (infliximab, adalimumab, certolizumab pagol, golimumab, natalizumab, vedolizumab).
  • - Able to take oral nutrition and medication intake for 6 months prior to and at time of study enrolment.

Exclusion Criteria:

  • - Medical Exclusion: - Short bowel syndrome.
  • - Hospitalized patients - Body mass Index <19 kg/m or ≥35.
  • - Current smoker.
  • - Harvey Bradshaw Index (HBI) >4 or a short Crohn's disease Activity Index (sCDAI) >150 - Known clinically significant cardiovascular disease/conditions - Known clinically significant liver/gallbladder/pancreatic disease/dysfunction - Known allergy to soy, wheat, peanuts - Celiac disease - Serious secondary illnesses of an acute or chronic nature, which in the opinion of the Investigator renders the patient unsuitable for inclusion into the study.
  • - Dementia.
  • - Uncontrolled Diabetes Type I type II (fasting plasma glucose 7.0mM diabetics or pre-diabetics) - Known drug abuse.
  • - Known parasitic disease of the digestive system.
  • - HIV-infection.
  • - Seizure disorder.
  • - Presence of an ileal or colonic stoma.
  • - Known previous or concurrent malignancy.
  • - Anticipated need for surgery within 6 weeks - Albumin<2.0mg/dl, within 4 weeks of screening (if tested as part of routine clinical care) - Current use of hormonal or estrogen replacement therapies.
  • - Documented C difficile colitis within four weeks of screening Dietary Exclusion: • Use of exclusively Soy-based diet within 4 weeks of screening Medication Exclusion: - Other conditions that would be a contraindication to and of the study diets (e.g. allergy to soy, wheat, peanuts) or preclude the participant fron completing the study - Use of antibiotics within last 60 days.
  • - Use of pre- or probiotics within last 60 days.
  • - Start or change dose of IBD related medications within 8 weeks prior to enrollment: thiopurines (azathioprine and 6-MP), methotrexate, natalizumab, or vedolizumab, anti-TNF agents (including infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi) or ustekinumab Other - Well-founded doubt about the patient's cooperation.
  • - Existing pregnancy, lactation, or intended pregnancy or impregnation within the next 3 months.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT04065048
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

N/A
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Case Western Reserve University
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Fabio Cominelli, MD, PhD
Principal Investigator Affiliation Case Western Reserve University, School of Medicine, Gastroenterology
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

OtherOtherNIHOther
Overall Status Not yet recruiting
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Crohn Disease
Additional Details

The Central Hypothesis The central hypothesis of this study is that amino acids sourced from soy protein, a lysine rich, non-animal dietary substrate can serve as a major nutrient source for bacterial phyla capable of butyrate synthesis in the gut, and that soy protein has a protective effect for epithelial integrity in periods of low-grade inflammation in Crohn's disease. To answer our central hypothesis, the human diet intervention study represents the one of two specific aims of a study that integrates both a human and experimental research design. Samples collected in the dietary study involving patients with CD (Specific Aim 1, see below) will be used to complete the objectives described under Specific Aim 2 (see below) in experimental mice. Case Western Reserve University's (CWRU) Institutional Animal Care and Use Committee (IACUC) has reviewed and approved the Animal Experimentation 2014-0158 described under Specific Aim 2. Study Objectives This single center open label study is designed to address the following objectives. Specific Aim 1: To compare the effectiveness of a soy-based diet dietary intervention given for 7 days to change the gut microbiota composition to that of baseline (pre-diet) in patients with Crohn's disease (CD) and in remission. Primary Objectives of Specific Aim 1 1. To monitor patients for clinical symptoms related to maintenance of clinical remission during study period. Clinical symptoms will be assessed using the short Crohn's Disease Activity Index (sCDAI), a reliable and valid tool for assessment of Crohn's disease activity. • Hypothesis: Patients will not experience any clinical symptoms indicative of loss of clinical remission or adverse events as both diet interventions include normal, healthy food. 2. To assess the feasibility of the study diets. Secondary Objectives of Specific Aim 1 1. To quantify change gut bacteria taxonomic profiles in stool samples collected from CD patients after a soy-based dietary intervention, for 7 days each;. • Hypothesis: Patients will have differences in their fecal bacterial composition after consuming a soy-based diet, compared their 'baseline' diet. 2. To quantify gut bacterial butyrate in stool samples collected from CD patients after a soy-based dietary intervention, for 7 days. • Hypothesis: Dietary substrates sourced from a soy-based diet promote butyrate synthesis through different bacterial community members. 3. To assess the proportion of patients who intend to continue the study diets when prepared food is no longer provided without cost, and the reasons for discontinuation of either diet (compared to resuming usual food habits). Dose Rationale of Specific Aim 1 Participants will be asked to exclusively eat for 7 days, a soy-based diet immediately followed by participants resume their usual dietary habits. The primary outcome (self-reported sCDAI) will be assessed during the 7 day period of the diet. The 7-day diet time period was chosen for two reasons. First, dietary interventions in humans, specifically those plant and animal protein based, have been shown to alter gut microbial communities, including microbial gene expression in a rapid, diet-specific manner in as little as days(Wu, et al.Science, 2011; David, et al. Nature, 2014). Therefore 7 days is sufficient to meet the purpose of specific aim 1. Second, we felt that patients would be more likely to adhere to a diet exclusively focused on one specific food type over a shorter, period (7 days) if they did not perceive a direct benefit and to this end, would be more willing to collect stool samples. Specific Aim 2: Determine the functional significance of Soy-based diet altered microbiota in germ-free SAMP1/YitFC (SAMP) mice. The purpose of Aim 2 is to perform fecal microbiota transplantation (FMT) experiments in germ-free (GF) SAMP mice to test directly that the soy-based diet altered microbiota (Specific Aim 1) has increased butyrate producing capacity and to determine whether this could protect epithelial integrity against mild inflammation. Fecal microbiota obtained from CD patients treated with soy diet (Aim 1) will be transplanted into germ-free SAMP mice to test dietary substrates (amino acids sourced from non-animal food) potential for maintaining epithelial integrity via butyrate as a surrogate treatment for maintaining clinical remission in CD patients with, or at risk for residual active disease. We expect to identify potential short-term diet based therapeutic modalities, in context to baseline microbiota, designed for enhancing the anti-inflammatory effects of commensal microbiota on epithelial integrity. Primary Objectives for Specific Aim 2 1. To determine whether the diet-altered fecal microbiota from CD patients (Specific Aim 1) has increased butyrate producing capacity following in recipient GF SAMP mice after FMT. • Hypothesis: Microbial alterations induced by a soy protein based diet has increased butyrate producing capacity and a soy protein can be a surrogate for butyrate production in the gut. 2. To determine the gut microbial metabolite profiles in recipient GF SAMP mice after FMT. • Hypothesis: Transplanted mice will exhibit a mirrored pattern of metabolite profiles found in respective human CD patient donors. 3. To determine whether FMT (as above) in recipient germ-free SAMP mice administered a low concentration of DSS could protect epithelial integrity against mild inflammation.

  • - Hypothesis: Microbial alterations induced by a soy protein based diet has a protective effect for epithelial integrity in periods of low-grade inflammation.
The overall objective of the study (Specific Aim 1 & 2) is to develop a strong foundation of preliminary evidence on functional understanding of how dietary substrates obtained from different food sources alter microbial communities and butyrate synthesis. Collected data will be or further characterization in future mechanistic studies, as well as prospective studies of the proposed diet therapy in patients with CD. The ultimate goal is to develop novel therapeutic, anti-inflammatory diet-based modality or microbial modulation, clinically relevant to CD subjects with residual active disease, in context to baseline microbial communities. RECRUITMENT METHODS Source of participants Research participants will be sourced from the gastroenterology outpatient clinic services of the Digestive Health Institute (DHI) at University Hospitals Cleveland Medical Center, Cleveland Ohio. Specifically this will include patients seen during their normally scheduled appointments by their treating gastroenterologist. Methods to identify Potential participants will be identified via review of clinical appointment schedules (day/morning before patient appointment) by the treating gastroenterologist. Alternatively, the treating gastroenterologist will ask suitable patients whether they are interested in participating in the described dietary intervention study during the patient appointment. The gastroenterologist will pre-screen for nominal eligibility based on current disease activity status using the Harvey Bradshaw Index (HBI, see below for more information). In addition, the gastroenterologist will evaluate whether the patient has been on a stable medication therapy regime for at least 2 months (see inclusion criteria for more information). Harvey Brashaw Index (HBI): The HBI is a valid tool for assessment of disease activity in CD patients. The HBI will be used to determine remission status and eligibility. Initial verbal consent will be obtained by the treating gastroenterologist. The HBI consists of only of clinical parameters, with the first three items scored for the previous day. The HBI is computed to include; general well-being (0-4), abdominal pain (0-3), number of liquid stools per day, abdominal mass (requires physical exam by gastroenterologist), and complications (e.g., arthralgia) Patients who score 4 or less on the HBI are very likely to be in remission according to the Crohn's Disease activity Index, another clinical tool to measure disease activity. Patients with a score of 9 or higher are considered to have severe disease. Because the clinical parameters of the HBI inherently overlap with those assessed in all patients by a treating gastroenterologist during any routine visit, the HBI will be used in this study to determine eligibility and identify suitable participants (i.e. CD patients in remission). Feasibility The Digestive Disease Institute at Case Medical University Hospitals has a very large patient volume with more than 49,000 annual patient visits registered, of which include 986 annual CD outpatient visits per year. The majority of CD outpatients are seen at the two flagship sites of the Digestive Health Institute (DHI), Case Medical Center (530 CD outpatients per year) and Ahuja Medical Center (260 CD outpatients per year), both free standing hospitals located in Cleveland Ohio. The remaining sites include Bedford medical center (6 cases annually), Conneaut Medical Center (22 cases annually), Geauga Medical Center (52 cases annually), Geneva Medical Center (68 cases annually) and Richmond Medical Center (48 cases annually). Participant screening and enrollment will occur only at one site, Case Medical Center. The Department of Gastroenterology has 44 full time gastroenterologists, all of whom the participating gastroenterologists in this study will be recruiting suitable participants for this study. On average, each doctor sees 40 outpatients per week, approximately 50% of which have CD. An estimated accrual rate of 1-2 eligible patients per month generates a conservative study accrual period of up to six months. Screening and Informed Consent Participants will be pre-screened for nominal eligibility during their appointment with their treating gastroenterologist. Once identified as potentially eligible based on the HBI and medication use, the investigator will be able to contact these patients to assess their interest in the study and set up initial appointment to undergo screening (visit 1) and enrollment in this study. All participants will be outpatients when entering the study. No data collection or other study procedures will take place until the potential participant provides written informed consent to participate in the research study. The informed consent, screening, enrollment and baseline data collection which make up visit 1 can occur on the same day or be completed across several days. The following screening and baseline data will be collected: participants' height, weight and vital signs, their medical history, surgical history (related to the disease), diet history, their symptoms and any medication they may be taking, including over-the-counter supplements/vitamin use. Their blood will be drawn to measure hematocrit levels (to obtain CDAI score). An additional tube of blood can be drawn for plasma evaluation and quantification of plasma metabolites. If visit 1 is >30 days since the appointment with the treating gastroenterologist a repeat physical exam will be performed by a gastroenterologist. Participants will collect a fresh stool sample no more than 7 days prior to start of the study diet and no more than 21 days after the baseline screening visit 1 is complete. Female participants will be asked to take a urine pregnancy test. One 24-hour dietary recall will be completed after the screening visit prior to start of the study diet. The primary investigator, a registered dietitian will complete this. The participant will complete daily online surveys regarding their Crohn's disease symptoms in order to calculate a sCDAI score. Participants will also be instructed about these online surveys they will receive throughout the study and when to collect stool samples. To enhance feasibility of stool sample collection, a Medical Courier Service (American Expediting®) will be available to participants for home collection of stool specimens (participants telephone for pick-up of sample; 24/7 service). The Medical Courier Service is compliant with OSHA, HIPAA DOT, and US DOT 49CFR 173.6 criteria for handling of medical specimens and ensuring a HIPAA secure chain-of-custody procedure for patient information (see section 4.9 Medical Courier Service for more details). All collected stool samples will be received and processed by the principal investigator (see section 5.0 Stool sample preparation, processing, and storage for more details). The participant must complete 5 to 7 days of sCDAI symptom recording (the daily online surveys) before the start of study diet. They should not complete the 5-7 days of sCDAI symptom recording more than 14 days prior to start of study diet. Also, the participant must complete 5-7 consecutive days of sCDAI symptom recording no more than 14 days after nominal eligibility is determined. Adherence to the diet and additional food items consumed (from allowed food lists provided to participants) will be recorded using photo food log (uploaded online) and food diary.

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Cleveland, Ohio

Status

Not yet recruiting

Address

University Hospitals Digestive Health Institute

Cleveland, Ohio, 44106

Site Contact

Alicia DePlatchett, MBA

aed76@case.edu

216-368-1674

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