Safety and Tolerability Trial of Microbial Inulinase
Condition: Digestive Health; Gastrointestinal Health
Study type: Interventional

Summary: 
      The objectives of this clinical trial are to: 1) assess the effect of microbial inulinase on
      gastrointestinal symptoms in healthy participants compared to a placebo, and 2) to assess the
      safety and tolerability of microbial inulinase in healthy participants compared to a placebo.
    

Detailed description: 
      Dietary FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols)
      can be digestively bothersome for certain fiber-intolerant individuals, as well as those with
      irritable bowel syndrome (Dionne et al.). Oral supplementation of microbial enzymes is a
      promising strategy to ameliorate gastrointestinal (GI) symptoms-such as bloating, abdominal
      discomfort, and gas-that are associated with food intolerances. Oral enzyme supplementation
      with fungal beta-galactosidase (lactase), fungal alpha-galactosidase, and a mixture of
      microbial and plant proteases have previously been clinically shown to effectively reduce GI
      symptoms associated with dairy, legume, and gluten consumption, respectively (Lin et al.; Di
      Stefano et al.; Ido et al.). While alpha-galactosidase effectively hydrolyzes galactan-type
      FODMAPs, there remains a need to target fructan-type FODMAPs. Preclinical data using an in
      vitro static GI digestion model showed that the microbial enzyme inulinase can effectively
      digest fructan-rich substrates (e.g., inulin from chicory root, garlic, and a high-fructan
      meal mash) better than control conditions under simulated gastric conditions (Guice et al.,
      submitted).

      The present study is a randomized, double-blind, placebo-controlled clinical trial to
      determine the safety and tolerability of microbial inulinase as a digestive enzyme supplement
      in healthy adults. This clinical trial will include 60 participants who are healthy adults
      between the ages of 20 to 60 and who regularly consume at least two meals daily. The study
      duration will be up to 62 days. This trial consists of one screening visit (Visit 1, Day -30
      to -15), a baseline visit (Visit 2, Day 1), and an end-of-study visit (Visit 3, Day 29 ± 3).

      To assess the effect of inulinase on GI-related symptoms, participants will fill out the
      paper Gastrointestinal Symptom Rating Scale (GSRS) on a weekly basis over the course of the
      study. The GSRS is a validated questionnaire containing 15 questions used to assess symptoms
      that are commonly associated with GI disorders (Machnicki et al.). All 15 questions are rated
      using a 7-point Likert scale, where higher ratings represent more discomfort. The GSRS score
      is determined by the score of five subscales: reflux, diarrhea, abdominal Pain, indigestion,
      and constipation. The reflux score will be calculated as an average score of questions 2 and
      3. The diarrhea score will be calculated as an average score of questions 11,12, and 14. The
      abdominal pain score will be calculated as an average score of questions 1, 4, and 5. The
      indigestion score will be calculated as an average score of questions 6, 7, 8, and 9. The
      constipation score will be calculated as an average score of questions 10, 13, and 15. Each
      subscale score is the domain score. The average of all 5 domain scores will give the GSRS
      score. The GSRS score and 5 sub-scale (domain) scores will be used for analysis. The scores
      in Visit 2 will be treated as baseline, and change from baseline to Week 1, Week 2, Week 3,
      and Week 4 will be calculated, as well as the proportion of participants showing improved
      scores.

      At screening Visit 1 (up to 30 days and no less than 15 days prior to the baseline visit),
      participants will arrive at the clinic in a fasting state (≥ 10 hours). After participants
      provide voluntary informed consent, the following information will be recorded, and
      procedures carried out:

        -  Collect demographic data (age, sex, ethnicity and race)

        -  Review medical/health history

        -  Review/record dietary and lifestyle habits

        -  Review/record use of concomitant treatments

        -  Review inclusion/exclusion criteria

        -  Take anthropometric measurements [height (screening only), weight) and vital signs
           [heart rate (HR) and blood pressure (BP)]

        -  Calculate body mass index (BMI; kg/m^2)

        -  Perform a brief symptom-based physical exam, if necessary

        -  Collect blood for hematology, clinical chemistry, lipid profile, and hemoglobin A1c
           (HbA1c)

        -  Dispense GSRS questionnaire for in-clinic completion

        -  Dispense GSRS questionnaire for at-home use

        -  Dispense study product (placebo only) and study diary

      After confirming eligibility, from Day -14 to Day -1 (the day prior to baseline visit on Day
      1), all participants will complete a 2-week run-in period where they will orally consume the
      placebo capsule twice daily with their usual two largest meals of the day (one capsule per
      meal) with the same two meals each day.

      At baseline Visit 2 (Day 1), participants will arrive at the clinic in a fasting state (≥ 10
      hours). The following visit procedures will occur:

        -  Collect and review any unused study product

        -  Review the study diary to assess compliance, concomitant treatments, medical conditions,
           and changes in health

        -  Review inclusion/exclusion criteria

        -  Review medical/health history

        -  Review any changes in dietary and lifestyle habits

        -  Take anthropometric measurements and vital signs (HR and BP)

        -  Calculate BMI using height collected from screening

        -  Collect blood for hematology, clinical chemistry, and lipid profiling

        -  Collect blood for lactate, insulin, uric acid, and high sensitivity C-reactive protein
           (hsCRP)

        -  Collect urine for pregnancy test

        -  Collect the GSRS questionnaire completed during the run-in period

        -  Dispense GSRS questionnaire for the participant to complete in-clinic

        -  Dispense GSRS questionnaire for at-home use

        -  Randomize the participant to inulinase or placebo

        -  Dose of study product in-clinic

        -  Adverse Event (AE) monitoring

        -  Dispense study products and study diary for home use by the participant

      At the baseline visit on Day 1, participants will be randomized in a 1:1 ratio to either
      study product [1,000 units of inulinase activity (INU) per serving] or placebo and then start
      the 28 ± 3 days of twice daily study product consumption. Study product will be taken in the
      same manner (1 capsule taken twice daily with their two usual larger meals of the day).

      At end-of-study Visit 3 (Day 29 ± 3), participants will arrive at the clinic in a fasting
      state (≥ 10 hours). The following visit procedures will occur:

        -  Return any unused study product and packaging of used study product

        -  Collect and review the study diary to assess compliance

        -  Review any changes in dietary and lifestyle habits

        -  Measure vital signs (BP and HR) and weight, and calculate BMI

        -  Collect urine for pregnancy test

        -  Collect blood for hematology, clinical chemistry, and lipid profiling

        -  Collect blood for lactate, insulin, uric acid, and hsCRP

        -  Collect the GSRS questionnaire and review for completion

        -  Dispense GSRS questionnaire for the participant to complete in-clinic

        -  AE monitoring
    

Intervention name(s): Inulinase; Maltodextrin placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Participants will consume one capsule containing 1,000 INU inulinase, twice daily, for 28 days. Participants will be directed to consume the capsules with their two largest meals.; Participants will consume one capsule containing maltodextrin, twice daily, for 28 days. Participants will be directed to consume the capsules with their two largest meals.
Other intervention name(s): Fructan hydrolyase; Beta-fructofuranosidase
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science