A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Determine the Safety and Tolerability of Microbial Inulinase
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Sponsor
- BIO-CAT, Inc.
- Enrollment
- 60
- Locations
- 2
- Primary Endpoint
- Gastrointestinal Symptom Rating Scale improvement
Study Overview
Brief 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
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Basic Science
- Masking
- Triple (Participant, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 20 Years to 60 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Healthy adult participants who are 20 to 60 years of age at screening (inclusive)
- •In good general health (no uncontrolled diseases or conditions) as deemed by the investigator and able to consume the study product
- •Regularly consumes at least 2 meals per day
- •Has a body mass index (BMI) between 18.5 to 29.9 kg/m^2 (inclusive) at Visit 2
- •Completes the run-in period with ≥ 90% product compliance for both consumption of doses and timing of doses as assessed by daily diary
- •Completes the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire during the run-in period
- •Individuals with childbearing potential must agree to practice an acceptable form of birth control for a certain time frame prior to the first dose of study product and throughout the study
- •Has maintained stable use of medication and supplements, and stable dietary and lifestyle habits, for the last 3 months prior to screening and agree to maintain them throughout the study
- •Agree to avoid strenuous exercise 24 hours prior to each visit
- •Willing to limit daily alcohol consumption to no more than 3-4 drinks per day throughout the study
- •Willing to maintain current use of cannabinoids (if applicable) throughout the study
- •Willing and able to agree to the requirements and restrictions of this study, be willing to give voluntary consent, be able to understand and read the questionnaires, and carry out all study-related procedures
Exclusion Criteria
- •Individuals who are lactating, pregnant, or planning to become pregnant during the study
- •Has a known sensitivity, intolerability, or allergy to any of the study products or their excipients
- •Received a vaccine for COVID-19 (coronavirus disease 2019) in the 2 weeks prior to screening or plans to receive a vaccine for COVID-19 during the study period, currently has COVID-19 or tests positive for COVID-19 within 28 days prior to baseline visit, or currently has any post COVID-19 condition(s) as defined by World Health Organization
- •Recent (within 2 weeks of Visit 1) history of an episode of acute gastrointestinal illness such as nausea, vomiting, or diarrhea
- •Have a history of irritable bowel syndrome, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), functional constipation or diarrhea (defined by the Rome IV diagnostic criteria), celiac disease, malabsorption, gastroparesis, diverticulosis, gastric or duodenal ulcers, pancreatitis, or eating disorder; or have a history of intestinal surgery (excluding appendectomy or herniorrhaphy) or bariatric surgery.
- •Have an abnormality or obstruction of the gastrointestinal tract precluding swallowing (e.g., dysphagia) and/or digestion (e.g., history of bowel obstruction)
- •Participated in upper gastrointestinal endoscopy and/or colonoscopy or preparation within 3 months prior to Visit 1
- •Diagnosed with hypercholesterolemia or hypertriglyceridemia [i.e., elevated fasting low-density lipoprotein (LDL) (≥ 135 mg/dL; ≥ 3.5 mmol/L) or elevated triglycerides (≥ 150 mg/dL; ≥ 1.7 mmol/L) at screening]
- •Has a history of heart disease/cardiovascular disease, uncontrolled hypertension (≥ 140 systolic or ≥ 90 diastolic mmHg), kidney disease (dialysis or renal failure), hepatic impairment or disease
- •Is Type I or Type II diabetic or pre-diabetic [i.e., elevated fasting blood glucose levels (≥ 100 mg/dL; ≥ 5.6 mmol/L) and/or elevated hemoglobin A1c (≥ 6.0%) at screening]
- •Has a history of liver or gallbladder disease or stomach ulcers
- •Has a positive medical history of unstable thyroid disease, previously diagnosed major affective disorder, psychiatric disorder that required hospitalization in the prior year, immune disorders and/or immunocompromised
- •Diagnosed with cancer (except localized skin cancer without metastases or in situ cervical cancer) within 5 years prior to the screening visit, or any clinically significant disease or disorder which, in the opinion of the investigator, may either put the potential participant at risk because of participation in the study, or influences the results or the potential participant's ability to participate in the study
- •Major surgery in 3 months prior to screening or planned major surgery during the study
- •History of alcohol or substance abuse (including cannabinoids) in the 12 months prior to screening (including having been hospitalized for such in an in-patient or out-patient intervention program)
- •Extreme dietary habits at the discretion of the Qualified Investigator, evidenced by a diet wherein the ratio of individual macronutrients and dietary fiber is markedly different than the typical American diet [e.g., ketogenic diet, Atkins diet, low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, vegetarian diet, fruitarian diet, etc.]
- •Use of any treatment listed in Study Protocol (No. B03-22-01-T0037) Section 6.5 (Concomitant Treatments) outside of the permitted time frames and/or conditions.
- •Receipt or use of investigational products in another research study within 28 days prior to baseline (Visit 2) or longer if the previous investigational product is deemed by the investigator to have lasting effects that might influence the eligibility criteria or outcomes of current study
- •Self-report of blood donation totaling between 101 mL to 449 mL of blood within 30 days prior to screening or a blood donation of more than 450 mL within 56 days prior to baseline
- •Self-report of donating plasma (e.g., plasmapheresis) within 14 days prior to screening.
- •Any other active or unstable medical conditions or use of medications/supplements/therapies that, in the opinion of the investigator, may adversely affect the participant's ability to complete the study or its measures or pose a significant risk to the participant
Outcomes
Primary Outcomes
Gastrointestinal Symptom Rating Scale improvement
Time Frame: 4 weeks
Between placebo and inulinase treatments, percentage of participants showing improvement from baseline to Day 28 as assessed by reduction of Gastrointestinal Symptom Rating scores (overall score and domain scores). All 15 questions are rated using a 7-point Likert scale (1 to 7), where lower ratings represent a better outcome or less discomfort.
Serum total cholesterol
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum total cholesterol concentration (mmol/L)
Serum insulin
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum insulin concentration (pmol/L)
Serum high-sensitivity C-reactive protein (hsCRP)
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum hsCRP concentration (mg/L)
Plasma high-density lipoprotein (HDL) cholesterol
Time Frame: 6 weeks
Between placebo and inulinase treatments, change from screening to Day 28 in fasting plasma HDL cholesterol concentration (mg/dL)
Serum total bilirubin
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum total bilirubin concentration (umol/L)
Whole blood hematocrit
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood hematocrit (as volume percent)
Whole blood hemoglobin
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood hemoglobin concentration (g/dL)
Gastrointestinal Symptom Rating Scale score
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 7, Day 14, Day 21, and Day 28 in Gastrointestinal Symptom Rating Scale scores (overall score and domain scores). All 15 questions are rated using a 7-point Likert scale (1 to 7), where lower ratings represent a better outcome or less discomfort.
Abdominal discomfort, bloating, and burping scores
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 7, Day 14, Day 21, and Day 28 on individual Gastrointestinal Symptom Rating Scale questions on abdominal discomfort, bloating, and burping. These 3 questions are rated using a 7-point Likert scale (1 to 7), where lower ratings represent a better outcome or less discomfort.
Plasma lactate
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting plasma lactate concentration (mmol/L)
Serum uric acid
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum uric acid concentration (umol/L)
Serum alanine transaminase
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum alanine transaminase concentration (U/L)
Serum aspartate transaminase
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum aspartate transaminase concentration (U/L)
Whole blood basophils
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood basophil count (x 10\^9/L)
Whole blood lymphocytes
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood lymphocyte count (x 10\^9/L)
Whole blood mean corpuscular hemoglobin
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood mean corpuscular hemoglobin (pg)
Whole blood neutrophils
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood neutrophil count (x 10\^9/L)
Serum low-density lipoprotein (LDL) cholesterol
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum LDL cholesterol concentration (mmol/L)
Serum creatinine
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum creatinine concentration (umol/L)
Serum potassium
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum potassium concentration (mmol/L)
Whole blood red blood cells
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood red blood cell count (x 10\^9/L)
Whole blood red blood cell distribution width
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood red blood cell distribution width
Whole blood hemoglobin A1c (HbA1c)
Time Frame: Day 1
Fasting whole blood HbA1c concentration at Day 1 (%)
Serum albumin
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum albumin concentration (g/L)
Serum sodium
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum sodium concentration (mmol/L)
Serum total protein
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum total protein concentration (g/L)
Whole blood eosinophils
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood eosinophil count (x 10\^9/L)
Serum high-density lipoprotein (HDL) cholesterol
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum HDL cholesterol concentration (mmol/L)
Serum triglycerides
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum triglycerides concentration (mmol/L)
Serum alkaline phosphatase
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum alkaline phosphatase concentration (U/L)
Serum chloride
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum chloride concentration (mmol/L)
Serum globulin
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum globulin concentration (g/L)
Serum glucose
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting serum glucose concentration (mmol/L)
Whole blood mean corpuscular volume
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood mean corpuscular volume (fL)
Whole blood monocytes
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood monocyte count (x 10\^9/L)
Whole blood platelets
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood platelet count (x 10\^9/L)
Estimated glomerular filtration (eGFR)
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in eGFR (mL/min/1.73m\^2)
Body weight
Time Frame: 4 weeks
Body weight (kg)
Body mass index
Time Frame: 4 weeks
Body mass index (kg/m\^2)
Whole blood mean corpuscular hemoglobin concentration
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood mean corpuscular hemoglobin concentration (g/L)
Whole blood mean platelet volume
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood mean platelet volume (fL)
Blood pressure
Time Frame: 4 weeks
Resting systolic blood pressure over resting diastolic blood pressure (mmHg/mmHg)
Incidence of adverse events
Time Frame: 4 weeks
Number of participants with adverse events
Incidence of serious adverse events
Time Frame: 4 weeks
Number of participants with serious adverse events
Whole blood white blood cells
Time Frame: 4 weeks
Between placebo and inulinase treatments, change from baseline to Day 28 in fasting whole blood white blood cell count (x 10\^9/L)
Heart rate
Time Frame: 4 weeks
Resting heart rate (beats per minute)
Secondary Outcomes
No secondary outcomes reported