Effect of Oral 6-bromotryptophan on Safety, Pharmacokinetics and Efficacy in Metabolic Syndrome Individuals (BROMO)

Effect of 4 Weeks of Oral 6-bromotryptophan on Safety, Pharmacokinetics and Efficacy in Metabolic Syndrome Individuals (2022)

Safety, pharmacokinetics and efficacy of a novel endogenous plasma metabolite, 6-bromotryptophan, will be established in metabolic syndrome/ insulin resistant participants.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus; Metabolic Syndrome
• Intervention / Treatment: Dietary supplement: Placebo; Dietary supplement: 6-BT

Detailed Description

Rationale:

A newly identified endogenous plasma microbiome-derived tryptophan metabolite, 6-bromotryptophan (6-BT), was associated with preserved beta-cell function and diminished circulating T cell count in (T1D) type 1 diabetes patients. Anti-inflammatory and insulin-secratogogue effects were established in in vitro- and murine studies in both the setting of type 1 and type 2 diabetes. Also, 6-BT did not show any toxic effects in cells or in vivo experiments. In order to obtain safety data before the investigators progress to an efficacy study in T1D, the investigators aim to perform a phase I/II trial of 6-BT in metabolic syndrome individuals. If safe, 6-BT may hold a promise as a food supplement in type 1 and 2 diabetes.

Objective: To assess safety, pharmacokinetics and efficacy of oral dosage of 6-BT in individuals with metabolic syndrome Study design: A phase I/II, dose finding, placebo controlled, double blinded trial.

Study population: Metabolic syndrome individuals or participants with insulin resistance, age 35-70 years, without use of medication.

Intervention (if applicable): Participants will be given placebo, 2mg, 4mg or 8mg of 6-BT capsules once daily for 4 weeks (n=9 per arm, total of 36 participants).

Main study parameters/endpoints:

The principal outcome will be patient safety and tolerability (biochemical parameters of kidney and liver function and complete blood count, adverse events) in relation to improvements in glucose homeostasis (mixed-meal tests and continuous glucose monitoring). Secondary read-outs will include changes in: immunological profile (ex vivo stimulation of monocytes, and immunophenotyping of peripheral blood mononuclear cells (PBMC)) and gut microbiome composition (16s ribosomal ribonucleic acid (rRNA) sequencing). Also, liver fat content will be determined before and at end of the trial by MRI. As this food derived metabolite is given to humans for the first time, the investigators will also study its pharmacokinetics by measuring serum 6-BT concentrations in serum and urine at different time-points after oral intake.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

6-BT is an endogenous (food tryptophan derived) metabolite found in the human circulation. Our previous trail has shown that fecal microbiota transplantations (FMT) can modulate and increase plasma 6-BT levels with a positive association with C-peptide (as marker of pancreatic beta cells function). Additionally, recent investigations have linked higher plasma 6-BT levels with lower risk of kidney disease progression, supporting the health benefits of 6-BT beyond T1D. Hence, the investigators do not foresee major adverse reactions. As there is an urgent need for halting diabetes progression, patients would benefit from the development of new endogenously occurring therapeutic agents.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Nordin MJ Hanssen, dr.; Phone Number: 020-56691111; Email: n.m.j.hanssen@amsterdamumc.nl

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1105AZ
      • Recruiting
      • Amsterdam UMC
      • Contact: N Hanssen, dr; Phone Number: 020-5669111; Email: n.m.j.hanssen@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Metabolic syndrome, defined as:

- ≥3 criteria out of the 5 following criteria:

• fasting plasma glucose ≥5.6 mmol/L
• triglycerides ≥1.7 mmol/L
• waist circumference ≥102 cm
• high-density lipoprotein cholesterol ≤1.04 mmol/
• blood pressure ≥130/85 mm Hg.

AND/ OR Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (>2.5)

• Male
• Caucasian
• 35-70 years old

Exclusion Criteria:

• Use of systemic medication (except for paracetamol), including proton pump inhibitors, antibiotics and pro-/prebiotics in the past three months or during the study period.
• A history of a cardiovascular event
• A history of cholecystectomy
• Overt untreated gastrointestinal disease or abnormal bowel habits
• Liver enzymes>2.5 fold higher than the upper limit of normal range
• Smoking
• Exclusion criterion for MRI liver (see E4_BROMO_vragenlijst MRI)
• Alcohol abuse

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; An oral placebo capsule once daily for 4 weeks	Dietary supplement: Placebo; A placebo capsule once daily for 4 weeks
Experimental: 2mg 6-BT; 2 mg of 6-BT as an oral capsule once daily for 4 weeks	Dietary supplement: 6-BT; 2,4 or 8mg of 6-BT once daily for 4 weeks
Experimental: 4mg 6-BT; 4 mg of 6-BT as an oral capsule once daily for 4 weeks	Dietary supplement: 6-BT; 2,4 or 8mg of 6-BT once daily for 4 weeks
Experimental: 8mg 6-BT; 8 mg of 6-BT as an oral capsule once daily for 4 weeks	Dietary supplement: 6-BT; 2,4 or 8mg of 6-BT once daily for 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Number of adverse events	4 weeks
renal function	Number of participants with a decreased kidney function, defined as a rise in serum creatinine of >26,5 micromol/L in 48 h	4 weeks
Questionnaires	Changes in Gastro-intestinal Quality of Life Index (GIQLI score) (points). The minimum and maximum score are 31 and 155 points respectively, and a higher score reflects a better outcome.	4 weeks
Occurence of anemia	Number of patients with Hb < 8,5 mmol/L	4 weeks
Changes in leucocytes	Number of patients with leucocytes <4,0 or >10,5 x10E9 cells/L	4 weeks
Changes in trombocytes	Number of patients with trombocytes <150 x 10E9 cells/L	4 weeks
Changes in aspartate aminotransferase (AST)	Number of patients with AST > 43 IU/L	4 weeks
Changes in alanine aminotransferas (ALT)	Number of patients with ALT > 45 IU/L	4 weeks
Changes in alkaline phosphatase (ALP)	Number of patients with ALP > 126 IU/L	4 weeks
Changes in Gamma-glutamyltransferase (GGT)	Number of patients with GGT > 117 IU/L	4 weeks
Changes in total bilirubin	Number of patients with total bilirubin > 24 micromol/L	4 weeks
Mixed meal test	Changes in area under the curve (AUC) of glucose after mixed-meal test	4 weeks
Mixed meal test	Changes in area under the curve (AUC) of insulin after mixed-meal test	4 weeks
Time-in-range	Increase in Time-in-range (TIR,%), a parameter of continuous glucose monitoring devices, where TIR can be between 0 and 100%. A higher TIR reflects a better outcome.	4 weeks
Continuous glucose monitoring	Decrease in glucose variability (GV, %), a parameter of continuous glucose monitoring devices, where GV can be between 0 and 100%. A lower GV reflects a better outcome.	4 weeks
Glycemic control	Changes in fasting glucose (mmol/L)	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intestinal microbiota composition	Changes from baseline of relative abundance (%) of bacterial phyla, genera and species between groups and within participants.	4 weeks
Immunologic profile	Absolute counts of different immunologic cell types using Cytometry by time of flight (CyTOF) mass cytometry at baseline, 4 weeks and 6 weeks.	6 weeks
6-BT pharmacokinetics	Quantitatively measuring plasma concentrations of 6-BT at -15, 30, 60, 90, 120, 240 and 300 minutes following 6-BT capsule ingestion	6-BT pharmacokinetics as described above will be performed at baseline and after 4 weeks.
Hepatic stiffness	Hepatic stiffness will be determined non-invasively by MRI using a special hepatic scanning protocol of 30 minutes	0 and 4 weeks
Hepatic fat content	Hepatic fat content will be determined non-invasively by MRI using a special hepatic scanning protocol of 30 minutes	0 and 4 weeks
Dietary intake	Participants are asked to fill out an online dietary questionnaire for the 3 days prior to study visit 2,3,4,5 and 7	4 weeks
Low-density lipoprotein (LDL)	Changes in LDL (mmol/L)	4 weeks
High-density lipoprotein (HDL)	Changes in HDL (mmol/L)	4 weeks
Triglycerides	Changes in triglycerides (mmol/L)	4 weeks

Collaborators and Investigators

• Sponsor: Nordin Hanssen
• Investigators: Principal Investigator: Nordin MJ Hanssen, dr., Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2023
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: April 20, 2023
• First Submitted That Met QC Criteria: July 25, 2023
• First Posted (Actual): August 2, 2023

Study Record Updates

• Last Update Posted (Actual): August 22, 2023
• Last Update Submitted That Met QC Criteria: August 18, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Insulin Resistance; Hyperinsulinism; Syndrome; Metabolic Syndrome
• Other Study ID Numbers: NL83061.018.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No