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

Sponsor

Nordin Hanssen (Other)

Overall Status

Recruiting

CT.gov ID

NCT05971524

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Metabolic Syndrome Diabetes Mellitus	Dietary Supplement: 6-BT Dietary Supplement: Placebo	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

36 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

A phase I/II, dose finding, placebo controlled, double blinded trialA phase I/II, dose finding, placebo controlled, double blinded trial

Masking:

Double (Participant, Investigator)

Masking Description:

To maintain the blinding of the subject and investigators, the identifying labels will be removed from the intervention product at the AMC pharmacy. The study product will be labelled with subject specific information prior to delivery to the study physician, who will hand over the intervention to the participant.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 4, 2023

Anticipated Primary Completion Date :

Feb 1, 2025

Anticipated Study Completion Date :

Feb 1, 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Adverse events [4 weeks]
Number of adverse events
renal function [4 weeks]
Number of participants with a decreased kidney function, defined as a rise in serum creatinine of >26,5 micromol/L in 48 h
Questionnaires [4 weeks]
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.
Occurence of anemia [4 weeks]
Number of patients with Hb < 8,5 mmol/L
Changes in leucocytes [4 weeks]
Number of patients with leucocytes <4,0 or >10,5 x10E9 cells/L
Changes in trombocytes [4 weeks]
Number of patients with trombocytes <150 x 10E9 cells/L
Changes in aspartate aminotransferase (AST) [4 weeks]
Number of patients with AST > 43 IU/L
Changes in alanine aminotransferas (ALT) [4 weeks]
Number of patients with ALT > 45 IU/L
Changes in alkaline phosphatase (ALP) [4 weeks]
Number of patients with ALP > 126 IU/L
Changes in Gamma-glutamyltransferase (GGT) [4 weeks]
Number of patients with GGT > 117 IU/L
Changes in total bilirubin [4 weeks]
Number of patients with total bilirubin > 24 micromol/L
Mixed meal test [4 weeks]
Changes in area under the curve (AUC) of glucose after mixed-meal test
Mixed meal test [4 weeks]
Changes in area under the curve (AUC) of insulin after mixed-meal test
Time-in-range [4 weeks]
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.
Continuous glucose monitoring [4 weeks]
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.
Glycemic control [4 weeks]
Changes in fasting glucose (mmol/L)

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

35 Years to 70 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Amsterdam UMC	Amsterdam	Noord-Holland	Netherlands	1105AZ

Sponsors and Collaborators

Nordin Hanssen

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Nordin Hanssen, dr., Amsterdam University Medical Centers (UMC), Location Academic Medical Center (AMC)

ClinicalTrials.gov Identifier:

NCT05971524

Other Study ID Numbers:

NL83061.018.22

First Posted:

Aug 2, 2023

Last Update Posted:

Aug 2, 2023

Last Verified:

Jul 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Additional relevant MeSH terms:

Metabolic Syndrome

Syndrome

Study Results

No Results Posted as of Aug 2, 2023