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

Diabetes Mellitus Clinical Trial

— BROMO  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05971524
• Other study ID #: NL83061.018.22
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 4, 2023
• Est. completion date: February 1, 2025

Study information

• Verified date: August 2023
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: Nordin MJ Hanssen, dr.
• Phone: 020-56691111
• Email: n.m.j.hanssen[@]amsterdamumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: February 1, 2025
• Est. primary completion date: February 1, 2025
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 35 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Metabolic Syndrome
• Syndrome

Intervention

Dietary Supplement:
• 6-BT
2,4 or 8mg of 6-BT once daily for 4 weeks
• Placebo
A placebo capsule once daily for 4 weeks

Locations

Country	Name	City	State
Netherlands	Amsterdam UMC	Amsterdam	Noord-Holland

Sponsors (1)

Lead Sponsor	Collaborator
Nordin Hanssen

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events	Number of adverse events	4 weeks
Primary	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
Primary	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
Primary	Occurence of anemia	Number of patients with Hb < 8,5 mmol/L	4 weeks
Primary	Changes in leucocytes	Number of patients with leucocytes <4,0 or >10,5 x10E9 cells/L	4 weeks
Primary	Changes in trombocytes	Number of patients with trombocytes <150 x 10E9 cells/L	4 weeks
Primary	Changes in aspartate aminotransferase (AST)	Number of patients with AST > 43 IU/L	4 weeks
Primary	Changes in alanine aminotransferas (ALT)	Number of patients with ALT > 45 IU/L	4 weeks
Primary	Changes in alkaline phosphatase (ALP)	Number of patients with ALP > 126 IU/L	4 weeks
Primary	Changes in Gamma-glutamyltransferase (GGT)	Number of patients with GGT > 117 IU/L	4 weeks
Primary	Changes in total bilirubin	Number of patients with total bilirubin > 24 micromol/L	4 weeks
Primary	Mixed meal test	Changes in area under the curve (AUC) of glucose after mixed-meal test	4 weeks
Primary	Mixed meal test	Changes in area under the curve (AUC) of insulin after mixed-meal test	4 weeks
Primary	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
Primary	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
Primary	Glycemic control	Changes in fasting glucose (mmol/L)	4 weeks
Secondary	Intestinal microbiota composition	Changes from baseline of relative abundance (%) of bacterial phyla, genera and species between groups and within participants.	4 weeks
Secondary	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
Secondary	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.
Secondary	Hepatic stiffness	Hepatic stiffness will be determined non-invasively by MRI using a special hepatic scanning protocol of 30 minutes	0 and 4 weeks
Secondary	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
Secondary	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
Secondary	Low-density lipoprotein (LDL)	Changes in LDL (mmol/L)	4 weeks
Secondary	High-density lipoprotein (HDL)	Changes in HDL (mmol/L)	4 weeks
Secondary	Triglycerides	Changes in triglycerides (mmol/L)	4 weeks