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

NCT ID: NCT05971524

Last Updated: 2023-08-22

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-05-04
• Study Completion Date: 2025-02-01

Brief Summary

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

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.

Conditions

Metabolic Syndrome; Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Placebo

An oral placebo capsule once daily for 4 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DIETARY_SUPPLEMENT

A placebo capsule once daily for 4 weeks

2mg 6-BT

2 mg of 6-BT as an oral capsule once daily for 4 weeks

Group Type: EXPERIMENTAL

6-BT

Intervention Type: DIETARY_SUPPLEMENT

2,4 or 8mg of 6-BT once daily for 4 weeks

4mg 6-BT

4 mg of 6-BT as an oral capsule once daily for 4 weeks

Group Type: EXPERIMENTAL

6-BT

Intervention Type: DIETARY_SUPPLEMENT

2,4 or 8mg of 6-BT once daily for 4 weeks

8mg 6-BT

8 mg of 6-BT as an oral capsule once daily for 4 weeks

Group Type: EXPERIMENTAL

6-BT

Intervention Type: DIETARY_SUPPLEMENT

2,4 or 8mg of 6-BT once daily for 4 weeks

Interventions

6-BT

2,4 or 8mg of 6-BT once daily for 4 weeks

Intervention Type: DIETARY_SUPPLEMENT

Placebo

A placebo capsule once daily for 4 weeks

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

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

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Nordin Hanssen

OTHER

Sponsor Role: lead

Responsible Party

Nordin Hanssen

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Nordin MJ Hanssen, dr.

Role: PRINCIPAL_INVESTIGATOR

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Locations

Amsterdam UMC

Amsterdam, North Holland, Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Nordin MJ Hanssen, dr.

Role: CONTACT

n.m.j.hanssen@amsterdamumc.nl

020-56691111

Facility Contacts

N Hanssen, dr

Role: primary

n.m.j.hanssen@amsterdamumc.nl

020-5669111

Other Identifiers

NL83061.018.22

Identifier Type: -

Identifier Source: org_study_id