Clinical trial NCT05971524: Effect of Oral 6-bromotryptophan on Safety, Pharmacokinetics and Efficacy in Metabolic Syndrome Individuals
Official title: Effect of 4 Weeks of Oral 6-bromotryptophan on Safety, Pharmacokinetics and Efficacy in Metabolic Syndrome Individuals (2022)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Metabolic Syndrome
Diabetes Mellitus
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
First posted: 2023-08-02
Enrollment: 36
Sex: MALE
Minimum age (years): 35
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A phase I/II, dose finding, placebo controlled, double blinded trial
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Adverse events
timeFrame: 4 weeks
measure: renal function
timeFrame: 4 weeks
measure: Questionnaires
timeFrame: 4 weeks
measure: Occurence of anemia
timeFrame: 4 weeks
measure: Changes in leucocytes
timeFrame: 4 weeks
measure: Changes in trombocytes
timeFrame: 4 weeks
measure: Changes in aspartate aminotransferase (AST)
timeFrame: 4 weeks
measure: Changes in alanine aminotransferas (ALT)
timeFrame: 4 weeks
measure: Changes in alkaline phosphatase (ALP)
timeFrame: 4 weeks
measure: Changes in Gamma-glutamyltransferase (GGT)
timeFrame: 4 weeks
measure: Changes in total bilirubin
timeFrame: 4 weeks
measure: Mixed meal test
timeFrame: 4 weeks
measure: Mixed meal test
timeFrame: 4 weeks
measure: Time-in-range
timeFrame: 4 weeks
measure: Continuous glucose monitoring
timeFrame: 4 weeks
measure: Glycemic control
timeFrame: 4 weeks
Secondary outcomes:
measure: Intestinal microbiota composition
timeFrame: 4 weeks
measure: Immunologic profile
timeFrame: 6 weeks
measure: 6-BT pharmacokinetics
timeFrame: 6-BT pharmacokinetics as described above will be performed at baseline and after 4 weeks.
measure: Hepatic stiffness
timeFrame: 0 and 4 weeks
measure: Hepatic fat content
timeFrame: 0 and 4 weeks
measure: Dietary intake
timeFrame: 4 weeks
measure: Low-density lipoprotein (LDL)
timeFrame: 4 weeks
measure: High-density lipoprotein (HDL)
timeFrame: 4 weeks
measure: Triglycerides
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
state: Noord-Holland
Study officials:
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Nordin MJ Hanssen, dr.
role: PRINCIPAL_INVESTIGATOR
References: