Trial of the Combination of Alpha-Lipoic Acid and Mirabegron in Women and in Men With Obesity

Study Description:

This is a single site, Phase II single-blinded, randomized placebo control crossover pilot study. This study aims to explore the effect of adding alphalipoic acid (ALA) to mirabegron (MG) on glucose metabolism and lipolysis rate. Participant target enrollment of 48 total otherwise healthy women (n=24) and men (n=24) with obesity who will be given one of two dosing assignments: MG 50 mg/d and ALA 2400 mg/d or MG 50 mg/d + placebo over 4 weeks followed by a 4-26-week washout period, after which time participant cross over to the opposite dosing assignment. Participants will undergo metabolic testing, safety assessments, and imaging before and after each of the two arms are completed. Women and men will be studied separately using the same protocol.

We hypothesize that in women and in men with obesity (BMI 30-45 kg/m^2), the increases in insulin sensitivity and beta3-AR agonist-induced lipolysis before and after four weeks of taking the dosing assignment will be higher in participants taking the combination MG 50 mg/d and ALA 2400 mg/d compared to taking MG 50 mg/d +placebo.

-Of note, based on our preliminary data and reports in the literature, a key secondary hypothesis is that in women and in men with obesity (BMI 30-45 kg/m^2), the increases in beta3-AR agonist-induced lipolysis before and after four weeks of dosing will be higher in participants taking the combination MG 50 mg/d and ALA 2400 mg/d compared to taking MG 50 mg/d + placebo.

Objectives:

• Primary objective: To compare the change in insulin sensitivity before and after four weeks of taking the combination of the MG 50 mg/d and ALA 2400 mg/d) compared to taking MG 50 mg/d + placebo.
• Secondary objectives:

• Assess the rate of steady-state whole-body lipolysis measured as the rate of isotope appearance (Ra) of [2H5] glycerol before and on MG 50 mg/d and ALA 2400 mg/d compared to MG 50 mg/d+ placebo.
• Determine serum lipids levels before and on MG 50 mg/d and ALA 2400 mg/d compared to MG 50 mg/d + placebo
• To determine the safety and tolerability of the combination of mirabegron (MG) at a dose of 50mg/d with alpha-lipoic acid (ALA) at a dose of 2400 mg/d.
• Assess adipose tissue inflammation and serum inflammatory markers before and on MG 50 mg/d and ALA 2400 mg/d compared to MG 50 mg/d+ placebo.

Endpoints:

• Primary Endpoint: the changes in the Insulin Sensitivity Index (SI) obtained from the FSIGT.
• Secondary Endpoints:

• Maximum observed plasma concentration of ALA and mirabegron (Cmax), time to maximum observed plasma concentration of ALA (Tmax), and area under the concentration-time curve from 0 to 6 hours post-dose.
• Changes in adipose tissue local inflammation before and on dosing assignments will be compared between the two study arms.
• Changes in serum cytokines before and after the dosing assignments will be compared between the two study arms.
• Changes in plasma lipids before and after dosing assignments will be compared between the two study arms.
• The rate of steady-state whole-body lipolysis measured as the rate of isotope appearance (Ra) of [2H5] glycerol before and on dosing assignments will be compared between the two study arms.
• Tertiary/Exploratory Endpoints:

• Assess the resting metabolic rate (RMR) before and on MG 50 mg/d and ALA 2400 mg/d compared to MG 50 mg/d+ placebo
• Assess body composition before and on MG 50 mg/d and ALA 2400 mg/d compared to MG 50 mg/d + placebo
• Assess changes in glucose turnover using labeled glucose and water before and on MG 50 mg/d and ALA 2400 mg/d compared to MG 50 mg/d + placebo
• Assess liver inflammation and fat content by FibroScan(R) before and on MG 50 mg/d and ALA 2400 mg/d compared to MG 50 mg/d+ placebo
• Determine serum levels of metabolic molecules and hormones before and on MG 50 mg/d and ALA 2400 g/d compared to MG 50 mg/d + placebo

• INCLUSION CRITERIA

To be eligible to participate in this study, an individual must meet all of the following criteria:

• Adults 18 to 65 years of age
• BMI greater than or equal to 30 kg/m^2 and less than or equal to 45 kg/m^2

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• Hypersensitivity and associated allergic reactions to mirabegron or alpha-lipoic acid (or similar drug substances or components).
• Abnormal bladder function, diagnosis of bladder outlet obstruction, urgency, and urinary frequency or use of antimuscarinic medication to treat overactive bladder (OAB).
• Type 1 diabetes mellitus; type 2 diabetes mellitus; or any person taking exogenous insulin therapy or any medication that is a hypoglycemic agent. (type 1 or Type 2 Diabetes mellitus, fasting serum glucose >125 mg/dL, and/or an HbA1c test >6.5%).
• Elevated resting blood pressure >140/90 mmHg.
• Individuals with eGFR <60 ml/min/1.72 m^2 and a urinary albumin/creatinine ratio UACR>300 mg/g.
• Hypo- or hyper-thyroid disease (TSH >5.0, or <0.4 MIU/L) that is controlled for less than one year or someone currently taking thyroid hormone replacement.
• Anemia, defined by hemoglobin <11.5 g/dL (females) or <13.5 g/dL (males); sickle cell anemia or other blood disorders; and/or wound healing problems.
• Cardiovascular disease, cardiac arrhythmias, orthostasis, unstable vasomotor system, or renal impairment.
• A clinically significant abnormal ECG and/or QTc interval above normal
• Moderate hepatic impairment (Child-Pugh Class B) or above
• Elevated liver enzymes >75 U/L (ALT or AST)
• Recent history in last 4 weeks of any local or systemic infectious disease with fever or requiring antibiotics
• Pregnancy, childbirth within the last year, or breastfeeding in the past 12 months.
• Individuals that have been on a very low-calorie diet (<800 kcal/d), self-reported weight loss >5% in the preceding six months, or those taking weight loss medications.
• History of seizure disorder.
• Addiction to alcohol or substances of abuse within the last 5 years.
• Self-reported current alcohol consumption of more than 2 servings of alcohol per day.
• Self-reported current use of nicotine and/or tobacco products.
• Current use of any drugs known to:

• Have major drug-drug interactions with mirabegron or alpha-lipoic acid
• Be CYP2D6 substrates
• Prolong QT interval
• Alter glucose metabolism or cause insulin resistance (in last six months)
• Treat diabetes mellitus
• Treat hypertension
• Be drugs of abuse
• Inability to provide informed consent.
• Unwilling or unable to eat metabolic meals, as determined by dietitian consult.
• Individuals with significant medical comorbidities or other factors that would render the individual s participation unsafe or affect the outcome of the study as assessed by the investigator.