Phase II Trial of the Combination of Alpha-lipoic Acid and Mirabegron in Women and in Men With Obesity
Status:
Not yet recruiting
Trial end date:
2023-12-29
Target enrollment:
Participant gender:
Summary
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. MG 50 mg/d with placebo or MG 50 mg/d + ALA
will be given to 48 total otherwise healthy women (24) and men (24) with obesity over 4 weeks
followed by a 4-12 week washout period, after which subjects cross over to the other
treatment. Subjects will undergo metabolic testing, safety assessments, and imaging before
and after each of the two treatment cycles. Women and men will be studied separately using
the same protocols.
We hypothesize that in women and in men with obesity (BMI 30-40 kg/m2), the increases in
insulin sensitivity before and after four weeks of treatment will be higher when subjects are
taking the combination MG 50 mg/d and ALA 2.4 g/d compared to when they are taking MG 50 mg/d
with 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 Grade 1 and 2 obesity (BMI 30-40
kg/m2), the increases in beta3-AR agonist-induced lipolysis before and after four weeks of
treatment will be higher in subjects taking the combination MG 50 mg/d and ALA 2.4 g/d
compared to taking MG 50 mg/d + placebo.
Objectives:
Primary objective:
To compare the changes in insulin sensitivity after four weeks of treatment with the
combination MG 50 mg/d and ALA 2.4 g/d to the changes after 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 treatment compared to MG + placebo.
While not optional, these studies are dependent on the availability of [2H5] glycerol.
- Determine serum lipids levels before and on treatment compared to MG + placebo
- To determine the safety and tolerability of the combination of ALA at dose 2.4 g/d given
with mirabegron (MG, 50 mg/d).
- Assess adipose tissue inflammation and serum inflammatory markers before and on
treatment compared to MG + placebo
Exploratory Objectives (optional):
- Assess the resting metabolic rate (RMR) before and on treatment compared to MG + placebo
- Assess body composition before and on treatment compared to MG + placebo
- Assess changes in glucose turnover using labeled glucose and water before and on
treatment compared to MG + placebo
- Assess liver inflammation and fat content by MRS/MRE before and on treatment compared to
MG + placebo
Endpoints:
Primary Endpoint: the changes in the Insulin Sensitivity Index (SI) obtained from the FSIGT.
Secondary Endpoints:
- Maximum observed plasma concentration of ALA (Cmax), time to maximum observed plasma
concentration of ALA (Tmax), and area under the
- concentration-time curve from 0 to 6 hours post-dose.
- The number of subjects that develop Serious or non-serious AEs during and 2 weeks after
treatment.
- Changes in adipose tissue local inflammation (crown-like structures) before and on
treatment will be compared between the two study arms.
- Changes in serum cytokines (IL-6, TNFalpha, IL-17A, IL-10), CRP before and after
treatment will be compared between the two study arms.
- Changes in plasma lipids before and after treatment 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 treatment will be compared between the two study
arms.
Exploratory endpoints
- Anterior abdominal wall adipose tissue-resident immune cells
- Liver inflammation and fibrosis via MR
- Bone marrow adipose tissue BMAT via MR
- Resting metabolic rate (RMR). respiratory quotient (RQ), % body fat
- Gluconeogenesis and glucose turnover using stable isotopes...
Phase:
Phase 2
Details
Lead Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)