Pre-diabetes
Conditions
Brief summary
Early Phase Pre-Clinical and Initial Clinical Research on (+)- Epicatechin.
Detailed description
This project is a double-blinded randomized Phase I study that will include dose-ranging one day PK and pharmacodynamic (PD) studies. Subjects will include healthy individuals and subjects who meet the American Diabetes Association (ADA) criteria for pre-diabetes, including IFG.
Interventions
DRUG(+)-Epicatechin
The drug to be tested is (+)-epicatechin, synthesized under GMP standards. Subjects will be given a single oral dose of (+)- epicatechin and followed on an inpatient basis over 24 hours. Three (3) different dose levels will be tested in a randomized, double-blind design: (+)- epicatechin 10 mg, 30 mg, or 100 mg. As this is a pilot study, a placebo arm will not be included.
Sponsors
National Institutes of Health (NIH)
National Center for Complementary and Integrative Health (NCCIH)
San Diego Veterans Healthcare System
University of California, San Diego
Veterans Medical Research Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy or pre-diabetic based on medical history * Male or female * Must be 21 to 75 years of age (inclusive) * Able to give informed consent to the procedures * If female, must be either postmenopausal or test negative for pregnancy at screening and on the day of the procedure. Women on estrogen therapy will be included. * If of childbearing potential, must practice and be willing to continue to practice appropriate birth control during the entire duration of the study * Medication use stable for 4 weeks * Body Mass Index (BMI) \> 27 kg/m\^2 * Definition of pre-diabetes: impaired fasting glucose (IFG, fasting glucose = 100-125 mg/dL) and elevated HbA1c (5.7-6.4%), each in the absence of other risk factors for diabetes
Exclusion criteria
* Type 2 diabetes * Pregnancy * Younger than 21 or older than 75 years of age * Clinically significant abnormalities in liver or kidney function (\>3x ULN), determined in the last 6 months by a certified clinical laboratory * Recent MI or stroke (within 6 months of screening) * Blood pressure (BP) \>160 mmHg Systolic and \>100 mmHg Diastolic * Medications - thiazolidinediones, any steroids, anti-depressants, weight loss drugs * Other diseases, besides type 2 diabetes, influencing carbohydrate metabolism
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | Baseline and 24 hours | This will be initial PK study on synthetic (+)-epicatechin in humans. Circulating and urinary concentrations of intact epicatechin and epicatechin metabolites, including specific enantiomers |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Major Safety Endpoints | Baseline and 24 hours | Clinically significant differences in the major safety endpoints are defined as: BP (10 mm Hg change), HR (10 bpm), creatinine (\>1.5 ULN), and highly conservative changes in alkaline phosphatase and liver transaminases (\>1.5 ULN). |
| Change From Baseline in Circulating Glucose Concentrations (mg/dL*24hr) | Baseline and 24 hours | — |
| Change From Baseline in Circulating Insulin Concentrations (uU/mL*24hr) | Baseline and 24 hours | — |
| Change From Baseline in Circulating C-Peptide Concentrations (ng/mL*24hr) | Baseline and 24 hours | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 10 mg (+)-Epicatechin 4 subjects randomized to one dose of 10 mg (+)-epicatechin taken orally
(+)-Epicatechin: The drug to be tested is (+)-epicatechin, synthesized under GMP standards. Subjects will be given a single oral dose of (+)- epicatechin and followed on an inpatient basis over 24 hours. Three (3) different dose levels will be tested in a randomized, double-blind design: (+)- epicatechin 10 mg, 30 mg, or 100 mg. As this is a pilot study, a placebo arm will not be included. | 4 |
| 30 mg (+)-Epicatechin 4 subjects randomized to one dose of 30 mg (+)-epicatechin taken orally
(+)-Epicatechin: The drug to be tested is (+)-epicatechin, synthesized under GMP standards. Subjects will be given a single oral dose of (+)- epicatechin and followed on an inpatient basis over 24 hours. Three (3) different dose levels will be tested in a randomized, double-blind design: (+)- epicatechin 10 mg, 30 mg, or 100 mg. As this is a pilot study, a placebo arm will not be included. | 4 |
| 100 mg (+)-Epicatechin 4 subjects randomized to one dose of 100 mg (+)-epicatechin taken orally
(+)-Epicatechin: The drug to be tested is (+)-epicatechin, synthesized under GMP standards. Subjects will be given a single oral dose of (+)- epicatechin and followed on an inpatient basis over 24 hours. Three (3) different dose levels will be tested in a randomized, double-blind design: (+)- epicatechin 10 mg, 30 mg, or 100 mg. As this is a pilot study, a placebo arm will not be included. | 4 |
| Total | 12 |
Baseline characteristics
| Characteristic | 10 mg (+)-Epicatechin | 30 mg (+)-Epicatechin | 100 mg (+)-Epicatechin | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 4 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 4 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment United States | 4 participants | 4 participants | 4 participants | 12 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 4 | 0 / 4 | 1 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 0 / 4 |
Outcome results
Primary
Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites
This will be initial PK study on synthetic (+)-epicatechin in humans. Circulating and urinary concentrations of intact epicatechin and epicatechin metabolites, including specific enantiomers
Time frame: Baseline and 24 hours
Population: Intent to treat population (all participants who receive the medication). Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | Methyl-epi-sulfate (AUC nM*hr) | 457.8 nM*hr | Standard Deviation 211.5 |
| 10 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | epicatechin-glucuronide (AUC nM*hr) | 3.375 nM*hr | Standard Deviation 2.488 |
| 10 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | Metabolites (AUC nM*hr) | 105.8 nM*hr | Standard Deviation 122.2 |
| 10 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | epicatechin-sulfate (AUC nM*hr) | 291.3 nM*hr | Standard Deviation 119.2 |
| 10 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | Total parent compound and metabolites (AUC nM*hr) | 840.3 nM*hr | Standard Deviation 311.1 |
| 30 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | epicatechin-glucuronide (AUC nM*hr) | 47.18 nM*hr | Standard Deviation 39.41 |
| 30 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | Metabolites (AUC nM*hr) | 132.7 nM*hr | Standard Deviation 148 |
| 30 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | epicatechin-sulfate (AUC nM*hr) | 1639 nM*hr | Standard Deviation 389 |
| 30 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | Methyl-epi-sulfate (AUC nM*hr) | 3190 nM*hr | Standard Deviation 496.6 |
| 30 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | Total parent compound and metabolites (AUC nM*hr) | 4996 nM*hr | Standard Deviation 570 |
| 100 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | Total parent compound and metabolites (AUC nM*hr) | 22563 nM*hr | Standard Deviation 10335 |
| 100 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | Methyl-epi-sulfate (AUC nM*hr) | 16699 nM*hr | Standard Deviation 7218 |
| 100 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | Metabolites (AUC nM*hr) | 162.3 nM*hr | Standard Deviation 209.8 |
| 100 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | epicatechin-glucuronide (AUC nM*hr) | 398.3 nM*hr | Standard Deviation 292.7 |
| 100 mg (+)-Epicatechin | Change From Baseline in Circulating Urinary Concentrations of Intact Epicatechin and Epi Metabolites | epicatechin-sulfate (AUC nM*hr) | 3031 nM*hr | Standard Deviation 1543 |
p-value: 0.05General linear mixed-effects models
Secondary
Change From Baseline in Circulating C-Peptide Concentrations (ng/mL*24hr)
Time frame: Baseline and 24 hours
Population: Intent to treat population (all participants who receive the medication). Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg (+)-Epicatechin | Change From Baseline in Circulating C-Peptide Concentrations (ng/mL*24hr) | 61.74 ng/mL*24hr | Standard Deviation 27.64 |
| 30 mg (+)-Epicatechin | Change From Baseline in Circulating C-Peptide Concentrations (ng/mL*24hr) | 57.56 ng/mL*24hr | Standard Deviation 28.56 |
| 100 mg (+)-Epicatechin | Change From Baseline in Circulating C-Peptide Concentrations (ng/mL*24hr) | 64.23 ng/mL*24hr | Standard Deviation 27.11 |
p-value: 0.05General linear mixed-effects models
Secondary
Change From Baseline in Circulating Glucose Concentrations (mg/dL*24hr)
Time frame: Baseline and 24 hours
Population: Intent to treat population (all participants who receive the medication). Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg (+)-Epicatechin | Change From Baseline in Circulating Glucose Concentrations (mg/dL*24hr) | 368.3 mg/dL*24hr | Standard Deviation 158.5 |
| 30 mg (+)-Epicatechin | Change From Baseline in Circulating Glucose Concentrations (mg/dL*24hr) | 342.6 mg/dL*24hr | Standard Deviation 193.5 |
| 100 mg (+)-Epicatechin | Change From Baseline in Circulating Glucose Concentrations (mg/dL*24hr) | 513.4 mg/dL*24hr | Standard Deviation 185.6 |
p-value: 0.05General linear mixed-effects models
Secondary
Change From Baseline in Circulating Insulin Concentrations (uU/mL*24hr)
Time frame: Baseline and 24 hours
Population: Intent to treat population (all participants who receive the medication). Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg (+)-Epicatechin | Change From Baseline in Circulating Insulin Concentrations (uU/mL*24hr) | 1192 uU/mL*24 hr | Standard Deviation 488.5 |
| 30 mg (+)-Epicatechin | Change From Baseline in Circulating Insulin Concentrations (uU/mL*24hr) | 707.2 uU/mL*24 hr | Standard Deviation 211.5 |
| 100 mg (+)-Epicatechin | Change From Baseline in Circulating Insulin Concentrations (uU/mL*24hr) | 1334 uU/mL*24 hr | Standard Deviation 666.5 |
p-value: 0.05General linear mixed-effects models
Secondary
Change From Baseline in Major Safety Endpoints
Clinically significant differences in the major safety endpoints are defined as: BP (10 mm Hg change), HR (10 bpm), creatinine (\>1.5 ULN), and highly conservative changes in alkaline phosphatase and liver transaminases (\>1.5 ULN).
Time frame: Baseline and 24 hours
Population: Intent to treat population (all participants who receive the medication). Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg (+)-Epicatechin | Change From Baseline in Major Safety Endpoints | 0 participants |
| 30 mg (+)-Epicatechin | Change From Baseline in Major Safety Endpoints | 0 participants |
| 100 mg (+)-Epicatechin | Change From Baseline in Major Safety Endpoints | 0 participants |
Comparison: Primary hypothesis: None of the doses of (+)-epicatechin will differ with regard to change from baseline in any of the major safety endpoints; heart rate, systolic and diastolic blood pressure.p-value: <0.0595% CI: [70.3, 85.5]ANOVA