Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 6181 | Other Identifier | CTRC |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Insulin resistance (IR) is an important contributor to increased cardiovascular disease risk in type 1 diabetes (T1D). Non-esterified fatty acid elevation is a significant contributor to IR in T1D and may be a target of intervention. The hypothesis of the study is that isolated fatty acid lowering with acipimox will improve insulin action and blood vessel function and have the benefit of reducing mitochondrial oxidant generation and improving mitochondrial function in T1D. Targeting IR through fatty acid lowering is a novel approach to T1D treatment that may significantly improve current management of TID and of cardiovascular disease (CVD) risk in this high risk population.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Acipimox | Experimental | Drug: acipimox |
|
| Placebo | Placebo Comparator | Drug: Placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acipimox | Drug | Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study | Evaluate the impact of Non esterified fatty acid (NEFA)-lowering on insulin sensitivity in T1D versus non-DM. Glucose infusion rate is reported normalized to lean body weight in kg and to final insulin concentration. The unit of measure reflects the rate at which glucose needs to be infused to maintain a normal blood sugar in the setting of a given serum insulin level from an insulin infusion. As such, a higher number means more glucose was needed and indicates greater sensitivity to insulin. | day 8 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| 24 Hour Mean Fatty Acid Levels | Assesses whether fatty acid level is consistently lowered by acipimox. Mean of fatty acid levels measured 22 times over 24 hours (hourly except 0100 and 0300 hours). | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Percent Flow-mediated Brachial Artery Dilation | To determine the effects of NEFA lowering and insulin sensitization on endothelial function. Measures percent change in brachial artery diameter with hyperemia after occlusion. | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| State 3 Mitochondrial Oxygen Consumption | Measures skeletal muscle mitochondrial function and effects of acipimox thereon, carbohydrate & lipid substrates. State 3 is fully active coupled oxygen flux using PMG or PMGS (pyruvate, malate, glutamate, +/- succinate) or OCMS (octanyl carnitine, malate, +/- succinate) as substrates. FCCP is added as an uncoupler to measure maximum possible O2 flux. Higher values reflect better mitochondrial function. | muscle biopsy on day 7 of each weeklong intervention period; max 16 weeks post enrollment |
| Measure | Description | Time Frame |
|---|---|---|
| Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6) | Interleukin 6 (IL6) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Oxidative Stress and Inflammatory Markers: TNFalpha |
| Measure | Description | Time Frame |
|---|---|---|
| Other Mitochondrial Measures: Mito Content and Electron Transport Chain Complexes | Mito content and electron transport chain complexes by western blot analysis. | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Oxidative Stress and Inflammatory Markers: Exploratory (Not Collected) |
Inclusion Criteria:
Men and women, with and without type 1 diabetes between 25-59 years of age,
HbA1c 6.0-9.5 (T1D only),
Subjects who are willing to commit to:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Irene Schauer, MD, PhD | University of Colorado, Denver | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Colorado Denver | Aurora | Colorado | 80045 | United States |
10 participants (7 withdrawals, 3 screen fails) were excluded from the study after enrollment, but prior to beginning the study. One T1D acipimox to placebo was withdrawn during the acipimox phase due to an SAE.
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Participants With T1 Diabetes: Acipimox, Then Placebo | Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. |
| FG001 | Participants Without T1 Diabetes: Acipimox, Then Placebo | Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. |
| FG002 | Participants With T1 Diabetes: Placebo, Then Acipimox | Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. |
| FG003 | Participants Without T1 Diabetes: Placebo, Then Acipimox | Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | All Participants With T1 Diabetes | Acipimox, Then Placebo: Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. Placebo, then Acipimox :Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study | Evaluate the impact of Non esterified fatty acid (NEFA)-lowering on insulin sensitivity in T1D versus non-DM. Glucose infusion rate is reported normalized to lean body weight in kg and to final insulin concentration. The unit of measure reflects the rate at which glucose needs to be infused to maintain a normal blood sugar in the setting of a given serum insulin level from an insulin infusion. As such, a higher number means more glucose was needed and indicates greater sensitivity to insulin. | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. | Posted | Mean | Standard Deviation | mg/kg*minute*microIU/mL*100 | day 8 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
Up to about Week 16
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | T1 Diabetes, Acipimox | Drug: acipimox Acipimox: Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| bradycardia | Cardiac disorders | Non-systematic Assessment |
Not provided
This study was stopped early for two reasons: one was the serious adverse event and the other was the fact that the fatty acid lowering effect of acipimox was more short-lived than expected and we did not see the intended overall fatty acid lowering.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Irene Schauer, MD | University of Colorado Denver | 3037241111 | clinicaresearchsupportcenter@ucdenver.edu |
Not provided
| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| D003920 | Diabetes Mellitus |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C027696 | acipimox |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| Placebo | Drug | Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day |
|
TNFalpha
| day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP) | high-sensitivity C-reactive protein (hsCRP) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Oxidative Stress and Inflammatory Markers: Adiponectin | adiponectin | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Oxidative Stress and Inflammatory Markers: Plasminogen Activator Inhibitor (PAI-1) | Plasminogen activator inhibitor (PAI-1) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Heart Rate Variability | Measure of autonomic function; ratio of fastest to slowest heart rate during valsalva maneuver. | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Arterial Stiffness (PWV) | Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec. Higher values reflect a stiffer vasculature. | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Arterial Stiffness (AI) | Augmentation index by Sphygmacor is a measure of aortic arterial stiffness. AI@75 is the ratio of augmented pressure/pulse pressure adjusted to a heart rate of 75. Higher values indicate stiffer vessels | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Metabolic Markers: Continuous Glucose Monitoring Measures | Continuous glucose monitoring measures for 3 days before clamp. Collected for participants with T1 Diabetes only. | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels | mean glucose and triglycerides for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300). | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Metabolic Markers: Insulin | mean insulin for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300). | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Metabolic Markers: Glycerol | mean glycerol for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300). | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Vascular Markers | endothelin 1 measured as a marker of vascular damage | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
thiobarbituric acid reactive substances (TBARs), glutathione disulfide (GSSG): reduced Glutathione (GSH) ratio; amplex red assay of hydrogen peroxide (H2O2) production, |
| day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| Counterregulatory Hormones | Planned glucagon and cortisol as a markers of counteregulation, but not done due to financial limitations | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
| BG001 | All Participants Without T1 Diabetes | Placebo, then Acipimox :Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. Acipimox, Then Placebo: Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Drug: acipimox Acipimox: Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. |
| OG001 | T1 Diabetes, Placebo | Drug: Placebo Placebo: Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day |
| OG002 | No T1 Diabetes, Acipimox | Drug: acipimox Acipimox: Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. |
| OG003 | No T1 Diabetes, Placebo | Drug: Placebo Placebo: Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day |
|
|
| Primary | 24 Hour Mean Fatty Acid Levels | Assesses whether fatty acid level is consistently lowered by acipimox. Mean of fatty acid levels measured 22 times over 24 hours (hourly except 0100 and 0300 hours). | Posted | Mean | Standard Deviation | microEq/L | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Primary | Percent Flow-mediated Brachial Artery Dilation | To determine the effects of NEFA lowering and insulin sensitization on endothelial function. Measures percent change in brachial artery diameter with hyperemia after occlusion. | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. | Posted | Mean | Standard Deviation | Percent change in BA diameter | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Primary | State 3 Mitochondrial Oxygen Consumption | Measures skeletal muscle mitochondrial function and effects of acipimox thereon, carbohydrate & lipid substrates. State 3 is fully active coupled oxygen flux using PMG or PMGS (pyruvate, malate, glutamate, +/- succinate) or OCMS (octanyl carnitine, malate, +/- succinate) as substrates. FCCP is added as an uncoupler to measure maximum possible O2 flux. Higher values reflect better mitochondrial function. | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Another participant did not have a muscle biopsy collected (T1D, Acipimox). | Posted | Mean | Standard Deviation | pmoles/mg/s | muscle biopsy on day 7 of each weeklong intervention period; max 16 weeks post enrollment |
|
|
|
| Secondary | Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6) | Interleukin 6 (IL6) | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. | Posted | Mean | Standard Deviation | picograms/mL | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Secondary | Oxidative Stress and Inflammatory Markers: TNFalpha | TNFalpha | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Two other participants (T1D, Acipimox; No T1D Acipimox) did not have data collected. | Posted | Mean | Standard Deviation | picograms/mL | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Secondary | Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP) | high-sensitivity C-reactive protein (hsCRP) | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Another participant from the Non T1D Placebo group did not have data collected. | Posted | Mean | Standard Deviation | mg/L | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Secondary | Oxidative Stress and Inflammatory Markers: Adiponectin | adiponectin | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Two participants (one in each of the Non-T1D study phases) did not have data collected. | Posted | Mean | Standard Deviation | micrograms/mL | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Secondary | Oxidative Stress and Inflammatory Markers: Plasminogen Activator Inhibitor (PAI-1) | Plasminogen activator inhibitor (PAI-1) | Measure was not collected due to funding limitations. | Posted | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
| Secondary | Heart Rate Variability | Measure of autonomic function; ratio of fastest to slowest heart rate during valsalva maneuver. | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. | Posted | Mean | Standard Deviation | ratio | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Secondary | Arterial Stiffness (PWV) | Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec. Higher values reflect a stiffer vasculature. | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Additionally, one participant in each of the T1D study phases did not have data collected. | Posted | Mean | Standard Deviation | m/sec | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Secondary | Arterial Stiffness (AI) | Augmentation index by Sphygmacor is a measure of aortic arterial stiffness. AI@75 is the ratio of augmented pressure/pulse pressure adjusted to a heart rate of 75. Higher values indicate stiffer vessels | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Additionally, one participant in each of the T1D study phases did not have data collected. | Posted | Mean | Standard Deviation | ratio | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Secondary | Metabolic Markers: Continuous Glucose Monitoring Measures | Continuous glucose monitoring measures for 3 days before clamp. Collected for participants with T1 Diabetes only. | 1 participant was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. | Posted | Mean | Standard Deviation | mmol/L | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Secondary | Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels | mean glucose and triglycerides for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300). | Posted | Mean | Standard Deviation | mg/dL | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Secondary | Metabolic Markers: Insulin | mean insulin for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300). | Posted | Mean | Standard Deviation | microIU/mL | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Secondary | Metabolic Markers: Glycerol | mean glycerol for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300). | Posted | Mean | Standard Deviation | micromoles/L | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Secondary | Vascular Markers | endothelin 1 measured as a marker of vascular damage | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. in addition, the last nonDM subjects did not have this collected due to funding limitations and futility based on prior results. | Posted | Mean | Standard Deviation | pg/mL | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
|
| Other Pre-specified | Other Mitochondrial Measures: Mito Content and Electron Transport Chain Complexes | Mito content and electron transport chain complexes by western blot analysis. | Originally described as secondary but were actually exploratory. Not done due to funding and tissue limitations. | Posted | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
| Other Pre-specified | Oxidative Stress and Inflammatory Markers: Exploratory (Not Collected) | thiobarbituric acid reactive substances (TBARs), glutathione disulfide (GSSG): reduced Glutathione (GSH) ratio; amplex red assay of hydrogen peroxide (H2O2) production, | These oxidative stress and inflammatory markers were collected, but assays were found to be unreliable. These measurements were originally erroneously described as secondary outcome measures, but are exploratory. | Posted | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
| Other Pre-specified | Counterregulatory Hormones | Planned glucagon and cortisol as a markers of counteregulation, but not done due to financial limitations | 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Incorrectly listed as secondary outcome. This was an exploratory outcome. | Posted | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment |
|
|
| 0 |
| 10 |
| 1 |
| 10 |
| 0 |
| 10 |
| EG001 | T1 Placebo | Drug: Placebo Placebo: Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day | 0 | 9 | 0 | 9 | 0 | 9 |
| EG002 | No T1 Diabetes, Acipimox | Drug: acipimox Acipimox: Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. | 0 | 8 | 0 | 8 | 0 | 8 |
| EG003 | No T1 Placebo | Drug: Placebo Placebo: Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day | 0 | 8 | 0 | 8 | 0 | 8 |
Not provided
Not provided
Not provided
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D006946 | Hyperinsulinism |
| PMGS State 3 Oxygen Flux |
|
| PMGS Uncoupled Max Oxygen Flux |
|
| OCM State 3 Oxygen Flux |
|
| OCMS State 3 Oxygen Flux |
|
| OCMS Uncoupled Max Oxygen Flux |
|
| triglycerides |
|