Effects of Acipimox on Insulin Action, Vascular Function, and Muscle Function in Type 1 Diabetes

NCT01816165 | Completed Phase 3 Results DMC

• 2 other identifiers: 11-06496181
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Type 1 Diabetes

Keywords

diabetes; insulin; blood vessel; type 1

Outcome Measures

Primary Outcomes (4)

• 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

Secondary Outcomes (13)

• Oxidative Stress and Inflammatory Markers: 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

  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)

  day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment

• Oxidative Stress and Inflammatory Markers: 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)

  day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment

Other Outcomes (3)

• Other Mitochondrial Measures: Mito Content and Electron Transport Chain Complexes

  day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment

• Oxidative Stress and Inflammatory Markers: Exploratory (Not Collected)

  day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment

• Counterregulatory Hormones

  day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment

Study Arms (2)

Acipimox

EXPERIMENTAL

Drug: acipimox

Drug: Acipimox

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Drug: Placebo

Interventions

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.

Also known as: Olbetam

Acipimox

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

Placebo

Eligibility Criteria

• Age: 25 Years - 59 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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:
• days of prescribed diet,
• two 44 hour inpatient stays, and
• two muscle biopsies.

You may not qualify if:

• Any comorbid condition associated with inflammation, insulin resistance, or dyslipidemia,
• Tobacco use,
• Pregnancy,
• Steroid use,
• Scheduled physical activity \>3 days a week,
• Angina or any other cardiovascular or pulmonary disease,
• History of chronic obstructive pulmonary disease or asthma,
• Systolic blood pressure \>190 at rest or \>250 with exercise, or
• Diastolic pressure \>95 at rest, or \>105 with exercise,
• Proteinuria (urine protein \>200 mg/dl), or
• Creatinine \> 2 mg/dl, suggestive of severe renal disease,
• Severe Proliferative retinopathy,
• Niacin treatment,
• History of peptic ulcers,
• History of hereditary angioedema, and

Sponsors & Collaborators

• University of Colorado, Denver: lead

Study Sites (1)

University of Colorado Denver

Aurora, Colorado, 80045, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Diabetes Mellitus; Insulin Resistance

Interventions

acipimox

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Hyperinsulinism

Limitations and Caveats

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.

Results Point of Contact

• Title: Irene Schauer, MD
• Organization: University of Colorado Denver

clinicaresearchsupportcenter@ucdenver.edu

3037241111

Study Officials

• Irene Schauer, MD, PhD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2012
• First Posted: March 22, 2013
• Study Start: June 1, 2011
• Primary Completion: June 24, 2015
• Study Completion: June 24, 2015
• Last Updated: January 21, 2022
• Results First Posted: January 21, 2022

Record last verified: 2021-12

Locations

US (1)