Sitagliptin and HIV

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by Washington University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Kevin Yarasheski, PhD, Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01552694
First received: March 8, 2012
Last updated: January 22, 2014
Last verified: January 2014
  Purpose

People living with human immunodeficiency virus infection (HIV) have 2-4fold greater risk for developing diabetes and heart disease than the general population. They need safe and effective treatments that reduce the risk for developing diabetes and heart disease, and improve their quality of life. This project will explore whether a new anti-diabetes medication (Januvia) with a novel mechanism of action reduces inflammation, and improves blood vessel function in HIV infected men and women with several risk factors for developing cardiovascular disease.


Condition Intervention Phase
Inflammation
Macrophage Infiltration
Cardiovascular Disease
Drug: Sitagliptin
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Double Blind, Randomized, Placebo Controlled Study to Determine the Physiological Effectiveness of Januvia (100 mg/d) for Reducing Inflammation and Increasing Endothelial Progenitor Cell Number in Human Immunodeficiency Virus (HIV) Infected Men and Women With Insulin Resistance and Central Adiposity.

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • inflammatory biomarkers [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    Fasting serum and plasma samples obtained at baseline, week 4 and 8 are batched for ELISA analysis (end of sudy) of hsCRP, IL-6 and D-dimer concentrations.


Secondary Outcome Measures:
  • adipose inflammation [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    Adipose tissue from obese, insulin resistant subjects is characterized by increased macrophage infiltration and overexpression of inflammatory cytokines/chemokines. In obese humans, the presence of CD68+ macrophages in direct contact with mature adipocytes has been noted in histologic sections of adipose tissue, and these appear as a macrophage "crown" around individual adipocytes. In adipocyte sections, we will use positive immunohistochemical staining for CD68 to quantify the density of macrophages and the frequency of "crown' like structures.

  • Blood endothelial progenitor cells [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    Monocytes are isolated from 20 mL blood. CD34+/VEGFR2+ and CD133+/CD34+/VEGFR2+ monocytes are counted (flow cytometry) and represent markers for endothelial progenitor cell number.


Estimated Enrollment: 36
Study Start Date: October 2012
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sitagliptin
100 mg sitagliptin/day for 2 months
Drug: Sitagliptin
Oral, 100 mg/day for 2 months
Other Name: Januvia
Placebo Comparator: Placebo
Matching placebo daily for 2 months
Drug: Placebo
oral, matching placebo daily for 2 months

Detailed Description:

People living with human immunodeficiency virus (HIV+) infection have a 2-fold greater prevalence and incidence of T2DM and cardiovascular disease (CVD) than the general population. The investigators lack safe and effective treatments for these HIV related cardiometabolic complications despite the fact that HIV infected adults represent an ideal clinical population in which to study interactions among chronic low-grade pro-inflammatory processes that are linked to the development of adipose accumulation, insulin resistance, ß-cell secretory failure, vascular endothelial dysfunction, atherosclerosis and CVD. Dipeptidyl peptidase-IV (DPP4)-inhibitors represent a new drug class that safely and effectively regulate glycemia in T2DM, but have not been adequately tested in HIV. Of note, pre-clinical studies suggest that DPP4-inhibitors have several pleiotropic actions that may specifically benefit people living with HIV infection. For example, DPP4 inhibition reduced adipose macrophage infiltration & inflammation and increased the number of bone-derived endothelial progenitor cells in the circulation. Our preliminary findings indicate that DPP4 inhibition is virologically and immunologically safe in non-diabetic HIV+ adults taking combination antiretroviral therapy (in preparation), but the potential pleiotropic benefits have not been examined in HIV. The investigators propose a randomized, double blind, placebo controlled physiological study to test 2 potential pleiotropic benefits of DPP4 inhibition (100 mg sitagliptin/d, 8 wk): reduce circulating and adipose-specific markers of inflammation; and increase endothelial progenitor cell numbers used for vascular repair in 36 HIV+ adults with insulin resistance, central adiposity and CVD risk factors. The investigators hypothesize that sitagliptin will reduce circulating cytokine levels, reduce adipose tissue macrophage number and inflammation, and increase the number of circulating endothelial progenitor cells in HIV infected men and women. These physiological studies will advance our understanding about the efficacy of DPP4 inhibition in this high-risk group, and may help prevent the inexorable transition from insulin resistance to T2DM and CVD in HIV infected men and women.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 18-65 yr old HIV infected men and women.
  • Stable (at least the past 6 months) on combined antiretroviral therapy (cART).
  • Stable immune (> 300 CD4+ T-cells/µL) and virologic (< 50 copies HIV RNA/mL) status.
  • Insulin resistant/impaired glucose tolerance (fasting glucose 100-125mg/dL, or 2-hr glucose 140-200mg/dL or fasting HOMA-IR= 2.5-6.0).
  • Waist circumference > 102 cm (men), > 88 cm (women).
  • BMI > 20 kg/m2.
  • Fasting hypertriglyceridemia > 150 mg/dL.
  • Low HDL-cholesterol (< 40 mg/dL in men or < 50 mg/dL in women).
  • Platelet count > 30,000/mm3.
  • Absolute neutrophil count > 750/mm3.
  • Transaminases < 2.5x the upper limit of normal.
  • Long-term non-progressors (not taking anti-HIV medications) are not eligible.

Exclusion Criteria:

  • Diabetes (T2DM, IDDM or diabetic ketoacidosis) or taking any glucose-lowering medication (e.g., insulin, TZDs, metformin, sulfonylurea).
  • Any agent that might artifactually alter glycemic control (e.g., glucocorticoids, megace, rhGH, GH-secretagogue, testosterone derivatives, creatine monohydrate, chromium picolinate, AA/protein supplements, medium- or long-chain fatty acids) during 6 months prior to or during enrollment.
  • History of serious CV disease. NYHA Functional Class III or IV (e.g., recent MI, unstable angina, edema, CHF, CAD, CABG, stroke, resting hypertension > 160/95 mmHg), irregular heart rhythm, resting ST-segment depression > 1mm). Treatment with medications for CV condition (e.g., α- or ß-blockers). Some BP-lowering medications (Ca++channel blocker, diuretic, or ACE inhibitor) are permitted.
  • Moderate to severe renal insufficiency. Serum creatinine > 1.7 mg/dL (men) > 1.5 mg/dL (women).
  • Plan or anticipate a change in anti-HIV medications during the study.
  • Lipid-lowering medications are permitted (fibrate or statin or niacin), but must be stable on that agent for at least 6 months prior to enrollment. Lipid-lowering agents cannot be started during the treatment period.
  • Chronic hepatitis B (HBV-surface antigen positive). Active hepatitis C (detectable Hep C RNA).
  • Positive urine drug test for opiates, methamphetamine, heroin, cocaine. Active substance abuse that the MD-scientist believes may compromise safety, compliance, interfere with study drug or data interpretation.
  • Hematocrit < 34% in men or < 25% in women with symptoms (fatigue, "tired-legs", shortness of breath). Hemoglobin < 10 gm/dL with symptoms.
  • Pregnant or nursing mothers. Women must agree to use an acceptable form of birth control during the study. If using birth control pills-must be stable on this medication for at least 6 months prior to enrollment.
  • Active malignancy or treatment with chemotherapeutic agents or radiation therapy or any cytokine or anti-cytokine therapy during 6 months prior to enrollment.
  • History of pancreatitis
  • > 10% unintentional weight loss during the 6 months prior to enrollment.
  • Reduced cognitive function/unable to provide voluntary informed consent. Prisoners are excluded.
  • Blinded investigational drugs for 3 months prior to enrollment that will not be unblinded before enrollment.
  • Nausea, vomiting, diarrhea (> 4 loose stools/day) that are unresponsive to treatment.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01552694

Contacts
Contact: Kevin E Yarasheski, PhD 3143628173 key@wustl.edu
Contact: Erin Laciny, MSEd 3147475371 elaciny@wustl.edu

Locations
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Erin Laciny, MSEd    314-747-5371    elaciny@wustl.edu   
Sub-Investigator: Dominic N Reeds, MD         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Kevin E Yarasheski, PhD Washington University School of Medicine
  More Information

Additional Information:
No publications provided

Responsible Party: Kevin Yarasheski, PhD, Professor of Medicine, Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01552694     History of Changes
Other Study ID Numbers: 41052, 41052
Study First Received: March 8, 2012
Last Updated: January 22, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Washington University School of Medicine:
cardiometabolic complications

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Cardiovascular Diseases
Inflammation
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Pathologic Processes
Sitagliptin
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 29, 2014