Exercise and Pioglitazone for HIV-Metabolic Syndromes

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Brief Title

Exercise and Pioglitazone for HIV-Metabolic Syndromes

Official Title

Exercise and Pioglitazone for HIV-Metabolic Syndromes

Brief Summary

      The purpose is to examine the safety and efficacy of 16wks of pioglitazone (Actos; 30mg/d)
      with and without aerobic and strength exercise training for reducing glucose intolerance and
      central adiposity in HIV-infected people. We anticipate that pioglitazone + exercise training
      will improve glucose metabolism and insulin sensitivity, and reduce central adiposity more
      than pioglitazone alone. These improvements should translate into reduced cardiovascular
      disease risk in HIV-infected people.
    

Detailed Description

      Our prior research has examined the pathogenesis and potential treatments for metabolic
      complications in people living with HIV. We have adopted the "lipotoxicity" hypothesis for
      Metabolic Syndrome X to explain the pathogenesis of impaired glucose tolerance (IGT) and fat
      redistribution in HIV: increased lipolysis and mobilization of lipids and free fatty acids
      from subcutaneous adipose depots leads to their excessive deposition in muscle and liver
      which contributes to dyslipidemia, insulin resistance, increased hepatic glucose output, and
      possibly visceral fat accumulation. Effective treatments have not been identified. Consensus
      groups recommend regular exercise and dietary modifications as primary and pharmacologic
      interventions as secondary treatments for the syndromes. We propose to test the efficacy of
      aerobic and weight lifting exercise training and an oral insulin-sensitizing agent
      (pioglitazone) as treatments for HIV-associated IGT and fat redistribution. We propose a
      4-month, 2-group randomized study to evaluate the efficacy of pioglitazone and exercise +
      pioglitazone in 40 men and 40 women living with HIV and IGT and fat redistribution. We will
      measure: insulin sensitivity, glucose disposal rate, hepatic glucose production rate
      (5hr-hyperinsulinemic euglycemic clamp with 6,6-[2H2]-glucose); whole-body and regional fat
      and muscle content (1H-MRI of the abdomen and thigh & DEXA), soleus muscle and liver lipid
      content (1H-MRS), muscle and fat PPARgamma/alpha mRNA and protein expression, serum lipid
      profiles, and serum adiponectin levels before and at the end of 4 months of treatment. We
      hypothesize that exercise training + pioglitazone will be more effective than pioglitazone
      alone at improving insulin sensitivity, reducing visceral fat, liver and muscle lipid
      content, and increasing peripheral subcutaneous fat content in HIV-infected people. We
      hypothesize that combined treatment will be more effective because exercise training will
      activate PPARalpha expression in muscle and pioglitazone will activate PPARy expression in
      fat and muscle. We anticipate that this project will provide direct evidence that supports
      the combined use of exercise training and pioglitazone in people living with HIV and
      experiencing metabolic and anthropomorphic disorders that increase cardiovascular disease
      risk.
    


Study Type

Interventional


Primary Outcome

Insulin-stimulated Glucose Disposal Rate

Secondary Outcome

 Visceral Fat Volume

Condition

HIV Infections

Intervention

Pioglitazone

Study Arms / Comparison Groups

 Pioglitazone
Description:  Pioglitazone (Actos; 30mg/day) for 16 weeks.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

44

Start Date

January 2005

Completion Date

December 2009

Primary Completion Date

December 2008

Eligibility Criteria

        Inclusion Criteria:

          1. 18-65 yr old HIV-infected men (n=40) and women (n=40).

          2. Source documentation of HIV status.

          3. Stable on highly active antiretroviral therapy (HAART) that may or may not include
             HIV-protease inhibitors for at least 3 months prior to enrollment. As of Jan 2005,
             HIV-infected long-term non-progressors will be included, even though they are not
             receiving HAART because it is likely that their disease status will not advance during
             the study period.

          4. Impaired glucose tolerance (IGT) or type 2 diabetes and fat redistribution. IGT is
             defined as: fasting (8hr) plasma glucose 100-126mg/dL or plasma glucose >140 mg/dL
             2-hours after a 75g-oral glucose load. This definition (proposed/revised May 2006)
             includes volunteers with adult onset type 2 diabetes (non-insulin dependent diabetes),
             because we believe that these volunteers may benefit from the potential
             glucose-lowering actions of pioglitazone with or without exercise training. Fat
             redistribution is defined as any 2 of the following: waist-to-hip ratio >0.85 women or
             >0.95 men, or trunk/appendicular adipose ratio using whole-body DEXA >0.85 women or
             >1.3 men, or <15% leg fat (DEXA; (leg fat/total body fat) x100), or visceral adiposity
             VAT >120 cm2 women or >140 cm2 men, or a VAT/TAT ratio >0.30 women or >0.40 men.
             Overall, the eligibility criteria are designed to include subjects with metabolic
             syndromes that increase CVD risk, and the potential to gain the greatest benefit from
             pioglitazone and exercise training. These inclusion criteria will help select/maintain
             homogeneous groups of study participants.

          5. Plasma HIV RNA (Roche Amplicor® assay) <5000 copies/ml OR a CD4 T-cell count >100
             cells/µL and stable for previous 3 months.

          6. BMI 20-40kg/m2.

          7. "Normal" blood chemistries for at least 1 month prior to enrollment; platelet count
             >30,000/mm3, absolute neutrophil count <750/mm3, transaminases <2.5x the upper limit
             of normal (ULN), creatinine <3x ULN, fasting triglycerides <500 mg/dL.

        Exclusion Criteria:

          1. Medications or agents that might alter/impair glucose metabolism (insulin,
             glucocorticoids, corticosteroids, megace) during the 3 months prior to enrollment or
             at any time during enrollment. Volunteers who developed type 2 diabetes after
             HIV-infection or after starting anti-HIV medications, who are receiving insulin
             sensitizers (metformin, meglitinides, alpha-glucosidase inhibitors) or insulin
             secretagogues (sulfonylureas), but still do not have their blood sugars in control
             (defined as IGT above) are eligible.

          2. Abnormal or unstable (for 3 months prior to enrollment) endocrine blood chemistries
             that might otherwise explain insulin resistance. TSH <0.2 or >12µIU/mL, morning
             cortisol >22µg/dL, IGF-1 <115ng/mL, total testosterone <200ng/dL (men) <15ng/dL
             (women). Use of testosterone, ACTH, thyroid hormone, or rhGH replacement to normalize
             low levels is permitted, but must be stable on hormone replacement for 3 months prior
             to enrollment and will not discontinue this replacement during enrollment. Hormone
             replacement cannot be started during treatment.

          3. Allergy or hypersensitivity to thiazolidinediones. Currently taking a
             thiazolidinedione.

          4. Anti-obesity or anorectic medications during the 3 months prior to enrollment or at
             any time during enrollment. Lipid-lowering medications are permitted (fibrate or
             statin), but the subject must be stable on that agent for at least 3 months prior to
             enrollment. Lipid-lowering agents cannot be started during the treatment period.

          5. Chronic hepatitis B infection (HB surface antigen positive). Active hepatitis C
             infection (detectable Hep C RNA). Those who have cleared hepatitis B or C infection
             are eligible. This was revised in May 2006 to better clarify some uncertainties about
             hepatitis and eligibility.

          6. History of serious cardiovascular conditions or NY Heart Association (NYHA) cardiac
             status Class III or IV, (e.g., recent MI, unstable angina, edema, CHF, CAD, CABG,
             valve disease (murmur), stroke, uncontrolled high blood pressure (resting >140/90 mmHg
             on 3 occasions), irregular heart rhythm, bundle-branch block, aortic stenosis, resting
             ST-segment depression >1mm) that would preclude exercise testing/training, or
             substantially increase risk of a CV-event during exercise, or would limit the subjects
             ability to participate in exercise training. Treatment with medications for a
             cardiovascular condition (cardiac glycosides, alpha- or beta-blockers). Some
             antihypertensive medications (Ca++-channel blocker, diuretic, or ACE inhibitor) will
             be permitted.

          7. Insulin-dependent diabetes mellitus (IDDM) or a history of ketoacidosis, symptomatic
             diabetic neuropathy or retinopathy, or renal disease (creatinine >3x ULN).

          8. Hematocrit <34% in men or <25% in women with symptoms (fatigue, "tired-legs",
             shortness of breath). Hemoglobin <10 gm/100ml with symptoms.

          9. History of eating disorder, significant GI-disease

         10. Nausea, vomiting, diarrhea (>4 loose stools/day) that are unresponsive to treatment
             during 2wks prior to enrollment or that persists for >2wks during enrollment.

         11. Active secondary infection. Any significant change in chronic suppressive therapy for
             an opportunistic infection during the 1-month prior to enrollment.

         12. During the 3 months prior to enrollment, regular aerobic or weight lifting exercise
             training that exceeds the minimum (45min/d, 3d/wk, >75% exercise capacity) required
             for the metabolic, biochemical, and anthropomorphic benefits of exercise to be
             attained as described in the American College of Sports Medicine Guidelines. In Apr
             2006, this exclusion criterion was modified in order to facilitate enrollment of
             volunteers who are moderately-highly active during the 3months prior to screening for
             this study. We will randomize volunteers who exercise regularly into the two treatment
             groups. This will reduce the potential confounding effects of regular exercise on the
             metabolic, biochemical, and anthropomorphic benefits of exercise training that is
             prescribed during the treatment phase. We have excluded several volunteers who are
             regular exercisers, and we believe we may be unnecessarily excluding them. They can be
             included, enrollment will be facilitated, and the study design will not be adversely
             affected, as long as we randomize them into pioglitazone or exercise+pioglitazone
             (1:1).

         13. Unwilling or unable to do supervised exercise 3 sessions/wk at the Medical School
             exercise facility. Any condition that might be contraindicated for exercise training
             (disabling joint, cartilage or muscle injury/disorder that prohibits or severely
             limits participation in regular exercise, disabling arthritis, severe physical
             disabilities, claudication, pulmonary disease, sinus tachycardia, arrhythmias,
             premature atrial or ventricular contractions).

         14. Pregnancy or nursing mothers. Women cannot be pregnant and must agree to use an
             acceptable form of birth control during the treatment period. If birth control pills
             are used, the woman must be stable on these medications for at least 6 months prior to
             enrollment. All metabolic testing will be done in the early follicular phase. Urine
             pregnancy tests (hCG) will be done at baseline and every month the woman is enrolled
             in the study.

         15. Pancreatitis within prior 1 year. Serum triglycerides >500mg/dL esp. with history of
             pancreatitis, or otherwise at high risk for pancreatitis.

         16. Medications that inhibit or slow blood coagulation (ie., blood thinners). Prothrombin
             (clotting) time exceeds 2 sec > control (only in subjects who agree to muscle/fat
             biopsies).

         17. Active malignancy or treatment with chemotherapeutic agents or radiation therapy
             during the 3 months prior to enrollment.

         18. Excessive weight loss (>10% body weight) during the 3 months prior to enrollment.
             History of hyperlactatemia or lactic acidosis, esp. with rapid weight loss.

         19. "Blinded" investigational drugs/medications during the 3 months prior to enrollment
             that will not be unblinded before enrollment. Open-label investigational drugs are
             permitted. Must be stable on these for 3 months prior to enrollment, must remain
             stable on them during the treatment period, and they must be known not to affect
             glucose, lipid, adipose tissue or liver metabolism.

         20. Non-prescription over the counter drugs/supplements that might alter glucose, lipid,
             or adipose tissue metabolism (eg., creatine monohydrate, chromium picolinate, amino
             acid/protein supplements, beta-hydroxy-beta-methyl-butyrate, anabolic-androgenic
             steroids, medium- or long-chain fatty acids, branched chain amino acid supplements,
             amino acids that potentially increase insulin or GH secretion (eg., arginine)) within
             1 month of enrollment. These supplements will not be permitted during the treatment
             period.

         21. Dementia or reduced cognitive function or unable to provide voluntary informed
             consent. Prisoners will not be enrolled.

         22. Active substance abuse (e.g., alcoholism, cocaine, heroin, crack, methamphetamine,
             phencyclidine). Upon evaluation, if the physician-investigator considers that this
             substance abuse does not put the volunteer at risk for an adverse (ie. cardiovascular)
             event, or if the physician-investigator feels that the volunteer will be reliable and
             compliant with the treatment regimens, and that this substance abuse will not
             interfere with the study medications, exercise regimens, or data interpretation, then
             at the physician-investigators discretion the volunteer may be eligible.

         23. Any cytokine or anti-cytokine therapy during the 3 months prior to enrollment.

         24. Patients felt by the Physician Investigator to have uncontrolled hypertension or other
             diseases (i.e. vasculitis, pulmonary HTN) that otherwise may be a cause of significant
             underlying or variable endothelial dysfunction

         25. Receiving vasoactive substances (i.e. nitrates, viagra) other than antihypertensives
             that cannot be discontinued at least 12 hours before endothelial function testing
             (BART).
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Kevin E Yarasheski, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00639457

Organization ID

DK 049393 (completed)

Secondary IDs

WU 157

Responsible Party

Principal Investigator

Study Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)


Study Sponsor

Kevin E Yarasheski, PhD, Principal Investigator, Washington University School of Medicine


Verification Date

September 2013