Metformin and Rosiglitazone, Alone or in Combination, in HIV-Infected Patients With Insulin and Fat Abnormalities

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Brief Title

Metformin and Rosiglitazone, Alone or in Combination, in HIV-Infected Patients With Insulin and Fat Abnormalities

Official Title

A Randomized, Double-Blind, Placebo-Controlled Study of Metformin and Rosiglitazone, Alone or in Combination, in HIV-Infected Subjects With Hyperinsulinemia and Elevated Waist/Hip Ratio

Brief Summary

      The purpose of this study is to see whether metformin alone, rosiglitazone alone, or
      metformin and rosiglitazone together will lower insulin levels in the blood and decrease fat
      in the abdomen or other parts of the body.

      Studies have shown that certain anti-HIV medications can cause a number of side effects,
      including high blood sugar (resulting from the body's failure to use insulin), high insulin,
      and excess fat build-up in the abdominal area. These side effects are known to increase the
      risk of heart disease. Metformin and rosiglitazone are 2 drugs that have been shown to lower
      insulin resistance and lessen abdominal fat in patients who are not HIV-infected. This study
      will investigate the use of these drugs in HIV-infected patients.
    

Detailed Description

      Recent studies have documented hyperglycemia, insulin resistance, and glucose intolerance in
      a seemingly increasing proportion of patients with HIV infection. Other studies have
      described a variety of syndromes of fat accumulation and fat loss, including abdominal
      obesity. Although initially attributed specifically to protease inhibitors (PI), these
      abnormalities also have been observed in antiretroviral-experienced but PI-naive patients.
      Hyperinsulinemia and abdominal obesity are strong independent risk factors for coronary
      artery disease. In noninfected patients, metformin and thiazolidinediones have been shown to
      reduce insulin resistance by different mechanisms and also to reduce visceral adiposity. This
      study investigates the use of metformin and rosiglitazone, a member of the thiazolidinedione
      class, in HIV-infected patients with hyperinsulinemia and central fat accumulation.

      At study entry, clinical and laboratory assessments are performed. A standard OGTT, with
      plasma samples drawn over 120 minutes, will be performed for glucose and insulin
      determinations. After completion of entry evaluations, patients are assigned randomly to 1 of
      4 double-blinded treatment arms:

      Arm A: Metformin plus rosiglitazone placebo. Arm B: Metformin placebo plus rosiglitazone. Arm
      C: Metformin plus rosiglitazone. Arm D: Metformin placebo plus rosiglitazone placebo.
      Patients who are still on study drugs at Week 16 (at either full or reduced dose) are
      switched to the open-label phase to receive the combination of metformin and rosiglitazone
      through Week 32. Patients have evaluations at Weeks 2, 4, 8, 12, 16, 18, 20, 24, 28, and 32.
      [AS PER AMENDMENT 02/05/02: Evaluations must be performed under fasting conditions.] Safety
      indices, fasting insulin and glucose levels, visceral [AS PER AMENDMENT 02/05/02: and
      subcutaneous abdominal] fat are assessed. [AS PER AMENDMENT 02/05/02: Patients who
      discontinue study treatment due to pregnancy during the study will have the Week 32
      evaluations (except CT and DEXA scans).] [AS PER AMENDMENT 02/05/02: A mid-thigh measurement
      was added to the study as a secondary endpoint to look for changes in extremity subcutaneous
      fat from therapy with rosiglitazone. Rosiglitazone and other peroxisome
      proliferator-activated receptor (PPAR) gamma activators increase subcutaneous adipogenesis
      and may thus increase subcutaneous fat and improve insulin resistance in this way.]
    


Study Type

Interventional




Condition

HIV Infections

Intervention

Metformin hydrochloride


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

105



Primary Completion Date

January 2006

Eligibility Criteria

        Inclusion Criteria

        Patients may be eligible for this study if they:

          -  Are HIV-positive.

          -  Have a viral load (level of HIV in the blood) below 10,000 copies/ml, within 30 days
             before study entry.

          -  Have a fasting blood insulin level at 15 micro IU/ml or greater; or a 2-hour insulin
             at least 75 micro IU/ml or greater following 75 g glucose load; or a 2-hour glucose
             greater than 140 mg/dl following 75 g glucose load AND fasting serum insulin at least
             10 micro IU/ml or greater, within 30 days before study entry.

          -  Meet physical restrictions based on the amount and location of body fat and also on
             height and weight.

          -  Have noticed changes in the location of their body fat during the course of their HIV
             disease.

          -  Are 18 to 65 years old.

          -  Have taken the same anti-HIV drugs for at least 60 days before study entry and do not
             plan to change these drugs for the entire study.

          -  If taking hormones, have been on the same treatment for at least 6 months before study
             entry and do not plan to change for the entire study. Hormones include birth control
             pills, estrogen, or progestin for women and testosterone for men. If hormones were
             taken and then stopped, the treatment must have ended at least 6 months before the
             patient enters the study.

          -  Have a negative pregnancy test within 30 days before taking the study drugs, if female
             and able to have children.

          -  Agree to avoid trying to become pregnant or causing someone to become pregnant. Agree
             not to donate sperm or participate in other fertilization procedures. If sexually
             active, agree to use [AS PER AMENDMENT 02/05/02: 1] effective method of birth control
             while taking the study medications and for at least 30 days after stopping the study
             medications. Women who are not able to give birth or whose male partner is sterile are
             not required to use birth control.

          -  Several changes have been made to this study. In earlier versions, a fasting blood
             insulin above 15 micro IU/ml was the only level accepted. Now there are several other
             insulin/glucose levels included. In addition, the timing of pregnancy tests has
             changed from 14 days to 30 days.

        Exclusion Criteria

        Patients will not be eligible for this study if they:

          -  Are allergic to metformin or rosiglitazone.

          -  Are pregnant or breast-feeding.

          -  Abuse drugs or alcohol.

          -  Have diarrhea, nausea, or vomiting.

          -  Have heart disease.

          -  Are taking or have taken drugs to control blood sugar.

          -  Have taken any of the following drugs within 6 months before study entry: high-dose
             estrogen, high-dose testosterone, high-dose testosterone gel, testosterone creams,
             growth hormone, steroids to increase body size, DHEA or androstenedione (sold over the
             counter), prednisone and other steroid drugs at high doses, drugs to increase
             appetite, experimental drugs to increase appetite or weight gain, drugs that affect
             the immune system, pentoxifylline, thalidomide, niacin (a multivitamin containing
             niacin is okay), hydroxyurea, and cimetidine.

          -  Are taking ritonavir with simvastatin or lovastatin (drugs to lower cholesterol).

          -  Are taking drugs not approved by the FDA or of unknown identity, in experimental
             studies.
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Kathleen Mulligan, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00015691

Organization ID

A5082

Secondary IDs

AACTG A5082

Responsible Party

Sponsor

Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)


Study Sponsor

Kathleen Mulligan, Study Chair, 


Verification Date

July 2013