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A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Effect of Leflunomide on HIV-1 Associated Immune Proliferation In Vivo

Phase 1
18 Years
65 Years
Not Enrolling
HIV Infections

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Trial Information

A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Effect of Leflunomide on HIV-1 Associated Immune Proliferation In Vivo

Increased T cell turnover is one of the main abnormalities observed in HIV infected patients
and one of the main mechanisms leading to CD4 lymphopenia. This has led to the hypothesis
that medications that act directly to suppress immune activation and normalize T cell
turnover, could be used in HIV infection. The purpose of this protocol is to evaluate the
effect of the immunomodulatory agent, leflunomide, on CD4+ T cell proliferation in HIV
infected adults. HIV infected adults who have stable HIV viral loads and are not taking
antiretrovirals will receive leflunomide or placebo for 28 days. CD4+ T cell proliferation
will be measured as percent Ki67 expression, and the change in expression from baseline to
day 28 will be compared between groups. Various studies measuring immune parameters such as
CD4+ and CD8+ T cells counts and level of activation will be collected as well as safety
studies and HIV viral loads. The primary study risk is adverse reaction to leflunomide.
The study will be double-blinded randomized 2:1 (leflunomide versus placebo) and will be
reviewed by a DSMB. Total enrollment for the study will be 18 patients.

Inclusion Criteria


- Age greater than or equal 18 and less than or equal to 65 years.

- HIV infected.

- CD4+ cell count greater than or equal to 350 cells/mm(3) at screening and historical
nadir (since diagnosis of HIV) of greater than or equal to 200 cells/mm(3).

- Plasma HIV viral load greater than or equal to 1,000 copies/mL at screening.

- Ability to understand and sign informed consent and willingness to comply with the
study requirements and clinic policies.

- Must have a primary care physician who will be taking care of patients for their HIV

- Female study subjects of reproductive potential (defined as girls who have reached
menarche or women who have not been post-menopausal for at least 24 consecutive
months, i.e., who have had menses within the preceding 24 months or have not
undergone a sterilization procedure (hysterectomy or bilateral oophorectomy), must
have a negative serum or urine pregnancy test.

- Agreement not to participate in a conception process (eg. active attempt to become
pregnant or impregnate, sperm donation, or in vitro fertilization) and to follow
strict contraceptive measures while on study.

- If participating in sexual activity that could lead to pregnancy, the study volunteer
must agree that two reliable methods of contraception will be used simultaneously
during the entire study. Acceptable forms of contraception include:

Condoms (male or female) with or without a spermicidal agent. Condoms are recommended
because their appropriate use is the only contraception method effective for preventing
HIV transmission.

Diaphragm or cervical cap with spermicide.


Hormonal-based contraception.

Study subjects who are not of reproductive potential (women who have been post-menopausal
for at least 24 consecutive months, women who have undergone hysterectomy or bilateral
oophorectomy, or prepubescent boys or men who have documented azoospermia) are eligible
without requiring the use of contraception.

Written or oral documentation communicated by clinician or clinician's staff of one of the

Physician report/letter.

Operative report or other source documentation in the patient record (a laboratory report
of azoospermia is required to document successful vasectomy).

Discharge summary.

Laboratory report of azoospermia.

FSH measurement elevated into the menopausal range as established by the reporting


- Current treatment with antiretrovirals or use of antiretrovirals within 12 weeks of

- Intention of start antiretroviral regimen within 64 day study period.

- Previous treatment with leflunomide.

- Previous treatment with IL-2.

- Treatment with immunomodulatory agents (including hydroxyurea, mycophenolate,
cyclosporine, rapamycin, anti-HIV vaccines, interleukins other than IL-2,
interferons) within 60 days of study.

- Treatment with systemic corticosteroids within 30 days of study.

- Inability or unwillingness to discontinue drugs (except NSAIDS) that are metabolized
by P450 2C9 isoenzyme (see Appendix A- Medications Metabolized by CYP 2C9 and
Contraindicated During Treatment Period).

- Inability or unwillingness to discontinue hepatotoxic drugs (eg. isoniazid, rifampin,
HMG CoA reductase inhibitors).

- Inability or unwillingness to discontinue drug that interact with cholestyramine (eg.
have diminished absorption with cholestyramine) (see Appendix B- Medications that
have Interactions with Cholestyramine).

- Current use of or known intolerance of cholestyramine or bile acid sequestering

- History of familial hyperlipoproteinemia type III, IV or V.

- Active bacterial infection within 4 weeks of screening.

- History of AIDS-defining illness (category C) (see Appendix C - CDC AIDS
Classification Criteria).

- Hepatitis B or C infection.

- Acute or chronic liver disease from any cause (eg. alcoholic hepatitis or alcohol
induced cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, sclerosing
cholangitis, Wilson's disease, hemochromatosis) which the investigator feels would
compromise the subject's safety.

- History of biliary obstruction.

- Current alcohol abuse or unwillingness to abstain from alcohol use for study period.

- History of hypertension that is not controlled (less than 140/80 mm/Hg) on a single
antihypertensive agent.

- Abnormal laboratory findings: hemoglobin less than 10 g/dL; ANC less than 1000/mm(3);
platelets less than 100,000/mm(3); creatine above the upper limit of normal; ALT or
alkaline phosphatase greater than 1.25 times the upper limit of normal; AST greater
than 1.25 times the upper limit of normal (subjects with isolated AST elevation,
higher than normal CPK values in the absence of liver disease and compatible history
such as intense exercise will be allowed to re-screen if the study investigators
suspect that the elevated AST is of muscular origin) direct bilirubin greater than
1.5 times the upper limit of normal; total bilirubin greater than 2 times the upper
limit of normal lipase greater than 1.5 times the upper limit of normal; PT greater
than 1.1 times the upper limit of normal; PTT greater than 1.5 times the upper limit
of normal.

- History of malignant neoplasm except in situ anogenital carcinoma, adequately treated
basal or squamous cell carcinoma of the skin or solid tumors treated with curative
therapy and disease free for at least five years.

- Significant medical or psychiatric disorder which the investigator feels would
interfere with the subject's ability to participate or would compromise safety.

- Women who are currently pregnant or breast-feeding.

- History of interstitial lung disease.

Type of Study:


Study Design:

Primary Purpose: Treatment


United States: Federal Government

Study ID:




Start Date:

January 2005

Completion Date:

May 2008

Related Keywords:

  • HIV Infections
  • Immunomodulatory Drug
  • Antiviral
  • Ki67+
  • Immune Activation
  • T Cell Proliferation
  • HIV
  • Activated CD4+T-cell
  • Proliferation
  • HIV Infections
  • Acquired Immunodeficiency Syndrome



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892