HIV InfectionsPhase 1NCT00101374
Effect of Leflunomide on T Cell Proliferation in HIV-Infected Patients
A Phase 1 study testing Leflunomide in people with HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
Trial summary
This study will evaluate the effect of leflunomide on the life cycle of a specific immune cell called CD4+ T cell in HIV-infected patients. Leflunomide is approved by the Food and Drug Administration for treating rheumatoid arthritis. It works by blocking cell division in activated T cells. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- HIV Infections
- What is being tested?
- Leflunomide
- How many people
- 41 participants
- Where
- 1 siteUnited States
- Study dates
- 5 Jan 2005to 21 May 2008
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 infection.
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- 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.
- IUD.
- 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 following:
- 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 laboratory.
Who cannot join
- Current treatment with antiretrovirals or use of antiretrovirals within 12 weeks of screening.
- 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.
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- 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 resins.
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Effect of Leflunomide on HIV-1 Associated Immune Proliferation In Vivo
This study will evaluate the effect of leflunomide on the life cycle of a specific immune cell called CD4+ T cell in HIV-infected patients. Leflunomide is approved by the Food and Drug Administration for treating rheumatoid arthritis. It works by blocking cell division in activated T cells. In HIV infection, the HIV virus causes increased activation of T cells. The activated cells become infected and die. Activation may also cause the death of T cells that are not infected with HIV. T cells are necessary for the body to fight infections and cancer. This study will see if leflunomide can block T-cell division and possibly reduce the number of cells that die, reduce the number of cells in which HIV can reproduce, and lead to a lower level of HIV virus in the body.
HIV-infected patients between 18 and 65 years of age who have 1) HIV viral levels of 1,000 copies/mL or more, 2) a CD4+ T-cell count of 350 cells/mm3 or more, and 3) a CD4+ T-cell count that has never been less than 200 cells/mm3 may be eligible for this study. Candidates are screened with a medical history, physical examination, blood and urine tests, chest x-ray, and electrocardiogram (EKG).
Participants are randomly assigned to take leflunomide or placebo (a substance with no active ingredient) every day for 28 days. They come to the clinic three times during the first 29 days of the study (days 1, 15, and 29) for a physical examination and review of any drug side effects. Patients taking placebo end their participation on day 29. Patients taking leflunomide stop taking the drug on day 29 and begin taking cholestyramine three times a day for 11 days out of the next 14 days to clear the leflunomide from their body. On day 43, they return to the clinic to have their leflunomide level checked to make sure that only very little or none of the drug remains in the body. If the level is low, patients end their participation on or around day 57. If the level remains high, they repeat the cholestyramine treatment.
Read the detailed description
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.
- Conditions
- HIV Infections
- Being tested
- Leflunomide
- Keywords
- Immunomodulatory Drug, Antiviral, Ki67+, Immune Activation, T Cell Proliferation, HIV, Activated CD4+T-cell, Proliferation
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LeflunomideDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jan 2005 (estimated)
- Study start5 Jan 2005
- Primary completion21 May 2008
- Study completion21 May 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Enrolment
- 41 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00101374
- Sponsor's protocol ID
- 050065
- Other IDs
- 05-I-0065
- Status last verified
- 2 Feb 2010
- First submitted
- 7 Jan 2005
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
Grossman Z, Meier-Schellersheim M, Sousa AE, Victorino RM, Paul WE. CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med. 2002 Apr;8(4):319-23. doi: 10.1038/nm0402-319. No abstract available.
PubMed 11927927McCune JM. The dynamics of CD4+ T-cell depletion in HIV disease. Nature. 2001 Apr 19;410(6831):974-9. doi: 10.1038/35073648.
PubMed 11309627Sousa AE, Carneiro J, Meier-Schellersheim M, Grossman Z, Victorino RM. CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J Immunol. 2002 Sep 15;169(6):3400-6. doi: 10.4049/jimmunol.169.6.3400.
PubMed 12218162Read SW, DeGrezia M, Ciccone EJ, DerSimonian R, Higgins J, Adelsberger JW, Starling JM, Rehm C, Sereti I. The effect of leflunomide on cycling and activation of T-cells in HIV-1-infected participants. PLoS One. 2010 Aug 3;5(8):e11937. doi: 10.1371/journal.pone.0011937.
PubMed 20689824
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Effect of Leflunomide on HIV-1 Associated Immune Proliferation In Vivo
- ClinicalTrials.gov ID
- NCT00101374
- Acronym / sponsor ID
- 050065
- Conditions
- HIV Infections
- Keywords
- Immunomodulatory Drug, Antiviral, Ki67+, Immune Activation, T Cell Proliferation, HIV, Activated CD4+T-cell, Proliferation
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 41 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- 5 Jan 2005
- Primary completion
- 21 May 2008 (actual)
- Study completion
- 21 May 2008 (actual)
- First posted
- 10 Jan 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will evaluate the effect of leflunomide on the life cycle of a specific immune cell called CD4+ T cell in HIV-infected patients. Leflunomide is approved by the Food and Drug Administration for treating rheumatoid arthritis. It works by blocking cell division in activated T cells. In HIV infection, the HIV virus causes increased activation of T cells. The activated cells become infected and die. Activation may also cause the death of T cells that are not infected with HIV. T cells are necessary for the body to fight infections and cancer. This study will see if leflunomide can block T-cell division and possibly reduce the number of cells that die, reduce the number of cells in which HIV can reproduce, and lead to a lower level of HIV virus in the body.
HIV-infected patients between 18 and 65 years of age who have 1) HIV viral levels of 1,000 copies/mL or more, 2) a CD4+ T-cell count of 350 cells/mm3 or more, and 3) a CD4+ T-cell count that has never been less than 200 cells/mm3 may be eligible for this study. Candidates are screened with a medical history, physical examination, blood and urine tests, chest x-ray, and electrocardiogram (EKG).
Participants are randomly assigned to take leflunomide or placebo (a substance with no active ingredient) every day for 28 days. They come to the clinic three times during the first 29 days of the study (days 1, 15, and 29) for a physical examination and review of any drug side effects. Patients taking placebo end their participation on day 29. Patients taking leflunomide stop taking the drug on day 29 and begin taking cholestyramine three times a day for 11 days out of the next 14 days to clear the leflunomide from their body. On day 43, they return to the clinic to have their leflunomide level checked to make sure that only very little or none of the drug remains in the body. If the level is low, patients end their participation on or around day 57. If the level remains high, they repeat the cholestyramine treatment.
Detailed description
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.
Study design
- Primary purpose
- Treatment
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- 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.
Key exclusion criteria (23 listed)
- Current treatment with antiretrovirals or use of antiretrovirals within 12 weeks of screening.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Leflunomide | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Background: PubMed 11927927Grossman Z, Meier-Schellersheim M, Sousa AE, Victorino RM, Paul WE. CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med. 2002 Apr;8(4):319-23. doi: 10.1038/nm0402-319. No abstract available.
- Background: PubMed 11309627McCune JM. The dynamics of CD4+ T-cell depletion in HIV disease. Nature. 2001 Apr 19;410(6831):974-9. doi: 10.1038/35073648.
- Background: PubMed 12218162Sousa AE, Carneiro J, Meier-Schellersheim M, Grossman Z, Victorino RM. CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J Immunol. 2002 Sep 15;169(6):3400-6. doi: 10.4049/jimmunol.169.6.3400.
- Derived from this study: PubMed 20689824Read SW, DeGrezia M, Ciccone EJ, DerSimonian R, Higgins J, Adelsberger JW, Starling JM, Rehm C, Sereti I. The effect of leflunomide on cycling and activation of T-cells in HIV-1-infected participants. PLoS One. 2010 Aug 3;5(8):e11937. doi: 10.1371/journal.pone.0011937.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Leflunomide in people with HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00101374, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.