Safety of Tofacitinib, an Oral Janus Kinase Inhibitor, in Systemic Lupus Erythematosus
Condition: Systemic Lupus Erythematosus
MeSH terms: Lupus Erythematosus, Systemic
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      Systemic lupus erythematosus (lupus) is an autoimmune disease that often involves many
      systems and organs of the body. Symptoms can include fever, joint pains, and rashes. Serious
      lupus can also damage organs like the kidneys, lungs, or brain. Drugs used for lupus can have
      serious side effects. Also, the drugs don t help some people. Researchers want to find new,
      more effective and safe treatments.

      Objective:

      To evaluate the safety and tolerability of the drug tofacitinib (study drug) in people with
      lupus.

      Eligibility:

      People ages 18 and older who have mild to moderate lupus and are not currently or haven t
      recently had certain lupus treatments.

      Design:

      Participants will be screened in another protocol.

      Participants will have 7 five-hour visits over about 3 months. They will fill out multiple
      questionnaires. They will have tests, including:

        -  Physical exam

        -  Blood and urine tests

        -  ECG/EKG: Soft electrodes are stuck to the skin to monitor the heart.

        -  Optional SphygmoCor: Cuffs are attached to the arm and thigh to measure blood pressure
           and flow speed.

        -  Optional Endopat: A thimble-shaped cup is placed on the finger to measure blood flow. A
           cuff is put on the arm to measure blood pressure and flow.

        -  Optional CAVI: ECG electrodes are placed on both wrists, a microphone placed on the
           chest, and a blood pressure cuff placed on each arm and leg to measure blood pressure
           and velocity.

      Participants will receive either the study drug or a placebo. They will take this twice a day
      by mouth for 56 days.

      Participants will be contacted by phone 4 times....
    

Detailed description: 
      BACKGROUND:

      Systemic Lupus Erythematosus (SLE) is an autoimmune disease with variegated clinical
      presentation resulting from involvement of multiple biologic pathways. The pathways that lead
      to loss of tolerance in SLE include: multiple autoreactive cell types (B, T, dendritic, Th17
      and regulatory T cells) and abnormal cytokine milieus, genetic factors, environmental and
      hormonal influences, all of which can influence cell differentiation patterns and reset
      tolerance checkpoints. In addition, recent studies indicate a putative role for neutrophils
      in lupus pathogenesis and associated end-organ damage. Currently available therapeutics are
      frequently inadequate to treat disease flares and simultaneously expose patients to
      potentially serious toxicities. Further, premature cardiovascular disease not explained by
      the Framingham risk equation has become one of the most important causes of morbidity and
      mortality in this patient population. To date, no treatment used in lupus appears to
      significantly decrease cardiovascular risk. Identifying a drug that has immunomodulatory
      effects and is also vasculoprotective is an unmet need in this disease.

      Tofacitinib is an orally administered Janus kinase (JAK) inhibitor that has recently been
      approved by the Food and Drug Administration for the treatment of moderate to severe
      rheumatoid arthritis (RA).

      The JAKs are a family of intracellular enzymes (JAK1, 2 and 3 and TYK2) that mediate
      signaling via a broad range of cytokine receptors. Targeting JAKs is an attractive
      therapeutic possibility for SLE for many reasons. Many of the inflammatory cytokines
      implicated in the pathogenesis of SLE signal via the JAK-STAT pathways. JAK inhibitors have
      been found to have efficacy in various murine models of lupus. Mice treated with a JAK2
      inhibitor exhibited reduced serum levels of IL-6, and IL-17 along with reduced numbers of
      long-lived autoantibody producing plasma cells in the spleen and bone marrow. Furthermore, we
      have found that administration of tofacitinib reduced serum levels of ANA, IL-6, and
      IFN-gamma; and ameliorated glomerulonephritis (unpublished data).

      This study therefore represents an innovative investigative measure of the safety and
      efficacy of JAK inhibition in SLE that is predicted by genetic predisposition. We will also
      investigate effects of tofacitinib on vascular function in SLE subjects and identify
      biomarkers that may be useful as endpoints in future studies.

      PRIMARY OBJECTIVE:

      To determine the safety and tolerability of tofacitinib in patients with SLE and mild to
      moderate disease activity.

      STUDY DESIGN:

      This is a Phase Ib, randomized, double blind, placebo controlled clinical trial of orally
      administered tofacitinib, 5 mg twice daily, for the treatment of SLE subjects with mild to
      moderate disease activity stratified by the presence or absence of STAT4 risk alleles.
    

Intervention name(s): Tofacitinib; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Oral administration of tofacitinib, 5 mg
Intervention MeSH terms: Tofacitinib
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Anti-DNA Antibody; Tofacitinib; Lupus; Safety