A Study to Assess CH1504 in Patients With Active Rheumatoid Arthritis
Condition: Arthritis, Rheumatoid
MeSH terms: Arthritis; Arthritis, Rheumatoid
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this trial is to assess the clinical effect of CH-1504 at doses of 0.25, 0.5
      and 1.0 mg per day in patients with active rheumatoid arthritis by determining the proportion
      of patients achieving an American College of Rheumatology (ACR) 20% improvement response.
    

Detailed description: 
      Rheumatoid Arthritis (RA) is a chronic inflammatory disease of unknown cause that leads to
      pain, stiffness, swelling and limitation of joint function. If left untreated, RA produces
      serious destruction of joints that frequently leads to permanent disability.

      Methotrexate (MTX) is currently the most commonly prescribed first-line disease modifying
      anti-rheumatic drug (DMARD) because of its early onset of action, good efficacy, and ease of
      administration. In addition, MTX can be combined with other FDA approved DMARDs, including
      gold compounds, sulfasalazine, hydroxychloroquine, TNF inhibitors, anakinra and leflunomide.
      However, the administration of MTX has been associated with serious side effects such as skin
      reactions, pneumonitis, gastrointestinal disturbances including diarrhea, ulcerative
      stomatitis and hemorrhagic enteritis, hepatotoxicity and renal toxicity. Overall it is
      estimated that up to 30% of all patients discontinue MTX therapy due to side effects.

      MTX enters cells via the Reduced Folate Carrier (RFC) system. Once inside cells, it is
      converted enzymatically to polyglutamylated derivatives. These metabolites cannot be readily
      effluxed and are retained in tissues. The accumulation of polyglutamyl metabolites of MTX for
      prolonged periods may play a significant role in both the efficacy and the toxicity of this
      compound. Methotrexate in its parent form only has activity against dihydrofolate reductase
      (DHFR). In order for it to have significant activity against other enzymes (i.e. Thymidylate
      Synthase (TS)) it must be polyglutamylated. However by being polyglutamylated the MTX
      metabolite is retained in the cell and may potentiate the cytotoxicity of MTX. In addition to
      polyglutamylation metabolism, MTX is also hydroxylated in the liver to a metabolite known as
      7-hydroxymethotrexate, which is also subject to polyglutamylation and cell retention. This
      metabolite has been implicated in liver and kidney toxicity of the parent compound, while
      contributing no role in efficacy.

      CH-1504 has been shown in vitro to be a nonpolyglutamylatable and nonhydroxylatable
      antifolate that is more efficiently taken up into cells by the reduced folate carrier (RFC)
      system than is MTX. CH-1504 has significant activity on both DHFR and TS enzymes without the
      need for polyglutamylation. The lack of hydroxylation potentially leads to enhanced levels of
      the active drug in the cell. Furthermore, the glutamyl moiety is not susceptible to being
      cleaved by carboxypeptidase. Thus CH-1504 may be referred to as a metabolically stable
      antifolate. It is our hypothesis that in the clinical setting CH-1504 will demonstrate the
      efficacy of classical antifolates (via folate enzyme inhibition) but will be devoid of the
      toxicity secondary to the formation of the polyglutamylated and hydroxylated metabolites,
      providing a significantly improved therapeutic index compared to classical antifolates, such
      as MTX.

      This study is a randomized, double-blind, methotrexate controlled study to assess the
      clinical effect of CH-1504 in patients with active rheumatoid arthritis by determining the
      proportion of patients achieving an ACR20 response after 12 weeks of treatment.

      Secondary objectives are:

        -  Assess the clinical efficacy of CH-1504 by proportion of patients achieving ACR50 and
           ACR70 responses.

        -  Assess the clinical efficacy of CH-1504 using EULAR "good" and "moderate" response
           criteria.

        -  Assess the clinical efficacy of CH-1504 using the difference from baseline of ACR core
           set and DAS28 of measures.

        -  Evaluate the safety and tolerability of CH-1504 in RA patients as determined by the
           frequency and severity of adverse events, laboratory abnormalities, and dropouts.

        -  Identify the dose response relationship of CH-1504
    

Intervention name(s): CH-1504; Methotrexate (MTX)
Intervention type(s): Drug; Drug
Intervention description(s): Comparison of different doses of CH-1504; 10mg/week for 2 weeks escalated to 15mg/week for 2 weeks escalated to 20mg/week for 8 weeks
Other intervention name(s): amethopterin (previous name for MTX)
Intervention MeSH terms: Methotrexate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Arthritis, Rheumatoid; Phase II; Rheumatoid Arthritis