A Study to Assess CH1504 in Patients With Active Rheumatoid Arthritis

Phase 2

Completed

Conditions: Arthritis, Rheumatoid

Interventions: Drug: CH-1504
Drug: Methotrexate (MTX)

Registration Number: NCT00658047

Lead Sponsor: Chelsea Therapeutics

Brief 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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 201

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
0.25 mg CH-1504	CH-1504	0.25 mg CH-1504
0.5 mg CH-1504	CH-1504	0.5 mg CH-1504
1.0 mg CH-1504	CH-1504	1.0 mg CH-1504
Methotrexate	Methotrexate (MTX)	Methotrexate (MTX) 10 mg/week for 2 weeks, 15 mg/week for 2 weeks, 20 mg/week for 8 weeks

Primary Outcome Measures

Name	Time	Method
Assess the clinical effect of CH-1504 (0.25, 0.5, and 1.0 mg po daily) by determining the proportion of patients achieving an ACR20 response.	3 months of treatment

Secondary Outcome Measures

Name	Time	Method
Assess the clinical efficacy of CH-1504 by proportion of patients achieving ACR50 and ACR70 responses.	3 months of treatment
Assess the clinical efficacy of CH-1504 using EULAR "good" and "moderate" response criteria.	3 months of treatment
Assess the clinical efficacy of CH-1504 using the difference from baseline of ACR core set and DAS28 of measures.	3 months of treatment
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.	3 months of treatment
Identify the dose response relationship of CH-1504.	3 months of treatment