Arthritis, RheumatoidPhase 2CH-1504-201NCT00658047
A Study to Assess CH1504 in Patients With Active Rheumatoid Arthritis
A Phase 2 study testing CH-1504 and Methotrexate (MTX) in people with Arthritis, Rheumatoid, run by Chelsea Therapeutics at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Arthritis, Rheumatoid
- What is being tested?
- CH-1504 and Methotrexate (MTX)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 201 participants
- Where
- 1 siteCanada
- Study dates
- Apr 2008to Jun 2009
- Phase
- Phase 2
- 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 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Inclusion; To be eligible for inclusion, each patient must fulfill the following criteria:
- Patients must be between the ages of 18 and 80;
- Have been diagnosed with active rheumatoid arthritis according to ACR criteria;
- Have at least 6 swollen joints (max = 66) and 6 tender joints (max = 68) at screening and baseline visits;
- Patients must have at least one of the following:
- C-reactive protein > 1.0 mg/dl at screening;
- erythrocyte sedimentation rate > 20 mm/Hr;
- Morning stiffness > 45 min. at screening;
- Patients must have blood test values per the following criteria:
- ALT, AST < 1.2 U/l x ULN
- Albumin > 2.5 g/dl
- Prothrombin Time < 1.2 INR
- Hb > 9.0 g/dl
- Hct > 35%
- WBC > 3000 μl (mm3)
- Neutrophils > 1000 μl (mm3)
- Platelets > 100000 μl
- Creatinine < 1.2 mg/dl
- Patients must have voluntarily signed the informed consent
Exclusion; Patients are not eligible for this study if they fulfill one or more of the following criteria:
- Patients who received previous methotrexate therapy;
- Patients who received previous therapy with any biologic agent;
- Previous biologic therapy for a disease other than RA is permitted so long as their last dose was more than 120 days prior to baseline;
- Patients currently taking sulfasalazine;
- Previous sulfasalazine therapy is permitted so long as their last dose was more than 30 days prior to baseline;
- Patients currently taking hydroxychloroquine;
- Previous hydroxychloroquine is permitted so long as their last dose was more than 120 days prior to baseline;
- Female patients of child bearing potential who are pregnant or who are not using two methods of contraception (at least one barrier: i.e. condom) with their partner;
- Male patients who are sexually active and not using two methods of contraception (at least one barrier: i.e. condom) with their partner;
- Patients with any current active infection or infections requiring IV drug therapy within 30 days of baseline or oral therapy within 15 days of Baseline;
- Patients that have had any surgical procedures within 30 days of baseline;
- Patients with a history of HIV, Hepatitis B or C;
- Patients who consume more than 7 units of alcohol per week (1 unit = 5 ounces/150 ml of wine = 1.5 ounces/45 ml spirits = 12 ounces/360 ml of beer);
- Patients currently receiving any investigational drug or have received an investigational drug within 30 days of baseline or 5 half-lives of the investigational drug (whichever is longer);
- Patients with a history of cancer within the past 5 years other than a successfully treated, non-metastatic cutaneous squamous cell or basal cell carcinoma or cervical cancer in situ;
- Patients with a history of, or any, disease associated with an inflammatory arthritis other than RA;
- Patients with a chest X-ray that indicates the presence of pulmonary fibrosis (Chest x-ray may be taken with in 28 days of screening);
- Patients receiving Probenecid;
- Patients who have received any steroid injections within 30 days of baseline;
- Patients with concomitant diseases that are unstable (i.e. cardiac, pulmonary) or that may affect drug activity (i.e. absorption, reactions, change in kinetics);
- Patients considered by the investigator to be an unsuitable candidate to receive CH-1504;
- Wheelchair or bed-bound patients.
Trial locations and contacts
1 site in 1 country.
Canada1 site
The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease
Toronto, Ontario, M5G 1X5
About this study
Official title: A Phase II, Multi-center, Randomized, Double-blind, Methotrexate Controlled Study to Assess the Clinical Efficacy, Safety, and Tolerability of CH-1504 in Subjects With Active Rheumatoid Arthritis
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.
Read the 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
- Conditions
- Arthritis, Rheumatoid
- Being tested
- CH-1504, Methotrexate (MTX)
- Keywords
- Arthritis, Rheumatoid, Phase II, Rheumatoid Arthritis
- Medical subject headings
- Arthritis, Rheumatoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CH-1504Drug
Comparison of different doses of CH-1504
Methotrexate (MTX)Drug
Also called amethopterin (previous name for MTX)
10mg/week for 2 weeks escalated to 15mg/week for 2 weeks escalated to 20mg/week for 8 weeks
| Study group | Role | What they receive |
|---|---|---|
| 0.25 mg CH-1504 | Experimental | 0.25 mg CH-1504 Receives: Drug: CH-1504 |
| 0.5 mg CH-1504 | Experimental | 0.5 mg CH-1504 Receives: Drug: CH-1504 |
| 1.0 mg CH-1504 | Experimental | 1.0 mg CH-1504 Receives: Drug: CH-1504 |
| Methotrexate | Active comparator | Methotrexate (MTX) 10 mg/week for 2 weeks, 15 mg/week for 2 weeks, 20 mg/week for 8 weeks Receives: Drug: Methotrexate (MTX) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 3 months of treatment
Secondary outcomes (5)
Assess the clinical efficacy of CH-1504 by proportion of patients achieving ACR50 and ACR70 responses.
Measured: 3 months of treatment
Assess the clinical efficacy of CH-1504 using EULAR "good" and "moderate" response criteria.
Measured: 3 months of treatment
Assess the clinical efficacy of CH-1504 using the difference from baseline of ACR core set and DAS28 of measures.
Measured: 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.
Measured: 3 months of treatment
Identify the dose response relationship of CH-1504.
Measured: 3 months of treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Apr 2008 (estimated)
- Study startApr 2008
- Primary completionFeb 2009
- Study completionJun 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Arthritis, RheumatoidStudies of the same condition, open and under way.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 201 participants (actual)
Sponsor and investigators
- Lead sponsor
- Chelsea Therapeutics
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Edward Keystone, MD, Principal investigator, The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00658047
- Sponsor's protocol ID
- CH-1504-201
- Acronym
- CH-1504-201
- Status last verified
- Apr 2013
- First submitted
- 8 Apr 2008
- Last updated
- 15 Apr 2013
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Keystone EC, Shirinsky VS, Simon LS, Pedder S, Hewitt LA; CH-1504 Study Group. Efficacy and safety of CH-1504, a metabolically stable antifolate, in patients with active rheumatoid arthritis: results of a phase II multicenter randomized study. J Rheumatol. 2011 Sep;38(9):1875-83. doi: 10.3899/jrheum.101038. Epub 2011 Jul 1.
PubMed 21724705
Study at a glance
From the registry record, last updated by the sponsor on 15 Apr 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II, Multi-center, Randomized, Double-blind, Methotrexate Controlled Study to Assess the Clinical Efficacy, Safety, and Tolerability of CH-1504 in Subjects With Active Rheumatoid Arthritis
- ClinicalTrials.gov ID
- NCT00658047
- Acronym / sponsor ID
- CH-1504-201 / CH-1504-201
- Conditions
- Arthritis, Rheumatoid
- Keywords
- Arthritis, Rheumatoid, Phase II, Rheumatoid Arthritis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 201 participants (actual)
- Lead sponsor
- Chelsea TherapeuticsIndustry (pharma, biotech, devices)
- Study start
- Apr 2008
- Primary completion
- Feb 2009 (actual)
- Study completion
- Jun 2009 (actual)
- First posted
- 14 Apr 2008 (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.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| 0.25 mg CH-1504 | Experimental | Drug: CH-15040.25 mg CH-1504 |
| 0.5 mg CH-1504 | Experimental | Drug: CH-15040.5 mg CH-1504 |
| 1.0 mg CH-1504 | Experimental | Drug: CH-15041.0 mg CH-1504 |
| Methotrexate | Active comparator | Drug: Methotrexate (MTX)Methotrexate (MTX) 10 mg/week for 2 weeks, 15 mg/week for 2 weeks, 20 mg/week for 8 weeks |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
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 |
|---|---|---|
| CH-1504Comparison of different doses of CH-1504 | Drug | 0.25 mg CH-1504, 0.5 mg CH-1504, 1.0 mg CH-1504 |
| Methotrexate (MTX)Also: amethopterin (previous name for MTX)10mg/week for 2 weeks escalated to 15mg/week for 2 weeks escalated to 20mg/week for 8 weeks | Drug | Methotrexate |
Primary outcome
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.
Time frame: 3 months of treatment
5 secondary outcomes
Assess the clinical efficacy of CH-1504 by proportion of patients achieving ACR50 and ACR70 responses.
Time frame: 3 months of treatment
Assess the clinical efficacy of CH-1504 using EULAR "good" and "moderate" response criteria.
Time frame: 3 months of treatment
Assess the clinical efficacy of CH-1504 using the difference from baseline of ACR core set and DAS28 of measures.
Time frame: 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.
Time frame: 3 months of treatment
Identify the dose response relationship of CH-1504.
Time frame: 3 months of treatment
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 15 Apr 2013.
- Derived from this study: PubMed 21724705Keystone EC, Shirinsky VS, Simon LS, Pedder S, Hewitt LA; CH-1504 Study Group. Efficacy and safety of CH-1504, a metabolically stable antifolate, in patients with active rheumatoid arthritis: results of a phase II multicenter randomized study. J Rheumatol. 2011 Sep;38(9):1875-83. doi: 10.3899/jrheum.101038. Epub 2011 Jul 1.
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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.
Edward Keystone, MD principal investigator
The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing CH-1504 and Methotrexate (MTX) in people with Arthritis, Rheumatoid, run by Chelsea Therapeutics at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
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 15 Apr 2013. 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 Canada. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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.
What does the primary outcome measure?
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. (time frame: 3 months of treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00658047, which also lists 1 linked publication.
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 15 Apr 2013.