Rheumatoid Arthritis
Conditions
Keywords
CombinatoRx, CRx-102, Rheumatoid Arthritis, Prednisolone, Dipyridamole, ACR20
Brief summary
CRx-102 is a synergistic combination drug candidate containing the cardiovascular drug dipyridamole and a very low dose of the glucocorticoid prednisolone. CRx-102 is believed to work through a novel mechanism of action in which dipyridamole selectively amplifies the anti-inflammatory and immunomodulatory activities of the glucocorticoid without replicating the dose-dependent adverse effects. CRx-102 has been associated with clinical benefit in proof of concept studies in subjects with hand Osteoarthritis (OA) and Rheumatoid Arthritis (RA). In this trial, CRx-102 will be given to subjects with active RA as an add-on therapy to existing stable doses of Disease Modifying Anti-Rheumatic Drugs (DMARDs) including methotrexate (MTX), sulfasalazine, hydroxychloroquine, leflunomide or azathioprine. MTX in combination with other DMARDs (e.g., sulfasalazine or hydroxychloroquine) will be permitted to reflect the current standard of care practices within rheumatology.
Detailed description
The study was discontinued before the enrollment objective was met. Preliminary review of the efficacy dataset revealed that the efficacy dataset was not robust enough to support an extensive formal efficacy analysis as described in the SAP. Therefore, only the CRP values over time and the percent change in C-reactive protein (CRP) values in the As-Treated population were calculated.
Interventions
prednisolone 2.7 mg plus dipyridamole 180 mg
DRUGprednisolone
prednisolone (2.7 mg)
DRUGdipyridamole
dipyridamole 360 mg
DRUGplacebo
placebo
Prednisolone 2.7 mg plus Dipyridamole 360 mg
Sponsors
Zalicus
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject must voluntarily give written informed consent * Subject must be ≥ 18 years of age * Subject must have RA (ACR criteria) * Subject must have at least 4 swollen joints and at least 6 tender joints at screening and baseline (28 joint count) * Subject must have a CRP \> Upper Limit of Normal at screening * Subject must have been on DMARD or DMARD combination (e.g. MTX + hydroxychloroquine) for at least 3 months and be on a stable dose of DMARD(s) for at least 6 weeks prior to screening. * For MTX subjects: MTX ≥ 7.5 mg weekly (po/sc/im) and willing to take folic acid or folinic acid supplementation * Subject willing to take concomitant multivitamin or the equivalent of 400 I.U. vitamin D and the equivalent of 1000 mg of elemental calcium daily
Exclusion criteria
* History of clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease * Wheelchair or bed bound * History of osteoporotic fracture * History of malignancy within the past 10 years. However, subjects with a history of treated or excised basal cell carcinoma or fewer than 3 squamous cell carcinomas are eligible to participate * History of lymphoma or chronic leukemia * Moles or lesions that are currently undiagnosed, but are suspicious for malignancy * Surgery within the previous 3 months (except for minor dental and cosmetic) * History of drug or alcohol abuse (as defined by the Investigator) * History of bleeding disorder * History of gastrointestinal bleeding within 5 years of screening * History of severe migraines or headaches * History of glaucoma * Active diabetic retinopathy * Visually compromising cataract * History of opportunistic infection within the previous 12 months * Active Tuberculosis (TB) * Serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia) within 3 months prior to screening * Fever or symptomatic viral or bacterial infection within 2 weeks prior to screening * Positive for Hepatitis C virus (HCV) antibody * Positive for HBsAg * Known positive HIV antibody * Has a history of hypersensitivity to glucocorticoids and/or dipyridamole * Treatment with oral, intra-articular, intramuscular, or intravenous glucocorticoids within 6 weeks prior to screening; inhaled glucocorticoid is permitted * Treatment with any tumor necrosis factor-alpha (TNFα) biologic, anakinra or abatacept within 2 months prior to screening * Treatment with rituximab * Treatment with another investigational drug 3 months prior to screening * Treatment with anticoagulants including: dipyridamole, warfarin, clopidogrel, ticlopidine; Acetylsalicylic acid \> 150 mg per day * Treatment with any concomitant medications that have not been at a stable dose for at least 28 days prior to screening * Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) laboratory values that exceed 1.5 x ULN * HbA1C value of \> 7.0% * Current enrollment in any other study with investigational drug or device * Female subject who is pregnant or lactating or of child bearing potential and not using acceptable methods of contraception (birth control pills, barriers or abstinence) * Unwilling or unable to comply with the requirements of this protocol, including the presence of any condition (physical, mental, or social) that is likely to affect the subject's return for follow-up visits on schedule * Other unspecified reasons that, in the opinion of the Investigator or sponsor make the subject unsuitable for enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute C-reactive Protein (CRP) Values at Day 98 - As Treated Population | Day 98 | Preliminary review of the efficacy dataset revealed that the efficacy dataset was not robust enough to support an extensive formal efficacy analysis as described in the SAP. Therefore, only the CRP values over time and the percent change in CRP values in the As-Treated population were calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Day 98 in C-reactive Protein (CRP) Values - As Treated Population | baseline to day 98 | Preliminary review of the efficacy dataset revealed that the efficacy dataset was not robust enough to support an extensive formal efficacy analysis as described in the SAP. Therefore, only the CRP values over time and the percent change in CRP values in the As-Treated population were calculated. |
| To Assess the Superiority of CRx-102 Compared to Prednisolone and Dipyridamole Using American College of Rheumatology Rating Scale (20% or More Improvement; ACR20) Calculated From Baseline to Day 98 in Subjects With Active Rheumatoid Arthritis | baseline to day 98 | Preliminary review of the efficacy dataset revealed that the efficacy dataset was not robust enough to support an extensive formal efficacy analysis as described in the SAP. Therefore, only the CRP values over time and the percent change in CRP values in the As-Treated population were calculated. |
| To Assess the Efficacy of CRx-102 Compared to Placebo Using ACR 20 Calculated From Baseline to Day 98 | baseline to 98 Days | Preliminary review of the efficacy dataset revealed that the efficacy dataset was not robust enough to support an extensive formal efficacy analysis as described in the SAP. Therefore, only the CRP values over time and the percent change in CRP values in the As-Treated population were calculated. |
Countries
Argentina, Canada, Estonia, Hungary, Lithuania, Mexico, Poland, Romania, Russia, Serbia, South Africa, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CRx-102 (2.7/180) Crx-102 (Dose 1) 2.7 mg prednisolone plus 180 mg dipyridamole | 4 |
| CRx-102 (2.7/360) Crx-102 (Dose 2)
2.7 mg prednisolone plus 360 mg dipyridamole | 22 |
| Prednisolone prednisolone
prednisolone: prednisolone (2.7 mg) | 13 |
| Dipyridamole dipyridamole
dipyridamole: dipyridamole (180 mg or 360 mg) | 8 |
| Placebo placebo
placebo: placebo | 4 |
| Total | 51 |
Baseline characteristics
| Characteristic | CRx-102 (2.7/180) | CRx-102 (2.7/360) | Prednisolone | Dipyridamole | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 51.8 years STANDARD_DEVIATION 5.5 | 56.2 years STANDARD_DEVIATION 11.96 | 55.8 years STANDARD_DEVIATION 11.32 | 56.5 years STANDARD_DEVIATION 12.76 | 58.8 years STANDARD_DEVIATION 9.54 | 56.0 years STANDARD_DEVIATION 11.09 |
| Sex: Female, Male Female | 2 Participants | 18 Participants | 5 Participants | 7 Participants | 3 Participants | 35 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 8 Participants | 1 Participants | 1 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 4 | 10 / 22 | 2 / 13 | 4 / 8 | 2 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 22 | 0 / 13 | 0 / 8 | 0 / 4 |
Outcome results
Primary
Absolute C-reactive Protein (CRP) Values at Day 98 - As Treated Population
Preliminary review of the efficacy dataset revealed that the efficacy dataset was not robust enough to support an extensive formal efficacy analysis as described in the SAP. Therefore, only the CRP values over time and the percent change in CRP values in the As-Treated population were calculated.
Time frame: Day 98
Population: As treated population
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| CRx-102 (2.7/180) | Absolute C-reactive Protein (CRP) Values at Day 98 - As Treated Population | 12.85 mg/L | Full Range 5.39 |
| CRx-102 (2.7/360) | Absolute C-reactive Protein (CRP) Values at Day 98 - As Treated Population | 14.25 mg/L | Full Range 15.52 |
| Prednisolone | Absolute C-reactive Protein (CRP) Values at Day 98 - As Treated Population | 21.85 mg/L | Full Range 27.1 |
| Dipyridamole | Absolute C-reactive Protein (CRP) Values at Day 98 - As Treated Population | 16.60 mg/L | Full Range 16.22 |
| Placebo | Absolute C-reactive Protein (CRP) Values at Day 98 - As Treated Population | 2.68 mg/L | Full Range 4.88 |
Secondary
Percent Change From Baseline to Day 98 in C-reactive Protein (CRP) Values - As Treated Population
Preliminary review of the efficacy dataset revealed that the efficacy dataset was not robust enough to support an extensive formal efficacy analysis as described in the SAP. Therefore, only the CRP values over time and the percent change in CRP values in the As-Treated population were calculated.
Time frame: baseline to day 98
Population: As treated population
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| CRx-102 (2.7/180) | Percent Change From Baseline to Day 98 in C-reactive Protein (CRP) Values - As Treated Population | -29.90 percentage of change from baseline | Full Range 18.45 |
| CRx-102 (2.7/360) | Percent Change From Baseline to Day 98 in C-reactive Protein (CRP) Values - As Treated Population | -40.84 percentage of change from baseline | Full Range 66.8 |
| Prednisolone | Percent Change From Baseline to Day 98 in C-reactive Protein (CRP) Values - As Treated Population | 15.92 percentage of change from baseline | Full Range 1453.54 |
| Dipyridamole | Percent Change From Baseline to Day 98 in C-reactive Protein (CRP) Values - As Treated Population | -33.67 percentage of change from baseline | Full Range 30.43 |
| Placebo | Percent Change From Baseline to Day 98 in C-reactive Protein (CRP) Values - As Treated Population | -27.64 percentage of change from baseline | — |
Secondary
To Assess the Efficacy of CRx-102 Compared to Placebo Using ACR 20 Calculated From Baseline to Day 98
Preliminary review of the efficacy dataset revealed that the efficacy dataset was not robust enough to support an extensive formal efficacy analysis as described in the SAP. Therefore, only the CRP values over time and the percent change in CRP values in the As-Treated population were calculated.
Time frame: baseline to 98 Days
Secondary
To Assess the Superiority of CRx-102 Compared to Prednisolone and Dipyridamole Using American College of Rheumatology Rating Scale (20% or More Improvement; ACR20) Calculated From Baseline to Day 98 in Subjects With Active Rheumatoid Arthritis
Preliminary review of the efficacy dataset revealed that the efficacy dataset was not robust enough to support an extensive formal efficacy analysis as described in the SAP. Therefore, only the CRP values over time and the percent change in CRP values in the As-Treated population were calculated.
Time frame: baseline to day 98