Multicenter Study to Evaluate CRx-102 vs. Each of Its Components to Treat Active Rheumatoid Arthritis (MARS-1)

• ClinicalTrials.gov Identifier: NCT00551707
• Recruitment Status: Completed
• First Posted: October 31, 2007
• Results First Posted: April 29, 2014
• Last Update Posted: April 29, 2014
• Sponsor: Zalicus
• Information provided by (Responsible Party): Zalicus

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Rheumatoid Arthritis	Drug: CRx-102 (2.7/180); Drug: prednisolone; Drug: dipyridamole; Drug: placebo; Drug: CRx-102 (2.7/360)	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Superiority of CRx-102 Over Each of Its Components When Given to Subjects With Active Rheumatoid Arthritis (RA)
• Study Start Date: October 2007
• Actual Primary Completion Date: November 2008
• Actual Study Completion Date: January 2009

Arms and Interventions

Arm	Intervention/treatment
Experimental: CRx-102 (2.7/180); CRx-102 dose 1 total daily dose during treatment period (days 14-98) 2.7 mg prednisolone plus 180 mg dipyridamole administered as 1.8 mg prednisolone plus 90 mg dipyridamole at 8 AM and 0.9 mg prednisolone plus 90 mg dipyridamole at 1 PM titration dose (days 0-13) 2.7 mg prednisolone plus 90 mg dipyridamole administered as 1.8 mg prednisolone plus 45 mg dipyridamole at 8 AM and 0.9 mg prednisolone plus 45 mg dipyridamole at 1 PM	Drug: CRx-102 (2.7/180); prednisolone 2.7 mg plus dipyridamole 180 mg; Other Name: prednisolone 2.7 mg plus dipyridamole 180 mg
Experimental: CRx-102 (2.7/360); CRx-102 Dose 2 total daily dose during treatment period (days 14-98) 2.7 mg prednisolone plus 360 mg dipyridamole administered as 1.8 mg prednisolone plus 180 mg dipyridamole at 8 AM and 0.9 mg prednisolone plus 180 mg dipyridamole at 1 PM titration dose 1 (days 0-6) 2.7 mg prednisolone plus 90 mg dipyridamole administered as 1.8 mg prednisolone plus 45 mg dipyridamole at 8 AM and 0.9 mg prednisolone plus 45 mg dipyridamole at 1 PM titration dose 2 (days 7-13) 2.7 mg prednisolone plus 180 mg dipyridamole administered as 1.8 mg prednisolone plus 90 mg dipyridamole at 8 AM and 0.9 mg prednisolone plus 90 mg dipyridamole at 1 PM	Drug: CRx-102 (2.7/180); prednisolone 2.7 mg plus dipyridamole 180 mg; Other Name: prednisolone 2.7 mg plus dipyridamole 180 mg; Drug: CRx-102 (2.7/360); Prednisolone 2.7 mg plus Dipyridamole 360 mg; Other Name: Prednisolone 2.7 mg plus Dipyridamole 360 mg
Active Comparator: Prednisolone; treatment dose ( days 0-98) total daily dose of 2.7 mg prednisolone administered as 1.8 mg prednisolone at 8 AM and 0.9 mg prednisolone at 1 PM	Drug: prednisolone; prednisolone (2.7 mg)
Active Comparator: Dipyridamole; total daily dose during treatment period (days 14-98) 360 mg dipyridamole administered as 180 mg dipyridamole at 8 AM and and 180 mg dipyridamole at 1 PM titration dose 1 (days 0-6) 90 mg dipyridamole administered 45 mg dipyridamole at 8 AM and 45 mg dipyridamole at 1 PM titration dose 2 (days 7-13) 180 mg dipyridamole administered as 90 mg dipyridamole at 8 AM and 90 mg dipyridamole at 1 PM	Drug: dipyridamole; dipyridamole 360 mg; Other Name: dipyridamole 360 mg
Placebo Comparator: Placebo; placebo administered twice per day at 8 AM and 1 PM	Drug: placebo; placebo

Outcome Measures

Primary Outcome Measures :

1. Absolute C-reactive Protein (CRP) Values at Day 98 - As Treated Population [ Time Frame: 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 Outcome Measures :

1. Percent Change From Baseline to Day 98 in C-reactive Protein (CRP) Values - As Treated Population [ Time Frame: 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.
2. 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 [ Time Frame: 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.
3. To Assess the Efficacy of CRx-102 Compared to Placebo Using ACR 20 Calculated From Baseline to Day 98 [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Alabama

Birmingham, Alabama, United States

Huntsville, Alabama, United States

United States, Arizona

Phoenix, Arizona, United States

United States, Arkansas

Little Rock, Arkansas, United States

United States, California

Anaheim, California, United States

La Jolla, California, United States

Westlake Village, California, United States

United States, Florida

Palm Harbor, Florida, United States

United States, Kentucky

Elizabethtown, Kentucky, United States

United States, New Jersey

Haddon Heights, New Jersey, United States

United States, Ohio

Mayfield Village, Ohio, United States

United States, Oklahoma

Oklahoma City, Oklahoma, United States

United States, Texas

Dallas, Texas, United States

Argentina

Rosario, Santa Fe, Argentina

Buenos Aires, Argentina

San Jan, Argentina

San Miguel de Tucuman, Argentina

Canada, Manitoba

Winnipeg, Manitoba, Canada

Canada, Newfoundland and Labrador

St. John's, Newfoundland and Labrador, Canada

Canada, Ontario

Hamilton, Ontario, Canada

Windsor, Ontario, Canada

Estonia

Tallinn, Estonia

Tartu, Estonia

Hungary

Bekescsaba, Hungary

Esztergom, Hungary

Szolnok, Hungary

Lithuania

Kaunas, Lithuania

Vilnius, Lithuania

Mexico

Aguas Calientes, Aguascalientes, Mexico

Vallarta Norte, Guadalajara, Mexico

Poland

Bialystok, Poland

Elblag, Poland

Katowice, Poland

Krakow, Poland

Lublin, Poland

Poznan, Poland

Torun, Poland

Warszawa, Poland

Romania

Bucuresti, Romania

Cluj Napoca, Romania

Timisoara, Romania

Russian Federation

Moscow, Russian Federation

St. Petersburg, Russian Federation

Serbia

Belgrade, Serbia

Niska Banja, Serbia

South Africa

Pretoria, Gauteng, South Africa

Cape Town, Western Cape, South Africa

Worcester, Western Cape, South Africa

Sponsors and Collaborators

Zalicus

Investigators

• Study Director: Margaret Lee, PhD; Zalicus

More Information

• Responsible Party: Zalicus
• ClinicalTrials.gov Identifier: NCT00551707
• Other Study ID Numbers: CRx-102-007
• First Posted: October 31, 2007
• Results First Posted: April 29, 2014
• Last Update Posted: April 29, 2014
• Last Verified: March 2014

Keywords provided by Zalicus:

CombinatoRx; CRx-102; Rheumatoid Arthritis; Prednisolone; Dipyridamole; ACR20

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Dipyridamole; Prednisolone hemisuccinate; Prednisolone phosphate; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Neuroprotective Agents; Protective Agents; Phosphodiesterase Inhibitors