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

Condition(s) targeted: Rheumatoid Arthritis

Intervention: CRx-102 (2.7/180) (Drug); prednisolone (Drug); dipyridamole (Drug); placebo (Drug); CRx-102 (2.7/360) (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: Zalicus

Official(s) and/or principal investigator(s):
Margaret Lee, PhD, Study Director, Affiliation: Zalicus

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.

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Absolute C-reactive Protein (CRP) Values at Day 98 - As Treated Population

Secondary outcome:

Percent Change From Baseline to Day 98 in C-reactive Protein (CRP) Values - As Treated Population

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

To Assess the Efficacy of CRx-102 Compared to Placebo Using ACR 20 Calculated From Baseline to Day 98

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Buenos Aires, Argentina

San Jan, Argentina

San Miguel de Tucuman, Argentina

Tallinn, Estonia

Tartu, Estonia

Bekescsaba, Hungary

Esztergom, Hungary

Szolnok, Hungary

Kaunas, Lithuania

Vilnius, Lithuania

Bialystok, Poland

Elblag, Poland

Katowice, Poland

Krakow, Poland

Lublin, Poland

Poznan, Poland

Torun, Poland

Warszawa, Poland

Bucuresti, Romania

Cluj Napoca, Romania

Timisoara, Romania

Moscow, Russian Federation

St. Petersburg, Russian Federation

Belgrade, Serbia

Niska Banja, Serbia

Aguas Calientes, Aguascalientes, Mexico

Birmingham, Alabama, United States

Huntsville, Alabama, United States

Phoenix, Arizona, United States

Little Rock, Arkansas, United States

Anaheim, California, United States

La Jolla, California, United States

Westlake Village, California, United States

Palm Harbor, Florida, United States

Pretoria, Gauteng, South Africa

Vallarta Norte, Guadalajara, Mexico

Elizabethtown, Kentucky, United States

Winnipeg, Manitoba, Canada

Haddon Heights, New Jersey, United States

St. John's, Newfoundland and Labrador, Canada

Mayfield Village, Ohio, United States

Oklahoma City, Oklahoma, United States

Hamilton, Ontario, Canada

Windsor, Ontario, Canada

Rosario, Santa Fe, Argentina

Dallas, Texas, United States

Cape Town, Western Cape, South Africa

Worcester, Western Cape, South Africa

Starting date: October 2007
Last updated: March 27, 2014