CRx-102 Osteoarthritis Multicenter Evaluation Trial

Phase 2

Terminated

Conditions: Knee Osteoarthritis

Interventions: Drug: CRx-102 (2.7/90)
Drug: CRx-102 (2.7/180)
Drug: Placebo
Drug: Prednisolone
Drug: CRx-102 (2.7/360)

Registration Number: NCT00521989

Lead Sponsor: Zalicus

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 OA and RA. This is the first study to explore the efficacy of CRx-102 in knee OA. It is considered a dose-finding study and will also compare the potential benefits of CRx-102 treatment to both prednisolone administered alone and to placebo in this indication.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 279

Inclusion Criteria

Subject must voluntarily give written informed consent
Subject must be ≥ 40 years of age
Knee pain for at least 6 months requiring NSAIDs or Coxibs for analgesia on the majority of days (≥ 15 days) during the preceding month
WOMAC pain score when walking on a flat surface (question #1) between 30-80 mm at Screening with at least a 10 mm increase following NSAID or Coxib discontinuation during the Screening period
Radiographic evidence of knee OA (Kellgren-Lawrence grade 2 or 3)
Functional class I, II, or III according to the American Rheumatism Association
Subject willing to take a multivitamin or the equivalent of at least 400 IU vitamin D and the equivalent of at least 1000 mg of elemental calcium daily

Exclusion Criteria

Predominant patellofemoral disease or clinically significant trauma to index knee
History of clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, osteoporotic and/or other major disease
History of malignancy within the past 10 years (except for excised or treated basal cell or fewer than 3 squamous cell skin carcinomas)
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/or cosmetic procedures)
History of drug or alcohol abuse (as defined by the Investigator)
History of bleeding disorder
History of GI bleeding within 5 years of Screening
History of severe migraines or headaches
History of glaucoma
Visually compromising cataract
Active diabetic retinopathy
History of osteoporotic fracture
History of opportunistic infection
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 (HCV) antibody
Positive for hepatitis B surface antigen (HBsAg)
Known positive history for human immunodeficiency virus (HIV) antibody
Surgery on the index knee within 1 year of Screening
History of hypersensitivity to steroids or dipyridamole
Treatment with oral, intramuscular, or intravenous glucocorticoids within 6 weeks prior to Screening; intra-articular glucocorticoids within 10 weeks prior to Screening; inhaled glucocorticoid is permitted
Treatment with injectable hyaluronic acid within 3 months of Screening
Treatment with another investigational drug, investigational device, or approved therapy for investigational use within 30 days prior to Screening
Treatment with NSAIDs (oral or topical), Coxibs or topical capsaicin
Treatment with anticoagulants including: dipyridamole, warfarin, clopidogrel, ticlopidine, or ASA > 81 mg per day
Treatment with any concomitant medications that have not been at a stable dose for at least 28 days prior to Screening
Treatment for osteoporosis such as bisphosphonates (e.g., Fosamax®, Actonel®), or teriparatide (e.g., Forteo®), or calcitonin (e.g., Miacalcin, Calcimar) must be at stable dosages for at least 3 months prior to Screening
ALT or AST laboratory values >1.5 X the ULN
HgbA1c value of >7.0%
Current enrollment in any other study with investigational drug or device
Female subject who is pregnant or lactating
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CRx-102 (2.7/90)	CRx-102 (2.7/90)	2.7 mg prednisolone plus 90 mg dipyridamole Subjects were dose twice daily through day 98. Prednisolone at 2.7 mg/d was administered as 1.8 mg at 8AM and 0.9 mg at 1PM. The dipyridamole dose was divided equally between the two time points, 8AM and 1PM
CRx-102 (2.7/180)	CRx-102 (2.7/180)	2.7 mg prednisolone plus 180 mg dipyridamole Subjects were dose twice daily through day 98. Prednisolone at 2.7 mg/d was administered as 1.8 mg at 8AM and 0.9 mg at 1PM. The dipyridamole dose was divided equally between the two time points, 8AM and 1PM
CRx-102 (2.7/360)	CRx-102 (2.7/90)	2.7 mg prednisolone plus 360 mg dipyridamole Subjects were dose twice daily through day 98. Prednisolone at 2.7 mg/d was administered as 1.8 mg at 8AM and 0.9 mg at 1PM. The dipyridamole dose was divided equally between the two time points, 8AM and 1PM
CRx-102 (2.7/360)	CRx-102 (2.7/360)	2.7 mg prednisolone plus 360 mg dipyridamole Subjects were dose twice daily through day 98. Prednisolone at 2.7 mg/d was administered as 1.8 mg at 8AM and 0.9 mg at 1PM. The dipyridamole dose was divided equally between the two time points, 8AM and 1PM
Placebo	Placebo	Placebo Subjects were dose twice daily through day 98.
Prednisolone	Prednisolone	2.7 mg prednisolone Subjects were dose twice daily through day 98. Prednisolone at 2.7 mg/d was administered as 1.8 mg at 8AM and 0.9 mg at 1PM.

Primary Outcome Measures

Name	Time	Method
Change From Baseline to Day 98 Using the WOMAC Pain Question #1	Baseline to Day 98	The WOMAC Index is a validated, 24-question self-administered assessment of three dimensions of pain, stiffness, and physical function for subjects with knee or hip OA. The WOMAC pain question #1 asks subjects to "think about the pain you felt in your (study joint) caused by your arthritis during the last 48 hours when walking on a flat surface." This is a visual analog scale (VAS) where the subject indicates pain severity by making a mark through a 100 mm horizontal line with "No Pain" on the left (0 mm) and "Extreme Pain" on the right (100 mm). The distance between the left end of the scale and the subject's mark is measured in millimeters. Lower values represent a better outcome.

Secondary Outcome Measures

Name	Time	Method
To Assess the Efficacy of the CRx-102 Compared to Placebo on the Change From Baseline to Day 98 Using the Full WOMAC Pain, Stiffness, Physical Function Parameters, and Patient Global Assessment VAS.	Day 98