COMET-1: CRx-102 Osteoarthritis Multicenter Evaluation Trial

• Sponsor: Zalicus (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00521989
• Collaborator: (none)
• Enrollment: 279
• Locations: 58
• Arms: 5
• Duration (Months): 23
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.2

Study Details

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 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.

Condition or Disease	Intervention/Treatment	Phase
Knee Osteoarthritis	Drug: CRx-102 (2.7/90); Drug: Prednisolone; Drug: Placebo; Drug: CRx-102 (2.7/180); Drug: CRx-102 (2.7/360)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 279 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy of CRx-102 in Subjects With Symptomatic Knee Osteoarthritis and Optional One-Year Extension
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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	Drug: CRx-102 (2.7/90); CRx-102 dose 1; Other Names: 2.7 mg prednisolone plus 90 mg dipyridamole
Experimental: 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	Drug: CRx-102 (2.7/180); CRx-102 dose 2; Other Names: Prednisolong 2.7 mg plus dipyridamole 180 mg
Experimental: 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	Drug: CRx-102 (2.7/90); CRx-102 dose 1; Other Names: 2.7 mg prednisolone plus 90 mg dipyridamole ; Drug: CRx-102 (2.7/360); CRx-102 dose 3; Other Names: 2.7 mg prednisolone plus 360 mg dipyridamole
Active Comparator: 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.	Drug: Prednisolone; Prednisolone; Other Names: 2.7 mg prednisolone
Placebo Comparator: Placebo Placebo Subjects were dose twice daily through day 98.	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. 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

1. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Huntsville	Alabama	United States
2		Chandler	Arizona	United States
3		Mesa	Arizona	United States
4		Phoenix	Arizona	United States
5		Tuscon	Arizona	United States
6		Little Rock	Arkansas	United States
7		Anaheim	California	United States
8		Rancho Mirage	California	United States
9		Upland	California	United States
10		Westlake Village	California	United States
11		Deland	Florida	United States
12		Jupiter	Florida	United States
13		Kissimee	Florida	United States
14		Largo	Florida	United States
15		Longwood	Florida	United States
16		Palm Harbor	Florida	United States
17		Sarasota	Florida	United States
18		Tampa	Florida	United States
19		Atlanta	Georgia	United States
20		Paducah	Kentucky	United States
21		Covington	Louisiana	United States
22		Towson	Maryland	United States
23		Brockton	Massachusetts	United States
24		Haverhill	Massachusetts	United States
25		Peabody	Massachusetts	United States
26		Worcester	Massachusetts	United States
27		Bingham Farms	Michigan	United States
28		Missoula	Montana	United States
29		Reno	Nevada	United States
30		Haddon Heights	New Jersey	United States
31		Voorhees	New Jersey	United States
32		Albuquerque	New Mexico	United States
33		New York	New York	United States
34		Plainview	New York	United States
35		Rochester	New York	United States
36		Hickory	North Carolina	United States
37		High Point	North Carolina	United States
38		Winston-Salem	North Carolina	United States
39		Fargo	North Dakota	United States
40		Cincinatti	Ohio	United States
41		Dayton	Ohio	United States
42		Mayfield Village	Ohio	United States
43		Oklahoma City	Oklahoma	United States
44		Eugene	Oregon	United States
45		Duncansville	Pennsylvania	United States
46		Pittsburgh	Pennsylvania	United States
47		W. Reading	Pennsylvania	United States
48		Cumberland	Rhode Island	United States
49		Warwick	Rhode Island	United States
50		Dallas	Texas	United States
51		Houston	Texas	United States
52		San Antonio	Texas	United States
53		Bountiful	Utah	United States
54		Sandy	Utah	United States
55		Roanoke	Virginia	United States
56		Virginia Beach	Virginia	United States
57		Tacoma	Washington	United States
58		Kitchener	Ontario	Canada

Sponsors and Collaborators

• Zalicus

Investigators

• Study Director: Margaret Lee, PhD, Zalicus

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Zalicus
• ClinicalTrials.gov Identifier: NCT00521989
• Other Study ID Numbers: CRx-102-006
• First Posted: Aug 29, 2007
• Last Update Posted: Apr 29, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by Zalicus: Osteoarthritis; Knee; CRx-102; prednisolone; dipyridamole; CombinatoRx; WOMAC
• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Dipyridamole; Prednisolone hemisuccinate; Prednisolone phosphate

Study Results

Participant Flow

Arm/Group Title	CRx-102 (2.7/90 mg)	CRx-102 (2.7/180 mg)	CRx-102 (2.7/360 mg)	Prednisolone	Placebo
Arm/Group Description	CRx-102 (Prednisolone 2.7 mg + Dipyridamole 90 mg) prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3)	CRx-102 Dose 2 (2.7 mg prednisolone + 180 mg dipyridamole) prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3)	CRx-102 Dose 3 (2.7 mg prednisolone + 360 mg dipyridamole) prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3)	Prednisolone 2.7 mg Prednisolone: Prednisolone	Placebo Placebo: Placebo
Period Title: Overall Study
STARTED	56	54	57	54	58
COMPLETED	36	37	41	42	35
NOT COMPLETED	20	17	16	12	23

Baseline Characteristics

Arm/Group Title	CRx-102 (2.7/90 mg)	CRx-102 (2.7/180 mg)	CRx-102 (2.7/360 mg)	Prednisolone	Placebo	Total
Arm/Group Description	CRx-102 (Prednisolone 2.7 mg + Dipyridamole 90 mg) prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3)	CRx-102 Dose 2 (2.7 mg prednisolone + 180 mg dipyridamole) prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3)	CRx-102 Dose 3 (2.7 mg prednisolone + 360 mg dipyridamole) prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3)	Prednisolone 2.7 mg Prednisolone: Prednisolone	Placebo Placebo: Placebo	Total of all reporting groups
Overall Participants	56	54	57	54	58	279
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.1 (9.35)	59.4 (10.02)	57.7 (9.03)	60.2 (8.65)	57.9 (7.46)	59.3 (8.96)
Sex: Female, Male (Count of Participants)
Female	37 66.1%	33 61.1%	38 66.7%	30 55.6%	37 63.8%	175 62.7%
Male	19 33.9%	21 38.9%	19 33.3%	24 44.4%	21 36.2%	104 37.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Day 98 Using the WOMAC Pain Question #1
Description	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.
Time Frame	Baseline to Day 98

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CRx-102 (2.7/90 mg)	CRx-102 (2.7/180 mg)	CRx-102 (2.7/360 mg)	Prednisolone	Placebo
Arm/Group Description	CRx-102 (Prednisolone 2.7 mg + Dipyridamole 90 mg) prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3)	CRx-102 Dose 2 (2.7 mg prednisolone + 180 mg dipyridamole) prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3)	CRx-102 Dose 3 (2.7 mg prednisolone + 360 mg dipyridamole) prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3)	Prednisolone 2.7 mg Prednisolone: Prednisolone	Placebo Placebo: Placebo
Measure Participants	56	54	57	54	58
Mean (Standard Deviation) [millimeters]	-32.4 (27.07)	-33.2 (32.02)	-37.3 (33.07)	-40.4 (30.04)	-34.6 (27.11)

2. Secondary Outcome

Title	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.
Time Frame	Day 98

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Placebo		Prednisolone		CRx-102 (2.7/90 mg)		CRx-102 (2.7/180 mg)		CRx-102 (2.7/360 mg)
Arm/Group Description	Placebo		Prednisolone 2.7 mg		CRx-102 dose 1 (2.7 mg prednisolone + 90 mg dipyridamole)		CRx-102 dose 2 (2.7 mg prednisolone + 180 mg dipyridamole)		CRx-102 dose 3 (2.7 mg prednisolone + 360 mg dipyridamole)
All Cause Mortality
	Placebo		Prednisolone		CRx-102 (2.7/90 mg)		CRx-102 (2.7/180 mg)		CRx-102 (2.7/360 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Prednisolone		CRx-102 (2.7/90 mg)		CRx-102 (2.7/180 mg)		CRx-102 (2.7/360 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/58 (1.7%)		1/54 (1.9%)		2/56 (3.6%)		1/54 (1.9%)		1/57 (1.8%)
Ear and labyrinth disorders
Vertigo	0/58 (0%)		0/54 (0%)		1/56 (1.8%)		0/54 (0%)		0/57 (0%)
General disorders
Chest Pain	0/58 (0%)		0/54 (0%)		0/56 (0%)		0/54 (0%)		1/57 (1.8%)
Hepatobiliary disorders
Cholelithiasis	0/58 (0%)		1/54 (1.9%)		1/56 (1.8%)		0/54 (0%)		0/57 (0%)
Cholecystitis acute	0/58 (0%)		0/54 (0%)		0/56 (0%)		1/54 (1.9%)		0/57 (0%)
Psychiatric disorders
Hallucination, auditory	1/58 (1.7%)		0/54 (0%)		0/56 (0%)		0/54 (0%)		0/57 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Prednisolone		CRx-102 (2.7/90 mg)		CRx-102 (2.7/180 mg)		CRx-102 (2.7/360 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/58 (32.8%)		26/54 (48.1%)		29/56 (51.8%)		29/54 (53.7%)		40/57 (70.2%)
Gastrointestinal disorders
Diarrhea	3/58 (5.2%)		4/54 (7.4%)		2/56 (3.6%)		4/54 (7.4%)		3/57 (5.3%)
Nausea	4/58 (6.9%)		3/54 (5.6%)		0/56 (0%)		4/54 (7.4%)		3/57 (5.3%)
General disorders
Fatigue	0/58 (0%)		1/54 (1.9%)		3/56 (5.4%)		1/54 (1.9%)		0/57 (0%)
Infections and infestations
Upper respiratory tract infection	1/58 (1.7%)		0/54 (0%)		4/56 (7.1%)		1/54 (1.9%)		1/57 (1.8%)
Urinary tract infection	0/58 (0%)		1/54 (1.9%)		3/56 (5.4%)		2/54 (3.7%)		1/57 (1.8%)
Musculoskeletal and connective tissue disorders
Back Pain	1/58 (1.7%)		3/54 (5.6%)		1/56 (1.8%)		1/54 (1.9%)		4/57 (7%)
Nervous system disorders
Headache	10/58 (17.2%)		14/54 (25.9%)		16/56 (28.6%)		17/54 (31.5%)		28/57 (49.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.