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

• Sponsor: Zalicus (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00551707
• Collaborator: (none)
• Enrollment: 51
• Locations: 48
• Arms: 5
• Duration (Months): 15
• Patients Per Site: 1.1
• Patients Per Site Per Month: 0.1

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 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
• 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: Oct 1, 2007
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Jan 1, 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 Names: 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 Names: prednisolone 2.7 mg plus dipyridamole 180 mg ; Drug: CRx-102 (2.7/360); Prednisolone 2.7 mg plus Dipyridamole 360 mg; Other Names: 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 Names: 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 [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 [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 [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 [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Huntsville	Alabama	United States
3		Phoenix	Arizona	United States
4		Little Rock	Arkansas	United States
5		Anaheim	California	United States
6		La Jolla	California	United States
7		Westlake Village	California	United States
8		Palm Harbor	Florida	United States
9		Elizabethtown	Kentucky	United States
10		Haddon Heights	New Jersey	United States
11		Mayfield Village	Ohio	United States
12		Oklahoma City	Oklahoma	United States
13		Dallas	Texas	United States
14		Rosario	Santa Fe	Argentina
15		Buenos Aires		Argentina
16		San Jan		Argentina
17		San Miguel de Tucuman		Argentina
18		Winnipeg	Manitoba	Canada
19		St. John's	Newfoundland and Labrador	Canada
20		Hamilton	Ontario	Canada
21		Windsor	Ontario	Canada
22		Tallinn		Estonia
23		Tartu		Estonia
24		Bekescsaba		Hungary
25		Esztergom		Hungary
26		Szolnok		Hungary
27		Kaunas		Lithuania
28		Vilnius		Lithuania
29		Aguas Calientes	Aguascalientes	Mexico
30		Vallarta Norte	Guadalajara	Mexico
31		Bialystok		Poland
32		Elblag		Poland
33		Katowice		Poland
34		Krakow		Poland
35		Lublin		Poland
36		Poznan		Poland
37		Torun		Poland
38		Warszawa		Poland
39		Bucuresti		Romania
40		Cluj Napoca		Romania
41		Timisoara		Romania
42		Moscow		Russian Federation
43		St. Petersburg		Russian Federation
44		Belgrade		Serbia
45		Niska Banja		Serbia
46		Pretoria	Gauteng	South Africa
47		Cape Town	Western Cape	South Africa
48		Worcester	Western Cape	South Africa

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: NCT00551707
• Other Study ID Numbers: CRx-102-007
• First Posted: Oct 31, 2007
• Last Update Posted: Apr 29, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by Zalicus: CombinatoRx; CRx-102; Rheumatoid Arthritis; Prednisolone; Dipyridamole; ACR20
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Dipyridamole; Prednisolone hemisuccinate; Prednisolone phosphate

Study Results

Participant Flow

Arm/Group Title	CRx-102 (2.7/180)	CRx-102 (2.7/360)	Prednisolone	Dipyridamole	Placebo
Arm/Group Description	CRx-102 dose 1 2.7 mg prednisolone plus 180 mg dipyridamole	Crx-102 (Dose 2) 2.7 mg prednisolone plus 360 mg dipyridamole	prednisolone prednisolone: prednisolone (2.7 mg)	dipyridamole dipyridamole: dipyridamole (360 mg)	placebo placebo: placebo
Period Title: Overall Study
STARTED	4	22	13	8	4
COMPLETED	4	16	10	4	3
NOT COMPLETED	0	6	3	4	1

Baseline Characteristics

Arm/Group Title	CRx-102 (2.7/180)	CRx-102 (2.7/360)	Prednisolone	Dipyridamole	Placebo	Total
Arm/Group Description	Crx-102 (Dose 1) 2.7 mg prednisolone plus 180 mg dipyridamole	Crx-102 (Dose 2) 2.7 mg prednisolone plus 360 mg dipyridamole	prednisolone prednisolone: prednisolone (2.7 mg)	dipyridamole dipyridamole: dipyridamole (180 mg or 360 mg)	placebo placebo: placebo	Total of all reporting groups
Overall Participants	4	22	13	8	4	51
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.8 (5.50)	56.2 (11.96)	55.8 (11.32)	56.5 (12.76)	58.8 (9.54)	56.0 (11.09)
Sex: Female, Male (Count of Participants)
Female	2 50%	18 81.8%	5 38.5%	7 87.5%	3 75%	35 68.6%
Male	2 50%	4 18.2%	8 61.5%	1 12.5%	1 25%	16 31.4%

Outcome Measures

1. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

As treated population

Arm/Group Title	CRx-102 (2.7/180)	CRx-102 (2.7/360)	Prednisolone	Dipyridamole	Placebo
Arm/Group Description	CRx-102 dose 1 2.7 mg prednisolone plus 180 mg dipyridamole	Crx-102 (Dose 2) 2.7 mg prednisolone plus 360 mg dipyridamole	prednisolone prednisolone: prednisolone (2.7 mg)	dipyridamole dipyridamole: dipyridamole (360 mg)	placebo placebo: placebo
Measure Participants	4	16	10	4	3
Median (Full Range) [percentage of change from baseline]	-29.90 (18.45)	-40.84 (66.80)	15.92 (1453.54)	-33.67 (30.43)	-27.64

2. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Primary Outcome

Title	Absolute C-reactive Protein (CRP) Values at Day 98 - As Treated Population
Description	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

Outcome Measure Data

Analysis Population Description

As treated population

Arm/Group Title	CRx-102 (2.7/180)	CRx-102 (2.7/360)	Prednisolone	Dipyridamole	Placebo
Arm/Group Description	Crx-102 (Dose 1) 2.7 mg prednisolone plus 180 mg dipyridamole	Crx-102 (Dose 2) 2.7 mg prednisolone plus 360 mg dipyridamole	prednisolone prednisolone: prednisolone (2.7 mg)	dipyridamole dipyridamole: dipyridamole 360 mg	placebo placebo: placebo
Measure Participants	4	16	10	4	3
Median (Full Range) [mg/L]	12.85 (5.39)	14.25 (15.52)	21.85 (27.10)	16.60 (16.22)	2.68 (4.88)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From subject entry into the study (defined as the time at which the informed consent form was signed) to the end of study visit at day 98
Arm/Group Title	CRx-102 (Dose 1)		CRx-102 (Dose 2)		Prednisolone		Dipyridamole		Placebo
Arm/Group Description	Crx-102 (Dose 1) CRx-102: prednisolone + dipyridamole		Crx-102 (Dose 2) CRx-102: prednisolone + dipyridamole		prednisolone prednisolone: prednisolone (2.7 mg)		dipyridamole dipyridamole: dipyridamole (180 mg or 360 mg)		placebo placebo: placebo
All Cause Mortality
	CRx-102 (Dose 1)		CRx-102 (Dose 2)		Prednisolone		Dipyridamole		Placebo
	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
	CRx-102 (Dose 1)		CRx-102 (Dose 2)		Prednisolone		Dipyridamole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/22 (0%)		0/13 (0%)		0/8 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	CRx-102 (Dose 1)		CRx-102 (Dose 2)		Prednisolone		Dipyridamole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		10/22 (45.5%)		2/13 (15.4%)		4/8 (50%)		2/4 (50%)
Gastrointestinal disorders
Nausea	0/4 (0%)		0/22 (0%)		0/13 (0%)		2/8 (25%)		1/4 (25%)
Dyspepsia	0/4 (0%)		1/22 (4.5%)		0/13 (0%)		0/8 (0%)		1/4 (25%)
General disorders
Oedema Peripheral	0/4 (0%)		2/22 (9.1%)		0/13 (0%)		0/8 (0%)		0/4 (0%)
Infections and infestations
Upper respiratory tract infection	0/4 (0%)		1/22 (4.5%)		1/13 (7.7%)		0/8 (0%)		0/4 (0%)
Nervous system disorders
Headache	0/4 (0%)		6/22 (27.3%)		1/13 (7.7%)		2/8 (25%)		2/4 (50%)

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 less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.