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A Phase II Trial Comparing Z-102 With Placebo In Patients With Moderate To Severe Rheumatoid Arthritis (Synergy)

Primary Purpose

Rheumatoid Arthritis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Prednisolone
dipyridamole
Prednisone
Z102
placebo
Sponsored by
Zalicus
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring Rheumatoid Arthritis, Moderate to severe

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Meet the ACR / EULAR criteria for classification of RA
  • Have moderate to severe RA, defined as involving a minimum (≥6 total swollen and ≥6 total tender) of the 28 joints assessed
  • Have screening CRP levels of at least 0.6 mg/dl and a DAS28-CRP score ≥4.5
  • Have been on a stable dose of conventional DMARD therapy for at least 90 days without dosage adjustment or modification and should be able to maintain the same dose of conventional DMARD therapy during study participation (with or without glucocorticoid therapy

Exclusion Criteria:

  • Treatment-refractory patients are excluded
  • Has active cardiovascular disease, unless well controlled by appropriate treatment for a minimum of 3 months prior to screening
  • Is taking aspirin for reasons other than for cardiovascular prophylaxis or their total daily dose is greater than 325 mg
  • Is currently taking steroids at a daily prednisone dose, or the equivalent, of >10 mg
  • Intraarticular, intramuscular, or intravenous glucocorticoids must not have been given at least 6 weeks prior to entering the study
  • The need to continue the use of one or multiple NSAID's at the same time, or the use of acetaminophen on a chronic basis
  • All opiate use is prohibited
  • Use of any other medications or herbs used for the treatment of pain is prohibited
  • Patients with a history of or currently active tuberculosis as per specific country guidelines are excluded
  • Has uncontrolled diabetes mellitus as defined by a serum glucose >126 mg/dl
  • Knowingly has HIV infection or hepatitis
  • Has undergone administration of any investigational drug within 30 days of study initiation
  • All biologic agents are excluded for 90 days prior to Screening and throughout the study.
  • Has undergone administration of rituximab or any B-cell depleting investigational drugs within 6 months of study initiation
  • Has had a history of alcohol or drug abuse within the past 2 years
  • Has a history of hypersensitivity to glucocorticoids and/or dipyridamole

Sites / Locations

  • Zalicus Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Active Comparator

Active Comparator

Active Comparator

Experimental

Placebo Comparator

Arm Label

Prednisolone

dipyridamole

prednisone

Z102 (2.7/360)

placebo

Arm Description

Prednisolone 2.7 mg daily for 12 weeks

Dipyridamole 360 mg daily for 12 weeks

Prednisone 5 mg daily for 12 weeks

Prednisolone 2.7 mg plus dipyridamole 360 mg daily for 12 weeks

Placebo daily for 12 weeks

Outcomes

Primary Outcome Measures

Change From Baseline in DAS28-CRP at 12 Weeks
The primary efficacy endpoint was the mean change in Disease Activity Score 28 using C-reactive protein (DAS28-CRP) from baseline to Week 12. The DAS28-CRP is a composite measure of inflammation in Rheumatoid Arthritis and incorporates a tender and swollen joint count, CRP and Patient Global Assessment of Disease Activity expressed in a Gaussian distribution of variables ranging from 0 to 10. A DAS28-CRP score of <3.2 suggests a low level of disease activity, while a score of >5.1 suggests a high level of disease activity. Using the DAS-CRP as a continuous scale allows investigators (and clinicians) to measure a clinically meaningful endpoint following institution of a therapeutic intervention. In RA, clinical remission would therefore be graded as a DAS28 score of ≤3.2 with disease flare accompanying scores of ≥5.1; well-controlled disease is best characterized as fitting in between these two scores.

Secondary Outcome Measures

Change From Baseline in DAS28-CRP Individual Components at 12 Weeks
The mean change in the individual components of the Disease Activity Score 28 using C-reactive protein (DAS28-CRP) from baseline to Week 12 which included individual assessment of Tender Joint Count (28-joint assessment), Swollen Joint Count (28-joint assessment), Patient Global Assessment of Disease Activity and absolute CRP level. In each case, higher scores indicate more disease activity. The DAS28-CRP is a composite measure of inflammation in Rheumatoid Arthritis and incorporates a tender and swollen joint count, CRP and Patient Global Assessment of Disease Activity expressed in a Gaussian distribution of variables ranging from 0 to 10. A DAS28-CRP score of <3.2 suggests a low level of disease activity, while a score of >5.1 suggests a high level of disease activity.
Percentage of Subjects Achieving ACR20, ACR50 and ACR70 at 12 Weeks
The American College of Rheumatology (ACR) 20 is a widely accepted composite index of improvement in RA proposed by the ACR (Fransen and van Riel 2009). ACR20 refers to a composite improvement of 20% in swollen joint count, tender joint count, and 3 or more of the following 5 measures:Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, Patient Pain VAS, Patient's self-addressed disability (HAQ) (Arnet 1988 and Felson 1995), Acute-phase reactant (ESR or CRP) The ACR 50 and ACR 70 are similar tools, used to indicate 50% and 70% improvement, respectively.
Multidimensional Assessment of Fatigue (MAF) at Week 12
The Multidimensional Assessment of Fatigue (MAF) scale contains 16 items and measures four dimensions of fatigue: severity (#1-2), distress (#3), degree of interference in activities of daily living (#4-14), and timing (#15-16). Fourteen items contain numerical rating scales (#1-14) and two items have multiple-choice responses (#15-16). Respondents are asked to reflect on fatigue patterns for the past week. To calculate the Global Fatigue Index (GFI): Convert item #15 to a 0-10 scale by multiplying each score by 2.5 and then sum items #1, 2, 3, average #4-14, and newly scored item #15. Scores range from 1 (no fatigue) to 50 (severe fatigue). Do not assign a score to items #4-14 if respondent indicated they "do not do any activity for reasons other than fatigue." If respondents select no fatigue on item #1, assign a zero to items #2-16. Item #16 is not included in the Global Fatigue Index.
Time to Failure (Days)
Patients will be monitored for addition of any DMARD or withdrawal due to flare. The time to failure is defined as the duration of study participation (in days) until a qualifying event or completion of study treatment, whichever comes first.

Full Information

First Posted
June 7, 2011
Last Updated
April 29, 2014
Sponsor
Zalicus
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1. Study Identification

Unique Protocol Identification Number
NCT01369745
Brief Title
A Phase II Trial Comparing Z-102 With Placebo In Patients With Moderate To Severe Rheumatoid Arthritis
Acronym
Synergy
Official Title
A Phase II, Double-Blind, Placebo-Controlled, Multi-Center, Randomized Withdrawal Design Trial Using Adaptive Randomization Comparing Z-102 With Placebo In Patients With Moderate To Severe Rheumatoid Arthritis
Study Type
Interventional

2. Study Status

Record Verification Date
April 2014
Overall Recruitment Status
Completed
Study Start Date
June 2011 (undefined)
Primary Completion Date
August 2012 (Actual)
Study Completion Date
September 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Zalicus

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Thus study will test an experimental drug called Z-102 (combination of prednisolone and dipyridamole) to treat patients with moderate to severe rheumatoid arthritis.
Detailed Description
The primary objective of the study was to demonstrate the efficacy of Z102 (2.7 mg prednisolone/360 mg dipyridamole) versus placebo on the Disease Activity Score 28 using C reactive protein (DAS28-CRP) in subjects with rheumatoid arthritis at the study endpoint of 12 weeks

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
Keywords
Rheumatoid Arthritis, Moderate to severe

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
294 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Prednisolone
Arm Type
Active Comparator
Arm Description
Prednisolone 2.7 mg daily for 12 weeks
Arm Title
dipyridamole
Arm Type
Active Comparator
Arm Description
Dipyridamole 360 mg daily for 12 weeks
Arm Title
prednisone
Arm Type
Active Comparator
Arm Description
Prednisone 5 mg daily for 12 weeks
Arm Title
Z102 (2.7/360)
Arm Type
Experimental
Arm Description
Prednisolone 2.7 mg plus dipyridamole 360 mg daily for 12 weeks
Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
Placebo daily for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Prednisolone
Intervention Description
Prednisolone 2.7 mg daily
Intervention Type
Drug
Intervention Name(s)
dipyridamole
Intervention Description
dipyridamole 360 mg daily
Intervention Type
Drug
Intervention Name(s)
Prednisone
Intervention Description
Prednisone 5 mg daily
Intervention Type
Drug
Intervention Name(s)
Z102
Other Intervention Name(s)
prednisolone, dipyridamole
Intervention Description
Prednisolone 2.7 mg plus dipyridamole 360 mg daily
Intervention Type
Other
Intervention Name(s)
placebo
Primary Outcome Measure Information:
Title
Change From Baseline in DAS28-CRP at 12 Weeks
Description
The primary efficacy endpoint was the mean change in Disease Activity Score 28 using C-reactive protein (DAS28-CRP) from baseline to Week 12. The DAS28-CRP is a composite measure of inflammation in Rheumatoid Arthritis and incorporates a tender and swollen joint count, CRP and Patient Global Assessment of Disease Activity expressed in a Gaussian distribution of variables ranging from 0 to 10. A DAS28-CRP score of <3.2 suggests a low level of disease activity, while a score of >5.1 suggests a high level of disease activity. Using the DAS-CRP as a continuous scale allows investigators (and clinicians) to measure a clinically meaningful endpoint following institution of a therapeutic intervention. In RA, clinical remission would therefore be graded as a DAS28 score of ≤3.2 with disease flare accompanying scores of ≥5.1; well-controlled disease is best characterized as fitting in between these two scores.
Time Frame
baseline to week 12
Secondary Outcome Measure Information:
Title
Change From Baseline in DAS28-CRP Individual Components at 12 Weeks
Description
The mean change in the individual components of the Disease Activity Score 28 using C-reactive protein (DAS28-CRP) from baseline to Week 12 which included individual assessment of Tender Joint Count (28-joint assessment), Swollen Joint Count (28-joint assessment), Patient Global Assessment of Disease Activity and absolute CRP level. In each case, higher scores indicate more disease activity. The DAS28-CRP is a composite measure of inflammation in Rheumatoid Arthritis and incorporates a tender and swollen joint count, CRP and Patient Global Assessment of Disease Activity expressed in a Gaussian distribution of variables ranging from 0 to 10. A DAS28-CRP score of <3.2 suggests a low level of disease activity, while a score of >5.1 suggests a high level of disease activity.
Time Frame
Baseline to week 12
Title
Percentage of Subjects Achieving ACR20, ACR50 and ACR70 at 12 Weeks
Description
The American College of Rheumatology (ACR) 20 is a widely accepted composite index of improvement in RA proposed by the ACR (Fransen and van Riel 2009). ACR20 refers to a composite improvement of 20% in swollen joint count, tender joint count, and 3 or more of the following 5 measures:Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, Patient Pain VAS, Patient's self-addressed disability (HAQ) (Arnet 1988 and Felson 1995), Acute-phase reactant (ESR or CRP) The ACR 50 and ACR 70 are similar tools, used to indicate 50% and 70% improvement, respectively.
Time Frame
Week 12
Title
Multidimensional Assessment of Fatigue (MAF) at Week 12
Description
The Multidimensional Assessment of Fatigue (MAF) scale contains 16 items and measures four dimensions of fatigue: severity (#1-2), distress (#3), degree of interference in activities of daily living (#4-14), and timing (#15-16). Fourteen items contain numerical rating scales (#1-14) and two items have multiple-choice responses (#15-16). Respondents are asked to reflect on fatigue patterns for the past week. To calculate the Global Fatigue Index (GFI): Convert item #15 to a 0-10 scale by multiplying each score by 2.5 and then sum items #1, 2, 3, average #4-14, and newly scored item #15. Scores range from 1 (no fatigue) to 50 (severe fatigue). Do not assign a score to items #4-14 if respondent indicated they "do not do any activity for reasons other than fatigue." If respondents select no fatigue on item #1, assign a zero to items #2-16. Item #16 is not included in the Global Fatigue Index.
Time Frame
week 12
Title
Time to Failure (Days)
Description
Patients will be monitored for addition of any DMARD or withdrawal due to flare. The time to failure is defined as the duration of study participation (in days) until a qualifying event or completion of study treatment, whichever comes first.
Time Frame
Baseline to 12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Meet the ACR / EULAR criteria for classification of RA Have moderate to severe RA, defined as involving a minimum (≥6 total swollen and ≥6 total tender) of the 28 joints assessed Have screening CRP levels of at least 0.6 mg/dl and a DAS28-CRP score ≥4.5 Have been on a stable dose of conventional DMARD therapy for at least 90 days without dosage adjustment or modification and should be able to maintain the same dose of conventional DMARD therapy during study participation (with or without glucocorticoid therapy Exclusion Criteria: Treatment-refractory patients are excluded Has active cardiovascular disease, unless well controlled by appropriate treatment for a minimum of 3 months prior to screening Is taking aspirin for reasons other than for cardiovascular prophylaxis or their total daily dose is greater than 325 mg Is currently taking steroids at a daily prednisone dose, or the equivalent, of >10 mg Intraarticular, intramuscular, or intravenous glucocorticoids must not have been given at least 6 weeks prior to entering the study The need to continue the use of one or multiple NSAID's at the same time, or the use of acetaminophen on a chronic basis All opiate use is prohibited Use of any other medications or herbs used for the treatment of pain is prohibited Patients with a history of or currently active tuberculosis as per specific country guidelines are excluded Has uncontrolled diabetes mellitus as defined by a serum glucose >126 mg/dl Knowingly has HIV infection or hepatitis Has undergone administration of any investigational drug within 30 days of study initiation All biologic agents are excluded for 90 days prior to Screening and throughout the study. Has undergone administration of rituximab or any B-cell depleting investigational drugs within 6 months of study initiation Has had a history of alcohol or drug abuse within the past 2 years Has a history of hypersensitivity to glucocorticoids and/or dipyridamole
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Margaret Lee, PhD
Organizational Affiliation
Zalicus, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Zalicus Investigational Site
City
Toledo
State/Province
Ohio
ZIP/Postal Code
43606
Country
United States

12. IPD Sharing Statement

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A Phase II Trial Comparing Z-102 With Placebo In Patients With Moderate To Severe Rheumatoid Arthritis

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