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

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Prednisolone
* Drug: dipyridamole
* Drug: Prednisone
* Drug: Z102
* Other: placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prednisolone<br>Prednisolone 2.7 mg daily for 12 weeks | Drug: Prednisolone<br>* Prednisolone 2.7 mg daily<br>|
| Active Comparator: dipyridamole<br>Dipyridamole 360 mg daily for 12 weeks | Drug: dipyridamole<br>* dipyridamole 360 mg daily<br>|
| Active Comparator: prednisone<br>Prednisone 5 mg daily for 12 weeks | Drug: Prednisone<br>* Prednisone 5 mg daily<br>|
| Experimental: Z102 (2.7/360)<br>Prednisolone 2.7 mg plus dipyridamole 360 mg daily for 12 weeks | Drug: Z102<br>* Prednisolone 2.7 mg plus dipyridamole 360 mg daily<br>* Other names: dipyridamole;|
| Placebo Comparator: placebo<br>Placebo daily for 12 weeks | Other: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to week 12 | 
| 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. | Week 12 | 
| 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. | week 12 | 
| 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. | Baseline to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, Moderate to severe