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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Prednisolone | Active Comparator | Prednisolone 2.7 mg daily for 12 weeks |
|
| dipyridamole | Active Comparator | Dipyridamole 360 mg daily for 12 weeks |
|
| prednisone | Active Comparator | Prednisone 5 mg daily for 12 weeks |
|
| Z102 (2.7/360) | Experimental | Prednisolone 2.7 mg plus dipyridamole 360 mg daily for 12 weeks |
|
| placebo | Placebo Comparator | Placebo daily for 12 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Prednisolone | Drug | Prednisolone 2.7 mg daily |
| |
| dipyridamole |
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Margaret Lee, PhD | Zalicus, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Zalicus Investigational Site | Toledo | Ohio | 43606 | United States |
A total of 294 subjects entered the titration phase. Of these, 258 subjects completed the titration phase, were randomized to treatment, received at least one dose of study drug and constitute the safety population. Of these, 252 subjects provided at least one post-baseline measurement of the primary endpoint and constitute the efficacy population.
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| ID | Title | Description |
|---|---|---|
| FG000 | Prednisolone | Prednisolone 2.7 mg once daily |
| FG001 | Dipyridamole | dipyridamole 360 mg once daily |
| FG002 | Prednisone | Prednisone 5 mg once daily |
| FG003 | Z102 | 2.7 mg prednisolone plus 360 mg dipyridamole once daily |
| FG004 | Placebo | placebo once daily |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
population randomized to double blind phase of study and recieved at least one dose of study drug
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| ID | Title | Description |
|---|---|---|
| BG000 | Prednisolone | Prednisolone 2.7 mg once daily The trial would progress from Stage 1 to Stage 2 if the posterior probability that Z102 is superior to placebo was greater than 0.975. |
| BG001 | Dipyridamole |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | The efficacy analysis population includes all 252 subjects who received at least one dose of study drug after randomization and who provided at least one post-baseline measurement of the primary endpoint | Posted | Mean | Standard Deviation | units on a scale | baseline to week 12 |
Adverse event data were collected from the time of consent through the end of study visit at 12 weeks.
Adverse events are reported for the safety population of 258 subjects randomized to the double blind study phase and who received at least one dose of study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Prednisolone | Prednisolone 2.7 mg daily |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Sciatica | Nervous system disorders | MedDRA (14.0) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA (14.0) | Non-systematic Assessment |
The study did not progress past the first stage of adaptive randomization. The number of subjects allocated to the dipyridamole 360 mg, prednisolone 2.7 mg, and prednisone 5 mg arms was insufficient to allow analysis of the secondary objectives.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Margaret Lee,PhD | Zalicus | 617-301-7142 | mlee@zalicus.com |
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| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
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| ID | Term |
|---|---|
| D011239 | Prednisolone |
| D004176 | Dipyridamole |
| D011241 | Prednisone |
| ID | Term |
|---|---|
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
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| Drug |
dipyridamole 360 mg daily |
|
| Prednisone | Drug | Prednisone 5 mg daily |
|
| Z102 | Drug | Prednisolone 2.7 mg plus dipyridamole 360 mg daily |
|
|
| placebo | Other |
|
| 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 |
dipyridamole 360 mg once daily The trial would progress from Stage 2 to Stage 3 if the posterior probability that Z102 is superior to dipyridamole was greater than 0.975.
| BG002 | Prednisone | Prednisone 5 mg once daily The trial would progress from Stage 2 to Stage 4 if the posterior probability that Z102 is superior to prednisolone 2.7 was greater than 0.975. |
| BG003 | Z102 | prednisolone 2.7 mg plus dipyridamole 360 mg once daily The trial would progress from Stage 3 to Stage 5 if the posterior probability that Z102 is superior to prednisolone 2.7 was greater than 0.975. |
| BG004 | Placebo | placebo once daily |
| BG005 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| ID | Title | Description |
|---|
| OG000 | Prednisolone | Prednisolone 2.7 mg once daily |
| OG001 | Dipyridamole | dipyridamole 360 mg once daily |
| OG002 | Prednisone | Prednisone 5 mg once daily |
| OG003 | Z102 | prednisolone 2.7 mg plus dipyridamole 360 mg once daily |
| OG004 | Placebo | placebo once daily |
|
|
| Secondary | 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. | Because the study never progressed past the first stage of the adaptive randomization, the number of subjects who were allocated to the dipyridamole 360 mg, prednisolone 2.7 mg, and prednisone 5 mg treatment arms was insufficient (underpowered) to allow analysis of the secondary objectives. | Posted | Baseline to week 12 |
|
|
| Secondary | 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. | Because the study never progressed past the first stage of the adaptive randomization, the number of subjects who were allocated to the dipyridamole 360 mg, prednisolone 2.7 mg, and prednisone 5 mg treatment arms was insufficient (underpowered) to allow analysis of the secondary objectives. | Posted | Week 12 |
|
|
| Secondary | 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. | Because the study never progressed past the first stage of the adaptive randomization, the number of subjects who were allocated to the dipyridamole 360 mg, prednisolone 2.7 mg, and prednisone 5 mg treatment arms was insufficient (underpowered) to allow analysis of the secondary objectives. | Posted | week 12 |
|
|
| Secondary | 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. | Because the study never progressed past the first stage of the adaptive randomization, the number of subjects who were allocated to the dipyridamole 360 mg, prednisolone 2.7 mg, and prednisone 5 mg treatment arms was insufficient (underpowered) to allow analysis of the secondary objectives. | Posted | Baseline to 12 weeks |
|
|
| 1 |
| 32 |
| 6 |
| 32 |
| EG001 | Dipyridamole | dipyridamole 360 mg once daily | 2 | 41 | 30 | 41 |
| EG002 | Prednisone | Prednisone 5 mg once daily | 0 | 18 | 5 | 18 |
| EG003 | Z102 | prednisolone 2.7 mg plus dipyridamole 360 mg once daily | 5 | 84 | 38 | 84 |
| EG004 | Placebo | placebo once daily | 4 | 83 | 33 | 83 |
| Hip Fracture | Injury, poisoning and procedural complications | MedDRA (14.0) | Non-systematic Assessment |
|
| Humerus Fracture | Injury, poisoning and procedural complications | MedDRA (14.0) | Non-systematic Assessment |
|
| Rheumatoid Arthritis | Musculoskeletal and connective tissue disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Haemolytic Anaemia | Blood and lymphatic system disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Ureteric Obstruction | Renal and urinary disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Deep Vein Thrombosis | Vascular disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Angina Pectoris | Cardiac disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Oedema Peripheral | General disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Calculus Ureteric | Renal and urinary disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Sciatica | Nervous system disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Rheumatoid Arthritis | Musculoskeletal and connective tissue disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Abdominal Upper Pain | Gastrointestinal disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Urinary Tract Infection | Infections and infestations | MedDRA (14.0) | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA (14.0) | Non-systematic Assessment |
|
| Rash Pustular | Infections and infestations | MedDRA (14.0) | Non-systematic Assessment |
|
| Respiratory Tract Infection | Infections and infestations | MedDRA (14.0) | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA (14.0) | Non-systematic Assessment |
|
| Oedema Peripheral | General disorders | MedDRA (14.0) | Non-systematic Assessment |
|
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| D003240 |
| Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D000072473 |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011244 | Pregnadienediols |