OSKIRA 4 SS: Randomised Double-Blind, Placebo-Controlled, Parallel Group Study in Patients With Active Rheumatoid Arthritis:Magnetic Resonance Imaging Sub-Study
Study Details
Study Description
Brief Summary
This is a sub-study of the OSKIRA-4 study, (D4300C0004, NCT01264770) to explore alternative and more sensitive modalities for measuring the beneficial effects of syk inhibition with fostamatinib in patients with active RA. This MRI sub-study was reported later than the main study due to recruitment delays at specialist imaging sites and so is registered and presented entirely separately to the main study results.
This study will investigate the impact of treatment on joint activity and damage by assessing synovitis, osteitis, bone erosions and joint space narrowing.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Detailed Description
Sub-study to OSKIRA-4: A Phase IIB, Multi-Centre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Fostamatinib Disodium Monotherapy Compared with Placebo or Adalimumab Monotherapy in Patients with Active Rheumatoid Arthritis: Magnetic Resonance Imaging Sub-Study Date: 21 March 2011 Version: 1 Primary objective: Assess the efficacy of fostamatinib in reducing joint synovial disease activity as measured by: - Change from baseline to Week 6 (versus placebo) in OMERACT RAMRIS synovitis score.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Dosing Group A Oral treatment and subcutaneous injection. |
Drug: Fostamatinib
Fostamatinib 100mg twice daily.
Drug: Placebo of Adalimumab
Placebo injection once every two weeks.
|
Active Comparator: Dosing Group D Oral treatment and subcutaneous injection. |
Drug: Adalimumab
Adalimumab 40 mg by subcutaneous injection every 2 weeks for 24 weeks.
Drug: Placebo of Fostamatinib
Placebo bid for 6 weeks.
|
Placebo Comparator: Dosing Group E Placebo bid for 6 weeks followed by switch to 100 mg fostamatinib bid for 24 weeks, plus placebo subcutaneous injection every 2 weeks. |
Drug: Fostamatinib
Fostamatinib 100mg twice daily.
Drug: Placebo of Fostamatinib
Placebo bid for 6 weeks.
Drug: Placebo of Adalimumab
Placebo injection once every two weeks.
|
Outcome Measures
Primary Outcome Measures
- OMERACT RAMRIS Synovitis Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) [Baseline, 6 and 24 weeks]
OMERACT RAMRIS synovitis score was based on 8 joints, scored from MRI images, and ranged from 0 to 24 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, OMERACT = Outcome Measures in Rheumatoid Arthritis Clinical Trials, PO = orally, RAMRIS = Rheumatoid Arthritis Magnetic Resonance Image Scoring system, SC = subcutaneous.
Other Outcome Measures
- OMERACT RAMRIS Osteitis Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) [Baseline, 6 and 24 weeks]
OMERACT RAMRIS osteitis score was based on 25 joints, scored from MRI images, and ranged from 0 to 75 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, OMERACT = Outcome Measures in Rheumatoid Arthritis Clinical Trials, PO = orally, RAMRIS = Rheumatoid Arthritis Magnetic Resonance Image Scoring system, SC = subcutaneous.
- Joint Space Narrowing - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) [Baseline, 6 and 24 weeks]
Joint space narrowing score was based on 20 joints, scored from MRI images and ranged from 0 to 80 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, JSN = joint space narrowing, MRI = magnetic resonance imaging, PO = orally, SC = subcutaneous.
- OMERACT RAMRIS Erosions Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) [Baseline, 6 and 24 weeks]
OMERACT RAMRIS erosions score was based on 25 joints and ranged from 0 to 250 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, OMERACT = Outcome Measures in Rheumatoid Arthritis Clinical Trials, PO = orally, RAMRIS = Rheumatoid Arthritis Magnetic Resonance Image Scoring system, SC = subcutaneous.
- DAS-CRP Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab [Baseline, 6 and 24 weeks]
DAS28-CRP: Disease Activity Score based on a count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (CRP) and the patient's own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. Mean changes from baseline in DAS28-CRP score are shown at each visit and are presented as decreases from baseline (defined as baseline minus post-baseline) with larger changes indicative of a better clinical condition. ANCOVA = analysis of covariance, BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, PO = orally, SC = subcutaneous.
Eligibility Criteria
Criteria
Inclusion Criteria: -
-
Male or female aged 18 and over
-
Active rheumatoid arthritis (RA) diagnosed after the age of 16
-
Diagnosis within 5 years prior to study visit 1 and inadequate response to treatment with a maximum 2 Disease-Modifying anti-rheumatic drug (DMARD) therapies, or
-
diagnosis within 5 years prior to study visit 1 and intolerance to DMARD therapy, or
-
diagnosis within 2 years prior to study visit 1 and no previous use of DMARDs
-
4 or more swollen joints and 4 or more tender/painful joints (from 28 joint count)
-
Either Erythrocyte Sedimentation Rate (ESR) blood result of 28mm/h or more, or
-
C-Reactive Protein (CRP) blood result of 10mg/L or more
-
At least 2 of the following:
-
documented history or current presence of positive rheumatoid factor (blood test),
-
radiographic erosion within 12 months prior to study enrolment,
-
presence of serum anti-cyclic citrullinated peptide antibodies (blood test)
-
Presence of at least one swollen hand or wrist joint.
-
Presence of synovitis on baseline MRI scan, defined as at least 1 joint with RAMRIS synovitis score of +1 or greater.
Exclusion Criteria:
-
Females who are pregnant or breast feeding
-
Poorly controlled hypertension
-
Liver disease or significant liver function test abnormalities
-
Certain inflammatory conditions (other than rheumatoid arthritis), connective tissue diseases or chronic pain disorders
-
Recent or significant cardiovascular disease
-
Significant active or recent infection including tuberculosis
-
Previously received treatment with a TNF alpha antagonist (including etanercept, certolizumab, adalimumab, infliximab, golimumab) or anakinra or previous treatment with other biological agent including rituximab, abatacept and tocilizumab
-
Use of any DMARDs within 6 weeks before first study visit
-
Severe renal impairment
-
Neutropenia
-
Unable to undergo an MRI examination (e.g. presence of a pacemaker, defibrillator, or other implanted metallic device such as anterior interbody cages, aneurysm clip or pedicle screws)
-
Known allergy to Gadolinium-based contrast agent,
-
Tattoos [in area of examination if contains metallic pigment]
-
Likely to require sedation for the procedure
-
eGFR less than 55 mL/min
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Research Site | Glendale | Arizona | United States | |
2 | Research Site | Paradise Valley | Arizona | United States | |
3 | Research Site | Phoenix | Arizona | United States | |
4 | Research Site | Brooklyn | New York | United States | |
5 | Research Site | Jackson | Tennessee | United States | |
6 | Research Site | Austin | Texas | United States | |
7 | Research Site | Pleven | Bulgaria | ||
8 | Research Site | Mississauga | Ontario | Canada | |
9 | Research Site | Prague | Czech Republic | ||
10 | Research Site | Hamburg | Germany | ||
11 | Research Site | Munich | Germany | ||
12 | Research Site | Balatonfüred | Hungary | ||
13 | Research Site | Budapest | Hungary | ||
14 | Research Site | Amsterdam | Netherlands | ||
15 | Research Site | Warsaw | Poland | ||
16 | Research Site | Yaroslavl | Russian Federation | ||
17 | Research Site | Durban | South Africa | ||
18 | Research Site | Pretoria | South Africa | ||
19 | Research Site | Stellenbosch | South Africa | ||
20 | Research Site | Manchester | United Kingdom | ||
21 | Research Site | Oxford | United Kingdom |
Sponsors and Collaborators
- AstraZeneca
Investigators
- Study Director: Neil MacKillop, MD PhD, AstraZeneca
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- D4300C00004Sub
Study Results
Participant Flow
Recruitment Details | 198 patients were enrolled: 34, 33 and 30 were randomised to Groups A, D and E (33, 28 and 29 received at least 1 dose of IP). Two of the randomised patients were in the main study (D4300C00004). |
---|---|
Pre-assignment Detail | A total of 101 patients failed screening. |
Arm/Group Title | FOSTA 100 MG PO BID | ADALIMUMAB 40 MG SC | PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|---|
Arm/Group Description | Dosing Group A | Dosing Group D | Dosing Group E |
Period Title: Overall Study | |||
STARTED | 33 | 28 | 29 |
Randomised But Did Not Receive Treatment | 1 | 5 | 1 |
COMPLETED | 12 | 14 | 13 |
NOT COMPLETED | 21 | 14 | 16 |
Baseline Characteristics
Arm/Group Title | FOSTA 100 MG PO BID | ADALIMUMAB 40 MG SC | PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID | Total |
---|---|---|---|---|
Arm/Group Description | Dosing Group A | Dosing Group D | Dosing Group E | Total of all reporting groups |
Overall Participants | 33 | 28 | 29 | 90 |
Age (years) [Mean (Standard Deviation) ] | ||||
Mean (Standard Deviation) [years] |
52
(11.3)
|
53
(12.5)
|
48
(14.7)
|
51
(12.9)
|
Sex: Female, Male (Count of Participants) | ||||
Female |
22
66.7%
|
22
78.6%
|
21
72.4%
|
65
72.2%
|
Male |
11
33.3%
|
6
21.4%
|
8
27.6%
|
25
27.8%
|
Race/Ethnicity, Customized (Number) [Number] | ||||
White |
24
72.7%
|
23
82.1%
|
21
72.4%
|
68
75.6%
|
Black or African American |
2
6.1%
|
1
3.6%
|
4
13.8%
|
7
7.8%
|
Indian or Pakistani |
5
15.2%
|
4
14.3%
|
0
0%
|
9
10%
|
Other |
2
6.1%
|
0
0%
|
4
13.8%
|
6
6.7%
|
Outcome Measures
Title | OMERACT RAMRIS Synovitis Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) |
---|---|
Description | OMERACT RAMRIS synovitis score was based on 8 joints, scored from MRI images, and ranged from 0 to 24 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, OMERACT = Outcome Measures in Rheumatoid Arthritis Clinical Trials, PO = orally, RAMRIS = Rheumatoid Arthritis Magnetic Resonance Image Scoring system, SC = subcutaneous. |
Time Frame | Baseline, 6 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The sub-study analysis set includes those patients who received at least 1 dose of investigational product in the MRI sub-study. Patients were analysed by randomised treatment, but only those with available images were included in the analysis. |
Arm/Group Title | FOSTA 100 MG PO BID | ADALIMUMAB 40 MG SC | PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|---|
Arm/Group Description | Dosing Group A | Dosing Group D | Dosing Group E |
Measure Participants | 33 | 28 | 29 |
6 weeks (n=25, 22, 20) |
-1.50
|
-0.50
|
0.00
|
24 weeks (n=18, 16, 18) |
-0.25
|
-1.03
|
0.00
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | FOSTA 100 MG PO BID, PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|
Comments | 6 weeks | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.022 |
Comments | A negative value for change from baseline in OMERACT RAMRIS synovitis score indicates a better clinical condition. | |
Method | Van Elteren | |
Comments | Estimated using the Van Elteren test stratified by DMARD naivety (DMARD naive vs DMARD-IR/intolerant). | |
Method of Estimation | Estimation Parameter | Treatment difference |
Estimated Value | -1.75 | |
Confidence Interval |
(2-Sided) 90% -2.75 to -0.42 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The point estimate for the median difference in change from baseline and associated 90% CI was calculated using the method of unstratified Hodges-Lehmann. A treatment difference <0 indicates a benefit towards fostamatinib. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | FOSTA 100 MG PO BID, ADALIMUMAB 40 MG SC |
---|---|---|
Comments | 24 weeks | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.402 |
Comments | A negative value for change from baseline in OMERACT RAMRIS synovitis score indicates a better clinical condition. | |
Method | Van Elteren | |
Comments | Estimated using the Van Elteren test stratified by DMARD naivety (DMARD naive vs DMARD-IR/intolerant). | |
Method of Estimation | Estimation Parameter | Treatment difference |
Estimated Value | 0.50 | |
Confidence Interval |
(2-Sided) 90% -1.00 to 2.00 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The point estimate for the median difference in change from baseline and associated 90% CI was calculated using the method of unstratified Hodges-Lehmann. A treatment difference <0 indicates a benefit towards fostamatinib. |
Title | OMERACT RAMRIS Osteitis Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) |
---|---|
Description | OMERACT RAMRIS osteitis score was based on 25 joints, scored from MRI images, and ranged from 0 to 75 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, OMERACT = Outcome Measures in Rheumatoid Arthritis Clinical Trials, PO = orally, RAMRIS = Rheumatoid Arthritis Magnetic Resonance Image Scoring system, SC = subcutaneous. |
Time Frame | Baseline, 6 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The sub-study analysis set includes those patients who received at least 1 dose of investigational product in the MRI sub-study. Patients were analysed by randomised treatment, but only those with available images were included in the analysis. |
Arm/Group Title | FOSTA 100 MG PO BID | ADALIMUMAB 40 MG SC | PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|---|
Arm/Group Description | Dosing Group A | Dosing Group D | Dosing Group E |
Measure Participants | 33 | 28 | 29 |
6 weeks (n=25, 22, 20) |
0.00
|
0.00
|
0.00
|
24 weeks (n=18, 16, 18) |
0.00
|
0.00
|
0.00
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | FOSTA 100 MG PO BID, PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|
Comments | 6 weeks | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.746 |
Comments | A negative value for change from baseline in OMERACT RAMRIS osteitis score indicates a better clinical condition. | |
Method | Van Elteren | |
Comments | Estimated using the Van Elteren test stratified by DMARD naivety (DMARD naive vs DMARD-IR/intolerant). | |
Method of Estimation | Estimation Parameter | Treatment difference |
Estimated Value | 0.00 | |
Confidence Interval |
(2-Sided) 90% -1.00 to 0.50 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The point estimate for the median difference in change from baseline and associated 90% CI was calculated using the method of unstratified Hodges-Lehmann. A treatment difference <0 indicates a benefit towards fostamatinib. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | FOSTA 100 MG PO BID, ADALIMUMAB 40 MG SC |
---|---|---|
Comments | 24 weeks | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.413 |
Comments | A negative value for change from baseline in OMERACT RAMRIS synovitis score indicates a better clinical condition. | |
Method | Van Elteren | |
Comments | Estimated using the Van Elteren test stratified by DMARD naivety (DMARD naive vs DMARD-IR/intolerant). | |
Method of Estimation | Estimation Parameter | Treatment difference |
Estimated Value | 1.00 | |
Confidence Interval |
(2-Sided) 90% -1.50 to 3.50 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The point estimate for the median difference in change from baseline and associated 90% CI was calculated using the method of unstratified Hodges-Lehmann. A treatment difference <0 indicates a benefit towards fostamatinib. |
Title | Joint Space Narrowing - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) |
---|---|
Description | Joint space narrowing score was based on 20 joints, scored from MRI images and ranged from 0 to 80 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, JSN = joint space narrowing, MRI = magnetic resonance imaging, PO = orally, SC = subcutaneous. |
Time Frame | Baseline, 6 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The sub-study analysis set includes those patients who received at least 1 dose of investigational product in the MRI sub-study. Patients were analysed by randomised treatment, but only those with available images were included in the analysis. |
Arm/Group Title | FOSTA 100 MG PO BID | ADALIMUMAB 40 MG SC | PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|---|
Arm/Group Description | Dosing Group A | Dosing Group D | Dosing Group E |
Measure Participants | 33 | 28 | 29 |
6 weeks (n=25, 22, 20) |
0.00
|
0.00
|
0.00
|
24 weeks (n=18, 16, 18) |
0.00
|
0.00
|
0.00
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | FOSTA 100 MG PO BID, PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|
Comments | 6 weeks | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.491 |
Comments | A negative value for change from baseline in JSN score indicates a better clinical condition. | |
Method | Van Elteren | |
Comments | Estimated using the Van Elteren test stratified by DMARD naivety (DMARD naive vs DMARD-IR/intolerant). | |
Method of Estimation | Estimation Parameter | Treatment difference |
Estimated Value | 0.00 | |
Confidence Interval |
(2-Sided) 90% 0.00 to 0.00 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The point estimate for the median difference in change from baseline and associated 90% CI was calculated using the method of unstratified Hodges-Lehmann. A treatment difference <0 indicates a benefit towards fostamatinib. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | FOSTA 100 MG PO BID, ADALIMUMAB 40 MG SC |
---|---|---|
Comments | 24 weeks | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.341 |
Comments | A negative value for change from baseline in JSN score indicates a better clinical condition. | |
Method | Van Elteren | |
Comments | Estimated using the Van Elteren test stratified by DMARD naivety (DMARD naive vs DMARD-IR/intolerant). | |
Method of Estimation | Estimation Parameter | Treatment difference |
Estimated Value | 0.00 | |
Confidence Interval |
(2-Sided) 90% 0.00 to 0.00 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The point estimate for the median difference in change from baseline and associated 90% CI was calculated using the method of unstratified Hodges-Lehmann. A treatment difference <0 indicates a benefit towards fostamatinib. |
Title | OMERACT RAMRIS Erosions Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) |
---|---|
Description | OMERACT RAMRIS erosions score was based on 25 joints and ranged from 0 to 250 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, OMERACT = Outcome Measures in Rheumatoid Arthritis Clinical Trials, PO = orally, RAMRIS = Rheumatoid Arthritis Magnetic Resonance Image Scoring system, SC = subcutaneous. |
Time Frame | Baseline, 6 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The sub-study analysis set includes those patients who received at least 1 dose of investigational product in the MRI sub-study. Patients were analysed by randomised treatment, but only those with available images were included in the analysis. |
Arm/Group Title | FOSTA 100 MG PO BID | ADALIMUMAB 40 MG SC | PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|---|
Arm/Group Description | Dosing Group A | Dosing Group D | Dosing Group E |
Measure Participants | 33 | 28 | 29 |
6 weeks (n=25, 22, 20) |
0.00
|
0.00
|
0.50
|
24 weeks (n=18, 16, 18) |
1.00
|
0.00
|
1.25
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | FOSTA 100 MG PO BID, PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|
Comments | 6 weeks | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.366 |
Comments | A negative value for change from baseline in OMERACT RAMRIS erosions score indicates a better clinical condition. | |
Method | Van Elteren | |
Comments | Estimated using the Van Elteren test stratified by DMARD naivety (DMARD naive vs DMARD-IR/intolerant). | |
Method of Estimation | Estimation Parameter | Treatment difference |
Estimated Value | 0.00 | |
Confidence Interval |
(2-Sided) 90% -0.50 to 0.00 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The point estimate for the median difference in change from baseline and associated 90% CI was calculated using the method of unstratified Hodges-Lehmann. A treatment difference <0 indicates a benefit towards fostamatinib. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | FOSTA 100 MG PO BID, ADALIMUMAB 40 MG SC |
---|---|---|
Comments | 24 weeks | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.053 |
Comments | A negative value for change from baseline in OMERACT RAMRIS erosions score indicates a better clinical condition. | |
Method | Van Elteren | |
Comments | Estimated using the Van Elteren test stratified by DMARD naivety (DMARD naive vs DMARD-IR/intolerant). | |
Method of Estimation | Estimation Parameter | Treatment difference |
Estimated Value | 1.25 | |
Confidence Interval |
(2-Sided) 90% 0.50 to 2.50 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The point estimate for the median difference in change from baseline and associated 90% CI was calculated using the method of unstratified Hodges-Lehmann. A treatment difference <0 indicates a benefit towards fostamatinib. |
Title | DAS-CRP Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab |
---|---|
Description | DAS28-CRP: Disease Activity Score based on a count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (CRP) and the patient's own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. Mean changes from baseline in DAS28-CRP score are shown at each visit and are presented as decreases from baseline (defined as baseline minus post-baseline) with larger changes indicative of a better clinical condition. ANCOVA = analysis of covariance, BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, PO = orally, SC = subcutaneous. |
Time Frame | Baseline, 6 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The sub-study analysis set includes those patients who received at least 1 dose of investigational product in the MRI sub-study. Patients were analysed by randomised treatment in accordance with the intention to treat principle. |
Arm/Group Title | FOSTA 100 MG PO BID | ADALIMUMAB 40 MG SC | PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|---|
Arm/Group Description | Dosing Group A | Dosing Group D | Dosing Group E |
Measure Participants | 33 | 28 | 29 |
6 weeks (n=32, 27, 27) |
1.4
(1.35)
|
1.1
(1.16)
|
0.5
(1.06)
|
24 weeks (n=20, 19, 17) |
1.1
(1.61)
|
1.5
(1.44)
|
1.6
(1.39)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | FOSTA 100 MG PO BID, PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|
Comments | Change from baseline at Week 6. Nonresponder imputation applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of parenteral steroids, or for patients with no post baseline data. Patients who prematurely withdrew due to project closure have no imputation applied. | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.006 |
Comments | ||
Method | ANCOVA | |
Comments | Includes terms for baseline as a continuous covariate and treatment and DMARD naivety (DMARD naive vs DMARD-IR/intolerant) as factors. | |
Method of Estimation | Estimation Parameter | Least Square Mean Treatment Difference |
Estimated Value | 0.89 | |
Confidence Interval |
(2-Sided) 90% 0.36 to 1.41 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | FOSTA 100 MG PO BID, PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
---|---|---|
Comments | Change from baseline at Week 24. Nonresponder imputation applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of parenteral steroids, or for patients with no post baseline data. Patients who prematurely withdrew due to project closure have no imputation applied. | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.496 |
Comments | ||
Method | ANCOVA | |
Comments | Includes terms for baseline as a continuous covariate and treatment and DMARD naivety (DMARD naive vs DMARD-IR/intolerant) as factors. | |
Method of Estimation | Estimation Parameter | Least Square Mean Treatment Difference |
Estimated Value | -0.34 | |
Confidence Interval |
(2-Sided) 90% -1.16 to 0.49 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Adverse Events
Time Frame | 24 weeks | |||||||
---|---|---|---|---|---|---|---|---|
Adverse Event Reporting Description | For placebo treated patients time frame includes both placebo(6 weeks) and fostamatinib(18 weeks) treatment. 1 SAE occurred in these treatment arms began during the 6 week placebo treated period | |||||||
Arm/Group Title | ADALIMUMAB 40 MG | FOSTA 100 MG BID | PLACEBO (6 WKS) THEN FOSTA 100 MG BID - FOSTA Period | PLACEBO (6 WKS) THEN FOSTA 100 MG BID - Placebo Period | ||||
Arm/Group Description | Dosing Group D | Dosing Group A | ||||||
All Cause Mortality |
||||||||
ADALIMUMAB 40 MG | FOSTA 100 MG BID | PLACEBO (6 WKS) THEN FOSTA 100 MG BID - FOSTA Period | PLACEBO (6 WKS) THEN FOSTA 100 MG BID - Placebo Period | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||
Serious Adverse Events |
||||||||
ADALIMUMAB 40 MG | FOSTA 100 MG BID | PLACEBO (6 WKS) THEN FOSTA 100 MG BID - FOSTA Period | PLACEBO (6 WKS) THEN FOSTA 100 MG BID - Placebo Period | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 3/28 (10.7%) | 3/33 (9.1%) | 0/22 (0%) | 1/29 (3.4%) | ||||
Infections and infestations | ||||||||
GASTROENTERITIS | 0/28 (0%) | 0 | 1/33 (3%) | 1 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
Injury, poisoning and procedural complications | ||||||||
FEMORAL NECK FRACTURE | 0/28 (0%) | 0 | 1/33 (3%) | 1 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
POST PROCEDURAL HAEMORRHAGE | 0/28 (0%) | 0 | 1/33 (3%) | 1 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
Musculoskeletal and connective tissue disorders | ||||||||
EXOSTOSIS | 0/28 (0%) | 0 | 0/33 (0%) | 0 | 0/22 (0%) | 0 | 1/29 (3.4%) | 1 |
INTERVERTEBRAL DISC PROTRUSION | 0/28 (0%) | 0 | 0/33 (0%) | 0 | 0/22 (0%) | 0 | 1/29 (3.4%) | 1 |
MUSCULOSKELETAL CHEST PAIN | 1/28 (3.6%) | 1 | 0/33 (0%) | 0 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
Respiratory, thoracic and mediastinal disorders | ||||||||
ASTHMA | 1/28 (3.6%) | 1 | 0/33 (0%) | 0 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
Vascular disorders | ||||||||
ORTHOSTATIC HYPOTENSION | 1/28 (3.6%) | 1 | 0/33 (0%) | 0 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||||
ADALIMUMAB 40 MG | FOSTA 100 MG BID | PLACEBO (6 WKS) THEN FOSTA 100 MG BID - FOSTA Period | PLACEBO (6 WKS) THEN FOSTA 100 MG BID - Placebo Period | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 7/28 (25%) | 17/33 (51.5%) | 7/22 (31.8%) | 4/29 (13.8%) | ||||
Gastrointestinal disorders | ||||||||
CONSTIPATION | 0/28 (0%) | 0 | 3/33 (9.1%) | 3 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
DIARRHOEA | 1/28 (3.6%) | 1 | 3/33 (9.1%) | 3 | 1/22 (4.5%) | 1 | 1/29 (3.4%) | 1 |
NAUSEA | 1/28 (3.6%) | 1 | 2/33 (6.1%) | 2 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
General disorders | ||||||||
INFLUENZA LIKE ILLNESS | 2/28 (7.1%) | 2 | 0/33 (0%) | 0 | 1/22 (4.5%) | 1 | 0/29 (0%) | 0 |
Infections and infestations | ||||||||
GASTROENTERITIS | 0/28 (0%) | 0 | 0/33 (0%) | 0 | 2/22 (9.1%) | 2 | 0/29 (0%) | 0 |
NASOPHARYNGITIS | 1/28 (3.6%) | 1 | 3/33 (9.1%) | 3 | 2/22 (9.1%) | 2 | 0/29 (0%) | 0 |
Investigations | ||||||||
ALANINE AMINOTRANSFERASE INCREASED | 0/28 (0%) | 0 | 3/33 (9.1%) | 3 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
ASPARTATE AMINOTRANSFERASE INCREASED | 0/28 (0%) | 0 | 2/33 (6.1%) | 2 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
GAMMA-GLUTAMYLTRANSFERASE INCREASED | 0/28 (0%) | 0 | 2/33 (6.1%) | 2 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
Musculoskeletal and connective tissue disorders | ||||||||
RHEUMATOID ARTHRITIS | 1/28 (3.6%) | 1 | 2/33 (6.1%) | 2 | 2/22 (9.1%) | 2 | 1/29 (3.4%) | 1 |
Nervous system disorders | ||||||||
HEADACHE | 0/28 (0%) | 0 | 0/33 (0%) | 0 | 0/22 (0%) | 0 | 2/29 (6.9%) | 2 |
DIZZINESS | 1/28 (3.6%) | 1 | 2/33 (6.1%) | 2 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
DYSGEUSIA | 0/28 (0%) | 0 | 2/33 (6.1%) | 2 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
Skin and subcutaneous tissue disorders | ||||||||
RASH MACULAR | 0/28 (0%) | 0 | 2/33 (6.1%) | 2 | 0/22 (0%) | 0 | 0/29 (0%) | 0 |
Vascular disorders | ||||||||
HYPERTENSION | 0/28 (0%) | 0 | 4/33 (12.1%) | 4 | 1/22 (4.5%) | 1 | 1/29 (3.4%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The disclosure restriction on the PI is that the sponsor can review and comment on results communications prior to publication. Sponsor will be allowed a review period of at least 60 days from submission but can request that publication be delayed for a period up to 6 months. Any reasonable comments made by the sponsor will be incorporated by the PI into the publication.
Results Point of Contact
Name/Title | Dave Goldstraw |
---|---|
Organization | AstraZeneca Pharmaceuticals |
Phone | +44 (0)1625 512415 |
dave.goldstraw@astrazeneca.com |
- D4300C00004Sub