OSKIRA 4 SS: Randomised Double-Blind, Placebo-Controlled, Parallel Group Study in Patients With Active Rheumatoid Arthritis:Magnetic Resonance Imaging Sub-Study

Sponsor
AstraZeneca (Industry)
Overall Status
Terminated
CT.gov ID
NCT02092961
Collaborator
(none)
198
21
3
28.9
9.4
0.3

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

Study Type:
Interventional
Actual Enrollment :
198 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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
Study Start Date :
Feb 1, 2011
Actual Primary Completion Date :
Jul 1, 2013
Actual Study Completion Date :
Jul 1, 2013

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

  1. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No

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 Balatonf├╝red 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.
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02092961
Other Study ID Numbers:
  • D4300C00004Sub
First Posted:
Mar 20, 2014
Last Update Posted:
Jun 25, 2014
Last Verified:
Apr 1, 2014
Keywords provided by AstraZeneca
Additional relevant MeSH terms:

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

1. Primary Outcome
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.
2. Other Pre-specified Outcome
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.
3. Other Pre-specified Outcome
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.
4. Other Pre-specified Outcome
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.
5. Other Pre-specified Outcome
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

[Not Specified]

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
Email dave.goldstraw@astrazeneca.com
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02092961
Other Study ID Numbers:
  • D4300C00004Sub
First Posted:
Mar 20, 2014
Last Update Posted:
Jun 25, 2014
Last Verified:
Apr 1, 2014