OSKIRA - 3: Evaluation of Effectiveness of Two Dosing Regimens of Fostamatinib Compared to Placebo in Patients With Rheumatoid Arthritis (RA) Who Are Taking Methotrexate and Have Had Inadequate Response to Single TNF-alpha Antagonist

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01197755
• Collaborator: (none)
• Enrollment: 323
• Locations: 136
• Arms: 3
• Duration (Months): 29
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the effectiveness of two dosing regimens of fostamatinib compared to placebo, in patients with rheumatoid arthritis (RA) who are taking methotrexate and have had an inadequate response to a single TNF-alpha antagonist. The study will last for approximately six months.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: fostamatinib; Drug: fostamatinib; Drug: placebo	Phase 3

Detailed Description

Sub-study:

Full title: Optional Genetic Research

Date: 18 June 2010

Version: 1

Objectives: To collect and store, with appropriate consent ,DNA samples for future exploratory research into genes/genetic variation that may influence response (ie, absorption, distribution, metabolism and excretion, safety, tolerability and efficacy) to fostamatinib disodium and/or methotrexate; and/or susceptibility to, progression of and prognosis of RA

Study Design

• Study Type: Interventional
• Actual Enrollment: 323 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: (OSKIRA-3): A Phase III, Multi-centre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Study of Two Dosing Regimens of Fostamatinib Disodium in Rheumatoid Arthritis Patients With Inadequate Response to a TNF-alpha Antagonist
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dosing Regimen A Oral Treatment	Drug: fostamatinib; fostamatinib 100 mg twice daily
Experimental: Dosing Regimen B Oral Treatment	Drug: fostamatinib; fostamatinib 100 mg twice daily/150 mg once daily
Placebo Comparator: Dosing Regimen C Oral Treatment	Drug: placebo; Placebo twice daily

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients Achieving ACR20 at Week 24, Comparison Between Fostamatinib and Placebo [24 weeks]

   ACR20: American College of Rheumatology 20% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily.

Secondary Outcome Measures

1. Proportion of Patients Achieving ACR20 at Week 1, Comparison Between Fostamatinib and Placebo [1 week]

   ACR20: American College of Rheumatology 20% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily.

2. Proportion of Patients Achieving ACR50 at Week 24, Comparison Between Fostamatinib and Placebo [24 weeks]

   ACR50: American College of Rheumatology 50% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily.

3. Proportion of Patients Achieving ACR70 at Week 24, Comparison Between Fostamatinib and Placebo [24 weeks]

   ACR70: American College of Rheumatology 70% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily.

4. ACRn - Comparison Between Fostamatinib and Placebo at Week 24 [Baseline and 24 weeks]

   ACRn: American College of Rheumatology index of RA improvement, based on smallest percentage improvement in the count of swollen joints (out of 28 joints), count of tender joints (out of 28 joints), or in blood test measures of inflammation (such as C-Reactive Protein) or the physician or patient's own assessments of disease activity, pain and physical function. Scores are reported as a percentage improvement on a scale of -100 to +100, with larger values representing a better clinical outcome. Mean refers to change at Week 24. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.

5. Proportion of Patients Achieving DAS28-CRP <2.6 at Week 24, Comparison Between Fostamatinib and Placebo [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 patients' own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. A DAS28-CRP score of <2.6 is indicative of remission of RA symptoms. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once daily.

6. Proportion of Patients Achieving DAS28-CRP <=3.2 at Week 12, Comparison Between Fostamatinib and Placebo [12 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 patients' own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. A DAS28-CRP score of <=3.2 indicates low disease activity. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once daily.

7. Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo [24 weeks]

   Change from baseline in DAS28-CRP at Week 24 was categorised using the European League Against Rheumatism (EULAR) response criteria. BID = twice daily, CRP = C-reactive protein, DAS28 = Disease Activity Score based on a 28-joint count, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once a day.

8. Proportion of Patients With a HAQ-DI Response at Week 24 - Comparison Between Fostamatinib and Placebo [24 weeks]

   HAQ-DI: Health Assessment Questionnaire - Disability Index, a measure of physical function. The HAQ-DI score is calculated by summing the category scores from 8 sub-categories (ie, scores for patient ability in dressing and grooming, rising, eating, walking, hygeine, reach, grip and common daily activities) and dividing by the number of categories completed. The HAQ-DI score takes values between 0 and 3, with a higher score indicating greater disability. A HAQ-DI response is a reduction from baseline in HAQ-DI greater than or equal to the minimally important difference (0.22). BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once a day.

9. Change From Baseline to Week 24 in mTSS Score, Comparison Between Fostamatinib and Placebo [Baseline and 24 weeks]

   mTSS: modified total sharp score, a measure of structural progression based upon X-rays. Hand and foot joints are scored for eroisions and joint space narrowing and the results summed to give a value between 0 and 488. A higher value represents more serious progression of the disease. After disregarding ineligible records, patients with 2 or more non-missing values had missing data imputed via linear extrapolation/interpolation methods. Patients with only 1 result were excluded from the analysis. ANCOVA = Analysis of covariance, BID = twice daily, IP = investigational product, PO = orally, QD = once a day.

10. SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Placebo at Week 24 [Baseline and 24 weeks]

    SF-36: 36 item short form health survey, as a measure of health-related quality of life. Scores for 8 sub-domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Function, Role-Emotional and Mental Health) are derived and normalised to a scale of 0 to 100. The physical and mental component scores (PCS and MCS) are derived by multiplying each of these 8 scores by a constant, summing them and standardising against a population with a mean of 50, standard deviation of 10. A higher score represents a better quality of life. Mean changes from baseline score are presented as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. Mean refers to change in scores at Week 24. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease modifying antirheumatic drugs, PO = orally, QD = once daily

11. SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Placebo at Week 24 [Baseline and 24 weeks]

    SF-36: 36 item short form health survey, as a measure of health-related quality of life. The SF-36 scores for 8 sub-domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Function, Role-Emotional and Mental Health) are derived and normalised to a scale of 0 to 100. The physical and mental component scores (PCS and MCS) are derived by multiplying each of these 8 scores by a constant, summing them and standardising against a population with a mean of 50, standard deviation of 10. A higher score represents a better quality of life. Mean changes from baseline score are presented as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. Mean refers to change in score at Week 24. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease modifying antirheumatic drugs, PO = orally, QD = once daily.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Active rheumatoid arthritis (RA) diagnosed after the age of 16

• Currently taking methotrexate

• 6 or more swollen joints and 6 or more tender/painful joints (from 28 joint count) and 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 one of the following: documented history of positive rheumatoid factor (blood test), current presence of rheumatoid factor (blood test), radiographic erosion within 12months prior to study enrolment, presence of serum anti-cyclic citrullinated peptide antibodies (blood test)

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

• Previous failure to respond to anakinra or previous treatment with biological agent (other than TNF alpha antagonists including rituximab, abatacept and tocilizumab)

• Severe renal impairment

• Neutropenia

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Anniston	Alabama	United States
2	Research Site	Huntsville	Alabama	United States
3	Research Site	Tuscaloosa	Alabama	United States
4	Research Site	Mesa	Arizona	United States
5	Research Site	Scottsdale	Arizona	United States
6	Research Site	Hot Springs	Arkansas	United States
7	Research Site	Glendale	California	United States
8	Research Site	La Jolla	California	United States
9	Research Site	Long Beach	California	United States
10	Research Site	Palo Alto	California	United States
11	Research Site	Santa Maria	California	United States
12	Research Site	Torrance	California	United States
13	Research Site	Tustin	California	United States
14	Research Site	Upland	California	United States
15	Research Site	Colorado Springs	Colorado	United States
16	Research Site	Bridgeport	Connecticut	United States
17	Research Site	Trumbull	Connecticut	United States
18	Research Site	Lewes	Delaware	United States
19	Research Site	Brandon	Florida	United States
20	Research Site	Jacksonville	Florida	United States
21	Research Site	Ocala	Florida	United States
22	Research Site	Orlando	Florida	United States
23	Research Site	Tampa	Florida	United States
24	Research Site	Venice	Florida	United States
25	Research Site	Zephyr Hills	Florida	United States
26	Research Site	Atlanta	Georgia	United States
27	Research Site	Canton	Georgia	United States
28	Research Site	Idaho Falls	Idaho	United States
29	Research Site	Decatur	Illinois	United States
30	Research Site	Cedar Rapids	Iowa	United States
31	Research Site	Bowling Green	Kentucky	United States
32	Research Site	Elizabethtown	Kentucky	United States
33	Research Site	Crofton	Maryland	United States
34	Research Site	Fall River	Massachusetts	United States
35	Research Site	Worcester	Massachusetts	United States
36	Research Site	Lansing	Michigan	United States
37	Research Site	Flowood	Mississippi	United States
38	Research Site	Florissant	Missouri	United States
39	Research Site	Richmond Heights	Missouri	United States
40	Research Site	Las Cruces	New Mexico	United States
41	Research Site	Albany	New York	United States
42	Research Site	Brooklyn	New York	United States
43	Research Site	Olean	New York	United States
44	Research Site	Rochester	New York	United States
45	Research Site	Roslyn	New York	United States
46	Research Site	Smithtown	New York	United States
47	Research Site	Charlotte	North Carolina	United States
48	Research Site	Durham	North Carolina	United States
49	Research Site	Greensboro	North Carolina	United States
50	Research Site	Dayton	Ohio	United States
51	Research Site	Mayfield Village	Ohio	United States
52	Research Site	Lake Oswego	Oregon	United States
53	Research Site	Duncansville	Pennsylvania	United States
54	Research Site	Philadelphia	Pennsylvania	United States
55	Research Site	Pittsburgh	Pennsylvania	United States
56	Research Site	West Reading	Pennsylvania	United States
57	Research Site	Charleston	South Carolina	United States
58	Research Site	Greenville	South Carolina	United States
59	Research Site	Hixson	Tennessee	United States
60	Research Site	Memphis	Tennessee	United States
61	Research Site	Nashville	Tennessee	United States
62	Research Site	Amarillo	Texas	United States
63	Research Site	Austin	Texas	United States
64	Research Site	Dallas	Texas	United States
65	Research Site	Houston	Texas	United States
66	Research Site	San Antonio	Texas	United States
67	Research Site	Tacoma	Washington	United States
68	Research Site	Buenos Aires	Caba	Argentina
69	Research Site	Cordoba	CRD	Argentina
70	Research Site	Rosario	Santa Fe	Argentina
71	Research Site	San Miguel de Tucuman	TUC	Argentina
72	Research Site	Buenos Aires		Argentina
73	Research Site	Ciudad de Buenos Aires		Argentina
74	Research Site	Quilmes		Argentina
75	Research Site	Rosario		Argentina
76	Research Site	San Juan		Argentina
77	Research Site	San Miguel de Tucuman		Argentina
78	Research Site	Brussels		Belgium
79	Research Site	Gent		Belgium
80	Research Site	Liege		Belgium
81	Research Site	Yvoir		Belgium
82	Research Site	Porto Alegre	Brasil	Brazil
83	Research Site	Goiania	GO	Brazil
84	Research Site	Curitiba	PR	Brazil
85	Research Site	Sao Paulo	SP	Brazil
86	Research Site	St John's	Newfoundland and Labrador	Canada
87	Research Site	Mississauga	Ontario	Canada
88	Research Site	Toronto	Ontario	Canada
89	Research Site	Pointe-claire	Quebec	Canada
90	Research Site	Rimouski	Quebec	Canada
91	Research Site	Bruntal		Czech Republic
92	Research Site	Ceske Budejovice		Czech Republic
93	Research Site	Hlucin		Czech Republic
94	Research Site	Ostrava-trebovice		Czech Republic
95	Research Site	Praha 2		Czech Republic
96	Research Site	Praha		Czech Republic
97	Research Site	Zlin		Czech Republic
98	Research Site	Orleans Cedex 1		France
99	Research Site	Hamburg	HH	Germany
100	Research Site	Aachen	Nordrhein Westfalen	Germany
101	Research Site	Leipzig	SN	Germany
102	Research Site	Erlangen		Germany
103	Research Site	Frankfurt		Germany
104	Research Site	Hamburg		Germany
105	Research Site	Heidelberg		Germany
106	Research Site	Muenchen		Germany
107	Research Site	Budapest		Hungary
108	Research Site	Ashkelon		Israel
109	Research Site	Haifa		Israel
110	Research Site	Kfar Saba		Israel
111	Research Site	Ramat Gan		Israel
112	Research Site	Tel-hashomer		Israel
113	Research Site	Jesi	AN	Italy
114	Research Site	Ferrara	FE	Italy
115	Research Site	Obrergon	SON	Mexico
116	Research Site	Chihuahua		Mexico
117	Research Site	DF		Mexico
118	Research Site	Monterrey		Mexico
119	Research Site	Saltillo		Mexico
120	Research Site	Lisboa		Portugal
121	Research Site	Porto		Portugal
122	Research Site	Cape Town		South Africa
123	Research Site	Pretoria		South Africa
124	Research Site	Stellenbosch		South Africa
125	Research Site	Barcelona		Spain
126	Research Site	Reading	Berkshire	United Kingdom
127	Research Site	Warrington	Cheshire	United Kingdom
128	Research Site	Maidstone	Kent	United Kingdom
129	Research Site	Eastbourne	Sussex	United Kingdom
130	Research Site	Cambridge		United Kingdom
131	Research Site	Christchurch		United Kingdom
132	Research Site	Ipswich		United Kingdom
133	Research Site	London		United Kingdom
134	Research Site	Nottingham		United Kingdom
135	Research Site	Westcliff-on-the Sea		United Kingdom
136	Research Site	Wirral		United Kingdom

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Neil MacKillop, MD PhD, AstraZeneca

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01197755
• Other Study ID Numbers: D4300C00003; 2010-020745-27
• First Posted: Sep 9, 2010
• Last Update Posted: Apr 7, 2014
• Last Verified: Feb 1, 2014

• Keywords provided by AstraZeneca: Rheumatoid Arthritis
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid

Study Results

Participant Flow

Recruitment Details	A total of 638 patients were enrolled: 105, 108 & 110 were randomised to Groups A, B & C respectively (105, 108 & 109 received at least 1 dose of investigational product).
Pre-assignment Detail	A total of 315 patients failed screening.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Period Title: Overall Study
STARTED	105	108	109
Randomised But Did Not Receive Treatment	0	0	1
COMPLETED	67	65	55
NOT COMPLETED	38	43	54

Baseline Characteristics

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO	Total
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Total of all reporting groups
Overall Participants	105	108	109	322
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54 (11.9)	51 (12.0)	53 (13.0)	53 (12.3)
Sex: Female, Male (Count of Participants)
Female	89 84.8%	87 80.6%	85 78%	261 81.1%
Male	16 15.2%	21 19.4%	24 22%	61 18.9%
Race/Ethnicity, Customized (Number) [Number]
White	86 81.9%	92 85.2%	91 83.5%	269 83.5%
Black or African American	9 8.6%	5 4.6%	9 8.3%	23 7.1%
Asian	0 0%	1 0.9%	0 0%	1 0.3%
American Indian or Alaska Native	1 1%	4 3.7%	1 0.9%	6 1.9%
Indian or Pakistani	2 1.9%	0 0%	1 0.9%	3 0.9%
Other	7 6.7%	6 5.6%	7 6.4%	20 6.2%

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients Achieving ACR20 at Week 24, Comparison Between Fostamatinib and Placebo
Description	ACR20: American College of Rheumatology 20% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set includes those patients who received at least 1 dose of investigational product. Patients were analysed by randomised treatment in accordance with the intention to treat principle.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Measure Participants	105	108	109
Number [Percentage of responders]	36.2	27.8	21.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	Week 24
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders at Week 24 with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportion
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 95%; 0.05 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.168
	Comments	Week 24
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders at Week 24 with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportion
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Proportion of Patients Achieving ACR20 at Week 1, Comparison Between Fostamatinib and Placebo
Description	ACR20: American College of Rheumatology 20% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily.
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

The full analysis set includes those patients who received at least 1 dose of investigational product. Patients were analysed by randomised treatment in accordance with the intention to treat principle.

Arm/Group Title	PLACEBO PO	Dosing Group A and B Combined PO
Arm/Group Description	Dosing Group C	Fostamatinib 100 mg BID (combined)
Measure Participants	109	213
Number [Percentage of responders]	3.7	25.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mantel Haenszel
	Comments	95% confidence intervals and p-values are calculated using a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportion
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 95%; 0.16 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Proportion of Patients Achieving ACR50 at Week 24, Comparison Between Fostamatinib and Placebo
Description	ACR50: American College of Rheumatology 50% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set includes those patients who received at least 1 dose of investigational product. Patients were analysed by randomised treatment in accordance with the intention to treat principle.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Measure Participants	105	108	109
Number [Percentage of responders]	18.1	13.0	8.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	Mantel Haenszel
	Comments	95% confidence intervals and p-values are calculated using a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportion
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; 0.02 to 0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.180
	Comments	Nominal p-value presented for Group B comparison. Formal statistical testing could not be carried out due to the predefined multiplicity procedure (primary variable comparison of Group B versus Group C was non-significant).
	Method	Mantel Haenszel
	Comments	95% confidence intervals and p-values are calculated using a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportion
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Proportion of Patients Achieving ACR70 at Week 24, Comparison Between Fostamatinib and Placebo
Description	ACR70: American College of Rheumatology 70% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set includes those patients who received at least 1 dose of investigational product. Patients were analysed by randomised treatment in accordance with the intention to treat principle.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Measure Participants	105	108	109
Number [Percentage of responders]	14.3	2.8	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mantel Haenszel
	Comments	95% confidence intervals and p-values are calculated using a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportion
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; 0.06 to 0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.891
	Comments	Nominal p-value presented for Group B comparison. Formal statistical testing could not be carried out due to the predefined multiplicity procedure (primary variable comparison of Group B versus Group C was non-significant).
	Method	Mantel Haenszel
	Comments	95% confidence intervals and p-values are calculated using a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportion
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	ACRn - Comparison Between Fostamatinib and Placebo at Week 24
Description	ACRn: American College of Rheumatology index of RA improvement, based on smallest percentage improvement in the count of swollen joints (out of 28 joints), count of tender joints (out of 28 joints), or in blood test measures of inflammation (such as C-Reactive Protein) or the physician or patient's own assessments of disease activity, pain and physical function. Scores are reported as a percentage improvement on a scale of -100 to +100, with larger values representing a better clinical outcome. Mean refers to change at Week 24. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set includes those patients who received at least 1 dose of investigational product. Patients were analysed by randomised treatment in accordance with the intention to treat principle.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Measure Participants	105	108	109
Mean (Standard Deviation) [Percentage improvement from baseline]	16.25 (36.994)	13.00 (24.718)	5.87 (26.726)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments	Nominal p-value presented for treatment comparison. ACRn was not formally tested within the predefined multiplicity procedure. As this is a non-parametric test p-values alone are presented rather than an estimated treatment difference.
	Method	Van Elteren
	Comments	P-values are estimated using the Van Elteren test stratified by pooled country.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	Nominal p-value presented for treatment comparison. ACRn was not formally tested within the predefined multiplicity procedure. As this is a non-parametric test p-values alone are presented rather than an estimated treatment difference.
	Method	Van Elteren
	Comments	P-values are estimated using the Van Elteren test stratified by pooled country.

6. Secondary Outcome

Title	Proportion of Patients Achieving DAS28-CRP <2.6 at Week 24, Comparison Between Fostamatinib and Placebo
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 patients' own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. A DAS28-CRP score of <2.6 is indicative of remission of RA symptoms. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once daily.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set includes those patients who received at least 1 dose of investigational product. Patients were analysed by randomised treatment in accordance with the intention to treat principle.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Measure Participants	105	108	109
Number [Percentage of responders]	11.4	7.4	3.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Regression, Logistic
	Comments	Odds ratio and 95% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.1
	Confidence Interval	(2-Sided) 95%; 1.21 to 13.91
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio of >1 indicates a benefit towards fostamatinib.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.197
	Comments	Nominal p-value presented for Group B comparison. Formal statistical testing could not be carried out due to the predefined multiplicity procedure (primary variable comparison of Group B versus Group C was non-significant).
	Method	Regression, Logistic
	Comments	Odds ratio and 95% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; 0.65 to 8.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio of >1 indicates a benefit towards fostamatinib.

7. Secondary Outcome

Title	Proportion of Patients Achieving DAS28-CRP <=3.2 at Week 12, Comparison Between Fostamatinib and Placebo
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 patients' own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. A DAS28-CRP score of <=3.2 indicates low disease activity. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once daily.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set includes those patients who received at least 1 dose of investigational product. Patients were analysed by randomised treatment in accordance with the intention to treat principle.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Measure Participants	105	108	109
Number [Percentage of responders]	18.1	20.4	5.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Regression, Logistic
	Comments	Odds ratio and 95% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.1
	Confidence Interval	(2-Sided) 95%; 1.54 to 10.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio of >1 indicates a benefit towards fostamatinib.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	Nominal p-value presented for Group B comparison. Formal statistical testing could not be carried out due to the predefined multiplicity procedure (primary variable comparison of Group B versus Group C was non-significant).
	Method	Regression, Logistic
	Comments	Odds ratio and 95% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95%; 1.79 to 12.30
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio of >1 indicates a benefit towards fostamatinib.

8. Secondary Outcome

Title	Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo
Description	Change from baseline in DAS28-CRP at Week 24 was categorised using the European League Against Rheumatism (EULAR) response criteria. BID = twice daily, CRP = C-reactive protein, DAS28 = Disease Activity Score based on a 28-joint count, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once a day.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set includes those patients who received at least 1 dose of investigational product. Patients were analysed by randomised treatment in accordance with the intention to treat principle.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Measure Participants	105	108	109
No response	46.7 (1.46)	54.6 (1.34)	67.9 (1.30)
Moderate response	29.5	34.3	26.6
Good response	23.8	11.1	5.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Nominal p value only. This was not included in the pre-defined multiplicity testing procedure.
	Method	Proportional odds model
	Comments	No response, moderate response and good response are included in the proportional odds model with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.27
	Confidence Interval	(2-Sided) 95%; 1.86 to 5.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio >1 indicates a benefit towards fostamatinib.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments	Nominal p-value only. This was not included in the pre-defined multiplicity testing procedure.
	Method	Proportional odds model
	Comments	No response, moderate response and good response are included in the proportional odds model with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.89
	Confidence Interval	(2-Sided) 95%; 1.07 to 3.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio >1 indicates a benefit towards fostamatinib.

9. Secondary Outcome

Title	Proportion of Patients With a HAQ-DI Response at Week 24 - Comparison Between Fostamatinib and Placebo
Description	HAQ-DI: Health Assessment Questionnaire - Disability Index, a measure of physical function. The HAQ-DI score is calculated by summing the category scores from 8 sub-categories (ie, scores for patient ability in dressing and grooming, rising, eating, walking, hygeine, reach, grip and common daily activities) and dividing by the number of categories completed. The HAQ-DI score takes values between 0 and 3, with a higher score indicating greater disability. A HAQ-DI response is a reduction from baseline in HAQ-DI greater than or equal to the minimally important difference (0.22). BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once a day.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set includes those patients who received at least 1 dose of investigational product. Patients were analysed by randomised treatment in accordance with the intention to treat principle.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Measure Participants	105	108	109
Number [Percentage of responders]	41.9	31.5	23.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Regression, Logistic
	Comments	Odds ratio and 95% confidence intervals are calculated using logistic regression with treatment and pooled country as factors
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.4
	Confidence Interval	(2-Sided) 95%; 1.33 to 4.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio >1 indicates a benefit towards fostamatinib.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.186
	Comments	Nominal p-value presented for Group B comparison. Formal statistical testing could not be carried out due to the predefined multiplicity procedure (primary variable comparison of Group B versus Group C was non-significant).
	Method	Regression, Logistic
	Comments	Odds ratio and 95% confidence intervals are calculated using logistic regression with treatment and pooled country as factors
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; 0.82 to 2.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio >1 indicates a benefit towards fostamatinib.

10. Secondary Outcome

Title	Change From Baseline to Week 24 in mTSS Score, Comparison Between Fostamatinib and Placebo
Description	mTSS: modified total sharp score, a measure of structural progression based upon X-rays. Hand and foot joints are scored for eroisions and joint space narrowing and the results summed to give a value between 0 and 488. A higher value represents more serious progression of the disease. After disregarding ineligible records, patients with 2 or more non-missing values had missing data imputed via linear extrapolation/interpolation methods. Patients with only 1 result were excluded from the analysis. ANCOVA = Analysis of covariance, BID = twice daily, IP = investigational product, PO = orally, QD = once a day.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set includes patients who received at least 1 dose of IP. Patients were analysed by randomised treatment in accordance with the intention to treat principle. Measurements at 2 timepoints are required for a patient to be included in the analysis; therefore patients with only 1 result have been excluded from the analysis population.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Measure Participants	81	87	88
Mean (Standard Deviation) [Units on a scale]	0.80 (2.636)	0.18 (3.455)	0.84 (1.989)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, PLACEBO PO
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.729
	Comments	Nominal p-value only. This was not included in the pre-defined multiplicity procedure. As this is a non-parametric test p-values alone are presented rather than an estimated treatment difference.
	Method	ANCOVA
	Comments	This was performed on the ranks of the change from baseline, by pooled country, including a term for the ranks of the baseline score as covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, PLACEBO PO
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	Nominal p-value only. This was not included in the pre-defined multiplicity procedure. As this is a non-parametric test p-values alone are presented rather than an estimated treatment difference.
	Method	ANCOVA
	Comments	This was performed on the ranks of the change from baseline, by pooled country, including a term for the ranks of the baseline score as covariate.

11. Secondary Outcome

Title	SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Placebo at Week 24
Description	SF-36: 36 item short form health survey, as a measure of health-related quality of life. Scores for 8 sub-domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Function, Role-Emotional and Mental Health) are derived and normalised to a scale of 0 to 100. The physical and mental component scores (PCS and MCS) are derived by multiplying each of these 8 scores by a constant, summing them and standardising against a population with a mean of 50, standard deviation of 10. A higher score represents a better quality of life. Mean changes from baseline score are presented as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. Mean refers to change in scores at Week 24. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease modifying antirheumatic drugs, PO = orally, QD = once daily
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set includes those patients who received at least 1 dose of investigational product. Patients were analysed by randomised treatment in accordance with the intention to treat principle.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Measure Participants	104	108	109
Mean (Standard Deviation) [Units on a scale]	5 (8.3)	4 (7.4)	2 (6.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	ANCOVA
	Comments	Improvement from baseline, including terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	2.60
	Confidence Interval	() 95%; 0.65 to 4.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.118
	Comments
	Method	ANCOVA
	Comments	Improvement from baseline, including terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	1.53
	Confidence Interval	(2-Sided) 95%; -0.39 to 3.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Placebo at Week 24
Description	SF-36: 36 item short form health survey, as a measure of health-related quality of life. The SF-36 scores for 8 sub-domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Function, Role-Emotional and Mental Health) are derived and normalised to a scale of 0 to 100. The physical and mental component scores (PCS and MCS) are derived by multiplying each of these 8 scores by a constant, summing them and standardising against a population with a mean of 50, standard deviation of 10. A higher score represents a better quality of life. Mean changes from baseline score are presented as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. Mean refers to change in score at Week 24. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease modifying antirheumatic drugs, PO = orally, QD = once daily.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set includes those patients who received at least 1 dose of investigational product. Patients were analysed by randomised treatment in accordance with the intention to treat principle.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C
Measure Participants	104	108	109
Mean (Standard Deviation) [Units on a scale]	2 (8.6)	2 (7.0)	2 (7.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.487
	Comments
	Method	ANCOVA
	Comments	Improvement from baseline, including terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.67
	Confidence Interval	() 95%; -1.23 to 2.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, PLACEBO PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.516
	Comments
	Method	ANCOVA
	Comments	Improvement from baseline, including terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; -1.26 to 2.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	FOSTA 100 MG BID PO		FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO		PLACEBO PO
Arm/Group Description	Dosing Group A		Dosing Group B		Dosing Group C
All Cause Mortality
	FOSTA 100 MG BID PO		FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO		PLACEBO PO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	FOSTA 100 MG BID PO		FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO		PLACEBO PO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/105 (6.7%)		7/108 (6.5%)		6/109 (5.5%)
Blood and lymphatic system disorders
ANAEMIA	0/105 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1
Cardiac disorders
ACUTE CORONARY SYNDROME	0/105 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1
ARTERIOSCLEROSIS CORONARY ARTERY	1/105 (1%)	1	0/108 (0%)	0	0/109 (0%)	0
CARDIAC FAILURE CONGESTIVE	0/105 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0
CARDIO-RESPIRATORY ARREST	0/105 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0
CORONARY ARTERY OCCLUSION	0/105 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0
Gastrointestinal disorders
CROHN'S DISEASE	0/105 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1
DIARRHOEA	0/105 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1
GASTRIC ULCER	1/105 (1%)	1	0/108 (0%)	0	0/109 (0%)	0
GASTRITIS	1/105 (1%)	1	0/108 (0%)	0	0/109 (0%)	0
VOMITING	0/105 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1
General disorders
NON-CARDIAC CHEST PAIN	1/105 (1%)	1	1/108 (0.9%)	1	0/109 (0%)	0
Hepatobiliary disorders
CHOLECYSTITIS	1/105 (1%)	1	0/108 (0%)	0	0/109 (0%)	0
Infections and infestations
DIVERTICULITIS	1/105 (1%)	1	0/108 (0%)	0	0/109 (0%)	0
ESCHERICHIA URINARY TRACT INFECTION	0/105 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1
GASTROENTERITIS	1/105 (1%)	1	2/108 (1.9%)	2	0/109 (0%)	0
GASTROENTERITIS BACTERIAL	1/105 (1%)	1	0/108 (0%)	0	0/109 (0%)	0
HERPES PHARYNGITIS	0/105 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	2
OROPHARYNGEAL CANDIDIASIS	0/105 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1
Metabolism and nutrition disorders
DIABETES MELLITUS	0/105 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1
HYPOKALAEMIA	1/105 (1%)	1	0/108 (0%)	0	0/109 (0%)	0
HYPONATRAEMIA	1/105 (1%)	1	0/108 (0%)	0	0/109 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
RENAL CELL CARCINOMA	0/105 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0
Nervous system disorders
SYNCOPE	0/105 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0
TRANSIENT GLOBAL AMNESIA	1/105 (1%)	1	0/108 (0%)	0	0/109 (0%)	0
Other (Not Including Serious) Adverse Events
	FOSTA 100 MG BID PO		FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO		PLACEBO PO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/105 (48.6%)		49/108 (45.4%)		46/109 (42.2%)
Gastrointestinal disorders
DIARRHOEA	21/105 (20%)	23	29/108 (26.9%)	31	7/109 (6.4%)	8
FLATULENCE	6/105 (5.7%)	7	2/108 (1.9%)	2	4/109 (3.7%)	4
NAUSEA	4/105 (3.8%)	5	7/108 (6.5%)	8	9/109 (8.3%)	9
VOMITING	1/105 (1%)	1	6/108 (5.6%)	6	4/109 (3.7%)	4
General disorders
FATIGUE	0/105 (0%)	0	0/108 (0%)	0	6/109 (5.5%)	6
Infections and infestations
NASOPHARYNGITIS	6/105 (5.7%)	6	4/108 (3.7%)	5	4/109 (3.7%)	4
UPPER RESPIRATORY TRACT INFECTION	6/105 (5.7%)	7	2/108 (1.9%)	2	1/109 (0.9%)	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA	6/105 (5.7%)	6	0/108 (0%)	0	5/109 (4.6%)	5
RHEUMATOID ARTHRITIS	4/105 (3.8%)	5	6/108 (5.6%)	9	11/109 (10.1%)	11
Nervous system disorders
DIZZINESS	7/105 (6.7%)	9	6/108 (5.6%)	6	2/109 (1.8%)	2
HEADACHE	8/105 (7.6%)	8	9/108 (8.3%)	9	11/109 (10.1%)	12
Vascular disorders
HYPERTENSION	14/105 (13.3%)	15	15/108 (13.9%)	15	9/109 (8.3%)	11

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.