OSKIRA-Asia-1: Evaluation of Safety and Effectiveness of Fostamatinib Compared to Placebo in Patients in Asia With Rheumatoid Arthritis

• Sponsor: AstraZeneca (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01569074
• Collaborator: (none)
• Enrollment: 163
• Locations: 35
• Arms: 5
• Duration (Months): 15
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the effectiveness of four dosing regimens of fostamatinib compared to placebo, in patients with rheumatoid arthritis (RA) who are taking methotrexate but not responding. The study will last for 12 weeks.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Fostamatinib; Drug: Fostamatinib; Drug: Fostamatinib; Drug: Fostamatinib; Drug: Placebo	Phase 2

Detailed Description

(OSKIRA-Asia-1): A Multi-centre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Dose Ranging Study in Asia Evaluating Efficacy and Safety of Fostamatinib in Patients with Active Rheumatoid Arthritis who are Inadequate Responders to Methotrexate Therapy

Study Design

• Study Type: Interventional
• Actual Enrollment: 163 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: (OSKIRA-Asia-1): A Multi-centre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Dose Ranging Study in Asia Evaluating Efficacy and Safety of Fostamatinib in Patients With Active Rheumatoid Arthritis Who Are Inadequate Responders to Methotrexate Therapy
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dosing A regimen Oral treatment	Drug: Fostamatinib; Fostamatinib 100mg twice daily for 12 weeks
Experimental: Dosing B regimen Oral treatment	Drug: Fostamatinib; Fostamatinib 100mg twice daily for 4 weeks, followed by150mg once daily up to Week 12
Experimental: Dosing C regimen Oral treatment	Drug: Fostamatinib; Fostamatinib 75mg twice daily for 12 weeks
Experimental: Dosign D regimen Oral treatment	Drug: Fostamatinib; Fostamatinib 50mg twice daily for 12 weeks
Placebo Comparator: Dosing E regimen Oral treatment	Drug: Placebo; Placebo twice daily for 12 weeks

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients Achieving ACR20 at Week 12, Comparison Between Fostamatinib and Placebo [12 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 a day.

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.

2. Proportion of Patients Achieving ACR50 at Week 12, Comparison Between Fostamatinib and Placebo [12 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 a day.

3. Proportion of Patients Achieving ACR70 at Week 12, Comparison Between Fostamatinib and Placebo [12 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 a day.

4. ACRn - Comparison Between Fostamatinib and Placebo at Week 12 [Baseline and 12 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 12. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.

5. 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 patient's own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. 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.

6. Proportion of Patients With DAS28-CRP EULAR Response at Week 12, Comparison Between Fostamatinib and Placebo [12 weeks]

   Change from baseline in DAS28-CRP at Week 12 was derived and categorised using the European League Against Rheumatism (EULAR) response criteria. BID = twice a day, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once a day.

7. Proportion of Patients With HAQ-DI Response at Week 12, Comparison Between Fostamatinib and Placebo [12 weeks]

   HAQ-DI: Health Assessment Questionnaire - Disability Index, a measure of physical function. The HAQ-DI score is calculated by summing scores from 8 sub-categories (ie, scores for patient ability in dressing and grooming, rising, eating, walking, hygiene, 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 higher score indicating greater disability. 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.

8. SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Placebo at Week 12 [Baseline and 12 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 mean of 50, standard deviation of 10. A higher score represents better quality of life. Mean changes from baseline 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 12. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.

9. SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Placebo at Week 12 [Baseline and 12 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 mean of 50, standard deviation of 10. A higher score represents better quality of life. Mean changes from baseline 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 12. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.

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

• 6 or more swollen joints and 6 or more tender/painful joints from certain joints in the hands, wrists, arms and knees

• At least one of: positive result for rheumatoid factor test, either in the past or currently (blood test); x-ray showing bone erosion within the last 12 months; presence of certain antibodies in the blood (blood test)

• Currently taking methotrexate for at least 4 months (and on a stable dose for at least 6 weeks)

Exclusion Criteria:

• Females who are pregnant or breast feeding

• Certain inflammatory conditions (other than rheumatoid arthritis), connective tissue diseases or chronic pain disorders.

• Previously taken, but not responded to, certain biological treatments for rheumatoid arthritis

• High blood pressure that is not controlled by medication

• Low levels of neutrophils in the blood (blood test).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	New Territories	HK	Hong Kong
2	Research Site	Hong Kong		Hong Kong
3	Research Site	Matsuyama	Ehime	Japan
4	Research Site	Fukuoka-shi	Fukuoka	Japan
5	Research Site	Kitakyushu-shi	Fukuoka	Japan
6	Research Site	Kurume	Fukuoka	Japan
7	Research Site	Sapporo	Hokkaido	Japan
8	Research Site	Kato-shi	Hyogo	Japan
9	Research Site	Kasama-shi	Ibaraki	Japan
10	Research Site	Kumamoto-shi	Kumamoto	Japan
11	Research Site	Sendai	Miyagi	Japan
12	Research Site	Isahaya	Nagasaki	Japan
13	Research Site	Nagasaki-shi	Nagasaki	Japan
14	Research Site	Omura-shi	Nagasaki	Japan
15	Research Site	Sasebo-shi	Nagasaki	Japan
16	Research Site	Shibata	Niigata	Japan
17	Research Site	Okayama-shi	Okayama	Japan
18	Research Site	Tomigusuku-shi	Okinawa	Japan
19	Research Site	Matsue-shi	Shimane	Japan
20	Research Site	Hamamatsu-shi	Shizuoka	Japan
21	Research Site	Itabashi	Tokyo	Japan
22	Research Site	Shinjuku	Tokyo	Japan
23	Research Site	Nagasaki		Japan
24	Research Site	Anyang-si	Gyeonggi-do	Korea, Republic of
25	Research Site	Gwangju		Korea, Republic of
26	Research Site	Incheon		Korea, Republic of
27	Research Site	Seoul		Korea, Republic of
28	Research Site	Chiayi		Taiwan
29	Research Site	Kaohsiung		Taiwan
30	Research Site	Taichung		Taiwan
31	Research Site	Taipei		Taiwan
32	Research Site	Bangkok		Thailand
33	Research Site	Singapore		Thailand
34	Research Site	Hanoi		Vietnam
35	Research Site	Ho Chi Minh		Vietnam

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Neil - Mackillop, MD, AstraZeneca

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01569074
• Other Study ID Numbers: D4300C00008
• First Posted: Apr 2, 2012
• 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 298 patients were enrolled: 31, 33, 33, 33 & 33 were randomised to Groups A, B, C, D & E respectively (all received at least 1 dose of investigational product).
Pre-assignment Detail	A total of 135 patients failed screening.

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Dosing Group D	Dosing Group E
Period Title: Overall Study
STARTED	31	33	33	33	33
Randomised But Did Not Receive Treatment	0	0	0	0	0
COMPLETED	24	24	21	25	25
NOT COMPLETED	7	9	12	8	8

Baseline Characteristics

Arm/Group Title	FOSTA 100 MG BID PO	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO	Total
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Dosing Group D	Dosing Group E	Total of all reporting groups
Overall Participants	31	33	33	33	33	163
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51 (14.3)	55 (10.4)	56 (11.5)	50 (11.4)	53 (11.3)	53 (11.9)
Sex: Female, Male (Count of Participants)
Female	31 100%	25 75.8%	27 81.8%	31 93.9%	28 84.8%	142 87.1%
Male	0 0%	8 24.2%	6 18.2%	2 6.1%	5 15.2%	21 12.9%
Race/Ethnicity, Customized (Number) [Number]
Asian	31 100%	33 100%	33 100%	33 100%	33 100%	163 100%
White	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Indian or Pakistani	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients Achieving ACR20 at Week 12, 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 a day.
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	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Dosing Group D	Dosing Group E
Measure Participants	26	29	27	28	28
Number [Percentage of responders]	53.8	55.2	25.9	46.4	32.1

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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.059
	Comments	Week 12
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 80%; 0.07 to 0.39
	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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.054
	Comments	Week 12
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 80%; 0.08 to 0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FOSTA 75 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.570
	Comments	Week 12
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 80%; -0.20 to 0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FOSTA 50 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.262
	Comments	Week 12
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 80%; -0.02 to 0.29
	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.
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. The fostamatinib 100 mg BID combined group contains 31 patients from Dosing Group A and 33 patients from Dosing Group B.

Arm/Group Title	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO	FOSTA 100 MG BID PO
Arm/Group Description	Dosing Group C	Dosing Group D	Dosing Group E	Dosing Group A
Measure Participants	33	33	33	64
Number [Percentage of responders]	21.2	18.2	15.2	25.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FOSTA 75 MG BID PO, FOSTA 50 MG BID PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.172
	Comments	Week 1
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 80%; 0.01 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID PO, FOSTA 75 MG BID PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.489
	Comments	Week 1
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 80%; -0.05 to 0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO, FOSTA 75 MG BID PO
	Comments	Non-responder imputation has been applied following premature withdrawal, or increased dose of methotrexate or any DMARD initiation, or following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.704
	Comments	Week 1
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 80%; -0.08 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Proportion of Patients Achieving ACR50 at Week 12, 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 a day.
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	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Dosing Group D	Dosing Group E
Measure Participants	26	29	27	28	28
Number [Percentage of responders]	30.8	34.5	7.4	10.7	14.3

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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.114
	Comments	Week 12
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 80%; 0.03 to 0.31
	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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.035
	Comments	Week 12
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 80%; 0.08 to 0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FOSTA 75 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.334
	Comments	Week 12
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 80%; -0.17 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FOSTA 50 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.645
	Comments	Week 12
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 80%; -0.13 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Proportion of Patients Achieving ACR70 at Week 12, 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 a day.
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	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Dosing Group D	Dosing Group E
Measure Participants	26	29	27	28	28
Number [Percentage of responders]	11.5	13.8	0	0	0

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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.028
	Comments	Week 12
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 80%; 0.05 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.021
	Comments	Week 12
	Method	Mantel Haenszel
	Comments	Treatment difference in proportion of responders, with a Mantel-Haenszel approach stratified by pooled country.
Method of Estimation	Estimation Parameter	Weighted difference in proportions
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 80%; 0.06 to 0.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	ACRn - Comparison Between Fostamatinib and Placebo at Week 12
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 12. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.
Time Frame	Baseline and 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	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Dosing Group D	Dosing Group E
Measure Participants	26	29	27	28	28
Mean (Standard Deviation) [Percentage improvement from baseline]	25.52 (37.029)	24.18 (39.925)	3.59 (29.774)	15.88 (24.354)	10.94 (28.302)

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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.073
	Comments	As this is a non-parametric test, p-values alone are presented rather than an estimated treatment difference.
	Method	Van Elteren
	Comments	P-value estimated using the Van Elteren method 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 increased dose of methotrexate or any DMARD initiation, or following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.065
	Comments	As this is a non-parametric test, p-values alone are presented rather than an estimated treatment difference.
	Method	Van Elteren
	Comments	P-value estimated using the Van Elteren test stratified by pooled country.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FOSTA 75 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.317
	Comments	As this is a non-parametric test, p-values alone are presented rather than an estimated treatment difference.
	Method	Van Elteren
	Comments	P-value estimated using the Van Elteren method stratified by pooled country.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FOSTA 50 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.263
	Comments	As this is a non-parametric test, p-values alone are presented rather than an estimated treatment difference.
	Method	Van Elteren
	Comments	P-value estimated using the Van Elteren method stratified by pooled country.

6. 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 patient's own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. 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	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Dosing Group D	Dosing Group E
Measure Participants	26	29	27	28	28
Number [Percentage of responders]	34.6 (0.81)	34.5 (0.82)	22.2 (0.77)	17.9 (0.75)	10.7

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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.033
	Comments
	Method	Regression, Logistic
	Comments	Odds ratio and 80% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.3
	Confidence Interval	(2-Sided) 80%; 1.94 to 14.31
	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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.033
	Comments
	Method	Regression, Logistic
	Comments	Odds ratio and 80% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.1
	Confidence Interval	(2-Sided) 80%; 1.92 to 13.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio of >1 indicates a benefit towards fostamatinib.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FOSTA 75 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.257
	Comments
	Method	Regression, Logistic
	Comments	Odds ratio and 80% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 80%; 0.89 to 6.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio of >1 indicates a benefit towards fostamatinib.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FOSTA 50 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.481
	Comments
	Method	Regression, Logistic
	Comments	Odds ratio and 80% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 80%; 0.63 to 5.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio of >1 indicates a benefit towards fostamatinib.

7. Secondary Outcome

Title	Proportion of Patients With DAS28-CRP EULAR Response at Week 12, Comparison Between Fostamatinib and Placebo
Description	Change from baseline in DAS28-CRP at Week 12 was derived and categorised using the European League Against Rheumatism (EULAR) response criteria. BID = twice a day, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once a day.
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	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Dosing Group D	Dosing Group E
Measure Participants	26	29	27	28	28
No response	30.8 (1.46)	41.4 (1.34)	48.1 (1.30)	17.9 (1.58)	35.7
Moderate response	34.6	24.1	29.6	64.3	53.6
Good response	34.6	34.5	22.2	17.9	10.7

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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.131
	Comments
	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	2.17
	Confidence Interval	(2-Sided) 80%; 1.12 to 4.20
	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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.423
	Comments
	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	1.49
	Confidence Interval	(2-Sided) 80%; 0.79 to 2.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio >1 indicates a benefit towards fostamatinib.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FOSTA 75 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.781
	Comments
	Method	Proportional odds model
	Comments	No response, moderate response and good response are included in the proportional odds model with treatment and country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 80%; 0.45 to 1.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio >1 indicates a benefit towards fostamatinib.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FOSTA 50 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.239
	Comments
	Method	Proportional odds model
	Comments	No response, moderate response and good response are included in the proportional odds model with treatment and country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.81
	Confidence Interval	(2-Sided) 80%; 0.95 to 3.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio >1 indicates a benefit towards fostamatinib

8. Secondary Outcome

Title	Proportion of Patients With HAQ-DI Response at Week 12, 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 scores from 8 sub-categories (ie, scores for patient ability in dressing and grooming, rising, eating, walking, hygiene, 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 higher score indicating greater disability. 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	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	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Dosing Group D	Dosing Group E
Measure Participants	26	29	27	28	28
Number [Percentage of responders]	69.2	48.3	44.4	46.4	50.0

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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.169
	Comments	Week 12
	Method	Regression, Logistic
	Comments	Odds ratio and 80% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.2
	Confidence Interval	(2-Sided) 80%; 1.06 to 4.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ration >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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.833
	Comments	Week 12
	Method	Regression, Logistic
	Comments	Odds ratio and 80% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 80%; 0.45 to 1.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio >1 indicates a benefit towards fostamatinib.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FOSTA 75 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.614
	Comments	Week 12
	Method	Regression, Logistic
	Comments	Odds ratio and 80% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 80%; 0.37 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio of >1 indicates a benefit towards fostamatinib.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FOSTA 50 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.748
	Comments	Week 12
	Method	Regression, Logistic
	Comments	Odds ratio and 80% confidence intervals are calculated using Logistic Regression with treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 80%; 0.42 to 1.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio of >1 indicates a benefit towards fostamatinib.

9. Secondary Outcome

Title	SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Placebo at Week 12
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 mean of 50, standard deviation of 10. A higher score represents better quality of life. Mean changes from baseline 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 12. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.
Time Frame	Baseline and 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	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Dosing Group D	Dosing Group E
Measure Participants	25	29	26	27	27
Mean (Standard Deviation) [Units on a scale]	7 (7.5)	4 (7.4)	3 (6.8)	5 (5.6)	3 (5.1)

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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.087
	Comments
	Method	ANCOVA
	Comments	Including terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	3.01
	Confidence Interval	(2-Sided) 80%; 0.76 to 5.26
	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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.881
	Comments
	Method	ANCOVA
	Comments	Including terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 80%; -1.91 to 2.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FOSTA 75 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.806
	Comments
	Method	ANCOVA
	Comments	Includes terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 80%; -2.64 to 1.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FOSTA 50 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.548
	Comments
	Method	ANCOVA
	Comments	Includes terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 80%; -1.17 to 3.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Placebo at Week 12
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 mean of 50, standard deviation of 10. A higher score represents better quality of life. Mean changes from baseline 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 12. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.
Time Frame	Baseline and 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	FOSTA 75 MG BID PO	FOSTA 50 MG BID PO	PLACEBO PO
Arm/Group Description	Dosing Group A	Dosing Group B	Dosing Group C	Dosing Group D	Dosing Group E
Measure Participants	25	29	26	27	27
Mean (Standard Deviation) [Units on a scale]	7 (8.7)	6 (7.7)	2 (7.0)	5 (8.9)	4 (7.9)

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 increased dose of methotrexate or any DMARD initiation, or following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.139
	Comments
	Method	ANCOVA
	Comments	Including terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	3.12
	Confidence Interval	(2-Sided) 80%; 0.42 to 5.82
	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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.223
	Comments
	Method	ANCOVA
	Comments	Including terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	2.47
	Confidence Interval	(2-Sided) 80%; -0.13 to 5.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FOSTA 75 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.432
	Comments
	Method	ANCOVA
	Comments	Includes terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-1.63
	Confidence Interval	(2-Sided) 80%; -4.30 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FOSTA 50 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 following receipt of any parenteral steroids, or for patients with no post baseline data. Subjects 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	0.481
	Comments
	Method	ANCOVA
	Comments	Includes terms for baseline as a continuous covariate and treatment and pooled country as factors.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	1.45
	Confidence Interval	(2-Sided) 80%; -1.19 to 4.09
	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		FOSTA 50 MG BID PO		FOSTA 75 MG BID PO		PLACEBO PO
Arm/Group Description	Dosing Group A		Dosing Group B		Dosing Group D		Dosing Group C		Dosing Group E
All Cause Mortality
	FOSTA 100 MG BID PO		FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO		FOSTA 50 MG BID PO		FOSTA 75 MG BID PO		PLACEBO PO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	FOSTA 100 MG BID PO		FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO		FOSTA 50 MG BID PO		FOSTA 75 MG BID PO		PLACEBO PO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/31 (3.2%)		1/33 (3%)		3/33 (9.1%)		0/33 (0%)		1/33 (3%)
Gastrointestinal disorders
DIARRHOEA	0/31 (0%)	0	1/33 (3%)	1	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0
Infections and infestations
LARYNGITIS VIRAL	1/31 (3.2%)	1	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0
Musculoskeletal and connective tissue disorders
OSTEOPOROSIS	0/31 (0%)	0	0/33 (0%)	0	1/33 (3%)	1	0/33 (0%)	0	0/33 (0%)	0
RHEUMATOID ARTHRITIS	0/31 (0%)	0	0/33 (0%)	0	1/33 (3%)	1	0/33 (0%)	0	1/33 (3%)	1
Nervous system disorders
CARPAL TUNNEL SYNDROME	0/31 (0%)	0	0/33 (0%)	0	1/33 (3%)	1	0/33 (0%)	0	0/33 (0%)	0
Vascular disorders
HYPERTENSION	1/31 (3.2%)	1	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0
Other (Not Including Serious) Adverse Events
	FOSTA 100 MG BID PO		FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO		FOSTA 50 MG BID PO		FOSTA 75 MG BID PO		PLACEBO PO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/31 (67.7%)		17/33 (51.5%)		17/33 (51.5%)		16/33 (48.5%)		15/33 (45.5%)
Blood and lymphatic system disorders
ANAEMIA	0/31 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	2/33 (6.1%)	2
LEUKOPENIA	0/31 (0%)	0	0/33 (0%)	0	2/33 (6.1%)	3	1/33 (3%)	1	2/33 (6.1%)	3
NEUTROPENIA	4/31 (12.9%)	6	2/33 (6.1%)	2	5/33 (15.2%)	7	4/33 (12.1%)	4	3/33 (9.1%)	5
Cardiac disorders
PALPITATIONS	0/31 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	2/33 (6.1%)	2
Gastrointestinal disorders
DIARRHOEA	5/31 (16.1%)	6	5/33 (15.2%)	5	1/33 (3%)	1	2/33 (6.1%)	2	0/33 (0%)	0
GASTRITIS	3/31 (9.7%)	3	1/33 (3%)	2	1/33 (3%)	2	0/33 (0%)	0	1/33 (3%)	1
NAUSEA	1/31 (3.2%)	1	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	3/33 (9.1%)	3
VOMITING	2/31 (6.5%)	2	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	1/33 (3%)	1
General disorders
PYREXIA	0/31 (0%)	0	1/33 (3%)	1	2/33 (6.1%)	2	2/33 (6.1%)	2	0/33 (0%)	0
Infections and infestations
CELLULITIS	1/31 (3.2%)	1	0/33 (0%)	0	2/33 (6.1%)	2	0/33 (0%)	0	0/33 (0%)	0
NASOPHARYNGITIS	2/31 (6.5%)	2	0/33 (0%)	0	3/33 (9.1%)	3	2/33 (6.1%)	2	0/33 (0%)	0
UPPER RESPIRATORY TRACT INFECTION	3/31 (9.7%)	3	2/33 (6.1%)	2	0/33 (0%)	0	1/33 (3%)	1	1/33 (3%)	1
VIRAL UPPER RESPIRATORY TRACT INFECTION	0/31 (0%)	0	1/33 (3%)	1	2/33 (6.1%)	2	0/33 (0%)	0	0/33 (0%)	0
Investigations
ALANINE AMINOTRANSFERASE INCREASED	0/31 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	2/33 (6.1%)	2
GAMMA-GLUTAMYLTRANSFERASE INCREASED	0/31 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	2/33 (6.1%)	2
Nervous system disorders
DIZZINESS	1/31 (3.2%)	1	0/33 (0%)	0	1/33 (3%)	2	1/33 (3%)	1	2/33 (6.1%)	2
HEADACHE	1/31 (3.2%)	1	2/33 (6.1%)	2	0/33 (0%)	0	1/33 (3%)	1	0/33 (0%)	0
Psychiatric disorders
INSOMNIA	0/31 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	2/33 (6.1%)	2
Respiratory, thoracic and mediastinal disorders
COUGH	0/31 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	3/33 (9.1%)	3	0/33 (0%)	0
Skin and subcutaneous tissue disorders
ALOPECIA	0/31 (0%)	0	0/33 (0%)	0	2/33 (6.1%)	2	0/33 (0%)	0	0/33 (0%)	0
PRURITUS	0/31 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	2/33 (6.1%)	2
Vascular disorders
HYPERTENSION	8/31 (25.8%)	8	6/33 (18.2%)	6	3/33 (9.1%)	3	6/33 (18.2%)	6	2/33 (6.1%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.