Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis
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.
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
Interventions
DRUGfostamatinib
fostamatinib 100 mg twice daily
DRUGplacebo
Placebo twice daily
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
Countries
Argentina, Belgium, Brazil, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Mexico, Portugal, South Africa, Spain, United Kingdom, United States
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 details
A total of 315 patients failed screening.
Participants by arm
| Arm | Count |
|---|---|
| FOSTA 100 MG BID PO Dosing Group A | 105 |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO Dosing Group B | 108 |
| PLACEBO PO Dosing Group C | 109 |
| Total | 322 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 10 | 10 |
| Overall Study | eg, change in circumstances | 7 | 3 | 2 |
| Overall Study | Entered the long-term extension study | 18 | 21 | 35 |
| Overall Study | Lack of therapeutic response | 0 | 7 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Severe non-compliance to the protocol | 2 | 1 | 2 |
| Overall Study | Study-specific discontinuation criteria | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | FOSTA 100 MG BID PO | FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | PLACEBO PO | Total |
|---|---|---|---|---|
| Age, Continuous | 54 years STANDARD_DEVIATION 11.9 | 51 years STANDARD_DEVIATION 12 | 53 years STANDARD_DEVIATION 13 | 53 years STANDARD_DEVIATION 12.3 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 4 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants | 5 Participants | 9 Participants | 23 Participants |
| Race/Ethnicity, Customized Indian or Pakistani | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 6 Participants | 7 Participants | 20 Participants |
| Race/Ethnicity, Customized White | 86 Participants | 92 Participants | 91 Participants | 269 Participants |
| Sex: Female, Male Female | 89 Participants | 87 Participants | 85 Participants | 261 Participants |
| Sex: Female, Male Male | 16 Participants | 21 Participants | 24 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 51 / 105 | 49 / 108 | 46 / 109 |
| serious Total, serious adverse events | 7 / 105 | 7 / 108 | 6 / 109 |
Outcome results
Primary
Proportion of Patients Achieving ACR20 at Week 24, Comparison Between Fostamatinib and Placebo
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| FOSTA 100 MG BID PO | Proportion of Patients Achieving ACR20 at Week 24, Comparison Between Fostamatinib and Placebo | 36.2 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving ACR20 at Week 24, Comparison Between Fostamatinib and Placebo | 27.8 Percentage of responders |
| PLACEBO PO | Proportion of Patients Achieving ACR20 at Week 24, Comparison Between Fostamatinib and Placebo | 21.1 Percentage of responders |
Comparison: 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.p-value: 0.00495% CI: [0.05, 0.28]Mantel Haenszel
Comparison: 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.p-value: 0.16895% CI: [-0.03, 0.18]Mantel Haenszel
Secondary
ACRn - Comparison Between Fostamatinib and Placebo at Week 24
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FOSTA 100 MG BID PO | ACRn - Comparison Between Fostamatinib and Placebo at Week 24 | 16.25 Percentage improvement from baseline | Standard Deviation 36.994 |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | ACRn - Comparison Between Fostamatinib and Placebo at Week 24 | 13.00 Percentage improvement from baseline | Standard Deviation 24.718 |
| PLACEBO PO | ACRn - Comparison Between Fostamatinib and Placebo at Week 24 | 5.87 Percentage improvement from baseline | Standard Deviation 26.726 |
Comparison: 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.p-value: 0.01Van Elteren
Comparison: 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.p-value: 0.019Van Elteren
Secondary
Change From Baseline to Week 24 in mTSS Score, Comparison Between Fostamatinib and Placebo
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FOSTA 100 MG BID PO | Change From Baseline to Week 24 in mTSS Score, Comparison Between Fostamatinib and Placebo | 0.80 Units on a scale | Standard Deviation 2.636 |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Change From Baseline to Week 24 in mTSS Score, Comparison Between Fostamatinib and Placebo | 0.18 Units on a scale | Standard Deviation 3.455 |
| PLACEBO PO | Change From Baseline to Week 24 in mTSS Score, Comparison Between Fostamatinib and Placebo | 0.84 Units on a scale | Standard Deviation 1.989 |
p-value: 0.729ANCOVA
p-value: 0.019ANCOVA
Secondary
Proportion of Patients Achieving ACR20 at Week 1, Comparison Between Fostamatinib and Placebo
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| FOSTA 100 MG BID PO | Proportion of Patients Achieving ACR20 at Week 1, Comparison Between Fostamatinib and Placebo | 3.7 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving ACR20 at Week 1, Comparison Between Fostamatinib and Placebo | 25.4 Percentage of responders |
Comparison: 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.p-value: <0.00195% CI: [0.16, 0.29]Mantel Haenszel
Secondary
Proportion of Patients Achieving ACR50 at Week 24, Comparison Between Fostamatinib and Placebo
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| FOSTA 100 MG BID PO | Proportion of Patients Achieving ACR50 at Week 24, Comparison Between Fostamatinib and Placebo | 18.1 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving ACR50 at Week 24, Comparison Between Fostamatinib and Placebo | 13.0 Percentage of responders |
| PLACEBO PO | Proportion of Patients Achieving ACR50 at Week 24, Comparison Between Fostamatinib and Placebo | 8.3 Percentage of responders |
Comparison: 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.p-value: 0.01495% CI: [0.02, 0.19]Mantel Haenszel
Comparison: 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.p-value: 0.1895% CI: [-0.02, 0.12]Mantel Haenszel
Secondary
Proportion of Patients Achieving ACR70 at Week 24, Comparison Between Fostamatinib and Placebo
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| FOSTA 100 MG BID PO | Proportion of Patients Achieving ACR70 at Week 24, Comparison Between Fostamatinib and Placebo | 14.3 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving ACR70 at Week 24, Comparison Between Fostamatinib and Placebo | 2.8 Percentage of responders |
| PLACEBO PO | Proportion of Patients Achieving ACR70 at Week 24, Comparison Between Fostamatinib and Placebo | 2.8 Percentage of responders |
Comparison: 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.p-value: <0.00195% CI: [0.06, 0.19]Mantel Haenszel
Comparison: 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.p-value: 0.89195% CI: [-0.04, 0.04]Mantel Haenszel
Secondary
Proportion of Patients Achieving DAS28-CRP <2.6 at Week 24, Comparison Between Fostamatinib and Placebo
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP <2.6 at Week 24, Comparison Between Fostamatinib and Placebo | 11.4 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving DAS28-CRP <2.6 at Week 24, Comparison Between Fostamatinib and Placebo | 7.4 Percentage of responders |
| PLACEBO PO | Proportion of Patients Achieving DAS28-CRP <2.6 at Week 24, Comparison Between Fostamatinib and Placebo | 3.7 Percentage of responders |
Comparison: 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.p-value: 0.02395% CI: [1.21, 13.91]Regression, Logistic
Comparison: 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.p-value: 0.19795% CI: [0.65, 8.23]Regression, Logistic
Secondary
Proportion of Patients Achieving DAS28-CRP <=3.2 at Week 12, Comparison Between Fostamatinib and Placebo
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP <=3.2 at Week 12, Comparison Between Fostamatinib and Placebo | 18.1 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving DAS28-CRP <=3.2 at Week 12, Comparison Between Fostamatinib and Placebo | 20.4 Percentage of responders |
| PLACEBO PO | Proportion of Patients Achieving DAS28-CRP <=3.2 at Week 12, Comparison Between Fostamatinib and Placebo | 5.5 Percentage of responders |
Comparison: 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.p-value: 0.00595% CI: [1.54, 10.92]Regression, Logistic
Comparison: 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.p-value: 0.00295% CI: [1.79, 12.3]Regression, Logistic
Secondary
Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo
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
Population: 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 | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo | Moderate response | 29.5 Percentage of responders | — |
| FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo | No response | 46.7 Percentage of responders | 1.46 |
| FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo | Good response | 23.8 Percentage of responders | — |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo | Moderate response | 34.3 Percentage of responders | — |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo | No response | 54.6 Percentage of responders | 1.34 |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo | Good response | 11.1 Percentage of responders | — |
| PLACEBO PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo | No response | 67.9 Percentage of responders | 1.3 |
| PLACEBO PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo | Good response | 5.5 Percentage of responders | — |
| PLACEBO PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo | Moderate response | 26.6 Percentage of responders | — |
Comparison: 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 datap-value: <0.00195% CI: [1.86, 5.76]Proportional odds model
Comparison: 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 datap-value: 0.02895% CI: [1.07, 3.31]Proportional odds model
Secondary
Proportion of Patients With a HAQ-DI Response at Week 24 - Comparison Between Fostamatinib and Placebo
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| FOSTA 100 MG BID PO | Proportion of Patients With a HAQ-DI Response at Week 24 - Comparison Between Fostamatinib and Placebo | 41.9 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients With a HAQ-DI Response at Week 24 - Comparison Between Fostamatinib and Placebo | 31.5 Percentage of responders |
| PLACEBO PO | Proportion of Patients With a HAQ-DI Response at Week 24 - Comparison Between Fostamatinib and Placebo | 23.9 Percentage of responders |
Comparison: 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.p-value: 0.00495% CI: [1.33, 4.45]Regression, Logistic
Comparison: 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.p-value: 0.18695% CI: [0.82, 2.79]Regression, Logistic
Secondary
SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Placebo at Week 24
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FOSTA 100 MG BID PO | SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Placebo at Week 24 | 2 Units on a scale | Standard Deviation 8.6 |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Placebo at Week 24 | 2 Units on a scale | Standard Deviation 7 |
| PLACEBO PO | SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Placebo at Week 24 | 2 Units on a scale | Standard Deviation 7.3 |
Comparison: 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.p-value: 0.48795% CI: [-1.23, 2.58]ANCOVA
Comparison: 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.p-value: 0.51695% CI: [-1.26, 2.51]ANCOVA
Secondary
SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Placebo at Week 24
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FOSTA 100 MG BID PO | SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Placebo at Week 24 | 5 Units on a scale | Standard Deviation 8.3 |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Placebo at Week 24 | 4 Units on a scale | Standard Deviation 7.4 |
| PLACEBO PO | SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Placebo at Week 24 | 2 Units on a scale | Standard Deviation 6.2 |
Comparison: 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.p-value: 0.00995% CI: [0.65, 4.56]ANCOVA
Comparison: 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.p-value: 0.11895% CI: [-0.39, 3.44]ANCOVA