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 but not responding. The study will last for 1 year.
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
Placebo for 24 weeks followed by fostamatinib 100 mg 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 12 months 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 a TNF alpha antagonist, anakinra or previous treatment with other biological agent * Severe renal impairment * Neutropenia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With 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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID=twice daily, CRP=C-reactive protein, DMARD=disease-modifying anti-rheumatic drug, PO=orally, QD=once a day. |
| Change From Baseline to Week 24 in mTSS, 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 erosions and joint space narrowing and the results summed to give a value between 0 and 448. A higher value represents more serious progression of the disease. After disregarding ineligible records, patients with 2 or more non-missing values have had missing data imputed via linear extrapolation/interpolation methods. Patients with only 1 result have been excluded from the analysis. ANCOVA=analysis of covariance, BID=twice daily, DMARD=disease-modifying anti-rheumatic drug, IP=investigational product, PO=orally, QD=once a day. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Achieving ACR70 up to Week 24 | 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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID=twice daily, CRP=C-reactive protein, DMARD=Disease-modifying anti-rheumatic drug, PO=orally, QD=once a day. |
| ACRn - Comparison Between Fostamatinib and Placebo at Week 24 | 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 CRP) 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. BID=twice daily, CI=confidence interval, CRP=C-reactive protein, DMARD=Disease-modifying anti-rheumatic drug, PO=orally, QD=once a day, RA=rheumatoid arthritis. Mean refers to change at Week 24. |
| Proportion of Patients Achieving DAS28-CRP <2.6 at Week 12 | 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. 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 a day. |
| Proportion of Patients Achieving DAS28-CRP <2.6 at Week 24 | 24 weeks | DAS28-CRP: Disease Activity Score based on a count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (CRP) and the patient's own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. 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 a day. |
| ACR20 - Proportion of Patients Achieving ACR20, Comparison Between Fostamatinib and Placebo at Week 1 | 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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID=twice daily, CRP=C-reactive protein, DMARD=Disease-modifying anti-rheumatic drug, PO=orally. |
| HAQ-DI Response - Comparison of the Change (>=0.22) From Baseline Between Fostamatinib and Placebo at Week 24 | Baseline and 24 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: 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. |
| 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, a measure of health-related QoL. Scores for 8 sub-domains (Physical Functioning, Role-physical, Bodily Pain, General Health, Vitality, Social Function, Role-emotional & Mental Health) are derived & normalised to a scale of 0-100. Physical Component Scores (PCS) are derived by multiplying each of these 8 scores by a constant, summing them & standardising against a population with mean of 50, standard deviation of 10. Higher scores represent a better QoL. Mean changes from baseline score are presented at each visit as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. ANCOVA=analysis of covariance, BID=twice daily, DMARD=disease modifying antirheumatic drug, PO=orally, QD=once daily, QoL=quality of life. |
| 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, a measure of health-related QoL. Scores for 8 sub-domains (Physical Functioning, Role-physical, Bodily Pain, General Health, Vitality, Social Function, Role-emotional & Mental Health) are derived & normalised to a scale of 0-100. Mental Component Scores (MCS) are derived by multiplying each of these 8 scores by a constant, summing them & standardising against a population with mean of 50, standard deviation of 10. Higher scores represent a better QoL. Mean changes from baseline score are presented at each visit as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. ANCOVA=analysis of covariance, BID=twice daily, DMARD=disease modifying antirheumatic drug, PO=orally, QD=once daily, QoL=quality of life. |
| Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24 | 24 weeks | Change in DAS28 was derived for each post baseline scheduled assessment and categorised using the European League Against Rheumatism (EULAR) response criteria. Non-responder imputation has been applied by carrying the baseline observation forward. 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. |
| Proportion of Patients Achieving ACR50 up to Week 24 | 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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID=twice daily, CRP=C-reactive protein, DMARD=Disease-modifying anti-rheumatic drug, PO=orally, QD=once a day. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Chile, Estonia, France, Hungary, India, Mexico, Peru, Poland, Slovakia, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 1475 patients were enrolled: 311, 306 & 306 were randomised to Groups A, B & C, respectively (310, 304 & 304 received at least 1 dose of IP).
Pre-assignment details
A total of 552 patients failed screening.
Participants by arm
| Arm | Count |
|---|---|
| FOSTA 100 MG BID PO Dosing Group A | 310 |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO Dosing Group B | 304 |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO Dosing Group C | 304 |
| Total | 918 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 25 | 28 | 24 |
| Overall Study | Dev. of study specific discont. criteria | 6 | 16 | 2 |
| Overall Study | Enrolment in long term extension | 42 | 36 | 87 |
| Overall Study | Lack of therapeutic response | 2 | 3 | 4 |
| Overall Study | Lost to Follow-up | 3 | 2 | 2 |
| Overall Study | Not reported | 24 | 25 | 21 |
| Overall Study | Severe non-compliance to protocol | 1 | 3 | 3 |
Baseline characteristics
| Characteristic | FOSTA 100 MG BID PO | FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | Total |
|---|---|---|---|---|
| Age, Continuous | 52 years STANDARD_DEVIATION 12.2 | 52 years STANDARD_DEVIATION 12 | 53 years STANDARD_DEVIATION 11.9 | 52 years STANDARD_DEVIATION 12 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 14 Participants | 12 Participants | 11 Participants | 37 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 10 Participants | 5 Participants | 18 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants | 5 Participants | 11 Participants | 25 Participants |
| Race/Ethnicity, Customized Indian or Pakistani | 20 Participants | 14 Participants | 19 Participants | 53 Participants |
| Race/Ethnicity, Customized Other | 46 Participants | 50 Participants | 49 Participants | 145 Participants |
| Race/Ethnicity, Customized White | 218 Participants | 213 Participants | 209 Participants | 640 Participants |
| Sex: Female, Male Female | 263 Participants | 254 Participants | 253 Participants | 770 Participants |
| Sex: Female, Male Male | 47 Participants | 50 Participants | 51 Participants | 148 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 169 / 310 | 191 / 304 | 64 / 304 | 80 / 304 |
| serious Total, serious adverse events | 24 / 310 | 24 / 304 | 12 / 304 | 5 / 304 |
Outcome results
Primary
Change From Baseline to Week 24 in mTSS, 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 erosions and joint space narrowing and the results summed to give a value between 0 and 448. A higher value represents more serious progression of the disease. After disregarding ineligible records, patients with 2 or more non-missing values have had missing data imputed via linear extrapolation/interpolation methods. Patients with only 1 result have been excluded from the analysis. ANCOVA=analysis of covariance, BID=twice daily, DMARD=disease-modifying anti-rheumatic drug, IP=investigational product, 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 IP. Patients were analysed by randomised treatment. Measurements at 2 timepoints are required in order 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, Comparison Between Fostamatinib and Placebo. | 0.45 Units on a scale | Standard Deviation 2.201 |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Change From Baseline to Week 24 in mTSS, Comparison Between Fostamatinib and Placebo. | 1.29 Units on a scale | Standard Deviation 13.38 |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | Change From Baseline to Week 24 in mTSS, Comparison Between Fostamatinib and Placebo. | 0.13 Units on a scale | Standard Deviation 2.142 |
Comparison: This analysis is performed using an ANCOVA model on the ranks of the change from baseline, by pooled country, including a term for the ranks of the baseline score as a covariate.p-value: 0.252Cochran-Mantel-Haenszel
Comparison: This analysis is performed using an ANCOVA model on the ranks of the change from baseline, by pooled country, including a term for the ranks of the baseline score as a covariate.p-value: 0.17Cochran-Mantel-Haenszel
Primary
Proportion of Patients With 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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID=twice daily, CRP=C-reactive protein, DMARD=disease-modifying anti-rheumatic drug, 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 ACR20 at Week 24, Comparison Between Fostamatinib and Placebo. | 49.0 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients With ACR20 at Week 24, Comparison Between Fostamatinib and Placebo. | 44.4 Percentage of responders |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | Proportion of Patients With ACR20 at Week 24, Comparison Between Fostamatinib and Placebo. | 34.2 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: [0.08, 0.22]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: 0.00695% CI: [0.03, 0.18]Mantel Haenszel
Secondary
ACR20 - Proportion of Patients Achieving ACR20, Comparison Between Fostamatinib and Placebo at Week 1
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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID=twice daily, CRP=C-reactive protein, DMARD=Disease-modifying anti-rheumatic drug, PO=orally.
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 | ACR20 - Proportion of Patients Achieving ACR20, Comparison Between Fostamatinib and Placebo at Week 1 | 18.2 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | ACR20 - Proportion of Patients Achieving ACR20, Comparison Between Fostamatinib and Placebo at Week 1 | 4.9 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: [0.1, 0.17]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 CRP) 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. BID=twice daily, CI=confidence interval, CRP=C-reactive protein, DMARD=Disease-modifying anti-rheumatic drug, PO=orally, QD=once a day, RA=rheumatoid arthritis. Mean refers to change at Week 24.
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 (MEAN) | Dispersion |
|---|---|---|---|
| FOSTA 100 MG BID PO | ACRn - Comparison Between Fostamatinib and Placebo at Week 24 | 26.13 Percentage improvement from baseline | Standard Deviation 30.833 |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | ACRn - Comparison Between Fostamatinib and Placebo at Week 24 | 20.06 Percentage improvement from baseline | Standard Deviation 28.599 |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | ACRn - Comparison Between Fostamatinib and Placebo at Week 24 | 12.92 Percentage improvement from baseline | Standard Deviation 26.611 |
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: <0.001Van Elteren
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: 0.002Van Elteren
Secondary
HAQ-DI Response - Comparison of the Change (>=0.22) From Baseline Between Fostamatinib and Placebo at Week 24
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: 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: 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 (NUMBER) |
|---|---|---|
| FOSTA 100 MG BID PO | HAQ-DI Response - Comparison of the Change (>=0.22) From Baseline Between Fostamatinib and Placebo at Week 24 | 54.8 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | HAQ-DI Response - Comparison of the Change (>=0.22) From Baseline Between Fostamatinib and Placebo at Week 24 | 50.3 Percentage of responders |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | HAQ-DI Response - Comparison of the Change (>=0.22) From Baseline Between Fostamatinib and Placebo at Week 24 | 35.2 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: [1.68, 3.26]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: <0.00195% CI: [1.38, 2.68]Regression, Logistic
Secondary
Proportion of Patients Achieving ACR50 up to Week 24
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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID=twice daily, CRP=C-reactive protein, DMARD=Disease-modifying anti-rheumatic drug, 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 Achieving ACR50 up to Week 24 | 26.1 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving ACR50 up to Week 24 | 18.4 Percentage of responders |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | Proportion of Patients Achieving ACR50 up to Week 24 | 9.9 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: [0.11, 0.22]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: 0.00295% CI: [0.03, 0.14]Mantel Haenszel
Secondary
Proportion of Patients Achieving ACR70 up to Week 24
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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID=twice daily, CRP=C-reactive protein, DMARD=Disease-modifying anti-rheumatic drug, 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 Achieving ACR70 up to Week 24 | 10.3 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving ACR70 up to Week 24 | 5.6 Percentage of responders |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | Proportion of Patients Achieving ACR70 up to Week 24 | 2.0 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: [0.05, 0.12]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: 0.01595% CI: [0.01, 0.07]Mantel Haenszel
Secondary
Proportion of Patients Achieving DAS28-CRP <2.6 at Week 12
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. 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 a day.
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 <2.6 at Week 12 | 10.3 Percentage of responders |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving DAS28-CRP <2.6 at Week 12 | 7.9 Percentage of responders |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP <2.6 at Week 12 | 2.0 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: [2.44, 14.64]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: [1.76, 11.02]Regression, Logistic
Secondary
Proportion of Patients Achieving DAS28-CRP <2.6 at Week 24
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. 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 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 Achieving DAS28-CRP <2.6 at Week 24 | 13.2 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 | 8.6 Percentage of responders |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP <2.6 at Week 24 | 4.9 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: [1.63, 5.67]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: 0.08395% CI: [0.93, 3.5]Regression, Logistic
Secondary
Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24
Change in DAS28 was derived for each post baseline scheduled assessment and categorised using the European League Against Rheumatism (EULAR) response criteria. Non-responder imputation has been applied by carrying the baseline observation forward. 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 | Good response | 26.1 Percentage of responders | — |
| FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24 | Moderate response | 39.0 Percentage of responders | — |
| FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24 | No response | 34.8 Percentage of responders | 1.46 |
| FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24 | Moderate response | 44.4 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 | No response | 41.1 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 | Good response | 14.5 Percentage of responders | — |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24 | No response | 53.0 Percentage of responders | 1.3 |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24 | Good response | 10.9 Percentage of responders | — |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24 | Moderate response | 36.2 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: [1.79, 3.3]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 data.p-value: 0.00495% CI: [1.16, 2.14]Proportional odds model
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, a measure of health-related QoL. Scores for 8 sub-domains (Physical Functioning, Role-physical, Bodily Pain, General Health, Vitality, Social Function, Role-emotional & Mental Health) are derived & normalised to a scale of 0-100. Mental Component Scores (MCS) are derived by multiplying each of these 8 scores by a constant, summing them & standardising against a population with mean of 50, standard deviation of 10. Higher scores represent a better QoL. Mean changes from baseline score are presented at each visit as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. ANCOVA=analysis of covariance, BID=twice daily, DMARD=disease modifying antirheumatic drug, PO=orally, QD=once daily, QoL=quality of life.
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 | 4 Units on a scale | Standard Deviation 9.5 |
| 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 | 4 Units on a scale | Standard Deviation 8.6 |
| PLACEBO (24 WKS) THEN 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 8.1 |
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: [0.54, 3.07]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: 0.01795% CI: [0.28, 2.83]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, a measure of health-related QoL. Scores for 8 sub-domains (Physical Functioning, Role-physical, Bodily Pain, General Health, Vitality, Social Function, Role-emotional & Mental Health) are derived & normalised to a scale of 0-100. Physical Component Scores (PCS) are derived by multiplying each of these 8 scores by a constant, summing them & standardising against a population with mean of 50, standard deviation of 10. Higher scores represent a better QoL. Mean changes from baseline score are presented at each visit as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. ANCOVA=analysis of covariance, BID=twice daily, DMARD=disease modifying antirheumatic drug, PO=orally, QD=once daily, QoL=quality of life.
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 | 6 Units on a scale | Standard Deviation 8 |
| 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 | 5 Units on a scale | Standard Deviation 6.7 |
| PLACEBO (24 WKS) THEN FOSTA 100 MG BID PO | SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Placebo at Week 24 | 3 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: <0.00195% CI: [1.16, 3.31]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: 0.0295% CI: [0.2, 2.35]ANCOVA