Rheumatoid Arthritis
Conditions
Keywords
RA
Brief summary
The purpose of this new research study is to gain additional information about how safe and effective R935788 is over a longer period of time.
Interventions
50 mg PO BID; 100 mg PO BID; 100 mg PO QD; 150 mg tablet PO QD
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must give written informed consent by signing an IRB/EC-approved Informed Consent Form (ICF) prior to admission to this study * Patients who are being treated in Study C-788-006X * Patients who completed Studies C-788-010 or C-788-011 and did not withdraw due to adverse events * Patients who withdrew from Study C-788-010 at Month 4 or Month 5 because of a pre-defined lack of efficacy * Females of childbearing potential must be fully informed of the potential for R788 to adversely affect the fetus and, if sexually active, must agree to use a well established method of birth control during the study (oral contraceptive, mechanical barrier, long acting hormonal agent). These patients must not be lactating and must have a negative pregnancy test at the time of entry and at each laboratory determination.
Exclusion criteria
* The patient has a history of, or a concurrent, clinically significant illness, medical condition (other than arthritis) or laboratory abnormality that, in the Investigator's opinion, could affect the conduct of the study. Specifically, excluded are patients with the following: 1. unresolved Grade 2 or greater toxicity in a RA protocol studying R788 2. uncontrolled or poorly controlled hypertension; 3. recent (within past 2 months) serious surgery or infectious disease; 4. recent history (since enrollment in prior R788 study) of, or treatment for, a malignancy other than non-melanomatous skin cancer, or any history of lymphoma; 5. known to be positive for Hepatitis B, Hepatitis C, HIV or Tuberculosis; 6. interstitial pneumonitis or active pulmonary infection; 7. known laboratory abnormalities: ALT \> 1.2 x ULN, creatinine \>1.5x ULN, an ANC \<2,500/mm3 or 2.5 x 109/L, lymphocyte count \< 600/mm3 or 0.6 x 109L, Hgb \< 9 g/dL or 5 mmol/L, platelet count \<125,000/mm3 or 125 x 109/L are excluded. * The patient has a history of substance abuse, drug addiction or alcoholism. Patients may consume up to 4 units of alcohol per week; however, alcohol should be avoided in the 72 hours prior to lab assessments. Patients who cannot reliably comply with this should be excluded. A unit of alcohol is defined as the following: Beer = 12 oz or 355 mL; wine = 5 oz or 148 mL; sweet dessert wine = 3 oz or 89 mL; 80 proof distilled spirits = 1.5 oz or 44 mL. * The patient is unable to report for clinical and laboratory monitoring as per protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Entry in extension to end of study, up to a maximum of 5 years. (Variable by subject - median duration of 3 years) | AE = adverse event, bid = twice daily, IP = investigational product, qd = once daily, SAE = serious adverse event |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DAS28-CRP Score | 3 years | The Disease Activity Score 28 using C-Reactive Protein (DAS28-CRP) is a measure of disease activity in rheumatoid arthritis (RA) and assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). These measures are then fed into a complex mathematical formula to produce the overall DAS on a scale from 1 to 10, where scores greater than 5.1 are considered to indicate active disease, scores less than 3.2 are considered to indicate with well controlled disease, and scores less than 2.6 are considered to indicate remission. bid = twice daily, CRP = C-reactive protein, DAS28 = Disease Activity Score based on a 28 joint count, n/a = not applicable, qd = once daily |
| HAQ-DI Score | 3 years | 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. |
Countries
Belgium, Bulgaria, Colombia, France, Germany, Italy, Mexico, Peru, Poland, Romania, United States
Participant flow
Recruitment details
A total of 624 patients were enrolled: 1, 59, 183 & 381 were allocated to the 50mg twice daily (bid), 100 mg once daily (qd), 150 mg qd and 100 mg bid groups, respectively. As this was a long-term extension study no specific end date was given. Patients who were ongoing when the study was terminated are shown as completers.
Pre-assignment details
Treatments were assigned according to those given in the qualifying studies. All patients received investigational product.
Participants by arm
| Arm | Count |
|---|---|
| Fostamatinib 50 mg Bid Oral treatment | 1 |
| Fostamatinib 100 mg qd Oral treatment | 59 |
| Fostamatinib 150 mg qd Oral treatment | 183 |
| Fostamatinib 100 mg Bid Oral treatment | 381 |
| Total | 624 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 13 | 26 | 57 |
| Overall Study | Death | 0 | 2 | 7 | 5 |
| Overall Study | Lack of Efficacy | 0 | 8 | 13 | 86 |
| Overall Study | Lost to Follow-up | 0 | 1 | 7 | 21 |
| Overall Study | Not reported | 0 | 0 | 3 | 7 |
| Overall Study | Physician Decision | 0 | 1 | 2 | 6 |
| Overall Study | Protocol Violation | 0 | 3 | 0 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 6 | 45 | 50 |
Baseline characteristics
| Characteristic | Fostamatinib 50 mg Bid | Fostamatinib 100 mg qd | Fostamatinib 150 mg qd | Fostamatinib 100 mg Bid | Total |
|---|---|---|---|---|---|
| Age, Continuous | 70 years | 51.4 years STANDARD_DEVIATION 11.15 | 51.7 years STANDARD_DEVIATION 13.32 | 53.8 years STANDARD_DEVIATION 12.36 | 53.0 years STANDARD_DEVIATION 12.58 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 1 Participants | 6 Participants | 14 Participants | 22 Participants |
| Race/Ethnicity, Customized Caucasian | 0 Participants | 18 Participants | 88 Participants | 184 Participants | 290 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 40 Participants | 88 Participants | 179 Participants | 307 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 53 Participants | 157 Participants | 324 Participants | 535 Participants |
| Sex: Female, Male Male | 0 Participants | 6 Participants | 26 Participants | 57 Participants | 89 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 | 306 / 381 | 49 / 59 | 141 / 183 | 1 / 1 |
| serious Total, serious adverse events | 77 / 381 | 2 / 59 | 34 / 183 | 1 / 1 |
Outcome results
Primary
Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category
AE = adverse event, bid = twice daily, IP = investigational product, qd = once daily, SAE = serious adverse event
Time frame: Entry in extension to end of study, up to a maximum of 5 years. (Variable by subject - median duration of 3 years)
Population: The full analysis set includes those patients who received at least 1 dose of investigational product, and were summarised according to treatment first received in this study (intention-to-treat principle).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fostamatinib 50 mg Bid | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any SAE (including fatal AEs) | 100 % of patients |
| Fostamatinib 50 mg Bid | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any AE leading to termination of study therapy | 0 % of patients |
| Fostamatinib 50 mg Bid | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any fatal AE | 0 % of patients |
| Fostamatinib 50 mg Bid | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any AE | 100 % of patients |
| Fostamatinib 100 mg qd | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any AE leading to termination of study therapy | 22.0 % of patients |
| Fostamatinib 100 mg qd | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any fatal AE | 1.7 % of patients |
| Fostamatinib 100 mg qd | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any SAE (including fatal AEs) | 3.4 % of patients |
| Fostamatinib 100 mg qd | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any AE | 91.5 % of patients |
| Fostamatinib 150 mg qd | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any AE | 90.7 % of patients |
| Fostamatinib 150 mg qd | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any SAE (including fatal AEs) | 18.6 % of patients |
| Fostamatinib 150 mg qd | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any fatal AE | 3.8 % of patients |
| Fostamatinib 150 mg qd | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any AE leading to termination of study therapy | 16.4 % of patients |
| Fostamatinib 100 mg Bid | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any fatal AE | 1.6 % of patients |
| Fostamatinib 100 mg Bid | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any SAE (including fatal AEs) | 20.2 % of patients |
| Fostamatinib 100 mg Bid | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any AE leading to termination of study therapy | 15.2 % of patients |
| Fostamatinib 100 mg Bid | Percentage of Patients Who Had at Least 1 Treatment Emergent Adverse Event in Any Category | Any AE | 88.7 % of patients |
Secondary
DAS28-CRP Score
The Disease Activity Score 28 using C-Reactive Protein (DAS28-CRP) is a measure of disease activity in rheumatoid arthritis (RA) and assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). These measures are then fed into a complex mathematical formula to produce the overall DAS on a scale from 1 to 10, where scores greater than 5.1 are considered to indicate active disease, scores less than 3.2 are considered to indicate with well controlled disease, and scores less than 2.6 are considered to indicate remission. bid = twice daily, CRP = C-reactive protein, DAS28 = Disease Activity Score based on a 28 joint count, n/a = not applicable, qd = once daily
Time frame: 3 years
Population: Number of participants are those with baseline data. Baseline defined at entry into qualifying study or at entry into this study if more than 14 days since last dose in qualifying study. As no imputation was applied, the numbers at subsequent visits are lower.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fostamatinib 50 mg Bid | DAS28-CRP Score | Quarter 12 (n=1, 30, 94, 174) | 2.31 scores on a scale | — |
| Fostamatinib 50 mg Bid | DAS28-CRP Score | Quarter 8 (n=1, 33, 114, 201) | 2.92 scores on a scale | — |
| Fostamatinib 50 mg Bid | DAS28-CRP Score | Baseline (n=1, 55, 181, 374) | 5.27 scores on a scale | — |
| Fostamatinib 50 mg Bid | DAS28-CRP Score | Quarter 4 (n=1, 41, 136, 254) | 2.00 scores on a scale | — |
| Fostamatinib 100 mg qd | DAS28-CRP Score | Quarter 12 (n=1, 30, 94, 174) | 3.36 scores on a scale | Standard Deviation 1.376 |
| Fostamatinib 100 mg qd | DAS28-CRP Score | Baseline (n=1, 55, 181, 374) | 5.34 scores on a scale | Standard Deviation 1.123 |
| Fostamatinib 100 mg qd | DAS28-CRP Score | Quarter 8 (n=1, 33, 114, 201) | 3.43 scores on a scale | Standard Deviation 1.412 |
| Fostamatinib 100 mg qd | DAS28-CRP Score | Quarter 4 (n=1, 41, 136, 254) | 3.57 scores on a scale | Standard Deviation 1.408 |
| Fostamatinib 150 mg qd | DAS28-CRP Score | Quarter 8 (n=1, 33, 114, 201) | 3.25 scores on a scale | Standard Deviation 1.29 |
| Fostamatinib 150 mg qd | DAS28-CRP Score | Quarter 4 (n=1, 41, 136, 254) | 3.46 scores on a scale | Standard Deviation 1.282 |
| Fostamatinib 150 mg qd | DAS28-CRP Score | Quarter 12 (n=1, 30, 94, 174) | 3.07 scores on a scale | Standard Deviation 1.055 |
| Fostamatinib 150 mg qd | DAS28-CRP Score | Baseline (n=1, 55, 181, 374) | 5.31 scores on a scale | Standard Deviation 1.162 |
| Fostamatinib 100 mg Bid | DAS28-CRP Score | Quarter 12 (n=1, 30, 94, 174) | 3.27 scores on a scale | Standard Deviation 1.373 |
| Fostamatinib 100 mg Bid | DAS28-CRP Score | Quarter 8 (n=1, 33, 114, 201) | 3.35 scores on a scale | Standard Deviation 1.484 |
| Fostamatinib 100 mg Bid | DAS28-CRP Score | Baseline (n=1, 55, 181, 374) | 5.36 scores on a scale | Standard Deviation 1.259 |
| Fostamatinib 100 mg Bid | DAS28-CRP Score | Quarter 4 (n=1, 41, 136, 254) | 3.44 scores on a scale | Standard Deviation 1.453 |
Secondary
HAQ-DI Score
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: 3 years
Population: Number of participants are those with baseline data. Baseline defined at entry into qualifying study or at entry into this study if more than 14 days since last dose in qualifying study. As no imputation was applied, the numbers at subsequent visits are lower.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fostamatinib 50 mg Bid | HAQ-DI Score | Quarter 4 (n=1, 41, 138, 254) | 0.57 Scores on a Scale | — |
| Fostamatinib 50 mg Bid | HAQ-DI Score | Quarter 8 (n=1, 33, 107, 201) | 0.43 Scores on a Scale | — |
| Fostamatinib 50 mg Bid | HAQ-DI Score | Baseline (n=1, 56, 181, 376) | 1.25 Scores on a Scale | — |
| Fostamatinib 50 mg Bid | HAQ-DI Score | Quarter 12 (n=1, 30, 94, 176) | 0.38 Scores on a Scale | — |
| Fostamatinib 100 mg qd | HAQ-DI Score | Quarter 8 (n=1, 33, 107, 201) | 1.00 Scores on a Scale | Standard Deviation 0.657 |
| Fostamatinib 100 mg qd | HAQ-DI Score | Quarter 12 (n=1, 30, 94, 176) | 1.01 Scores on a Scale | Standard Deviation 0.651 |
| Fostamatinib 100 mg qd | HAQ-DI Score | Quarter 4 (n=1, 41, 138, 254) | 1.00 Scores on a Scale | Standard Deviation 0.677 |
| Fostamatinib 100 mg qd | HAQ-DI Score | Baseline (n=1, 56, 181, 376) | 1.50 Scores on a Scale | Standard Deviation 0.735 |
| Fostamatinib 150 mg qd | HAQ-DI Score | Quarter 8 (n=1, 33, 107, 201) | 1.02 Scores on a Scale | Standard Deviation 0.72 |
| Fostamatinib 150 mg qd | HAQ-DI Score | Quarter 12 (n=1, 30, 94, 176) | 0.98 Scores on a Scale | Standard Deviation 0.718 |
| Fostamatinib 150 mg qd | HAQ-DI Score | Baseline (n=1, 56, 181, 376) | 1.46 Scores on a Scale | Standard Deviation 0.707 |
| Fostamatinib 150 mg qd | HAQ-DI Score | Quarter 4 (n=1, 41, 138, 254) | 1.07 Scores on a Scale | Standard Deviation 0.726 |
| Fostamatinib 100 mg Bid | HAQ-DI Score | Quarter 4 (n=1, 41, 138, 254) | 0.99 Scores on a Scale | Standard Deviation 0.722 |
| Fostamatinib 100 mg Bid | HAQ-DI Score | Baseline (n=1, 56, 181, 376) | 1.46 Scores on a Scale | Standard Deviation 0.715 |
| Fostamatinib 100 mg Bid | HAQ-DI Score | Quarter 12 (n=1, 30, 94, 176) | 0.96 Scores on a Scale | Standard Deviation 0.687 |
| Fostamatinib 100 mg Bid | HAQ-DI Score | Quarter 8 (n=1, 33, 107, 201) | 0.95 Scores on a Scale | Standard Deviation 0.703 |