Evaluation of Effectiveness of Two Dosing Regimens of Fostamatinib Compared to Placebo in Patients With Rheumatoid Arthritis (RA) Who Are Taking Disease Modifying Anti-rheumatic Drug (DMARD) But Not Responding. (OSKIRA - 2)

• ClinicalTrials.gov Identifier: NCT01197534
• Recruitment Status: Completed
• First Posted: September 9, 2010
• Results First Posted: April 17, 2014
• Last Update Posted: April 17, 2014
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: September 8, 2010
• First Posted Date: September 9, 2010
• Results First Submitted Date: November 22, 2013
• Results First Posted Date: April 17, 2014
• Last Update Posted Date: April 17, 2014
• Study Start Date: September 2010
• Actual Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 13, 2014)

Proportion of Patients With ACR20 at Week 24, Comparison Between Fostamatinib and Placebo [ Time Frame: 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. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.

• Original Primary Outcome Measures (submitted: September 8, 2010): Proportion of patients with ACR20 compared to placebo (ACR20 = American College of Rheumatology 20% response criteria) [ Time Frame: 24 weeks ]

Current Secondary Outcome Measures (submitted: March 13, 2014)

• Proportion of Patients Achieving ACR20, Comparison Between Fostamatinib and Placebo at Week 1 [ Time Frame: 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. BID = twice daily, CRP = C-reactive protein, DMARD = Disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.
• Proportion of Patients Achieving ACR50, Comparison Between Fostamatinib and Placebo at Week 24 [ Time Frame: 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. BID = twice daily, CRP = C-reactive protein, DMARD = Disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.
• Proportion of Patients Achieving ACR70, Comparison Between Fostamatinib and Placebo at Week 24 [ Time Frame: 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. 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 [ Time Frame: 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 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. Mean refers to change at Week 24.
• Proportion of Patients Achieving DAS28-CRP <2.6 at Week 12, Comparison Between Fostamatinib and Placebo [ Time Frame: 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, Comparison Between Fostamatinib and Placebo [ Time Frame: 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.
• Proportion of Patients Achieving DAS28 EULAR Response at Week 24 [ Time Frame: 24 weeks ]
  Change in DAS28 was derived for each post baseline scheduled assessment and categorised using the European League Against Rheumatism (EULAR) response criteria. BID = twice daily, 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.
• HAQ-DI Response - Comparison of the Change(>=0.22) From Baseline Between Fostamatinib and Placebo at Week 24 [ Time Frame: Baseline and 24 weeks ]
  HAQ-DI: Health Assessment Questionnaire - Disability Index, a measure of physical function. The HAQ-DI score is then calculated by summing the category 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 a higher score indicating greater disability. The HAQ-DI response is a reduction from baseline in HAQ-DI score 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, Comparison Between Fostamatinib and Placebo [ Time Frame: 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 were excluded from the analysis. ANCOVA = analysis of covariance, BID = twice daily, IP = investigational product, QD = once a day.
• SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Placebo at Week 24 [ Time Frame: Baseline and 24 weeks ]
  SF-36: 36-item Short Form Health Survey, 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 0-100. Physical and mental component scores (PCS and MCS) are derived by multiplying each of these 8 scores by a constant, summing them and standardising against a population with mean of 50+/- 10. Higher scores represent 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. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease modifying antirheumatic drugs, PO = orally, QD = once a day.
• SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Placebo at Week 24 [ Time Frame: Baseline and 24 weeks ]
  SF-36: 36-item Short Form Health Survey, 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 0-100. Physical and mental component scores (PCS and MCS) are derived by multiplying each of these 8 scores by a constant, summing them and standardising against a population with mean of 50+/- 10. Higher scores represent 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. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease modifying antirheumatic drugs, PO = orally, QD = once a day.

Original Secondary Outcome Measures (submitted: September 8, 2010)

• Proportion of patients with ACR20, ACR50, ACR70, ACR-N compared to placebo (ACR50 = American College of Rheumatology 50% response criteria, ACR70 = American College of Rheumatology 70% response criteria, ACR N = numeric index of the ACR response [ Time Frame: 52 Weeks ]
• Proportion of patients with DAS28 and DAS28 EULAR response criteria compared to baseline DAS28 = Disease Activity Score based on a 28 joint count; EULAR = European League Against Rheumatism) [ Time Frame: 52 Weeks ]
• Health Assessment Questionnaire - Disability Index (HAQ-DI). [ Time Frame: 52 Weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of Effectiveness of Two Dosing Regimens of Fostamatinib Compared to Placebo in Patients With Rheumatoid Arthritis (RA) Who Are Taking Disease Modifying Anti-rheumatic Drug (DMARD) But Not Responding.
• Official Title: (OSKIRA-2): A Phase III, Multi-centre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Study of Two Dosing Regimens of Fostamatinib Disodium in Rheumatoid Arthritis Patients With an Inadequate Response to DMARDs
• 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 disease modifying anti-rheumatic drug (DMARD) 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

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Rheumatoid Arthritis

Intervention

• Drug: fostamatinib
  fostamatinib 100 mg twice daily
• Drug: fostamatinib
  fostamatinib 100 mg twice daily/ 150 mg once daily
• Drug: placebo, fostamatinib
  Placebo for 24 weeks followed by fostamatinib 100 mg twice daily.

Study Arms

• Experimental: Dosing Regimen A
  Oral Treatment
  Intervention: Drug: fostamatinib
• Experimental: Dosing Regimen B
  Oral Treatment
  Intervention: Drug: fostamatinib
• Placebo Comparator: Dosing Regimen C
  Oral Treatment
  Intervention: Drug: placebo, fostamatinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 8, 2012): 913
• Original Estimated Enrollment (submitted: September 8, 2010): 900
• Actual Study Completion Date: March 2013
• Actual Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Active rheumatoid arthritis (RA) diagnosed after the age of 16
• Treatment with one the following disease modifying anti-rheumatic drug: methotrexate, sulfasalazine, hydroxychloroquine or chloroquine
• 4 or more swollen joints and 4 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Czech Republic, Germany, India, Israel, Italy, Latvia, Lithuania, Portugal, Romania, Serbia, South Africa, Spain, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT01197534
• Other Study ID Numbers: D4300C00002; 2010-020744-35 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: AstraZeneca
• Original Responsible Party: Medical Science Director, AstraZeneca
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Neil MacKillop, MD PhD; AstraZeneca

• PRS Account: AstraZeneca
• Verification Date: March 2014