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Evaluation of Effectiveness of Two Dosing Regimens of Fostamatinib Compared to Placebo in Patients With Rheumatoid Arthritis (RA) Who Are Taking Methotrexate But Not Responding. (OSKIRA - 1)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01197521
First received: September 8, 2010
Last updated: February 27, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: fostamatinib
Drug: placebo, fostamatinib
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: (OSKIRA-1): 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 Methotrexate

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Proportion of Patients With ACR20 at Week 24, Comparison Between Fostamatinib and Placebo. [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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. [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • ACR20 - Proportion of Patients Achieving ACR20, Comparison Between Fostamatinib and Placebo at Week 1 [ Time Frame: 1 week ] [ Designated as safety issue: No ]
    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.

  • Proportion of Patients Achieving ACR50 up to Week 24 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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.

  • Proportion of Patients Achieving ACR70 up to Week 24 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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 EULAR Response at Week 24 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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.

  • HAQ-DI Response - Comparison of the Change (>=0.22) From Baseline Between Fostamatinib and Placebo at Week 24 [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]
    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.


Enrollment: 923
Study Start Date: September 2010
Study Completion Date: November 2012
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dosing Regimen A
Oral Treatment
Drug: fostamatinib
fostamatinib 100 mg twice daily
Experimental: Dosing Regimen B
Oral Treatment
Drug: fostamatinib
fostamatinib 100 mg twice daily/150 mg once daily
Placebo Comparator: Dosing Regimen C
Oral Treatment
Drug: placebo, fostamatinib
Placebo for 24 weeks followed by fostamatinib 100 mg twice daily

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01197521

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Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Neil MacKillop, MD PhD AstraZeneca
  More Information

Additional Information:
No publications provided

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01197521     History of Changes
Other Study ID Numbers: D4300C00001, 2010-020743-12
Study First Received: September 8, 2010
Results First Received: November 22, 2013
Last Updated: February 27, 2014
Health Authority: United States: Food and Drug Administration
Belgium: Federal Agency for Medicinal Products and Health Products
Bulgaria: Bulgarian Drug Agency
Estonia: The State Agency of Medicine
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Hungary: National Institute of Pharmacy
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Slovakia: State Institute for Drug Control
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Ukraine: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Australia: Department of Health and Ageing Therapeutic Goods Administration
India: Drugs Controller General of India
Argentina: National Administration of Drugs, Food & Medical Technology (ANMAT)
Brazil: National Health Surveillance Agency
Chile: Instituto de Salud Pública de Chile
Mexico: Federal Commission for Sanitary Risks Protection
Peru: General Directorate of Pharmaceuticals, Devices, and Drugs

Keywords provided by AstraZeneca:
Rheumatoid Arthritis

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Methotrexate
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014