Evaluation of Efficacy and Safety of Fostamatinib Monotherapy Compared With Adalimumab Monotherapy in Patients With Rheumatoid Arthritis (RA) (OSKIRA -4)

This study has been terminated.
(AZ decision to discontinue fostamatinib development in RA; rights to fostamatinib returned to Rigel Pharmaceuticals.)
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01264770
First received: December 17, 2010
Last updated: April 3, 2014
Last verified: April 2014
  Purpose

The purpose of the study is to evaluate the improvements in signs and symptoms of rheumatoid arthritis (RA) for fostamatinib compared to placebo or adalimumab in patients who are Disease-Modifying anti-rheumatic drug (DMARD) naïve, DMARD intolerant or have had an inadequate response to DMARDs. The study will last for approximately six months


Condition Intervention Phase
Rheumatoid Arthritis
Drug: Fostamatinib and placebo injections
Drug: Adalimumab and placebo of fostamatinib
Drug: Placebo of fostamatinib, fostamatinib, and placebo injections
Phase 2

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-4): A Phase IIB, Multi-Centre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Fostamatinib Disodium Monotherapy Compared With Adalimumab Monotherapy in Patients With Active Rheumatoid Arthritis

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • DAS28-CRP Score - Change From Baseline to Week 6 Compared to Placebo [ Time Frame: Baseline and 6 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. Mean changes from baseline in DAS28-CRP score are shown at each visit and are presented as decreases from baseline (defined as baseline minus post-baseline) with larger changes indicative of a better clinical condition. ANCOVA = analysis of covariance, BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, QD = once a day, SC = subcutaneous.

  • DAS28-CRP Score - Change From Baseline to Week 24 Compared to Adalimumab [ Time Frame: Baseline and 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. Mean changes from baseline in DAS28-CRP score are shown at each visit and are presented as decreases from baseline (defined as baseline minus post-baseline) with larger changes indicative of a better clinical condition. Non-responder imputation has been applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, QD = once a day, SC = subcutaneous.


Secondary Outcome Measures:
  • DAS28 EULAR Response at Week 6 [ Time Frame: 6 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, 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, SC = subcutaneous.

  • DAS28 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, 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, SC = subcutaneous.

  • Proportion of Patients Achieving ACR20 up to Week 24 [ Time Frame: 6 and 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, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.

  • Proportion of Patients Achieving ACR50 up to Week 24 [ Time Frame: 6 and 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, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.

  • Proportion of Patients Achieving ACR70 up to Week 24 [ Time Frame: 6 and 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, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.

  • ACRn - Comparison Between Fostamatinib and Placebo at Week 6 [ Time Frame: Baseline and 6 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 and patient's own asessment 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. Non-responder imputation has been applied by carrying the baseline observation forward. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous. Mean refers to change at Week 6. Treatment difference: difference between fostamatinib and placebo groups.

  • ACRn - Comparison Between Fostamatinib and Adalimumab at Week 24 [ Time Frame: Baseline and 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 and patient's own asessment 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. 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, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous. Mean refers to change at Week 24. Treatment difference: difference between fostamatinib and adalimumab groups.

  • HAQ-DI - Comparison of the Change From Baseline Between Fostamatinib and Placebo at Week 6 [ Time Frame: Baseline and 6 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 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. Non-responder imputation has been applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.

  • HAQ-DI - Comparison of the Change From Baseline Between Fostamatinib and Adalimumab 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 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. Non-responder imputation has been applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.

  • SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Adalimumab 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 & Mental Component Scores (PCS & 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. Non-responder imputation applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, PO = orally, QD = once a day, QoL = quality of life, SC = subcutaneous.

  • SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Adalimumab 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 & Mental Component Scores (PCS & 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. Non-responder imputation applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, PO = orally, QD = once a day, QoL = quality of life, SC = subcutaneous.


Enrollment: 644
Study Start Date: January 2011
Study Completion Date: August 2013
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dosing Group A
Oral treatment and subcutaneous injection
Drug: Fostamatinib and placebo injections
Fostamatinib 100mg twice daily and placebo injection once every two weeks
Experimental: Dosing Group B
Oral treatment and subcutaneous injection
Drug: Fostamatinib and placebo injections
Fostamatinib 100mg twice daily / fostamatinib 150mg once daily and placebo injection once every two weeks
Experimental: Dosing Group C
Oral treatment and subcutaneous injection
Drug: Fostamatinib and placebo injections
Fostamatinib 100mg twice daily / fostamatinib 100mg once daily and placebo injection once every two weeks.
Active Comparator: Dosing Group D
Oral treatment and subcutaneous injection
Drug: Adalimumab and placebo of fostamatinib
Adalimumab 40mg injection once every two weeks and placebo to fostamatinib twice daily.
Other Name: Humira®
Placebo Comparator: Dosing Group E
Oral treatment and subcutaneous injection
Drug: Placebo of fostamatinib, fostamatinib, and placebo injections
Placebo injection once every two weeks. Placebo to fostamatinib for six weeks, followed by fostamatinib 100mg twice daily (Group F) / fostamatinib 100mg twice daily then 150mg once daily (Group G).

Detailed Description:

Sub-study:

Full title: Optional Genetic Research

Date: 10 September 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 adalimumab; and/or susceptibility to, progression of and prognosis of RA

The main study recruitment is complete, and sub study recruitment will continue until the target is reached, estimated to be June 2013

Sub-study:

Full title: (Sub-study to OSKIRA-4): A Phase IIB, Multi-Centre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Fostamatinib Disodium Monotherapy Compared with Placebo or Adalimumab Monotherapy in Patients with Active Rheumatoid Arthritis: Magnetic Resonance Imaging Sub-Study

Date: 21 March 2011

Version: 1

Primary objective: Assess the efficacy of fostamatinib in reducing joint synovial disease activity as measured by:

  • Change from baseline to Week 6 (versus placebo) in OMERACT RAMRIS synovitis score.
  Eligibility

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

Inclusion Criteria:

  • Male or female aged 18 and over
  • Active rheumatoid arthritis (RA) diagnosed after the age of 16 and diagnosis within 5 years prior to study visit 1 and inadequate response to treatment with a maximum 2 Disease-Modifying anti-rheumatic drug (DMARD) therapies, or diagnosis within 5 years prior to study visit 1 and intolerance to DMARD therapy, or diagnosis within 2 years prior to study visit 1 and no previous use of DMARDs
  • 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 2 of the following: documented history or current presence of positive 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
  • Previously received treatment with a TNF alpha antagonist (including etanercept, certolizumab, adalimumab, infliximab, golimumab) or anakinra or previous treatment with other biological agent including rituximab, abatacept and tocilizumab
  • Use of any DMARDs within 6 weeks before first study visit
  • 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: NCT01264770

  Show 109 Study Locations
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Neil MacKillop, MD PhD AstraZeneca
  More Information

No publications provided

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01264770     History of Changes
Other Study ID Numbers: D4300C00004, 2010-023692-26
Study First Received: December 17, 2010
Results First Received: November 22, 2013
Last Updated: April 3, 2014
Health Authority: Argentina: National Administration of Drugs, Food & Medical Technology (ANMAT)
Australia: Department of Health and Ageing Therapeutic Goods Administration
Belgium: Federal Agency for Medicinal Products and Health Products
Brazil: National Health Surveillance Agency
Bulgaria: Bulgarian Drug Agency
Canada: Health Canada
Chile: Instituto de Salud Pública de Chile
Czech Republic: State Institute for Drug Control
Estonia: The State Agency of Medicine
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Hungary: National Institute of Pharmacy
India: Drugs Controller General of India
Israel: Ministry of Health
Italy: National Monitoring Centre for Clinical Trials - Ministry of Health
Latvia: State Agency of Medicines
Lithuania: State Medicine Control Agency - Ministry of Health
Mexico: Federal Commission for Sanitary Risks Protection
Peru: General Directorate of Pharmaceuticals, Devices, and Drugs
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Portugal: National Pharmacy and Medicines Institute
Romania: National Medicines Agency
Russia: Public Health Institute
Serbia and Montenegro: Agency for Drugs and Medicinal Devices
Slovakia: State Institute for Drug Control
South Africa: Medicines Control Council
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Ukraine: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration

Keywords provided by AstraZeneca:
Rheumatoid Arthritis
OSKIRA
fostamatinib

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Adalimumab
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antirheumatic Agents

ClinicalTrials.gov processed this record on August 19, 2014