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

Rheumatoid Arthritis Clinical Trial

— OSKIRA -4  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01264770
• Other study ID #: D4300C00004
• Secondary ID: 2010-023692-26
• Status: Terminated
• Phase: Phase 2
• First received: December 17, 2010
• Last updated: April 3, 2014
• Start date: January 2011
• Est. completion date: August 2013

Study information

• Verified date: April 2014
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: National Administration of Drugs, Food & Medical Technology (ANMAT)Australia: Department of Health and Ageing Therapeutic Goods AdministrationBelgium: Federal Agency for Medicinal Products and Health ProductsBrazil: National Health Surveillance AgencyBulgaria: Bulgarian Drug AgencyCanada: Health CanadaChile: Instituto de Salud Pública de ChileCzech Republic: State Institute for Drug ControlEstonia: The State Agency of MedicineFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesHungary: National Institute of PharmacyIndia: Drugs Controller General of IndiaIsrael: Ministry of HealthItaly: National Monitoring Centre for Clinical Trials - Ministry of HealthLatvia: State Agency of MedicinesLithuania: State Medicine Control Agency - Ministry of HealthMexico: Federal Commission for Sanitary Risks ProtectionPeru: General Directorate of Pharmaceuticals, Devices, and DrugsPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Portugal: National Pharmacy and Medicines InstituteRomania: National Medicines AgencyRussia: Public Health InstituteSerbia and Montenegro: Agency for Drugs and Medicinal DevicesSlovakia: State Institute for Drug ControlSouth Africa: Medicines Control CouncilSpain: Agencia Española de Medicamentos y Productos SanitariosUkraine: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 644
• Est. completion date: August 2013
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Fostamatinib and placebo injections
Fostamatinib 100mg twice daily and placebo injection once every two weeks
• Fostamatinib and placebo injections
Fostamatinib 100mg twice daily / fostamatinib 150mg once daily and placebo injection once every two weeks
• Fostamatinib and placebo injections
Fostamatinib 100mg twice daily / fostamatinib 100mg once daily and placebo injection once every two weeks.
• Adalimumab and placebo of fostamatinib
Adalimumab 40mg injection once every two weeks and placebo to fostamatinib twice daily.
• 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).

Locations

Country	Name	City	State
Bulgaria	Research Site	Pleven
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Ruse
Bulgaria	Research Site	Sevlievo
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Veliko Tarnovo
Canada	Research Site	Mississauga	Ontario
Czech Republic	Research Site	Brno
Czech Republic	Research Site	Bruntal
Czech Republic	Research Site	Hlucin
Czech Republic	Research Site	Liberec
Czech Republic	Research Site	Ostrava
Czech Republic	Research Site	Ostrava - Poruba
Czech Republic	Research Site	Ostrava - Trebovice
Czech Republic	Research Site	Praha
Czech Republic	Research Site	Praha 11
Czech Republic	Research Site	Praha 2
Czech Republic	Research Site	Praha 4
Czech Republic	Research Site	Zlin
Germany	Research Site	Dresden
Germany	Research Site	Hamburg
Germany	Research Site	Muenchen
Hungary	Research Site	Balatonfured
Hungary	Research Site	Balatonfüred
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Zalaegerszeg
Netherlands	Research Site	Amsterdam
Poland	Research Site	Bytom
Poland	Research Site	Chelm Slaski
Poland	Research Site	Grodzisk Mazowiecki
Poland	Research Site	Lódz
Poland	Research Site	Sroda Wielkopolska
Poland	Research Site	Warszawa
Poland	Research Site	Wroclaw
Poland	Research Site	Zyrardow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Nizhny Novgorod
Russian Federation	Research Site	Petrozavodsk
Russian Federation	Research Site	Ryazan
Russian Federation	Research Site	St. Petersburg
Russian Federation	Research Site	Voronezh
Russian Federation	Research Site	Yaroslavl
Slovakia	Research Site	Trebisov
Slovakia	Research Site	Trnava
South Africa	Research Site	Cape Town	Western Cape
South Africa	Research Site	Cape Town
South Africa	Research Site	Durban
South Africa	Research Site	Durban	Kwazulu Natal
South Africa	Research Site	Pretoria
South Africa	Research Site	Pretoria	Gauteng
South Africa	Research Site	Stellenbosch
Ukraine	Research Site	Donetsk
Ukraine	Research Site	Ivano-frankivsk
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Lutsk
Ukraine	Research Site	Lviv
Ukraine	Research Site	Odessa
Ukraine	Research Site	Simferopol
Ukraine	Research Site	Zaporyzhzhya
United Kingdom	Research Site	Basingstoke
United Kingdom	Research Site	Eastbourne
United Kingdom	Research Site	Eastbourne	Sussex
United Kingdom	Research Site	London	Greater London
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Reading	Berkshire
United Kingdom	Research Site	Wolverhampton
United States	Research Site	Albuquerque	New Mexico
United States	Research Site	Austin	Texas
United States	Research Site	Birmingham	Alabama
United States	Research Site	Bowling Green	Kentucky
United States	Research Site	Bridgeport	Connecticut
United States	Research Site	Brooklyn	New York
United States	Research Site	Charlotte	North Carolina
United States	Research Site	Chicago	Illinois
United States	Research Site	Colorado Springs	Colorado
United States	Research Site	Daytona Beach	Florida
United States	Research Site	Duncansville	Pennsylvania
United States	Research Site	Elizabethtown	Kentucky
United States	Research Site	Glendale	Arizona
United States	Research Site	Greenville	South Carolina
United States	Research Site	Houston	Texas
United States	Research Site	Huntington Beach	California
United States	Research Site	Jackson	Tennessee
United States	Research Site	Jacksonville	Florida
United States	Research Site	Kalamazoo	Michigan
United States	Research Site	Kalispell	Montana
United States	Research Site	Knoxville	Tennessee
United States	Research Site	Las Cruces	New Mexico
United States	Research Site	Long Beach	California
United States	Research Site	Memphis	Tennessee
United States	Research Site	Mesa	Arizona
United States	Research Site	Mesquite	Texas
United States	Research Site	Miami	Florida
United States	Research Site	Nashua	New Hampshire
United States	Research Site	Ocala	Florida
United States	Research Site	Oxon Hill	Maryland
United States	Research Site	Palm Harbor	Florida
United States	Research Site	Perrysburg	Ohio
United States	Research Site	Phoenix	Arizona
United States	Research Site	Pinellas Park	Florida
United States	Research Site	Plano	Texas
United States	Research Site	Richmond Heights	Missouri
United States	Research Site	San Antonio	Texas
United States	Research Site	Scottsdale	Arizona
United States	Research Site	South Bend	Indiana
United States	Research Site	Venice	Florida

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Bulgaria,  Canada,  Czech Republic,  Germany,  Hungary,  Netherlands,  Poland,  Russian Federation,  Slovakia,  South Africa,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	DAS28-CRP Score - Change From Baseline to Week 6 Compared to Placebo	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.	Baseline and 6 weeks	No
Primary	DAS28-CRP Score - Change From Baseline to Week 24 Compared to Adalimumab	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.	Baseline and 24 weeks	No
Secondary	DAS28 EULAR Response at Week 6	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.	6 weeks	No
Secondary	DAS28 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, 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.	24 weeks	No
Secondary	Proportion of Patients Achieving ACR20 up to Week 24	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.	6 and 24 weeks	No
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, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.	6 and 24 weeks	No
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, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.	6 and 24 weeks	No
Secondary	ACRn - Comparison Between Fostamatinib and Placebo at Week 6	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.	Baseline and 6 weeks	No
Secondary	ACRn - Comparison Between Fostamatinib and Adalimumab 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 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.	Baseline and 24 weeks	No
Secondary	HAQ-DI - Comparison of the Change From Baseline Between Fostamatinib and Placebo at Week 6	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.	Baseline and 6 weeks	No
Secondary	HAQ-DI - Comparison of the Change From Baseline Between Fostamatinib and Adalimumab at Week 24	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.	Baseline and 24 weeks	No
Secondary	SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Adalimumab 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 & 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.	Baseline and 24 weeks	No
Secondary	SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Adalimumab 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 & 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.	Baseline and 24 weeks	No