Efficacy and Safety Study of R935788 Tablets to Treat Rheumatoid Arthritis (Taski-3)

A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Dose Study of R935788 in Patients With Rheumatoid Arthritis Who Have Failed at Least One Biologic

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00665626

Acronym

Taski-3

Enrollment

219

Registered

2008-04-24

Start date

2008-05-31

Completion date

2009-06-30

Last updated

2017-05-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Rheumatoid Arthritis

Brief summary

The purpose of this study is to determine whether the Spleen Tyrosine Kinase (Syk) Inhibitor, R935788 (R788) at a dose of 100 mg, tablet, orally, twice-a-day is effective in the treatment of Rheumatoid Arthritis in patients who have 'failed' a biologic therapy.

Interventions

DRUGFostamatinib disodium (R935788)

R935788 100 mg tablet, orally, twice-a-day

DRUGPlacebo

Placebo, orally, twice-a-day

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Patients must give written informed consent by signing an IRB/EC-approved Informed Consent Form (ICF) prior to admission to this study. * Males and females, 18 years of age or older, with active RA for at least 12 months prior to Day 1 dosing * Are currently receiving or previously had received a biologic therapy with an inhibitor of TNF, rituximab, abatacept, or anakinra at an approved labeled dose for ≥3 months prior to Day 1 dosing and are designated as biologic therapy failures for lack of efficacy, safety, or tolerability. * Patients may receive stable doses of methotrexate (MTX), azathioprine (not in combination with MTX), leflunomide (not in combination with MTX), sulfasalazine, chloroquine, hydroxychloroquine, gold, NSAIDs (including COX2 inhibitors), minocycline, or doxycycline. The dose must have been stable for at least 30 days prior to Day 1 dosing and must not be changed during the washout, screening and treatment periods, unless dictated by tolerability requirements. Patients who are taking MTX must have been receiving weekly MTX doses (7.5-25 mg/week) for a minimum of 3 months prior to Day 1 dosing and must be receiving a stable MTX dose, with no change in route, for the previous 6 weeks prior to Day 1 dosing. Patients who are receiving MTX must also be receiving folic or folinic acid supplementation at a stable dose for at least 6 weeks prior to Day 1 dosing. * 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 urine pregnancy test at the time of randomization and at each laboratory determination. * The patient must otherwise be in good health as determined by the Investigator on the basis of medical history, physical examination, and laboratory screening tests during the screening period. See

Exclusion criteria

for specific exclusions. * In the Investigator's opinion, the patient has the ability to understand the nature of the study and any hazards of participation, and to communicate satisfactorily with the Investigator and to participate in, and to comply with, the requirements of the entire protocol.

Design outcomes

Primary

Measure	Time frame	Description
American College of Rheumatology 20 (ACR20) Response at 3 Months	3 months	The number of participants with greater than or equal to 20% improvement in tender and swollen joint counts, AND in any 3 of the following: physician's assessment of disease activity, patient's assessment of disease activity, patient's assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI); and CRP or ESR, after 3 months

Secondary

Measure	Time frame	Description
American College of Rheumatology 70 (ACR70) Response at 3 Months	3 months	The number of participants with greater than or equal to 70% improvement in tender and swollen joint counts, AND in any 3 of the following: physician's assessment of disease activity, patient's assessment of disease activity, patient's assessment of pain, HAQ-DI; and CRP or ESR, whichever was elevated at baseline, after 3 months
American College of Rheumatology Index of Improvement (ACRn) at 3 Months	3 months	The index of improvement in RA, where 0 indicates no improvement and 100 indicates a 100% improvement across all signs and symptoms of RA after 3 months of treatment
Disease Activity Score-C-Reactive Protein (DAS28-CRP) <2.6 at 3 Months	3 months	Number of participants with DAS28-CRP (measuring RA symptoms including: tender joint count, swollen joint count, patient's assessment of disease activity, and CRP in patients with high CRP at baseline), of less than 2.6. The DAS runs from 0 to 10 - higher scores indicate worse symptoms. A score of less than 2.6 indicates remission of RA symptoms
Disease Activity Score-C-Reactive Protein (DAS28-CRP) <3.2 at 3 Months	3 months	Number of participants with DAS28-CRP (measuring RA symptoms including: tender joint count, swollen joint count, patient's assessment of disease activity, and CRP in patients with high CRP at baseline), of less than 3.2. The DAS runs from 0 to 10 - higher scores indicate worse symptoms. A score of less than 3.2 indicates low disease activity.
Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <2.6 at 3 Months	3 months	Number of participants with DAS28-ESR (measuring RA symptoms including: tender joint count, swollen joint count, patient's assessment of disease activity, and ESR in patients with high ESR at baseline), of less than 2.6. The DAS runs from 0 to 10 - higher scores indicate worse symptoms. A score of less than 2.6 indicates remission of RA symptoms
Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <3.2 at 3 Months	3 months	Number of participants with DAS28-ESR (measuring RA symptoms including: tender joint count, swollen joint count, patient's assessment of disease activity, and ESR in patients with high ESR at baseline), of less than 3.2. The DAS runs from 0 to 10 - higher scores indicate worse symptoms. A score of less than 3.2 indicates low disease activity.
American College of Rheumatology 20 (ACR20) Response at Week 1	1 week	The number of participants with greater than or equal to 20% improvement in tender and swollen joint counts, AND in any 3 of the following: physician's assessment of disease activity, patient's assessment of disease activity, patient's assessment of pain, HAQ-DI; and CRP or ESR, whichever was elevated at baseline, after 1 week.
American College of Rheumatology 20 (ACR20) Response at Week 2	2 weeks	The number of participants with greater than or equal to 20% improvement in tender and swollen joint counts, AND in any 3 of the following: physician's assessment of disease activity, patient's assessment of disease activity, patient's assessment of pain, HAQ-DI; and CRP or ESR, whichever was elevated at baseline, after 2 weeks
Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) Erosion Score at 3 Months	Baseline to 3 months	Change from baseline in RAMRIS erosion score (a measure of bone erosion in the hands and wrists), calculated as the score at 3 months minus the score at baseline. The erosion score runs from 0 to 250 with lower values indicating a better clinical condition. A negative change indicates an improvement in symptoms.
Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) Osteitis Score at 3 Months	Baseline to 3 months	Change from baseline in RAMRIS osteitis score (a measure of bone inflammation in the hands and wrists), calculated as the score at 3 months minus the score at baseline. The osteitis score runs from 0 to 75 with lower values indicating a better clinical condition. A negative change indicates an improvement in symptoms.
Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) Synovitis Score at 3 Months	Baseline to 3 months	Change from baseline in RAMRIS synovitis score (a measure of inflammation in the joints of the hands and wrists), calculated as the score at 3 months minus the score at baseline. The synovitis score runs from 0 to 24 with lower values indicating a better clinical condition. A negative change indicates an improvement in symptoms.
Alanine Aminotransferase (ALT) >1.5x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with ALT (a test of liver function) values greater than 1.5 times the ULN
Alanine Aminotransferase (ALT) >1.5-2x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with ALT (a test of liver function) values greater than 1.5 to 2 times the ULN
Alanine Aminotransferase (ALT) >2-3x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with ALT (a test of liver function) values greater than 2 to 3 times the ULN
American College of Rheumatology 50 (ACR50) Response at 3 Months	3 months	The number of participants with greater than or equal to 50% improvement in tender and swollen joint counts, AND in any 3 of the following: physician's assessment of disease activity, patient's assessment of disease activity, patient's assessment of pain, HAQ-DI; and CRP or ESR, whichever was elevated at baseline, after 3 months
Alanine Aminotransferase (ALT) >3-5x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with ALT (a test of liver function) values greater than 3 to 5 times the ULN
Alanine Aminotransferase (ALT) >5-10x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with ALT (a test of liver function) values greater than 5 to 10 times the ULN
Alanine Aminotransferase (ALT) >10x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with ALT (a test of liver function) values greater than 10 times the ULN
Aspartate Aminotransferase (AST) >1.5x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with AST (a test of liver function) values greater than 1.5 times the ULN
Aspartate Aminotransferase (AST) >1.5-2x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with AST (a test of liver function) values greater than 1.5 to 2 times the ULN
Aspartate Aminotransferase (AST) >2-3x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with AST (a test of liver function) values greater than 2 to 3 times the ULN
Aspartate Aminotransferase (AST) >3x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with AST (a test of liver function) values greater than 3 times the ULN
Aspartate Aminotransferase (AST) >3-5x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with AST (a test of liver function) values greater than 3 to 5 times the ULN
Aspartate Aminotransferase (AST) >5-10x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with AST (a test of liver function) values greater than 5 to 10 times the ULN
Aspartate Aminotransferase (AST) >10x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with AST (a test of liver function) values greater than 10 times the ULN
Alkaline Phosphatase >1.5x Upper Limit of Normal (ULN) and >1.5x Baseline	Any time between baseline and 3 months	The number of participants with alkaline phosphatase (a test of liver function) values greater than 1.5 times the ULN and greater than 1.5 times baseline
Bilirubin >1.5x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with bilirubin (a test of liver function) values greater than 1.5 times the ULN
Bilirubin >2x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with bilirubin (a test of liver function) values greater than 2 times the ULN
Absolute Neutrophil Count (ANC) <1500/mm3	Any time between baseline and 3 months	The number of participants with ANC values less than 1500/mm3
Alanine Aminotransferase (ALT) >3x Upper Limit of Normal (ULN)	Any time between baseline and 3 months	The number of participants with ALT (a test of liver function) values greater than 3 times the ULN

Countries

Belgium, Colombia, France, Germany, Italy, Peru, United States

Participant flow

Recruitment details

The first participant received the first dose of study drug on 28 May 2008; the last participant completed the study on 09 June 2009. Participants were recruited from centers in the United States, Europe and Latin America.

Pre-assignment details

Male/female participants who had active rheumatoid arthritis (RA) for a minimum of 12 months and who had failed prior biologic therapy were randomly assigned to receive R788 100 mg twice daily or placebo. It was planned to randomize approximately 195 participants.

Participants by arm

Arm	Count
Placebo Placebo to R788, oral tablets, twice daily, double-blind	73
R788 100 mg Bid R788 100 mg, oral tablets, twice daily, double-blind	146
Total	219

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	9
Overall Study	Death	1	0
Overall Study	Did not fulfil inclusion criteria	0	1
Overall Study	Due to exclusion criteria	0	1
Overall Study	Lack of Efficacy	8	5
Overall Study	Lost to Follow-up	0	2
Overall Study	Protocol Violation	0	2
Overall Study	Unably to comply with dosing regimen	0	1
Overall Study	Withdrawal by Subject	0	1

Baseline characteristics

Characteristic	Placebo	R788 100 mg Bid	Total
Age, Continuous	56.0 Years STANDARD_DEVIATION 12.29	56.0 Years STANDARD_DEVIATION 11.45	56.0 Years STANDARD_DEVIATION 11.71
Sex: Female, Male Female	59 Participants	117 Participants	176 Participants
Sex: Female, Male Male	14 Participants	29 Participants	43 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	20 / 73	74 / 146
serious Total, serious adverse events	1 / 73	13 / 146

Outcome results

Primary

American College of Rheumatology 20 (ACR20) Response at 3 Months

The number of participants with greater than or equal to 20% improvement in tender and swollen joint counts, AND in any 3 of the following: physician's assessment of disease activity, patient's assessment of disease activity, patient's assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI); and CRP or ESR, after 3 months

Time frame: 3 months