Efficacy and Safety of Different Doses of BIRB 796 BS in Patients With Active Rheumatoid Arthritis
Primary Purpose
Arthritis, Rheumatoid
Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
BIBR 796 BS
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Arthritis, Rheumatoid
Eligibility Criteria
Inclusion Criteria:
- Male or female from 18 to 75 years of age
- Diagnosis of Rheumatoid Arthritis (RA) established according to ACR criteria and date of diagnosis >1 year to ≤ 15 years. The exclusion of patients with a disease duration > 15 years was deleted in Amendment 2, effective January 22, 2002
- Patient belonging to functional class I, II, or III
- Failure of at least one Disease Modifying Antirheumatic Drug (DMARD) due to inefficacy
- Active disease, documented at visit 3, defined by ≥10 swollen joints in a 66 joint count and ≥ 12 tender joints in a 68 joint count
- CRP ≥ 2.0 mg/dl at visit 1 or visit 2
- Written informed consent in accordance with Good Clinical Practice and local legislation given prior to any study procedures, including washout of prohibited medications
Exclusion Criteria:
- Pregnancy (to be excluded by serum and urine β Human Chorion-Gonadotropin-test in women of childbearing potential) or breast feeding
- Female of childbearing potential (not 6 months post-menopausal or surgically sterilized) not using an approved form of birth control (hormonal contraceptives, oral or injectable/implantable, intra-uterine device (IUD))
- Inflammatory rheumatic disease other than RA
- Active vasculitis or any history of vasculitis (characterised by e.g. nail bed hemorrhages or infarcts, vasculitic purpura, ulcers or gangrenes, multisensory neuropathy, vasculitic retinopathy or scleritis of eyes). Isolated rheumatoid nodules of the skin are not a criterion for exclusion
- Treatment failure to a TNF-blocking agent. Treatment failure is defined as not achieving at least an ACR 20 response (e.g. in a clinical trial) or - in clinical practice - having the TNF-blocking agent discontinued due to ineffectiveness
- DMARD treatment within 4 weeks before visit 3
Last dose given within the specified time period before visit 3 for one of the following compounds or drugs:
- Infliximab (Remicade®): 3 months
- D2E7 (a human TNF-α antibody): 3 months
- Leflunomide (Arava®): 1 year, with exception of patients having undergone elimination therapy (colestyramin 8 grams t.i.d. po for eleven consecutive days), this exclusion criterion was deleted in Amendment 1, effective September 3, 2001
- Drug classified as proton pump inhibitor: 7 days
- Drug classified as H2-receptor-blocker or antacid: 2 days
- Investigational agent: 5-fold of the respective plasma half life or 4 weeks, whichever is longer
- Treatment with systemic corticosteroids in a dose higher than 10 mg/day prednisone equivalent within 4 weeks prior to visit 3
- Change in treatment with nonsteroidal antiinflammatory drugs (NSAIDs) or systemic corticosteroids within 4 weeks prior to visit 3
- Synovectomy, joint surgery, radio-/chemo synoviorthesis or steroid injections (intraarticular, intravenous or intramuscular) within 4 weeks before visit 3
- Active infection or serious infectious diseases resulting in hospitalisation or requiring systemic anti-infective therapy within 4 weeks before visit 3
- Serologic evidence of active hepatitis B and/or C
- Known HIV-infection
- History of prior tuberculosis infection or suspicion of active infection at screening based on chest x-ray done within 6 month before visit 1
- History of cardiovascular, renal, neurologic, psychiatric, liver, gastrointestinal, immunologic or endocrine dysfunction if they are clinically significant. A clinically significant disease is defined as one which in the opinion of the investigator may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient's ability to participate in the study
- Recent history of heart failure, defined according to New York Heart Association criteria as being stage III or IV (i.e. three years or less) or myocardial infarction (i.e. one year or less) or patients with any cardiac arrhythmia requiring drug therapy. This exclusion criterion was slightly modified in Amendment 2, effective January 22, 2002.
- ECG results outside of the reference range of clinical relevance including, but not limited to QTcB > 480 msec, PR interval > 240 msec, QRS interval > 110 msec
- History of malignant disease in the last 5 years or suspicion of active malignant disease except successfully treated squamous or basal cell carcinoma of the skin
- Clinically significant abnormal baseline hematology, blood chemistry or urinalysis if the abnormality defines a disease listed as an exclusion criterion
Any of the following specific laboratory abnormalities:
- Alanine aminotransferase, aspartate aminotransferase, or total bilirubin greater than upper limit of normal (ULN) at visit 1 or measured within the last six months before visit 3. This exclusion criterion was modified in Amendment 1, effective September 3, 2001, allowing for a retest at Visit 2.
- Gamma-Glutamyltransferase, alkaline phosphatase or Lactate Dehydrogenase greater than 1.5 x ULN at visit 1
- creatinine or white blood cell count greater than 1.5 x ULN at visit 1
- History of drug or alcohol abuse within the past two years or active drug or alcohol abuse, present alcohol intake more than three drinks per day
- Inability to comply with the protocol
- Participation in another clinical trial within 30 days before visit 3
- Previous enrolment in this trial
- Hypersensitivity to trial drug
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Experimental
Active Comparator
Arm Label
BIBR 796 BS, low dose
BIBR 796 BS, medium dose 1
BIBR 796 BS, medium dose 2
BIBR 796 BS, high dose
Placebo
Arm Description
twice daily doses of 5 mg for 4 weeks
twice daily doses of 10 mg for 4 weeks
twice daily doses of 20 mg for 4 weeks
twice daily doses of 30 mg for 4 weeks
Outcomes
Primary Outcome Measures
Absolute difference to baseline in concentrations of C-reactive Protein (CRP)
Secondary Outcome Measures
Absolute difference to baseline in tender joint count (TJC, 68 joint count)
Absolute difference to baseline in swollen joint count (SJC, 66 joint count)
Patients assessment of pain on a visual analogue scale (VAS)
Patients global assessment of disease activity (PADA) on a VAS
Physicians global assessment of disease activity on a VAS
Assessment of physical function by a standardised health assessment questionnaire (HAQ)
Absolute difference to baseline in Erythrocyte sedimentation rate (ESR)
Absolute difference to baseline in Cytokines Tumor Necrosis Factor (TNF)-α, soluble TNF-Receptor (sTNF-R), Interleukin (IL)-1ra, IL-6
Absolute difference to baseline in Matrix metalloprotease-3 (MMP-3)
Absolute difference to baseline in Vascular endothelial growth factor (VEGF)
Number of responders to American College of Rheumatology (ACR) preliminary response criteria for 20% improvement (ACR 20), ACR 50, ACR 70
Number of responders to European League against Rheumatism (EULAR) response criteria
Number of drop-outs due to lack of efficacy, according to final assessment of investigator
Assessment of maximum concentration (Cmax)
Assessment of area under the curve (AUC) at steady state
Number of patients with Adverse events
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02209779
Brief Title
Efficacy and Safety of Different Doses of BIRB 796 BS in Patients With Active Rheumatoid Arthritis
Official Title
A Randomised, Parallel, Double-blind, Placebo-controlled Study to Investigate Efficacy and Safety of Different Doses (5, 10, 20 and 30 mg) of BIRB 796 BS Administered Twice a Day Orally Over 4 Weeks in Patients With Active Rheumatoid Arthritis Who Have Failed at Least One DMARD
Study Type
Interventional
2. Study Status
Record Verification Date
August 2014
Overall Recruitment Status
Completed
Study Start Date
May 2001 (undefined)
Primary Completion Date
June 2002 (Actual)
Study Completion Date
undefined (undefined)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Boehringer Ingelheim
4. Oversight
5. Study Description
Brief Summary
The objective was to determine the effects of BIRB 796 BS on CRP and clinical parameters in Rheumatoid Arthritis as measures of efficacy, and on population pharmacokinetics and safety parameters
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Arthritis, Rheumatoid
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Double
Allocation
Randomized
Enrollment
167 (Actual)
8. Arms, Groups, and Interventions
Arm Title
BIBR 796 BS, low dose
Arm Type
Experimental
Arm Description
twice daily doses of 5 mg for 4 weeks
Arm Title
BIBR 796 BS, medium dose 1
Arm Type
Experimental
Arm Description
twice daily doses of 10 mg for 4 weeks
Arm Title
BIBR 796 BS, medium dose 2
Arm Type
Experimental
Arm Description
twice daily doses of 20 mg for 4 weeks
Arm Title
BIBR 796 BS, high dose
Arm Type
Experimental
Arm Description
twice daily doses of 30 mg for 4 weeks
Arm Title
Placebo
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
BIBR 796 BS
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Absolute difference to baseline in concentrations of C-reactive Protein (CRP)
Time Frame
before and after 4 weeks of treatment
Secondary Outcome Measure Information:
Title
Absolute difference to baseline in tender joint count (TJC, 68 joint count)
Time Frame
before and after 4 weeks of treatment
Title
Absolute difference to baseline in swollen joint count (SJC, 66 joint count)
Time Frame
before and after 4 weeks of treatment
Title
Patients assessment of pain on a visual analogue scale (VAS)
Time Frame
up to 57 days
Title
Patients global assessment of disease activity (PADA) on a VAS
Time Frame
up to 57 days
Title
Physicians global assessment of disease activity on a VAS
Time Frame
up to 57 days
Title
Assessment of physical function by a standardised health assessment questionnaire (HAQ)
Time Frame
up to 57 days
Title
Absolute difference to baseline in Erythrocyte sedimentation rate (ESR)
Time Frame
up to 57 days
Title
Absolute difference to baseline in Cytokines Tumor Necrosis Factor (TNF)-α, soluble TNF-Receptor (sTNF-R), Interleukin (IL)-1ra, IL-6
Time Frame
Day 1, 8 and 29
Title
Absolute difference to baseline in Matrix metalloprotease-3 (MMP-3)
Time Frame
Day 1, 8 and 29
Title
Absolute difference to baseline in Vascular endothelial growth factor (VEGF)
Time Frame
Day 1, 8 and 29
Title
Number of responders to American College of Rheumatology (ACR) preliminary response criteria for 20% improvement (ACR 20), ACR 50, ACR 70
Time Frame
after 4 weeks of treatment
Title
Number of responders to European League against Rheumatism (EULAR) response criteria
Time Frame
after 4 weeks of treatment
Title
Number of drop-outs due to lack of efficacy, according to final assessment of investigator
Time Frame
after 4 weeks of treatment
Title
Assessment of maximum concentration (Cmax)
Time Frame
Day 15, 22, 29
Title
Assessment of area under the curve (AUC) at steady state
Time Frame
Day 15, 22, 29
Title
Number of patients with Adverse events
Time Frame
up to day 73
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female from 18 to 75 years of age
Diagnosis of Rheumatoid Arthritis (RA) established according to ACR criteria and date of diagnosis >1 year to ≤ 15 years. The exclusion of patients with a disease duration > 15 years was deleted in Amendment 2, effective January 22, 2002
Patient belonging to functional class I, II, or III
Failure of at least one Disease Modifying Antirheumatic Drug (DMARD) due to inefficacy
Active disease, documented at visit 3, defined by ≥10 swollen joints in a 66 joint count and ≥ 12 tender joints in a 68 joint count
CRP ≥ 2.0 mg/dl at visit 1 or visit 2
Written informed consent in accordance with Good Clinical Practice and local legislation given prior to any study procedures, including washout of prohibited medications
Exclusion Criteria:
Pregnancy (to be excluded by serum and urine β Human Chorion-Gonadotropin-test in women of childbearing potential) or breast feeding
Female of childbearing potential (not 6 months post-menopausal or surgically sterilized) not using an approved form of birth control (hormonal contraceptives, oral or injectable/implantable, intra-uterine device (IUD))
Inflammatory rheumatic disease other than RA
Active vasculitis or any history of vasculitis (characterised by e.g. nail bed hemorrhages or infarcts, vasculitic purpura, ulcers or gangrenes, multisensory neuropathy, vasculitic retinopathy or scleritis of eyes). Isolated rheumatoid nodules of the skin are not a criterion for exclusion
Treatment failure to a TNF-blocking agent. Treatment failure is defined as not achieving at least an ACR 20 response (e.g. in a clinical trial) or - in clinical practice - having the TNF-blocking agent discontinued due to ineffectiveness
DMARD treatment within 4 weeks before visit 3
Last dose given within the specified time period before visit 3 for one of the following compounds or drugs:
Infliximab (Remicade®): 3 months
D2E7 (a human TNF-α antibody): 3 months
Leflunomide (Arava®): 1 year, with exception of patients having undergone elimination therapy (colestyramin 8 grams t.i.d. po for eleven consecutive days), this exclusion criterion was deleted in Amendment 1, effective September 3, 2001
Drug classified as proton pump inhibitor: 7 days
Drug classified as H2-receptor-blocker or antacid: 2 days
Investigational agent: 5-fold of the respective plasma half life or 4 weeks, whichever is longer
Treatment with systemic corticosteroids in a dose higher than 10 mg/day prednisone equivalent within 4 weeks prior to visit 3
Change in treatment with nonsteroidal antiinflammatory drugs (NSAIDs) or systemic corticosteroids within 4 weeks prior to visit 3
Synovectomy, joint surgery, radio-/chemo synoviorthesis or steroid injections (intraarticular, intravenous or intramuscular) within 4 weeks before visit 3
Active infection or serious infectious diseases resulting in hospitalisation or requiring systemic anti-infective therapy within 4 weeks before visit 3
Serologic evidence of active hepatitis B and/or C
Known HIV-infection
History of prior tuberculosis infection or suspicion of active infection at screening based on chest x-ray done within 6 month before visit 1
History of cardiovascular, renal, neurologic, psychiatric, liver, gastrointestinal, immunologic or endocrine dysfunction if they are clinically significant. A clinically significant disease is defined as one which in the opinion of the investigator may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient's ability to participate in the study
Recent history of heart failure, defined according to New York Heart Association criteria as being stage III or IV (i.e. three years or less) or myocardial infarction (i.e. one year or less) or patients with any cardiac arrhythmia requiring drug therapy. This exclusion criterion was slightly modified in Amendment 2, effective January 22, 2002.
ECG results outside of the reference range of clinical relevance including, but not limited to QTcB > 480 msec, PR interval > 240 msec, QRS interval > 110 msec
History of malignant disease in the last 5 years or suspicion of active malignant disease except successfully treated squamous or basal cell carcinoma of the skin
Clinically significant abnormal baseline hematology, blood chemistry or urinalysis if the abnormality defines a disease listed as an exclusion criterion
Any of the following specific laboratory abnormalities:
Alanine aminotransferase, aspartate aminotransferase, or total bilirubin greater than upper limit of normal (ULN) at visit 1 or measured within the last six months before visit 3. This exclusion criterion was modified in Amendment 1, effective September 3, 2001, allowing for a retest at Visit 2.
Gamma-Glutamyltransferase, alkaline phosphatase or Lactate Dehydrogenase greater than 1.5 x ULN at visit 1
creatinine or white blood cell count greater than 1.5 x ULN at visit 1
History of drug or alcohol abuse within the past two years or active drug or alcohol abuse, present alcohol intake more than three drinks per day
Inability to comply with the protocol
Participation in another clinical trial within 30 days before visit 3
Previous enrolment in this trial
Hypersensitivity to trial drug
12. IPD Sharing Statement
Links:
URL
http://trials.boehringer-ingelheim.com
Description
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Efficacy and Safety of Different Doses of BIRB 796 BS in Patients With Active Rheumatoid Arthritis
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