Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effects of Multiple Rising Subcutaneous Doses of BI 655064 in Healthy Volunteers and in Rheumatoid Arthritis Patients With Prior Inadequate Response to Methotrexate Therapy
- Conditions
- Arthritis, RheumatoidHealthy
- Interventions
- Drug: BI 655064Drug: Placebo matching BI 655064
- Registration Number
- NCT01751776
- Lead Sponsor
- Boehringer Ingelheim
- Brief Summary
To evaluate the safety and tolerability of multiple doses of BI 655064 administered subcutaneously in healthy volunteers (HVs) and in rheumatoid arthritis (RA) patients. To explore the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of multiple doses of BI 655064 in healthy volunteers (HVs) and rheumatoid arthritis (RA) patients. To assess clinical effect of BI 655064 in RA patients with prior inadequate response to methotrexate (MTX) after 12 weeks of treatment
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 107
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1, BI 655064 240mg (HV) BI 655064 Part 1, Healthy volunteers (HV): 240mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 8 weeks follow-up period. Part 2, Placebo BI 655064 120mg (RA) Placebo matching BI 655064 Part 2, patients with Rheumatoid arthritis (RA) who had prior inadequate response to Methotrexat (MTX) therapy: Placebo matching BI 655064 120 milligram (mg) injected subcutaneous on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (once weekly for 12 weeks) followed by 8 weeks follow-up period. Part 2, BI 655064 120mg (RA) BI 655064 Part 2, patients with RA who had prior inadequate response to MTX therapy: 120 milligram (mg) of BI 655064 injected subcutaneous on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (once weekly for 12 weeks) followed by 8 weeks follow-up period. Part 1, Placebo BI 655064 80/120mg (HV) Placebo matching BI 655064 Part 1, Healthy volunteers (HV): Placebo matching BI 655064 80 or 120 milligram (mg) injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period. Part 1, Placebo BI 655064 180/240mg (HV) Placebo matching BI 655064 Part 1, Healthy volunteers (HV): Placebo matching BI 655064 180 or 240 mg injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks (180mg dosing group) or 8 weeks (240mg dosing group) follow-up period. Part 1, BI 655064 80mg (HV) BI 655064 Part 1, Healthy volunteers (HV): 80 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period. Part 1, BI 655064 120mg (HV) BI 655064 Part 1, Healthy volunteers (HV): 120 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period. Part 1, BI 655064 180mg (HV) BI 655064 Part 1, Healthy volunteers (HV): 180 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.
- Primary Outcome Measures
Name Time Method Part 1: Cmax After the First and Last Dose From first day of drug administration till end of trial, up to 77 days. Detailed PK can be found in the endpoint description. Part 1: This outcome measure presents the maximum measured concentration of BI 655064 in plasma (Cmax) after the first and last (fourth) dose. More detailed time frame: Pharmacokinetic (PK) sample times: 0:30 hour (h) prior first administration of BI 655064 and 1 h, 8 h, 12 h, 24 h, 48 h, 72 h, 84 h, 96 h, 108 h, 120 h, 144 h, 167:30 h, 335:30 h, 503:30 h, 505 h, 516 h, 528 h, 552 h, 576 h, 600 h, 624 h, 648 h, 672 h, 696 h, 744 h, 816 h, 912 h, 1008 h, 1176 h, 1344 h, 1512 h, 1848 h thereafter; further administration times for BI 655064: 168 h, 336 h, and 504 h after first administration.
Part 1: AUC 0-infinity After the Last Dose PK sample times: 1 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 192 h, 240 h, 312 h, 408 h, 504 h, 672 h, 840 h, 1008 h, 1344 h after the last administration of BI 655064 on day 22 Part 1: Area under the concentration-time curve of BI 655064 in plasma over the time interval from 0 extrapolated to infinite (AUC 0-infinity).
Part 1: AUCtau After the Last Dose PK sample times: 1 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 192 h, 240 h, 312 h, 408 h, 504 h, 672 h, 840 h, 1008 h, 1344 h after the last administration of trial drug on day 22 Area under the concentration-time curve of BI 655064 in plasma after the 4th dose over a uniform dosing interval t (AUC t,4) after the first and 4th dose. AUCtau is synonymous with AUC0-168.
Part 1: Percentage of Subjects With Drug Related Adverse Events from first administration of study medication (day 1) up to day 64 (dosing groups 80, 120, 180mg) or up to day 78 post-treatment (dosing group 240mg) In Part 1 (Phase Ib): The primary safety endpoint was the percentage of subjects with AEs related to treatment with trial medication.
Part 2: American College of Rheumatology (ACR)20 Response Rate at Week 12 at week 12 (day 85) from the initiation of study treatment ACR 20 criteria at week 12 relative to the patient's status at baseline: that is, at least 20 percent (%) improvement in swollen joint count, at least 20% improvement in tender joint count, and at least 20% improvement in ≥3 of the following 5 variables: 1) patient's assessment of pain on the visual analogue scale (VAS), rated on a scale of 1 to 10; 2) patient's global assessment of disease on the VAS, rated on a scale of 1 to 10; 3) investigator's global assessment of disease on the VAS; 4) patient's assessment of disability on the health assessment questionnaire (HAQ), rated on a scale of 1 to 3; and 5) concentrations of acute phase reactants. For all scales (1-4): smaller values better. The ACR20 were evaluated descriptively. The data were analysed with a Bayesian approach using an informative prior for the placebo treatment group; predictive probability that the treatment difference was larger than 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% or 45% was to be evaluated.
- Secondary Outcome Measures
Name Time Method Part 2: ACR50 Response Rates at Week 12 at week 12 (day 85) ACR 50 criteria at week 12 relative to the patient's status at baseline: that is, at least 50 % improvement in swollen joint count, at least 50% improvement in tender joint count, and at least 50% improvement in ≥3 of the following 5 variables: 1) patient's assessment of pain on the visual analogue scale (VAS), rated on a scale of 1 to 10; 2) patient's global assessment of disease on the VAS, rated on a scale of 1 to 10; 3) investigator's global assessment of disease on the VAS; 4) patient's assessment of disability on the health assessment questionnaire (HAQ), rated on a scale of 1 to 3; and 5) concentrations of acute phase reactants. For all scales (1-4): smaller values better. The percentage of subjects with ACR50 response is presented.
Part 2: ACR70 Response Rates at Week 12 at week 12 (day 85) ACR70 criteria at week 12 relative to the patient's status at baseline: that is, at least 70 % improvement in swollen joint count, at least 70% improvement in tender joint count, and at least 70% improvement in ≥3 of the following 5 variables: 1) patient's assessment of pain on the visual analogue scale (VAS), rated on a scale of 1 to 10; 2) patient's global assessment of disease on the VAS, rated on a scale of 1 to 10; 3) investigator's global assessment of disease on the VAS; 4) patient's assessment of disability on the health assessment questionnaire (HAQ), rated on a scale of 1 to 3; and 5) concentrations of acute phase reactants. For all scales (1-4): smaller values better). The percentage of subjects with ACR50 response is presented.
Part 2: EULAR DAS28-ESR at Week 12 baseline (day 1) and week 12 (day 85) Response as assessed by European League Against Rheumatism (EULAR) using Disease activity score in 28 joints and the erythrocyte sedimentation rate (DAS28-ESR) at week 12. In this outcome measure the frequency of EULAR response rates (change from the day of first dose to the day of visit 14 in week 12) are presented. DAS28-ESR is calculated as 0.56\*√(TJC) + 0.28\*√(SJC) + 0.70 \*Ln(ESR) + 0.014\*VAS. The total score ranges from 0 to 9.4, where a higher score indicates a better outcome.
EULAR response states were classified as follows:
good responders were patients with an improvement of \>1.2 and a present score of ⩽3.2;
moderate responders were patients with an improvement of \>0.6 to ⩽1.2 and a present score of ⩽5.1, or an improvement of \>1.2 and a present score of \>3.2;
non-responders were any patients with an improvement of ⩽0.6, or patients with an improvement of \>0.6 to ⩽1.2 and a present score of \>5.1.
Improvement (impr.) is abbreviated in the category names.Part 2: Percentage of Patients With a Decrease in DAS28-CRP of >1.2 at Week 12 baseline (day 1) and week 12 (day 85) Percentage of patients who had a decrease of \>1.2 on the Disease activity score in 28 joints and C-reactive protein (DAS28-CRP) at week 12 (day 85) compared to baseline. The adjusted absolute risk difference was adjusted for treatment, region and anti-TNF history. DAS28-CRP is calculated using Tender Joint Count 28 (TJC28), Swollen Joint Count 28 (SJC28), C-reactive protein (CRP) (in mg/L), Patient's Global Assessment of Arthritis Disease Activity (PtGA) (visual analogue scale with values from 0=best to 100=worst), where the total score is calculated as follows: 0.56\*√(TJC) + 0.28\*√(SJC) + 0.36\*Ln(CRP+1) + 0.014\*VAS + 0.96. The total score ranges from 1.0 to 9.4, where a higher score indicates a better outcome.
Part 2: Change in DAS28-CRP Score at Week 12 baseline (day 1) and week 12 (day 85) Change at week 12 in the Disease activity score in 28 joints and C-reactive protein (DAS28-CRP) compared with the score at baseline. The mean was adjusted for region, anti-TNF history and baseline DAS28-CRP. DAS28-CRP is calculated using Tender Joint Count 28 (TJC28), Swollen Joint Count 28 (SJC28), C-reactive protein (CRP) (in mg/L), Patient's Global Assessment of Arthritis Disease Activity (PtGA) (visual analogue scale with values from 0=best to 100=worst), where the total score is calculated as follows: 0.56\*√(TJC) + 0.28\*√(SJC) + 0.36\*Ln(CRP+1) + 0.014\*VAS + 0.96. The total score ranges from 1.0 to 9.4, where a higher score indicates a better outcome.
Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12 baseline (day 1) and week 12 (day 85) Assessed by European League Against Rheumatism (EULAR) categorization as good, moderate, or nonresponders based on improvement from baseline using the DAS28-CRP at week 12. In this outcome measure the frequency of EULAR response rates (change from the day of first dose to the day of visit 14 in week 12) are presented. DAS28-CRP is calculated as 0.56\*√(TJC) + 0.28\*√(SJC) + 0.36\*Ln(CRP+1) + 0.014\*VAS + 0.96. The total score ranges from 1.0 to 9.4, where a higher score indicates a better outcome.
EULAR response states were classified as follows:
good responders were patients with an improvement of \>1.2 and a present score of ⩽3.2;
moderate responders were patients with an improvement of \>0.6 to ⩽1.2 and a present score of ⩽5.1, or an improvement of \>1.2 and a present score of \>3.2;
non-responders were any patients with an improvement of ⩽0.6, or patients with an improvement of \>0.6 to ⩽1.2 and a present score of \>5.1.
Improvement (impr.) is abbreviated in the category names.
Trial Locations
- Locations (25)
1293.2.00028 Boehringer Ingelheim Investigational Site
🇨🇿Zlin, Czechia
1293.2.00024 Boehringer Ingelheim Investigational Site
🇨🇿Uherske Hradiste, Czechia
1293.2.00049 Boehringer Ingelheim Investigational Site
🇨🇿Olomouc, Czechia
1293.2.00021 Boehringer Ingelheim Investigational Site
🇪🇸A Coruña, Spain
1293.2.00039 Boehringer Ingelheim Investigational Site
🇵🇱Bialystok, Poland
1293.2.00025 Boehringer Ingelheim Investigational Site
🇵🇱Lublin, Poland
1293.2.00010 Boehringer Ingelheim Investigational Site
🇩🇪Berlin, Germany
1293.2.00015 Boehringer Ingelheim Investigational Site
🇩🇪Bad Kreuznach, Germany
1293.2.00032 Boehringer Ingelheim Investigational Site
🇳🇱Leeuwarden, Netherlands
1293.2.00043 Boehringer Ingelheim Investigational Site
🇩🇪München, Germany
1293.2.00012 Boehringer Ingelheim Investigational Site
🇩🇪Zerbst, Germany
1293.2.00031 Boehringer Ingelheim Investigational Site
🇳🇱Amsterdam, Netherlands
1293.2.00013 Boehringer Ingelheim Investigational Site
🇩🇪Berlin, Germany
1293.2.00038 Boehringer Ingelheim Investigational Site
🇳🇱Leiden, Netherlands
1293.2.00001 Boehringer Ingelheim Investigational Site
🇳🇿Grafton Auckland NZ, New Zealand
1293.2.00040 Boehringer Ingelheim Investigational Site
🇳🇱Sneek, Netherlands
1293.2.00034 Boehringer Ingelheim Investigational Site
🇵🇱Bydgoszcz, Poland
1293.2.00041 Boehringer Ingelheim Investigational Site
🇵🇱Bydgoszcz, Poland
1293.2.00050 Boehringer Ingelheim Investigational Site
🇵🇱Poznan, Poland
1293.2.00022 Boehringer Ingelheim Investigational Site
🇪🇸Granada, Spain
1293.2.00026 Boehringer Ingelheim Investigational Site
🇵🇱Warszawa, Poland
1293.2.00016 Boehringer Ingelheim Investigational Site
🇪🇸La Laguna (Sta Cruz Tenerife), Spain
1293.2.00017 Boehringer Ingelheim Investigational Site
🇪🇸Barcelona, Spain
1293.2.00020 Boehringer Ingelheim Investigational Site
🇪🇸Santiago de Compostela, Spain
1293.2.00023 Boehringer Ingelheim Investigational Site
🇵🇱Warsaw, Poland