A Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of VAY736 in Rheumatoid Arthritis Patients
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 65
- Locations
- 2
- Primary Endpoint
- Safety and tolerability as measured by the number of patients wth adverse events
Study Overview
Brief Summary
This study investigated the safety and tolerability of VAY736 administered as single ascending doses of intravenous infusion, subcutaneous injection and repeated subcutaneous injections in rheumatoid arthritis patients.
Detailed Description
This study had three sequential parts which investigated the safety and tolerability of VAY736 administered as single ascending doses of intravenous infusion (Part 1), single ascending doses of subcutaneous injection (Part 2), and repeated subcutaneous injections of fixed doses (Part 3), respectively, in rheumatoid arthritis patients. Part 1 was double blind, placebo controlled, with 11 cohorts. Part 2 was open-label study with 2 dosing cohorts. Part 3 was open-label study with 1 fixed-dose cohort.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Care Provider, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Active disease despite methotrexate treatment 5 to 20 mg/week for Parts 1 and 2; methotrexate treatment 5 to 20 mg/week for Part 3
- •Fulfilled 2010 American College of Rheumatolody (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis for Part 1 and Part
- •For Part 3, fulfilled 2010 American College of Rheumatolody (ACR)/)/European League Against Rheumatism (EULAR) classification criteria or/and 1987 American College of Rheumatolody (ACR) classification criteria for rheumatoid arthritis;
- •Methotrexate ≥ 16 weeks, stable dose ≥ 8 weeks
Exclusion Criteria
- •Previous treatment with a B cell-depleting biologic agent.
- •Autoimmune disease other than RA except concurrent Sjogren's syndrome
- •Adult juvenile rheumatoid arthritis
- •ARA functional class IV disease of ACR Revised Steinbrocker Classification
Outcomes
Primary Outcomes
Safety and tolerability as measured by the number of patients wth adverse events
Time Frame: 27-188 weeks
Part 1 The number of patients with adverse events after single intravenous (i.v.) dose of VAY736. Patients are assessed weekly up to 34 weeks post dose or until B cells reach the recovery criteria Part 2 The number of patients with adverse events after single subcutaneous (s.c.) dose of VAY736. Patients are assessed weekly, bi-weekly, then every 4, 8 and 12 weeks up to 188 weeks post dose or until B cells reach the recovery criteria. Part 3 The number of patients with adverse events after repeated subcutaneous (s.c) injections of a fixed dose of VAY736. Patients are assessed bi-weekly, then every 4 weeks and 8 weeks up to 27 weeks from the first dose.
Absolute bioavailability of VAY736: The ratio of area under curve (AUC) for s.c dose and for intravenous dose
Time Frame: 188 weeks
Part 2 The ratio of area under curve (AUC) for single s.c dose and intravenous dose is determined
Plasma pharmacokinetics of VAY736: The area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCtau)
Time Frame: 27 weeks
In Part 3: After the first and last s.c. doses, the area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCtau) will be determined
Plasma pharmacokinetics of VAY736: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast)
Time Frame: 27 weeks
In Part 3: After the first and last s.c. doses, the Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) will be determined.
Plasma pharmacokinetics of VAY736: Observed maximum plasma concentration following drug administration (Cmax)
Time Frame: 27 weeks
In Part 3: After the first and last s.c. doses, the Observed maximum plasma concentration following drug administration (Cmax) will be determined
Plasma pharmacokinetics of VAY736: Time to reach the maximum concentration after drug administration (Tmax)
Time Frame: 27 weeks
In Part 3: After the first and last s.c. doses, the time to reach the maximum concentration after drug administration (Tmax) will be determined
Plasma pharmacokinetics of VAY736: The terminal elimination half-life (T1/2)
Time Frame: 27 weeks
In Part 3: After the first and last s.c. doses, the terminal elimination half-life (T1/2) will be determined
Plasma pharmacokinetics of VAY736: Area under the plasma concentration-time curve from time zero to infinity (AUCinf)
Time Frame: 27 weeks
In Part 3: After the first and last s.c. doses, Area under the plasma concentration-time curve from time zero to infinity (AUCinf) will be determined.
Plasma pharmacokinetics of VAY736: concentration of VAY736 during the treatment period, before each dose (Ctrough)
Time Frame: 27 weeks
In Part 3: After the first and last s.c. doses, the concentration of VAY736 during the treatment period, before each dose (Ctrough) will be determined
Safety and tolerability as measured by the percentage of patients wth adverse events
Time Frame: 27-188 weeks
Part 1 The percentage of patients with adverse events after single intravenous (i.v.) dose of VAY736. Patients are assessed weekly up to 34 weeks post dose or until B cells reach recovery criteria. Part 2 The percentage of patients with adverse events after single subcutaneous (s.c.) dose of VAY736. Patients are assessed weekly, bi-weekly, then every 4, 8 and 12 weeks up to 68 weeks post dose or until B cells reach recovery criteria.. Part 3 The percentage of patients with adverse events after repeated subcutaneous (s.c) injections of a fixed dose of VAY736. Patients are assessed bi-weekly, then every 4 weeks and 8 weeks up to 27 weeks from the first dose.
Secondary Outcomes
- pharmacodynamics of VAY736(27-188 weeks)
- Immunogenicity of VAY736(27-188 weeks)
- Plasma bioavailability of VAY736: The ratio of area under curve (AUC) for repeated s.c doses and for intravenous dose(27 weeks)
- Plasma pharmacokinetics of VAY736: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast)(34-188 weeks)
- Plasma pharmacokinetics of VAY736: Area under the plasma concentration-time curve from time zero to infinity (AUCinf)(34-188 weeks)
- Plasma pharmacokinetics of VAY736: Observed maximum plasma concentration following drug Administration (Cmax)(34-188 weeks)
- Plasma pharmacokinetics of VAY736: Time to reach the maximum concentration after drug administration (Tmax)(34-188 weeks)