Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of VAY736 in Rheumatoid Arthritis Patients

Phase 1

Completed

• Conditions: Rheumatoid Arthritis
• Interventions: Biological: VAY736 placebo; Biological: VAY736

• Registration Number: NCT02675803
• Lead Sponsor: Novartis Pharmaceuticals

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 Timeline

• Study Start: 2010-12-20
• Study First Submitted: 2015-07-09
• Study First Submitted QC: 2016-02-02
• Study First Posted: 2016-02-05
• Primary Completion: 2018-01-22
• Study Completion: 2018-01-22
• Status Verified: 2019-01
• Last Update Submitted: 2020-12-09
• Last Update Posted: 2020-12-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 65

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 2. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	VAY736 placebo	VAY736 placebo
VAY736	VAY736	VAY736 active

Primary Outcome Measures

Name	Time	Method
Safety and tolerability as measured by the number of patients wth adverse events	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	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)	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)	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)	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)	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)	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)	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)	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	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 Outcome Measures

Name	Time	Method
pharmacodynamics of VAY736	27-188 weeks	B cell depletion/recovery after single i.v. dose of VAY736, single s.c. dose of VAY736 and multiple fixed s.c. doses of VAY736 administration in the 3 parts of the study
Immunogenicity of VAY736	27-188 weeks	Immunogenicity after administration of single i.v. dose of VAY736, single s.c. dose of VAY736 and multiple fixed s.c. doses of VAY736 in 3 parts of the study.
Plasma bioavailability of VAY736: The ratio of area under curve (AUC) for repeated s.c doses and for intravenous dose	27 weeks	Part 3 The ratio of area under curve (AUC) for repeated s.c doses and for intravenous dose is determined
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	The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) will be determined after single i.v. dose and s.c. dose of VAY736 in Part 1 and Part 2 respectively
Plasma pharmacokinetics of VAY736: Area under the plasma concentration-time curve from time zero to infinity (AUCinf)	34-188 weeks	The area under the plasma concentration-time curve from time zero to infinity (AUCinf) will be determined after single i.v. dose and s.c. dose of VAY736 in Part 1 and Part 2 respectively.
Plasma pharmacokinetics of VAY736: Observed maximum plasma concentration following drug Administration (Cmax)	34-188 weeks	The Observed maximum plasma concentration following drug administration (Cmax) will be determined after single i.v. dose and s.c. dose of VAY736 in Part 1 and Part 2 respectively
Plasma pharmacokinetics of VAY736: Time to reach the maximum concentration after drug administration (Tmax)	34-188 weeks	The time to reach the maximum concentration after drug administration (Tmax) will be determined after single i.v. dose and s.c. dose of VAY736 in Part 1 and Part 2 respectively

Trial Locations

Locations (1)

Novartis Investigative Site; 🇩🇪 Berlin, Germany