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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of VAY736 in Rheumatoid Arthritis Patients

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: VAY736
* Biological: VAY736 placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VAY736<br>VAY736 active | Biological: VAY736<br>* VAY736 treatment<br>|
| Placebo Comparator: Placebo<br>VAY736 placebo | Biological: VAY736 placebo<br>* VAY736 placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability as measured by the number of patients wth adverse events | 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. | 27-188 weeks | 
| Absolute bioavailability of VAY736: The ratio of area under curve (AUC) for s.c dose and for intravenous dose | Part 2 The ratio of area under curve (AUC) for single s.c dose and intravenous dose is determined | 188 weeks | 
| Plasma pharmacokinetics of VAY736: The area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCtau) | 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 | 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) | 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. | 27 weeks | 
| Plasma pharmacokinetics of VAY736: Observed maximum plasma concentration following drug administration (Cmax) | In Part 3: After the first and last s.c. doses, the Observed maximum plasma concentration following drug administration (Cmax) will be determined | 27 weeks | 
| Plasma pharmacokinetics of VAY736: Time to reach the maximum concentration after drug administration (Tmax) | 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 | 27 weeks | 
| Plasma pharmacokinetics of VAY736: The terminal elimination half-life (T1/2) | In Part 3: After the first and last s.c. doses, the terminal elimination half-life (T1/2) will be determined | 27 weeks | 
| Plasma pharmacokinetics of VAY736: Area under the plasma concentration-time curve from time zero to infinity (AUCinf) | 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. | 27 weeks | 
| Plasma pharmacokinetics of VAY736: concentration of VAY736 during the treatment period, before each dose (Ctrough) | 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 | 27 weeks | 
| Safety and tolerability as measured by the percentage of patients wth adverse events | 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. | 27-188 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pharmacodynamics of VAY736 | 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 | 27-188 weeks | 
| Immunogenicity of VAY736 | 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. | 27-188 weeks | 
| Plasma bioavailability of VAY736: The ratio of area under curve (AUC) for repeated s.c doses and for intravenous dose | Part 3 The ratio of area under curve (AUC) for repeated s.c doses and for intravenous dose is determined | 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) | 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 | 34-188 weeks | 
| Plasma pharmacokinetics of VAY736: Area under the plasma concentration-time curve from time zero to infinity (AUCinf) | 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. | 34-188 weeks | 
| Plasma pharmacokinetics of VAY736: Observed maximum plasma concentration following drug Administration (Cmax) | 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 | 34-188 weeks | 
| Plasma pharmacokinetics of VAY736: Time to reach the maximum concentration after drug administration (Tmax) | 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 | 34-188 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid arthritis