A Study To Evaluate the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of ASP2408 After Multiple Dose Subcutaneous Injections in Patients With Rheumatoid Arthritis on Methotrexate

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Study To Evaluate the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of ASP2408 After Subcutaneous Injections in Patients With Rheumatoid Arthritis on Methotrexate

The purpose of this study is to assess the safety, tolerability and pharmacokinetics (PK) of two dosing regimens of multiple, subcutaneous (sc) injections of ASP2408 in patients with Rheumatoid Arthritis (RA) on Methotrexate (MTX) and to evaluate the pharmacodynamics (PD) of ASP2408.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis; Pharmacokinetics of ASP2408
• Intervention / Treatment: Drug: Placebo; Drug: ASP2408

Detailed Description

This is an ascending dose frequency study. There are two cohorts of active and placebo patients. The first cohort is dosed every 4 weeks for a total of 3 doses. The second cohort is dosed every two weeks for a total of 3 doses.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Pinnacle Research Group, LLC
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center for Clinical Research
  • Texas
    • Dallas, Texas, United States, 75231
      • Metroplex Clinical Research Center, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject weighs at least 50 kg.
• Subject has a body mass index (BMI) of ≤ 35 kg/m2.
• Subject's 12-lead electrocardiogram (ECG) results are normal at Screening and Day 1 prior to study drug dosing or, if abnormal, the abnormality is not clinically significant as determined by the Investigator.
• Subject has Rheumatoid Arthritis (RA) that was diagnosed according to the 1987 revised criteria of the American College of Rheumatology (ACR) ≥ 6 months prior to Screening.
• Subject meets the ACR 1991 revised criteria for Global Functional Status in RA, Class I, II or III at Screening.

• Subject MUST be on concomitant methotrexate (MTX):

  • for ≥ 3 months prior to Day 1, AND
  • at a stable dose (10 - 25 mg/week) for ≥ 28 days prior to Day 1 and throughout the study.

• Subject's other related medications taken for the treatment of RA at the time of Screening must meet the noted stability requirements and remain on a stable regimen, as follows:

  • Non-steroidal anti-inflammatory drugs (NSAIDs), selective cyclooxy-genase-2 (COX-2) inhibitors, oral corticosteroids (≤ 10 mg of prednisone, or equivalent, daily) or low dose opioids (≤ 30 mg of oral morphine, or equivalent, daily) must be stable for ≥ 28 days prior to Screening and remain so throughout the Treatment and Observation Period.
• Hydroxychloroquine (Plaquenil®) and sulfasalazine must have started ≥ 2 months, and be stable for ≥ 28 days, prior to Day 1.

Exclusion Criteria:

• Subject has an ongoing infection or has had an infection requiring intravenous antibiotics within 1 month prior to Day 1.
• Subject has a past history of serious opportunistic infection.
• Subject has a positive Mantoux tuberculin skin or QuantiFERON-TB Gold test within 90 days of, or at Screening, and has not completed an adequate course of antimicrobial therapy per CDC guidelines.
• Subject received any live or live-attenuated vaccine within 30 days prior to Day 1.

• Subject received any of the following:

  • Anakinra (Kineret®), etanercept (Enbrel®), or adalimumab (Humira®) within 60 days prior to Day 1.
  • Rituximab (Rituxan®) or any other anti-CD20 antibody within 180 days prior to Day 1.
  • Leflunomide (Arava®) within 60 days prior to drug dosing on Day 1, unless the subject has undergone cholestyramine washout at least 30 days prior to Day 1.
  • Oral or injectable gold, azathioprine, penicillamine, cyclosporine, or tacrolimus within 30 days prior to Day 1.
  • Cyclophosphamide within 180 days prior to Day 1.
• Subject has received any CTLA4-Ig molecule (including, but not limited to abatacept [Orencia®] and belatacept [Nulojix]).
• Subject has participated in a previous clinical study with treatment with ASP2408 or ASP2409 or has participated in another dose cohort of the current trial.
• Subject has previously participated in any interventional clinical study, or has received an experimental agent within 56 days or 5 half-lives, whichever is longer, prior to Day 1.
• Subject has a history of prolonged QT syndrome.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ASP2408 low dosing frequency	Drug: ASP2408; subcutaneous injection
Experimental: ASP2408 high dosing frequency	Drug: ASP2408; subcutaneous injection
Experimental: Placebo low dosing frequency	Drug: Placebo; subcutaneous injection
Experimental: Placebo high dosing frequency	Drug: Placebo; subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameter of ASP2408: AUCtau	Area Under the Concentration-Time curve for a dosing interval (AUCtau)	Days 1, 2, 3, 4, 5, 6, 8, 10, 15, 22, 36, 38, 43, 50, 57, 66, 71, 78, 85, 113, 141
Pharmacokinetic parameter of ASP2408: Cmax	Maximum Concentration (Cmax)	Days 1, 2, 3, 4, 5, 6, 8, 10, 15, 22, 36, 38, 43, 50, 57, 66, 71, 78, 85, 113, 141
Pharmacokinetic parameter of ASP2408: Tmax	Time to Attain Cmax (Tmax)	Days 1, 2 ,3, 4, 5, 6, 8, 10, 15, 22, 36, 38, 43, 50, 57, 66, 71, 78, 85, 113, 141
Pharmacokinetic parameter of ASP2408: Ctrough	Trough Concentration (Ctrough)	Days 1, 2, 3, 4, 5, 6, 8, 10, 15, 22, 36, 38, 43, 50, 57, 66, 71, 78, 85, 113, 141
Safety assessed by adverse events (AEs), laboratory tests, electrocardiograms (ECGs), physical examinations, pulse oximetry, vital signs and Anti-ASP2408 antibody (ADA) formulation		Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of pharmacokinetics of ASP2408: t1/2, Vz/F, CL/F,	Apparent Terminal Elimination Half-life (t1/2), Volume of distribution (Vz/F), Apparent Body Clearance (CL/F)	Days 1, 2, 3, 4, 5, 6, 8, 10, 15, 22, 36, 38, 43, 50, 57, 66, 71, 78, 85, 113, 141
Pharmacodynamic parameter of ASP2408: CD86 receptor occupancy	Cluster of Differentiation 86, a co-stimulatory ligand on antigen-presenting cells; alternate notation for B7.2 (CD86)	Days 1, 2, 3, 4, 5, 6, 8, 10, 15, 22,36, 38, 43, 50, 57, 66, 71, 72, 78, 85,113, 141

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: January 30, 2014
• First Submitted That Met QC Criteria: January 30, 2014
• First Posted (Estimate): February 3, 2014

Study Record Updates

• Last Update Posted (Estimate): February 6, 2014
• Last Update Submitted That Met QC Criteria: February 5, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: Rheumatoid Arthritis; methotrexate; ASP2408
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: 2408-CL-0201