Clinical trial NCT02698657: A Study to Assess the Safety, Tolerability, and Pharmacokinetics of ASP5094 Following Multiple Intravenous Doses in Subjects With Rheumatoid Arthritis on Methotrexate
Official title: A Phase 1, Randomized, Placebo-controlled, Dose Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of ASP5094 Following Multiple Intravenous Doses in Subjects With Rheumatoid Arthritis on Methotrexate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Rheumatoid Arthritis (RA)
Keywords: Rheumatoid arthritis (RA)
Methotrexate
ASP5094
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2016-03-04
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of multiple ascending intravenous doses of ASP5094 in male and female subjects with rheumatoid arthritis (RA) on methotrexate (MTX).


Eligibility criteria: Inclusion Criteria:

* Subject has a body mass index (BMI) of ≤ 35 kg/m2, inclusive, and must weigh at least 50 kg at screening.
* Subject has absolute neutrophil count within normal limits at screening. The assessment may be repeated once during screening.
* Subject has 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 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 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:

  * Nonsteroidal antiinflammatory drugs (NSAIDs), selective cyclooxygenase-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,
  * Hydroxychloroquine (Plaquenil®) and sulfasalazine (e.g., Azulfidine®) must have started ≥ 2 months, and be stable for ≥ 28 days, prior to day 1.
* Female subject must be either:

  * Of nonchildbearing potential: postmenopausal (defined as at least 1 year without any menses) prior to screening, or documented surgically sterile
  * Or, if of childbearing potential, Agree not to try to become pregnant during the study and for 60 days after the final study drug administration; must have a negative urine pregnancy test at screening and day 1, And, if heterosexually active, agree to consistently use 2 forms of highly effective birth control† (at least 1 of which must be a barrier method) starting at screening and throughout the study period and for 60 days after the final study drug administration.
* Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 60 days.
* Female subject must not donate ova starting at screening and throughout the study period, and for 60 days after the final study drug administration.
* Male subject and his female spouse/partner who is of childbearing potential must be using highly effective forms of contraception consisting of 2 forms of birth control† (1 of which must be a barrier method) starting at screening and continue throughout the study period and for 60 days after the final study drug administration.
* Male subject must not donate sperm starting at screening and throughout the study period, and for 60 days after the final study drug administration
* Subject agrees not to participate in another interventional study while participating in the present study, defined as signing the informed consent form until completion of the last study visit.

Exclusion Criteria:

* Subject has an ongoing clinically significant systemic disease such as uncompensated heart failure, uncontrolled diabetes mellitus, severe hepatic failure, severe pulmonary disease or inflammatory bowel disease.
* Subject has a history of any malignancy in the past 5 years, except for adequately-treated, nonmelanoma skin cancer and adequately-treated in-situ cervical cancer.
* Subject has a history of severe allergic or anaphylactic reactions to drugs.
* Subject has a history of consuming more than 14 units of alcoholic beverages per week or has a history of alcoholism or drug/chemical/ substance abuse within past 6 months prior to screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits).
* Subject has an ongoing infection or has had an infection requiring intravenous antibiotics within 1 month prior to day 1.
* Subject has a known history of a positive test for human immunodeficiency virus (HIV) antibody.
* Subject has a past history of serious opportunistic infection.
* Subject has a positive QuantiFERON-TB Gold test within 90 days of, or at screening, and has not completed an adequate course of antimicrobial therapy per Centers for Disease Control or local guidelines.
* Subject's laboratory test results at screening or prior to study drug dosing on day 1:

  * Outside the normal limits and considered by the investigator to be clinically significant with regard to the remaining per-protocol laboratory tests, and/or
  * Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) are \> 2 times the upper limit of normal.
* Subject received any live or live-attenuated vaccine within 30 days prior to day 1.
* Subject received any of the following:

  * Oral or injectable gold, azathioprine, penicillamine, cyclosporine, tacrolimus or tofacitinib (Xeljanz®) within 30 days prior to day 1.
  * Anakinra (Kineret®), etanercept (Enbrel®), adalimumab (Humira®), tocilizumab (Actemra®), infliximab (Remicade®), or golimumab (Simponi®) within 60 days prior to day 1.
  * Leflunomide (Arava®) within 60 days prior to day 1, unless the subject has undergone cholestyramine washout at least 30 days prior to day 1.
  * Certolizumab (Cimzia®) and abatacept (Orencia®) within 90 days prior to day 1.
  * Rituximab (Rituxan®) or any other antiCD20 antibody, and cyclophosphamide within 180 days prior to day 1.
  * Treatment with any other conventional disease modifying antirheumatic drugs (DMARDs), or treatment with any other biologics not previously noted within 28 days or 5 half-lives, whichever is longer, prior to day 1.
* Subject has participated in a previous clinical study with treatment with ASP5094 or has participated in another dose cohort of the current trial.
* Subject has previously received an experimental agent within 28 days or 5 half-lives, whichever is longer, prior to day 1.
* Subject has had any significant blood loss, donated 1 unit (450 mL) of blood or more, or received a transfusion of any blood or blood products within 60 days or donated plasma within 7 days prior to day 1.
* Subject had surgery or has a planned elective surgery (including oral surgery) within 1 month prior to screening and 3 months after last study drug administration.
* Subject has a wound that is currently healing.
* Subject has any other condition, which in the opinion of the investigator, precludes the subject's participation in the trial.
* Subject is an employee of the Astellas group or vendors involved in the study.

Primary outcomes:
measure: Number of Participants with Treatment-Emergent Adverse Events
timeFrame: From first dose of study drug up to end of study (up to 141 days)
measure: Change from Baseline in Total Lymphocyte Counts
timeFrame: Baseline and days 29, 57, 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: CD19
timeFrame: Baseline and days 29 (predose), 57 (predose), 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: CD19/Lymphocytes
timeFrame: Baseline and days 29 (predose), 57 (predose), 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: CD3
timeFrame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: CD3/Lymphocytes
timeFrame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: CD4
timeFrame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: CD4/Lymphocytes
timeFrame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: CD8
timeFrame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: CD8/Lymphocytes
timeFrame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: Granulocytes
timeFrame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: Granulocytes/Leukocytes
timeFrame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: Natural Killer Cell Subset/Lymphocytes
timeFrame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
measure: Change from Baseline in Peripheral Lymphocyte Subsets: Natural Killer Cells
timeFrame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
measure: Number of Participants with Anti-ASP5094 Antibody Formation
timeFrame: Days 1 (predose), 29 (predose), 57 (predose), 71, 85, 113 and 141
measure: Area under the concentration-time curve from the time of dosing on day 1 to the end of the 4-week dosing interval for ASP5094 (AUC)
timeFrame: Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
measure: Maximum Concentration (Cmax) of ASP5094
timeFrame: Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
measure: Time to maximum concentration (tmax) of ASP5094
timeFrame: Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
measure: Concentration immediately prior to dosing at multiple dosing (Ctrough) for ASP5094
timeFrame: Predose on days 29, 57, and 85
measure: Accumulation ratio calculated using the maximum concentration (R3ac[Cmax]) for ASP5094
timeFrame: Day 57 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
measure: Accumulation ratio calculated using the area under the concentration-time curve (R3ac[AUC]) for ASP5094
timeFrame: Day 57 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
Secondary outcomes:
measure: Terminal elimination half-life (t1/2)
timeFrame: Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
measure: Total clearance after intravenous dosing (CL)
timeFrame: Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
measure: Volume of distribution after intravenous dosing during the terminal elimination phase (VzF)
timeFrame: Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
measure: Percentage of Fluctuation
timeFrame: Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Site US10002
state: Alabama
city: DeBary
country: United States
facility: Site US10008
state: Florida
city: Jacksonville
country: United States
facility: Site US10004
state: Florida
city: Miami Lakes
country: United States
facility: Site US10009
state: Florida
city: Duncansville
country: United States
facility: Site US10003
state: Pennsylvania
city: Memphis
country: United States
facility: Site US10010
state: Tennessee
city: Dallas
country: United States
facility: Site US10001
state: Texas
city: Elblag
country: Poland
facility: Site PL48009
city: Krakow
country: Poland
facility: Site PL48011
city: Lodz
country: Poland
facility: Site PL48006
city: Stalowa Wola
country: Poland
facility: Site PL48007
city: Warszawa
country: Poland
facility: Site PL48003
city: Wroclaw
country: Poland
facility: Site PL48008
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Senior Medical Director
role: STUDY_DIRECTOR
References: