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
Overview
- Phase
- Phase 1
- Intervention
- ASP5094
- Conditions
- Rheumatoid Arthritis (RA)
- Sponsor
- Astellas Pharma Global Development, Inc.
- Enrollment
- 30
- Locations
- 13
- Primary Endpoint
- Maximum Concentration (Cmax) of ASP5094
- Status
- Completed
- Last Updated
- last year
Overview
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).
Investigators
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
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
- •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
Arms & Interventions
ASP5094 Dose Escalation
Three sequential cohorts will receive increasing intravenous doses of ASP5094. After all subjects in a cohort have completed study procedures the overall safety and tolerability of the dose will be determined after evaluation of the safety data. If there are no events which meet the stopping criteria, the next sequential cohort will begin enrollment while the current subjects continue through the third dose and the remainder of the study.
Intervention: ASP5094
Placebo Dose Escalation
Three sequential cohorts will receive increasing intravenous doses of Placebo. After all subjects in a cohort have completed study procedures the overall safety and tolerability of the dose will be determined after evaluation of the safety data. If there are no events which meet the stopping criteria, the next sequential cohort will begin enrollment while the current subjects continue through the third dose and the remainder of the study.
Intervention: Placebo
Outcomes
Primary Outcomes
Maximum Concentration (Cmax) of ASP5094
Time Frame: Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
Change from Baseline in Peripheral Lymphocyte Subsets: CD3/Lymphocytes
Time Frame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
Change from Baseline in Peripheral Lymphocyte Subsets: CD8/Lymphocytes
Time Frame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
Time to maximum concentration (tmax) of ASP5094
Time Frame: Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
Change from Baseline in Total Lymphocyte Counts
Time Frame: Baseline and days 29, 57, 85, 113, 141
Change from Baseline in Peripheral Lymphocyte Subsets: CD19/Lymphocytes
Time Frame: Baseline and days 29 (predose), 57 (predose), 85, 113, 141
Change from Baseline in Peripheral Lymphocyte Subsets: CD4
Time Frame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
Number of Participants with Anti-ASP5094 Antibody Formation
Time Frame: Days 1 (predose), 29 (predose), 57 (predose), 71, 85, 113 and 141
Change from Baseline in Peripheral Lymphocyte Subsets: CD19
Time Frame: Baseline and days 29 (predose), 57 (predose), 85, 113, 141
Change from Baseline in Peripheral Lymphocyte Subsets: CD3
Time Frame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
Change from Baseline in Peripheral Lymphocyte Subsets: CD4/Lymphocytes
Time Frame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
Change from Baseline in Peripheral Lymphocyte Subsets: CD8
Time Frame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
Change from Baseline in Peripheral Lymphocyte Subsets: Granulocytes/Leukocytes
Time Frame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
Change from Baseline in Peripheral Lymphocyte Subsets: Granulocytes
Time Frame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
Number of Participants with Treatment-Emergent Adverse Events
Time Frame: From first dose of study drug up to end of study (up to 141 days)
A treatment-emergent adverse event (TEAE) is defined as a newly occurring or worsening adverse event (AE) observed after starting administration of study drug up until the end of study visit, inclusive. This includes abnormal laboratory tests, vital signs or electrocardiogram data that are defined as AEs if the abnormality induces clinical signs or symptoms, requires active intervention, interruption or discontinuation of study drug or is clinically significant in the investigator's opinion. A serious AE (SAE) is defined as an AE with an outcome that results in death, is life-threatening, results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, results in congenital anomaly, or birth defect or requires inpatient hospitalization or leads to prolongation of hospitalization.
Change from Baseline in Peripheral Lymphocyte Subsets: Natural Killer Cell Subset/Lymphocytes
Time Frame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
Concentration immediately prior to dosing at multiple dosing (Ctrough) for ASP5094
Time Frame: Predose on days 29, 57, and 85
Change from Baseline in Peripheral Lymphocyte Subsets: Natural Killer Cells
Time Frame: Baseline and Days 29 (predose), 57 (predose), 85, 113, 141
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)
Time Frame: Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
Accumulation ratio calculated using the area under the concentration-time curve (R3ac[AUC]) for ASP5094
Time Frame: Day 57 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
Accumulation ratio calculated using the maximum concentration (R3ac[Cmax]) for ASP5094
Time Frame: Day 57 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose
Secondary Outcomes
- Total clearance after intravenous dosing (CL)(Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose)
- Volume of distribution after intravenous dosing during the terminal elimination phase (VzF)(Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose)
- Terminal elimination half-life (t1/2)(Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose)
- Percentage of Fluctuation(Day 1 predose, 0.5, 24, 96, 168, 216, 336, 504, 672 hours postdose)