A Dose Escalation Study to Assess Safety, Tolerability and Pharmacokinetics of ASP2409 Following a Single Intravenous Dose in Patients With Rheumatoid Arthritis on Methotrexate

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, tolerability and pharmacokinetics (PK) of single, ascending, intravenous (IV) doses of ASP2409 in patients with Rheumatoid Arthritis (RA) on methotrexate (MTX) and to evaluate the pharmacodynamics (PD) of ASP2409.

Detailed Description
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This is a dose-escalation study. Sequential cohorts of subjects will receive increasing doses of ASP2409 or matching placebo. Subjects in all cohorts will stay confined in the unit for 3 days. All subjects will have scheduled outpatient visits and be followed for a minimum of 90 days.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Assess the Safety, Tolerability and Pharmacokinetics of ASP2409 Following a Single Intravenous Dose in Patients With Rheumatoid Arthritis on Methotrexate

Conditions
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Rheumatoid Arthritis, Pharmacokinetics of ASP2409

Intervention / Treatment
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* Drug: ASP2409
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 or, if abnormal, the abnormality is not clinically significant Female subject must be either: Of non-childbearing potential: post-menopausal (defined as at least 1 year without any menses) prior to Screening, or documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening). Or, if of childbearing potential: must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day -1. must use two forms of birth control (at least one of which must be a barrier method) starting at Screening and throughout the Treatment and Observation Period, and for ≥ 120 days after final study drug administration. Acceptable forms include: Established use or oral, injected or implanted hormonal methods of contraception. Placement of an intrauterine device (IUD) or intrauterine system (IUS). Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault cap) with spermicidal foam/gel/film/ cream/suppository. Female subject must not be breastfeeding at Screening or during the Treatment and Observation period and for ≥ 120 days after final study drug administration. Female subject must not donate ova starting at Screening and throughout the Treatment and Observation period and for ≥ 120 days after final study drug administration. Male subject must not donate sperm starting at Screening and throughout the Treatment and Observation period and for at least ≥ 120 days after final study drug administration. Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and continue throughout the Treatment and Observation period and for ≥ 120 days after final study drug administration. 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 study drug infusion, AND at a stable dose (10 - 25 mg/week) for ≥ 28 days prior to study drug infusion and throughout the study. Subjects on the following medications must remain on a stable regimen: non-steroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, hydroxychloroquine (Plaquenil®), sulfasalazine, oral corticosteroids (≤ 10 mg of prednisone, or equivalent, daily) or low dose opioids (≤ 30 mg of oral morphine, or equivalent, daily) for ≥ 28 days prior to Screening and remain so throughout the Treatment and Observation Period. (The start of Plaquenil and sulfasalazine must be ≥ 2 months prior to study drug infusion.) Subject is highly likely to comply with the protocol and complete the study. Exclusion Criteria: Subject has an ongoing clinically significant systemic disease such as uncompensated heart failure, uncontrolled diabetes mellitus, severe hepatic failure or severe pulmonary disease. Subject has a history of any malignancy except for adequately-treated, non-melanoma skin cancer and adequately-treated in-situ cervical cancer. Subject has a history of severe allergic or anaphylactic reactions. 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: one unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits). Subject has a positive test for alcohol or drugs of abuse (excluding drugs prescribed to subject) at Screening or Day -1. Subject has/had a viral, bacterial (including upper respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to Day -1. Subject has a past history of serious opportunistic infection. Subject is known positive for human immunodeficiency virus (HIV) antibody. Subject has a positive tuberculosis (TB) skin test or Quantiferon Gold test at Screening. Subject has a positive test for hepatitis C antibody, or positive test for hepatitis B surface antigen (HBsAg), or positive hepatitis B core antibody at Screening. Subject's laboratory test results at Screening: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), are ˃ 2 times the upper limit of normal, AND/OR are outside the normal limits and considered by the Investigator to be clinically significant with regard to the remaining per-protocol laboratory tests. Subject received any live or live attenuated vaccine within 30 days prior to study drug infusion. Subject received any systemic immunosuppressant agent, other than (MTX) or stable steroid regimen, within 2 months prior to study drug infusion. Subject has previously received any antibody or therapeutic biologic product within 56 days or 5 half-lives, whichever is longer, prior to study drug infusion. 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 study drug infusion. Subject is participating in another clinical trial or has participated in another dose group of the current trial. Subject has had any significant blood loss, donated one 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 clinic admission on Day -1. Subject has taken Orencia® (abatacept), Nulojix® (belatacept) or any other CTLA4-Ig molecule. Subject has any other condition which precludes the subject's participation in the trial. Subject has a history of prolonged QT syndrome.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP2409 Dose Escalation<br> | Drug: ASP2409<br>* intravenous (IV)<br>|
| Placebo Comparator: Placebo Dose Escalation<br> | Drug: Placebo<br>* intravenous (IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of ASP2409 concentration: Area under the concentration - time curve from time 0 up to the last quantifiable concentration (AUClast) |  | Days 1-8, Days 15, 22, 29, 43, 60, 90, and 120 | 
| Pharmacokinetics of ASP2409 concentration: Area under the concentration - time curve from time 0 extrapolated to infinity (AUCinf) |  | Days 1-8, Days 15, 22, 29, 43, 60, 90, and 120 | 
| Pharmacokinetics of ASP2409 concentration: Maximum concentration (Cmax) |  | Days 1-8, Days 15, 22, 29, 43, 60, 90, and 120 | 
| Safety assessed by adverse events |  | Up to 1 year | 
| Safety assessed by laboratory tests |  | Up to 1 year | 
| Safety assessed by electrocardiograms (ECGs) |  | Up to 1 year | 
| Safety assessed by physical examinations |  | Up to 1 year | 
| Safety assessed by vital signs |  | Up to 1 year | 
| Safety assessed by anti-ASP2409 antibody formation |  | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of pharmacokinetics of ASP2409 concentration: tmax, t1/2, Vz, Vss, CLtot | Time to attain Cmax (tmax), apparent terminal elimination half-life (t1/2), terminal phase volume (Vz), volume of distribution at steady-state (Vss), and total body clearance (CLtot) | Days 1-8, Days 15, 22, 29, 43, 60, 90, and 120 | 
| Pharmacodynamics of ASP2409: CD86 receptor occupancy | Cluster of Differentiation 86 (CD86), a co-stimulatory ligand on lymphocytes | Days 1-3, Days 5, 8, 15, 22, 29, 43, 60, and 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASP2409, Rheumatoid Arthritis, methotrexate