A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ASP3700 in Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of ascending multiple oral doses of ASP3700 in healthy subjects.

Detailed Description
-----------------
Subjects will be confined in the clinic for 18 days.

Official Title
-----------------
A Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Ascending Multiple Oral Doses of ASP3700 in Healthy Subjects

Conditions
-----------------
Healthy Volunteers, Pharmacokinetics of ASP3700

Intervention / Treatment
-----------------
* Drug: ASP3700
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject has a skin type I, II or III (Fitzpatrick classification). Subject has a body mass index (BMI) of 18.5 to 30.0 kg/m2, inclusive. The subject weighs at least 50 kg at screening. Exclusion Criteria: Female subject who has been pregnant within 6 months prior to screening assessment or breast feeding within 3 months prior to screening. Subject has a known or suspected hypersensitivity to ASP3700 or any components of the formulation used. Subject does not respond to the capsaicin challenge at screening or day -1. A nonresponder is defined by a dermal blood flow (DBF) of ≤ 100% increase from baseline (normal skin) compared to DBF 30 minutes after application of 0.4 mL (approximately 300 µg) of capsaicin cream (Axsain®, 0.075% capsaicin w/w). Subject does not respond to the histamine challenge at screening or day -1. A nonresponder is defined by an insufficient wheal (mean diameter < 0.5 cm) and/or flare (mean diameter < 2 cm) reaction (visually assessed and measured by trained staff member) after 10 minutes of the histamine intradermal injection. Subject has a history of suicide attempt or suicidal behavior. Any suicidal ideation within the last 3 months (a level of 4 or 5 for any 1 item on the scale), or who are at significant risk to commit suicide, as judged by the investigator using the C-SSRS at screening and on admission to the clinical unit on day -1. Subject has any of the liver function tests (aspartate aminotransferase [AST], Alanine aminotransferase [ALT], alkaline phosphatase [ALP], gamma glutamyl transferase, total bilirubin [TBL]) above the upper limit of normal (ULN). In such a case the assessment may be repeated once on day -1. Subject has any clinically significant history of allergic conditions (including drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). Subject has a history of clinically significant reaction to cannabis or synthetic cannabinoids as judged by the investigator. Subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy, as judged by the investigator. Subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (noncutaneous) infection within 1 week prior to admission to the clinical unit. Subject has any clinically significant abnormality following the investigator's review of the physical examination, electrocardiogram (ECG) and protocol defined clinical laboratory tests at screening or day -1. Subject has a mean pulse < 40 or > 90 bpm; mean systolic blood pressure (SBP) > 140 mmHg; mean diastolic blood pressure (DBP) > 90 mmHg (vital sign measurements taken in triplicate after subject has been resting in supine position for 5 minutes; pulse will be measured automatically) on day -1. If the mean pulse, mean SBP or mean DBP is out of the range as specified above, 1 additional triplicate measurement may be taken. Subject has a mean QTc(F) interval of > 430 ms (for males) and > 450 ms (for females) at day -1. If the mean QTc(F) exceeds the limits above, 1 additional triplicate ECG can be taken. Subject uses any prescribed or nonprescribed drugs (including antihistamines, vitamins, natural and herbal remedies, e.g., St. John's wort) in the 2 weeks prior to study drug administration, except for occasional use of paracetamol (up to 2 g/day). Subject has used nicotine-containing products within 6 months prior to admission to the clinical unit on day -1. Subject has a history of drinking > 21 units of alcohol per week for male subjects or > 14 units of alcohol for female subjects (1 unit = 10 g pure alcohol = 250 mL of beer [5%] or 35 mL of spirits [35%] or 100 mL of wine [12%]) within 3 months prior to admission to the clinical unit on day -1. Subject has used any drugs of abuse within 3 months prior to admission to the clinical unit on day -1. Subject has used any inducer of metabolism (e.g., barbiturates, rifampin) in the 3 months prior to admission to the clinical unit on day -1. Subject has consumed grapefruit, grapefruit-containing products, Seville orange-containing products, caffeine, xanthine, quinidine or theobromine containing products within 72 hours prior to admission to the clinical unit on day -1. Subject has had a significant blood loss, donated 1 unit (500 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 admission to the clinical unit on day -1. Subject has a positive serology test for hepatitis B surface antigen (HBsAg), hepatitis A virus antibodies (immunoglobulin M) (antiHAV [IgM]), hepatitis C virus antibodies (antiHCV), or antibodies to human immunodeficiency virus type 1 (HIV-1) and/or type 2 (HIV-2) at screening. Subject has participated in any clinical study or has been treated with any investigational drugs within 3 months or 5 half-lives, whichever is longer, prior to screening. Subject has a skin disease, acute or chronic (e.g., atopic dermatitis) or any active dermatological conditions, local pigmentary disorders, or body art (e.g., tattoos) that might interfere with the clinical study assessments. Subject has any condition which, in the investigator's opinion, makes the subject unsuitable for clinical study participation. Subject is an employee of the Astellas Group or Contract Research Organization (CRO) involved in the clinical study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP3700 multiple ascending dose cohort<br> | Drug: ASP3700<br>* Oral<br>|
| Placebo Comparator: Placebo cohort<br> | Drug: Placebo<br>* Oral<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as assessed by adverse events |  | up to end of study visit (up to 26 days) | 
| Safety as assessed by vital signs |  | up to end of study visit (up to 26 days) | 
| Safety as assessed by orthostatic evaluation |  | Days 1 and 14 | 
| Safety as assessed by laboratory tests | Laboratory tests include hematology, biochemistry and urinalysis. | up to end of study visit (up to 26 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile: Routine 12-lead ECG, C-SSRS, ARCI-49, Bond and Lader VAS, continuous cardiac monitoring (12-lead Holter ECG), exploratory sex hormone-related and renal biomarkers | Electrocardiogram (ECG); Columbia-Suicide Severity Rating Scale (C-SSRS); Addiction Research Center Inventory(ARCI)-49 (49-item); Visual Analog Scale (VAS). | up to end of study visit (up to 26 days) | 
| Pharmacokinetics profile of ASP3700 (plasma): Cmax, tmax, tlag | Maximum concentration (Cmax); time of maximum concentration (tmax); time prior to the time corresponding to the first measurable (nonzero) concentration (tlag) | Cmax, tmax = Days 1 and 14; tlag = Day 1 | 
| Pharmacokinetics profile of ASP3700 (plasma): AUCtau, CL/F, λz, MRT, t1/2, Vz/F, Rac (AUC), Rac (Cmax), PTR | Area under the concentration-time curve from the time of dosing to the start of the next dosing interval (AUCtau); apparent oral clearance (CL/F); terminal elimination rate constant (λz); mean residence time (MRT); terminal elimination half-life (t1/2); apparent volume of distribution during terminal elimination phase after extravascular dosing (Vz/F); accumulation ratio based on AUE (Rac[AUC]); accumulation ratio based on Cmax (Rac[Cmax]); peak-trough ration (PTR) | Day 14 | 
| Pharmacokinetics parameter of ASP3700 (plasma): Ctrough | Concentration immediately prior to dosing at multiple dosing (Ctrough) | Days 4, 6, 8, 10, 14 and 15 | 
| Pharmacokinetics profile of ASP3700 (urine): Ae24, Ae24%, Aetau, Aetau% | Cumulative amount of drug excreted in the urine from Time Zero to 24 hours (Ae24); percent fraction of administered drug excreted unchanged in the urine from time zero to 24 hours (Ae24%); cumulative amount of drug excreted in the urine over the dosing interval at steady-state (Aetau); percent fraction of administered drug excreted unchanged in the urine over the dosing interval at steady-state (Aetau%) | Ae24, Ae24% = Day 1; Aetau, Aetau% = Day14 | 
| Pharmacokinetics parameter of ASP3700 (urine): CLR | Renal clearance (CLR) | Days 1 and 14 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ASP3700, Healthy volunteers, Pharmacokinetics, Pharmacodynamics