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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending oral doses of ASP3700 in healthy male subjects. This study will also explore the effect of itraconazole (another drug) on the PK of ASP3700, as well as to evaluate the safety and tolerability of ASP3700 alone and in combination with itraconazole in healthy male subjects.

Detailed Description
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This study consists of 2 parts: Part 1 is a single ascending dose study where subjects will receive either ASP3700 or matching placebo; Part 2 is a drug-drug interaction (DDI) open-label, crossover study comprised of 1 sequence with 2 investigational periods where subjects will receive ASP3700 alone and in combination with itraconazole.

Official Title
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A Phase 1, Single Ascending Oral Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of ASP3700 in Healthy Male Subjects, Including a Drug-drug Interaction Part With Itraconazole

Conditions
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Healthy Volunteers, Pharmacokinetics of ASP3700

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has a body mass index range of 18.5 - 30.0 kg/m2. The subject weighs at least 50 kg. Subject and his female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and continue throughout the clinical study period and for 90 days after the final study drug administration. Subject must not donate sperm starting at screening and throughout the clinical study period and for 90 days after the final study drug administration. Exclusion Criteria: Subject has a known or suspected hypersensitivity to ASP3700 (parts 1 and 2) or itraconazole (part 2 only) or significant adverse reactions to historical cannabinoid use or any components of the formulations used. Subject has any of the liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, gamma-glutamyl transaminase, total bilirubin [TBL]) above the upper limit of normal (ULN). In such a case the assessment may be repeated once (upon admission to the clinical unit). Subject has a history of a suicide attempt or suicidal behavior. Any recent suicidal ideation within the last 3 months or who are at significant risk to commit suicide, as judged by the Investigator using the C-SSRS (a level of 4 or 5) at screening or upon admission to the clinical unit. Subject has any clinically significant abnormality following the Investigator's review of the physical examination, ECG and clinical study protocol-defined clinical laboratory tests at screening or upon admission to the clinical unit. Subject has a pulse rate < 40 or > 90 beats per minute; mean SBP > 140 mmHg; mean DBP > 90 mmHg (vital signs measurements taken in triplicate after subject has been resting in supine position for 5 minutes; pulse rate will be measured automatically) upon admission to the clinical unit. Subject has a mean corrected QT interval using Fridericia's formula (QTcF) interval > 430 ms at day -1. If the mean QTcF exceeds the limits above, 1 additional triplicate ECG can be taken. Subject has a history of smoking more than 10 cigarettes (or equivalent amount of tobacco) per day within 3 months prior to admission to the clinical unit. Subject has a history of drinking more than 21 units of alcohol per week (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. Subject has consumed grapefruit, grapefruit-containing products or Seville orange-containing products within 72 hours prior to admission to the clinical unit.

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

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP3700 single ascending dose cohort<br>Part 1 | Drug: ASP3700<br>* oral<br>|
| Placebo Comparator: Placebo single ascending dose cohort<br>Part 1 | Drug: Placebo<br>* oral<br>|
| Experimental: ASP3700 alone<br>Part 2 | Drug: ASP3700<br>* oral<br>|
| Active Comparator: ASP3700 and itraconazole<br>Part 2 | Drug: ASP3700<br>* oral<br>Drug: itraconazole<br>* oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as assessed by adverse events (Part 1) |  | up to end of study visit (up to 16 days) | 
| Safety as assessed by vital signs (Part 1) |  | up to end of study visit (up to 16 days) | 
| Safety as assessed by laboratory tests (Part 1) | Laboratory tests includes the measurement of sex-hormone related biomarkers and exploratory renal biomarkers. | up to end of study visit (up to 16 days) | 
| Safety as assessed by electrocardiogram (ECG) measurements (Part 1) | ECG measurements include routine 12-lead ECG, continuous cardiac monitoring (Holter ECG) and real-time cardiac monitoring (ECG telemetry) | up to end of study visit (up to 16 days) | 
| Safety as assessed by Bond and Lader VAS (Part 1) | visual analogue scale (VAS) | Up to Day 2 | 
| Safety as assessed by C-SSRS (Part 1) | Columbia - Suicide Severity Rating Scale (C-SSRS) | Up to end of study visit (up to 16 days) | 
| Safety as assessed by ARCI-49 (Part 1) | Addiction Research Center Inventory (ARCI)-49 (49-item) | Up to Day 2 | 
| Pharmacokinetic parameter of itraconazole (plasma): Ctrough (Part 2) | Concentration immediately prior to dosing at multiple dosing | Days 3-13 | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (plasma): AUCinf (Part 2) | Area under the concentration-time curve from time of dosing extrapolated to time infinity (AUCinf) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (plasma): AUCinf (%extrap) (Part 2) | Percentage of AUCinf due to extrapolation from tlast to time infinity (AUCinf [%extrap]) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (plasma): AUClast (Part 2) | Area under the concentration-time curve from the time of dosing to the last measurable concentration (AUClast) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (plasma): Cmax (Part 2) | Maximum concentration (Cmax) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (plasma):λz (Part 2) | Terminal elimination rate constant (λz) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (plasma): MRT (Part 2) | Mean residence time (MRT) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (plasma): tlag (Part 2) | Time prior to the time corresponding to the first measurable (nonzero) concentration (tlag) | Day 1 (period 1 and 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (plasma): tmax (Part 2) | Time of maximum concentration (tmax) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (plasma): t1/2 (Part 2) | Terminal elimination half-life (t1/2) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (plasma): Vz/F (Part 2) | Apparent volume of distribution during the terminal elimination phase after extravascular dosing (Vz/F) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (urine): Aelast (Part 2) | Cumulative amount of study drug excreted into urine from time of dosing up to the collection time of the last measurable concentration (Aelast) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (urine): Aeinf (Part 2) | Cumulative amount of study drug excreted into urine from time of dosing extrapolated to time infinity (Aeinf) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (urine): Aelast% (Part 2) | Percentage of study drug excreted into urine from the time of dosing up to the collection time of the last measurable concentration (Aelast%) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (urine): Aeinf% (Part 2) | Percentage of study drug excreted into urine from time of dosing extrapolated to time infinity (Aeinf%) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Pharmacokinetic parameter of ASP3700 with and without itraconazole (urine): CLR (Part 2) | Renal clearance (CLR) | Days 1-7 (period 1) and Days 1-13 (period 2) | 
| Safety as assessed by orthostatic evaluation (or blood pressure change in orthostatic challenge test) (Part 1) |  | Up to Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of pharmacokinetics of ASP3700: AUCinf, AUCinf(%extrap), AUClast, Cmax, CL/F, λz, MRT, tlag, tmax, t½, Vz/F (plasma) (Part 1) |  | up to Day 7 | 
| Title: Composite of pharmacokinetics of ASP3700: Aelast, Aeinf, Aelast%, Aeinf%, CLR (urine) (Part 1) |  | up to Day 7 | 
| Safety as assessed by adverse events, vital signs, orthostatic evaluation, laboratory tests, ECG measurements, C-SSRS, Bond & Lader VAS, ARCI-49 (Part 2) |  | Days 1-7 (period 1) and Days 1-13 (period 2) and at end of study visit (up to 22 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers, Pharmacokinetics, ASP3700, Itraconazole, Drug-drug interaction