First-in-human: Single Ascending Dose, Food Effect, Drug-drug Interaction, Multiple Ascending Dose, Proof of Pharmacology

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) and pharmacodynamics (PD) of single and multiple ascending oral doses of ASP6282 in healthy male and female subjects. 1 cohort (elderly) receives also a midazolam dosing. This study will also explore the effect of itraconazole (another drug) on the PK of ASP6282, as well as to evaluate the safety and tolerability of ASP6282 alone and in combination with itraconazole in healthy male and female subjects. Also, this study is to evaluate the PD and PK effects of single oral doses of ASP6282 on pilocarpine-induced salivation and pupil diameter in healthy nonelderly male and female subjects.

Detailed Description
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This study consists of three parts. Part 1 is Single Ascending Dose Including Food Effect and Drug-drug Interaction (DDI) with Itraconazole. There will be a washout between treatment period 1 and 2 in the DDI arm of Part 1; Part 2 is a Multiple Ascending Dose (MAD); Part 3, with a treatment period 1, 2 and 3 is Proof of Pharmacology. There will be a washout between each treatment period

Official Title
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A Phase 1 Combined Single and Multiple Ascending Oral Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ASP6282 in Healthy Nonelderly and Elderly Male and Female Subjects, Including a Food Effect Cohort and Drug-drug Interaction Cohort With Itraconazole

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: ASP6282
* Drug: Itraconazole
* Drug: Pilocarpine
* Drug: Placebo
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has a body mass index (BMI) range of 18.5 to 30.0 kg/m2, inclusive. The subject weighs at least 50 kg [screening]. Female subject must not donate ova starting at screening and throughout the clinical study period, and for 28 days after the final study drug administration. Male 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. Male subject must not donate sperm starting at screening and throughout the clinical study period, and for 90 days after last study drug administration. Subject agrees not to participate in another interventional study while participating in the present clinical study, defined as signing the informed consent form until completion of the last study visit. Germany only: Female subject must either: Be 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 clinical study and for 90 days after the final study drug administration, Must have a negative serum pregnancy test at day -1, and If heterosexually active, agree to consistently use a form of highly effective birth control in combination with a barrier method starting at screening and continuing throughout the clinical study period, and for 90 days after the final study drug administration. Or agree to stay abstinent, if abstinence is the preferred and usual lifestyle of the subject, starting at screening and continuing throughout the clinical study period and for 90 days after the final study drug administration. Female subject must agree not to breastfeed starting at screening and throughout the clinical study period, and for 90 days after the final study drug administration. Female subject must not donate ova starting at screening and throughout the clinical study period, and for 90 days after the final study drug administration. Exclusion Criteria: Female subject who has been pregnant within 6 months prior to screening assessment or breastfeeding within 3 months prior to screening. Subject has a known or suspected hypersensitivity to ASP6282, itraconazole (part 1 - DDI only) or pilocarpine (part 3 - Proof of pharmacology (PoP) only) or any components of the formulations used. Subject uses a CYP3A4 metabolized substrate that can prolong the QT interval, e.g., astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine. Subject uses any of the following medication: atorvastatin, lovastatin and simvastatin, triazolam, midazolam, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine), eletriptan and nisodipine. Subject with evidence of ventricular dysfunction such as congestive heart failure or a history of congestive heart failure. Subject has clinically significant, cardiorenal disease, asthma and/or any other disease at risk for cholinergic agonists. Subject has a condition of the eye which could be affected by the intake of pilocarpine (e.g., acute iritis) (part 3 - PoP only). Subject has any of the liver chemistry tests (Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), Total bilirubin (TBL) above the Upper limit of normal (ULN)). In such a case, the assessment may be repeated once on Day -1 (in part 1 - DDI: treatment period 1 only). 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 chronic bronchitis and/or chronic obstructive pulmonary disease, or known or suspected cholelithiasis or biliary tract disease, or peptic ulceration or cognitive or psychiatric disturbances, or renal or hepatic insufficiency, or narrow-angle glaucoma. 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 on Day -1. 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 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 signs measurements taken in triplicate after subject has been resting in supine position for 5 minutes; pulse will be measured automatically) on admission to the clinical unit on Day -1. If the mean blood pressure exceeds the limits above, 1 additional triplicate can be taken. Subject has a mean corrected QT interval using Fridericia's formula (QTcF) > 430 ms (for male subjects) and > 450 ms (for female subjects) at screening. If the mean QTcF exceeds the limits above, 1 additional triplicate ECG can be taken at screening. Subject uses any prescribed or nonprescribed drugs (including vitamins, natural and herbal remedies, e.g., St. John's wort) in the 2 weeks prior to first study drug administration, except for occasional use of paracetamol (up to 2 g/day) (all parts) and except for use of contraceptives or hormone replacement therapy (except for part 1- DDI). Subject has a history of smoking within 6 months prior to first study drug administration on day 1. Subject has a history of drinking > 21 units of alcohol/week for male subjects or > 14 units of alcohol/week 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 consumed grapefruit/Seville oranges, grapefruit-containing products or Seville orange-containing products within 72 hours prior to admission to the clinical unit on Day -1. Subject uses any inducer of metabolism (e.g., barbiturates, rifampin) within 1 month prior to admission to the clinical unit on Day -1. Subject uses any drugs of abuse within 3 months prior to admission to the clinical unit on Day -1. Subject had 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 (anti-HAV) (immunoglobulin M [IgM]), hepatitis C virus antibodies (anti-HCV), or antibodies to human immunodeficiency virus type 1 (HIV-1) and/or type 2 (HIV-2) at screening. Subject participated in any clinical study or has been treated with any investigational drugs within 90 days prior to screening. Germany only: Subject has a mean pulse < 50 or > 90 bpm; mean systolic blood pressure (SBP) > 140 mmHg; mean diastolic blood pressure (DBP) > 90 mmHg (vital signs measurements taken in triplicate after subject has been resting in supine position for 5 minutes; pulse will be measured automatically) on admission to the clinical unit on day -1. (For elderly subjects the following criteria apply: SBP > 160 mmHg and DBP > 100 mmHg). If the mean blood pressure exceeds the limits above, 1 additional triplicate can be taken. Subject has a mean corrected QT interval using Fridericia's formula (QTcF) > 430 ms (for male subjects) and > 450 ms (for female subjects) at day -1. If the mean QTcF exceeds the limits above, 1 additional triplicate ECG can be taken at day -1. Subject has a positive serology test for hepatitis B surface antigen (HBsAg), hepatitis B core antibodies, hepatitis A virus antibodies (anti-HAV) (immunoglobulin M [IgM]), hepatitis C virus antibodies (anti-HCV), or antibodies to human immunodeficiency virus type 1 (HIV-1) and/or type 2 (HIV-2) at screening. Subject is unable to communicate, read and understand German, or has any other condition which, in the investigator's opinion, makes the subject unsuitable for clinical study participation. Subject is a vulnerable subject (e.g., subject kept in detention). Subject has a known or suspected hypersensitivity to ASP6282, itraconazole (part 1 - DDI only), pilocarpine (part 3 - PoP only) or midazolam (part 2 - elderly cohort only) or any components of the formulations used. Subject uses any prescribed or nonprescribed drugs (including vitamins, natural and herbal remedies, e.g., St. John's wort) in the 2 weeks prior to first study drug administration, except for occasional use of paracetamol (up to 2 g/day) (all parts) and except for use of hormone replacement therapy (except for part 1 - DDI).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: ASP6282 single ascending dose (fasted)<br>Part 1 | Drug: ASP6282<br>* oral<br>|
| Placebo Comparator: Placebo single ascending dose (fasted)<br>Part 1 | Drug: Placebo<br>* oral<br>|
| Experimental: ASP6282 single dose (fed)<br>Part 1 | Drug: ASP6282<br>* oral<br>|
| Placebo Comparator: Placebo single dose (fed)<br>Part 1 | Drug: Placebo<br>* oral<br>|
| Experimental: ASP6282 single dose (fasted)<br>Part 1 Period 1 | Drug: ASP6282<br>* oral<br>|
| Experimental: Itraconazole multiple dose and ASP6282 single dose (fasted)<br>Part 1 Period 2 | Drug: ASP6282<br>* oral<br>Drug: Itraconazole<br>* oral<br>|
| Experimental: ASP6282 multiple ascending dose (nonelderly and elderly)<br>Part 2. Germany only: once daily dosing, optional twice daily dosing. Midazolam dosing elderly only, exploratory for DDI purpose | Drug: ASP6282<br>* oral<br>Drug: Midazolam<br>* oral<br>* Other names: Versed;|
| Placebo Comparator: Placebo multiple ascending dose (nonelderly and elderly)<br>Part 2. Germany only: once daily dosing, optional twice daily dosing | Drug: Placebo<br>* oral<br>|
| Experimental: ASP6282 and pilocarpine<br>Part 3 | Drug: ASP6282<br>* oral<br>Drug: Pilocarpine<br>* oral<br>|
| Other: Placebo and pilocarpine<br>Part 3 | Drug: Pilocarpine<br>* oral<br>Drug: Placebo<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 10 days; Part 2 up to 18 days | 
| Safety as assessed by vital signs | Vital signs include: blood pressure, pulse rate and body temperature | Part 1: up to 10 days; Part 2 up to 18 days | 
| Safety as assessed by safety laboratory tests | Laboratory tests include: hematology, biochemistry and urinalysis | Part 1: up to 10 days; Part 2 up to 18 days | 
| Safety as assessed by electrocardiogram (ECG) measurements (Part 1) | ECG measurements include routine ECG | From screening to end of study visit (ESV) (up to day 10) | 
| Safety as assessed by continuous cardiac monitoring (Part 1) | 12- lead ECG continuous cardiac monitoring, real-time cardiac monitoring (telemetry), cardiac troponin | From day 1 up to day 5 | 
| Safety as assessed by electrocardiogram (ECG) measurements (Part 2) | ECG measurements include routine 12- lead ECG, cardiac troponin | From screening to ESV (Up to day 18) | 
| Safety as assessed by continuous electrocardiogram (ECG) measurements (Part 2) | Twelve lead continuous cardiac monitoring, cardiac troponin | From screening up to day 15 | 
| Safety as assessed by the Orthostatic challenge test (OCT) (Part 1) | Blood pressure measurement | From day -1 up to day 5 | 
| Pharmacodynamic parameter salivary secretion at specified timepoints (Part 3) | Measured (mg/min) salivary secretion at specific timepoints | Day 1, each treatment period | 
| Pharmacodynamic parameter salivary secretion AUEsal (Part 3) | Area under the effect curve salivary secretion (AUEsal) | Day 1, each treatment period | 
| Pharmacodynamic parameter salivary secretion Emax,sal (Part 3) | Maximum pharmacodynamic effect salivary secretion (Emax,sal) | Day 1, each treatment period | 
| Pharmacodynamic parameter salivary secretion tmax,sal (Part 3) | Time at maximum concentration salivary secretion (tmax,sal) | Day 1, each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics profile of ASP6282 (plasma): AUCinf, AUClast, Cmax, CL/F, tlag, tmax, t½, Vz/F (Part 1) | Area under the concentration-time curve from the time of dosing extrapolated to time infinity (AUCinf); Area under the concentration-time curve from the time of dosing to the last measurable concentration (AUClast); Maximum concentration (Cmax); Apparent total systemic clearance after extravascular dosing (CL/F); Time prior to the time corresponding to the first measurable (nonzero) concentration (tlag);Time at maximum concentration (tmax); Terminal elimination half-life (t½); Apparent volume of distribution during the terminal elimination phase after extravascular dosing (Vz/F) | Day 1 up to Day 5, each treatment period | 
| Pharmacokinetics profile of ASP6282 (urine): Aelast, Aelast%, Aeinf, Aeinf%, CLR (Part 1) | Cumulative amount of study drug excreted into urine from time of dosing up to the collection time of the last measurable concentration (Aelast); Percentage of study drug dose excreted into urine from time of dosing up to the collection time of the last measurable concentration (Aelast%); Cumulative amount of study drug excreted into urine from time of dosing extrapolated to time infinity (Aeinf); Percentage of study drug dose excreted into urine from time of dosing extrapolated to time infinity (Aeinf%); Renal clearance (CLR) | Day 1 up to Day 4, each treatment period | 
| Pharmacokinetic parameter of Itraconazole (plasma) Ctrough (Part 1) | DDI arm only. Concentration immediately prior to dosing at multiple dosing (Ctrough) | Day 1 up to Day 5, each treatment period | 
| Pharmacokinetics profile of ASP6282 (plasma): AUC24, tlag, AUCtau, CL/F, PTR, Rac(AUC), Cmax, tmax, t½, Vz/F (Part 2) | Area under the concentration-time curve from the time of dosing to 24 hours postdose (AUC24); Area under the concentration-time curve from the time of dosing to the start of the next dosing interval (AUCtau); Peak trough ratio (PTR), Accumulation ratio calculated using the area under the concentration-time curve (Rac(AUC)) | Day 1 up to Day 20 | 
| Pharmacokinetics profile of ASP6282 (urine): Aetau, Aetau%, CLR (Part 2) | Percentage of study drug dose excreted into urine over the time interval between consecutive dosing (Aetau%) | Day 14 | 
| Pharmacokinetics profile of ASP6282 (plasma): AUC6, AUCinf, AUClast, Cmax, CL/F, tlag, tmax, t½, Vz/F (Part 3) | Area under the concentration-time curve from the time of dosing to 6 hours Postdose (AUC6) | Day 1 up to Day 5, per treatment period | 
| Pharmacokinetics profile of Pilocarpine (plasma): AUC6, Cmax, tmax (Part 3) |  | Day 1, per treatment period | 
| Pharmacodynamic profile pupil diameter pupS, AUEpupS, Emax,pupS, tmax,pupS, (Part 1, Part 2) | Part 1: exclusive DDI arm. Pupil diameter, scotopic lighting condition (pupS); Area under the effect curve pupil diameter, scotopic lighting condition (AUEpupS); Maximum pharmacodynamic effect pupil diameter, scotopic lighting condition (Emax,pupS), Time at maximum concentration pupil diameter, scotopic lighting condition (tmax,pupS) | Part 1: Day 1; Part 2: Day -1 and Day 14 | 
| Pharmacodynamic profile salivary secretion AUEsal, Emax,sal, tmax,sal (Part 1, Part 2) | Part 1: exclusive DDI arm | Part 1: Screening and Day 1; Part 2: Day -1 and Day 14 | 
| Pharmacodynamic profile of Bond and Lader VAS (Part 1, Part 2) | Visual analogue scale (VAS) | Part 1: Day 1; Part 2: Day -1 and Day 14 | 
| Safety profile assessed by nature, frequency and severity of adverse events, vital signs, safety laboratory tests and 12 lead ECG (Part 3) |  | Screening, Day -1 and ESV (Day 10) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, ASP6282, Pharmacodynamics, Drug-drug interaction, Midazolam, Safety and tolerability, Healthy volunteers, Itraconazole