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

NCT02420782 | Completed Phase 1

• 2 other identifiers: 6282-CL-00012015-000093-35
• Study Type: interventional
• Target: 116
• Locations: 2 countries
• Sites: 2

Brief Summary

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.

Conditions

Healthy Volunteers

Keywords

Pharmacokinetics; ASP6282; Pharmacodynamics; Drug-drug interaction; Midazolam; Safety and tolerability; Healthy volunteers; Itraconazole

Outcome Measures

Primary Outcomes (12)

• 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 Outcomes (11)

• Pharmacokinetics profile of ASP6282 (plasma): AUCinf, AUClast, Cmax, CL/F, tlag, tmax, t½, Vz/F (Part 1)

  Day 1 up to Day 5, each treatment period

• Pharmacokinetics profile of ASP6282 (urine): Aelast, Aelast%, Aeinf, Aeinf%, CLR (Part 1)

  Day 1 up to Day 4, each treatment period

• Pharmacokinetic parameter of Itraconazole (plasma) Ctrough (Part 1)

  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)

  Day 1 up to Day 20

• Pharmacokinetics profile of ASP6282 (urine): Aetau, Aetau%, CLR (Part 2)

  Day 14

Study Arms (10)

ASP6282 single ascending dose (fasted)

EXPERIMENTAL

Part 1

Drug: ASP6282

Placebo single ascending dose (fasted)

PLACEBO COMPARATOR

Part 1

Drug: Placebo

ASP6282 single dose (fed)

EXPERIMENTAL

Part 1

Drug: ASP6282

Placebo single dose (fed)

PLACEBO COMPARATOR

Part 1

Drug: Placebo

ASP6282 single dose (fasted)

EXPERIMENTAL

Part 1 Period 1

Drug: ASP6282

Itraconazole multiple dose and ASP6282 single dose (fasted)

EXPERIMENTAL

Part 1 Period 2

Drug: ASP6282; Drug: Itraconazole

ASP6282 multiple ascending dose (nonelderly and elderly)

EXPERIMENTAL

Part 2. Germany only: once daily dosing, optional twice daily dosing. Midazolam dosing elderly only, exploratory for DDI purpose

Drug: ASP6282; Drug: Midazolam

Placebo multiple ascending dose (nonelderly and elderly)

PLACEBO COMPARATOR

Part 2. Germany only: once daily dosing, optional twice daily dosing

Drug: Placebo

ASP6282 and pilocarpine

EXPERIMENTAL

Part 3

Drug: ASP6282; Drug: Pilocarpine

Placebo and pilocarpine

OTHER

Part 3

Drug: Pilocarpine; Drug: Placebo

Interventions

ASP6282 DRUG

oral

ASP6282 and pilocarpine; ASP6282 multiple ascending dose (nonelderly and elderly); ASP6282 single ascending dose (fasted); ASP6282 single dose (fasted); ASP6282 single dose (fed); Itraconazole multiple dose and ASP6282 single dose (fasted)

Itraconazole DRUG

oral

Itraconazole multiple dose and ASP6282 single dose (fasted)

Pilocarpine DRUG

oral

ASP6282 and pilocarpine; Placebo and pilocarpine

Placebo DRUG

oral

Placebo and pilocarpine; Placebo multiple ascending dose (nonelderly and elderly); Placebo single ascending dose (fasted); Placebo single dose (fed)

Midazolam DRUG

oral

Also known as: Versed

ASP6282 multiple ascending dose (nonelderly and elderly)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Astellas Pharma Europe B.V.: lead

Study Sites (2)

Site DE49001

Berlin, 14050, Germany

Location

Site GB44001

Harrow, HA1 3UJ, United Kingdom

Location

MeSH Terms

Interventions

Itraconazole; Pilocarpine; Midazolam

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Alkaloids; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Medical Monitor

  Clinical Pharmacology & Exploratory Development (CPED)

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 15, 2015
• First Posted: April 20, 2015
• Study Start: May 1, 2015
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2016
• Last Updated: July 1, 2016

Record last verified: 2016-06

Locations

GB (1); DE (1)