Clinical trial NCT02420782: First-in-human: Single Ascending Dose, Food Effect, Drug-drug Interaction, Multiple Ascending Dose, Proof of Pharmacology
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Pharmacokinetics
ASP6282
Pharmacodynamics
Drug-drug interaction
Midazolam
Safety and tolerability
Healthy volunteers
Itraconazole
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2015-04-20
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

Detailed description: 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

Eligibility criteria: 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:

    1. Postmenopausal (defined as at least 1 year without any menses) prior to screening, or,
    2. Documented surgically sterile.
  * Or, if of childbearing potential:

    1. Agree not to try to become pregnant during the clinical study and for 90 days after the final study drug administration,
    2. Must have a negative serum pregnancy test at day -1, and
    3. 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.
    4. 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).

Primary outcomes:
measure: Safety as assessed by adverse events
timeFrame: Part 1: up to 10 days; Part 2 up to 18 days
measure: Safety as assessed by vital signs
timeFrame: Part 1: up to 10 days; Part 2 up to 18 days
measure: Safety as assessed by safety laboratory tests
timeFrame: Part 1: up to 10 days; Part 2 up to 18 days
measure: Safety as assessed by electrocardiogram (ECG) measurements (Part 1)
timeFrame: From screening to end of study visit (ESV) (up to day 10)
measure: Safety as assessed by continuous cardiac monitoring (Part 1)
timeFrame: From day 1 up to day 5
measure: Safety as assessed by electrocardiogram (ECG) measurements (Part 2)
timeFrame: From screening to ESV (Up to day 18)
measure: Safety as assessed by continuous electrocardiogram (ECG) measurements (Part 2)
timeFrame: From screening up to day 15
measure: Safety as assessed by the Orthostatic challenge test (OCT) (Part 1)
timeFrame: From day -1 up to day 5
measure: Pharmacodynamic parameter salivary secretion at specified timepoints (Part 3)
timeFrame: Day 1, each treatment period
measure: Pharmacodynamic parameter salivary secretion AUEsal (Part 3)
timeFrame: Day 1, each treatment period
measure: Pharmacodynamic parameter salivary secretion Emax,sal (Part 3)
timeFrame: Day 1, each treatment period
measure: Pharmacodynamic parameter salivary secretion tmax,sal (Part 3)
timeFrame: Day 1, each treatment period
Secondary outcomes:
measure: Pharmacokinetics profile of ASP6282 (plasma): AUCinf, AUClast, Cmax, CL/F, tlag, tmax, t½, Vz/F (Part 1)
timeFrame: Day 1 up to Day 5, each treatment period
measure: Pharmacokinetics profile of ASP6282 (urine): Aelast, Aelast%, Aeinf, Aeinf%, CLR (Part 1)
timeFrame: Day 1 up to Day 4, each treatment period
measure: Pharmacokinetic parameter of Itraconazole (plasma) Ctrough (Part 1)
timeFrame: Day 1 up to Day 5, each treatment period
measure: Pharmacokinetics profile of ASP6282 (plasma): AUC24, tlag, AUCtau, CL/F, PTR, Rac(AUC), Cmax, tmax, t½, Vz/F (Part 2)
timeFrame: Day 1 up to Day 20
measure: Pharmacokinetics profile of ASP6282 (urine): Aetau, Aetau%, CLR (Part 2)
timeFrame: Day 14
measure: Pharmacokinetics profile of ASP6282 (plasma): AUC6, AUCinf, AUClast, Cmax, CL/F, tlag, tmax, t½, Vz/F (Part 3)
timeFrame: Day 1 up to Day 5, per treatment period
measure: Pharmacokinetics profile of Pilocarpine (plasma): AUC6, Cmax, tmax (Part 3)
timeFrame: Day 1, per treatment period
measure: Pharmacodynamic profile pupil diameter pupS, AUEpupS, Emax,pupS, tmax,pupS, (Part 1, Part 2)
timeFrame: Part 1: Day 1; Part 2: Day -1 and Day 14
measure: Pharmacodynamic profile salivary secretion AUEsal, Emax,sal, tmax,sal (Part 1, Part 2)
timeFrame: Part 1: Screening and Day 1; Part 2: Day -1 and Day 14
measure: Pharmacodynamic profile of Bond and Lader VAS (Part 1, Part 2)
timeFrame: Part 1: Day 1; Part 2: Day -1 and Day 14
measure: Safety profile assessed by nature, frequency and severity of adverse events, vital signs, safety laboratory tests and 12 lead ECG (Part 3)
timeFrame: Screening, Day -1 and ESV (Day 10)
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Site DE49001
city: Harrow
country: United Kingdom
facility: Site GB44001
Study officials:
affiliation: Clinical Pharmacology & Exploratory Development (CPED)
name: Medical Monitor
role: STUDY_DIRECTOR
References: