A Phase I Study in Healthy Volunteers to Assess the Effect of Cytochrome3A4 (CYP3A4) Inhibitors (Diltiazem and Itraconazole) on the Pharmacokinetics (PK) of AZD3293 and the Effects of AZD3293 on the Pharmacokinetics of Midazolam, a Cytochrome 3A4 and Cytochrome 3A5 (CYP3A4/CYP3A5) Substrate (AZD3293DDI)

A Phase I, Single-center, Open-label, 3-group, Fixed-sequence Study to Assess the Effect of Itraconazole, a Potent CYP3A4 Inhibitor, or Diltiazem, a Moderate CYP3A4 Inhibitor, on the Pharmacokinetics of AZD3293 and the Effects of AZD3293 on the Pharmacokinetics of Midazolam, a CYP3A4/CYP3A5 Substrate, in Healthy Young Male and Female Volunteers

This study is a single-center, open-label, 3-group, fixed-sequence drug-drug interaction study to assess the effect of coadministration of multiple-dose itraconazole or diltiazem on the single-dose PK of AZD3293 and the effects of coadministration of single- and multiple-dose AZD3293 on the single-dose PK of midazolam. The study will also evaluate the safety and tolerability of single and multiple oral doses of AZD3293, alone and in combination with itraconazole, diltiazem, and midazolam in healthy young subjects.AZD3293 is being developed for the treatment of Alzheimer's disease

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers; Pharmacologic Action
• Intervention / Treatment: Drug: Group 1 AZD3293; Drug: Group 1 Itraconazole; Drug: Group 2 AZD3293; Drug: Group 2 Diltiazem; Drug: Group 3 AZD3293; Drug: Group 3 Midazolam

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Cypress, California, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provision of signed, written, and dated informed consent prior to any study-specific procedures Male and nonfertile female healthy subjects, aged 18 to 55 years at the time of consent
• Body weight ≥50 to ≤100 kg and body mass index (BMI) ≥19 to ≤30 kg/m2
• Clinically normal findings on physical examination in relation to age, as judged by the Investigator
• Male healthy subjects must be willing to use barrier contraception, ie, condoms, even if their partners are post-menopausal, surgically sterile, or using accepted contraceptive methods, from the first day of dosing until 3 months after the last dose of investigational product (IP)

Exclusion Criteria:

• Participation in any prior study of AZD3293
• History of any clinically significant disease or disorder which, in the opinion of the Investigator, may put the subject at risk because of participation in the study, may influence the results, or may limit the subject's ability to participate in the study
• History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs
• History of previous or ongoing psychiatric disease/condition including psychosis, affective disorder, anxiety disorder, borderline state and personality disorder according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV), as assessed by the Mini-International Neuropsychiatric Interview (MINI)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Group 1 AZD3293-itraconazole; Subjects from Group 1 will receive a single dose of AZD3293 as an oral solution on Day 1 . In Group 1, itraconazole will be administered orally twice daily starting on Day 5 for 9 consecutive days (Days 5 to 13). On Day 8, a single dose of AZD3293 will be coadministered as an oral solution after the morning dose of itraconazole. Group 1 subjects will be discharged on Day 14.	Drug: Group 1 AZD3293; AZD3293 oral solution; Other Names: beta secretase inhibitor; Drug: Group 1 Itraconazole; itraconazole capsule; Other Names: azole antifungal
EXPERIMENTAL: Group 2 AZD3293-diltiazem; Subjects from Group 2 will receive a single dose of AZD3293 as an oral solution on Day 1 . In Group 2, diltiazem will be administered orally once daily starting on Day 5, for 9 consecutive days (Days 5 to 13). On Day 8, a single dose of AZD3293 will be coadministered as an oral solution after the diltiazem dose. Group 2 subjects will be discharged on Day 14.	Drug: Group 2 AZD3293; AZD3293 oral solution; Other Names: beta secretase inhibitor; Drug: Group 2 Diltiazem; Diltiazem ER tablet; Other Names: calcium channel blocker
EXPERIMENTAL: Group 3 AZD3293-midazolam; Subjects from Group 3 will receive a single dose of midazolam on Day 1 . AZD3293 will be administered as an oral solution once daily starting on Day 2 for 9 consecutive days (Days 2 to 10) followed by a 7 day wash-out period. On Day 8 and Day 17 a single dose of midazolam will be administered. Group 3 subjects will be discharged on Day 18	Drug: Group 3 AZD3293; AZD3293 oral solution; Other Names: beta secretase inhibitor; Drug: Group 3 Midazolam; midazolam syrup; Other Names: benzodiazepine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effect of multiple-dose co-administration of CYP3A4 inhibitors on the single-dose PK of AZD3293 measured by assessment of area under the curve over the time (AUC) and maximum concentration	In Group 1, serial blood samples for AZD3293 plasma concentrations will be collected from predose to 96 hours after administration of AZD3293 on Day 1 and from predose to 144 hours after study drug administration on Day 8. Sparse blood samples for itraconazole plasma concentrations will be collected at predose (prior to administration of AZD3293) on Day 1 and 2 hours after the morning dose of itraconazole on Day 5 through Day 13. In Group 2, serial blood samples for AZD3293 plasma concentrations will be collected from predose to 96 hours after administration of AZD3293 on Day 1 and from predose to 144 hours after study drug administration on Day 8. Sparse blood samples for diltiazem plasma concentrations will be collected at predose (prior to administration of AZD3293) on Day 1 and 3 hours after diltiazem administration on Day 5 through Day 13.	up to day 13
The effect of multiple-dose AZD3293 administration (including the reversibilityof any of its effects) on the single-dose PK of a CYP3A4/CYP3A5 substrate (midazolam) by assessment of area under the curve over the time (AUC) and maximum concentration	Serial blood samples for midazolam plasma concentrations will be collected from predose to 24 hours after administration of midazolam on Day 1 and Day 17 and for 48 hours after administration of midazolam on Day 8. Sparse blood samples for AZD3293 plasma concentrations will be collected at predose (prior to administration of midazolam) on Day 1 and 2 hours after AZD3293 administration on Day 2 through Day 10.	up to day 17

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety profile in terms of Adverse events assessment	from Baseline and up to day 18
Safety and tolerability in terms of lab tests assessment (hematology, chemistry, urinalysis)	from Baseline and up to day 18
Safety and tolerability in terms of vital signs assessment (blood pressure, pulse and body temperature) and physical exams	from baseline and up till day 18
Safety and tolerability by assessing changes in electrocardiogram (ECG) parameters	from Baseline and up to day 18
Safety and tolerability by assessing telemetry records	from baseline and up to day 13
Suicidality mesured by Columbia-Suicide Severity Rating Scale (C-SSRS)	from Baseline and up till day 18

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Apinya Vutikullird, DO, WCCT Global

Study record dates

Study Major Dates

• Study Start: December 1, 2013
• Primary Completion (ACTUAL): February 1, 2014
• Study Completion (ACTUAL): February 1, 2014

Study Registration Dates

• First Submitted: December 10, 2013
• First Submitted That Met QC Criteria: December 10, 2013
• First Posted (ESTIMATE): December 13, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): April 28, 2014
• Last Update Submitted That Met QC Criteria: April 25, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Pharmacokinetics; healthy volunteers; phase I; AZD3293; drug interactions; itraconazole; diltiazem; medazolam
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Anti-Infective Agents; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Hormones, Hormone Substitutes, and Hormone Antagonists; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Calcium-Regulating Hormones and Agents; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Midazolam; Itraconazole; Diltiazem; Calcium Channel Blockers
• Other Study ID Numbers: D5010C00004