Healthy Japanese Young and Elderly Male and Non-fertile Female Volunteers
Conditions
Keywords
AZD3293, Healthy volunteers, Young volunteers, Elderly volunteers, Japanese volunteers, Phase 1, Single and multiple ascending dose study
Brief summary
This study consists of two parts, ie, single dose part with young healthy subjects (Part 1) and single and multiple dose part with elderly healthy subjects (Part 2), to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD3293 following single and multiple ascending dose administration to healthy subjects.
Detailed description
This is a Phase I, randomised, double-blind, placebo-controlled, single centre study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD3293 following single and multiple ascending dose administration to healthy subjects. This study consists of two parts, ie, single dose part with young healthy subjects (Part 1) and single and multiple dose part with elderly healthy subjects (Part 2). The study design allows a gradual escalation of dosage levels between sequential cohorts with safety monitoring to ensure the safety of the healthy subjects.
Interventions
DRUGAZD3293
Oral solution
DRUGPlacebo
Oral solution
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy Japanese elderly and young males and females (of non-childbearing potential) * Body mass index (BMI) between 17 and 27 kg/m2 and weigh at least 40 kg and no more than 100 kg
Exclusion criteria
* Psychiatric disease/condition, GI, renal, hepatic, cardiovascular, psychiatric, or retinal diseases or disorders * Use of antipsychotic drugs , or chronic use of antidepressant or anxiolytic drugs. * Frequent use (more than 2 days per week during the last 12 weeks) of tobacco or other nicotine products. * Neurological disease, including seizures, recent memory impairment, or clinically significant head injury.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety - Adverse Events | Day of first dose to follow up | Safety - Number of subjects reporting any adverse events during the study |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK Cmax - Overall Study | 0, 0.5,1,2,3,4,8,12,24,48 hr single dose, multiple dose does not include 48 hr | Pharmacokinetic maximum concentration |
| PK AUC - Overall Study (SAD & MAD Parts) | 0,0.5,1,2,3,4,8,12,24,48 hr single dose, multiple dose does not include 48 hr | Pharmacokintic Area Under the Curve (0 to t) |
| Biomarker | Pre dose vs Day 14 | Biomarker (Abeta 1-40; A beta 1-42) % change from baseline |
Countries
Japan
Participant flow
Recruitment details
Healthy subjects, adult and elderly Japanese vlounteers, male and female (non-fertile); First patient enrolled 24 Dec 2013, last patient completed 29 Jul 2014
Pre-assignment details
Single Japanese Centre: SAD Part 1: 24 young adult subjects in 3 cohorts of 8, 2 placebo and 6 active AZD3293 dose (15 mg, 50 mg, 150 mg); MAD Part 2:16 elderly subjects in 2 Cohorts of 8, randomized 2 placebo and 6 active dose AZD3293 (15 mg, 50 mg) - Only data on subjests enrolled into cohorts was included in the data base for reporting
Participants by arm
| Arm | Count |
|---|---|
| Placebo Part 1 Placebo Part 1 - SAD | 6 |
| AZD3293 15 mg Part 1 AZD3293 15 mg Part 1 - SAD | 6 |
| AZD3293 50 mg Part 1 AZD3293 50 mg Part 1 - SAD | 6 |
| AZD3293 150 mg Part 1 AZD3293 150 mg Part 1 - SAD | 6 |
| AZD3293 15 mg Part 2 AZD3293 15 mg Part 2 -MAD | 6 |
| AZD3293 50 mg Part 2 AZD3293 50 mg Part 2 - MAD | 6 |
| Placebo Part 2 Placebo Part 2 - MAD | 4 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Part 2 - Elderly Subjects Cohorts 4 & 5 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo Part 1 | AZD3293 15 mg Part 1 | AZD3293 50 mg Part 1 | AZD3293 150 mg Part 1 | AZD3293 15 mg Part 2 | AZD3293 50 mg Part 2 | Placebo Part 2 |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous Elderly Adults | 63.8 Years STANDARD_DEVIATION 4.8 | NA Years | NA Years | NA Years | NA Years | 65.5 Years STANDARD_DEVIATION 3.8 | 64.2 Years STANDARD_DEVIATION 5 | 60.5 Years STANDARD_DEVIATION 5.4 |
| Age, Continuous Young adult | 26.9 Years STANDARD_DEVIATION 7.8 | 28.8 Years STANDARD_DEVIATION 9.1 | 32.2 Years STANDARD_DEVIATION 9.7 | 23.8 Years STANDARD_DEVIATION 5 | 22.7 Years STANDARD_DEVIATION 3.3 | NA Years | NA Years | NA Years |
| Race/Ethnicity, Customized Asian | 40 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 40 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Female | 12 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Male | 28 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 2 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 6 | 1 / 6 | 1 / 6 | 0 / 6 | 2 / 6 | 2 / 6 | 1 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 4 |
Outcome results
Primary
Safety - Adverse Events
Safety - Number of subjects reporting any adverse events during the study
Time frame: Day of first dose to follow up
Population: Safety
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD3293 15 mg Part 1 | Safety - Adverse Events | 1 Participants |
| AZD3293 50 mg Part 1 | Safety - Adverse Events | 1 Participants |
| AZD3293 150 mg Part 1 | Safety - Adverse Events | 0 Participants |
| AZD3293 15 mg Part 2 | Safety - Adverse Events | 2 Participants |
| AZD3293 50 mg Part 2 | Safety - Adverse Events | 2 Participants |
| AZD3293 50 mg Part 2 | Safety - Adverse Events | 1 Participants |
| Placebo Part 2 | Safety - Adverse Events | 1 Participants |
Secondary
Biomarker
Biomarker (Abeta 1-40; A beta 1-42) % change from baseline
Time frame: Pre dose vs Day 14
Population: Pharmacodynamic
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD3293 15 mg Part 1 | Biomarker | Plasma Abeta(1-42) Day 14 | NA % change from baseline | — |
| AZD3293 15 mg Part 1 | Biomarker | Plasma Abeta (1-42) Day 1 | 4.80 % change from baseline | Standard Deviation 9.78 |
| AZD3293 15 mg Part 1 | Biomarker | CSF Abeta(1-40) Day 14 | NA % change from baseline | — |
| AZD3293 15 mg Part 1 | Biomarker | Plasma Abeta(1-40), Day 1 | -9.03 % change from baseline | Standard Deviation 14.3 |
| AZD3293 15 mg Part 1 | Biomarker | Plasma Abeta(1-40) Day 14 | NA % change from baseline | — |
| AZD3293 15 mg Part 1 | Biomarker | CSF Abeta(1-42) Day 14 | NA % change from baseline | — |
| AZD3293 50 mg Part 1 | Biomarker | Plasma Abeta(1-40), Day 1 | -69.6 % change from baseline | Standard Deviation 8.36 |
| AZD3293 50 mg Part 1 | Biomarker | CSF Abeta(1-40) Day 14 | NA % change from baseline | — |
| AZD3293 50 mg Part 1 | Biomarker | Plasma Abeta(1-42) Day 14 | NA % change from baseline | — |
| AZD3293 50 mg Part 1 | Biomarker | Plasma Abeta (1-42) Day 1 | -58.3 % change from baseline | Standard Deviation 22.3 |
| AZD3293 50 mg Part 1 | Biomarker | CSF Abeta(1-42) Day 14 | NA % change from baseline | — |
| AZD3293 50 mg Part 1 | Biomarker | Plasma Abeta(1-40) Day 14 | NA % change from baseline | — |
| AZD3293 150 mg Part 1 | Biomarker | CSF Abeta(1-42) Day 14 | NA % change from baseline | — |
| AZD3293 150 mg Part 1 | Biomarker | Plasma Abeta(1-40) Day 14 | NA % change from baseline | — |
| AZD3293 150 mg Part 1 | Biomarker | Plasma Abeta(1-42) Day 14 | NA % change from baseline | — |
| AZD3293 150 mg Part 1 | Biomarker | CSF Abeta(1-40) Day 14 | NA % change from baseline | — |
| AZD3293 150 mg Part 1 | Biomarker | Plasma Abeta(1-40), Day 1 | -75.8 % change from baseline | Standard Deviation 6.34 |
| AZD3293 150 mg Part 1 | Biomarker | Plasma Abeta (1-42) Day 1 | -71.9 % change from baseline | Standard Deviation 9.74 |
| AZD3293 15 mg Part 2 | Biomarker | CSF Abeta(1-42) Day 14 | NA % change from baseline | — |
| AZD3293 15 mg Part 2 | Biomarker | Plasma Abeta(1-40), Day 1 | -62.7 % change from baseline | Standard Deviation 37.6 |
| AZD3293 15 mg Part 2 | Biomarker | Plasma Abeta (1-42) Day 1 | -79.4 % change from baseline | Standard Deviation 4.84 |
| AZD3293 15 mg Part 2 | Biomarker | Plasma Abeta(1-40) Day 14 | NA % change from baseline | — |
| AZD3293 15 mg Part 2 | Biomarker | CSF Abeta(1-40) Day 14 | NA % change from baseline | — |
| AZD3293 15 mg Part 2 | Biomarker | Plasma Abeta(1-42) Day 14 | NA % change from baseline | — |
| AZD3293 50 mg Part 2 | Biomarker | CSF Abeta(1-40) Day 14 | -50.4 % change from baseline | Standard Deviation 7.49 |
| AZD3293 50 mg Part 2 | Biomarker | Plasma Abeta (1-42) Day 1 | -73.7 % change from baseline | Standard Deviation 4.03 |
| AZD3293 50 mg Part 2 | Biomarker | CSF Abeta(1-42) Day 14 | -63.2 % change from baseline | Standard Deviation 9.12 |
| AZD3293 50 mg Part 2 | Biomarker | Plasma Abeta(1-42) Day 14 | -77.6 % change from baseline | Standard Deviation 4.73 |
| AZD3293 50 mg Part 2 | Biomarker | Plasma Abeta(1-40) Day 14 | -74.7 % change from baseline | Standard Deviation 5.28 |
| AZD3293 50 mg Part 2 | Biomarker | Plasma Abeta(1-40), Day 1 | -65.9 % change from baseline | Standard Deviation 4.54 |
| AZD3293 50 mg Part 2 | Biomarker | Plasma Abeta(1-40) Day 14 | -77.0 % change from baseline | Standard Deviation 3.36 |
| AZD3293 50 mg Part 2 | Biomarker | CSF Abeta(1-40) Day 14 | -76.6 % change from baseline | Standard Deviation 3.96 |
| AZD3293 50 mg Part 2 | Biomarker | Plasma Abeta (1-42) Day 1 | -77.1 % change from baseline | Standard Deviation 5.31 |
| AZD3293 50 mg Part 2 | Biomarker | CSF Abeta(1-42) Day 14 | -79.3 % change from baseline | Standard Deviation 4.69 |
| AZD3293 50 mg Part 2 | Biomarker | Plasma Abeta(1-40), Day 1 | -70.2 % change from baseline | Standard Deviation 3.76 |
| AZD3293 50 mg Part 2 | Biomarker | Plasma Abeta(1-42) Day 14 | -78.6 % change from baseline | Standard Deviation 4.27 |
| Placebo Part 2 | Biomarker | Plasma Abeta(1-40) Day 14 | -5.1 % change from baseline | Standard Deviation 8.56 |
| Placebo Part 2 | Biomarker | Plasma Abeta (1-42) Day 1 | 12.4 % change from baseline | Standard Deviation 16.9 |
| Placebo Part 2 | Biomarker | Plasma Abeta(1-42) Day 14 | 15.9 % change from baseline | Standard Deviation 19.9 |
| Placebo Part 2 | Biomarker | CSF Abeta(1-40) Day 14 | -8.0 % change from baseline | Standard Deviation 22.7 |
| Placebo Part 2 | Biomarker | CSF Abeta(1-42) Day 14 | 1.75 % change from baseline | Standard Deviation 21.9 |
| Placebo Part 2 | Biomarker | Plasma Abeta(1-40), Day 1 | -7.4 % change from baseline | Standard Deviation 3.89 |
Secondary
PK AUC - Overall Study (SAD & MAD Parts)
Pharmacokintic Area Under the Curve (0 to t)
Time frame: 0,0.5,1,2,3,4,8,12,24,48 hr single dose, multiple dose does not include 48 hr
Population: healthy Japanese participants
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AZD3293 15 mg Part 1 | PK AUC - Overall Study (SAD & MAD Parts) | Single dose | 839 hr.ng/mL | Geometric Coefficient of Variation 28.1 |
| AZD3293 15 mg Part 1 | PK AUC - Overall Study (SAD & MAD Parts) | MAD -Day 14 Steady state | NA hr.ng/mL | — |
| AZD3293 15 mg Part 1 | PK AUC - Overall Study (SAD & MAD Parts) | MAD -Day 10 Steady state | NA hr.ng/mL | — |
| AZD3293 50 mg Part 1 | PK AUC - Overall Study (SAD & MAD Parts) | MAD -Day 10 Steady state | NA hr.ng/mL | — |
| AZD3293 50 mg Part 1 | PK AUC - Overall Study (SAD & MAD Parts) | Single dose | 2810 hr.ng/mL | Geometric Coefficient of Variation 17.6 |
| AZD3293 50 mg Part 1 | PK AUC - Overall Study (SAD & MAD Parts) | MAD -Day 14 Steady state | NA hr.ng/mL | — |
| AZD3293 150 mg Part 1 | PK AUC - Overall Study (SAD & MAD Parts) | MAD -Day 10 Steady state | NA hr.ng/mL | — |
| AZD3293 150 mg Part 1 | PK AUC - Overall Study (SAD & MAD Parts) | Single dose | 10700 hr.ng/mL | Geometric Coefficient of Variation 10.1 |
| AZD3293 150 mg Part 1 | PK AUC - Overall Study (SAD & MAD Parts) | MAD -Day 14 Steady state | NA hr.ng/mL | — |
| AZD3293 15 mg Part 2 | PK AUC - Overall Study (SAD & MAD Parts) | Single dose | 877 hr.ng/mL | Geometric Coefficient of Variation 12.5 |
| AZD3293 15 mg Part 2 | PK AUC - Overall Study (SAD & MAD Parts) | MAD -Day 14 Steady state | 1030 hr.ng/mL | Geometric Coefficient of Variation 12.8 |
| AZD3293 15 mg Part 2 | PK AUC - Overall Study (SAD & MAD Parts) | MAD -Day 10 Steady state | 1060 hr.ng/mL | Geometric Coefficient of Variation 18.3 |
| AZD3293 50 mg Part 2 | PK AUC - Overall Study (SAD & MAD Parts) | MAD -Day 10 Steady state | 3540 hr.ng/mL | Geometric Coefficient of Variation 37.3 |
| AZD3293 50 mg Part 2 | PK AUC - Overall Study (SAD & MAD Parts) | Single dose | 3070 hr.ng/mL | Geometric Coefficient of Variation 27.7 |
| AZD3293 50 mg Part 2 | PK AUC - Overall Study (SAD & MAD Parts) | MAD -Day 14 Steady state | 3280 hr.ng/mL | Geometric Coefficient of Variation 30.4 |
Secondary
PK Cmax - Overall Study
Pharmacokinetic maximum concentration
Time frame: 0, 0.5,1,2,3,4,8,12,24,48 hr single dose, multiple dose does not include 48 hr
Population: Pharmacokinetic
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AZD3293 15 mg Part 1 | PK Cmax - Overall Study | Single dose | 82.5 ng/mL | Geometric Coefficient of Variation 20.9 |
| AZD3293 15 mg Part 1 | PK Cmax - Overall Study | MAD - Day 14 steady state | NA ng/mL | — |
| AZD3293 15 mg Part 1 | PK Cmax - Overall Study | MAD -Day 10 steady state | NA ng/mL | — |
| AZD3293 50 mg Part 1 | PK Cmax - Overall Study | MAD -Day 10 steady state | NA ng/mL | — |
| AZD3293 50 mg Part 1 | PK Cmax - Overall Study | Single dose | 395 ng/mL | Geometric Coefficient of Variation 24.9 |
| AZD3293 50 mg Part 1 | PK Cmax - Overall Study | MAD - Day 14 steady state | NA ng/mL | — |
| AZD3293 150 mg Part 1 | PK Cmax - Overall Study | MAD -Day 10 steady state | NA ng/mL | — |
| AZD3293 150 mg Part 1 | PK Cmax - Overall Study | Single dose | 1480 ng/mL | Geometric Coefficient of Variation 14.4 |
| AZD3293 150 mg Part 1 | PK Cmax - Overall Study | MAD - Day 14 steady state | NA ng/mL | — |
| AZD3293 15 mg Part 2 | PK Cmax - Overall Study | Single dose | 86.6 ng/mL | Geometric Coefficient of Variation 31.7 |
| AZD3293 15 mg Part 2 | PK Cmax - Overall Study | MAD - Day 14 steady state | 119 ng/mL | Geometric Coefficient of Variation 23.3 |
| AZD3293 15 mg Part 2 | PK Cmax - Overall Study | MAD -Day 10 steady state | 115 ng/mL | Geometric Coefficient of Variation 29.7 |
| AZD3293 50 mg Part 2 | PK Cmax - Overall Study | MAD -Day 10 steady state | 465 ng/mL | Geometric Coefficient of Variation 42.2 |
| AZD3293 50 mg Part 2 | PK Cmax - Overall Study | Single dose | 395 ng/mL | Geometric Coefficient of Variation 38.5 |
| AZD3293 50 mg Part 2 | PK Cmax - Overall Study | MAD - Day 14 steady state | 502 ng/mL | Geometric Coefficient of Variation 30.6 |