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The purpose of this study is to assess the effect of food timing on pharmacokinetics (PK) of AZD0585 and the effect of food timing on tolerability and safety of AZD0585 in healthy male Japanese subjects.
This study is an open-label, randomized, cross-over design with three single-dose treatment periods and a washout of at least 10 days in between each treatment visit. The study period consists of 5 visits to the study centre: Visit 1 (enrolment), Visit 2 (first single-dose treatment), Visit 3 (second single-dose treatment), Visit 4 (third single-dose treatment) and Visit 5 (follow-up).
Target subject population is healthy male Japanese subjects aged 20-45 years. Following an overnight fast of at least 10 hours, a single dose of 4 g AZD0585 will be administered on 3 separate occasions (fasting, before meal, and after meal) in a randomized crossover fashion with different food restrictions.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fasting | Experimental | Each subject will receive a single oral dose of 4 g AZD0585 on Day 1 of Visits 2, 3, and 4. Each dose will be administered at the end of a 10-hour fast. |
|
| Before meal | Experimental | Each subject will receive a single oral dose of 4 g AZD0585 on Day 1 of Visits 2, 3, and 4. Each dose will be administered before consumption of a low calorie, low-fat breakfast (within 30 minutes before starting food intake). |
|
| After meal | Experimental | Each subject will receive a single oral dose of 4 g AZD0585 on Day 1 of Visits 2, 3, and 4. Each dose will be administered after consumption of a low calorie, low-fat breakfast (within 30 minutes after starting food intake). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AZD0585 | Drug | Following an overnight fast of at least 10 hours, a single dose of 4 g AZD0585 will be administered on 3 separate occasions (fasting, before meal, and after meal) in a randomized crossover fashion with different food restrictions. |
| Measure | Description | Time Frame |
|---|---|---|
| The Effect of Food Timing (Fasting, Before Meal, and After Meal) on Pharmacokinetics (PK; AUC) of AZD0585 in Healthy Male Japanese. | To investigate the effect of food timing on PK (area under the plasma concentration-time curve from time zero to infinity [AUC]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total eicosapentaenoic acid (EPA) and total docosahexaenoic acid (DHA), and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal). | Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). |
| The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (Cmax) of AZD0585 in Healthy Male Japanese. | To investigate the effect of food timing on PK (maximum plasma concentration [Cmax]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total EPA and total DHA, and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal). Analyses of the outcome measures presented are for baseline-adjusted data for total EPA and DHA since the presence of endogenous levels of these fatty acids would likely contribute to intra-subject variability and affect the analyses and interpretation. The geometric mean was calculated as the exponential of the arithmetic mean calculated from data on a log scale. | Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). |
| The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (AUC0-72) of AZD0585 in Healthy Male Japanese. | To investigate the effect of food timing on PK (area under the plasma concentration-time curve from time zero to 72 hours [AUC0-72]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total EPA and total DHA, and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal). Analyses of the outcome measures presented are for baseline-adjusted data for total EPA and DHA since the presence of endogenous levels of these fatty acids would likely contribute to intra-subject variability and affect the analyses and interpretation. The geometric mean was calculated as the exponential of the arithmetic mean calculated from data on a log scale. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kei Sakamoto, MD, PhD | Sugioka Memorial Hospital, Medical Co. LTA | Principal Investigator |
| Torbjörn Lundström, MD | AstraZeneca | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Fukuoka | Japan |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28344197 | Derived | Shimada H, Nilsson C, Noda Y, Kim H, Lundstrom T, Yajima T. Effects of Food on the Pharmacokinetics of Omega-3-Carboxylic Acids in Healthy Japanese Male Subjects: A Phase I, Randomized, Open-label, Three-period, Crossover Trial. J Atheroscler Thromb. 2017 Sep 1;24(9):980-987. doi: 10.5551/jat.38737. Epub 2017 Mar 24. |
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Subjects were randomized to 3 sequences (ABC, BCA or CAB; A=fasting, B=before meal, C=after meal) with a 1:1:1 ratio. 72 subjects were enrolled; 42 randomized and 30 excluded (8 did not fulfil eligibility criteria and 22 refused participation).
The enrollment period started 4 March 2015 and the last subject last visit was 12 May 2015. This was a 3-period crossover study with a minimum 10-day washout period between each treatment visit (Period 1=Visit 2; Period 2=Visit 3; Period 3=Visit 4).
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| ID | Title | Description |
|---|---|---|
| FG000 | Sequence ABC | Subjects randomized to treatment sequence ABC: A=fasting / B=before meal / C=after meal. Following an overnight fast of at least 10 hours, a single oral dose of 4 g AZD0585 was administered on 3 separate occasions (fasting, before meal, and after meal) in a randomized crossover fashion with different food restrictions. |
| FG001 | Sequence BCA | Subjects randomized to treatment sequence BCA: B=before meal / C=after meal / A=fasting. Following an overnight fast of at least 10 hours, a single oral dose of 4 g AZD0585 was administered on 3 separate occasions (fasting, before meal, and after meal) in a randomized crossover fashion with different food restrictions. |
| FG002 | Sequence CAB | Subjects randomized to treatment sequence CAB: C=after meal / A=fasting / B=before meal. Following an overnight fast of at least 10 hours, a single oral dose of 4 g AZD0585 was administered on 3 separate occasions (fasting, before meal, and after meal) in a randomized crossover fashion with different food restrictions. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 (Visit 2) |
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| Period 2 (Visit 3) |
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| Period 3 (Visit 4) |
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All randomized subjects (n = 42) were included in the baseline analysis.
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| ID | Title | Description |
|---|---|---|
| BG000 | AZD0585 | All subjects received a single oral dose of 4 g AZD0585 on 3 separate occasions (fasting, before meal, and after meal) in a randomized crossover fashion with different food restrictions. Each dose was administered on Day 1 of each separate treatment period: Period 1=Visit 2; Period 2=Visit 3; Period 3=Visit 4. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on Pharmacokinetics (PK; AUC) of AZD0585 in Healthy Male Japanese. | To investigate the effect of food timing on PK (area under the plasma concentration-time curve from time zero to infinity [AUC]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total eicosapentaenoic acid (EPA) and total docosahexaenoic acid (DHA), and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal). | The PK set included all healthy subjects in the safety population (ie, who received at least 1 administration of AZD0585 and for whom any post-dose data were available) with at least 1 detectable total EPA and total DHA plasma concentration. | Posted | Geometric Mean | Geometric Coefficient of Variation | milligram x hour /millilitre (mg⋅h/mL) | Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). |
|
All adverse events (AEs) were collected from randomisation (Visit 2, Day 1) until the follow up visit (Visit 5).
Visits 2, 3 and 4 comprised 3 separate treatment periods with a washout period of at least 10 days between each treatment visit.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Fasting | Each subject received a single oral dose of 4 g AZD0585 on Day 1 of Visits 2, 3, and 4. Each dose was administered at the end of a 10-hour fast. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA (v18.0) | Non-systematic Assessment |
Statistical analysis is not provided for the treatment comparisons of AUC for the parameter total DHA (not possible to calculate in majority of subjects). Therefore, AUC(0-72) alone represents total plasma exposure in the bioavailability comparison.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Stefan C Carlsson, MD, PhD, Global Clinical Lead | AstraZeneca Pharmaceuticals | +46 31 7761000 | ClinicalTrialTransparency@astrazeneca.com |
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| Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). |
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| NOT COMPLETED |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Fasting |
Each subject received a single oral dose of 4 g AZD0585 on Day 1 of Visits 2, 3, and 4. Each dose was administered at the end of a 10-hour fast. |
| OG001 | Before Meal | Each subject received a single oral dose of 4 g AZD0585 on Day 1 of Visits 2, 3, and 4. Each dose was administered before consumption of a low calorie, low-fat breakfast (within 30 minutes before starting food intake). |
| OG002 | After Meal | Each subject received a single oral dose of 4 g AZD0585 on Day 1 of Visits 2, 3, and 4. Each dose was administered after consumption of a low calorie, low-fat breakfast (within 30 minutes after starting food intake). |
|
|
|
| Primary | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (Cmax) of AZD0585 in Healthy Male Japanese. | To investigate the effect of food timing on PK (maximum plasma concentration [Cmax]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total EPA and total DHA, and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal). Analyses of the outcome measures presented are for baseline-adjusted data for total EPA and DHA since the presence of endogenous levels of these fatty acids would likely contribute to intra-subject variability and affect the analyses and interpretation. The geometric mean was calculated as the exponential of the arithmetic mean calculated from data on a log scale. | The PK set included all healthy subjects in the safety population (ie, who received at least 1 administration of AZD0585 and for whom any post-dose data were available) with at least 1 detectable total EPA and total DHA plasma concentration. | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram/millilitre (mcg/mL) | Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). |
|
|
|
|
| Primary | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (AUC0-72) of AZD0585 in Healthy Male Japanese. | To investigate the effect of food timing on PK (area under the plasma concentration-time curve from time zero to 72 hours [AUC0-72]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total EPA and total DHA, and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal). Analyses of the outcome measures presented are for baseline-adjusted data for total EPA and DHA since the presence of endogenous levels of these fatty acids would likely contribute to intra-subject variability and affect the analyses and interpretation. The geometric mean was calculated as the exponential of the arithmetic mean calculated from data on a log scale. | The PK set included all healthy subjects in the safety population (ie, who received at least 1 administration of AZD0585 and for whom any post-dose data were available) with at least 1 detectable total EPA and total DHA plasma concentration. | Posted | Geometric Mean | Geometric Coefficient of Variation | mg⋅h/mL | Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). |
|
|
|
|
| 0 |
| 42 |
| 5 |
| 42 |
| EG001 | Before Meal | Each subject received a single oral dose of 4 g AZD0585 on Day 1 of Visits 2, 3, and 4. Each dose was administered before consumption of a low calorie, low-fat breakfast (within 30 minutes before starting food intake). | 0 | 42 | 6 | 42 |
| EG002 | After Meal | Each subject received a single oral dose of 4 g AZD0585 on Day 1 of Visits 2, 3, and 4. Each dose was administered after consumption of a low calorie, low-fat breakfast (within 30 minutes after starting food intake). | 0 | 42 | 1 | 42 |
| Presyncope | Nervous system disorders | MedDRA (v18.0) | Non-systematic Assessment |
|
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| Total DHA (n=42, 42, 42) |
|
Total EPA: Ratio of Before meal to After meal. Primary comparisons for total EPA were based on a linear mixed-effect model. This model included log-transformed PK parameter (Cmax) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect. |
| Geometric LS mean ratio |
| 0.44 |
| 2-Sided |
| 95 |
| 0.33 |
| 0.59 |
| No |
| Superiority or Other |
| Total DHA: Ratio of Fasting to After meal. Primary comparisons for total DHA were based on a linear mixed-effect model. This model included log-transformed PK parameter (Cmax) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect. | Geometric LS mean ratio | 0.46 | 2-Sided | 95 | 0.36 | 0.57 | No | Superiority or Other |
| Total DHA: Ratio of Before meal to After meal. Primary comparisons for total DHA were based on a linear mixed-effect model. This model included log-transformed PK parameter (Cmax) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect. | Geometric LS mean ratio | 0.57 | 2-Sided | 95 | 0.45 | 0.71 | No | Superiority or Other |
| Total DHA (n=42, 42, 42) |
|
Total EPA: Ratio of Before Meal to After meal. Primary comparisons for total EPA were based on a linear mixed-effect model. This model included log-transformed PK parameter (AUC0-72) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect. |
| Geometric LS mean ratio |
| 0.55 |
| 95 |
| 0.44 |
| 0.69 |
| No |
| Superiority or Other |
| Total DHA: Ratio of Fasting to After meal. Primary comparisons for total DHA were based on a linear mixed-effect model. This model included log-transformed PK parameter (AUC0-72) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect. | Geometric LS mean ratio | 0.87 | 2-Sided | 95 | 0.73 | 1.04 | No | Superiority or Other |
| Total DHA: Ratio of Before meal to After meal. Primary comparisons for total DHA were based on a linear mixed-effect model. This model included log-transformed PK parameter (AUC0-72) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect. | Geometric LS mean ratio | 0.86 | 2-Sided | 95 | 0.72 | 1.02 | No | Superiority or Other |