A Single Ascending Dose Study To Assess The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of AZD9567.
Sponsor
AstraZeneca (Industry)
Overall Status
Completed
CT.gov ID
NCT02512575
Collaborator
(none)
72
1
3
10.3
7
Study Details
Study Description
Brief Summary
This is a Phase I, first-in-human (FIH), randomized, single-blind, placebo-controlled, single ascending dose sequential group study in healthy male subjects. The objectives are to study the safety, tolerability, pharmacokinetics and effects on glucose homeostasis (pharmacodynamics) of AZD9567, an oral differentiated non-steroidal selective glucocorticoid receptor modulator (SGRM). The study will also assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of prednisolone 60 mg in comparison with high doses of AZD9567 and placebo.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This is a Phase I, first-in-human (FIH), randomized, single-blind, placebo-controlled, single ascending dose sequential group study in healthy male subjects. The objectives are to study the safety, tolerability, pharmacokinetics and effects on glucose homeostasis (pharmacodynamics) of AZD9567. Additional exploratory variables (Inflammation biomarkers, ECG modelling and taste assessment) will also be evaluated. The study will also assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of prednisolone 60 mg in comparison with high doses of AZD9567 and placebo. The study will be conducted at a single study centre with a planned number of subjects of up to 72 healthy males, aged 18 to 55 years.
Study Design
Study Type:
Interventional
Actual Enrollment
:
72 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Single (Participant)
Primary Purpose:
Basic Science
Official Title:
A Phase I, Randomized, Single-Blind, Placebo-Controlled Study To Assess The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Single Ascending Oral Doses Of AZD9567 In Healthy Subjects.
Actual Study Start Date
:
Nov 18, 2015
Actual Primary Completion Date
:
Sep 26, 2016
Actual Study Completion Date
:
Sep 26, 2016
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: AZD9567 oral suspension In Part A: up to 8 cohorts with single ascending doses (starting at 2 mg up to 155 mg). In Part B: one cohort with a single dose |
Drug: AZD9567 Monohydrat
AZD9567 oral suspension 0.5 to 10 mg/ml
|
| Placebo Comparator: Placebo Subjects randomized to placebo in the first 8 cohorts will receive the same dose volume of oral suspension as subjects on AZD9567 and subjects randomized to placebo in cohort 9(prednisolone cohort) will receive the same number of capsules as subjects on prednisolone. |
Drug: Placebo oral suspension/ Placebo capsule
Matching placebo
|
| Experimental: Prednisolone capsules Within each cohort 6 subjects will be randomized to receive prednisolone 60mg oral capsules and 2 subjects randomized to receive matching placebo in a fasted state. Sentinel dosing will not be employed for the prednisolone cohort. The SRC will not be required to evaluate the prednisolone cohort. This cohort can be performed at any time during clinical execution of the study provided the protocol amendment was approved. |
Drug: Prednisolone
Prednisolone 60mg oral capsules (12 capsules of 5 mg each).
|
Outcome Measures
Primary Outcome Measures
- Safety and Tolerability of AZD9567 by Assessing the Number of Participants With Adverse Events [At screening, Day -2, Day -1, Day 1 (at pre-dose; 3 & 12 hours post-dose), Day 2 (24 hours post-dose), Day 3 and follow-up (7 to 10 days post-dose)]
Safety and tolerability variables included AEs, vital signs (blood pressure and pulse), ECGs (12-lead ECGs, safety ECGs and telemetry), clinical laboratory safety evaluations (haematology, clinical chemistry [including osteocalcin], coagulation, urinalysis [including 24 hour urine cortisol per day {tU-cortisol}]) and physical examinations. Note: No clinically relevant findings were noted in clinical laboratory results and vial signs assessments. Hence, none of the laboratory or vital signs findings were reported as AEs.
- Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Observed Maximum Plasma Concentration (Cmax) [On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose)]
To assess the Cmax of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. Cmax was taken directly from the individual concentration-time curve.
- Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Time to Reach Maximum Plasma Concentration(Tmax) [On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose)]
To assess the tmax of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. tmax was taken directly from the individual concentration-time curve.
- Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Terminal Half-life (t½λz) [On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose)]
To assess t½λz of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. t½λz was estimated as (ln2)/λz.
- Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Area Under the Plasma Concentration-curve From Time Zero to the Time of Last Quantifiable Analyte Concentration (AUC(0-last)) [On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose)]
To assess AUC(0-last) of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state.
- Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Area Under the Plasma Concentration-curve From Time Zero Extrapolated to Infinity (AUC) [On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose)]
To assess AUC of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. AUC was estimated by AUC(0-last) + Clast/λz. Clast - the last observed quantifiable concentration.
Secondary Outcome Measures
- Secondary Outcome: Relative Change From Baseline of AUC0-4h for Plasma Glucose to Assess the Effects on Glucose Homeostasis (Oral Glucose Tolerance Test [OGTT]) [At Day -1 (baseline) and Day 1 (pre glucose intake and at 30, 60, 90, 120, 150, 180 and 240 minutes post glucose intake)]
To assess the effect of AZD9567 and prednisolone on OGTT after administration of 75 g glucose solution, blood samples were collected pre glucose intake and at post glucose intake for the analyses of plasma glucose. AUC0-4h relative change between Day 1 and Day -1 was calculated for each subject in a specific treatment group. Note: Total AUC0-4h was calculated using the linear trapezoidal method. Statistical analysis for the change in OGTT plasma glucose total AUC0-4h values were assessed via an analysis of variance (ANCOVA), with treatment as fixed effect.
- Relative Change From Baseline of AUC0-4h for Serum Insulin to Assess the Effects on Glucose Homeostasis (Oral Glucose Tolerance Test [OGTT]) [At Day -1 (baseline) and Day 1 (pre glucose intake and at 30, 60, 90, 120, 150, 180 and 240 minutes post glucose intake)]
To assess the effect of AZD9567 and prednisolone on OGTT after administration of 75 g glucose solution, blood samples were collected pre glucose intake and at post glucose intake for the analyses of serum insulin. AUC0-4h relative change between Day 1 and Day -1 was calculated for each subject in a specific treatment group. Note: Total AUC0-4h was calculated using the linear trapezoidal method. Statistical analysis for the change in OGTT serum insulin total AUC0-4h values were assessed via an analysis of variance (ANCOVA), with treatment as fixed effect.
- Relative Change From Baseline of AUC0-4h for Serum C-peptide to Assess the Effects on Glucose Homeostasis (Oral Glucose Tolerance Test [OGTT]) [At Day -1 (baseline) and Day 1 (pre glucose intake and at 30, 60, 90, 120, 150, 180 and 240 minutes post glucose intake)]
To assess the effect of AZD9567 and prednisolone on OGTT after administration of 75 g glucose solution, blood samples were collected pre glucose intake and at post glucose intake for the analyses of serum C-peptide. AUC0-4h relative change between Day 1 and Day -1 was calculated for each subject in a specific treatment group. Note: Total AUC0-4h was calculated using the linear trapezoidal method. Statistical analysis for the change in OGTT serum C-peptide total AUC0-4h values were assessed via an analysis of variance (ANCOVA), with treatment as fixed effect.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 55 Years
Sexes Eligible for Study:
Male
Accepts Healthy Volunteers:
Yes
Inclusion Criteria:
-
Provision of signed and dated, written informed consent prior to any study specific procedures.
-
Healthy male subjects aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture.
-
Have a body mass index (BMI) between 18 and 29.9 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
-
Normal OGTT at screening (<7.8 mmol/L).
-
Serum cortisol levels within normal limits at screening (collected as part of the clinical chemistry panel).
-
Able to understand, read and speak the German language.
Exclusion Criteria:
-
History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
-
History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
-
History of or active or latent tuberculosis (TB), or at risk for having acquired TB (social workers or prison staff in countries with endemic rates of TB, having lived with patients with known TB).
-
History suggesting abnormal immune function, as judged by the investigator.
-
Any contraindications to be treated with prednisolone (allergy to any ingredient, systemic fungal infection, certain type of malaria, inflammation of the optic nerve, or herpes infection of the eye, scheduled to have a live or attenuated live vaccination or taking mifepristone).
-
History of severe affective disorder including depressive or manic-depressive illness them self or first degree relatives.
-
History of previous steroid psychosis
-
Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
-
Any latent or chronic infections (e.g., recurrent sinusitis, genital or ocular herpes, urinary tract infection) or at risk of infection (surgery, trauma, or significant infection), or history of skin abscesses within 90 days prior to the first administration of IMP.
-
Any clinically important laboratory abnormalities (clinical chemistry, hematology, coagulation or urinalysis results), as judged by the investigator. In particular a subject with an abnormal value in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), creatinine, thyroid-stimulating hormone (TSH), fasting glucose, International Normalised Ratio (INR), haemoglobin (Hb), white blood cell (WBC), absolute neutrophil or platelet count will be excluded.
-
Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV).
-
Abnormal vital signs, after 10 minutes supine rest, defined as any of the following: Systolic BP (SBP) < 90mmHg or ≥ 140 mmHg, Diastolic BP (DBP) < 50mmHg or ≥ 90 mmHg, Pulse < 45 or > 85 beats per minute (bpm).
-
Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG, as considered by the investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy.
-
Prolonged QTcF > 450 ms or family history of long QT syndrome.
-
PR(PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation).
-
PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block, or AV dissociation
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Berlin | Germany | 14050 |
Sponsors and Collaborators
- AstraZeneca
Investigators
- Principal Investigator: Rainhard Fuhr, Dr. med., PAREXEL International GmbH, Berlin
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02512575
Other Study ID Numbers:
- D6470C00001
- 2015-002002-37
First Posted:
Jul 31, 2015
Last Update Posted:
Oct 4, 2018
Last Verified:
Sep 1, 2018
Keywords provided by AstraZeneca
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | Phase 1, single-center (Berlin), randomized, single-blind, placebo-controlled study carried on 72 healthy male participants (8 subjects per cohort). In Cohort 1-8, participants were randomized to AZD9567:placebo (6:2). In Cohort 9, participants were randomized to prednisolone:placebo (6:2). Participants received treatment in a fasted state |
|---|---|
| Pre-assignment Detail | Screening period (Day -28 to Day -3). For Cohort 7, screening period was up to 21 days |
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg | Prednisolone - 60 mg | Pooled Placebo |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state | In Cohort 9, participants received orally single dose of prednisolone 60 mg capsule in the fasted state | In Cohort 1-8, participants were randomized to AZD9567:placebo (6:2). In Cohort 9, participants were randomized to prednisolone:placebo (6:2) |
| Period Title: Overall Study | ||||||||||
| STARTED | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 18 |
| COMPLETED | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 18 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg | Prednisolone - 60 mg | Pooled Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state | In Cohort 9, participants received orally single dose of prednisolone 60 mg capsule in the fasted state | In Cohort 1-8, participants were randomized to AZD9567:placebo (6:2). In Cohort 9, participants were randomized to prednisolone:placebo (6:2) | Total of all reporting groups |
| Overall Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 18 | 72 |
| Age (Years) [Mean (Standard Deviation) ] | |||||||||||
| Cohort 1-8 AZD9567 |
44
(10)
|
35
(14)
|
35
(8)
|
35
(9)
|
38
(12)
|
34
(9)
|
41
(8)
|
32
(8)
|
0
(0)
|
0
(0)
|
37
(10)
|
| Cohort 9 Prenisolone |
0
(0)
|
0
(0)
|
0
(0)
|
0
(0)
|
0
(0)
|
0
(0)
|
0
(0)
|
0
(0)
|
36
(9)
|
0
(0)
|
36
(9)
|
| Pooled Placebo |
0
(0)
|
0
(0)
|
0
(0)
|
0
(0)
|
0
(0)
|
0
(0)
|
0
(0)
|
0
(0)
|
0
(0)
|
37
(11)
|
37
(11)
|
| Sex: Female, Male (Count of Participants) | |||||||||||
| Female |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Male |
6
100%
|
6
100%
|
6
100%
|
6
100%
|
6
100%
|
6
100%
|
6
100%
|
6
100%
|
6
100%
|
18
100%
|
72
100%
|
Outcome Measures
| Title | Safety and Tolerability of AZD9567 by Assessing the Number of Participants With Adverse Events |
|---|---|
| Description | Safety and tolerability variables included AEs, vital signs (blood pressure and pulse), ECGs (12-lead ECGs, safety ECGs and telemetry), clinical laboratory safety evaluations (haematology, clinical chemistry [including osteocalcin], coagulation, urinalysis [including 24 hour urine cortisol per day {tU-cortisol}]) and physical examinations. Note: No clinically relevant findings were noted in clinical laboratory results and vial signs assessments. Hence, none of the laboratory or vital signs findings were reported as AEs. |
| Time Frame | At screening, Day -2, Day -1, Day 1 (at pre-dose; 3 & 12 hours post-dose), Day 2 (24 hours post-dose), Day 3 and follow-up (7 to 10 days post-dose) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants who received at least one dose of IMP and for whom any safety post-dose data were available were included in the safety analysis for the study. IMP includes AZD9567, Prednisolone 60 mg and placebo. |
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg | Prednisolone - 60 mg | Pooled Placebo |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state | In Cohort 9, participants received orally single dose of prednisolone 60 mg capsule in the fasted state | In Cohort 1-8, participants were randomized to AZD9567:placebo (6:2). In Cohort 9, participants were randomized to prednisolone:placebo (6:2) |
| Measure Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 18 |
| Any AE |
0
0%
|
0
0%
|
1
16.7%
|
0
0%
|
0
0%
|
2
33.3%
|
1
16.7%
|
0
0%
|
0
0%
|
3
16.7%
|
| Any AE (including events with outcome =death) |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Any serious adverse event (SAE) (including death) |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Any AE leading to discontinuation of AZD9567 |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Title | Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Observed Maximum Plasma Concentration (Cmax) |
|---|---|
| Description | To assess the Cmax of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. Cmax was taken directly from the individual concentration-time curve. |
| Time Frame | On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set who received a dose of AZD9567 and had at least one of the parameters Cmax, AUC / AUC(0-last) evaluable. All protocol deviations were considered for the severity/impact and were accounted when participants were assigned to the PK analysis sets. |
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state |
| Measure Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 |
| Geometric Mean (Geometric Coefficient of Variation) [nmol/L] |
184.9
(20.18)
|
751.6
(25.03)
|
1327
(17.28)
|
2536
(38.33)
|
4261
(13.88)
|
5835
(14.14)
|
6080
(21.30)
|
6900
(33.97)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 2 mg, AZD9567 - 10 mg, AZD9567 - 20 mg, AZD9567 - 40 mg, AZD9567 - 80 mg, AZD9567 - 100 mg, AZD9567 - 125 mg, AZD9567 - 155 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Slope |
| Estimated Value | 0.847 | |
| Confidence Interval |
(2-Sided) 90% 0.807 to 0.887 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.0238 |
|
| Estimation Comments | ||
| Title | Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Time to Reach Maximum Plasma Concentration(Tmax) |
|---|---|
| Description | To assess the tmax of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. tmax was taken directly from the individual concentration-time curve. |
| Time Frame | On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set consisted of all participants in the safety analysis set who received a dose of AZD9567 and had at least one of the parameters Cmax, AUC / AUC(0-last) evaluable. All protocol deviations were considered for the severity/impact and were accounted when participants were assigned to the PK analysis sets. |
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state |
| Measure Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 |
| Median (Full Range) [Hours] |
0.50
(20.18)
|
0.75
(25.03)
|
0.51
(17.28)
|
0.75
(38.33)
|
1.00
(13.88)
|
1.00
(14.14)
|
1.00
(21.30)
|
1.25
(33.97)
|
| Title | Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Terminal Half-life (t½λz) |
|---|---|
| Description | To assess t½λz of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. t½λz was estimated as (ln2)/λz. |
| Time Frame | On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set consisted of all participants in the safety analysis set who received a dose of AZD9567 and had at least one of the parameters Cmax, AUC / AUC(0-last) evaluable. All protocol deviations were considered for the severity/impact and were accounted when participants were assigned to the PK analysis sets. |
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state |
| Measure Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 |
| Mean (Standard Deviation) [Hours] |
4.716
(0.8182)
|
5.444
(2.157)
|
3.929
(1.237)
|
4.199
(1.417)
|
5.286
(1.469)
|
5.297
(1.041)
|
4.664
(1.052)
|
6.449
(1.778)
|
| Title | Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Area Under the Plasma Concentration-curve From Time Zero to the Time of Last Quantifiable Analyte Concentration (AUC(0-last)) |
|---|---|
| Description | To assess AUC(0-last) of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. |
| Time Frame | On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set consisted of all participants in the safety analysis set who received a dose of AZD9567 and had at least one of the parameters Cmax, AUC / AUC(0-last) evaluable. All protocol deviations were considered for the severity/impact and were accounted when participants were assigned to the PK analysis sets. |
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state |
| Measure Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 |
| Geometric Mean (Geometric Coefficient of Variation) [h*nmol/L] |
940.6
(40.32)
|
5069
(41.83)
|
7598
(28.12)
|
13860
(62.81)
|
31600
(34.57)
|
41850
(27.82)
|
40930
(14.32)
|
56940
(36.80)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 2 mg, AZD9567 - 10 mg, AZD9567 - 20 mg, AZD9567 - 40 mg, AZD9567 - 80 mg, AZD9567 - 100 mg, AZD9567 - 125 mg, AZD9567 - 155 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Slope |
| Estimated Value | 0.930 | |
| Confidence Interval |
(2-Sided) 90% 0.869 to 0.991 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.0364 |
|
| Estimation Comments | ||
| Title | Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Area Under the Plasma Concentration-curve From Time Zero Extrapolated to Infinity (AUC) |
|---|---|
| Description | To assess AUC of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. AUC was estimated by AUC(0-last) + Clast/λz. Clast - the last observed quantifiable concentration. |
| Time Frame | On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set consisted of all participants in the safety analysis set who received a dose of AZD9567 and had at least one of the parameters Cmax, AUC / AUC(0-last) evaluable. All protocol deviations were considered for the severity/impact and were accounted when participants were assigned to the PK analysis sets. |
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state |
| Measure Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 |
| Geometric Mean (Geometric Coefficient of Variation) [h*nmol/L] |
1007
(38.22)
|
5266
(42.57)
|
7670
(28.26)
|
14000
(62.53)
|
31840
(34.55)
|
42080
(27.83)
|
41290
(14.63)
|
57500
(37.51)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 2 mg, AZD9567 - 10 mg, AZD9567 - 20 mg, AZD9567 - 40 mg, AZD9567 - 80 mg, AZD9567 - 100 mg, AZD9567 - 125 mg, AZD9567 - 155 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Slope |
| Estimated Value | 0.917 | |
| Confidence Interval |
(2-Sided) 90% 0.856 to 0.978 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.0364 |
|
| Estimation Comments | ||
| Title | Secondary Outcome: Relative Change From Baseline of AUC0-4h for Plasma Glucose to Assess the Effects on Glucose Homeostasis (Oral Glucose Tolerance Test [OGTT]) |
|---|---|
| Description | To assess the effect of AZD9567 and prednisolone on OGTT after administration of 75 g glucose solution, blood samples were collected pre glucose intake and at post glucose intake for the analyses of plasma glucose. AUC0-4h relative change between Day 1 and Day -1 was calculated for each subject in a specific treatment group. Note: Total AUC0-4h was calculated using the linear trapezoidal method. Statistical analysis for the change in OGTT plasma glucose total AUC0-4h values were assessed via an analysis of variance (ANCOVA), with treatment as fixed effect. |
| Time Frame | At Day -1 (baseline) and Day 1 (pre glucose intake and at 30, 60, 90, 120, 150, 180 and 240 minutes post glucose intake) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The pharmacodynamics (PD) analysis set consisted of all participants who received a dose of AZD9567/placebo and who had at least one pre-dose and one post-dose measurement for one of plasma glucose, insulin and C-peptide, and who had no major protocol deviations thought to have impacted the analysis of the PD data. |
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg | Prednisolone - 60 mg | Pooled Placebo |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state | In Cohort 9, participants received orally single dose of prednisolone 60 mg capsule in the fasted state | In Cohort 1-8, participants were randomized to AZD9567:placebo (6:2). In Cohort 9, participants were randomized to prednisolone:placebo (6:2) |
| Measure Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 18 |
| Geometric Mean (95% Confidence Interval) [min*mmol/L] |
1.04
|
1.01
|
1.07
|
1.06
|
1.08
|
1.17
|
1.16
|
1.20
|
1.19
|
1.01
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 2 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.03 | |
| Confidence Interval |
(2-Sided) 90% 0.960 to 1.11 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 10 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.00 | |
| Confidence Interval |
(2-Sided) 90% 0.929 to 1.08 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 20 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.06 | |
| Confidence Interval |
(2-Sided) 90% 0.987 to 1.14 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 40 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.06 | |
| Confidence Interval |
(2-Sided) 95% 0.983 to 1.13 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 80 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.07 | |
| Confidence Interval |
(2-Sided) 90% 0.995 to 1.15 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 100 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.17 | |
| Confidence Interval |
(2-Sided) 90% 1.09 to 1.25 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 125 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.15 | |
| Confidence Interval |
(2-Sided) 90% 1.07 to 1.24 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 155 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.20 | |
| Confidence Interval |
(2-Sided) 90% 1.11 to 1.29 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 9
| Statistical Analysis Overview | Comparison Group Selection | Prednisolone - 60 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.19 | |
| Confidence Interval |
(2-Sided) 90% 1.11 to 1.27 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Relative Change From Baseline of AUC0-4h for Serum Insulin to Assess the Effects on Glucose Homeostasis (Oral Glucose Tolerance Test [OGTT]) |
|---|---|
| Description | To assess the effect of AZD9567 and prednisolone on OGTT after administration of 75 g glucose solution, blood samples were collected pre glucose intake and at post glucose intake for the analyses of serum insulin. AUC0-4h relative change between Day 1 and Day -1 was calculated for each subject in a specific treatment group. Note: Total AUC0-4h was calculated using the linear trapezoidal method. Statistical analysis for the change in OGTT serum insulin total AUC0-4h values were assessed via an analysis of variance (ANCOVA), with treatment as fixed effect. |
| Time Frame | At Day -1 (baseline) and Day 1 (pre glucose intake and at 30, 60, 90, 120, 150, 180 and 240 minutes post glucose intake) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PD analysis set consisted of all participants who received a dose of AZD9567/placebo and who had at least one pre-dose and one post-dose measurement for one of plasma glucose, insulin and C-peptide, and who had no major protocol deviations thought to have impacted the analysis of the PD data. |
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg | Prednisolone - 60 mg | Pooled Placebo |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state | In Cohort 9, participants received orally single dose of prednisolone 60 mg capsule in the fasted state | In Cohort 1-8, participants were randomized to AZD9567:placebo (6:2). In Cohort 9, participants were randomized to prednisolone:placebo (6:2) |
| Measure Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 18 |
| Geometric Mean (95% Confidence Interval) [min*pmol/L] |
1.19
|
1.20
|
1.03
|
1.04
|
0.999
|
0.980
|
1.15
|
1.16
|
0.784
|
1.14
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 2 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.05 | |
| Confidence Interval |
(2-Sided) 90% 0.872 to 1.26 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 10 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.05 | |
| Confidence Interval |
(2-Sided) 90% 0.874 to 1.26 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 20 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.907 | |
| Confidence Interval |
(2-Sided) 90% 0.745 to 1.10 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 40 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.914 | |
| Confidence Interval |
(2-Sided) 90% 0.762 to 1.10 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 80 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.876 | |
| Confidence Interval |
(2-Sided) 90% 0.728 to 1.05 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 100 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.860 | |
| Confidence Interval |
(2-Sided) 90% 0.716 to 1.03 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 125 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.01 | |
| Confidence Interval |
(2-Sided) 90% 0.842 to 1.21 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 155 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 1.02 | |
| Confidence Interval |
(2-Sided) 90% 0.846 to 1.22 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 9
| Statistical Analysis Overview | Comparison Group Selection | Prednisolone - 60 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.687 | |
| Confidence Interval |
(2-Sided) 90% 0.572 to 0.825 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Relative Change From Baseline of AUC0-4h for Serum C-peptide to Assess the Effects on Glucose Homeostasis (Oral Glucose Tolerance Test [OGTT]) |
|---|---|
| Description | To assess the effect of AZD9567 and prednisolone on OGTT after administration of 75 g glucose solution, blood samples were collected pre glucose intake and at post glucose intake for the analyses of serum C-peptide. AUC0-4h relative change between Day 1 and Day -1 was calculated for each subject in a specific treatment group. Note: Total AUC0-4h was calculated using the linear trapezoidal method. Statistical analysis for the change in OGTT serum C-peptide total AUC0-4h values were assessed via an analysis of variance (ANCOVA), with treatment as fixed effect. |
| Time Frame | At Day -1 (baseline) and Day 1 (pre glucose intake and at 30, 60, 90, 120, 150, 180 and 240 minutes post glucose intake) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PD analysis set consisted of all participants who received a dose of AZD9567/placebo and who had at least one pre-dose and one post-dose measurement for one of plasma glucose, insulin and C-peptide, and who had no major protocol deviations thought to have impacted the analysis of the PD data. |
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg | Prednisolone - 60 mg | Pooled Placebo |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state | In Cohort 9, participants received orally single dose of prednisolone 60 mg capsule in the fasted state | In Cohort 1-8, participants were randomized to AZD9567:placebo (6:2). In Cohort 9, participants were randomized to prednisolone:placebo (6:2) |
| Measure Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 18 |
| Geometric Mean (95% Confidence Interval) [min*nmol/L] |
1.06
|
1.04
|
1.02
|
0.933
|
0.919
|
1.00
|
0.983
|
0.968
|
0.749
|
1.08
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 2 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.982 | |
| Confidence Interval |
(2-Sided) 90% 0.861 to 1.12 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 10 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.961 | |
| Confidence Interval |
() 90% 0.846 to 1.09 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 20 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.942 | |
| Confidence Interval |
(2-Sided) 90% 0.829 to 1.07 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 40 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.861 | |
| Confidence Interval |
(2-Sided) 90% 0.757 to 0.979 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 80 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.848 | |
| Confidence Interval |
(2-Sided) 90% 0.745 to 0.964 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 100 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.927 | |
| Confidence Interval |
(2-Sided) 90% 0.815 to 1.05 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 125 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.907 | |
| Confidence Interval |
(2-Sided) 90% 0.798 to 1.03 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | AZD9567 - 155 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.893 | |
| Confidence Interval |
(2-Sided) 90% 0.784 to 1.02 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 9
| Statistical Analysis Overview | Comparison Group Selection | Prednisolone - 60 mg, Pooled Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio (Active Vs Placebo) |
| Estimated Value | 0.691 | |
| Confidence Interval |
() 90% 0.608 to 0.785 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | At screening, Day -2, Day -1, Day 1 (at pre-dose; 3 & 12 hours post-dose), Day 2 (24 hours post-dose), Day 3 and follow-up (7 to 10 days after dose) | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Standard adverse event collection. An adverse event is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product | |||||||||||||||||||
| Arm/Group Title | AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg | Prednisolone - 60 mg | Pooled Placebo | ||||||||||
| Arm/Group Description | In Cohort 1, participants received single dose of AZD8567 2 mg oral suspension in the fasted state | In Cohort 2, participants received single dose of AZD8567 10 mg oral suspension in the fasted state | In Cohort 3, participants received single dose of AZD8567 20 mg oral suspension in the fasted state | In Cohort 4, participants received single dose of AZD8567 40 mg oral suspension in the fasted state | In Cohort 5, participants received single dose of AZD8567 80 mg oral suspension in the fasted state | In Cohort 6, participants received single dose of AZD8567 100 mg oral suspension in the fasted state | In Cohort 7, participants received single dose of AZD8567 125 mg oral suspension in the fasted state | In Cohort 8, participants received single dose of AZD8567 155 mg oral suspension in the fasted state | In Cohort 9, participants received orally single dose of prednisolone 60 mg capsule in the fasted state | In Cohort 1-8, participants were randomized to AZD9567:placebo (6:2). In Cohort 9, participants were randomized to prednisolone:placebo (6:2) | ||||||||||
All Cause Mortality |
||||||||||||||||||||
| AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg | Prednisolone - 60 mg | Pooled Placebo | |||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||||||||
Serious Adverse Events |
||||||||||||||||||||
| AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg | Prednisolone - 60 mg | Pooled Placebo | |||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/18 (0%) | ||||||||||
Other (Not Including Serious) Adverse Events |
||||||||||||||||||||
| AZD9567 - 2 mg | AZD9567 - 10 mg | AZD9567 - 20 mg | AZD9567 - 40 mg | AZD9567 - 80 mg | AZD9567 - 100 mg | AZD9567 - 125 mg | AZD9567 - 155 mg | Prednisolone - 60 mg | Pooled Placebo | |||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/6 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/6 (0%) | 2/6 (33.3%) | 1/6 (16.7%) | 0/6 (0%) | 0/6 (0%) | 3/18 (16.7%) | ||||||||||
| Gastrointestinal disorders | ||||||||||||||||||||
| Nausea | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 1/18 (5.6%) | ||||||||||
| General disorders | ||||||||||||||||||||
| Chest pain | 0/6 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/18 (0%) | ||||||||||
| Feeling hot | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/18 (0%) | ||||||||||
| Vessel puncture site pain | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 1/18 (5.6%) | ||||||||||
| Infections and infestations | ||||||||||||||||||||
| Nasopharyngitis | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/18 (0%) | ||||||||||
| Oral herpes | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 1/18 (5.6%) | ||||||||||
| Nervous system disorders | ||||||||||||||||||||
| Dizziness | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/18 (0%) | ||||||||||
| Skin and subcutaneous tissue disorders | ||||||||||||||||||||
| Hyperhidrosis | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 1/18 (5.6%) | ||||||||||
| Vascular disorders | ||||||||||||||||||||
| Hot flush | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/6 (0%) | 0/18 (0%) | ||||||||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
All clinical study findings and documents will be regarded as confidential. The investigator and members of his/her research team must not disclose such information without prior written approval from the sponsor.
Results Point of Contact
| Name/Title | Global Clinical Leader |
|---|---|
| Organization | AstraZeneca AB |
| Phone | +46 766 346712 |
| clinicaltrialtransparency@astrazeneca.com |
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02512575
Other Study ID Numbers:
- D6470C00001
- 2015-002002-37
First Posted:
Jul 31, 2015
Last Update Posted:
Oct 4, 2018
Last Verified:
Sep 1, 2018