治験レーダー

Change From Baseline in Glucose Area Under the Plasma Concentration Versus Time Curve From Zero to 4 Hours Post-dose AUC(0-4)

The change from baseline in glucose AUC(0-4) was analysed to determine the Pharmacodynamic (PD) effect of AZD9567 compared to Prednisolone following a standardised Mixed meal tolerance test (MMTT). In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Days -1 (baseline), and Days 4 (Treatment period 1 and 2)

Mean Glucose Level as Determined Via the Continuous Glucose Monitoring (CGM) System

The mean glucose levels in mmol/L at 48-72 h was analysed to determine the effect of AZD9567 on CGM compared to prednisolone. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

48 to 72 hours

Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing

The mean glucose level in mmol/L was analysed to determine the effect of AZD9567 on CGM compared to prednisolone. For the calculation of the rise in mean glucose levels, the baseline was the average of the values from -24 hours to first dosing on Day 1 of each period. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

Baseline and up to 72 hours (Treatment period 1 and 2)

Change From Baseline in Fasting Glucose

Pharmacodynamic effects (fasting glucose) of AZD9567 following a MMTT were evaluated as compared to prednisolone. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Insulin)

Effects of AZD9567 on insulin AUC(0-4) were assessed following MMTT compared to prednisolone. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon)

Effects of AZD9567 on glucagon AUC(0-4) were assessed following MMTT in comparison to prednisolone. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon-like Peptide-1 [GLP-1])

Effects of AZD9567 on GLP-1 AUC(0-4) were assessed following MMTT in comparison to prednisolone. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucose-dependent Insulin Releasing Polypeptide [GIP])

Effects of AZD9567 on GIP AUC(0-4) were assessed following MMTT in comparison to prednisolone. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline in AUC(0-4) on C-peptide

Effects of AZD9567 on C-peptide AUC(0-4) were assessed through a MMTT in comparison to prednisolone. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline in Ratio of Insulin to Glucose Level Between 10 and 0 Minutes (ΔI10/ΔG10)

Effects of AZD9567 on ΔI10/ΔG10 of beta cell function from the MMTT compared to Prednisolone was evaluated. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline in Ratio of Insulin to Glucose Level Between 30 and 0 Minutes [ΔI30/ΔG30])

Effects of AZD9567 on ΔI30/ΔG30 of beta cell function from the MMTT compared to Prednisolone was evaluated. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline in Ratio of C-peptide to Glucose Level Between 10 and 0 Minutes (ΔC10/ΔG10)

Effects of AZD9567 on ΔC10/ΔG10 of beta cell function from the MMTT compared to Prednisolone was evaluated. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline in Ratio of C-peptide to Glucose Level Between 30 and 0 Minutes (ΔC30/ΔG30)

Effects of AZD9567 on ΔC30/ΔG30 of beta cell function from the MMTT compared to Prednisolone was evaluated. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline in 24-hour Urinary Potassium Excretion

The concentration of potassium in urine was measured over 24 hours to determine the effect of AZD9567 on urinary potassium (U-K) excretion compared to prednisolone. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline in 24-hour Urinary Sodium Excretion

The concentration of sodium in urine was measured over 24 hours to determine the effect of AZD9567 on urinary-sodium (U-Na) excretion compared to prednisolone. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Quantifiable Concentration (AUClast)

AUClast of AZD9567 following once daily dosing was evaluated.

Upto 30 hours post dose (Treatment period 1 and 2)

Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours Post-dose [AUC(0-24)]

AUC(0-24) of AZD9567 following once daily dosing was evaluated.

24 hours post dose

Area Under the Plasma Concentration Versus Time Curve From Zero to 6 Hours Post-dose [AUC(0-6)]

AUC(0-6) of AZD9567 following once daily dosing was evaluated.

6 hours post dose

Maximum Observed Drug Concentration (Cmax)

Cmax of AZD9567 following once daily dosing was evaluated.

Upto 30 hours post dose (Treatment period 1 and 2)

Time to Reach Maximum Observed Drug Concentration (Tmax)

Tmax of AZD9567 following once daily dosing was evaluated.

Upto 30 hours post dose (Treatment period 1 and 2)

Terminal Elimination Half-life (t½λz)

t½λz of AZD9567 following once daily dosing was evaluated.

Upto 30 hours post dose (Treatment period 1 and 2)

Apparent Total Body Clearance of Drug From Plasma After Extravascular (CL/F)

CL/F of AZD9567 following once daily dosing was evaluated.

Upto 30 hours post dose (Treatment period 1 and 2)

Apparent Volume of Distribution Following Extravascular Administration (Vz/F)

Vz/F of AZD9567 was derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara).

Upto 30 hours post dose (Treatment period 1 and 2)

Tumour Necrosis Factor Alpha (TNFα) Concentrations

Relationship between AZD9567 exposure and inhibition of LPS-stimulated TNFα release for high and low dose comparison (Cohort 1 and Cohort 2) was assessed. LPS-stimulated TNFα concentration was measured.

On Days 3 (Treatment period 1 and 2)

Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Free Fatty Acids)

Effects of AZD9567 on free fatty acids were evaluated following a MMTT compared to prednisolone. In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline in Homeostatic Model Assessment- Insulin Resistance (HOMA-IR)

The HOMA-IR was calculated based on glucose and insulin measured prior to MMTT. HOMA-IR= Glucose(mmol/L) x Insulin (mU/L) / 22.5 HOMA-IR score estimates the degree of insulin resistance. Higher range indicates greater insulin resistance (i.e. high diabetes risk), while lower range indicates insulin sensitivity (i.e. low diabetes risk) In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Change From Baseline in HOMA-insulin Sensitivity (HOMA-S)

Insulin sensitivity is a term used to indicate the responsiveness of the peripheral tissue cells to insulin, and their resultant capacity to uptake glucose out of the bloodstream. HOMA-S score estimates the degree of insulin sensitivity. HOMA-S was calculated as the reciprocal of HOMA-IR. Higher values indicates greater insulin sensitivity (i.e. low diabetes risk), while lower values indicates insulin resistance (i.e. high diabetes risk) In Cohort 1 and 2, Placebo was not administered, therefore in Placebo row the participants analyzed is kept as 0. In Cohort 3, AZD9567 was not administered, therefore in AZD9567 row the participants analyzed is kept 0.

On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)

Number of Participants With Adverse Events

Safety and tolerability of AZD9567 was assessed.

From screening up to 79 days