Diabetes Mellitus, Type 2
Conditions
Keywords
Type 2 Diabetes Mellitus, Glucose Homeostasis, Pharmacodynamic, AZD9567, Prednisolone
Brief summary
The study is intended to assess the effect on glycaemic control of AZD9567, as measured by the glucose AUC(0-4) versus baseline following a standardised mixed meal tolerance test (MMTT), compared to prednisolone in adults with type 2 diabetes mellitus (T2DM). The study will also evaluate the safety, tolerability, and pharmacokinetics (PK) of AZD9567.
Detailed description
This is a randomised, double blind, multi-centre, double dummy, and two-way cross-over study. There will be a total of three cohorts. Each cohort will be treated for two 72-hour periods in a cross-over design, with a 3-week washout period between treatment periods. The total length of participant engagement (from screening to follow-up) is 79 days.
Interventions
DRUGAZD9567
Participants will receive 72 mg/day (oral suspension) of AZD9567 for 3 consecutive days of each treatment period in Cohort 1 and 40 mg/day for 3 consecutive days of each treatment period in Cohort 2.
DRUGPrednisolone
Participants will receive 40 mg/day of prednisolone for 3 consecutive days of each treatment period in Cohort 1, 20 mg/day of prednisolone for 3 consecutive days of each treatment period in Cohort 2, and 5 mg/day prednisolone for 3 consecutive days of each treatment period in Cohort 3.
OTHERPlacebo
Participants will receive placebo for 3 consecutive days of each treatment period in Cohort 3.
Sponsors
Parexel
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Both participants and investigators will be blinded. Investigators will remain blinded to each participant's assigned study intervention throughout the course of the study. In order to maintain this blind, a third party will be responsible for the reconstitution and dispensation of all study interventions.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Participants with diagnosis of T2DM for 6 months prior to screening: HbA1c in the diabetes range or fasting plasma glucose 126 -220 mg/dL. * On stable metformin therapy for at least 4 weeks, where no significant dose change (increase or decrease ≥ 500 mg/day) has occurred prior to screening and HbA1c 6% - 9.5%, or on dual therapy with metformin in combination with SGLT2i or DPP4i and HbA1c 6% - 8%. Participants on dual therapy will require 2 weeks wash-out of SGLT2i or DPP4i. * Venous access suitable for multiple cannulations * Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. * Female participants must be not lactating and not of childbearing potential. * If sexually active, nonsterilized males who have a female partner of childbearing potential must practice effective contraceptive measures. * Capable of giving signed informed consent. * Provision of informed consent prior to any study specific procedures.
Exclusion criteria
* History or presence of type 1 diabetes. * History of severe hypoglycaemia or hypoglycaemia unawareness within the last 6 months. * History or presence of diabetic foot ulcers * Participants with advanced diabetic complications. * History of clinically significant lactic acidosis or ketoacidosis following diagnosis with T2DM. * History of, or known significant infection or positivity at Visit 1, including hepatitis A, B, or C, HIV, tuberculosis that may put the participant at risk during participation in the study. * History and / or presence of COVID-19. * Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before Visit 1. * History of or current alcohol or drug abuse (including marijuana), as judged by the investigator. * Previous psychiatric disorders. * Any latent, acute, or chronic infections or at risk of infection, or history of skin abscesses within 90 days prior to the first administration of investigational medicinal product (IMP) at the discretion of the investigator. * History of adrenal insufficiency. * History or current inflammatory disorder. * Any other condition that, in the opinion of the investigator, would interfere with evaluations of the IMP or interpretation of participant safety or study results. * History of severe allergy/hypersensitivity to AZD9567 or any of the excipients of the product, or ongoing clinically important allergy/hypersensitivity as judged by the investigator. * Oral or parenteral steroids 8 weeks prior to randomisation and during the study. Topical and inhaled steroids 4 weeks prior to randomisation are acceptable. * Use of any prohibited medication during the study or if the required washout time of such medication was not adhered to. * Receipt of live or live attenuated vaccine within 4 weeks prior to the first administration of IMP. * Planned in-patient surgery, major dental procedure, or hospitalisation during the study. * Previous participation or participation in any other research study within 1 month prior to Visit 1. * Patient treated with any investigational drug within 30 days (or 5 half-lives, whichever is longer) prior to Visit 1. * Uncontrolled hypertension (BP \> 160 mmHg systolic or \> 95 mmHg diastolic). * Diagnosis of heart failure and current symptoms regardless of definition, ie, HfpEF, HfrEF. * Acute coronary syndrome / unstable angina, coronary intervention procedures (percutaneous coronary intervention or coronary artery bypass graft) within the past 6 months. * Stroke within the past 3 months. * QTcF \> 470 ms or family history of long QT-syndrome. * AV-block II-III or sinus node dysfunction with significant pause, not treated with pacemaker.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glucose Area Under the Plasma Concentration Versus Time Curve From Zero to 4 Hours Post-dose AUC(0-4) | On Days -1 (baseline), and Days 4 (Treatment period 1 and 2) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours Post-dose [AUC(0-24)] | 24 hours post dose | AUC(0-24) of AZD9567 following once daily dosing was evaluated. |
| Area Under the Plasma Concentration Versus Time Curve From Zero to 6 Hours Post-dose [AUC(0-6)] | 6 hours post dose | AUC(0-6) of AZD9567 following once daily dosing was evaluated. |
| Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Baseline and up to 72 hours (Treatment period 1 and 2) | 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. |
| Change From Baseline in Fasting Glucose | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Insulin) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon-like Peptide-1 [GLP-1]) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Maximum Observed Drug Concentration (Cmax) | Upto 30 hours post dose (Treatment period 1 and 2) | Cmax of AZD9567 following once daily dosing was evaluated. |
| Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucose-dependent Insulin Releasing Polypeptide [GIP]) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Change From Baseline in AUC(0-4) on C-peptide | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Change From Baseline in Ratio of Insulin to Glucose Level Between 10 and 0 Minutes (ΔI10/ΔG10) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Change From Baseline in Ratio of Insulin to Glucose Level Between 30 and 0 Minutes [ΔI30/ΔG30]) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Change From Baseline in Ratio of C-peptide to Glucose Level Between 10 and 0 Minutes (ΔC10/ΔG10) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Mean Glucose Level as Determined Via the Continuous Glucose Monitoring (CGM) System | 48 to 72 hours | 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. |
| Change From Baseline in 24-hour Urinary Potassium Excretion | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Change From Baseline in 24-hour Urinary Sodium Excretion | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Quantifiable Concentration (AUClast) | Upto 30 hours post dose (Treatment period 1 and 2) | AUClast of AZD9567 following once daily dosing was evaluated. |
| Time to Reach Maximum Observed Drug Concentration (Tmax) | Upto 30 hours post dose (Treatment period 1 and 2) | Tmax of AZD9567 following once daily dosing was evaluated. |
| Terminal Elimination Half-life (t½λz) | Upto 30 hours post dose (Treatment period 1 and 2) | t½λz of AZD9567 following once daily dosing was evaluated. |
| Apparent Total Body Clearance of Drug From Plasma After Extravascular (CL/F) | Upto 30 hours post dose (Treatment period 1 and 2) | CL/F of AZD9567 following once daily dosing was evaluated. |
| Apparent Volume of Distribution Following Extravascular Administration (Vz/F) | Upto 30 hours post dose (Treatment period 1 and 2) | Vz/F of AZD9567 was derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara). |
| Tumour Necrosis Factor Alpha (TNFα) Concentrations | On Days 3 (Treatment period 1 and 2) | 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. |
| Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Free Fatty Acids) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Change From Baseline in Homeostatic Model Assessment- Insulin Resistance (HOMA-IR) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Change From Baseline in HOMA-insulin Sensitivity (HOMA-S) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
| Number of Participants With Adverse Events | From screening up to 79 days | Safety and tolerability of AZD9567 was assessed. |
| Change From Baseline in Ratio of C-peptide to Glucose Level Between 30 and 0 Minutes (ΔC30/ΔG30) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) | 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. |
Countries
Germany
Participant flow
Recruitment details
This study was conducted in Germany between 26 November 2020 and 09 June 2021.
Pre-assignment details
Patients with type 2 diabetes mellitus who met all the eligibility criteria were randomised in a ratio of 1:1 to a cohort and sequence group. Each cohort was treated for two 72 hour periods in a cross-over design, with a 3-week washout period between treatment periods.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Patients were randomised in a ratio of 1:1 to receive 72 mg AZD9567 followed by 40 mg prednisolone or 40 mg prednisolone followed by 72 mg AZD9567 | 27 |
| Cohort 2 Patients were randomised in a ratio of 1:1 to receive 40 mg AZD9567 followed by 20 mg prednisolone or 20 mg prednisolone followed by 40 mg AZD9567 | 8 |
| Cohort 3 Patients were randomised in a ratio of 1:1 to receive placebo followed by 5 mg prednisolone or 5 mg prednisolone followed by placebo | 9 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 (72 Hours) | Positive SARS-CoV-2 rapid test for patient's daughter | 0 | 0 | 0 | 1 | 0 | 0 |
| Treatment Period 1 (72 Hours) | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| Age, Continuous | 67.3 Years STANDARD_DEVIATION 6.41 | 64.4 Years STANDARD_DEVIATION 9.32 | 66.6 Years STANDARD_DEVIATION 5.36 | 66.6 Years STANDARD_DEVIATION 6.75 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 8 Participants | 9 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 7 Participants | 9 Participants | 42 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Male | 23 Participants | 6 Participants | 8 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 27 | 0 / 8 | 0 / 8 | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 4 / 27 | 7 / 27 | 2 / 8 | 5 / 8 | 1 / 9 | 0 / 9 |
| serious Total, serious adverse events | 0 / 27 | 0 / 27 | 0 / 8 | 0 / 8 | 0 / 9 | 0 / 9 |
Outcome results
Primary
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.
Time frame: On Days -1 (baseline), and Days 4 (Treatment period 1 and 2)
Population: Full Analysis Set (FAS) consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Glucose Area Under the Plasma Concentration Versus Time Curve From Zero to 4 Hours Post-dose AUC(0-4) | AZD9567 | -190.0296 minute*millimole/liter (min*mmol/L) | Standard Error 63.8805 |
| Cohort 1 | Change From Baseline in Glucose Area Under the Plasma Concentration Versus Time Curve From Zero to 4 Hours Post-dose AUC(0-4) | Prednisolone | -57.0768 minute*millimole/liter (min*mmol/L) | Standard Error 63.8762 |
| Cohort 2 | Change From Baseline in Glucose Area Under the Plasma Concentration Versus Time Curve From Zero to 4 Hours Post-dose AUC(0-4) | AZD9567 | -182.7172 minute*millimole/liter (min*mmol/L) | Standard Error 149.86 |
| Cohort 2 | Change From Baseline in Glucose Area Under the Plasma Concentration Versus Time Curve From Zero to 4 Hours Post-dose AUC(0-4) | Prednisolone | -40.6842 minute*millimole/liter (min*mmol/L) | Standard Error 141.7154 |
| Cohort 3 | Change From Baseline in Glucose Area Under the Plasma Concentration Versus Time Curve From Zero to 4 Hours Post-dose AUC(0-4) | Prednisolone | -184.9677 minute*millimole/liter (min*mmol/L) | Standard Error 88.9807 |
| Cohort 3 | Change From Baseline in Glucose Area Under the Plasma Concentration Versus Time Curve From Zero to 4 Hours Post-dose AUC(0-4) | Placebo | -311.8506 minute*millimole/liter (min*mmol/L) | Standard Error 88.5443 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.03695% CI: [-256.5082, -9.3973]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.43295% CI: [-554.8722, 270.8061]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.0395% CI: [-236.0426, -17.7233]Mixed Models Analysis
Secondary
Apparent Total Body Clearance of Drug From Plasma After Extravascular (CL/F)
CL/F of AZD9567 following once daily dosing was evaluated.
Time frame: Upto 30 hours post dose (Treatment period 1 and 2)
Population: PKAS consisted of all patients in the FAS with at least 1 quantifiable AZD9567 concentration and no important protocol deviations, or AEs considered to have an effect upon PK.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Apparent Total Body Clearance of Drug From Plasma After Extravascular (CL/F) | 4.766 Liter/hour (L/h) | Standard Deviation 1.896 |
| Cohort 2 | Apparent Total Body Clearance of Drug From Plasma After Extravascular (CL/F) | 4.924 Liter/hour (L/h) | Standard Deviation 2.098 |
Secondary
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).
Time frame: Upto 30 hours post dose (Treatment period 1 and 2)
Population: PKAS consisted of all patients in the FAS with at least 1 quantifiable AZD9567 concentration and no important protocol deviations, or AEs considered to have an effect upon PK.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Apparent Volume of Distribution Following Extravascular Administration (Vz/F) | 45.11 Liter | Standard Deviation 11.39 |
| Cohort 2 | Apparent Volume of Distribution Following Extravascular Administration (Vz/F) | 41.75 Liter | Standard Deviation 14.19 |
Secondary
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.
Time frame: 24 hours post dose
Population: PKAS consisted of all patients in the FAS with at least 1 quantifiable AZD9567 concentration and no important protocol deviations, or AEs considered to have an effect upon PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours Post-dose [AUC(0-24)] | 32920 h*nmol/L | Geometric Coefficient of Variation 41.32 |
| Cohort 2 | Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours Post-dose [AUC(0-24)] | 17790 h*nmol/L | Geometric Coefficient of Variation 44.86 |
Secondary
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.
Time frame: 6 hours post dose
Population: PKAS consisted of all patients in the FAS with at least 1 quantifiable AZD9567 concentration and no important protocol deviations, or AEs considered to have an effect upon PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Area Under the Plasma Concentration Versus Time Curve From Zero to 6 Hours Post-dose [AUC(0-6)] | 17050 h*nmol/L | Geometric Coefficient of Variation 30.45 |
| Cohort 2 | Area Under the Plasma Concentration Versus Time Curve From Zero to 6 Hours Post-dose [AUC(0-6)] | 9914 h*nmol/L | Geometric Coefficient of Variation 35.06 |
Secondary
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.
Time frame: Upto 30 hours post dose (Treatment period 1 and 2)
Population: Pharmacokinetic analysis set (PKAS) consisted of all patients in the FAS with at least 1 quantifiable AZD9567 concentration and no important protocol deviations, or adverse events (AEs) considered to have an effect upon PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Quantifiable Concentration (AUClast) | 34400 hour*nanomole/liter (h*nmol/L) | Geometric Coefficient of Variation 42.97 |
| Cohort 2 | Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Quantifiable Concentration (AUClast) | 18410 hour*nanomole/liter (h*nmol/L) | Geometric Coefficient of Variation 46.06 |
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Free Fatty Acids) | AZD9567 | -18.1304 min*mmol/L | Standard Error 1.7543 |
| Cohort 1 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Free Fatty Acids) | Prednisolone | -14.1238 min*mmol/L | Standard Error 1.7542 |
| Cohort 2 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Free Fatty Acids) | AZD9567 | -14.0582 min*mmol/L | Standard Error 3.7038 |
| Cohort 2 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Free Fatty Acids) | Prednisolone | -19.8117 min*mmol/L | Standard Error 3.706 |
| Cohort 3 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Free Fatty Acids) | Prednisolone | -4.1625 min*mmol/L | Standard Error 3.7212 |
| Cohort 3 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Free Fatty Acids) | Placebo | 4.8995 min*mmol/L | Standard Error 3.7153 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.10395% CI: [-8.888, 0.8748]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.00595% CI: [2.6034, 8.9036]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.02395% CI: [1.674, 16.4499]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon) | AZD9567 | -36.9846 min*pmol/L | Standard Error 216.5777 |
| Cohort 1 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon) | Prednisolone | 965.6018 min*pmol/L | Standard Error 216.6054 |
| Cohort 2 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon) | AZD9567 | 552.0634 min*pmol/L | Standard Error 213.93 |
| Cohort 2 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon) | Prednisolone | 511.0798 min*pmol/L | Standard Error 213.597 |
| Cohort 3 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon) | Prednisolone | 259.9835 min*pmol/L | Standard Error 298.9801 |
| Cohort 3 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon) | Placebo | 361.3971 min*pmol/L | Standard Error 348.5104 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.00395% CI: [-1620.215, -384.9577]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.86595% CI: [-526.6968, 608.664]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.75495% CI: [-628.8097, 831.637]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon-like Peptide-1 [GLP-1]) | Prednisolone | 1841.8853 min*pmol/L | Standard Error 328.8877 |
| Cohort 1 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon-like Peptide-1 [GLP-1]) | AZD9567 | 615.9803 min*pmol/L | Standard Error 328.8418 |
| Cohort 2 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon-like Peptide-1 [GLP-1]) | AZD9567 | 322.5690 min*pmol/L | Standard Error 454.2028 |
| Cohort 2 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon-like Peptide-1 [GLP-1]) | Prednisolone | 789.5492 min*pmol/L | Standard Error 450.2548 |
| Cohort 3 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon-like Peptide-1 [GLP-1]) | Prednisolone | 575.6726 min*pmol/L | Standard Error 318.1088 |
| Cohort 3 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon-like Peptide-1 [GLP-1]) | Placebo | 200.3565 min*pmol/L | Standard Error 317.6326 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.00495% CI: [-2007.2241, -444.5859]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.31395% CI: [-1521.5088, 587.5485]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.40495% CI: [-1433.6265, 682.9943]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucose-dependent Insulin Releasing Polypeptide [GIP]) | AZD9567 | 3658.9885 min*pmol/L | Standard Error 584.5079 |
| Cohort 1 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucose-dependent Insulin Releasing Polypeptide [GIP]) | Prednisolone | 3293.3563 min*pmol/L | Standard Error 596.7472 |
| Cohort 2 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucose-dependent Insulin Releasing Polypeptide [GIP]) | AZD9567 | 3842.9307 min*pmol/L | Standard Error 1303.1553 |
| Cohort 2 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucose-dependent Insulin Releasing Polypeptide [GIP]) | Prednisolone | 3654.6947 min*pmol/L | Standard Error 1289.5516 |
| Cohort 3 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucose-dependent Insulin Releasing Polypeptide [GIP]) | Prednisolone | 3271.5164 min*pmol/L | Standard Error 823.9967 |
| Cohort 3 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucose-dependent Insulin Releasing Polypeptide [GIP]) | Placebo | 2210.0670 min*pmol/L | Standard Error 827.7335 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.60895% CI: [-1097.7973, 1829.0618]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.89795% CI: [-3214.3323, 3590.8043]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.38195% CI: [-3588.2233, 1465.3244]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Insulin) | AZD9567 | 15319.3857 minute*picomole/liter (min*pmole/L) | Standard Error 4165.9135 |
| Cohort 1 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Insulin) | Prednisolone | -5179.3659 minute*picomole/liter (min*pmole/L) | Standard Error 3989.2683 |
| Cohort 2 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Insulin) | AZD9567 | 13413.1929 minute*picomole/liter (min*pmole/L) | Standard Error 4791.9873 |
| Cohort 2 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Insulin) | Prednisolone | 10091.7869 minute*picomole/liter (min*pmole/L) | Standard Error 5461.2631 |
| Cohort 3 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Insulin) | Prednisolone | 4915.4115 minute*picomole/liter (min*pmole/L) | Standard Error 7049.546 |
| Cohort 3 | Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Insulin) | Placebo | 2216.5532 minute*picomole/liter (min*pmole/L) | Standard Error 7049.0432 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: <0.00195% CI: [10819.2, 30178.2]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.65995% CI: [-12975.8, 19618.6]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.52195% CI: [-14849, 9451.3]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in 24-hour Urinary Potassium Excretion | AZD9567 | -2.92 mmol/day | Standard Error 3.27 |
| Cohort 1 | Change From Baseline in 24-hour Urinary Potassium Excretion | Prednisolone | -1.19 mmol/day | Standard Error 3.27 |
| Cohort 2 | Change From Baseline in 24-hour Urinary Potassium Excretion | AZD9567 | -6.05 mmol/day | Standard Error 4.3 |
| Cohort 2 | Change From Baseline in 24-hour Urinary Potassium Excretion | Prednisolone | 4.92 mmol/day | Standard Error 4.29 |
| Cohort 3 | Change From Baseline in 24-hour Urinary Potassium Excretion | Prednisolone | -2.49 mmol/day | Standard Error 9.08 |
| Cohort 3 | Change From Baseline in 24-hour Urinary Potassium Excretion | Placebo | -2.85 mmol/day | Standard Error 9.07 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.64695% CI: [-9.4, 5.95]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.1195% CI: [-25.39, 3.44]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.93295% CI: [-10.32, 9.61]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in 24-hour Urinary Sodium Excretion | AZD9567 | 17.4 mmol/day | Standard Error 11 |
| Cohort 1 | Change From Baseline in 24-hour Urinary Sodium Excretion | Prednisolone | 9.7 mmol/day | Standard Error 11 |
| Cohort 2 | Change From Baseline in 24-hour Urinary Sodium Excretion | AZD9567 | 39.9 mmol/day | Standard Error 20.4 |
| Cohort 2 | Change From Baseline in 24-hour Urinary Sodium Excretion | Prednisolone | 17.6 mmol/day | Standard Error 20.3 |
| Cohort 3 | Change From Baseline in 24-hour Urinary Sodium Excretion | Prednisolone | -18.1 mmol/day | Standard Error 21.4 |
| Cohort 3 | Change From Baseline in 24-hour Urinary Sodium Excretion | Placebo | 12.9 mmol/day | Standard Error 21.3 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.53395% CI: [-17.4, 32.7]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.31195% CI: [-26.7, 71.3]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.20495% CI: [-21.9, 83.9]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in AUC(0-4) on C-peptide | AZD9567 | 85.3305 minute*nanomole/L (min*nmol/L) | Standard Error 13.4279 |
| Cohort 1 | Change From Baseline in AUC(0-4) on C-peptide | Prednisolone | 24.9094 minute*nanomole/L (min*nmol/L) | Standard Error 13.4282 |
| Cohort 2 | Change From Baseline in AUC(0-4) on C-peptide | AZD9567 | 82.1134 minute*nanomole/L (min*nmol/L) | Standard Error 22.9858 |
| Cohort 2 | Change From Baseline in AUC(0-4) on C-peptide | Prednisolone | 55.6606 minute*nanomole/L (min*nmol/L) | Standard Error 22.6155 |
| Cohort 3 | Change From Baseline in AUC(0-4) on C-peptide | Prednisolone | 24.7245 minute*nanomole/L (min*nmol/L) | Standard Error 22.2183 |
| Cohort 3 | Change From Baseline in AUC(0-4) on C-peptide | Placebo | 0.7002 minute*nanomole/L (min*nmol/L) | Standard Error 22.0424 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: <0.00195% CI: [29.4904, 91.3518]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.43295% CI: [-44.9414, 97.8471]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.28295% CI: [-74.0731, 26.0245]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Fasting Glucose | AZD9567 | -1.14 mmol/L | Standard Error 0.17 |
| Cohort 1 | Change From Baseline in Fasting Glucose | Prednisolone | -1.06 mmol/L | Standard Error 0.17 |
| Cohort 2 | Change From Baseline in Fasting Glucose | AZD9567 | -0.95 mmol/L | Standard Error 0.36 |
| Cohort 2 | Change From Baseline in Fasting Glucose | Prednisolone | -0.91 mmol/L | Standard Error 0.35 |
| Cohort 3 | Change From Baseline in Fasting Glucose | Prednisolone | -1.15 mmol/L | Standard Error 0.2 |
| Cohort 3 | Change From Baseline in Fasting Glucose | Placebo | -1.15 mmol/L | Standard Error 0.2 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.75395% CI: [-0.55, 0.4]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.80295% CI: [-0.46, 0.37]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.98595% CI: [-0.37, 0.37]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in HOMA-insulin Sensitivity (HOMA-S) | AZD9567 | 0.0134 Score | Standard Deviation 0.2352 |
| Cohort 1 | Change From Baseline in HOMA-insulin Sensitivity (HOMA-S) | Prednisolone | 0.0328 Score | Standard Deviation 0.14 |
| Cohort 2 | Change From Baseline in HOMA-insulin Sensitivity (HOMA-S) | AZD9567 | -0.0360 Score | Standard Deviation 0.199 |
| Cohort 2 | Change From Baseline in HOMA-insulin Sensitivity (HOMA-S) | Prednisolone | -0.0799 Score | Standard Deviation 0.2077 |
| Cohort 3 | Change From Baseline in HOMA-insulin Sensitivity (HOMA-S) | Prednisolone | 0.0750 Score | Standard Deviation 0.0949 |
| Cohort 3 | Change From Baseline in HOMA-insulin Sensitivity (HOMA-S) | Placebo | 0.1468 Score | Standard Deviation 0.093 |
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Homeostatic Model Assessment- Insulin Resistance (HOMA-IR) | AZD9567 | -0.4406 Score | Standard Deviation 1.9875 |
| Cohort 1 | Change From Baseline in Homeostatic Model Assessment- Insulin Resistance (HOMA-IR) | Prednisolone | -0.7023 Score | Standard Deviation 1.5896 |
| Cohort 2 | Change From Baseline in Homeostatic Model Assessment- Insulin Resistance (HOMA-IR) | AZD9567 | -0.1738 Score | Standard Deviation 0.7576 |
| Cohort 2 | Change From Baseline in Homeostatic Model Assessment- Insulin Resistance (HOMA-IR) | Prednisolone | 0.0721 Score | Standard Deviation 0.9606 |
| Cohort 3 | Change From Baseline in Homeostatic Model Assessment- Insulin Resistance (HOMA-IR) | Prednisolone | -0.5662 Score | Standard Deviation 0.7364 |
| Cohort 3 | Change From Baseline in Homeostatic Model Assessment- Insulin Resistance (HOMA-IR) | Placebo | -0.9280 Score | Standard Deviation 0.8173 |
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 10 and 0 Minutes (ΔC10/ΔG10) | AZD9567 | -0.0004 Ratio | Standard Error 0.0095 |
| Cohort 1 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 10 and 0 Minutes (ΔC10/ΔG10) | Prednisolone | -0.0103 Ratio | Standard Error 0.0092 |
| Cohort 2 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 10 and 0 Minutes (ΔC10/ΔG10) | AZD9567 | 0.0059 Ratio | Standard Error 0.0041 |
| Cohort 2 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 10 and 0 Minutes (ΔC10/ΔG10) | Prednisolone | 0.0026 Ratio | Standard Error 0.0047 |
| Cohort 3 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 10 and 0 Minutes (ΔC10/ΔG10) | Prednisolone | -0.0033 Ratio | Standard Error 0.0064 |
| Cohort 3 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 10 and 0 Minutes (ΔC10/ΔG10) | Placebo | -0.0024 Ratio | Standard Error 0.0057 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.22695% CI: [-0.0072, 0.0271]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.61995% CI: [-0.0128, 0.0195]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.91795% CI: [-0.0189, 0.0207]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 30 and 0 Minutes (ΔC30/ΔG30) | AZD9567 | 0.0012 Ratio | Standard Error 0.0005 |
| Cohort 1 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 30 and 0 Minutes (ΔC30/ΔG30) | Prednisolone | 0.0005 Ratio | Standard Error 0.0005 |
| Cohort 2 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 30 and 0 Minutes (ΔC30/ΔG30) | AZD9567 | 0.0007 Ratio | Standard Error 0.0005 |
| Cohort 2 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 30 and 0 Minutes (ΔC30/ΔG30) | Prednisolone | 0.0004 Ratio | Standard Error 0.0005 |
| Cohort 3 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 30 and 0 Minutes (ΔC30/ΔG30) | Prednisolone | -0.0010 Ratio | Standard Error 0.0005 |
| Cohort 3 | Change From Baseline in Ratio of C-peptide to Glucose Level Between 30 and 0 Minutes (ΔC30/ΔG30) | Placebo | 0.0002 Ratio | Standard Error 0.0005 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.35795% CI: [-0.0008, 0.0022]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: 0.67695% CI: [-0.0012, 0.0017]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.09695% CI: [-0.0002, 0.0026]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Ratio of Insulin to Glucose Level Between 10 and 0 Minutes (ΔI10/ΔG10) | AZD9567 | -0.5249 Ratio | Standard Error 0.6632 |
| Cohort 1 | Change From Baseline in Ratio of Insulin to Glucose Level Between 10 and 0 Minutes (ΔI10/ΔG10) | Prednisolone | 0.0774 Ratio | Standard Error 0.6674 |
| Cohort 2 | Change From Baseline in Ratio of Insulin to Glucose Level Between 10 and 0 Minutes (ΔI10/ΔG10) | AZD9567 | NA Ratio | — |
| Cohort 2 | Change From Baseline in Ratio of Insulin to Glucose Level Between 10 and 0 Minutes (ΔI10/ΔG10) | Prednisolone | NA Ratio | — |
| Cohort 3 | Change From Baseline in Ratio of Insulin to Glucose Level Between 10 and 0 Minutes (ΔI10/ΔG10) | Prednisolone | -0.8153 Ratio | Standard Error 0.8305 |
| Cohort 3 | Change From Baseline in Ratio of Insulin to Glucose Level Between 10 and 0 Minutes (ΔI10/ΔG10) | Placebo | -0.3532 Ratio | Standard Error 0.6893 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.53195% CI: [-2.5463, 1.3416]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.68295% CI: [-2.0933, 3.0176]Mixed Models Analysis
Secondary
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.
Time frame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Ratio of Insulin to Glucose Level Between 30 and 0 Minutes [ΔI30/ΔG30]) | AZD9567 | 0.1203 Ratio | Standard Error 0.0726 |
| Cohort 1 | Change From Baseline in Ratio of Insulin to Glucose Level Between 30 and 0 Minutes [ΔI30/ΔG30]) | Prednisolone | 0.0530 Ratio | Standard Error 0.0755 |
| Cohort 2 | Change From Baseline in Ratio of Insulin to Glucose Level Between 30 and 0 Minutes [ΔI30/ΔG30]) | AZD9567 | 0.1824 Ratio | Standard Error 0.0773 |
| Cohort 2 | Change From Baseline in Ratio of Insulin to Glucose Level Between 30 and 0 Minutes [ΔI30/ΔG30]) | Prednisolone | 0.0943 Ratio | Standard Error 0.1264 |
| Cohort 3 | Change From Baseline in Ratio of Insulin to Glucose Level Between 30 and 0 Minutes [ΔI30/ΔG30]) | Prednisolone | -0.1047 Ratio | Standard Error 0.0665 |
| Cohort 3 | Change From Baseline in Ratio of Insulin to Glucose Level Between 30 and 0 Minutes [ΔI30/ΔG30]) | Placebo | 0.0209 Ratio | Standard Error 0.0599 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: 0.52695% CI: [-0.152, 0.2866]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mgp-value: 0.56995% CI: [-0.2653, 0.4416]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.16695% CI: [-0.0677, 0.3191]Mixed Models Analysis
Secondary
Maximum Observed Drug Concentration (Cmax)
Cmax of AZD9567 following once daily dosing was evaluated.
Time frame: Upto 30 hours post dose (Treatment period 1 and 2)
Population: PKAS consisted of all patients in the FAS with at least 1 quantifiable AZD9567 concentration and no important protocol deviations, or AEs considered to have an effect upon PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Maximum Observed Drug Concentration (Cmax) | 4501 nmol/L | Geometric Coefficient of Variation 26.9 |
| Cohort 2 | Maximum Observed Drug Concentration (Cmax) | 2939 nmol/L | Geometric Coefficient of Variation 31.5 |
Secondary
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.
Time frame: 48 to 72 hours
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Mean Glucose Level as Determined Via the Continuous Glucose Monitoring (CGM) System | AZD9567 | 8.5730 millimole/liter (mmol/L) per day | Standard Error 0.3114 |
| Cohort 1 | Mean Glucose Level as Determined Via the Continuous Glucose Monitoring (CGM) System | Prednisolone | 10.0797 millimole/liter (mmol/L) per day | Standard Error 0.315 |
| Cohort 2 | Mean Glucose Level as Determined Via the Continuous Glucose Monitoring (CGM) System | AZD9567 | 7.7870 millimole/liter (mmol/L) per day | Standard Error 0.2517 |
| Cohort 2 | Mean Glucose Level as Determined Via the Continuous Glucose Monitoring (CGM) System | Prednisolone | 8.8969 millimole/liter (mmol/L) per day | Standard Error 0.2494 |
| Cohort 3 | Mean Glucose Level as Determined Via the Continuous Glucose Monitoring (CGM) System | Prednisolone | 7.4238 millimole/liter (mmol/L) per day | Standard Error 0.2889 |
| Cohort 3 | Mean Glucose Level as Determined Via the Continuous Glucose Monitoring (CGM) System | Placebo | 7.2638 millimole/liter (mmol/L) per day | Standard Error 0.2888 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg)p-value: <0.00195% CI: [-2.082, -0.9314]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg)p-value: <0.00195% CI: [-1.7257, -0.4941]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg)p-value: 0.54795% CI: [-0.693, 0.3729]Mixed Models Analysis
Secondary
Number of Participants With Adverse Events
Safety and tolerability of AZD9567 was assessed.
Time frame: From screening up to 79 days
Population: Safety Analysis Set (SAF) consisted of all patients who were randomised to one of the 2 sequence groups within the cohort and have received at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Participants With Adverse Events | Any SAE (including events with outcome = death) | 0 Participants |
| Cohort 1 | Number of Participants With Adverse Events | Any AE leading to drug interruption | 0 Participants |
| Cohort 1 | Number of Participants With Adverse Events | Any AE with outcome = death | 0 Participants |
| Cohort 1 | Number of Participants With Adverse Events | Any Adverse Event (AE) | 4 Participants |
| Cohort 1 | Number of Participants With Adverse Events | Any AE leading to withdrawal from study | 0 Participants |
| Cohort 1 | Number of Participants With Adverse Events | Any AE leading to discontinuation of Investigational Product | 0 Participants |
| Cohort 2 | Number of Participants With Adverse Events | Any Adverse Event (AE) | 7 Participants |
| Cohort 2 | Number of Participants With Adverse Events | Any AE leading to discontinuation of Investigational Product | 0 Participants |
| Cohort 2 | Number of Participants With Adverse Events | Any AE leading to withdrawal from study | 0 Participants |
| Cohort 2 | Number of Participants With Adverse Events | Any AE leading to drug interruption | 0 Participants |
| Cohort 2 | Number of Participants With Adverse Events | Any AE with outcome = death | 0 Participants |
| Cohort 2 | Number of Participants With Adverse Events | Any SAE (including events with outcome = death) | 0 Participants |
| Cohort 3 | Number of Participants With Adverse Events | Any AE leading to withdrawal from study | 0 Participants |
| Cohort 3 | Number of Participants With Adverse Events | Any AE leading to drug interruption | 0 Participants |
| Cohort 3 | Number of Participants With Adverse Events | Any AE leading to discontinuation of Investigational Product | 0 Participants |
| Cohort 3 | Number of Participants With Adverse Events | Any Adverse Event (AE) | 2 Participants |
| Cohort 3 | Number of Participants With Adverse Events | Any SAE (including events with outcome = death) | 0 Participants |
| Cohort 3 | Number of Participants With Adverse Events | Any AE with outcome = death | 0 Participants |
| Cohort 2: Prednisolone 20mg | Number of Participants With Adverse Events | Any Adverse Event (AE) | 5 Participants |
| Cohort 2: Prednisolone 20mg | Number of Participants With Adverse Events | Any AE leading to withdrawal from study | 0 Participants |
| Cohort 2: Prednisolone 20mg | Number of Participants With Adverse Events | Any SAE (including events with outcome = death) | 0 Participants |
| Cohort 2: Prednisolone 20mg | Number of Participants With Adverse Events | Any AE with outcome = death | 0 Participants |
| Cohort 2: Prednisolone 20mg | Number of Participants With Adverse Events | Any AE leading to discontinuation of Investigational Product | 0 Participants |
| Cohort 2: Prednisolone 20mg | Number of Participants With Adverse Events | Any AE leading to drug interruption | 0 Participants |
| Cohort 3: Placebo | Number of Participants With Adverse Events | Any SAE (including events with outcome = death) | 0 Participants |
| Cohort 3: Placebo | Number of Participants With Adverse Events | Any AE with outcome = death | 0 Participants |
| Cohort 3: Placebo | Number of Participants With Adverse Events | Any Adverse Event (AE) | 1 Participants |
| Cohort 3: Placebo | Number of Participants With Adverse Events | Any AE leading to withdrawal from study | 0 Participants |
| Cohort 3: Placebo | Number of Participants With Adverse Events | Any AE leading to drug interruption | 0 Participants |
| Cohort 3: Placebo | Number of Participants With Adverse Events | Any AE leading to discontinuation of Investigational Product | 0 Participants |
| Cohort 3: Prednisolone 5mg | Number of Participants With Adverse Events | Any AE leading to withdrawal from study | 0 Participants |
| Cohort 3: Prednisolone 5mg | Number of Participants With Adverse Events | Any Adverse Event (AE) | 0 Participants |
| Cohort 3: Prednisolone 5mg | Number of Participants With Adverse Events | Any AE with outcome = death | 0 Participants |
| Cohort 3: Prednisolone 5mg | Number of Participants With Adverse Events | Any SAE (including events with outcome = death) | 0 Participants |
| Cohort 3: Prednisolone 5mg | Number of Participants With Adverse Events | Any AE leading to discontinuation of Investigational Product | 0 Participants |
| Cohort 3: Prednisolone 5mg | Number of Participants With Adverse Events | Any AE leading to drug interruption | 0 Participants |
Secondary
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.
Time frame: Baseline and up to 72 hours (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | AZD9567 (24 to 48 h) | 0.8011 mmol/L per day | Standard Error 0.2978 |
| Cohort 1 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Prednisolone (00 to 24 h) | 2.7086 mmol/L per day | Standard Error 0.2938 |
| Cohort 1 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Prednisolone (24 to 48 h) | 2.6653 mmol/L per day | Standard Error 0.3044 |
| Cohort 1 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | AZD9567 (00 to 24 hours [h]) | 1.2071 mmol/L per day | Standard Error 0.2869 |
| Cohort 1 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Prednisolone (48 to 72 h) | 2.4527 mmol/L per day | Standard Error 0.3274 |
| Cohort 1 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | AZD9567 (48 to 72 h) | 0.8529 mmol/L per day | Standard Error 0.321 |
| Cohort 2 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Prednisolone (24 to 48 h) | 1.3206 mmol/L per day | Standard Error 0.2448 |
| Cohort 2 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | AZD9567 (00 to 24 hours [h]) | 0.4070 mmol/L per day | Standard Error 0.2509 |
| Cohort 2 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Prednisolone (00 to 24 h) | 1.2545 mmol/L per day | Standard Error 0.246 |
| Cohort 2 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | AZD9567 (24 to 48 h) | 0.5428 mmol/L per day | Standard Error 0.2483 |
| Cohort 2 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | AZD9567 (48 to 72 h) | 0.0744 mmol/L per day | Standard Error 0.2714 |
| Cohort 2 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Prednisolone (48 to 72 h) | 1.2174 mmol/L per day | Standard Error 0.2664 |
| Cohort 3 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Placebo (00 to 24 h) | -0.0477 mmol/L per day | Standard Error 0.1547 |
| Cohort 3 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Prednisolone (48 to 72 h) | -0.2202 mmol/L per day | Standard Error 0.2229 |
| Cohort 3 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Prednisolone (00 to 24 h) | 0.3123 mmol/L per day | Standard Error 0.1549 |
| Cohort 3 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Placebo (48 to 72 h) | -0.3500 mmol/L per day | Standard Error 0.2224 |
| Cohort 3 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Prednisolone (24 to 48 h) | -0.2415 mmol/L per day | Standard Error 0.2898 |
| Cohort 3 | Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing | Placebo (24 to 48 h) | -0.3260 mmol/L per day | Standard Error 0.2894 |
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg \[00 to 24 h\])p-value: <0.00195% CI: [-2.2258, -0.7773]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg \[24 to 48 h\])p-value: <0.00195% CI: [-2.5611, -1.1674]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 72mg vs Prednisolone 40mg \[48 to 72 h\])p-value: <0.00195% CI: [-2.3025, -0.8971]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg \[00 to 24 h\])p-value: 0.01395% CI: [-1.4465, -0.2484]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg \[24 to 48 h\])p-value: 0.06195% CI: [-1.6022, 0.0466]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (AZD9567 40mg vs Prednisolone 20mg \[48 to 72 h\])p-value: 0.00395% CI: [-1.7622, -0.5238]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5 mg \[00 to 24 h\])p-value: 0.12595% CI: [-0.8338, 0.1138]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5 mg \[24 to 48 h\])p-value: 0.8495% CI: [-0.9706, 0.8016]Mixed Models Analysis
Comparison: Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5 mg \[48 to 72 h\])p-value: 0.57195% CI: [-0.646, 0.3864]Mixed Models Analysis
Secondary
Terminal Elimination Half-life (t½λz)
t½λz of AZD9567 following once daily dosing was evaluated.
Time frame: Upto 30 hours post dose (Treatment period 1 and 2)
Population: PKAS consisted of all patients in the FAS with at least 1 quantifiable AZD9567 concentration and no important protocol deviations, or AEs considered to have an effect upon PK.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Terminal Elimination Half-life (t½λz) | 6.99 hours | Standard Deviation 1.44 |
| Cohort 2 | Terminal Elimination Half-life (t½λz) | 6.16 hours | Standard Deviation 1.08 |
Secondary
Time to Reach Maximum Observed Drug Concentration (Tmax)
Tmax of AZD9567 following once daily dosing was evaluated.
Time frame: Upto 30 hours post dose (Treatment period 1 and 2)
Population: PKAS consisted of all patients in the FAS with at least 1 quantifiable AZD9567 concentration and no important protocol deviations, or AEs considered to have an effect upon PK.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Time to Reach Maximum Observed Drug Concentration (Tmax) | 0.50 hours |
| Cohort 2 | Time to Reach Maximum Observed Drug Concentration (Tmax) | 0.50 hours |
Secondary
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.
Time frame: On Days 3 (Treatment period 1 and 2)
Population: FAS consisted of all randomised patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (0h) | 21000.1 nanogram/liter (ng/L) | Standard Deviation 15413.92 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (0h) | 21361.5 nanogram/liter (ng/L) | Standard Deviation 18124.6 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (1h) | 9100.2 nanogram/liter (ng/L) | Standard Deviation 6248.93 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (1h) | 3581.1 nanogram/liter (ng/L) | Standard Deviation 3642.93 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (2h) | 8170.7 nanogram/liter (ng/L) | Standard Deviation 5053.69 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (2h) | 1648.2 nanogram/liter (ng/L) | Standard Deviation 1109.64 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (4h) | 7534.6 nanogram/liter (ng/L) | Standard Deviation 4519.5 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (4h) | 2293.1 nanogram/liter (ng/L) | Standard Deviation 1329.6 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (8h) | 10674.4 nanogram/liter (ng/L) | Standard Deviation 7731.94 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (8h) | 4585.7 nanogram/liter (ng/L) | Standard Deviation 4453.61 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (12h) | 13332.5 nanogram/liter (ng/L) | Standard Deviation 10831.44 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (12h) | 12415.5 nanogram/liter (ng/L) | Standard Deviation 9474.44 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (24h) | 22136.7 nanogram/liter (ng/L) | Standard Deviation 13414.45 |
| Cohort 1 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (24h) | 23292.9 nanogram/liter (ng/L) | Standard Deviation 15548.12 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (12h) | 14695.0 nanogram/liter (ng/L) | Standard Deviation 11422.87 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (0h) | 23525.0 nanogram/liter (ng/L) | Standard Deviation 15260.57 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (4h) | 4292.0 nanogram/liter (ng/L) | Standard Deviation 3207.76 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (0h) | 12385.0 nanogram/liter (ng/L) | Standard Deviation 11835.31 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (24h) | 19741.3 nanogram/liter (ng/L) | Standard Deviation 11048.74 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (1h) | 8122.5 nanogram/liter (ng/L) | Standard Deviation 5303.16 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (8h) | 13023.8 nanogram/liter (ng/L) | Standard Deviation 8946.33 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (1h) | 3617.5 nanogram/liter (ng/L) | Standard Deviation 1552.62 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (12h) | 16790.0 nanogram/liter (ng/L) | Standard Deviation 8010.23 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (2h) | 8098.0 nanogram/liter (ng/L) | Standard Deviation 7709.06 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (8h) | 7247.5 nanogram/liter (ng/L) | Standard Deviation 2889.87 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (2h) | 1421.1 nanogram/liter (ng/L) | Standard Deviation 591.8 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | Prednisolone (24h) | 20920.0 nanogram/liter (ng/L) | Standard Deviation 14802.66 |
| Cohort 2 | Tumour Necrosis Factor Alpha (TNFα) Concentrations | AZD9567 (4h) | 8898.8 nanogram/liter (ng/L) | Standard Deviation 5249.73 |