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| Name | Class |
|---|---|
| Parexel | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 | Experimental | Participants will be randomised in a ratio of 1:1 to receive AZD9567 and prednisolone over two 72 hour periods in a cross over design (72 mg AZD9567 followed by 40 mg prednisolone [AB sequence group] or 40 mg prednisolone followed by 72 mg AZD9567 [BA sequence group]). |
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| Cohort 2 | Experimental | Participants will be randomised in a ratio of 1:1 to receive AZD9567 and prednisolone over two 72 hour periods in a cross over design (40 mg AZD9567 followed by 20 mg prednisolone [AB sequence group] or 20 mg prednisolone followed by 40 mg AZD9567 [BA sequence group]). |
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| Cohort 3 | Active Comparator | Participants will be randomised in a ratio of 1:1 to receive placebo and prednisolone over two 72 hour periods in a cross over design (placebo followed by 5 mg prednisolone [AB sequence group] or 5 mg prednisolone followed by placebo [BA sequence group]). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AZD9567 | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tim Heise | Profil Institut fur Stoffwechselforschung GmbH | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Mainz | 55116 | Germany | |||
| Research Site |
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| Label | URL |
|---|---|
| Statistical Analysis Plan (SAP) | View source |
| Protocol | View source |
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Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.
Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
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.
This study was conducted in Germany between 26 November 2020 and 09 June 2021.
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1: 72 mg AZD9567 First, Then 40 mg Prednisolone | Patients were randomised in a ratio of 1:1 to receive 72 mg AZD9567 followed by 40 mg prednisolone |
| FG001 | Cohort 1:40 mg Prednisolone First, Then 72 mg AZD9567 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Treatment Period 1 (72 Hours) |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 3, 2021 | Apr 28, 2022 |
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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.
| Prednisolone | Drug | 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. |
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| Placebo | Other | Participants will receive placebo for 3 consecutive days of each treatment period in Cohort 3. |
|
| 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 |
| Mannheim |
| 68167 |
| Germany |
| Research Site | Neuss | 41460 | Germany |
| CSR Synopsis | View source |
Patients were randomised in a ratio of 1:1 to receive 40 mg prednisolone followed by 72 mg AZD9567
| FG002 | Cohort 2: 40 mg AZD9567 First, Then 20 mg Prednisolone | Patients were randomised in a ratio of 1:1 to receive 40 mg AZD9567 followed by 20 mg prednisolone |
| FG003 | Cohort 2: 20mg Prednisolone First, Then 40 mg AZD9567 | Patients were randomised in a ratio of 1:1 to receive 20 mg prednisolone followed by 40 mg AZD9567 |
| FG004 | Cohort 3: Placebo First, Then 5 mg Prednisolone | Patients were randomised in a ratio of 1:1 to receive placebo followed by 5 mg prednisolone |
| FG005 | Cohort 3: 5 mg Prednisolone First, Then Placebo | Patients were randomised in a ratio of 1:1 to receive 5 mg prednisolone followed by placebo |
| COMPLETED |
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| NOT COMPLETED |
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| Washout Period (3 Weeks) |
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| Treatment Period 2 (72 Hours) |
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Full Analysis Set (FAS) consisted of all randomised patients who received at least 1 dose of study treatment.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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 |
| BG002 | 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 |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Full Analysis Set (FAS) consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | minute*millimole/liter (min*mmol/L) | On Days -1 (baseline), and Days 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | millimole/liter (mmol/L) per day | 48 to 72 hours |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | mmol/L per day | Baseline and up to 72 hours (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | mmol/L | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | minute*picomole/liter (min*pmole/L) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | min*pmol/L | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | min*pmol/L | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | min*pmol/L | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | minute*nanomole/L (min*nmol/L) | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | Ratio | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | Ratio | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | Ratio | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | Ratio | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | mmol/day | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | mmol/day | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | hour*nanomole/liter (h*nmol/L) | Upto 30 hours post dose (Treatment period 1 and 2) |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*nmol/L | 24 hours post dose |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*nmol/L | 6 hours post dose |
|
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| Secondary | Maximum Observed Drug Concentration (Cmax) | Cmax of AZD9567 following once daily dosing was evaluated. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | nmol/L | Upto 30 hours post dose (Treatment period 1 and 2) |
|
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| Secondary | Time to Reach Maximum Observed Drug Concentration (Tmax) | Tmax of AZD9567 following once daily dosing was evaluated. | 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. | Posted | Median | Full Range | hours | Upto 30 hours post dose (Treatment period 1 and 2) |
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| Secondary | Terminal Elimination Half-life (t½λz) | t½λz of AZD9567 following once daily dosing was evaluated. | 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. | Posted | Mean | Standard Deviation | hours | Upto 30 hours post dose (Treatment period 1 and 2) |
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| Secondary | Apparent Total Body Clearance of Drug From Plasma After Extravascular (CL/F) | CL/F of AZD9567 following once daily dosing was evaluated. | 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. | Posted | Mean | Standard Deviation | Liter/hour (L/h) | Upto 30 hours post dose (Treatment period 1 and 2) |
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| 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). | 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. | Posted | Mean | Standard Deviation | Liter | Upto 30 hours post dose (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Mean | Standard Deviation | nanogram/liter (ng/L) | On Days 3 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Least Squares Mean | Standard Error | min*mmol/L | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Mean | Standard Deviation | Score | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| 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. | FAS consisted of all randomised patients who received at least 1 dose of study treatment. | Posted | Mean | Standard Deviation | Score | On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2) |
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| Secondary | Number of Participants With Adverse Events | Safety and tolerability of AZD9567 was assessed. | 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. | Posted | Count of Participants | Participants | From screening up to 79 days |
|
From Screening up to Final/ end of treatment visit (Day 79).
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. The SAF was analysed according to actual treatment.
Three additional arms were created to capture Adverse Events for each treatment within the cohort.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort 1: AZD9567 72mg | 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 AZD956 | 0 | 27 | 0 | 27 | 4 | 27 |
| EG001 | Cohort 1: Prednisolone 40mg | 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 AZD956 | 0 | 27 | 0 | 27 | 7 | 27 |
| EG002 | Cohort 2: AZD9567 40mg | 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 | 0 | 8 | 0 | 8 | 2 | 8 |
| EG003 | Cohort 2: Prednisolone 20mg | 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 AZD956 | 0 | 8 | 0 | 8 | 5 | 8 |
| EG004 | Cohort 3: Placebo | Patients were randomised in a ratio of 1:1 to receive placebo followed by 5 mg prednisolone or 5 mg prednisolone followed by placebo | 0 | 9 | 0 | 9 | 1 | 9 |
| EG005 | Cohort 3: Prednisolone 5mg | Patients were randomised in a ratio of 1:1 to receive placebo followed by 5 mg prednisolone or 5 mg prednisolone followed by placebo | 0 | 9 | 0 | 9 | 0 | 9 |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cellulitis | Infections and infestations | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Conjunctivitis | Infections and infestations | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Pollakiuria | Renal and urinary disorders | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Administration site phlebitis | General disorders | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Catheter site erythema | General disorders | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Fatigue | General disorders | MedDRA version 24.0 | Non-systematic Assessment |
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| Mucosal inflammation | General disorders | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Haematochezia | Gastrointestinal disorders | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Catheter site related reaction | General disorders | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Blood pressure increased | Investigations | MedDRA version 24.0 | Non-systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA version 24.0 | Non-systematic Assessment |
|
No unpublished information may be disclosed without prior written approval from AstraZeneca.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Global Clinical Head | AstraZeneca Clinical Study Information Center | 1-877-240-94 79 | information.center@astrazeneca.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 28, 2021 | Apr 28, 2022 | SAP_001.pdf |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C000712985 | AZD9567 |
| D011239 | Prednisolone |
| ID | Term |
|---|---|
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
Not provided
Not provided
| Male |
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| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
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| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
|
| Prednisolone |
|
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| Placebo |
|
|
| Mixed Models Analysis |
| 0.432 |
| Mean Difference (Final Values) |
| -142.0330 |
| 2-Sided |
| 95 |
| -554.8722 |
| 270.8061 |
| Other |
| Pairwise Comparisons with Prednisolone (Placebo vs Prednisolone 5mg) | Mixed Models Analysis | 0.030 | Mean Difference (Final Values) | -126.8829 | 2-Sided | 95 | -236.0426 | -17.7233 | Other |
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Patients were randomised in a ratio of 1:1 to receive placebo followed by 5 mg prednisolone or 5 mg prednisolone followed by placebo
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Patients were randomised in a ratio of 1:1 to receive placebo followed by 5 mg prednisolone or 5 mg prednisolone followed by placebo |
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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
| OG004 | Cohort 3: Placebo | Patients were randomised in a ratio of 1:1 to receive placebo followed by 5 mg prednisolone or 5 mg prednisolone followed by placebo |
| OG005 | Cohort 3: Prednisolone 5mg | Patients were randomised in a ratio of 1:1 to receive placebo followed by 5 mg prednisolone or 5 mg prednisolone followed by placebo |
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