Study to Assess the Effect on Glucose Homeostasis of Two Dose Levels of AZD9567, Compared to Prednisolone, in Adults With Type 2 Diabetes

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 2a Randomised, Double Blind, Multi-centre Study to Assess the Effect on Glucose Homeostasis of Two Dose Levels of AZD9567, Compared to Prednisolone, in Adults With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: AZD9567
* Drug: Prednisolone
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>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]). | Drug: AZD9567<br>* 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.<br>Drug: Prednisolone<br>* 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.<br>|
| Experimental: Cohort 2<br>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]). | Drug: AZD9567<br>* 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.<br>Drug: Prednisolone<br>* 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.<br>|
| Active Comparator: Cohort 3<br>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]). | Drug: Prednisolone<br>* 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.<br>Other: Placebo<br>* Participants will receive placebo for 3 consecutive days of each treatment period in Cohort 3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in glucose AUC(0-4) versus baseline compared to prednisolone following a standardised MMTT | The change from baseline in glucose AUC(0-4) will be analysed using a mixed model repeated measures (MMRM) with baseline included as covariate. | On Days -1, 4, 27, and 31 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean daily glucose at 48 - 72 hours treatment as determined from multiple measures via the Continuous Glucose Monitoring (CGM) system | The mean daily glucose will be analysed using a MMRM analysis with baseline as covariate. | On Days -2, 3, 26 and 30 | 
| Rise in mean daily glucose over 24-hour periods from start of IMP dosing (0 - 24 hours, 24 - 48 hours, 48 - 72 hours) | The mean daily glucose will be analysed using an MMRM analysis with baseline as covariate. | On Days 1, 2, 3, 28, 29, 30 | 
| Change from baseline in fasting glucose | Pharmacodynamic effects of AZD9567 will be evaluated as compared to prednisolone. | On Days -1, 4, 27, and 31 | 
| Change from baseline AUC(0-4) on hormones related to glucose homeostasis | Effects on insulin, glucagon, GLP-1 and GIP of AZD9567 following MMTT in comparison to prednisolone will be assessed. | On Days -1, 4, 27, and 31 | 
| Change from baseline in AUC(0-4) on C-peptide | Pharmacodynamic effects of AZD9567 on glucose homeostasis through a MMTT in comparison to prednisolone will be assessed. | On Days -1, 4, 27, and 31 | 
| MMTT derived first phase insulin response | Pharmacodynamic effects of AZD9567 on derived measures of beta cell function from the MMTT compared to prednisolone will be evaluated. | On Days -1, 4, 27, and 31 | 
| 24-hour potassium concentration | The concentration of potassium in urine will be measured over 24 hours. | On Days -1, 3, 27 and 30 | 
| 24-hour sodium concentration | The concentration of sodium in urine will be measured over 24 hours. | On Days -1, 3, 27 and 30 | 
| Area under the plasma concentration versus time curve from zero to the last quantifiable concentration (AUClast) | AUClast will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara). | On Days 3, 4, 30, and 31 (Pre-dose, Post-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 30 hours) | 
| Area under the plasma concentration versus time curve from zero to 24 hours post-dose [AUC(0-24)] | AUC(0-24) will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara). | On Days 3, 4, 30, and 31 (Pre-dose, Post-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 30 hours) | 
| Area under the plasma concentration versus time curve from zero to 6 hours post-dose [AUC(0-6)] | AUC(0-6) will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara). | On Days 3, 4, 30, and 31 (Pre-dose, Post-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 30 hours) | 
| Maximum observed drug concentration (Cmax) | Cmax will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara). | On Days 3, 4, 30, and 31 (Pre-dose, Post-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 30 hours) | 
| Time to reach maximum observed drug concentration (tmax) | Tmax will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara). | On Days 3, 4, 30, and 31 (Pre-dose, Post-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 30 hours) | 
| Terminal elimination half-life (t½λz) | t½λz will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara). | On Days 3, 4, 30, and 31 (Pre-dose, Post-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 30 hours) | 
| Apparent total body clearance of drug from plasma after extravascular (CL/F) | CL/F will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara). | On Days 3, 4, 30, and 31 (Pre-dose, Post-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 30 hours) | 
| Apparent volume of distribution following extravascular administration (Vz/F) | Vz/F will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara). | On Days 3, 4, 30, and 31 (Pre-dose, Post-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 30 hours) | 
| TNFα concentrations | Relationship between AZD9567 exposure and inhibition of LPS-stimulated TNFα release for high and low dose comparison (Cohort 1 and Cohort 2) will be assessed. | On Days 3 and 30 (Pre-dose, Post-dose 1, 2, 4, 8, 12, and 24 hours | 
| Change in free fatty acids | Pharmacodynamic effects of AZD9567 will be evaluated following a MMTT compared to prednisolone. | On Days -1, 4, 27, and 31 | 
| Homeostatic model assessment- insulin resistance (HOMA-IR) | Pharmacodynamic effects of AZD9567 on derived measures of beta cell function from the MMTT compared to prednisolone will be evaluated. | On Days -1, 4, 27, and 31 | 
| HOMA-insulin sensitivity | Pharmacodynamic effects of AZD9567 on derived measures of beta cell function from the MMTT compared to prednisolone will be evaluated. | On Days -1, 4, 27, and 31 | 
| Safety and tolerability of AZD9567 by assessing the number of participants with adverse events | Safety and tolerability will be assessed using variables like AEs/SAEs, vital signs, ECGs, changes in clinical chemistry/haematology parameters, morning serum cortisol, and adrenocorticotropic hormone. | From screening up to 79 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, Glucose Homeostasis, Pharmacodynamic, AZD9567, Prednisolone