Study to Assess the Effect on Glucose Homeostasis of Two Dose Levels of AZD9567, Compared to Prednisolone, in Adults With Type 2 Diabetes
- Conditions
- Diabetes Mellitus, Type 2
- Interventions
- Registration Number
- NCT04556760
- Lead Sponsor
- AstraZeneca
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 46
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Cohort 1 AZD9567 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 \[BA sequence group\]). Cohort 1 Prednisolone 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 \[BA sequence group\]). Cohort 2 AZD9567 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 \[BA sequence group\]). Cohort 2 Prednisolone 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 \[BA sequence group\]). Cohort 3 Placebo 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 \[BA sequence group\]). Cohort 3 Prednisolone 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 \[BA sequence group\]).
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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.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 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.
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.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.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.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.
Maximum Observed Drug Concentration (Cmax) Upto 30 hours post dose (Treatment period 1 and 2) Cmax 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.
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.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).
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.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 (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.Terminal Elimination Half-life (t½λz) Upto 30 hours post dose (Treatment period 1 and 2) t½λz of AZD9567 following once daily dosing was evaluated.
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 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.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 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.
Trial Locations
- Locations (1)
Research Site
🇩🇪Neuss, Germany