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

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04556760
• Other study ID #: D6470C00005
• Status: Completed
• Phase: Phase 2
• Start date: November 26, 2020
• Est. completion date: June 9, 2021

Study information

• Verified date: June 2021
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: June 9, 2021
• Est. primary completion date: June 9, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• AZD9567
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.
• Prednisolone
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.

Other:
• Placebo
Participants will receive placebo for 3 consecutive days of each treatment period in Cohort 3.

Locations

Country	Name	City	State
Germany	Research Site	Mainz
Germany	Research Site	Mannheim
Germany	Research Site	Neuss

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Change from baseline in fasting glucose	Pharmacodynamic effects of AZD9567 will be evaluated as compared to prednisolone.	On Days -1, 4, 27, and 31
Secondary	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
Secondary	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
Secondary	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
Secondary	24-hour potassium concentration	The concentration of potassium in urine will be measured over 24 hours.	On Days -1, 3, 27 and 30
Secondary	24-hour sodium concentration	The concentration of sodium in urine will be measured over 24 hours.	On Days -1, 3, 27 and 30
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Terminal elimination half-life (t½?z)	t½?z 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)
Secondary	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)
Secondary	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)
Secondary	TNFa concentrations	Relationship between AZD9567 exposure and inhibition of LPS-stimulated TNFa 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
Secondary	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
Secondary	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
Secondary	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
Secondary	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