Clinical trial NCT04556760: Study to Assess the Effect on Glucose Homeostasis of Two Dose Levels of AZD9567, Compared to Prednisolone, in Adults With Type 2 Diabetes
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 2
Keywords: Type 2 Diabetes Mellitus
Glucose Homeostasis
Pharmacodynamic
AZD9567
Prednisolone
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2020-09-21
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in Glucose Area Under the Plasma Concentration Versus Time Curve From Zero to 4 Hours Post-dose AUC(0-4)
timeFrame: On Days -1 (baseline), and Days 4 (Treatment period 1 and 2)
Secondary outcomes:
measure: Mean Glucose Level as Determined Via the Continuous Glucose Monitoring (CGM) System
timeFrame: 48 to 72 hours
measure: Rise in Mean Glucose Levels Over 24-hour Periods From Start of IMP Dosing
timeFrame: Baseline and up to 72 hours (Treatment period 1 and 2)
measure: Change From Baseline in Fasting Glucose
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Insulin)
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon)
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucagon-like Peptide-1 [GLP-1])
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Glucose-dependent Insulin Releasing Polypeptide [GIP])
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline in AUC(0-4) on C-peptide
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline in Ratio of Insulin to Glucose Level Between 10 and 0 Minutes (ΔI10/ΔG10)
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline in Ratio of Insulin to Glucose Level Between 30 and 0 Minutes [ΔI30/ΔG30])
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline in Ratio of C-peptide to Glucose Level Between 10 and 0 Minutes (ΔC10/ΔG10)
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline in Ratio of C-peptide to Glucose Level Between 30 and 0 Minutes (ΔC30/ΔG30)
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline in 24-hour Urinary Potassium Excretion
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline in 24-hour Urinary Sodium Excretion
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Quantifiable Concentration (AUClast)
timeFrame: Upto 30 hours post dose (Treatment period 1 and 2)
measure: Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours Post-dose [AUC(0-24)]
timeFrame: 24 hours post dose
measure: Area Under the Plasma Concentration Versus Time Curve From Zero to 6 Hours Post-dose [AUC(0-6)]
timeFrame: 6 hours post dose
measure: Maximum Observed Drug Concentration (Cmax)
timeFrame: Upto 30 hours post dose (Treatment period 1 and 2)
measure: Time to Reach Maximum Observed Drug Concentration (Tmax)
timeFrame: Upto 30 hours post dose (Treatment period 1 and 2)
measure: Terminal Elimination Half-life (t½λz)
timeFrame: Upto 30 hours post dose (Treatment period 1 and 2)
measure: Apparent Total Body Clearance of Drug From Plasma After Extravascular (CL/F)
timeFrame: Upto 30 hours post dose (Treatment period 1 and 2)
measure: Apparent Volume of Distribution Following Extravascular Administration (Vz/F)
timeFrame: Upto 30 hours post dose (Treatment period 1 and 2)
measure: Tumour Necrosis Factor Alpha (TNFα) Concentrations
timeFrame: On Days 3 (Treatment period 1 and 2)
measure: Change From Baseline AUC(0-4) on Hormones Related to Glucose Homeostasis (Free Fatty Acids)
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline in Homeostatic Model Assessment- Insulin Resistance (HOMA-IR)
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Change From Baseline in HOMA-insulin Sensitivity (HOMA-S)
timeFrame: On Day -1 (Baseline), and Day 4 (Treatment period 1 and 2)
measure: Number of Participants With Adverse Events
timeFrame: From screening up to 79 days
Other outcomes:
Locations:
city: Mainz
country: Germany
facility: Research Site
city: Mannheim
country: Germany
facility: Research Site
city: Neuss
country: Germany
facility: Research Site
Study officials:
affiliation: Profil Institut fur Stoffwechselforschung GmbH
name: Tim Heise
role: PRINCIPAL_INVESTIGATOR
References: