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

• ClinicalTrials.gov Identifier: NCT04556760
• Recruitment Status: Recruiting
• First Posted: September 21, 2020
• Last Update Posted: January 11, 2021
• Sponsor: AstraZeneca
• Collaborator: Parexel
• Information provided by (Responsible Party): AstraZeneca

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 2	Drug: AZD9567; Drug: Prednisolone; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: 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.
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: November 26, 2020
• Estimated Primary Completion Date: May 7, 2021
• Estimated Study Completion Date: May 7, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; 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; 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.; Drug: 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.
Experimental: Cohort 2; 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; 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.; Drug: 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.
Active Comparator: Cohort 3; 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; 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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Mean daily glucose at 48 - 72 hours treatment as determined from multiple measures via the Continuous Glucose Monitoring (CGM) system [ Time Frame: On Days -2, 3, 26 and 30 ]
   The mean daily glucose will be analysed using a MMRM analysis with baseline as covariate.
2. Rise in mean daily glucose over 24-hour periods from start of IMP dosing (0 - 24 hours, 24 - 48 hours, 48 - 72 hours) [ Time Frame: On Days 1, 2, 3, 28, 29, 30 ]
   The mean daily glucose will be analysed using an MMRM analysis with baseline as covariate.
3. Change from baseline in fasting glucose [ Time Frame: On Days -1, 4, 27, and 31 ]
   Pharmacodynamic effects of AZD9567 will be evaluated as compared to prednisolone.
4. Change from baseline AUC(0-4) on hormones related to glucose homeostasis [ Time Frame: On Days -1, 4, 27, and 31 ]
   Effects on insulin, glucagon, GLP-1 and GIP of AZD9567 following MMTT in comparison to prednisolone will be assessed.
5. Change from baseline in AUC(0-4) on C-peptide [ Time Frame: On Days -1, 4, 27, and 31 ]
   Pharmacodynamic effects of AZD9567 on glucose homeostasis through a MMTT in comparison to prednisolone will be assessed.
6. MMTT derived first phase insulin response [ Time Frame: On Days -1, 4, 27, and 31 ]
   Pharmacodynamic effects of AZD9567 on derived measures of beta cell function from the MMTT compared to prednisolone will be evaluated.
7. 24-hour potassium concentration [ Time Frame: On Days -1, 3, 27 and 30 ]
   The concentration of potassium in urine will be measured over 24 hours.
8. 24-hour sodium concentration [ Time Frame: On Days -1, 3, 27 and 30 ]
   The concentration of sodium in urine will be measured over 24 hours.
9. Area under the plasma concentration versus time curve from zero to the last quantifiable concentration (AUClast) [ Time Frame: 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) ]
   AUClast will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara).
10. Area under the plasma concentration versus time curve from zero to 24 hours post-dose [AUC(0-24)] [ Time Frame: 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) ]
    AUC(0-24) will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara).
11. Area under the plasma concentration versus time curve from zero to 6 hours post-dose [AUC(0-6)] [ Time Frame: 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) ]
    AUC(0-6) will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara).
12. Maximum observed drug concentration (Cmax) [ Time Frame: 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) ]
    Cmax will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara).
13. Time to reach maximum observed drug concentration (tmax) [ Time Frame: 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) ]
    Tmax will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara).
14. Terminal elimination half-life (t½λz) [ Time Frame: 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) ]
    t½λz will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara).
15. Apparent total body clearance of drug from plasma after extravascular (CL/F) [ Time Frame: 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) ]
    CL/F will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara).
16. Apparent volume of distribution following extravascular administration (Vz/F) [ Time Frame: 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) ]
    Vz/F will be derived using standard non-compartmental methods using WinNonLin version 8.1 or higher (Certara).
17. TNFα concentrations [ Time Frame: On Days 3 and 30 (Pre-dose, Post-dose 1, 2, 4, 8, 12, and 24 hours ]
    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.
18. Change in free fatty acids [ Time Frame: On Days -1, 4, 27, and 31 ]
    Pharmacodynamic effects of AZD9567 will be evaluated following a MMTT compared to prednisolone.
19. Homeostatic model assessment- insulin resistance (HOMA-IR) [ Time Frame: On Days -1, 4, 27, and 31 ]
    Pharmacodynamic effects of AZD9567 on derived measures of beta cell function from the MMTT compared to prednisolone will be evaluated.
20. HOMA-insulin sensitivity [ Time Frame: On Days -1, 4, 27, and 31 ]
    Pharmacodynamic effects of AZD9567 on derived measures of beta cell function from the MMTT compared to prednisolone will be evaluated.
21. Modified Matsuda index [ Time Frame: On Days -1, 4, 27, and 31 ]
    Pharmacodynamic effects of AZD9567 on derived measures of beta cell function from the MMTT compared to prednisolone will be evaluated.
22. Safety and tolerability of AZD9567 by assessing the number of participants with adverse events [ Time Frame: From screening up to 79 days ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Participants with diagnosis of T2DM for 6 months prior to screening: HbA1c in the diabetes range or fasting blood 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 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 prior screen failure in the current study, 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.

Contacts and Locations

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

Locations

Germany

Research Site; Not yet recruiting

Berlin, Germany, 14050

Research Site; Recruiting

Mainz, Germany, 55116

Research Site; Not yet recruiting

Mannheim, Germany, 68167

Research Site; Not yet recruiting

Neuss, Germany, 41460

Sponsors and Collaborators

AstraZeneca

Parexel

Investigators

• Principal Investigator: Tim Heise; Profil Institut fur Stoffwechselforschung GmbH

More Information

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04556760
• Other Study ID Numbers: D6470C00005
• First Posted: September 21, 2020
• Last Update Posted: January 11, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: 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.

Access Criteria

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.

• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:

Type 2 Diabetes Mellitus; Glucose Homeostasis; Pharmacodynamic; AZD9567; Prednisolone

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Prednisolone; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents