| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the pharmacodynamic (PD) effect of AZD9567 on glucose homeostasis compared to prednisolone
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| E.2.2 | Secondary objectives of the trial |
• To determine the effect of AZD9567 on continuous glucose monitoring (CGM) compared to prednisolone
• To determine the PD effect of AZD9567 following a Mixed Meal Tolerance Test (MMTT) compared to prednisolone
• To determine the PD effect of AZD9567 on glucose homeostasis through an MMTT in comparison to prednisolone
• To determine the PD effect of AZD9567 on derived measures of beta cell function from the MMTT compared to prednisolone
• To determine the effect of AZD9567 on urinary sodium (U-Na) and urinary potassium (U-K) excretion compared to prednisolone
• To evaluate the PK of AZD9567 following once daily dosing
• To collect plasma samples for analysis of prednisolone.
• To explore the relationship between AZD9567 exposure and inhibition of LPS stimulated TNFα release for high and low dose comparison (Cohort 1 and Cohort 2)
Safety Objective
• To evaluate the safety and tolerability of AZD9567 in relation to prednisolone |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be aged 18 to 75 years of age inclusive, at the time of Visit 1.
2. Participants with diagnosis of T2DM for 6 months prior to screening: HbA1c in the diabetes range or fasting blood glucose 126 220 mg/dL.
3. 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.
4. Venous access suitable for multiple cannulations.
5. Sex: males and females.
Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
(a) Male participants: All male participants must be willing to avoid fathering a child by either true abstinence or use (together with their female partner/spouse) a highly effective contraception form of birth control in combination with a barrier method, starting from the time of study intervention administration until 3 months after the Final/ET visit. Acceptable methods of preventing pregnancy are provided below.
6. Female participants must be not lactating and not of childbearing potential, defined as those who are surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or are postmenopausal (defined as at least 1 year since last menses and having an elevated [> 40 mIU/mL] FSH laboratory value at screening).
If sexually active, nonsterilized males who have a female partner of childbearing potential must practice two effective contraceptive measures from screening through at least 28 days after the last dose of IMP has been administered. Note: Male condom plus spermicide is only considered an effective contraceptive measure when used together with another method based on following list (none of the listed methods are intended to be used alone). Highly Effective Methods of Contraception include:
(a) Tubal occlusion
(b) Copper T intrauterine device
(c) Levonorgestrel-releasing intrauterine system (eg, Mirena®)
(d) Medroxyprogesterone injections (eg, Depo-Provera®)
(e) Etonogestrel implants (eg, Implanon®, Norplan®)
(f) Combined pills
(g) Norelgestromin/ethinyl estradiol transdermal system (eg, Ortho Evra®)
(h) Intravaginal device (eg, NuvaRing®)
(i) Desogestrel (Cerazette®).
7. Capable of giving signed informed consent.
8. Provision of informed consent prior to any study specific procedures. |
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| E.4 | Principal exclusion criteria |
1. History or presence of type 1 diabetes.
2. History of severe hypoglycaemia or hypoglycaemia unawareness within the last 6 months.
3. History or presence of diabetic foot ulcers.
4. Participants with advanced diabetic complications (eg, symptomatic nephropathy, gastroparesis, proliferative retinopathy, significant atherosclerotic disease, congestive, heart failure etc).
5. History of clinically significant lactic acidosis or ketoacidosis following diagnosis with T2DM.
6. History of, or known significant infection or positivity at Visit 1, including hepatitis A, B, or C, HIV, tuberculosis (ie, positive result for interferon-γ release assay, QuantiFERON® TB Gold), that may put the participant at risk during participation in the study.
7. History and / or presence of COVID-19:
(a) Participants who have had a severe course of COVID-19 (ie, hospitalisation, extracorporeal membrane oxygenation [ECMO], mechanically ventilated)
(b) Participants with clinical signs and symptoms consistent with COVID-19, eg, fever, dry cough, dyspnoea, sore throat, fatigue, or confirmed current infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission to the CRU
(c) Participants with confirmed COVID-19 infection by PCR test before randomisation.
8. Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before Visit 1.
9. History of or current alcohol or drug abuse (including marijuana), as judged by the investigator.
10. Previous psychiatric disorders, including but not limited to:
(a) Participants have been committed to an institution by way of official or judicial order
(b) Any active psychiatric illness associated with unstable weight control or which would result in inability to comply with study requirements
(c) History of severe affective disorder including major depressive or maniac-depressive illness
(d) History of previous steroid psychosis.
11. 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.
12. History of adrenal insufficiency.
13. History or current inflammatory disorder.
14. 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, including, but not limited to:
(a) History of previous gastric/duodenal ulcers or surgery affecting the upper GI tract likely to affect the interpretation of safety and tolerability data
(b) History of cholelithiasis leading to episodes of acute cholecystitis not treated by cholecystectomy, or known biliary disease
(c) History or presence of dyspepsia or oral intolerance to steroids
(d) History of cancer, with the exception of non-melanoma skin cancer which is considered cured based on investigator assessment
(e) History or presence of any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
15. 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.
16. Oral or parenteral steroids 8 weeks prior to randomisation and during the study. Topical and inhaled steroids 4 weeks prior to randomisation are acceptable.
17. Use of any prohibited medication during the study or if the required washout time of such medication was not adhered to.
18. Receipt of live or live attenuated vaccine within 4 weeks prior to the first administration
of IMP.
19. Planned in-patient surgery, major dental procedure, or hospitalisation during the study.
20. Previous participation or prior screen failure in the current study, or participation in any other research study within 1 month prior to Visit 1.
21. Patient treated with any investigational drug within 30 days (or 5 half-lives, whichever is longer) prior to Visit 1.
22. Uncontrolled hypertension (BP > 160 mmHg systolic or > 95 mmHg diastolic).
23. Diagnosis of heart failure and current symptoms regardless of definition, ie, HfpEF, HfrEF.
24. Acute coronary syndrome / unstable angina, coronary intervention procedures (percutaneous coronary intervention or coronary artery bypass graft) within the past 6 months.
25. Stroke within the past 3 months.
26. QTcF > 470 ms or family history of long QT-syndrome.
27. AV-block II-III or sinus node dysfunction with significant pause, not treated with pacemaker. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in glucose AUC(0 4) versus baseline compared to prednisolone following a standardised MMTT |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
A standardised mixed meal will be administered on day 1 and day 4 in each treatment period.
Blood samples to be taken 15 mins pre- and 10, 20, 30, 60, 75, 120, 180, 240 min post-mixed meal intake. |
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| E.5.2 | Secondary end point(s) |
• Mean daily glucose at 48 – 72 hours treatment as determined from multiple measures via the CGM system
• Rise in mean daily glucose over 24 hour periods from start of IMP dosing (0 – 24 hours, 24 – 48 hours, 48 – 72 hours)
• Change from baseline in fasting glucose
• Change from baseline AUC(0 4) on hormones related to glucose homeostasis (insulin, glucagon, GLP-1, GIP, FFAs)
• Change from baseline in AUC(0 4) on plasma glucose, insulin, and C-peptide
• MMTT derived first phase insulin response (ΔI15/ΔG15, ΔI30/ΔG30, ΔC15/ΔG15, ΔC30/ΔG30)
• HOMA IR, HOMA S, Modified Matsuda index
• 24-hour urinary sodium and potassium concentration
• Plasma PK parameters
• Plasma concentrations of prednisolone
• TNFα concentrations
Safety:
AEs/SAEs, Vital signs, ECGs, Changes in clinical chemistry/haematology parameters, Morning serum cortisol, ACTH
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Refer to section E.5.2.
Endpoints related to MMTT see section E.5.1.1.
Plasma PK: at Day 3 in both treatment periods. Pre-dose, Post-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 30 h.
TNFa concentrations: at Day 3 in both treatment periods. Pre-dose, Post dose 1, 2, 4, 8, 12, 24 h. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of study is defined as the last date reported in the ‘End of Study’ CRF for all participants. Justification: If the last subject dies or withdraws from the study (among other examples), the end of study would not be the last visit but a but a specific event (death, withdrawal). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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