E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adverse effects of prescribed glucocorticoid therapy |
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E.1.1.1 | Medical condition in easily understood language |
Side effects of prescribed steroids |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068501 |
E.1.2 | Term | Cushing's syndrome, steroid-induced |
E.1.2 | System Organ Class | 100000004860 |
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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 |
Our main research objectives is…
1. To demonstrate the beneficial effect of the selective 11β-HSD1 inhibitor, AZD4017, upon the prednisolone-induced deterioration in glucose uptake into skeletal muscle and glucose production by the liver.
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E.2.2 | Secondary objectives of the trial |
Our secondary research objectives are...
1. To determine the impact of AZD4017 on the anti-inflammatory actions of Prednisolone.
2. To identify the tissue-specific (skeletal muscle, adipose) mechanisms underpinning the response to Prednisolone therapy administered in conjunction with AZD4017. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Male volunteers without diabetes (HbA1C < 48mmol/mol at screening) • BMI 20-30kg/m2 • Age 18-60years • Individuals (identified from Oxford Biobank) with fasting insulin and / or glucose and / or insulin resistance as measured by HOMA IR in the 40th-60th percentile • BP<160/100mmHg with stable antihypertensive therapy for >3months • Stable lipid lowering therapy for >3 months • No contraindications to AZD4017 or prednisolone treatment • Study participants who are sexually active with a female partner of childbearing potential must be surgically sterilised, practicing abstinence, or agree, along with their partners, to use two forms of highly effective methods of birth control (i.e. condom plus another highly effective method defined below), and not rely on barrier methods and spermicide alone, from the time of screening until 1 week after final dose of study drug. Male study participants must also not donate sperm from the time of screening until 1 week after final dose of study drug.
Highly effective methods of contraception are defined as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (either oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (either oral [specifically Cerazette], injectable or implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner or sexual abstinence.
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E.4 | Principal exclusion criteria |
• Age <18 or >60years • Body mass index <20 or >30kg/m2 • A diagnosis of diabetes (type 1 or type 2) • A blood haemoglobin <120mg/dL • Haemorrhagic disorders • Anticoagulant treatment • Renal impairment with eGFR <60ml/min • Abnormal liver chemistry with AST, ALT and/or GGT and/or bilirubin >ULN • Glucocorticoid therapy (including inhaled, topical or oral) within the last 6 months • Concomitant anti-inflammatory medication including NSAIDs, disease modifying anti-rheumatic drugs (DMARDs) / steroid-sparing medications (e.g. methotrexate, sulphasalzine, hydroxychloroquine, azathioprine, leflunamide, biologics [anti-TNFa, IL-1ra]) • Any medical condition in the opinion of the investigator that might impact upon safety or validity of the results – recent (within 2 weeks) or active infection, known liver disease, known thyroid disease, active malignancy, existing inflammatory condition (e.g. inflammatory athropathy, inflammatory bowel disease, autoimmune disease, connective tissue disease) • Participation in another IMP trial / study within the past 6 months |
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E.5 End points |
E.5.1 | Primary end point(s) |
The change in glucose disposal as measured during a hyperinsulinaemic euglycaemic clamp.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Investigations will be performed at baseline and after 7 days of treatment |
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E.5.2 | Secondary end point(s) |
Determine if AZD4017 can limit the detrimental effect of prednisolone (20mg) on hepatic insulin sensitivity as measured across a 2-step hyperinsulinaemic euglycaemic clamp. Define the changes in blood pressure associated with prednisolone and AZD4017 administration Define the changes in adipose tissue and skeletal muscle gene expression profile associated with prednisolone and AZD4017 administration Define the change in whole body oxidation associated with prednisolone and AZD4017 administration. Define the changes in circulating inflammatory cytokines and inflammatory response in circulating inflammatory cells associated with prednisolone and AZD4017 administration. Define the changes in urinary steroid metabolite profile associated with prednisolone and AZD4017 administration. Define the changes in body composition (total and regional lean and fat mass) associated with prednisolone and AZD4017 administration using DXA. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Investigations will be performed at baseline and after 6 or 7 days of treatment |
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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 | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | Yes |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 31 |