A Single Ascending Dose Study To Assess The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of AZD9567.

Study Overview
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Brief Summary
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This is a Phase I, first-in-human (FIH), randomized, single-blind, placebo-controlled, single ascending dose sequential group study in healthy male subjects. The objectives are to study the safety, tolerability, pharmacokinetics and effects on glucose homeostasis (pharmacodynamics) of AZD9567, an oral differentiated non-steroidal selective glucocorticoid receptor modulator (SGRM). The study will also assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of prednisolone 60 mg in comparison with high doses of AZD9567 and placebo.

Detailed Description
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This is a Phase I, first-in-human (FIH), randomized, single-blind, placebo-controlled, single ascending dose sequential group study in healthy male subjects. The objectives are to study the safety, tolerability, pharmacokinetics and effects on glucose homeostasis (pharmacodynamics) of AZD9567. Additional exploratory variables (Inflammation biomarkers, ECG modelling and taste assessment) will also be evaluated. The study will also assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of prednisolone 60 mg in comparison with high doses of AZD9567 and placebo. The study will be conducted at a single study centre with a planned number of subjects of up to 72 healthy males, aged 18 to 55 years.

Official Title
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A Phase I, Randomized, Single-Blind, Placebo-Controlled Study To Assess The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Single Ascending Oral Doses Of AZD9567 In Healthy Subjects.

Conditions
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Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Healthy Subjects, Rheumatoid Arthritis

Intervention / Treatment
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* Drug: AZD9567 Monohydrat
* Drug: Placebo oral suspension/ Placebo capsule
* Drug: Prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated, written informed consent prior to any study specific procedures. Healthy male subjects aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture. Have a body mass index (BMI) between 18 and 29.9 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive. Normal OGTT at screening (<7.8 mmol/L). Serum cortisol levels within normal limits at screening (collected as part of the clinical chemistry panel). Able to understand, read and speak the German language. Exclusion Criteria: History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study. History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs. History of or active or latent tuberculosis (TB), or at risk for having acquired TB (social workers or prison staff in countries with endemic rates of TB, having lived with patients with known TB). History suggesting abnormal immune function, as judged by the investigator. Any contraindications to be treated with prednisolone (allergy to any ingredient, systemic fungal infection, certain type of malaria, inflammation of the optic nerve, or herpes infection of the eye, scheduled to have a live or attenuated live vaccination or taking mifepristone). History of severe affective disorder including depressive or manic-depressive illness them self or first degree relatives. History of previous steroid psychosis Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP. Any latent or chronic infections (e.g., recurrent sinusitis, genital or ocular herpes, urinary tract infection) or at risk of infection (surgery, trauma, or significant infection), or history of skin abscesses within 90 days prior to the first administration of IMP. Any clinically important laboratory abnormalities (clinical chemistry, hematology, coagulation or urinalysis results), as judged by the investigator. In particular a subject with an abnormal value in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), creatinine, thyroid-stimulating hormone (TSH), fasting glucose, International Normalised Ratio (INR), haemoglobin (Hb), white blood cell (WBC), absolute neutrophil or platelet count will be excluded. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV). Abnormal vital signs, after 10 minutes supine rest, defined as any of the following: Systolic BP (SBP) < 90mmHg or ≥ 140 mmHg, Diastolic BP (DBP) < 50mmHg or ≥ 90 mmHg, Pulse < 45 or > 85 beats per minute (bpm). Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG, as considered by the investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy. Prolonged QTcF > 450 ms or family history of long QT syndrome. PR(PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation). PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block, or AV dissociation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD9567 oral suspension<br>In Part A: up to 8 cohorts with single ascending doses (starting at 2 mg up to 155 mg). In Part B: one cohort with a single dose | Drug: AZD9567 Monohydrat<br>* AZD9567 oral suspension 0.5 to 10 mg/ml<br>|
| Placebo Comparator: Placebo<br>Subjects randomized to placebo in the first 8 cohorts will receive the same dose volume of oral suspension as subjects on AZD9567 and subjects randomized to placebo in cohort 9(prednisolone cohort) will receive the same number of capsules as subjects on prednisolone. | Drug: Placebo oral suspension/ Placebo capsule<br>* Matching placebo<br>|
| Experimental: Prednisolone capsules<br>Within each cohort 6 subjects will be randomized to receive prednisolone 60mg oral capsules and 2 subjects randomized to receive matching placebo in a fasted state. Sentinel dosing will not be employed for the prednisolone cohort. The SRC will not be required to evaluate the prednisolone cohort. This cohort can be performed at any time during clinical execution of the study provided the protocol amendment was approved. | Drug: Prednisolone<br>* Prednisolone 60mg oral capsules (12 capsules of 5 mg each).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of AZD9567 by Assessing the Number of Participants With Adverse Events | Safety and tolerability variables included AEs, vital signs (blood pressure and pulse), ECGs (12-lead ECGs, safety ECGs and telemetry), clinical laboratory safety evaluations (haematology, clinical chemistry [including osteocalcin], coagulation, urinalysis [including 24 hour urine cortisol per day {tU-cortisol}]) and physical examinations. Note: No clinically relevant findings were noted in clinical laboratory results and vial signs assessments. Hence, none of the laboratory or vital signs findings were reported as AEs. | At screening, Day -2, Day -1, Day 1 (at pre-dose; 3 & 12 hours post-dose), Day 2 (24 hours post-dose), Day 3 and follow-up (7 to 10 days post-dose) | 
| Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Observed Maximum Plasma Concentration (Cmax) | To assess the Cmax of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. Cmax was taken directly from the individual concentration-time curve. | On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose) | 
| Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Time to Reach Maximum Plasma Concentration(Tmax) | To assess the tmax of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. tmax was taken directly from the individual concentration-time curve. | On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose) | 
| Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Terminal Half-life (t½λz) | To assess t½λz of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. t½λz was estimated as (ln2)/λz. | On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose) | 
| Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Area Under the Plasma Concentration-curve From Time Zero to the Time of Last Quantifiable Analyte Concentration (AUC(0-last)) | To assess AUC(0-last) of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. | On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose) | 
| Rate and Extent of Absorption of Single Ascending Doses of AZD9567 by Assessment of Area Under the Plasma Concentration-curve From Time Zero Extrapolated to Infinity (AUC) | To assess AUC of AZD9567 oral suspension following 8 single ascending doses (2, 10, 20, 40, 80, 100, 125 and 155 mg) in Cohorts 1 to 8 in the fasted state. AUC was estimated by AUC(0-last) + Clast/λz. Clast - the last observed quantifiable concentration. | On Day 1 (at pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post-dose), Day 2 (24 hours post-dose) and Day 3 (48 hours post-dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Outcome: Relative Change From Baseline of AUC0-4h for Plasma Glucose to Assess the Effects on Glucose Homeostasis (Oral Glucose Tolerance Test [OGTT]) | To assess the effect of AZD9567 and prednisolone on OGTT after administration of 75 g glucose solution, blood samples were collected pre glucose intake and at post glucose intake for the analyses of plasma glucose. AUC0-4h relative change between Day 1 and Day -1 was calculated for each subject in a specific treatment group. Note: Total AUC0-4h was calculated using the linear trapezoidal method. Statistical analysis for the change in OGTT plasma glucose total AUC0-4h values were assessed via an analysis of variance (ANCOVA), with treatment as fixed effect. | At Day -1 (baseline) and Day 1 (pre glucose intake and at 30, 60, 90, 120, 150, 180 and 240 minutes post glucose intake) | 
| Relative Change From Baseline of AUC0-4h for Serum Insulin to Assess the Effects on Glucose Homeostasis (Oral Glucose Tolerance Test [OGTT]) | To assess the effect of AZD9567 and prednisolone on OGTT after administration of 75 g glucose solution, blood samples were collected pre glucose intake and at post glucose intake for the analyses of serum insulin. AUC0-4h relative change between Day 1 and Day -1 was calculated for each subject in a specific treatment group. Note: Total AUC0-4h was calculated using the linear trapezoidal method. Statistical analysis for the change in OGTT serum insulin total AUC0-4h values were assessed via an analysis of variance (ANCOVA), with treatment as fixed effect. | At Day -1 (baseline) and Day 1 (pre glucose intake and at 30, 60, 90, 120, 150, 180 and 240 minutes post glucose intake) | 
| Relative Change From Baseline of AUC0-4h for Serum C-peptide to Assess the Effects on Glucose Homeostasis (Oral Glucose Tolerance Test [OGTT]) | To assess the effect of AZD9567 and prednisolone on OGTT after administration of 75 g glucose solution, blood samples were collected pre glucose intake and at post glucose intake for the analyses of serum C-peptide. AUC0-4h relative change between Day 1 and Day -1 was calculated for each subject in a specific treatment group. Note: Total AUC0-4h was calculated using the linear trapezoidal method. Statistical analysis for the change in OGTT serum C-peptide total AUC0-4h values were assessed via an analysis of variance (ANCOVA), with treatment as fixed effect. | At Day -1 (baseline) and Day 1 (pre glucose intake and at 30, 60, 90, 120, 150, 180 and 240 minutes post glucose intake) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD9567, Healthy subjects, Phase 1, placebo controlled, single ascending dose, Pharmacokinetics, Pharmacodynamics, Rheumatoid Arthritis