Atuliflapon

The clinical efficacy of Atuliflapon Dose A will be assessed by calculating a Hazard Ratio between the treatment arms, Atuliflapon Dose A vs. placebo, in a selected population (based on biomarker level). CompEx Asthma, a novel composite endpoint for exacerbations, captures asthma-worsening episodes based on a combination of diary events (worsening in daily peak expiratory flow (PEF), asthma symptoms and reliever medication use) plus severe asthma exacerbation events.

Creatinine-normalized u-LTE4 is calculated as uLTE4/creatinine

Relative bioavailability (Frel) of the Test Formulation in the fasted state (Treatment A) compared to Reference Formulation in the fasted state (Treatment C) using AUCinf will be assessed.

Relative bioavailability (Frel) of the Test Formulation in the fasted state (Treatment A) compared to Reference Formulation in the fasted state (Treatment C) using AUClast will be assessed.

Relative bioavailability (Frel) of the Test Formulation in the fasted state (Treatment A) compared to Reference Formulation in the fasted state (Treatment C) using Cmax will be assessed.

Relative bioavailability (Frel) of the Test Formulation in the fasted state (Treatment A) compared to Reference Formulation in the fasted state (Treatment C) using C24 will be assessed.

Relative bioavailability (Frel) of Treatment B (fed state, Test Formulation) versus Treatment A (fasted state, Test Formulation) using AUCinf will be assessed.

Relative bioavailability (Frel) of Treatment B (fed state, Test Formulation) versus Treatment A (fasted state, Test Formulation) using AUClast will be assessed.

Relative bioavailability (Frel) of Treatment B (fed state, Test Formulation) versus Treatment A (fasted state, Test Formulation) using C24 will be assessed.

Relative bioavailability (Frel) of Treatment B (fed state, Test Formulation) versus Treatment A (fasted state, Test Formulation) using Cmax will be assessed.

Comparison of Cmax calculated when midazolam alone and calculated when midazolam was taken together with AZD5718

Comparison of AUCinf calculated when midazolam alone and calculated when midazolam was taken together with AZD5718

Comparison of AUClast calculated when midazolam alone and calculated when midazolam was taken together with AZD5718

Comparison of tmax calculated when midazolam alone and calculated when midazolam was taken together with AZD5718

Comparison of t1/2 calculated when midazolam alone and calculated when midazolam was taken together with AZD5718

AZD5718 Plasma concentrations will be evaluated at trough and also at the expected time of tmax

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers

Assessment of the total radioactivity by measuring the amount of AZD5718 excreted (Ae)

Assessment of the total radioactivity by measuring the amount of AZD5718 excreted and expressed as a percentage of the administered dose (Fe)

Assessment of the total radioactivity by measuring the cumulative amount of AZD5718 excreted (CumAe)

Assessment of the total radioactivity by measuring the cumulative amount of AZD5718 excreted and expressed as a percentage of the administered dose (CumFe)

Assessment of metabolites and structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry

Assessment of metabolites and structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry

Assessment of metabolites and structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry

Assessment of AZD5718 and total radioactivity by measuring the time to maximum concentration (tmax)

Assessment of AZD5718 and total radioactivity by measuring the maximum plasma concentration (cmax)

Assessment of AZD5718 and total radioactivity by measuring the concentration time curve to the last quantifiable concentration (AUC last)

Assessment of AZD5718 and total radioactivity by measuring the concentration time curve from time zero to the last quantifiable concentration (AUC0-inf)

Assessment of AZD5718 and total radioactivity by measuring the Elimination Half-life (t1/2,λz)

Assessment of the oral clearance of AZD5718 by measuring the apparent oral clearance (CL/F)

Assessment of the oral PK (pharmacokinetics) of AZD5718by measuring the Apparent Volume of Distribution (Vz/F)

Assessment of the oral PK (pharmacokinetics) by measuring the renal clearance (Clr)

To assess the adverse events as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. Adverse Events will be collected from the start of randomization throughout the treatment period up to and including the follow-up visit. Serious adverse events (SAEs) will be recorded from the time of informed consent.

To assess the vital sign as a variable of safety and tolerability variable of AZD5718 following oral administration of single and multiple ascending doses.

To assess the vital sign as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

To assess any clinically important abnormalities in the cardiovascular system functioning as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. A 12-lead 10-second safety ECG will be performed with the Schiller Cardiovit CS-200 recorder immediately following all scheduled dECGs. 12-lead continuous dECG will be recorded over at least 5 minutes with the Schiller Cardiovit CS-200 recorder and transmitted to the AstraZeneca central dECG repository, according to AstraZeneca ECG Center´s standard procedures for settings, recording, and transmission of dECGs. For dECG, QTcF (QT interval corrected for heart rate using Fridericia's formula) will be calculated as QTcF =(QT\*(RR/1000)\^(-1/3)), where RR (the time between corresponding points on 2 consecutive R waves on ECG) is presented in milliseconds. Heart rate (HR) will also be calculated, based on the RR interval.

To assess any clinically important abnormalities in the cardiovascular system functioning (heart beat/rythm) using 2-lead real-time telemetry ECG as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. The telemetry monitoring system will be reviewed by the Investigator or research nurse and paper printouts of any clinically important events will be stored as source data.

To assess any clinically important abnormal findings in physical conditions as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. The complete physical examinations include an assessment of the general appearance, skin, cardiovascular, respiratory, abdomen, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems. The brief physical examinations include an assessment of the general appearance, skin, cardiovascular system, respiratory and abdomen. Any new or aggravated clinically relevant abnormal medical finding at a physical examination as compared with the baseline assessment will be reported as an adverse event.

To assess the leukocyte count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

To assess the vital sign as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (sodium) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess urinalysis (glucose) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the RBC count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

To assess the Hb as a criterion of safety and tolerability variable of AZD5718 following oral administration of single and multiple ascending doses.

To assess the HCT as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

To assess the MCV as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

To assess the MCH as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

To assess the MCHC as a variable of safety and tolerability variable of AZD5718 following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (potassium) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (urea) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (creatinine) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (albumin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (calcium) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (phosphate) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (glucose (fasting)) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (insulin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (fibrinogen) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (thyroid-stimulating hormone) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess urinalysis (blood) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses. If urinalysis is positive for blood, a microscopy test will be performed to assess RBC, white blood cell \[WBC\], casts \[cellular, granular, hyaline\]).

To assess urinalysis (protein) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses. If urinalysis is positive for protein, a microscopy test will be performed to assess RBC, WBC, casts \[cellular, granular, hyaline\]).

To assess urinalysis (urine creatinine) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the differential count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

To assess the platelets as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

To assess the reticulocytes absolute count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (CRP) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (Free T4) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (ALP) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (ALT) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (AST) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (GGT) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (total bilirubin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (unconjugated bilirubin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (glutamate dehydrogenase) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

To assess the clinical chemistry value (LDH) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.