A Study to Evaluate the Safety and Pharmacokinetics with MEDI8367 Administered in Healthy Subjects, and in Subjects with Chronic Kidney Disease

Exclusion Criteria

• • History of any disease or condition that, in the opinion of the site PI and/or medical monitor, would place the subject at an unacceptable risk to participate in this study or interfere with evaluation of the investigational product or interpretation of subject safety or study results, including, but not limited to:
• a. History of any blood brain barrier (BBB) breakdown such as, but not limited to, recent traumatic brain/spinal injury, multiple sclerosis, active central nervous system vasculitis, recent stroke or cerebral hemorrhage, neurosurgery, meningoencephalitis, active or uncontrolled seizures, or lumbar puncture within the preceding 6 months.
• b. Prior malignancy other than non-melanoma skin cancer or cervical cancer in situ treated with apparent success with curative therapy (response duration of > 5 years).
• c. Subjects with renal allografts.
• • Proliferative retinopathy confirmed by retinal imaging at the Screening Visit
• .
• • History or presence of hematological, hepatic or renal disease (except Cohort 6) or any other condition known to interfere with administration, absorption, distribution, metabolism or excretion of drugs.
• • Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP.
• • Any clinically relevant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during screening or Day -1 that, in the opinion of the site PI or medical monitor, may compromise the safety of the subject in the study, interfere with the evaluation of the IMP, or reduce the subjects’ ability to participate in the study.
• Note: Abnormal urinary findings will not exclude subjects in Cohort 6.
• • Any laboratory values with the following deviations at screening or admission (for Cohort 6 see below):
• (a) ALT > Upper limit of normal (ULN).
• (b) AST > ULN.
• (c) Total bilirubin (TBL) > ULN (unless due to Gilbert’s syndrome).
• (d) Creatinine > ULN.
• (e) WBC count < lower limit of normal (LLN).
• (f) Hb < LLN.
• (g) Impaired renal function, defined as eGFR < 90 mL/min/1.73 m2 based on the CKD-EPI equation.
• • Any positive result at the Screening Visit for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV).
• • Abnormal vital signs at Screening or Visit 2 (Day -1), after 10 minutes supine rest, defined as any of the following:
• a. SBP < 90 mmHg or ≥ 140 mmHg.
• b. DBP < 50 mmHg or ≥ 90 mmHg.
• c. HR < 45 or > 85 beats per minute (bpm).
• • Any clinically important abnormalities in rhythm, conduction or morphology of the resting 12-lead ECG as considered by the site PI that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology or left ventricular hypertrophy, at screening or admission.
• a. Prolonged QTcF > 450 ms.
• b. Family history of long QT syndrome.
• c. PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation).
• d. PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation.
• e. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms. Subjects with QRS > 110 ms but < 120 ms are acceptable if there is no evidence of e.g., ventricular hypertrophy or pre-excitation.
• • Known or suspected history of drug abuse as judged by the site PI.
• • History of alcohol and/or substance abuse within the last 6 months or excessive intake of alcohol as judged by the site PI.
• • Positive screen for drugs of abuse, including recreational marijuana, at the Screening Visit or upon admission to the Clinical Unit/study. Subjects who utilize benzodiazepines for chronic anxiety or sleep disorders may be permitted to enter the study.
• • History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the site PI or history of hypersensitivity to drugs with a similar chemical structure or class to MEDI8367.
• a. History of severe allergic reaction requiring hospitalization or,
• b. History of severe reaction to any medication including biologic agents or human
• gamma globulin therapy or,
• c. History of allergy or reaction to any component of the IMP formulation.
• • Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, mega-dose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals with the 2 weeks or 5 half-lives prior to the first administration of IMP (Day 1) (whichever is longer). Further clarification regarding specific medications is provided below:
• a. Female subjects will be allowed to take hormone replacement therapy.
• b. Current or previous use of systemic corticosteroids within 60 days prior to Day 1 is prohibited
• c. Topical, intra-articular, nasal, inhaled, and ophthalmic corticosteroids are permitted.
• d. Antiplatelet therapy (i.e., aspirin, clopidogrel [Plavix], ticagrelor [Brilinta], or prasugrel), anticoagulation therapy (i.e., warfarin, factor Xa inhibitors, direct thrombin inhibitors, or heparin), and thrombolytic use, in the past month prior to Day 1 or planned use during the duration of the study, are prohibited.
• • Plasma donation within one month of the Screening Visit or any blood donation/blood loss > 500 mL during the 3 months prior to Day 1 (or > 1200 mL in the year prior to Day 1).
• • Has received another new chemical or biologic entity (defined as a compound which has not been approved for marketing) within 4 months or 5 half-lives prior to the Screening Visit (whichever is longer), or planned participation in such a study prior to the end of the follow-up period.
• Note: subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded.
• • Scheduled surgery, including dental surgery, within 8 weeks of the scheduled completion date of the study.
• • Involvement of any AstraZeneca, Clinical Unit, Contract Research Organization (CRO), or study site employee or their close relatives, regardless of the employee’s role.
• • Judgement by the site PI that the subject should not participate in the study if they have any ongoing or recent (i.e., during the Screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.
• • Subjects who cannot communicate reliably with the site PI.
• • Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
• The following exclusion criteria apply to subjects in Cohort 6 (subjects with CKD):
• • Clinically significant late diabetic complications, including symptoms consistent with angina, congestive heart failure, and peripheral arterial disease (claudication), or other complications such as proliferative retinopathy, maculopathy, or gastroparesis.
• • Chronic kidney disease due to abnormal anatomy of the urinary system or autosomal dominant polycystic kidney disease (ADPKD).
• • Aggressive or serious neuropathies, in particular immune related demyelinating neuropathies such as Guillain-Barré, or one of its variants.
• • Any laboratory values with the following deviations at screening or admission:
• a. ALT > 2 x ULN.
• b. AST > 2 x ULN.
• c. TBL > ULN (unless due to Gilbert’s syndrome).
• d. Hb <100 g/L
• e. Glycated hemoglobin (HbA1C) > 10.5% measured at the Screening Visit.
• • Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, mega-dose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals with the 2 weeks or 5 half-lives prior to the first administration of IMP (Day 1) (whichever is longer). Further clarification regarding specific medications is provided below:
• a. Subjects may take their usual prescribed medication, or any other medication taken on the advice of their physician with the exception of systemic corticosteroids. They should have been on a stable drug regimen with no changes in agents or doses for at least 4 weeks prior to participation in the study. Dose adjustment of the next/previous titration dose within 2 weeks of the Screening Visit is acceptable.
• b. Any serum creatinine-altering drugs within 1 month prior to the Screening Visit including but not limited to amphotericin, cimetidine, clofibrate, dronedarone, ketoconazole, probenecid, ranolazine, trimethoprim, aminoglycosides, or cephalosporins are prohibited.
• c. Use of insulin is prohibited.