Clinical Trials/NCT04365218

NCT04365218

Completed

Phase 1

A Phase I Randomized, Blinded, Placebo-controlled Study to Evaluate the Safety and Pharmacokinetics of MEDI8367 Administered as Single Ascending Doses in Healthy Subjects, and as a Single Dose in Healthy Subjects of Japanese-descent and in Subjects With Chronic Kidney Disease

AstraZeneca1 site in 1 country12 target enrollmentJuly 22, 2020

ConditionsChronic Kidney Disease

InterventionsMEDI8367 Placebo

DrugsMEDI8367 Placebo

Overview

Phase: Phase 1
Intervention: MEDI8367
Conditions: Chronic Kidney Disease
Sponsor: AstraZeneca
Enrollment: 12
Locations: 1
Primary Endpoint: Number of subjects with adverse events (AEs) and serious adverse events (SAEs)
Status: Completed
Last Updated: 4 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

This Phase I First in Human (FIH) study is being conducted to determine the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity profile of MEDI8367 across the dose range.

Detailed Description

This is a Phase I, FIH, randomized, blinded, placebo-controlled study, to evaluate the safety and PK of MEDI8367 as single ascending doses (SAD) in healthy subjects and as a single dose in healthy subjects of Japanese-descent and in subjects with chronic kidney disease (CKD). Six cohorts, Cohorts 1 to 5 (healthy volunteers including Japanese subjects in Cohort 5) each consisting of 8 subjects (total 40 subjects), and Cohort 6 (subjects with CKD) consisting of 30 subjects, will participate in the study. The starting dose is dose A of MEDI8367 with up to 3 dose escalations planned (provisional doses of dose B, dose C, and dose D). The study will comprise of: * A Screening Period of maximum 28 days; * A Treatment Period during which subjects will be resident at the Clinical Unit/non-clinical sites from the day before investigational medicinal product (IMP) administration (Day -1) until at least 72 hours after IMP administration; discharged on Day 4; and * A Follow-up Period (out-patient) with 8 visits; the final Follow-up Visit (Visit 10) within 90 ± 4 days after the last IMP dose. The study day for the last visit may be adjusted based on PK/PD results from the current and previous cohorts. Dosing for Cohorts 1 to 4 and Cohort 6 will proceed with 2 subjects in a sentinel cohort, such that one subject will be randomized to receive MEDI8367 and one subject will be randomized to receive placebo. The blinded safety data from the sentinel subjects up to 3 days post-dose will be reviewed by the site Principal Investigator (PI) before the remaining subjects in the cohort are dosed. Dosing is proposed to continue based on a lack of significant safety findings in the first 2 subjects dosed per cohort. The remaining 6 subjects in Cohorts 1 to 4, respectively, and 28 subjects in Cohort 6, will be dosed at least 3 days after the sentinel cohort.

Registry

clinicaltrials.gov

Start Date

July 22, 2020

End Date

January 3, 2021

Last Updated

4 years ago

Study Type

Interventional

Study Design

Sequential

Sex

All

Investigators

Sponsor

AstraZeneca

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Provision of signed and dated, written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the USA) prior to any study specific procedures.
•Male and/or female subjects aged 18 to 55 years (for Cohort 6 see below), inclusive, at the Screening Visit.
•Females must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit/study site, must not be lactating and must be of non-childbearing potential, confirmed at the Screening Visit by fulfilling one of the following criteria:
•Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and FSH levels in the postmenopausal range.
•Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
•Non-sterilized male subjects who are sexually active with a female partner of childbearing potential must use a male condom with spermicide starting from the time of IMP administration until 3 months after the final Follow-up Visit. It is strongly recommended for the female partner of a male subject to also use a highly effective method of contraception throughout this period.
•Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive, at the Screening Visit.
•Ability and willingness to adhere to the visit/protocol schedule and complete the Follow-up Period.
•The subjects in Cohort 5 (subjects of Japanese descent) must fulfil the following additional criterion:
•Subjects must be of Japanese descent, defined as having 4 grandparents who are Japanese. This includes second and third generation subjects of Japanese descent whose parents or grandparents are living in a country other than Japan.

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:
•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.
•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).
•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
•Any laboratory values with the following deviations at screening or admission (for Cohort 6 see below):

Intervention: Placebo

Outcomes

Primary Outcomes

Number of subjects with adverse events (AEs) and serious adverse events (SAEs)

Time Frame: From screening (Day -28) to follow-up period (Day 90 ± 4 days)

To assess AEs as a variable of safety and tolerability of SC of MEDI8367

Number of subjets with abnormal retinal imaging

Time Frame: From screening (Day -28) up to follow-up period (Day 90 ± 4 days)

To assess retinal imaging as a variable of safety and tolerability of MEDI8367. The presence of proliferative retinopathy or any other new retinal changes will be recorded. Any new or aggravated clinically relevant abnormal retinal imaging finding compared to the baseline assessment will be reported as an AE

Number of subjects with abnormal Hemoglobin (Hb) level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in Hb as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal physical examination

Time Frame: From screening (Day -28) up to follow-up period (Day 90 ± 4 days)

To assess change in physical examination as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal creatinine level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess creatinine level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal blood urea nitrogen level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess blood urea nitrogen level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urea level.

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To asses urea level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal bicarbonate level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To asses bicarbonate level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal creatine kinase (CK) level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To asses CK level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal structured neurological assessment

Time Frame: From screening (Day -28 ) up to follow-up period (Day 90 ± 4 days)

To assess change in structured neurological assessment as safety and tolerability of MEDI8367. Any new or aggravated clinically relevant abnormal neurological examination finding compared to the baseline assessment will be reported as an AE

Number of subjects with abnormal systolic blood pressure (SBP)

Time Frame: From screening (Day -28) up to follow-up period (Day 90 ± 4 days)

To assess supine position SBP as a variable of safety and tolerability of MEDI8367

Number of patients with abnormal diastolic blood pressure (DBP)

Time Frame: From screening (Day -28) up to follow-up period (Day 90 ± 4 days)

To assess supine position DBP as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal HR

Time Frame: From screening (Day -28) up to follow-up period (Day 90 ± 4 days)

To assess change in supine position HR as a variable of safety and tolerability of MEDI8367

Number of subjects with respiratory rate

Time Frame: From screening (Day -28) up to follow-up period (Day 90 ± 4 days)

To assess change in supine position respiratory rate as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal oral body temperature

Time Frame: From screening (Day -28) up to follow-up period (Day 90 ± 4 days)

To assess change in oral body temperature as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal electrocardiogram (ECG)

Time Frame: From screening (Day -28) up to follow-up period (Day 90 ± 4 days)

To assess electrical activity changes in ECG as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal red blood cells (RBC) count

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess RBC count as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal white blood cells (WBC) count

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess WBC count as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal differential WBC count

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess differential WBC count as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal hematocrit (HCT)

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess HCT as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal mean corpuscular volume (MCV)

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess MCV as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal mean corpuscular hemoglobin (MCH)

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess MCH as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal reticulocytes absolute count

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess reticulocytes absolute count as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal mean corpuscular hemoglobin concentration (MCHC)

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess MCHC as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal platelets count

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess platelets count as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal follicle stimulating hormone (FSH)/luteinizing hormone (LH) level

Time Frame: From screening (Day -28) to treatment period (Day -1)

To asses FSH/LH level for postmenopausal females as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal C-reactive protein (CRP) level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To asses CRP level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal cystatin C level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To asses cystatin C level in Cohort 6 only (subjects with CKD) as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal glucose (fasting) level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To asses glucose (fasting) level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal potassium level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess potassium level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal sodium level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess sodium level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal phosphate level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess phosphate level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal calcium level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess calcium level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal chloride level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess chloride level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal alkaline phosphatase (ALP)

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess ALP level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal bilirubin level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess bilirubin level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal alanine aminotransferase (ALT)

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess ALT as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal aspartate aminotransferase (AST)

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess AST as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal albumin level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess albumin level as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine protein level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine protein as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine glucose level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess changes in abnormal urine glucose as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine pH

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine pH as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine ketone level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine ketone as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine bilirubin level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine bilirubin as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine blood level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine blood as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine color.

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine color as a variable of safety and tolerability of MEDI8367 following SC administration of SAD.

Number of subjects with abnormal urine appearance.

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine apperance as a variable of safety and tolerability of MEDI8367 following SC administration of SAD.

Number of subjects with abnormal urine specific gravity level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine specific gravity as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine leukocyte esterase level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine leukocyte esterase as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine urobilinogen level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine urobilinogen as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine nitrite level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine nitrite as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine RBC level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine microscopy included RBC as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine WBC level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine microscopy included WBC as a variable of safety and tolerability of MEDI8367

Number of subjects with abnormal urine casts level

Time Frame: From screening (Day -28 to Day -2) through follow-up period (up to Day 90 ± 4 days)

To assess change in urine microscopy casts as a variable of safety and tolerability of MEDI8367

Secondary Outcomes

Plasma PK analysis: Maximum observed serum drug concentration (Cmax)(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Plasma PK analysis: Time to reach maximum observed concentration (tmax)(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Plasma PK analysis: Terminal half-life (t½)(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Plasma PK analysis: Area under the plasma concentration-time curve from zero to the last quantifiable concentration (AUClast)(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Plasma PK analysis: Area under plasma concentration-time curve from zero to infinity (AUCinf)(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Plasma PK analysis: Apparent total body clearance of drug from serum after extravascular administration (CL/F)(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Plasma PK analysis: Volume of distribution (apparent) following extravascular administration (based on terminal phase; Vz/F)(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Plasma PK analysis: Volume of distribution (apparent) at steady state following extravascular administration (Vss/F)(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Plasma PK analysis: Area under plasma concentration-time curve from zero to the last quantifiable concentration divided by the dose administered (AUClast/D)(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Plasma PK analysis: Area under plasma concentration-time curve from zero to infinity divided by the dose administered (AUCinf/D)(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Plasma PK analysis: Maximum observed serum drug concentration divided by the dose administered (Cmax/D).(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Immunogenecity: ADA titer(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))
Immunogenecity: Anti-drug antibody (ADA) incidence.(From treatment period (Day 1) to follow-up period (up to Day 90 ± 4 days))