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

NCT04365218 | Completed Phase 1 FDA Drug

• 1 other identifier: D6361C00001
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Chronic Kidney Disease

Keywords

First-in-human, Single Ascending Dose

Outcome Measures

Primary Outcomes (54)

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

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

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

• Number of subjects with abnormal systolic blood pressure (SBP)

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

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

• Number of patients with abnormal diastolic blood pressure (DBP)

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

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

• Number of subjects with abnormal HR

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

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

• Number of subjects with respiratory rate

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

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

• Number of subjects with abnormal oral body temperature

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

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

• Number of subjects with abnormal electrocardiogram (ECG)

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

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

• Number of subjects with abnormal physical examination

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

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

• Number of subjects with abnormal structured neurological assessment

  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

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

• Number of subjets with abnormal retinal imaging

  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

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

• Number of subjects with abnormal Hemoglobin (Hb) level

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

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

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

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

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

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

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

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

• Number of subjects with abnormal differential WBC count

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

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

• Number of subjects with abnormal hematocrit (HCT)

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

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

• Number of subjects with abnormal mean corpuscular volume (MCV)

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

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

• Number of subjects with abnormal mean corpuscular hemoglobin (MCH)

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

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

• Number of subjects with abnormal reticulocytes absolute count

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

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

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

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

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

• Number of subjects with abnormal platelets count

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

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

• Number of subjects with abnormal creatinine level

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

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

• Number of subjects with abnormal blood urea nitrogen level

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

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

• Number of subjects with abnormal urea level.

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

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

• Number of subjects with abnormal bicarbonate level

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

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

• Number of subjects with abnormal creatine kinase (CK) level

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

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

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

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

  From screening (Day -28) to treatment period (Day -1)

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

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

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

• Number of subjects with abnormal cystatin C level

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

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

• Number of subjects with abnormal glucose (fasting) level

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

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

• Number of subjects with abnormal potassium level

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

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

• Number of subjects with abnormal sodium level

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

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

• Number of subjects with abnormal phosphate level

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

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

• Number of subjects with abnormal calcium level

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

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

• Number of subjects with abnormal chloride level

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

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

• Number of subjects with abnormal alkaline phosphatase (ALP)

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

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

• Number of subjects with abnormal bilirubin level

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

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

• Number of subjects with abnormal alanine aminotransferase (ALT)

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

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

• Number of subjects with abnormal aspartate aminotransferase (AST)

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

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

• Number of subjects with abnormal albumin level

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

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

• Number of subjects with abnormal urine protein level

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

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

• Number of subjects with abnormal urine glucose level

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

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

• Number of subjects with abnormal urine pH

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

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

• Number of subjects with abnormal urine ketone level

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

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

• Number of subjects with abnormal urine bilirubin level

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

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

• Number of subjects with abnormal urine blood level

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

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

• Number of subjects with abnormal urine color.

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

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

• Number of subjects with abnormal urine appearance.

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

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

• Number of subjects with abnormal urine specific gravity level

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

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

• Number of subjects with abnormal urine leukocyte esterase level

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

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

• Number of subjects with abnormal urine urobilinogen level

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

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

• Number of subjects with abnormal urine nitrite level

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

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

• Number of subjects with abnormal urine RBC level

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

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

• Number of subjects with abnormal urine WBC level

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

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

• Number of subjects with abnormal urine casts level

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

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

Secondary Outcomes (13)

• 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)

Study Arms (6)

Cohort 1 (Dose A)

EXPERIMENTAL

6 subjects will be randomized to receive MEDI8367 Dose A and 2 subjects will be randomized to receive placebo.

Drug: MEDI8367; Drug: Placebo

Cohort 2 (Dose B)

EXPERIMENTAL

6 subjects will be randomized to receive MEDI8367 Dose B and 2 subjects will be randomized to receive placebo.

Drug: MEDI8367; Drug: Placebo

Cohort 3 (Dose C)

EXPERIMENTAL

6 subjects will be randomized to receive MEDI8367 Dose C and 2 subjects will be randomized to receive placebo.

Drug: MEDI8367; Drug: Placebo

Cohort 4 (Dose D)

EXPERIMENTAL

6 subjects will be randomized to receive MEDI8367 Dose D and 2 subjects will be randomized to receive placebo.

Drug: MEDI8367; Drug: Placebo

Cohort 5 (Dose D)

EXPERIMENTAL

6 subjects will be randomized to receive MEDI8367 Dose D or the highest tolerable dose based on Cohorts 1 to 4 and 2 subjects will be randomized to receive placebo.

Drug: MEDI8367; Drug: Placebo

Cohort 6 (Dose D)

EXPERIMENTAL

15 subjects will be randomized to receive MEDI8367 Dose D or the highest tolerable dose based on Cohorts 1 to 4 and 15 subjects will be randomized to receive placebo.

Drug: MEDI8367; Drug: Placebo

Interventions

MEDI8367 DRUG

Subjects will receive subcutaneous (SC) single dose of MEDI8367, depending upon dose escalation strategy and Safety Review Committee results. The maximum dose will not exceed 600 mg. The dose will be administered as a single injection or multiple injections in the abdomen region.

Cohort 1 (Dose A); Cohort 2 (Dose B); Cohort 3 (Dose C); Cohort 4 (Dose D); Cohort 5 (Dose D); Cohort 6 (Dose D)

Placebo DRUG

Saline solution for injection and the placebo volume to be administered will be equivalent to the MEDI8367 volume administered for each dosing cohort.

Cohort 1 (Dose A); Cohort 2 (Dose B); Cohort 3 (Dose C); Cohort 4 (Dose D); Cohort 5 (Dose D); Cohort 6 (Dose D)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• The subjects in Cohort 6 (subjects with CKD) must fulfil the following additional criteria:
• Male and/or female subjects aged 18 to 70 years, inclusive, at the Screening Visit.
• Have a BMI between 18 and 45 kg/m2 inclusive and weigh at least 50 kg and no more than 150 kg inclusive, at the Screening Visit.
• Subjects must have CKD, defined as:
• An estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and

You may not qualify if:

• 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 6.
• Any laboratory values with the following deviations at screening or admission (for Cohort 6 see below):
• ALT \> Upper limit of normal (ULN).
• AST \> ULN.
• Total bilirubin (TBL) \> ULN (unless due to Gilbert's syndrome).
• Creatinine \> ULN.
• WBC count \< lower limit of normal (LLN).

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Glendale, California, 91206, United States

Location

MeSH Terms

Conditions

Renal Insufficiency, Chronic

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Dr David Han, MD

  PAREXEL Early Phase Clinical Unit-Los Angeles

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This study is blinded for subjects, Investigator and site staff, and Contract Research Organization staff with regard to treatment (MEDI8367 or placebo) at each dose level. The Sponsor will be unblinded to treatment allocation.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 30, 2020
• First Posted: April 28, 2020
• Study Start: July 22, 2020
• Primary Completion: January 3, 2021
• Study Completion: January 3, 2021
• Last Updated: April 21, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

US (1)