A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD8233 in Healthy Male Subjects With Increased Elevated LDL-C Levels.

NCT03593785 | Completed Phase 1 FDA Drug

• 1 other identifier: D7990C00001
• Study Type: interventional
• Target: 73
• Locations: 1 country
• Sites: 1

Brief Summary

AZD8233 has not been evaluated in clinical studies previously. This is a first-in-human (FiH) study. This study will assess the safety, tolerability and pharmacokinetics (PK) of AZD8233, following subcutaneous (SC) administration of single ascending dose (SAD) of AZD8233. This study will also investigate the pharmacodynamics (PD) of AZD8233 by investigating the effect of AZD8233 on levels of cholesterol and related biomarkers.

Conditions

Hypercholesterolemia

Keywords

Cholesterol; Biomarkers

Outcome Measures

Primary Outcomes (43)

• Number of subjects with adverse events (AEs) due to AZD8233 SC SAD treatment

  To assess AEs as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses. Serious AEs will be recorded from the time of informed consent.

  From randomization to 4 months follow-up

• Vital sign: Blood pressure [BP]

  To assess supine position systolic and diastolic BP as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses. Both SBP and DBP will be collected after the subject has rested in the supine position for at least 10 minutes.

  From screening to 4 month follow-up.

• Vital sign: Pulse rate

  To assess supine position pulse rate as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses. Pulse rate will be collected after the subject has rested in the supine position for at least 10 minutes.

  From screening to 4 month follow-up.

• Vital sign: Oral body temperature

  To assess oral body temperature as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses. Body temperature will be collected after the subject has rested in the supine position for at least 10 minutes.

  From screening to 4 month follow-up.

• Number of patients with abnormal findings in Resting 12-lead Electrocardiogram (ECG)

  To assess any clinically significant abnormalities in the cardiovascular system functioning using a 12-lead ECG as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses. ECG evaluations will be recorded after approximately 10 min resting in supine position.

  From screening to 4 month follow-up.

• Physical examination

  To assess physical examination as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses. Full (general appearance, skin, cardiovascular, respiratory, abdomen, head, and neck \[including ears, eyes, nose, and throat\], lymph nodes, thyroid, musculoskeletal and neurological systems) and brief (Abbreviated; general appearance, skin, cardiovascular system, respiratory and abdomen) physical examinations will be performed.

  From screening to 4 month follow-up.

• Laboratory assessments: Haematology - Blood cells count

  To assess red blood cells ( RBC) and white blood cells (WBC) count as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Haematology - Hemoglobin (Hb)

  To assess Hb as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Haematology - Haematocrit (HCT)

  To assess HCT (volume percentage of RBC in blod) as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Haematology - Mean corpuscular volume (MCV)

  To assess MCV as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Haematology - Mean corpuscular hemoglobin (MCH)

  To assess MCH as a variable of safety and tolerability following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Haematology - Mean corpuscular hemoglobin concentration (MCHC)

  To assess MCHC as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Haematology - Differential count

  To assess differential WBC count absolute count of neutrophils, lymphocytes, monocytes, eosinophils and basophils as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Haematology - Platelets

  To assess platelets count as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Haematology - Reticulocytes absolute count

  To assess reticulocytes absolute count as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Serum clinical chemistry - Electrolytes

  To assess serum level of sodium, potassium, calcium and phosphate as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Serum clinical chemistry - Urea

  To assess serum level of urea as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Serum clinical chemistry - Creatinine

  To assess serum level of creatinine as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Serum clinical chemistry - Glucose (fasting)

  To assess serum fasting glucose level as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Serum clinical chemistry - Liver enzymes

  To assess serum of Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and Gamma glutamyl transpeptidase (GGT) as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Serum clinical chemistry - Total Bilirubin

  To assess serum bilirubin (total) level as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Serum clinical chemistry - Cell enzymes

  To assess serum glutamate dehydrogenase and lactate dehydrogenase level as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Coagulation

  To assess activated partial thrombin time (aPTT) and prothrombin time (PT) as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Lipid Panel

  To assess serum level of high density lipoprotein, low density lipoprotein, triglycerides and total cholesterol as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Clinical Urinalysis - Glucose

  To assess urine glucose level as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Clinical Urinalysis - Protein

  To assess urine protein level as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Clinical Urinalysis - Blood

  To assess presence of blood in urine as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Clinical Urinalysis - Creatinine

  To assess urine creatinine level as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Clinical Urinalysis - Microscopy evaluation

  If protein or blood present in urine, levels of RBC, WBC, Casts (Cellular, Granular, Hyaline) will be assessed as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Renal Safety Biomarkers - Serum Creatinine

  To assess renal biomarker by evaluation of serum creatinine level, as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Renal Safety Biomarkers - Urine protein

  To assess renal biomarker by evaluation of urine protein level, as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Renal Safety Biomarkers - Estimated glomerular filtration rate (eGFR)

  To assess renal biomarker by evaluation of eGFR, as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Renal Safety Biomarkers -Urine Kidney Injury Molecule-1 (KIM-1)

  To assess renal biomarker by evaluation of urine KIM-1 level, as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Renal Safety Biomarkers - Urine Neutrophil gelatinase-associated lipocalin (NGAL)

  To assess renal biomarker by evaluation of NGAL level in urine, as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Renal Safety Biomarkers - Urine Alpha-glutathione S-transferase (Alpha-GST)

  To assess renal biomarker by evaluation of Alpha-GST level in urine, as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Immune Activation Response: High Sensitivity - C-reactive protein (hs-CRP)

  To assess hs-CRP level as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  Days 1 to 3 (pre-dose, 2, 4, 24 and 48 hours post-dose).

• Complement Activation panel

  To assess chemotactic factors (C3a, C5a and Bp) levels as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  Day -1 and Days 1 to 3 (2, 4 and 24 hours post-dose).

• Injection Site Reaction Examinations

  To assess injection site reactions in terms of size (mm), color (pale/light red/dark red) and itching (yes or no) as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  At Days 1 to 4, week 1 to 14 and week 16.

• Number of patients with abnormal findings in Telemetry

  To assess heart rhythm and QRS pattern (heart conduction) as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses. ECG evaluations will be recorded after approximately 10 min resting in supine position.

  At Day -1 and Days 1 to 3 (Pre-dose to 24 hours post-dose)

• Laboratory assessments: Serum clinical chemistry - Creatine kinase

  To assess serum level of creatine kinase as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Serum clinical chemistry - Bicarbonate

  To assess serum level of Bicarbonate as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Serum clinical chemistry - Direct bilirubin

  To assess serum level of direct bilirubin as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

• Laboratory assessments: Serum clinical chemistry -Uric acid

  To assess serum level of Uric acid as a variable of safety and tolerability of AZD8233 following SC administration of single ascending doses.

  From screening to 4 month follow-up.

Secondary Outcomes (17)

• Plasma PK analysis: Time delay between drug administration and the first observed concentration in plasma (tlag)

  At treatment Days 1 to 3 (Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours post-dose); Day 4 (72 hours post-dose); week 1 to 14 (1, 2, 4, 6, 8 and 12 weeks post-dose) and Final Follow-up Visit/ET Visit

• Plasma PK analysis: Time to reach peak or maximum observed concentration following drug administration (tmax)

  At treatment Days 1 to 3 (Pre-dose and then at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours post-dose); Day 4 (72 hours post-dose); week 1 to 14 (at 1, 2, 4, 6, 8 and 12 weeks post-dose) and Final Follow-up Visit/ET Visit

• Plasma PK analysis: Maximum observed plasma concentration (Cmax)

  At treatment Days 1 to 3 (Pre-dose and then at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours post-dose); Day 4 (72 hours post-dose); week 1 to 14 (at 1, 2, 4, 6, 8 and 12 weeks post-dose) and Final Follow-up Visit/ET Visit

• Plasma PK analysis: Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC[0-last])

  At treatment Days 1 to 3 (Pre-dose and then at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours post-dose); Day 4 (72 hours post-dose); week 1 to 14 (at 1, 2, 4, 6, 8 and 12 weeks post-dose) and Final Follow-up Visit/ET Visit

• Plasma PK analysis: Area under the concentration-time curve from time zero to 48 hours post-dose (AUC[0-48])

  At treatment Days 1 to 3 (Pre-dose and then at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours post-dose); Day 4 (72 hours post-dose); week 1 to 14 (at 1, 2, 4, 6, 8 and 12 weeks post-dose) and Final Follow-up Visit/ET Visit

Study Arms (5)

Cohort 1

EXPERIMENTAL

On Day 1, randomized subjects will receive single SC dose of AZD8233 dose 1 injection (6 subjects) or matching placebo (2 subjects).

Drug: AZD8233

Cohort 2

EXPERIMENTAL

On Day 1, randomized subjects will receive single SC dose of AZD8233 dose 2 injection (6 subjects) or matching placebo (2 subjects).

Drug: AZD8233

Cohort 3

EXPERIMENTAL

On Day 1, randomized subjects will receive single SC dose of AZD8233 dose 3 injection (6 subjects) or matching placebo (2 subjects).

Drug: AZD8233

Cohort 4

EXPERIMENTAL

On Day 1, randomized subjects will receive single SC dose of AZD8233 dose 4 injection (6 subjects) or matching placebo (2 subjects).

Drug: AZD8233

Cohort 5

EXPERIMENTAL

On Day 1, randomized subjects will receive single SC dose of AZD8233 dose 5 injection (6 subjects) or matching placebo (2 subjects).

Drug: AZD8233

Interventions

AZD8233 DRUG

Randomized subjects will receive single SC dose of AZD8233 (dose 1, dose 2, dose 3, dose 4 and dose 5) injection.

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5

Eligibility Criteria

• Age: 18 Years - 60 Years
• Gender Eligibility Details: Healthy male subjects with elevated LDL-C levels, aged 18 to 60 years that weigh at least 60 kg and no more than 100 kg inclusive.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent before any study specific procedures.
• Healthy male subjects aged 18 to 60 years (inclusive at Screening Visit) with suitable veins for cannulation or repeated venipuncture.
• Have a body mass index (BMI) between 18 and 32 kg/m2 inclusive and weigh at least 60 kg and no more than 100 kg inclusive at the Screening Visit and Day -1.
• Have a LDL-C ≥ 100 mg/dL \< 190 mg/dL at the Screening Visit and Day -1, test may be repeated once for each visit at the discretion of the Investigator if out of the range.
• Provision of signed, written and dated informed consent for optional genetic/biomarker research. If a subject declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this protocol.

You may not qualify if:

• 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 GI, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
• Any clinically important illness, medical/surgical procedure or trauma within 4weeks of the first administration of IMP.
• Any laboratory values with the following deviations at the Screening Visit and/or Day -1, test may be repeated once for each visit at the discretion of the Investigator if out of range:
• Alanine aminotransferase (ALT)\> upper limit of normal (ULN). 4.2.Aspartate aminotransferase (AST)\> ULN. 4.3.Creatinine \> ULN. 4.4.White blood cell (WBC)\< LLN. 4.5.Hemoglobin\< LLN. 4.6.Platelet count ≤150000/μL. 4.7.Activated partial thrombin time greater than ULN and PT greater than ULN. 4.8.Have an eGFR \< 60mL/min. 4.9.Have an urinary albumin-to-creatinine ratio(ACR)\> 3mg/μmol (30mg/g).
• Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus (HIV).
• Abnormal vital signs, after 10 minutes supine rest, with the following deviations at the Screening Visit and/or Day -1, test may be repeated once for each visit at the discretion of the Investigator if out of range:
• Systolic BP\< 90mmHgor\> 140mmHg. 7.2.Diastolic BP\< 50mmHgor \> 90mmHg. 7.3.Heart rate \< 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 at the Screening Visit or Day -1, test may be repeated once for each visit, at the discretion of the Investigator if out of range.
• Prolonged QTcF \> 450 ms. 8.2. Shortened QTcF \< 340 ms. 8.3. Family history of long QT syndrome. 8.4. 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 atrioventricular (AV) block, or AV dissociation.
• 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 \< 115 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 Investigator.
• Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the previous 3 months before the Screening Visit.
• History of alcohol abuse or excessive intake of alcohol as judged by the Investigator.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Glendale, California, 91206, United States

Location

MeSH Terms

Conditions

Hypercholesterolemia

Condition Hierarchy (Ancestors)

Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• David Han, M.D

  PAREXEL Early Phase Clinical Unit-Los Angeles

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: This study is single-blind with regard to treatment (AZD8233 or placebo) at each dose level. AZD8233 and placebo will be matched for formulation, appearance and amount. Subjects randomized to placebo will receive the same volume of injection as subjects on active drug.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 10, 2018
• First Posted: July 20, 2018
• Study Start: August 3, 2018
• Primary Completion: December 19, 2020
• Study Completion: December 19, 2020
• Last Updated: January 25, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• 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)