To Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD8233 After Multiple Dose Administration in Subjects With Dyslipidemia

NCT04155645 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: D7990C00002
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 7

Brief Summary

This is a Phase I study to assess the safety, tolerability and pharmacokinetics (PK), and pharmacodynamics (PD) of AZD8233, following subcutaneous (SC) administration of multiple ascending doses (MAD) of AZD8233 in subjects with confirmed dyslipidemia with or without type 2 diabetes.

Conditions

Dyslipidemia

Keywords

Multiple Ascending Dose; AZD8233; Safety; Tolerability; PK; PD

Outcome Measures

Primary Outcomes (42)

• Number of subjects with adverse events (AEs) due to AZD8233 SC multiple ascending dose treatment.

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

  From randomization to final Follow-up Visit (Week 16 post last dose).

• Vital sign: Systolic blood pressure (SBP)

  To assess SBP as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses. BP will be collected after the subject has rested in the supine position for at least 5 minutes.

  From screening to final Follow-up Visit (Week 16 post last dose).

• Vital sign: Pulse rate

  To assess supine position pulse as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses. Pulse rate will be collected after the subject has rested in the supine position for at least 5 minutes.

  From screening visit to final Follow-up Visit (Week 16 post last dose).

• Vital sign: Oral body temperature

  To assess the oral body temperature as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  Day -1 to final Follow-up Visit (Week 16 post last dose).

• Number of patients with abnormal findings in resting 12-lead Electrocardiogram (ECG) and digital ECG (dECG).

  To assess the 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 multiple ascending doses. ECG evaluations will be recorded after approximately 10 min resting in supine position. dECGs will be done only on Days 1 and 57 (pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24, 36 and 48 hours post-dose), and Days 8 and 29 (pre-dose).

  From screening to final Follow-up Visit (Week 16 post last dose).

• Number of subject with abnormal findings in cardiac telemetry

  To assess cardiac telemetry as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  At Day -1, Days 1 to 3 (pre-dose to 24 hours post-dose), and Day 57 (pre-dose to 24 hours post-dose).

• Physical examination

  To assess physical examination as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses. Complete (general appearance, respiratory, cardiovascular, abdomen, skin, head and neck \[including ears, eyes, nose and throat\], lymph nodes, thyroid, musculoskeletal \[including spine and extremities\] and neurological systems).

  From screening to final Follow-up Visit (Week 16 post last 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 multiple ascending doses.

  From randomization to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Hematology - Blood cells count

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

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Hematology - Hemoglobin (Hb)

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

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Hematology - Hematocrit (HCT)

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

  From screening to final Follow-up Visit (Week 16 post last dose).

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

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

  From screening to final Follow-up Visit (Week 16 post last dose).

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

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

  From screening to final Follow-up Visit (Week 16 post last dose).

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

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

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Hematology - Differential WBC 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 multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Hematology - Platelet count and platelet function assessment.

  To assess platelet count and platelet function in platelet rich plasma (PRP) using Light Transmission Aggregometry (LTA) as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Hematology - Reticulocytes absolute count

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

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Serum clinical chemistry - Electrolytes

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

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Serum clinical chemistry - Blood urea nitrogen (BUN)

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

  From screening to final Follow-up Visit (Week 16 post last dose).

• 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 multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

• 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 multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Serum clinical chemistry - Creatine kinase

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

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Serum clinical chemistry - Direct bilirubin

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

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Serum clinical chemistry - Hemoglobin A1c (HbA1c)

  To assess the level of HbA1c as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Serum clinical chemistry - Liver enzymes

  To assess the level 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 multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Serum clinical chemistry - Total bilirubin

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

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Serum clinical chemistry - Cell enzymes

  To assess the level of serum glutamate dehydrogenase (GLDH) and lactate dehydrogenase (LDH) as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Serum clinical chemistry - Bicarbonate

  To assess the level of bicarbonate as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Serum clinical chemistry - Uric acid

  To assess the level of uric acid as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

• Laboratory assessments: Coagulation

  To assess activated partial thrombin time (aPTT), prothrombin time (PT), and International normalized ratio (INR) as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

• Renal safety biomarkers - Urine clusterin

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

  Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

• Renal safety biomarkers - Urine cystatin-C

  To assess renal biomarker by evaluation of urine cystatin-C level as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

• Renal safety biomarkers - Urine N-acetyl-beta-D-glucosaminidase (NAG)

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

  Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

• Renal safety biomarkers - Urine albumin

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

  Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

• Renal safety biomarkers - Urine creatinine

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

  Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

• Renal safety biomarkers - Urine Kidney injury molecule1 (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 multiple ascending doses.

  Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

• Renal safety biomarkers - Urine Neutrophil gelatinase-associated lipocalin (NGAL)

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

  Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

• Renal safety biomarkers - Urine Osteopontin

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

  Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

• Renal safety biomarkers - Urine total protein

  To assess renal biomarker by evaluation of urine protein (total) level as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).

• 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 multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

• Complement Activation panel

  To assess chemotactic factor (C3a, Bb, and C5a) levels as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  Days 1 and 57 (pre-dose, 1, 2, and 4 hours post-dose).

• Laboratory assessments: Clinical urinalysis

  To assess urine sample for proteins, blood, creatinine, microscopy evaluation as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.

  From screening to final Follow-up Visit (Week 16 post last dose).

Secondary Outcomes (17)

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

  Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.

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

  Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.

• Plasma PK analysis: Observed maximum plasma concentration (Cmax).

  Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.

• Plasma PK analysis: Area under the plasma concentration-curve from time zero to time last value above the limit of quantification (AUC[0-last]).

  Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.

• Plasma PK analysis: Area under the concentration-time curve from time zero to 24 hours post-dose (AUC[0-24]).

  Days 1 and 57 (Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose); Day 8 (pre-dose), Days 15, 22, 29 (pre-dose), Days 36 and 44.

Study Arms (3)

Cohort 1

EXPERIMENTAL

On Days 1, 8, 29, and 57, randomized subjects will receive SC dose of AZD8233 dose 1 injection (8 subjects) or matching placebo (3 subjects).

Drug: AZD8233 subcutaneous injection; Drug: Placebo

Cohort 2

EXPERIMENTAL

On Days 1, 8, 29, and 57, randomized subjects will receive SC dose of AZD8233 dose 2 injection (8 subjects) or matching placebo (3 subjects).

Drug: AZD8233 subcutaneous injection; Drug: Placebo

Cohort 3

EXPERIMENTAL

On Days 1, 8, 29, and 57, randomized subjects will receive SC dose of AZD8233 dose 3 injection (8 subjects) or matching placebo (3 subjects).

Drug: AZD8233 subcutaneous injection; Drug: Placebo

Interventions

AZD8233 subcutaneous injection DRUG

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

Cohort 1; Cohort 2; Cohort 3

Placebo DRUG

Randomized subjects will receive SC dose of placebo injection.

Cohort 1; Cohort 2; Cohort 3

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated, written informed consent before any study specific procedures.
• Must be willing and able to comply with all required study procedures.
• Male or female subjects aged 18 to 65 years at signing of informed consent.
• Females must not be pregnant and must have a negative urine pregnancy test at the Screening Visit and on admission to the Clinical Unit, must not be lactating; or must be of non-childbearing potential, confirmed at the Screening Visit by fulfilling one of the following criteria:
• Postmenopausal defined as 12 months with no menses without an alternative medical cause.
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
• Have suitable veins for cannulation or repeated venipuncture.
• Have a body mass index between 25 and 40 kg/m2.
• Have a Low-density lipoprotein (LDL) cholesterol \> 70 but \<190 mg/dL (4.9 mmol/L).
• Calculated glomerular filtration rate \> 60 mL/min by estimated glomerular filtration rate using chronic kidney disease epidemiology equations.
• Subjects should be receiving moderate- or high-intensity statin therapy as defined by the American College of Cardiology/American Heart Association guideline on blood cholesterol management
• Subjects should be on stable medication for a certain time period prior to randomization.
• Provision of signed, written, and dated informed consent for mandatory and optional genetic research. All subjects in the study, except for healthy volunteers, need to consent to the mandatory genetic component of the study and sign the consent form for the main study.
• If a healthy volunteer population is included by the SRC, then screen for eligibility criteria and study restrictions for healthy volunteer population.

You may not qualify if:

• History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
• Any uncontrolled or serious disease, or any medical (known major active infection or major hematological, renal, metabolic, gastrointestinal or endocrine dysfunction) or surgical condition that, in the opinion of the Investigator, may either interfere with participation in the clinical study and/or put the participant at significant risk.
• Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding (frequent bleeding gums or nose bleeds).
• History of major bleed or high-risk of bleeding diathesis.
• Subjects ≥ 20 years of age with a high 10-year risk of heart disease or stroke as calculated using the atherosclerotic cardiovascular disease (ASCVD) Risk Estimator.
• Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in-situ, or Stage 1 prostate carcinoma) within the last 10 years.
• Recipient of any major organ transplant, eg, lung, liver, heart, bone marrow, renal.
• LDL or plasma apheresis within 12 months prior to randomization.
• Uncontrolled hypertension defined as supine SBP \>160 mmHg or DBP \>90 mmHg.
• Heart rate after 10 minutes supine rest \<50 or \>100 bpm.
• Any laboratory values with the following deviations at the Screening Visit or Day -1, test may be repeated at the discretion of the Investigator if abnormal: Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus; ALT \> 1.5 times (Upper limit of normal \[ULN\]); AST \>1.5 times ULN; Creatinine \> 1.5 mg/dL; WBC \< lower limit of normal (LLN); Hemoglobin \< 12 g/dL in men or \< 11 g/dL in women; Platelet count ≤ LLN; activated partial thromboplastin time \> ULN and prothrombin time \> ULN; urinary albumin-to-creatinine ratio \> 11 mg/μmol.
• 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 (QTcF \> 450 ms) changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy, test may be repeated at the discretion of the Investigator if abnormal.
• Males who are unwilling to use an acceptable method of birth control during the entire study period. Acceptable methods of preventing pregnancy are true abstinence or use together, with their female partner/spouse, birth control pills, injections, implants, patches, or intrauterine devices in combination with a barrier method. A barrier method is not necessary if the female partner is sterilized.
• Known or suspected history of drug abuse by the Investigator. 15, Smokers with \> 10 cigarettes/day and unable to comply with the nicotine restriction during the study.
• \. History of alcohol abuse or excessive intake of alcohol as judged by the Investigator.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (7)

Research Site

Chula Vista, California, 91911, United States

Location

Research Site

Glendale, California, 91206, United States

Location

Research Site

La Mesa, California, 91942, United States

Location

Research Site

Jacksonville, Florida, 32216, United States

Location

Research Site

Orlando, Florida, 32806, United States

Location

Research Site

Port Orange, Florida, 32127, United States

Location

Research Site

Brooklyn, Maryland, 21225, United States

Location

Related Publications (1)

• Clewe O, Rekic D, Quartino AL, Carlsson B, Higashimori M, Wernevik L, Hofherr A, Ryden-Bergsten T, Nilsson C, Knochel J. Population pharmacokinetics of a novel PCSK9 antisense oligonucleotide. Br J Clin Pharmacol. 2024 Jun;90(6):1503-1513. doi: 10.1111/bcp.16046. Epub 2024 Mar 19.

  PMID: 38504437 DERIVED

MeSH Terms

Conditions

Dyslipidemias

Condition Hierarchy (Ancestors)

Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• David Han, MD

  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 regards to treatment (AZD8233 or placebo) at each dose level. AZD8233 and placebo will be matched for 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: November 5, 2019
• First Posted: November 7, 2019
• Study Start: November 21, 2019
• Primary Completion: June 7, 2021
• Study Completion: June 7, 2021
• Last Updated: June 30, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the European Federation of Pharmaceutical Industries and Associations 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 (7)