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

A Phase I Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD8233 Following Multiple Ascending Subcutaneous Dose Administration in Subjects With Dyslipidemia With or Without Type 2 Diabetes

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.

Study Overview

• Status: Completed
• Conditions: Dyslipidemia
• Intervention / Treatment: Drug: AZD8233 subcutaneous injection; Drug: Placebo

Detailed Description

This study is a Phase 1, randomized, single-blind, placebo-controlled, multiple dose group design in up to 33 male or female subjects with dyslipidemia with or without Type 2 diabetes and performed at multiple study centers. The planned number of cohorts is 3 but up to 5 cohorts may be included if the Safety Review Committee (SRC) considers it necessary. The 3 multiple dose levels of SC AZD8233 planned are:

• Cohort 1: Dose 1 (starting dose).
• Cohort 2: Dose 2 (provisional dose).
• Cohort 3: Dose 3 (provisional dose). Within each of these cohorts, 8 subjects will be randomized to receive AZD8233 and 3 subjects randomized to receive placebo. Cohorts 2 and 3 may be run in parallel if Cohort 3 is a lower dose. If Cohort 3 is a higher dose, the cohorts will be run sequentially. At any time, the dose levels may be adapted by the SRC based on emerging data. The expected duration of each patient in this study is up to 28 weeks with a maximum of 17 visits. Screening will be completed between Days -28 and -1. Each subject will receive single doses of AZD8233 or placebo on Days 1, 8, 29, and 57. The treatment period will consist of 58 days (up to Visit 9), followed by a follow-up period (up to Visit 17).

Following review of data, the SRC may decide to adjust the following for subsequent cohorts:

• The timing and amount of the loading dose.
• The length of the stay at the study site, the timing and number of assessments and/or samples.
• As decided by the SRC, blood and urine samples collected in the study may be used to address any of the other pre-specified study objectives.
• Each subject will be followed up for 16 weeks post last dose.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Chula Vista, California, United States, 91911
      • Research Site
    • Glendale, California, United States, 91206
      • Research Site
    • La Mesa, California, United States, 91942
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Research Site
    • Orlando, Florida, United States, 32806
      • Research Site
    • Port Orange, Florida, United States, 32127
      • Research Site
  • Maryland
    • Brooklyn, Maryland, United States, 21225
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Provision of signed and dated, written informed consent before any study specific procedures.
2. Must be willing and able to comply with all required study procedures.
3. Male or female subjects aged 18 to 65 years at signing of informed consent.

4. 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.
5. Have suitable veins for cannulation or repeated venipuncture.
6. Have a body mass index between 25 and 40 kg/m2.
7. Have a Low-density lipoprotein (LDL) cholesterol > 70 but <190 mg/dL (4.9 mmol/L).
8. Calculated glomerular filtration rate > 60 mL/min by estimated glomerular filtration rate using chronic kidney disease epidemiology equations.
9. 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
10. Subjects should be on stable medication for a certain time period prior to randomization.
11. 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.
12. If a healthy volunteer population is included by the SRC, then screen for eligibility criteria and study restrictions for healthy volunteer population.

Exclusion criteria:

1. History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
2. 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.
3. 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).
4. History of major bleed or high-risk of bleeding diathesis.
5. 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.
6. 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.
7. Recipient of any major organ transplant, eg, lung, liver, heart, bone marrow, renal.
8. LDL or plasma apheresis within 12 months prior to randomization.
9. Uncontrolled hypertension defined as supine SBP >160 mmHg or DBP >90 mmHg.
10. Heart rate after 10 minutes supine rest <50 or >100 bpm.
11. 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.
12. 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.
13. 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.
14. 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.

16. History of alcohol abuse or excessive intake of alcohol as judged by the Investigator.

17. Positive screen for drugs of abuse at the Screening Visit or admission to the study site.

18. Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate,) as judged by the Investigator.

19. Use of drugs with cytochrome 450 enzyme inducing properties such as St John's Wort within 3 weeks before the first administration of investigational medicinal product (IMP).

20. Insulin or glucagon-like peptide 1 receptor agonist therapy during last 3 months prior to randomization.

21. Anti-platelet therapy, other than low dose aspirin ≤ 100 mg/day, within 1 month prior to randomization.

22. Mipomersen, or lomitapide within 12 months prior to randomization. 23. Proprotein convertase subtilisin/kexin type 9 inhibition treatment within 6 months prior to randomization.

24. Use of any herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or 5 half-lives, whichever is longer.

25. Previous administration of AZD8233/AZD6615. 26. Received another new chemical entity within 30 days of last follow-up to first administration of the IMP of this study or 5 half-lives from last dose to first administration of IMP, whichever is the longest.

27. Plasma donation within 1 month of the Screening Visit or any blood donation/blood loss > 500 mL during the 3 months before the Screening Visit.

28. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD8233.

29. Involvement of any Astra Zeneca or study site employee or their close relatives.

30. Subjects who cannot communicate reliably with the Investigator. 31. Vulnerable subjects, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

32. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP. History or evidence of any other clinically significant disorder (eg, cognitive impairment), condition or disease other than those outlined above that, in the opinion of the Investigator or AstraZeneca physician, if consulted, may compromise the ability of the subject to give written informed consent, would pose a risk to subject safety, or interfere with the study evaluation, procedures or completion.

33. Subject likely to not be available to complete all protocol required study visits or procedures, to the best of the subject's and Investigator's knowledge.

34. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1; 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; Randomized subjects will receive SC dose of AZD8233 (dose 1, dose 2, and dose 3) injection.; Drug: Placebo; Randomized subjects will receive SC dose of placebo injection.
EXPERIMENTAL: Cohort 2; 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; Randomized subjects will receive SC dose of AZD8233 (dose 1, dose 2, and dose 3) injection.; Drug: Placebo; Randomized subjects will receive SC dose of placebo injection.
EXPERIMENTAL: Cohort 3; 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; Randomized subjects will receive SC dose of AZD8233 (dose 1, dose 2, and dose 3) injection.; Drug: Placebo; Randomized subjects will receive SC dose of placebo injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma PK analysis: Time delay between drug administration and the first observed concentration in plasma (tlag).	To characterize the tlag of AZD8233 following SC administration of multiple ascending doses.	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).	To characterize the tmax of AZD8233 following SC administration of multiple ascending doses.	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).	To characterize the Cmax of AZD8233 following SC administration of multiple ascending doses.	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]).	To characterize the AUC(0-last) of AZD8233 following SC administration of multiple ascending doses.	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]).	To characterize the AUC(0-24) of AZD8233 following SC administration of multiple ascending doses.	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 48 hours post-dose (AUC[0-48]).	To characterize the AUC(0-48) of AZD8233 following SC administration of multiple ascending doses.	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 extrapolated to infinity (AUC).	To characterize the AUC of AZD8233 following SC administration of multiple ascending doses. AUC is estimated by AUC(0-last) + Clast/λz where Clast is the last observed quantifiable concentration.	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-time curve from time during the dosing interval (AUCt).	To characterize the AUCt of AZD8233 following SC administration of multiple ascending doses.	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 trough plasma drug concentration (Ctrough).	To characterize the Ctrough of AZD8233 following SC administration of multiple ascending doses.	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: Apparent total body clearance of drug from plasma after extravascular administration (CL/F).	To characterize the CL/F of AZD8233 following SC administration of multiple ascending doses.	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: Apparent volume of distribution for parent drug at terminal phase (extravascular administration) (Vz/F).	To characterize the Vz/F of AZD8233 following SC administration of multiple ascending doses; estimated by dividing the apparent clearance (CL/F) by λz.	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: Half-life associated with the terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2).	To characterize the t1/2 of AZD8233 following SC administration of multiple ascending doses.	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: Mean Residence Time (MRT).	To characterize the MRT of AZD8233 following SC administration of multiple ascending doses.	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.
Urine PK analysis: Amount excreted in urine (Ae).	To characterize the Ae of AZD8233 following SC administration of multiple ascending doses.	Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).
Urine PK analysis: Fraction excreted unchanged in urine (Fe).	To characterize the Fe of AZD8233 following SC administration of multiple ascending doses.	Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).
Urine PK analysis: Renal clearance (CLR).	To characterize the CLR of AZD8233 following SC administration of multiple ascending doses.	Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).
PD analysis: Levels of dyslipidemia related biomarkers.	To assess the effect of AZD8233 on levels of dyslipidemia related biomarkers.	At screening, Day -1, Days 1 to 3 and Days 57 to 58 (pre-dose and 48 hours post-dose), Day 8 (pre-dose), Days 15, 22, Day 29 (pre-dose), Days 36, 44, Day 56, week 2 to 14 (at 2, 4, 6, 8, 10, 12, and 14 weeks) and week 16 post-dose.

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel
• Investigators: Principal Investigator: David Han, MD, PAREXEL Early Phase Clinical Unit-Los Angeles

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 21, 2019
• Primary Completion (ACTUAL): June 7, 2021
• Study Completion (ACTUAL): June 7, 2021

Study Registration Dates

• First Submitted: November 5, 2019
• First Submitted That Met QC Criteria: November 5, 2019
• First Posted (ACTUAL): November 7, 2019

Study Record Updates

• Last Update Posted (ACTUAL): June 30, 2021
• Last Update Submitted That Met QC Criteria: June 29, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Safety; PK; Tolerability; PD; Multiple Ascending Dose; AZD8233
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias
• Other Study ID Numbers: D7990C00002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing 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.
• IPD Sharing 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No