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
Overview
- Phase
- Phase 1
- Intervention
- AZD8233 subcutaneous injection
- Conditions
- Dyslipidemia
- Sponsor
- AstraZeneca
- Enrollment
- 34
- Locations
- 1
- Primary Endpoint
- Vital sign: Systolic blood pressure (SBP)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
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.
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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/m
- •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.
Exclusion Criteria
- Not provided
Arms & Interventions
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).
Intervention: AZD8233 subcutaneous injection
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).
Intervention: Placebo
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).
Intervention: AZD8233 subcutaneous injection
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).
Intervention: Placebo
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).
Intervention: AZD8233 subcutaneous injection
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).
Intervention: Placebo
Outcomes
Primary Outcomes
Vital sign: Systolic blood pressure (SBP)
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
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.
Vital sign: Pulse rate
Time Frame: From screening visit to final Follow-up Visit (Week 16 post last dose).
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.
Vital sign: Oral body temperature
Time Frame: Day -1 to final Follow-up Visit (Week 16 post last dose).
To assess the oral body temperature as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Hematology - Hemoglobin (Hb)
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess Hb as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Number of subjects with adverse events (AEs) due to AZD8233 SC multiple ascending dose treatment.
Time Frame: From randomization to final Follow-up Visit (Week 16 post last dose).
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.
Number of patients with abnormal findings in resting 12-lead Electrocardiogram (ECG) and digital ECG (dECG).
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
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).
Number of subject with abnormal findings in cardiac telemetry
Time Frame: At Day -1, Days 1 to 3 (pre-dose to 24 hours post-dose), and Day 57 (pre-dose to 24 hours post-dose).
To assess cardiac telemetry as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Hematology - Mean corpuscular hemoglobin concentration (MCHC)
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess MCHC as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Hematology - Blood cells count
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
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.
Laboratory assessments: Hematology - Platelet count and platelet function assessment.
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
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.
Laboratory assessments: Hematology - Reticulocytes absolute count
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess Reticulocytes absolute count as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Serum clinical chemistry - Electrolytes
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess serum level of sodium, potassium, calcium as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Physical examination
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
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).
Injection site reaction examinations
Time Frame: From randomization to final Follow-up Visit (Week 16 post last dose).
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.
Laboratory assessments: Hematology - Hematocrit (HCT)
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess HCT as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Hematology - Mean corpuscular volume (MCV)
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess MCV as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Hematology - Mean corpuscular hemoglobin (MCH)
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess MCH as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Hematology - Differential WBC count
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
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.
Laboratory assessments: Serum clinical chemistry - Blood urea nitrogen (BUN)
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess serum level of BUN as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Serum clinical chemistry - Creatinine
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess serum level of creatinine as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Coagulation
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
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.
Laboratory assessments: Serum clinical chemistry - Liver enzymes
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
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.
Laboratory assessments: Serum clinical chemistry - Glucose (fasting)
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess serum fasting glucose level as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Serum clinical chemistry - Creatine kinase
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess the level of serum creatine kinase as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Serum clinical chemistry - Direct bilirubin
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess the level of serum bilirubin (direct) as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Serum clinical chemistry - Hemoglobin A1c (HbA1c)
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess the level of HbA1c as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Serum clinical chemistry - Cell enzymes
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
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.
Laboratory assessments: Serum clinical chemistry - Uric acid
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess the level of uric acid as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Renal safety biomarkers - Urine clusterin
Time Frame: Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
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.
Renal safety biomarkers - Urine cystatin-C
Time Frame: Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
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.
Renal safety biomarkers - Urine N-acetyl-beta-D-glucosaminidase (NAG)
Time Frame: Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
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.
Renal safety biomarkers - Urine albumin
Time Frame: Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
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.
Laboratory assessments: Serum clinical chemistry - Total bilirubin
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess the level of serum bilirubin (total) as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Laboratory assessments: Serum clinical chemistry - Bicarbonate
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess the level of bicarbonate as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Renal safety biomarkers - Urine creatinine
Time Frame: Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
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.
Renal safety biomarkers - Urine Osteopontin
Time Frame: Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
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.
Renal safety biomarkers - Urine Kidney injury molecule1 (KIM-1)
Time Frame: Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
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.
Renal safety biomarkers - Urine Neutrophil gelatinase-associated lipocalin (NGAL)
Time Frame: Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
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.
Renal safety biomarkers - Urine total protein
Time Frame: Screening, Day 1 (pre-dose, 24 hours and 48 hours post-dose), Days 8 and 29 (pre-dose), and Day 57 (pre-dose).
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.
Immune Activation Response - High-sensitivity C-reactive protein (hs-CRP)
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
To assess hs-CRP level as a variable of safety and tolerability of AZD8233 following SC administration of multiple ascending doses.
Complement Activation panel
Time Frame: Days 1 and 57 (pre-dose, 1, 2, and 4 hours post-dose).
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.
Laboratory assessments: Clinical urinalysis
Time Frame: From screening to final Follow-up Visit (Week 16 post last dose).
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.
Secondary Outcomes
- 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: 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: 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: 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.)
- Plasma PK analysis: Area under the concentration-time curve from time zero extrapolated to infinity (AUC).(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]).(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).(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).(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).(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).(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).(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).(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: Fraction excreted unchanged in urine (Fe).(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).(Treatment Days 1 to 3 (Pre-dose and intervals 0-6, 6-12 hours and 12-24 hours post-dose).)
- Urine PK analysis: Amount excreted in urine (Ae).(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.(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.)