A Study to Investigate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD1705 in Participants With Dyslipidemia

Cardiovascular Clinical Trial

Official title:

A Phase I Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD1705 Following Single and Multiple Ascending Doses in Participants With Dyslipidemia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06238466
• Other study ID #: D7650C00001
• Status: Recruiting
• Phase: Phase 1
• Start date: January 16, 2024
• Est. completion date: September 9, 2025

Study information

• Verified date: May 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD1705 in participants with dyslipidemia.

Description:

This is a first time in human study in male and female (of non-childbearing potential) participants with dyslipidemia. The study consists of two parts:

1. Part A (single ascending dose): Part A of the study will include three parts: A1 for non-Asian participants, A2 for Japanese participants, and A3 for Chinese participants. Parts A2 and A3 are optional.

2. Part B (multiple ascending dose): Part B of the study will include three parts: B1 for non-Asian participants receiving moderate- or high-intensity statin therapy, B2 for Japanese participants not receiving statin therapy, and B3 for participants who are receiving moderate- or high-intensity statin therapy, with the additional diagnosis of type 2 diabetes (T2D), and with HbA1c < 7.5%. Parts B2 and B3 are optional.

The study will comprise of:

• A Screening Period of maximum 60 days for both Part A and Part B.

• Part A: A single dose of AZD1705 with an in-clinic period of 3 days.

• An outpatient Follow-up Period of approximately 16 weeks.

• Part B: 2 doses of AZD1705, given 28 days apart with an in-clinic period.

• An outpatient Follow-up Period of approximately 20 weeks.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 112
• Est. completion date: September 9, 2025
• Est. primary completion date: September 9, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Male and female of non-childbearing potential participants with suitable veins for cannulation or repeated venipuncture.

• All females must have a negative pregnancy test.

• Participants with elevated lipids.

• BMI between 18 and 35 kg/m^2.

Part B1 - Should be receiving moderate- or high-intensity statin therapy.

Part B3

• Should be receiving moderate- or high-intensity statin therapy.

• Diagnosed with T2D with hemoglobin A1c (HbA1c) < 7.5% level.

Parts B1 and B3

• Participants should be on stable statin medication for = 3 months before Screening with no planned medication or dose change during study participation.

Parts A2 and B2:

• Participants are to be Japanese, defined as having both parents and 4 grandparents who are Japanese.

Part A3:

• Participants are to be Chinese, defined as having both parents and 4 grandparents who are Chinese.

Exclusion Criteria:

• History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study.

• 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 clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.

• Any laboratory values with the following deviations at the Screening Visit or on admission to the Clinical Unit. Abnormal values may be repeated once at the discretion of the Investigator:

1. Alanine aminotransferase > 1.5 × upper limit of normal (ULN).

2. Aspartate aminotransferase > 1.5 × ULN.

3. Total bilirubin > ULN (Gilbert's syndrome).

4. Estimated glomerular filtration rate < 60 milliliter (mL)/minute/1.73 m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 2021 (National Kidney Foundation).

5. Hemoglobin < lower limit normal (LLN).

• Any clinically important abnormalities in hematology, coagulation, clinical chemistry, or urinalysis results other than those described under exclusion criterion number 4, at Screening and/or first admission to the study unit, as judged by the Investigator. Abnormal values may be repeated once at the discretion of the Investigator.

• Any positive result at Screening for serum Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb), Hepatitis C virus antibody (HCV Ab), or Human immunodeficiency virus (HIV).

• Abnormal vital signs, after 5 minutes supine rest, at Screening and/or first admission to the study unit, defined as any of the following:

1. Systolic blood pressure (BP) = 90 millimeters of mercury (mmHg) or > 140 mmHg (Part A) or > 150 mmHg (Part B).

2. Diastolic BP < 50 mmHg or > 90 mmHg.

3. Heart rate < 45 or > 90 beats per minute (bpm). Note: Blood pressure will be measured in triplicates and the mean value will be used. Where the values are outside the required range at admission, then based on medical history, one retest may be performed at this visit.

• Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead ECG, at Screening and/or first admission to the study unit, as judged by the Investigator, that may interfere with the interpretation of QT interval corrected for heart rate (QTc) interval changes, including abnormal ST-T-wave morphology, particularly in the protocol-defined primary lead or left ventricular hypertrophy.

1. Prolonged ECG interval measured from the onset of the QRS complex to the end of the T wave (QT) corrected for heart rate using Fridericia's correction (QTcF) > 450 ms.

2. Family history of long QT syndrome.

3. Time from the onset of the P wave to the start of the QRS complex (PR) (PQ) interval shortening < 120 milliseconds (ms) (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation).

4. PR (PQ) interval prolongation (> 220 ms), persistent or intermittent second-degree atrioventricular (AV) block (participants with Wenckebach block while asleep are acceptable), third-degree AV block, or AV dissociation.

5. Persistent or intermittent complete Bundle branch block (BBB), Intermittent bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with ECG interval measured from the onset of the QRS complex to the J point (QRS) > 110 ms.

• Participants with QRS > 110 ms but < 115 ms (Part A) or < 120 ms (Part B) are acceptable if there is no evidence of ventricular hypertrophy or pre-excitation.

• Smokers who smoke > 10 cigarettes/day and are unable to comply with the nicotine restriction during the study.

• Known or suspected history of alcohol or drug abuse or those who consume > 3 units of alcohol per day for males or > 2 units of alcohol per day for females (where 1 unit being equal to approximately half pint [284 mL] of beer, one small glass [125 mL] of wine, or one measure [25 mL] of spirits) as judged by the Investigator.

• Positive screen for drugs of abuse or alcohol at Screening or on each admission to the Clinical Unit.

• 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 study compound.

• Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) defined as the regular consumption of more than 500 mg of caffeine per day (one cup ~100 mg caffeine; one cup of tea ~30 mg caffeine) or would likely be unable to refrain from the use of caffeine-containing beverages during confinement at the investigational site.

• Plasma donation within one month of the Screening Visit or any blood donation/blood loss > 500 mL during the 3 months prior to the Screening Visit.

• Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 30 days or 5 half-lives (whichever is longest) of the first administration of investigational medicinal product (IMP). The period of exclusion begins after the final dose.

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the Clinical Unit).

• Judgment by the Investigator that the participant should not participate in the study if they have any ongoing or recent (ie, during the Screening Period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.

• Participants who are vegans or have medical dietary restrictions.

• Participants who cannot communicate reliably with the Investigator.

• Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

• Clinical signs and symptoms consistent with COVID-19, eg, fever, dry cough, dyspnea, sore throat, fatigue, or confirmed infection by appropriate laboratory test within the last 4 weeks prior to Screening or on admission as per site standard practice.

• Low-density lipoprotein (LDL) or plasma apheresis within 12 months prior to randomization.

Part A Only:

• Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, mega dose vitamins (intake of 20 to 600 times the recommended daily dose), and minerals during the 2 weeks prior to the first administration of study intervention or longer if the medication has a long half-life.

• On statin therapy.

• Urine albumin: creatinine ratio > 30 mg/g.

Part B Only:

• Use of any herbal remedies, mega dose vitamins, and minerals during the two weeks prior to the first administration of study intervention or 5 half-lives, whichever is longer.

• Urine albumin: creatinine ratio > 100 mg/g.

Parts B1 and B3 Only:

• Contraindication to Magnetic Resonance Imaging (MRI) such as: participants with pacemakers, metallic cardiac valves, magnetic material such as surgical clips, implanted electronic infusion pumps or other conditions that would preclude proximity to a strong magnetic field; participants with a history of extreme claustrophobia; or participants who cannot fit inside the MRI scanner cavity.

Related Conditions & MeSH terms

• Cardiovascular
• Dyslipidemias

Intervention

Drug:
• AZD1705
Participants will receive AZD1705 subcutaneously on Day 1 in Part A, and Days 1 and 29 in Part B.

Other:
• Placebo
Participants will receive placebo on Day 1 in Part A, and Days 1 and 29 in Part B.

Locations

Country	Name	City	State
United States	Research Site	Baltimore	Maryland
United States	Research Site	Glendale	California
United States	Research Site	Jacksonville	Florida
United States	Research Site	Overland Park	Kansas
United States	Research Site	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with adverse events (AEs) and serious adverse events (SAEs)	To assess the safety and tolerability of AZD1705 following subcutaneous administration of single ascending doses (Part A) and multiple ascending doses (Part B) in participants with dyslipidemia	Part A: From Screening (Day -60 to Day -2) until Day 113. Part B: From Screening until Day 141
Secondary	Area under plasma concentration-time curve from zero extrapolated to infinity (AUCinf)	To characterize the single and repeated dose PK of AZD1705 following subcutaneous administration in participants with dyslipidemia.	Part A: Day 1 to 113. Part B: Day 1 to 141
Secondary	Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast)	To characterize the single and repeated dose PK of AZD1705 following subcutaneous administration in participants with dyslipidemia.	Part A: Day 1 to 113. Part B: Day 1 to 141
Secondary	Maximum observed plasma (peak) drug concentration (Cmax)	To characterize the single and repeated dose PK of AZD1705 following subcutaneous administration in participants with dyslipidemia.	Part A: Day 1 to 113. Part B: Day 1 to 141
Secondary	Cumulative amount of drug excreted unchanged (Ae)	To characterize the single and repeated dose PK of AZD1705 following subcutaneous administration in participants with dyslipidemia.	Part A: Day 1 to 4. Part B: Day 1 to 4, and 29 to 30
Secondary	Fraction of drug excreted unchanged (fe)	To characterize the single and repeated dose PK of AZD1705 following subcutaneous administration in participants with dyslipidemia.	Part A: Day 1 to 4. Part B: Day 1 to 4, and 29 to 30
Secondary	Rate of renal clearance of drug (CLR)	To characterize the single and repeated dose PK of AZD1705 following subcutaneous administration in participants with dyslipidemia.	Part A: Day 1 to 4. Part B: Day 1 to 4, and 29 to 30
Secondary	Change from baseline in target plasma protein	To assess the effect of single and repeated subcutaneous AZD1705 administration on target plasma protein levels in participants with dyslipidemia.	Part A: Baseline to Day 113. Part B: Baseline to Day 141
Secondary	Change from baseline in low-density lipoprotein cholesterol (LDL-C)	To assess the effect of single and repeated subcutaneous AZD1704 administration on levels of LDL-C in circulation in participants with dyslipidemia.	Part A: Baseline to Day 113. Part B: Baseline to Day 141
Secondary	Change from baseline in Apolipoprotein B (ApoB)	To assess the effect of single and repeated subcutaneous AZD1704 administration on levels of ApoB in circulation in participants with dyslipidemia.	Part A: Baseline to Day 113. Part B: Baseline to Day 141
Secondary	Change from baseline in triglycerides	To assess the effect of single and repeated subcutaneous AZD1704 administration on levels of triglycerides in circulation in participants with dyslipidemia.	Part A: Baseline to Day 113. Part B: Baseline to Day 141