Hyperlipidaemia
Conditions
Keywords
AZD8233, Efficacy, PK, PD, Safety, Tolerability
Brief summary
AZD8233 is a PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. This study aims to evaluate safety, efficacy and tolerability of AZD8233.
Detailed description
This is a randomized parallel, double-blind, placebo-controlled Phase 2b study in approximately 376 participants with hyperlipidaemia. The primary objective of the study is to assess the safety and tolerability of AZD8233 as compared with placebo, and the effect of AZD8233 versus placebo on relative change in LDL-C. The study will be conducted at up to 100 sites in up to 8 countries. The screening period starts up to 28 days before the randomization visit and ends on Day -1. Eligible participants will attend 1 enrollment visit and 15 visits during the treatment period and 2 additional visits during the safety follow up period.
Interventions
DRUGAZD8233
PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.
DRUGPlacebo
Placebo solution
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Participant must be 18 to 75 years of age, inclusive, at the time of signing the informed consent * Participants who have a fasting LDL-C ≥ 70 mg/dL (1.8 mmol/L) but \< 190 mg/dL (4.9 mmol/L) at screening * Participants who have fasting triglycerides \< 400 mg/dL (\< 4.52 mmol/L) at screening * Participants are receiving a stable dose (≥ 3 months) of maximally tolerated statin and/or ezetimibe therapy * Male or female of non-childbearing potential * Signed and dated written informed consent prior to any mandatory study specific procedures, sampling, and analyses
Exclusion criteria
* eGFR \< 40 mL/min/1.73m2 using the CKD-EPI * History or presence of gastrointestinal, hepatic or renal disease or any other conditions known to interfere with absorption, distribution, metabolism or excretion of drugs * Any uncontrolled or serious disease, or any medical (eg,. known major active infection or major haematological, 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 (according to the investigator's judgment) if he/she participates in the clinical study * Poorly controlled T2DM, defined as HbA1c \> 10% * Acute ischaemic cardiovascular events including stroke within 30 days, or heart failure with New York Heart Association (NYHA) Class III to IV * 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) * High-risk of bleeding diathesis or anti-platelet therapy other than low dose aspirin (≤100mg/day). * Malignancy within the last 10 years * Recipient of any major organ transplant * LDL or plasma apheresis within 12 months prior to randomisation * Uncontrolled hypertension defined as average 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; 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 (HIV) * ALT \> 1.5 × ULN * AST \> 1.5 × ULN * TBL \> ULN * ALP \> 1.5 × ULN * WBC \< lower limit of normal (LLN). * Haemoglobin \< 12 g/dL in males or \< 11 g/dL in females * Platelet count ≤ LLN * aPTT \> ULN or Prothrombin Time \> ULN * UACR \> 11 mg/mmol (100 mg/g) * UPCR \> 300 mg/g * Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG * QTcF \> 470 ms; high degree atrioventricular (AV)-block grade II-III and sinus node dysfunction with significant sinus pause untreated with pacemaker; and cardiac tachyarrhythmias * History of drug and/or alcohol abuse or a positive screen for drugs of abuse * Use of warfarin, direct or indirect thrombin inhibitors or factor Xa inhibitors * Mipomersen, or lomitapide within 12 months prior to randomisation * Any fibrate therapy other than fenofibrate; if the participant is on fenofibrate therapy, the dose should be stable for at least 6 weeks prior to randomisation * Previous administration of AZD8233/AZD6615) or inclisiran (LEQVIO ® Novartis) * Use of evolocumab (REPATHA® Amgen) and alirocumab (PRALUENT® Regeneron) within 3 months of screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Emergent Platelet Count Abnormalities | Treatment emergent includes results after the first dose of IP through study competition, planned visit date Day 281. | Treatment emergent platelet count abnormalities by pre-specified criteria by treatment. |
| Vital Sign - Systolic Blood Pressure | Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281. | Mean and standard deviation of Systolic Blood Pressure at each scheduled visit by treatment. |
| Vital Sign - Diastolic Blood Pressure | Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281. | Mean and standard deviation of Diastolic Blood Pressure at each scheduled visit by treatment. |
| Vital Sign - Pulse Rate | Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281. | Mean and standard deviation of Pulse rate at each scheduled visit by treatment. |
| Percentage Change From Baseline on Serum LDL-C | From baseline to Day 197 | Percentage change in Low-density Lipoprotein Cholesterol (LDL-C) from baseline to Day 197. |
| Number of Subjects With Adverse Events (AEs) | On-study includes adverse events with an onset date on or after the date of first dose of IP through study competition, planned visit date Day 281. | Please refer to the adverse event module for specifics. |
| Vital Signs - Temperature | Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281. | Mean and standard deviation of Temperature at each scheduled visit by treatment. |
| Vital Sign - Weight | Baseline and Day 281. | Mean and standard deviation of Weight at each scheduled visit by treatment. |
| Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Baseline, Days 85, 169, 225, and 281. | Number of participants With an ECG Determined to be Abnormal and Clinically Significant at each scheduled visit by treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentration of AZD8233 | Pre-dose of Day 29, Day 85, Day 141, Day 183, Day 197 | AZD8233 full length ASO concentrations in plasma were summarised by descriptive statistics by sampling time point and listed on individual level based on the PK analysis set. |
| Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Pre-dose of Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169, Day 197, Day 281 | Number of ADA positive subjects at each time point during the treatment period and follow-up period. |
| Percentage Change From Baseline on Serum PCSK9 | From baseline to Day 197 | Percentage change in Proprotein convertase subtilisin/kexin type-9 (PCSK9) from baseline to Day 197. |
Countries
Czechia, Denmark, Hungary, Netherlands, Poland, Slovakia, Spain, United States
Participant flow
Recruitment details
This study was conducted at a total of 66 study centres in 8 countries: Czech Republic (10 centres), Denmark (8 centres), Hungary (4 centres), Netherlands (6 centres), Poland (8 centres), Slovakia (7 centres), Spain (7 centres), and United States (16 centres). First subject enrolled: 07 July 2021 and Last subject last visit: 15 July 2022.
Participants by arm
| Arm | Count |
|---|---|
| AZD8233 AZD8233 for subcutaneous use. | 206 |
| Placebo Matching placebo solution for subcutaneous injection. | 205 |
| Total | 411 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Reported by investigator as completed but did not fulfil the Completed study definition. | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | AZD8233 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 62.4 Years STANDARD_DEVIATION 8.1 | 62.2 Years STANDARD_DEVIATION 7.7 | 62.3 Years STANDARD_DEVIATION 7.9 |
| LDL-C | 103 mg/dL STANDARD_DEVIATION 31.8 | 107.4 mg/dL STANDARD_DEVIATION 31.9 | 105.2 mg/dL STANDARD_DEVIATION 31.9 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants | 3 Participants | 12 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 194 Participants | 199 Participants | 393 Participants |
| Region of Enrollment Czech Republic | 45 Participants | 44 Participants | 89 Participants |
| Region of Enrollment Denmark | 31 Participants | 21 Participants | 52 Participants |
| Region of Enrollment Hungary | 15 Participants | 14 Participants | 29 Participants |
| Region of Enrollment Netherlands | 12 Participants | 7 Participants | 19 Participants |
| Region of Enrollment Poland | 4 Participants | 10 Participants | 14 Participants |
| Region of Enrollment Slovakia | 35 Participants | 43 Participants | 78 Participants |
| Region of Enrollment Spain | 16 Participants | 27 Participants | 43 Participants |
| Region of Enrollment USA | 48 Participants | 39 Participants | 87 Participants |
| Sex: Female, Male Female | 101 Participants | 94 Participants | 195 Participants |
| Sex: Female, Male Male | 105 Participants | 111 Participants | 216 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 207 | 0 / 203 |
| other Total, other adverse events | 69 / 207 | 62 / 203 |
| serious Total, serious adverse events | 18 / 207 | 12 / 203 |
Outcome results
Primary
Number of Participants With an ECG Determined to be Abnormal and Clinically Significant
Number of participants With an ECG Determined to be Abnormal and Clinically Significant at each scheduled visit by treatment
Time frame: Baseline, Days 85, 169, 225, and 281.
Population: Safety analysis set, the number analyzed represents the number of participants with available ECG data at that time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD8233 | Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Day 85 | 1 Participants |
| AZD8233 | Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Day 225 | 0 Participants |
| AZD8233 | Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Day 169 | 0 Participants |
| AZD8233 | Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Day 281 | 0 Participants |
| AZD8233 | Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Baseline | 0 Participants |
| Placebo | Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Day 281 | 0 Participants |
| Placebo | Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Baseline | 0 Participants |
| Placebo | Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Day 85 | 1 Participants |
| Placebo | Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Day 169 | 0 Participants |
| Placebo | Number of Participants With an ECG Determined to be Abnormal and Clinically Significant | Day 225 | 0 Participants |
Primary
Number of Subjects With Adverse Events (AEs)
Please refer to the adverse event module for specifics.
Time frame: On-study includes adverse events with an onset date on or after the date of first dose of IP through study competition, planned visit date Day 281.
Population: The safety analysis set consists of all subjects who have received at least one dose of investigational product. Erroneously treated subjects (e.g., those randomised to treatment A but actually given treatment B) are accounted for in the treatment group of the treatment they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD8233 | Number of Subjects With Adverse Events (AEs) | 141 Participants |
| Placebo | Number of Subjects With Adverse Events (AEs) | 127 Participants |
Primary
Percentage Change From Baseline on Serum LDL-C
Percentage change in Low-density Lipoprotein Cholesterol (LDL-C) from baseline to Day 197.
Time frame: From baseline to Day 197
Population: Full analysis set includes all subjects who were randomly assigned to study intervention. Subjects were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD8233 | Percentage Change From Baseline on Serum LDL-C | -56.7 percent change |
| Placebo | Percentage Change From Baseline on Serum LDL-C | 5.6 percent change |
p-value: <0.00195% CI: [-68, -56.6]ANCOVA
Primary
Treatment Emergent Platelet Count Abnormalities
Treatment emergent platelet count abnormalities by pre-specified criteria by treatment.
Time frame: Treatment emergent includes results after the first dose of IP through study competition, planned visit date Day 281.
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD8233 | Treatment Emergent Platelet Count Abnormalities | Platelet count > ULN | 26 Participants |
| AZD8233 | Treatment Emergent Platelet Count Abnormalities | Platelet count < 150 x 10^9/L | 19 Participants |
| AZD8233 | Treatment Emergent Platelet Count Abnormalities | Platelet count < 75 x 10^9/L | 1 Participants |
| AZD8233 | Treatment Emergent Platelet Count Abnormalities | >30% decrease from baseline | 14 Participants |
| AZD8233 | Treatment Emergent Platelet Count Abnormalities | Platelet count < 50 x 10^9/L | 0 Participants |
| AZD8233 | Treatment Emergent Platelet Count Abnormalities | <150 x 10^9/L or >30% decrease from baseline | 28 Participants |
| AZD8233 | Treatment Emergent Platelet Count Abnormalities | Platelet count < 100 x 10^9/L | 2 Participants |
| AZD8233 | Treatment Emergent Platelet Count Abnormalities | <150 x 10^9/L and >30% decrease from baseline | 5 Participants |
| AZD8233 | Treatment Emergent Platelet Count Abnormalities | Platelet count < LLN | 9 Participants |
| Placebo | Treatment Emergent Platelet Count Abnormalities | <150 x 10^9/L and >30% decrease from baseline | 9 Participants |
| Placebo | Treatment Emergent Platelet Count Abnormalities | Platelet count < LLN | 11 Participants |
| Placebo | Treatment Emergent Platelet Count Abnormalities | Platelet count > ULN | 20 Participants |
| Placebo | Treatment Emergent Platelet Count Abnormalities | Platelet count < 50 x 10^9/L | 0 Participants |
| Placebo | Treatment Emergent Platelet Count Abnormalities | Platelet count < 75 x 10^9/L | 1 Participants |
| Placebo | Treatment Emergent Platelet Count Abnormalities | Platelet count < 100 x 10^9/L | 2 Participants |
| Placebo | Treatment Emergent Platelet Count Abnormalities | Platelet count < 150 x 10^9/L | 21 Participants |
| Placebo | Treatment Emergent Platelet Count Abnormalities | >30% decrease from baseline | 14 Participants |
| Placebo | Treatment Emergent Platelet Count Abnormalities | <150 x 10^9/L or >30% decrease from baseline | 26 Participants |
Primary
Vital Sign - Diastolic Blood Pressure
Mean and standard deviation of Diastolic Blood Pressure at each scheduled visit by treatment.
Time frame: Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281.
Population: Safety analysis set, the number analyzed represents the number of participants with available diastolic blood pressure data at that time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD8233 | Vital Sign - Diastolic Blood Pressure | Day 57 | 78.714 mmHg | Standard Deviation 7.799 |
| AZD8233 | Vital Sign - Diastolic Blood Pressure | Day 141 | 78.698 mmHg | Standard Deviation 8.505 |
| AZD8233 | Vital Sign - Diastolic Blood Pressure | Day 29 | 78.408 mmHg | Standard Deviation 8.157 |
| AZD8233 | Vital Sign - Diastolic Blood Pressure | Day 169 | 78.139 mmHg | Standard Deviation 8.489 |
| AZD8233 | Vital Sign - Diastolic Blood Pressure | Day 85 | 78.867 mmHg | Standard Deviation 8.053 |
| AZD8233 | Vital Sign - Diastolic Blood Pressure | Day 197 | 78.382 mmHg | Standard Deviation 7.736 |
| AZD8233 | Vital Sign - Diastolic Blood Pressure | Day 15 | 78.318 mmHg | Standard Deviation 8.06 |
| AZD8233 | Vital Sign - Diastolic Blood Pressure | Day 225 | 78.582 mmHg | Standard Deviation 8.313 |
| AZD8233 | Vital Sign - Diastolic Blood Pressure | Day 113 | 79.164 mmHg | Standard Deviation 8.393 |
| AZD8233 | Vital Sign - Diastolic Blood Pressure | Day 281 | 78.812 mmHg | Standard Deviation 8.484 |
| AZD8233 | Vital Sign - Diastolic Blood Pressure | Baseline | 78.937 mmHg | Standard Deviation 7.608 |
| Placebo | Vital Sign - Diastolic Blood Pressure | Day 281 | 78.601 mmHg | Standard Deviation 7.249 |
| Placebo | Vital Sign - Diastolic Blood Pressure | Baseline | 78.562 mmHg | Standard Deviation 6.134 |
| Placebo | Vital Sign - Diastolic Blood Pressure | Day 15 | 78.559 mmHg | Standard Deviation 6.946 |
| Placebo | Vital Sign - Diastolic Blood Pressure | Day 29 | 79.611 mmHg | Standard Deviation 6.779 |
| Placebo | Vital Sign - Diastolic Blood Pressure | Day 57 | 79.369 mmHg | Standard Deviation 7.12 |
| Placebo | Vital Sign - Diastolic Blood Pressure | Day 85 | 79.081 mmHg | Standard Deviation 7.575 |
| Placebo | Vital Sign - Diastolic Blood Pressure | Day 113 | 79.584 mmHg | Standard Deviation 7.152 |
| Placebo | Vital Sign - Diastolic Blood Pressure | Day 141 | 78.836 mmHg | Standard Deviation 7.758 |
| Placebo | Vital Sign - Diastolic Blood Pressure | Day 169 | 78.402 mmHg | Standard Deviation 7.359 |
| Placebo | Vital Sign - Diastolic Blood Pressure | Day 197 | 78.615 mmHg | Standard Deviation 7.432 |
| Placebo | Vital Sign - Diastolic Blood Pressure | Day 225 | 78.988 mmHg | Standard Deviation 7.254 |
Primary
Vital Sign - Pulse Rate
Mean and standard deviation of Pulse rate at each scheduled visit by treatment.
Time frame: Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281.
Population: Safety analysis set, the number analyzed represents the number of participants with available pulse rate data at that time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD8233 | Vital Sign - Pulse Rate | Day 57 | 69.58 beats/min | Standard Deviation 10.59 |
| AZD8233 | Vital Sign - Pulse Rate | Day 141 | 70.85 beats/min | Standard Deviation 11.1 |
| AZD8233 | Vital Sign - Pulse Rate | Day 29 | 68.52 beats/min | Standard Deviation 9.91 |
| AZD8233 | Vital Sign - Pulse Rate | Day 169 | 69.35 beats/min | Standard Deviation 10.44 |
| AZD8233 | Vital Sign - Pulse Rate | Day 85 | 68.90 beats/min | Standard Deviation 9.87 |
| AZD8233 | Vital Sign - Pulse Rate | Day 197 | 70.69 beats/min | Standard Deviation 12.26 |
| AZD8233 | Vital Sign - Pulse Rate | Day 15 | 70.63 beats/min | Standard Deviation 10.07 |
| AZD8233 | Vital Sign - Pulse Rate | Day 225 | 69.56 beats/min | Standard Deviation 10.17 |
| AZD8233 | Vital Sign - Pulse Rate | Day 113 | 70.77 beats/min | Standard Deviation 10.58 |
| AZD8233 | Vital Sign - Pulse Rate | Day 281 | 68.39 beats/min | Standard Deviation 9.99 |
| AZD8233 | Vital Sign - Pulse Rate | Baseline | 68.93 beats/min | Standard Deviation 11.52 |
| Placebo | Vital Sign - Pulse Rate | Day 281 | 69.31 beats/min | Standard Deviation 10.9 |
| Placebo | Vital Sign - Pulse Rate | Baseline | 67.88 beats/min | Standard Deviation 10.47 |
| Placebo | Vital Sign - Pulse Rate | Day 15 | 69.48 beats/min | Standard Deviation 10.42 |
| Placebo | Vital Sign - Pulse Rate | Day 29 | 68.90 beats/min | Standard Deviation 10.05 |
| Placebo | Vital Sign - Pulse Rate | Day 57 | 69.90 beats/min | Standard Deviation 11.56 |
| Placebo | Vital Sign - Pulse Rate | Day 85 | 69.53 beats/min | Standard Deviation 11.1 |
| Placebo | Vital Sign - Pulse Rate | Day 113 | 70.03 beats/min | Standard Deviation 10.48 |
| Placebo | Vital Sign - Pulse Rate | Day 141 | 70.00 beats/min | Standard Deviation 10.84 |
| Placebo | Vital Sign - Pulse Rate | Day 169 | 68.38 beats/min | Standard Deviation 10.31 |
| Placebo | Vital Sign - Pulse Rate | Day 197 | 69.43 beats/min | Standard Deviation 8.94 |
| Placebo | Vital Sign - Pulse Rate | Day 225 | 68.79 beats/min | Standard Deviation 10.48 |
Primary
Vital Signs - Temperature
Mean and standard deviation of Temperature at each scheduled visit by treatment.
Time frame: Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281.
Population: Safety analysis set, the number analyzed represents the number of participants with available temperature data at that time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD8233 | Vital Signs - Temperature | Day 57 | 36.340 Celsius | Standard Deviation 0.42 |
| AZD8233 | Vital Signs - Temperature | Day 141 | 36.335 Celsius | Standard Deviation 0.398 |
| AZD8233 | Vital Signs - Temperature | Day 29 | 36.360 Celsius | Standard Deviation 0.422 |
| AZD8233 | Vital Signs - Temperature | Day 169 | 36.304 Celsius | Standard Deviation 0.454 |
| AZD8233 | Vital Signs - Temperature | Day 85 | 36.360 Celsius | Standard Deviation 0.416 |
| AZD8233 | Vital Signs - Temperature | Day 197 | 36.299 Celsius | Standard Deviation 0.477 |
| AZD8233 | Vital Signs - Temperature | Day 15 | 36.344 Celsius | Standard Deviation 0.404 |
| AZD8233 | Vital Signs - Temperature | Day 225 | 36.327 Celsius | Standard Deviation 0.472 |
| AZD8233 | Vital Signs - Temperature | Day 113 | 36.359 Celsius | Standard Deviation 0.391 |
| AZD8233 | Vital Signs - Temperature | Day 281 | 36.353 Celsius | Standard Deviation 0.396 |
| AZD8233 | Vital Signs - Temperature | Baseline | 36.434 Celsius | Standard Deviation 0.437 |
| Placebo | Vital Signs - Temperature | Day 281 | 36.391 Celsius | Standard Deviation 0.363 |
| Placebo | Vital Signs - Temperature | Baseline | 36.369 Celsius | Standard Deviation 0.389 |
| Placebo | Vital Signs - Temperature | Day 15 | 36.387 Celsius | Standard Deviation 0.378 |
| Placebo | Vital Signs - Temperature | Day 29 | 36.361 Celsius | Standard Deviation 0.386 |
| Placebo | Vital Signs - Temperature | Day 57 | 36.396 Celsius | Standard Deviation 0.368 |
| Placebo | Vital Signs - Temperature | Day 85 | 36.362 Celsius | Standard Deviation 0.363 |
| Placebo | Vital Signs - Temperature | Day 113 | 36.399 Celsius | Standard Deviation 0.348 |
| Placebo | Vital Signs - Temperature | Day 141 | 36.373 Celsius | Standard Deviation 0.341 |
| Placebo | Vital Signs - Temperature | Day 169 | 36.353 Celsius | Standard Deviation 0.411 |
| Placebo | Vital Signs - Temperature | Day 197 | 36.352 Celsius | Standard Deviation 0.316 |
| Placebo | Vital Signs - Temperature | Day 225 | 36.365 Celsius | Standard Deviation 0.37 |
Primary
Vital Sign - Systolic Blood Pressure
Mean and standard deviation of Systolic Blood Pressure at each scheduled visit by treatment.
Time frame: Baseline, Days 15, 29, 57, 85, 113, 141, 169, 197, 225, and 281.
Population: Safety analysis set, the number analyzed represents the number of participants with available systolic blood pressure data at that time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD8233 | Vital Sign - Systolic Blood Pressure | Day 57 | 130.754 mmHg | Standard Deviation 12.536 |
| AZD8233 | Vital Sign - Systolic Blood Pressure | Day 141 | 131.386 mmHg | Standard Deviation 14.246 |
| AZD8233 | Vital Sign - Systolic Blood Pressure | Day 29 | 130.741 mmHg | Standard Deviation 13.363 |
| AZD8233 | Vital Sign - Systolic Blood Pressure | Day 169 | 130.959 mmHg | Standard Deviation 11.874 |
| AZD8233 | Vital Sign - Systolic Blood Pressure | Day 85 | 131.913 mmHg | Standard Deviation 12.083 |
| AZD8233 | Vital Sign - Systolic Blood Pressure | Day 197 | 129.351 mmHg | Standard Deviation 14.236 |
| AZD8233 | Vital Sign - Systolic Blood Pressure | Day 15 | 130.438 mmHg | Standard Deviation 13.541 |
| AZD8233 | Vital Sign - Systolic Blood Pressure | Day 225 | 131.188 mmHg | Standard Deviation 14.578 |
| AZD8233 | Vital Sign - Systolic Blood Pressure | Day 113 | 131.974 mmHg | Standard Deviation 12.622 |
| AZD8233 | Vital Sign - Systolic Blood Pressure | Day 281 | 130.048 mmHg | Standard Deviation 13.288 |
| AZD8233 | Vital Sign - Systolic Blood Pressure | Baseline | 130.918 mmHg | Standard Deviation 13.284 |
| Placebo | Vital Sign - Systolic Blood Pressure | Day 281 | 131.043 mmHg | Standard Deviation 13.069 |
| Placebo | Vital Sign - Systolic Blood Pressure | Baseline | 131.325 mmHg | Standard Deviation 11.281 |
| Placebo | Vital Sign - Systolic Blood Pressure | Day 15 | 131.198 mmHg | Standard Deviation 12.711 |
| Placebo | Vital Sign - Systolic Blood Pressure | Day 29 | 133.152 mmHg | Standard Deviation 11.881 |
| Placebo | Vital Sign - Systolic Blood Pressure | Day 57 | 131.465 mmHg | Standard Deviation 14.073 |
| Placebo | Vital Sign - Systolic Blood Pressure | Day 85 | 132.111 mmHg | Standard Deviation 12.238 |
| Placebo | Vital Sign - Systolic Blood Pressure | Day 113 | 132.493 mmHg | Standard Deviation 12.022 |
| Placebo | Vital Sign - Systolic Blood Pressure | Day 141 | 132.041 mmHg | Standard Deviation 14.081 |
| Placebo | Vital Sign - Systolic Blood Pressure | Day 169 | 132.706 mmHg | Standard Deviation 12.481 |
| Placebo | Vital Sign - Systolic Blood Pressure | Day 197 | 133.149 mmHg | Standard Deviation 11.838 |
| Placebo | Vital Sign - Systolic Blood Pressure | Day 225 | 133.165 mmHg | Standard Deviation 12.746 |
Primary
Vital Sign - Weight
Mean and standard deviation of Weight at each scheduled visit by treatment.
Time frame: Baseline and Day 281.
Population: Safety analysis set, the number analyzed represents the number of participants with available weight data at that time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD8233 | Vital Sign - Weight | Baseline | 86.642 kg | Standard Deviation 17.054 |
| AZD8233 | Vital Sign - Weight | Day 281 | 85.493 kg | Standard Deviation 16.561 |
| Placebo | Vital Sign - Weight | Day 281 | 88.759 kg | Standard Deviation 18.11 |
| Placebo | Vital Sign - Weight | Baseline | 88.750 kg | Standard Deviation 17.566 |
Secondary
Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period
Number of ADA positive subjects at each time point during the treatment period and follow-up period.
Time frame: Pre-dose of Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169, Day 197, Day 281
Population: The safety analysis set consists of all subjects who have received at least one dose of investigational product. Erroneously treated subjects (e.g., those randomised to treatment A but actually given treatment B) are accounted for in the treatment group of the treatment they actually received. The number analyzed represents the number of participants with available ADA data at that time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD8233 | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 29 | 15 Participants |
| AZD8233 | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 141 | 25 Participants |
| AZD8233 | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 85 | 18 Participants |
| AZD8233 | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 169 | 31 Participants |
| AZD8233 | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 57 | 16 Participants |
| AZD8233 | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 197 | 37 Participants |
| AZD8233 | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 113 | 21 Participants |
| AZD8233 | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 281 | 40 Participants |
| AZD8233 | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 1 | 6 Participants |
| Placebo | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 281 | 3 Participants |
| Placebo | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 1 | 4 Participants |
| Placebo | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 29 | 3 Participants |
| Placebo | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 57 | 3 Participants |
| Placebo | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 85 | 3 Participants |
| Placebo | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 113 | 3 Participants |
| Placebo | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 141 | 2 Participants |
| Placebo | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 169 | 2 Participants |
| Placebo | Anti-drug Antibodies (ADAs) During the Treatment Period and Follow-up Period | Day 197 | 3 Participants |
Secondary
Percentage Change From Baseline on Serum PCSK9
Percentage change in Proprotein convertase subtilisin/kexin type-9 (PCSK9) from baseline to Day 197.
Time frame: From baseline to Day 197
Population: Full analysis set includes all subjects who were randomly assigned to study intervention. Subjects will be analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD8233 | Percentage Change From Baseline on Serum PCSK9 | -77.5 percent change |
| Placebo | Percentage Change From Baseline on Serum PCSK9 | -0.8 percent change |
p-value: <0.00195% CI: [-81.7, -71.7]ANCOVA
Secondary
Plasma Concentration of AZD8233
AZD8233 full length ASO concentrations in plasma were summarised by descriptive statistics by sampling time point and listed on individual level based on the PK analysis set.
Time frame: Pre-dose of Day 29, Day 85, Day 141, Day 183, Day 197
Population: The PK analysis set consists of all subjects who receive at least 1 dose of AZD8233, for whom at least 1 post-dose PK concentration assessment is available. Subjects were allocated to the actual treatment received. The number analyzed represents the number of participants with available PK data at that time point, including lower limit of quantification (LLoQ) observations, but not included in the calculation of summary statistics of Geometric Mean and Geometric Coefficient of Variation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AZD8233 | Plasma Concentration of AZD8233 | Day 29 | 0.2648 ng/mL | Geometric Coefficient of Variation 82.8352 |
| AZD8233 | Plasma Concentration of AZD8233 | Day 85 | 0.3927 ng/mL | Geometric Coefficient of Variation 84.9378 |
| AZD8233 | Plasma Concentration of AZD8233 | Day 141 | 0.5749 ng/mL | Geometric Coefficient of Variation 161.9301 |
| AZD8233 | Plasma Concentration of AZD8233 | Day 183 | 1.0441 ng/mL | Geometric Coefficient of Variation 178.5196 |
| AZD8233 | Plasma Concentration of AZD8233 | Day 197 | 0.6975 ng/mL | Geometric Coefficient of Variation 208.2431 |