E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Dyslipidemia, especially: evaluation of low-density lipoprotein cholesterol reduction at steady state at different doses of AZD8233 in order to select a therapeutic dose. |
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E.1.1.1 | Medical condition in easily understood language |
Dyslipidemia: abnormal levels (elevated) of lipids (fats), including cholesterol and triglycerides, in the blood. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10058108 |
E.1.2 | Term | Dyslipidaemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the effect of AZD8233 on level of dyslipidemia related biomarker (LDL-C) across different dose levels (absolute change from baseline in log transformed LDL-C in plasma). |
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E.2.2 | Secondary objectives of the trial |
To assess the effect of different doses of AZD8233 on PCSK9 versus placebo (absolute change from baseline in log-transformed PCSK9 in plasma) To assess the effect of different doses of AZD8233 on LDL-C versus placebo (percentage change from baseline in levels of LDL-C in plasma) To assess the effect of AZD8233 on other lipid parameters versus placebo (levels of other lipid parameters, including:TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a), Triglycerides, Remnants cholesterol) To evaluate the PK of AZD8233 (plasma parameters: population PK parameters to be reported in a separate report) To evaluate the immunogenicity of AZD8233 (development of ADA and titer (if participants are ADA positive) during treatment and follow-up) To assess the safety and tolerability of AZD8233 (safety and tolerability will be evaluated in terms of AEs, vital signs, ECG, and clinical laboratory evaluations including platelet count) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Participant must be 18 to 75 years of age, inclusive, at the time of signing the informed consent. Type of Participant and Disease Characteristics: Participants who have a fasting LDL-C ≥ 70 mg/dL (1.8 mmol/L) but < 190 mg/dL (4.9 mmol/L) at screening (visit 2). Have fasting triglycerides < 400 mg/dL (< 4.52 mmol/L) at screening (visit 2). Should be receiving moderate- or high-intensity statin therapy (refer to Appendix H) as defined by the ACC/AHA guidelines on blood cholesterol management, or according to local guidelines. Should be on stable medication for ≥ 3 months prior to screening with no planned medication or dose change during study participation. The exception to this restriction is for fenofibrate; if the participant is receiving fenofibrate, the therapy must be stable for at least 6 weeks prior to randomization at a dose that is appropriate for the duration of the study in the judgement of the Investigator. Other fibrate therapy (and derivatives) are prohibited. Weight: Body mass index between 19 and 40 kg/m2. Sex: male or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. (a) Male participants: • Males must be surgically sterile or using, in conjunction with their female partner, a highly effective method of contraception for the duration of the study (from the time they sign consent) and for 3 months after the final follow up visit to prevent pregnancy in a partner. Acceptable methods of contraception include birth control pills, injections, implants, or patches, IUDs, tubal ligation/occlusion, and vasectomy. A barrier method is not necessary if the female partner is sterilized. Male study participants must not donate or bank sperm during this same time period. (b) Female participants: • Female participants must not be pregnant and must have a negative pregnancy test at screening and randomisation, must not be lactating, and must not be of childbearing potential. Women not of childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative medical cause. The following age-specific requirements apply: Women < 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and FSH levels in the postmenopausal range. Women ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment. |
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E.4 | Principal exclusion criteria |
Medical Conditions Estimated glomerular filtration rate < 40 mL/min/1.73m2 using the Chronic Kidney Disease-Epidemiology Collaboration equation (visit 1). - 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. - Poorly controlled type 2 diabetes mellitus, defined as HbA1c > 10% (visit 1). - Acute ischaemic cardiovascular event in the last 12 months prior to randomization. - Heart failure with New York Heart Association (NYHA) Class III-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 as judged by the Investigator. - Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in-situ, or Stage 1 prostate carcinoma) within the last 10 years. - Recipient of any major organ transplant, eg, lung, liver, heart, bone marrow, renal. - LDL or plasma apheresis within 12 months prior to randomization. - Uncontrolled hypertension defined as sitting SBP > 160 mmHg or DBP > 90 mmHg (visit 1 or 3). - Heart rate after 10 minutes supine rest < 50 bpm or > 100 bpm (visit 1 or 3). - Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities in the 12 lead ECG as judged by the Investigator. -QTcF > 470 ms; high degree atrioventricular-block grade II-III and sinus node dysfunction with significant sinus pause untreated with pacemaker; and cardiac tachyarrhythmias. - Mipomersen, or lomitapide within 12 months prior to randomization. - Previous administration of AZD8233/AZD6615 or other PCSK9 inhibition treatment (approved or investigational). - Received another new chemical entity (defined as a compound which has not been approved for marketing) within 30 days of last follow-up to first administration of the study intervention of this study or 5 half-lives from last dose to first administration of study intervention, whichever is the longest. - Optional Genetic Sampling Optional Genetic Sampling should be in line with following exclusion criteria: Previous allogeneic bone marrow transplant ; Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary objective: to assess the effect of different doses of AZD8233 on LDL-C versus placebo (absolute change from baseline in log transformed LDL-C in plasma). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
D1; D8; D22; D29; D43; D57; D71 (treatment period); D85, D99, D113, D127, D141, D155; D169 (safety follow-up period) |
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E.5.2 | Secondary end point(s) |
To assess the effect of different doses of AZD8233 on PCSK9 versus placebo (absolute change from baseline in log-transformed PCSK9 in plasma) To assess the effect of different doses of AZD8233 on LDL-C versus placebo (percentage change from baseline in levels of LDL-C in plasma) To assess the effect of AZD8233 on other lipid parameters versus placebo (levels of other lipid parameters, including:TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a), Triglycerides, Remnants cholesterol) To evaluate the PK of AZD8233 (plasma parameters: population PK parameters to be reported in a separate report) To evaluate the immunogenicity of AZD8233 (development of ADA and titer (if participants are ADA positive) during treatment and follow-up) To assess the safety and tolerability of AZD8233 (safety and tolerability will be evaluated in terms of AEs, vital signs, ECG, and clinical laboratory evaluations including platelet count) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Absolute change from baseline in log-transformed PCSK9 in plasma; Percentage change from baseline in levels of LDL-C in plasma; Levels of other lipid parameters, including:TC, HDL-C, Non-HDL-C, VLDL-C, ApoA1, ApoB, Lp(a), Triglycerides, Remnants cholesterol): D1; D8; D22; D29; D43; D57; D71; D85, D99; D113; D127; D141; D155; D169. Plasma PK parameters: D8; D29; D43; D57; D71; D85; D113; D141; D169. Development of ADA and titer (if participants are ADA positive):D1; D8; D29; D57; D85; D99; D113; D127; D141; D155; D169. Safety and tolerability: AEs, vital signs, ECG, and clinical laboratory evaluations including platelet count): D-42 to D-8 (screening visit#1); D1; D8; D22; D29; D43; D57; D71; D85; D99; D113; D127; D141; D155; D169. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity:Blood samples collection for immunogenicity assessments (ADA). Exploratory biomarkers analysis: Blood and urine samples collection for potential future exploratory research aimed at exploring biomarkers involved in PK, PD, safety and tolerability related to AZD8233 treatment or cardiometabolic diseases. Optional: DNA storage from blood samples for future exploratory research into genes/genetic variation that may influence response to treatment. |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
Denmark |
Slovakia |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of the trial correspond to the last patient last visit completion (final Follow-up Visit - D169). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |