Clinical trial NCT07000136: A Phase III Study to Assess the Effect of AZD0780 on LDL-C in Patients With HeFH
Official title: A Phase III, Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Effect of AZD0780 on Low-Density Lipoprotein Cholesterol in Patients With Heterozygous Familial Hypercholesterolaemia
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Heterozygous Familial Hypercholesterolaemia
Keywords: Low-Density Lipoprotein Cholesterol
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2025-06-02
Enrollment: 405
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: International, multi-centre, randomised, double-blind, placebo-controlled, parallel-group
Primary purpose: TREATMENT

Brief summary: This is a study to evaluate the efficacy and safety of AZD0780 in adults with HeFH and elevated LDL-C, either with clinical ASCVD and LDL-C levels of 55 mg/dL or higher or without clinical ASCVD and LDL-C levels of 70 mg/dL or higher. AZD0780 is a small molecule that reduces the amount of LDL-C in the blood. Placebo will be used for comparison, and neither the participants nor the Investigators will know who is receiving the AZD0780 medication and who is receiving the placebo until the end of study.

The total length of the study for an individual participant will be up to approximately 56 weeks, including a screening period of up to 14 days, treatment with AZD0780 or placebo for 52 weeks, and a safety follow-up period of 10 days.

Detailed description: This is a randomised, double-blind, placebo-controlled, parallel-group Phase III study to evaluate the effect on the reduction of LDL-C and the safety and tolerability of AZD0780 versus placebo, administered as xx mg once daily orally, on top of maximally tolerated lipid-lowering regimen including maximally tolerated statin therapy. The target population is adults ≥ 18 years of age with HeFH either with ASCVD and LDL-C ≥ 55 mg/dL, or without clinical ASCVD and LDL-C ≥ 70 mg/dL. The study will be conducted at approximately 170 centres in approximately 25 countries.

The screening period is up to 14 days (and may be conditionally extended), starts at the date of signed informed consent, and ends on the day before the randomisation visit. Participants will be randomised in a 2:1 ratio to either AZD0780 or placebo for a treatment period of 52 weeks and a 10-day safety follow-up. Those randomised to the AZD0780 group will receive AZD0780 xx mg orally once daily during the treatment period, while those in the placebo group will receive matching placebo. The study will include approximately 405 randomised participants. An independent data monitoring committee will, on a regular basis, review accumulating data from the study, evaluate adverse effects of the IMP, and make recommendations regarding whether to halt or modify the study.

Eligibility criteria: Inclusion Criteria:

* ≥ 18 years of age at the time of signing the ICF.
* Diagnosis of HeFH by genetic confirmation or a definite clinical diagnosis, ie, a score \> x using the Dutch Lipid Network \[Nordestgaard et al 2013\] or equivalent as per internationally accepted diagnostic algorithms (AHA \[Gidding et al 2015\], US MEDPED \[Williams et al 1993\], Simon Broome \[Scientific Steering Committee on behalf of the Simon Broome Register Group 1991\], or Japanese Atherosclerosis Society Guidelines \[Okamura et al 2024\])
* Fasting serum by central laboratory at screening as follows: LDL-C ≥ 55 mg/dL (≥ 1.4 mmol/L) in participants with HeFH and clinical ASCVD or ≥ 70 mg/dL (≥ 1.8 mmol/L) in HeFH without clinical ASCVD. Clinical ASCVD is defined as MI, stable or unstable angina, coronary or other arterial revascularisation, ischaemic stroke, or peripheral artery disease.
* Participants should be receiving a maximally tolerated lipid lowering regimen including a maximally tolerated statin. Ezetimibe is further strongly recommended.

  1. Participants must achieve a stable dose (\> 28 days) of lipid lowering therapies before screening.
  2. Participants who are judged by the treating physician not to tolerate high intensity statins (according to guidelines, typically, atorvastatin ≥ 40 mg once daily or rosuvastatin ≥ 20 mg once daily) may be included if treated with a low- or moderate intensity statin dose.
  3. Participants not receiving any statins must have documented intolerable side effects to at least 2 different statins, including one at the lowest standard dose or on a chronic medication that would prohibit the use of a statin (according to the prescribing information for the statin in question).

Exclusion criteria:

* Homozygous familial hypercholesterolaemia, LDL apheresis or plasma apheresis within 12 months prior to screening, or any other underlying known disease or condition that may interfere with interpretation of the clinical study results as judged by the Investigator.
* Any of the following laboratory values at screening:

  * Calculated eGFR \< 15 mL/min/1.73 m2
  * AST or ALT \> 3 × ULN
  * TBL \> 2 × ULN (except for patients with Gilberts syndrome, where TBL 3 × ULN is acceptable provided direct bilirubin \< 1.5 × ULN)
  * Fasting triglycerides ≥ 400 mg/dL (≥ 4.52 mmol/L)
  * Creatine kinase \> 5 × ULN
  * Urine albumin-to-creatinine ratio ≥ 500 mg/g
* Uncontrolled type 2 diabetes mellitus defined as HbA1C ≥ 9.5% at screening
* Inadequately treated hypothyroidism defined as TSH \> 1.5 ULN at screening or participants whose thyroid replacement therapy was initiated or modified within the last 3 months prior to screening
* Use of mipomersen or lomitapide (cholesterol-lowering medications) within 12 months prior to screening or planned use during the study.
* Use of gemfibrozil within 1 week prior to screening or planned use during the study.
* Use of PCSK-9 inhibitors: evolocumab/alirocumab within 12 weeks of the screening visit or planned use during the study or inclisiran within 18 months of the screening visit or planned use during the study. Any other approved PCSK-9 inhibitor use within 5 half lives prior to the screening visit or planned use during the study.

Primary outcomes:
measure: Relative change in LDL-C from baseline to 12 weeks
timeFrame: Baseline - 12 weeks
Secondary outcomes:
measure: Relative change in LDL-C from baseline to 12 weeks
timeFrame: Baseline - 12 weeks
measure: Indicator for LDL-C < 70 mg/dL (< 1.8 mmol/L) at 12 weeks
timeFrame: Baseline - 12 weeks
measure: Indicator for LDL-C < 55 mg/dL (< 1.4 mmol/L) at 12 weeks
timeFrame: Baseline - 12 weeks
measure: Relative change in LDL-C from baseline to 28 weeks
timeFrame: Baseline - 28 weeks
measure: Relative change in LDL-C from baseline to 52 weeks
timeFrame: Baseline - 52 weeks
measure: Relative change in Apo B from baseline to 12 weeks
timeFrame: Baseline - 12 weeks
measure: Relative change in non-HDL-C from baseline to 12 weeks
timeFrame: Baseline - 12 weeks
measure: Relative change in total cholesterol from baseline to 12 weeks
timeFrame: Baseline - 12 weeks
measure: Relative change in Lp(a) from baseline to 12 weeks
timeFrame: Baseline - 12 weeks
Other outcomes:
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city: Ho Chi Minh City
country: Vietnam
facility: Research Site
city: Ho Chi Minh City
country: Vietnam
facility: Research Site
city: Ho Chi Minh
country: Vietnam
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Study officials:
References: