AZD0780 + Ezetimibe for High Cholesterol

Recruiting at 2 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: AstraZeneca

Must be taking: Ezetimibe

Must not be taking: PCSK9 inhibitors

Disqualifiers: Gastrointestinal, Hepatic, Renal, others

Trial Summary

What is the purpose of this trial?

The main aim of this study is to assess the effects of AZD0780 when added on top of ezetimibe or ezetimibe and rosuvastatin or ezetimibe and bempedoic acid.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken any lipid-lowering therapy or AZD0780 in the 3 months before the trial, or PCSK9 inhibitors in the last 12 months.

What data supports the effectiveness of the drug AZD0780 + Ezetimibe for high cholesterol?

Research shows that adding ezetimibe to statin therapy can effectively lower cholesterol levels in patients who have not reached their cholesterol goals with statins alone. This suggests that combining ezetimibe with other treatments, like AZD0780, might also help reduce cholesterol. ^{1 2 3 4 5}

Is the combination of AZD0780 and Ezetimibe safe for humans?

Ezetimibe has been studied for safety in various conditions, showing it is generally safe for lowering cholesterol levels. However, there is no specific safety data available for the combination of AZD0780 and Ezetimibe. ^{6 7 8 9 10}

How does the drug AZD0780 + Ezetimibe differ from other treatments for high cholesterol?

AZD0780 combined with Ezetimibe is unique because it potentially offers a new mechanism of action or combination that could enhance cholesterol-lowering effects beyond what is achieved with Ezetimibe or statins alone. Ezetimibe works by reducing cholesterol absorption in the intestines, and when combined with another agent like AZD0780, it may provide a more comprehensive approach to managing high cholesterol. ^{11 12 13 14 15}

Eligibility Criteria

This trial is for healthy adults with high LDL-C (bad cholesterol) levels. Participants must be over 18, weigh at least 50 kg, and have a BMI above 18. Women must not be pregnant or able to become pregnant, while sexually active men need to use contraception. Cholesterol and triglyceride levels are specified for eligibility.

Inclusion Criteria

My LDL cholesterol is between 100 and 190 mg/dL.

I am not pregnant, as confirmed by a blood test.

I am a woman who cannot become pregnant because I am postmenopausal or have been surgically sterilized.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Run-in

Participants undergo a run-in period to stabilize conditions before treatment

4 weeks

Treatment

Participants receive AZD0780 or placebo in combination with ezetimibe, ezetimibe/rosuvastatin, or ezetimibe/bempedoic acid

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

2 visits (in-person)

Treatment Details

Interventions

• AZD0780 (Other)

Trial Overview The study tests AZD0780's effects on lowering bad cholesterol when combined with ezetimibe alone or alongside rosuvastatin or bempedoic acid. It compares these combinations against a placebo to evaluate safety, tolerability, and effectiveness in managing high cholesterol.

Participant Groups

Group I: Rosuvastatin + Ezetimibe + AZD0780 Experimental Treatment 3 Interventions

Participants will receive rosuvastatin 20 mg, ezetimibe 10 mg and AZD0780 QD for 4 weeks.

Group II: Ezetimibe + AZD0780 Experimental Treatment 2 Interventions

Participants will receive ezetimibe 10 mg and AZD0780 once daily (QD) for 4 weeks.

Group III: Bempedoic Acid + Ezetimibe + AZD0780 (Optional Cohort) Experimental Treatment 3 Interventions

Participants will receive bempedoic acid 180 mg, ezetimibe 10 mg and AZD0780 QD for 4 weeks.

Group IV: Ezetimibe + Placebo Placebo Group 2 Interventions

Participants will receive ezetimibe 10 mg and placebo QD for 4 weeks.

Group V: Rosuvastatin + Ezetimibe + Placebo Placebo Group 3 Interventions

Participants will receive rosuvastatin 20 mg, ezetimibe 10 mg and placebo QD for 4 weeks.

Group VI: Bempedoic Acid + Ezetimibe + Placebo (Optional Cohort) Placebo Group 3 Interventions

Participants will receive bempedoic acid 180 mg, ezetimibe 10 mg and placebo QD for 4 weeks.

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

In a meta-analysis of 13 studies involving 5080 patients, adding ezetimibe to statin therapy resulted in a significantly greater reduction in LDL cholesterol levels compared to simply doubling the statin dose, with a weighted mean difference of -15.3%.

Patients receiving the ezetimibe-statin combination were more likely to achieve their LDL cholesterol treatment goals, with an odds ratio of 2.45, indicating that this combination therapy is more effective than increasing statin dosage alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: systematic review and meta-analysis. Mikhailidis, DP., Lawson, RW., McCormick, AL., et al.[2022]

In a study of 450 patients with coronary heart disease who were not meeting LDL cholesterol goals on atorvastatin, co-administering ezetimibe significantly increased the percentage of patients achieving the LDL-C target of ≤2.6 mmol/l (81.3% vs. 21.8% with placebo).

The combination of ezetimibe and atorvastatin resulted in greater reductions in LDL-C and other cholesterol markers, while also being well tolerated and showing a safety profile similar to atorvastatin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ezetimibe co-administered with ongoing atorvastatin therapy in achieving low-density lipoprotein goal in patients with hypercholesterolemia and coronary heart disease. Cruz-Fernández, JM., Bedarida, GV., Adgey, J., et al.[2018]

In a study involving 538 patients with primary hypercholesterolemia, the combination of ezetimibe 10 mg and pravastatin resulted in significant reductions in LDL cholesterol (LDL-C) by 34-41% and triglycerides (TG) by 21-23% compared to pravastatin alone.

The combined treatment was well tolerated, showing a safety profile similar to that of pravastatin alone and placebo, indicating it is a safe and effective option for managing cholesterol levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Melani, L., Mills, R., Hassman, D., et al.[2019]

Ezetimibe significantly reduces low-density lipoprotein cholesterol (LDL-C) levels in HIV-positive patients with hyperlipidaemia, with a net change of approximately -23.56 mg/dL based on randomized controlled trials and -23.89 mg/dL in single-arm trials.

In addition to lowering LDL-C, ezetimibe also leads to significant reductions in total cholesterol (TC) and triglycerides (TG), making it a potential treatment option for HIV patients with elevated lipid levels, especially when statins cannot be used due to drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of ezetimibe in human immunodeficiency virus patients treated for hyperlipidaemia: a systematic review and meta-analysis. Nirmala, N., Avendano, EE., Morin, RA.[2022]

In the PRECISE-IVUS trial involving 246 patients, the combination of atorvastatin and ezetimibe significantly reduced coronary plaque volume in patients who had prior statin therapy, indicating enhanced antiatherosclerotic effects in this group.

Patients with statin pretreatment showed a greater reduction in atheroma volume with the atorvastatin/ezetimibe combination compared to atorvastatin alone, suggesting that this combination may be particularly beneficial for those who do not respond adequately to statins alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic effect of ezetimibe addition on coronary atheroma regression in patients with prior statin therapy: Subanalysis of PRECISE-IVUS trial. Tsujita, K., Yamanaga, K., Komura, N., et al.[2018]

In a study of 827 patients with primary hypercholesterolemia, ezetimibe 10 mg/day significantly reduced low-density lipoprotein cholesterol (LDL-C) by an average of 17.7% compared to a 0.8% increase with placebo, demonstrating its efficacy in lowering cholesterol levels.

Ezetimibe was well tolerated and had a safety profile similar to placebo, without affecting lipid-soluble vitamins or cortisol production, suggesting it is a safe option for managing cholesterol levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Knopp, RH., Gitter, H., Truitt, T., et al.[2019]

Ezetimibe 10 mg/day significantly reduced plasma sitosterol levels by 43.9% and campesterol levels by 50.8% over two years in patients with homozygous sitosterolemia, demonstrating its long-term efficacy.

The treatment was well tolerated, with no significant adverse effects reported, indicating a favorable safety profile for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of ezetimibe 10 mg in patients with homozygous sitosterolemia: a 2-year, open-label extension study. Lütjohann, D., von Bergmann, K., Sirah, W., et al.[2015]

In a study involving 17,999 post-acute coronary syndrome patients over 6 years, adding ezetimibe to statin therapy significantly reduced the risk of cardiovascular events, regardless of whether patients had low-density lipoprotein cholesterol (LDL-C) levels above or below 70 mg/dL.

The benefits of ezetimibe were consistent across different baseline LDL-C levels, indicating that intensive lipid-lowering therapy is effective even for patients with LDL-C <70 mg/dL, without any significant safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline Low-Density Lipoprotein Cholesterol and Clinical Outcomes of Combining Ezetimibe With Statin Therapy in IMPROVE-IT. Oyama, K., Giugliano, RP., Blazing, MA., et al.[2022]

PCSK9 inhibitors and ezetimibe are effective in reducing cardiovascular events, providing a strong option for patients at high risk of heart disease.

The clinical practice guideline offers risk-stratified recommendations, helping healthcare providers tailor treatment plans based on individual patient risk levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recommendations for use of ezetimibe and/or PCSK9 inhibitors in patients with elevated LDL-C. Kelsey, MD., Newby, LK.[2022]

A systematic review of 48 randomized controlled trials involving 28,444 participants found that ezetimibe is not associated with significant adverse effects, such as cancer, fractures, or gastrointestinal issues, indicating it is a safe option for lipid-lowering treatment.

Ezetimibe showed little to no difference in adverse events compared to placebo and other lipid-lowering agents, suggesting its efficacy in lowering lipids without increasing the risk of undesirable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of ezetimibe in lipid-lowering treatment: systematic review and meta-analysis of randomised controlled trials and cohort studies. Wang, Y., Zhan, S., Du, H., et al.[2023]

In a phase III trial involving 109 patients with hypercholesterolemia, the fixed-dose combination of pitavastatin and ezetimibe (K-924) significantly reduced LDL cholesterol levels by an average of 30.3% after 52 weeks, with 91.8% of patients achieving their LDL-C management target.

K-924 was found to be well-tolerated, with only one reported adverse drug reaction, indicating that it is a safe option for intensifying cholesterol-lowering therapy without adding more medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Efficacy and Safety of K-924 Pitavastatin/Ezetimibe Fixed-dose Combination in Patients with Hypercholesterolemia: A Phase III, Multi-center, Open-label Trial. Ako, J., Yokote, K., Tsujita, K., et al.[2023]

A study involving 59 healthy Chinese volunteers demonstrated that the test ezetimibe tablet is bioequivalent to Ezetrol® under both fasting and fed conditions, meeting the regulatory criteria for pharmacokinetic parameters like Cmax and AUC.

No severe adverse events were reported during the study, indicating that both formulations of ezetimibe are safe for use in the tested population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and bioequivalence of Ezetimibe tablet versus Ezetrol®:an open-label, randomized, two-sequence crossover study in healthy Chinese subjects. Sun, F., Liu, Y., Li, T., et al.[2023]

In a study of 374,786 adults aged 66 and older who experienced a myocardial infarction, only 1.9% initiated ezetimibe and 0.4% initiated a PCSK9 inhibitor, indicating low uptake of these recommended treatments for very high-risk ASCVD patients.

The analysis revealed significant disparities in treatment initiation based on race and sex, with non-Hispanic Black patients showing lower rates of initiation for both ezetimibe and PCSK9 inhibitors compared to non-Hispanic White patients, and women being more likely than men to start these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Race/ethnic and sex differences in the initiation of non-statin lipid-lowering medication following myocardial infarction. Colvin, CL., Poudel, B., Bress, AP., et al.[2022]

Ezetimibe is a new lipid-lowering medication that works by blocking the absorption of cholesterol in the intestines, and it is particularly effective when used alongside statins to further reduce cholesterol levels in patients with high cholesterol.

The combination of ezetimibe and statins significantly lowers total and LDL cholesterol, improving the chances of patients reaching recommended cholesterol targets, although further large-scale studies are needed to confirm its impact on reducing heart disease risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ezetimibe (Ezetrol)]. Scheen, AJ.[2015]

Ezetimibe, a cholesterol absorption inhibitor, was found to be safe and well tolerated in a study involving eight healthy male volunteers who received a single 20-mg dose, with no adverse events reported.

The drug was rapidly absorbed and extensively metabolized, primarily through glucuronidation, with significant enterohepatic recycling, indicating a complex metabolic pathway that aids in its efficacy for treating primary hypercholesterolemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects. Patrick, JE., Kosoglou, T., Stauber, KL., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: systematic review and meta-analysis. [2022]

2. India pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ezetimibe co-administered with ongoing atorvastatin therapy in achieving low-density lipoprotein goal in patients with hypercholesterolemia and coronary heart disease. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Effectiveness of ezetimibe in human immunodeficiency virus patients treated for hyperlipidaemia: a systematic review and meta-analysis. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Synergistic effect of ezetimibe addition on coronary atheroma regression in patients with prior statin therapy: Subanalysis of PRECISE-IVUS trial. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. [2019]

7. India pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of ezetimibe 10 mg in patients with homozygous sitosterolemia: a 2-year, open-label extension study. [2015]

8. United States pubmed.ncbi.nlm.nih.gov

Baseline Low-Density Lipoprotein Cholesterol and Clinical Outcomes of Combining Ezetimibe With Statin Therapy in IMPROVE-IT. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Recommendations for use of ezetimibe and/or PCSK9 inhibitors in patients with elevated LDL-C. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Safety of ezetimibe in lipid-lowering treatment: systematic review and meta-analysis of randomised controlled trials and cohort studies. [2023]

11. Japan pubmed.ncbi.nlm.nih.gov

Long-term Efficacy and Safety of K-924 Pitavastatin/Ezetimibe Fixed-dose Combination in Patients with Hypercholesterolemia: A Phase III, Multi-center, Open-label Trial. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and bioequivalence of Ezetimibe tablet versus Ezetrol®:an open-label, randomized, two-sequence crossover study in healthy Chinese subjects. [2023]

13. United States pubmed.ncbi.nlm.nih.gov

Race/ethnic and sex differences in the initiation of non-statin lipid-lowering medication following myocardial infarction. [2022]

14. Belgium pubmed.ncbi.nlm.nih.gov

[Ezetimibe (Ezetrol)]. [2015]

15. United States pubmed.ncbi.nlm.nih.gov

Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects. [2022]