The primary objective of this study is to evaluate the effect of obicetrapib on LDL-C levels at Day 84. The secondary objectives of this study include the following: - To evaluate the effect of obicetrapib on fasting apolipoprotein B (ApoB), non-…
ID
Source
Brief title
Condition
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the percent change from Baseline to Day 84 in
fasting LDL-C in the obicetrapib group compared to the placebo group.
Secondary outcome
Secondary efficacy endpoints: 1. Percent change from Baseline to Days 180 and 365 in fasting LDL-C in the obicetrapib group compared to the placebo group; 2. Percent change from Baseline to Days 84, 180, and 365 in fasting ApoB in the obicetrapib group compared to the placebo group; 3. Percent change from Baseline to Days 84, 180, and 365 in fasting non-HDL-C in the obicetrapib group compared to the placebo group; 4. Percent change from Baseline to Days 84, 180, and 365 in fasting HDL-C in the obicetrapib group compared to the placebo group; 5. Percent change from Baseline to Days 84 and 365 in fasting Lp(a) in the obicetrapib group compared to the placebo group; 6. Percent change from Baseline to Days 84, 180, and 365 in fasting TC in the obicetrapib group compared to the placebo group; and 7. Percent change from Baseline to Days 84, 180, and 365 in fasting TG in the obicetrapib group compared to the placebo group. The exploratory efficacy endpoints include the following: - Individual responsiveness defined as the number of participants reaching on treatment fasting LDL-C levels of <40 mg/dL (<1.04 mmol/L), <55 mg/dL (<1.42 mmol/L), <70 mg/dL (<1.81 mmol/L), and <100 mg/dL (<2.59 mmol/L) at Days 84 and 365; - Individual responsiveness defined as the number of participants reaching on treatment fasting non-HDL-C levels of <85 mg/dL (<2.20 mmol/L), <100 mg/dL (<2.59 mmol/L), and <130 mg/dL (<3.37 mmol/L) at Days 84 and 365; - Individual responsiveness defined as the number of participants reaching on treatment fasting ApoB levels of <65 mg/dL (<0.65 g/L), <80 mg/dL (<0.80 g/L), and <130 mg/dL (<1.30 g/L) at Days 84 and 365; - Percent change from Baseline to Days 84 and 365 in fasting ApoA1 in the obicetrapib group compared to the placebo group; and - Trough levels of obicetrapib from Baseline to Day 365 in the obicetrapib group.
Background summary
HeFH is a genetic condition that increases the levels of *bad cholesterol* (LDL-
C) in your blood.
A high level of bad cholesterol is a major risk factor for the development of
disease of the heart and blood vessels. Lowering the *bad cholesterol* has been
shown to reduce the risk of death, heart attack, and other major heart and
blood vessel problems
Your *bad cholesterol* blood level remains high despite use of the maximum
tolerated dose of the medication you currently take, or you are unable to take
*bad cholesterol* lowering medication because you cannot tolerate statins or
other medicines that lower your *bad cholesterol*.
People with high *bad cholesterol* levels often have low levels of *good
cholesterol* (HDL-C, in their blood. This can be the consequence of a specific
protein which can reduce the good cholesterol and increase the *bad
cholesterol*. Obicetrapib, the study medicine, is designed to block this
specific protein, which should lead to lower *bad cholesterol* levels. This may
help lower the risk of cardiovascular problems, though this has yet to be
proven.
Study objective
The primary objective of this study is to evaluate the effect of obicetrapib on
LDL-C levels at Day 84.
The secondary objectives of this study include the following:
- To evaluate the effect of obicetrapib on fasting apolipoprotein B (ApoB),
non-high-density lipoprotein cholesterol (non HDL C), high-density lipoprotein
cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) at Days 84,
180, and 365;
- To evaluate the effect of obicetrapib on fasting LDL-C levels at Days 180 and
365;
- To evaluate the effect of obicetrapib on fasting lipoprotein (a) (Lp[a]) at
Days 84 and 365; and
- To evaluate the safety and tolerability profile of obicetrapib in a
representative population of adult males and females with HeFH, assessed by
adverse events (AEs), events of special interest (ESIs), vital signs (including
blood pressure), electrocardiogram (ECG) measurements, and clinical laboratory
values.
The exploratory objectives of this study include the following:
- To evaluate the effect of obicetrapib on the following:
o Number of participants reaching prespecified fasting LDL-C, non-HDL-C, and
ApoB
levels at Days 84 and 365; and
o Fasting apolipoprotein A1 (ApoA1) at Days 84 and 365.
- To evaluate trough levels of obicetrapib from Baseline to Day 365 in the
obicetrapib group.
Study design
This study will be a multisite, placebo-controlled, double-blind, randomized, Phase 3 study in approximately 300 participants with a history of HeFH who are not adequately controlled by their lipid-modifying therapy to evaluate the efficacy, safety, and tolerability of obicetrapib. Informed consent will be obtained from participants before the initiation of any study-specific procedures. Approximately 300 eligible participants will be randomized in a 2:1 ratio, respectively, to the following treatment groups: • Obicetrapib group: One 10 mg obicetrapib tablet once daily; or • Placebo group: 1 placebo tablet once daily. At least 70% of the participants enrolled into this study must be taking HISs. HeFH diagnosis is defined by existing confirmation via genetic testing, WHO Criteria/Dutch Lipid Clinical Network Criteria with a score of >8 points, and/or Simon Broome Register Diagnostic Criteria. Starting on Day 1, each participant will self-administer their assigned study drug once daily until Day 365. During the Treatment Period, participants will return to the study site for efficacy and safety assessments. An End of Study (EOS) Visit will be conducted approximately 35 days after the participant*s last dose of study drug, during which vital signs; limited serum chemistry, hematology, and coagulation parameters; pharmacokinetics; concomitant medications; and AEs will be assessed. The study will be governed by a Steering Committee, and a Data and Safety Monitoring Board will provide independent oversight of participant safety. The responsibilities, procedures, and workflow for these committees will be defined in separate charters outside of the protocol.
Intervention
The study drugs used in this study are as follows:
- 10 mg obicetrapib tablet; or
- Placebo tablet.
All study drugs will be administered by the participant orally, once daily at
approximately the same time on Days 1 to 365. Study drug should be administered
with water.
Study burden and risks
The primary pharmacology in in vitro, ex vivo, and in vivo studies has
demonstrated that obicetrapib has the ability to inhibit CETP, decrease LDL-C
levels, increase HDL-C levels, and importantly, reduce the number of
atherogenic ApoB-containing particles in a way that is useful in the treatment
of dyslipidemia.
In clinical studies in healthy volunteers, obicetrapib was generally well
tolerated in single doses up to 150 mg and multiple doses up to 25 mg/day for
21 days. In clinical studies in patients, obicetrapib was also well tolerated
after daily dosing of 10 mg for 12 weeks, both alone and in combination with 2
different statins. Near maximal effects were observed with the 10 mg
obicetrapib dose. At this dose level, CETP activity was reduced, and HDL-C
levels were increased while LDL-C levels decreased. There were no dose-related
AEs identified and no clinically significant changes in vital signs, ECGs, or
hematology or biochemistry parameters in any clinical studies. A statistically
significant reduction in Lp(a) levels from Baseline was also observed at the 10
mg obicetrapib dose level. Therefore, the present study will utilize a dose of
10 mg obicetrapib in participants with a history of HeFH who are not adequately
controlled by their maximally tolerated lipid-modifying therapy.
Gooimeer 2-35
Naarden 1411 DC
NL
Gooimeer 2-35
Naarden 1411 DC
NL
Listed location countries
Age
Inclusion criteria
1. Are willing and able to give written informed consent before initiation of any study-related procedures and willing to comply with all required study procedures; 2. Are male or female and >=18 years of age at Screening; o Females may be enrolled if all 3 of the following criteria are met: -They are not pregnant; -They are not breastfeeding; and -They do not plan on becoming pregnant during the study. o Females of childbearing potential must have a negative urine pregnancy test at Screening. 3. Have a history of HeFH as defined by at least 1 of the following: o Genotyping by a central laboratory; o Clinical assessment using the WHO Criteria/Dutch Lipid Clinical Network Criteria with a score of >8 points; and/or o Meet the Simon Broome Register Diagnostic Criteria for definite or possible Familial Hypercholesterolemia (FH). 4. Are on maximally tolerated lipid-modifying therapy, as an adjunct to diet, defined as follows: o A statin at a maximally tolerated stable dose; o Ezetimibe for at least 8 weeks with or without maximally tolerated statin prior to Screening; o Bempedoic acid for at least 8 weeks in combination with maximally tolerated statin prior to Screening; o A proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeted therapy alone or in combination with other lipid-modifying therapy for at least 4 stable doses prior to Screening; 5. Have a fasting serum LDL-C >=70 mg/dL (>=1.81 mmol/L) at Screening; 6. Have fasting TG <400 mg/dL (<4.52 mmol/L) at Screening; and 7. Have an estimated glomerular filtration rate >=30 mL/min/1.73 m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration equation at Screening. Other protocol-defined criteria apply.
Exclusion criteria
1. Have current or any previous history of New York Heart Association class III or IV heart failure (HF) or left ventricular ejection fraction <30%; 2. Have been hospitalized for HF within 5 years prior to Screening; 3. Have had any of the following clinical events within 3 months prior to Screening: o Non-fatal myocardial infarction; o Non-fatal stroke; o Non-elective coronary revascularization; and/or o Hospitalization for unstable angina and/or chest pain. 4. Have uncontrolled severe hypertension, defined as either systolic blood pressure >=160 mmHg or diastolic blood pressure >=100 mmHg prior to Randomization taken as the average of triplicate measurements. One triplicate retest will be allowed during the same visit, at which point if the retest result is no longer exclusionary, the participant may be randomized; 5. Have a formal diagnosis of homozygous FH; 6. Have active liver disease, defined as any known current infectious, neoplastic, or metabolic pathology of the liver; unexplained elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper limit of normal (ULN); or total bilirubin >2 x ULN at Screening; 7. Have glycosylated hemoglobin >=10.0% (>=0.100 hemoglobin fraction) or a fasting glucose >=270 mg/dL (>=15.0 mmol/L) at Screening; 8. Have thyroid-stimulating hormone >1.5 X ULN at Screening; 9. Have creatine kinase >3 x ULN at Screening; 10. Have a history of a malignancy that required surgery (excluding local and wide local excision), radiation therapy, and/or systemic therapy during the 3 years prior to Randomization; 11. Have a known history of alcohol and/or drug abuse within 5 years prior to Randomization; 12. Have received treatment with other investigational products or devices within 30 days of Screening or 5 half-lives of the previous investigational product, whichever is longer; 13.Are taking gemfibrozil; 14. Have planned use of other investigational products or devices during the course of the study; 15. Have participated in any clinical study evaluating obicetrapib; 16. Have a known allergy or hypersensitivity to the study drug, placebo, or any of the excipients in the study drug or placebo; or 17. Have any participant condition that, according to the Investigator, could interfere with the conduct of the study, such as, but not limited to, the following: o Are unable to communicate or to cooperate with the Investigator; o Are unable to understand the protocol requirements, instructions and study-related restrictions, and the nature, scope, and possible consequences of the study (including participants whose cooperation is doubtful due to drug abuse or alcohol dependency); o Are unlikely to comply with the protocol requirements, instructions, and study-related restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study); o Have any medical or surgical condition which, in the opinion of the Investigator, would put the participant at increased risk from participating in the study; or o Are directly involved in the conduct of the study. Other protocol-defined criteria apply.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-005064-22-NL |
| ClinicalTrials.gov | NCT05425745 |
| CCMO | NL81010.100.22 |