Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020) (REALIZE)
Primary Purpose
Hyperlipoproteinemia Type II, Hypercholesterolemia, Familial
Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Anacetrapib
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Hyperlipoproteinemia Type II
Eligibility Criteria
Inclusion Criteria:
- If of reproductive potential, must agree to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control for the duration of the study
- Diagnosed with Heterozygous Familial Hypercholesterolemia (HeFH)
- Have been treated with an optimal dose of statin for at least 6 weeks
Exclusion Criteria:
- Received treatment with low-density lipoprotein (LDL) apheresis within 4 weeks of screening or expect to undergo treatment with LDL apheresis during the course of the study
- Homozygous familial hypercholesterolemia
- Severe chronic heart failure
- Uncontrolled hypertension
- Uncontrolled cardiac arrhythmias, myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), unstable angina, or stroke within 3 months
- Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins
- Active or chronic hepatobiliary, hepatic, or gall bladder disease
- Pregnant or breast-feeding, or plans to become pregnant during the study or within 2 years after stopping study medication
- History of ileal bypass, gastric bypass, or other significant condition associated with malabsorption
- Human immunodeficiency virus (HIV) positive
- History of malignancy ≤5 years
- Donated blood products or has had phlebotomy of >300 mL within 8 weeks or intends to donate 250 mL of blood products or receive blood products within the projected duration of the study
- Currently taking medications that are potent inhibitors or inducers of cytochrome P450 3A4 (CYP3A) (including but not limited to cyclosporine, systemic itraconazole or ketoconazole, erythromycin, clarithromycin, or telithromycin, nefazodone, protease inhibitors, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St John's wort) or has discontinued treatment <3 weeks prior
- Consumes more than 2 alcoholic drinks per day
- Currently participating or has participated in a study with an investigational compound or device within 3 months
- Receiving treatment with systemic corticosteroids or taking systemic anabolic agents
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Anacetrapib
Placebo
Arm Description
Participants were administered one tablet of 100 mg anacetrapib orally once daily with a meal for 52 weeks during the treatment period.
Participants were administered one matching placebo tablet orally once daily with a meal for 52 weeks during the treatment period.
Outcomes
Primary Outcome Measures
Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) - Treatment Phase
LDL-C levels were measured at baseline and week 52 (or at discontinuation) using a beta quantification method. The Treatment Phase was the period from the date of the participant's first dose of study treatment (randomization visit, Visit 3) to the participant's last visit on treatment (discontinuation visit or Visit 8 [Week 52]).
Percentage of Participants With Any Adverse Event - Treatment Phase
An adverse event (AE) or experience was any unfavorable and unintended change in the structure (signs), function (symptoms), or chemistry (laboratory data) of the body temporally associated with any use of a study treatment, whether or not considered related to the use of the study treatment. Any worsening of a preexisting condition which was temporally associated with the use of the study treatment is also an AE. The percentage of participants with any adverse event during the treatment phase is presented.
Percentage of Participants With Any Treatment-Related Adverse Event - Treatment Phase
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of the treatment. Any worsening of a preexisting condition which was temporally associated with the use of the study treatment was also an AE. AEs reported by the investigator as definitely, probably or possibly related to study treatment were considered treatment-related. The percentage of participants with any treatment-related adverse event during the treatment phase is presented.
Percentage of Participants With Any Serious Adverse Event - Treatment Phase
A serious adverse experience (SAE) was any adverse event that occurred at any dose that resulted in death or was life threatening, resulted in a persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, or was a congenital anomaly/birth defect. The percentage of participants with any serious adverse event during the treatment phase is presented.
Percentage of Participants Discontinuing Study Treatment Due to an Adverse Event - Treatment Phase
An adverse event (AE) was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of the drug. Any worsening of a preexisting condition which was temporally associated with the use of the study drug was also an AE. The percentage of participants who discontinued study treatment due to an AE during the treatment phase is presented.
Percentage of Participants With Changes in Systolic Blood Pressure (SBP) >= 10 mm Hg
Participants had SBP assessed at baseline and throughout the 52-week treatment period. Percentage of participants who had a SBP reading that was >= 10 mm Hg higher than their baseline SBP for any assessment performed during the treatment phase is presented.
Percentage of Participants With Changes in SBP >= 15 mm Hg
Participants had SBP assessed at baseline and throughout the 52-week treatment period. The percentage of participants who had a SBP reading that was >= 15 mm Hg higher than their baseline SBP for any assessment performed during the treatment phase is presented.
Percentage of Participants With Changes in Diastolic Blood Pressure (DBP) >= 10 mm Hg
Participants had DBP assessed at baseline and throughout the 52-week treatment period. The percentage of participants who had a DBP reading that was >= 10 mm Hg higher than their baseline DBP for any assessment performed during the treatment phase is presented.
Percentage of Participants With Sodium Levels > Upper Limit of Normal (ULN)
Participants had sodium levels assessed throughout the 52-week treatment period. The percentage of participants who had any sodium level that was greater than the ULN of 145 mEq/L during the treatment phase is presented.
Percentage of Participants With Chloride Levels > ULN
Participants had chloride levels assessed throughout the 52-week treatment period. The percentage of participants who had any chloride level that was > the ULN of 110 mEq/L during the treatment phase is presented.
Percentage of Participants With Potassium Levels < Lower Limit of Normal (LLN)
Participants had potassium levels assessed throughout the 52-week treatment period. The percentage of participants who had any potassium level that was < the LLN of 3.5 mEq/L during the treatment phase is presented.
Percentage of Participants With Bicarbonate Levels > ULN
Participants had bicarbonate levels assessed throughout the 52-week treatment period. The percentage of participants who had any bicarbonate level that was > the ULN of 33 mEq/L during the treatment phase is presented.
Percentage of Participants With Consecutive Changes in Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) of >=3 x ULN
Participants had AST and ALT levels assessed throughout the 52-week treatment period. The percentage of participants who had 2 consecutive assessments of either AST or ALT that were 3 x ULN or greater during the treatment phase is presented.
Percentage of Participants With Creatine Kinase (CK) Level >=10 x ULN
Participants had CK levels assessed throughout the 52-week treatment period. The percentage of participants who had any CK level that was >=10 x ULN during the treatment phase is presented.
Percentage of Participants With CK Level >=10 x ULN With Muscle Spasms
Participants had CK levels assessed throughout the 52-week treatment period. The percentage of participants who had any CK level that was >=10 x ULN and had associated muscle spasms during the treatment phase is presented.
Percentage of Participants Adjudicated Cardiovascular (CV) SAE
An AE or suspected adverse reaction was considered an SAE if it resulted in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. All events were adjudicated by an expert committee independent of the Sponsor. The percentage of participants that experienced adjudicated SAEs of CV death, non-fatal stroke, non-fatal myocardial infarction, or unstable angina during the treatment phase is presented.
Percentage of Participants Who Died From Any Cause - Treatment Phase
The percentage of participants who died from any cause during the treatment phase is presented. All deaths were adjudicated by an expert committee independent of the Sponsor.
Secondary Outcome Measures
Percent Change From Baseline in High-Density Lipoprotein Cholesterol Levels
The efficacy of adding anacetrapib 100 mg relative to placebo on plasma concentrations of high-density lipoprotein cholesterol (HDL-C) was evaluated at Week 0 (start of treatment phase) and Week 52 (end of treatment phase) or at discontinuation.
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol Levels
The efficacy of adding anacetrapib 100 mg was evaluated relative to placebo on plasma concentrations of non-high-density lipoprotein cholesterol (HDL-C) for the FAS population at Week 0 (start of treatment phase) and Week 52 (end of treatment phase) or at discontinuation.
Percent Change From Baseline in Apolipoprotein (Apo) B Levels
The efficacy of adding anacetrapib 100 mg was evaluated relative to placebo on plasma concentrations of apolipoprotein (Apo) B for the FAS population at Week 0 (start of treatment phase) and Week 52 (end of treatment phase) or at discontinuation.
Percent Change From Baseline in Apolipoprotein (Apo) A-1 Levels
The efficacy of adding anacetrapib 100 mg was evaluated relative to placebo on plasma concentrations of Apo A-1 for the FAS population at Week 0 (start of treatment phase) and Week 52 (end of treatment phase) or at discontinuation.
Percent Change From Baseline in Lipoprotein(a) (Lp[a]) Levels
The efficacy of adding anacetrapib 100 mg was evaluated relative to placebo on plasma concentrations of lipoprotein(a) (Lp[a]) for the FAS population at Week 0 (start of treatment phase) and Week 52 (end of treatment phase) or at discontinuation.
Full Information
NCT ID
NCT01524289
First Posted
January 30, 2012
Last Updated
September 27, 2019
Sponsor
Merck Sharp & Dohme LLC
1. Study Identification
Unique Protocol Identification Number
NCT01524289
Brief Title
Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
Acronym
REALIZE
Official Title
A 1-Year, Worldwide, Multicenter, Double-Blind, Randomized, Parallel, Placebo-Controlled Study to Assess the Efficacy and Tolerability of Anacetrapib When Added to Ongoing Statin Therapy With or Without Other Lipid Modifying Medication(s) in Patients With Heterozygous Familial Hypercholesterolemia
Study Type
Interventional
2. Study Status
Record Verification Date
September 2019
Overall Recruitment Status
Completed
Study Start Date
February 3, 2012 (Actual)
Primary Completion Date
February 12, 2014 (Actual)
Study Completion Date
November 13, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck Sharp & Dohme LLC
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The objective of this study is to evaluate the efficacy and tolerability of adding anacetrapib to ongoing statin therapy in participants with heterozygous familial hypercholesterolemia (HeFH).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyperlipoproteinemia Type II, Hypercholesterolemia, Familial
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
306 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Anacetrapib
Arm Type
Experimental
Arm Description
Participants were administered one tablet of 100 mg anacetrapib orally once daily with a meal for 52 weeks during the treatment period.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants were administered one matching placebo tablet orally once daily with a meal for 52 weeks during the treatment period.
Intervention Type
Drug
Intervention Name(s)
Anacetrapib
Other Intervention Name(s)
MK-0859
Intervention Description
One oral tablet, orally once daily for 52 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
One oral tablet once daily for 52 weeks
Primary Outcome Measure Information:
Title
Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) - Treatment Phase
Description
LDL-C levels were measured at baseline and week 52 (or at discontinuation) using a beta quantification method. The Treatment Phase was the period from the date of the participant's first dose of study treatment (randomization visit, Visit 3) to the participant's last visit on treatment (discontinuation visit or Visit 8 [Week 52]).
Time Frame
Baseline and Week 52
Title
Percentage of Participants With Any Adverse Event - Treatment Phase
Description
An adverse event (AE) or experience was any unfavorable and unintended change in the structure (signs), function (symptoms), or chemistry (laboratory data) of the body temporally associated with any use of a study treatment, whether or not considered related to the use of the study treatment. Any worsening of a preexisting condition which was temporally associated with the use of the study treatment is also an AE. The percentage of participants with any adverse event during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With Any Treatment-Related Adverse Event - Treatment Phase
Description
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of the treatment. Any worsening of a preexisting condition which was temporally associated with the use of the study treatment was also an AE. AEs reported by the investigator as definitely, probably or possibly related to study treatment were considered treatment-related. The percentage of participants with any treatment-related adverse event during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With Any Serious Adverse Event - Treatment Phase
Description
A serious adverse experience (SAE) was any adverse event that occurred at any dose that resulted in death or was life threatening, resulted in a persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, or was a congenital anomaly/birth defect. The percentage of participants with any serious adverse event during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants Discontinuing Study Treatment Due to an Adverse Event - Treatment Phase
Description
An adverse event (AE) was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of the drug. Any worsening of a preexisting condition which was temporally associated with the use of the study drug was also an AE. The percentage of participants who discontinued study treatment due to an AE during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With Changes in Systolic Blood Pressure (SBP) >= 10 mm Hg
Description
Participants had SBP assessed at baseline and throughout the 52-week treatment period. Percentage of participants who had a SBP reading that was >= 10 mm Hg higher than their baseline SBP for any assessment performed during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With Changes in SBP >= 15 mm Hg
Description
Participants had SBP assessed at baseline and throughout the 52-week treatment period. The percentage of participants who had a SBP reading that was >= 15 mm Hg higher than their baseline SBP for any assessment performed during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With Changes in Diastolic Blood Pressure (DBP) >= 10 mm Hg
Description
Participants had DBP assessed at baseline and throughout the 52-week treatment period. The percentage of participants who had a DBP reading that was >= 10 mm Hg higher than their baseline DBP for any assessment performed during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With Sodium Levels > Upper Limit of Normal (ULN)
Description
Participants had sodium levels assessed throughout the 52-week treatment period. The percentage of participants who had any sodium level that was greater than the ULN of 145 mEq/L during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With Chloride Levels > ULN
Description
Participants had chloride levels assessed throughout the 52-week treatment period. The percentage of participants who had any chloride level that was > the ULN of 110 mEq/L during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With Potassium Levels < Lower Limit of Normal (LLN)
Description
Participants had potassium levels assessed throughout the 52-week treatment period. The percentage of participants who had any potassium level that was < the LLN of 3.5 mEq/L during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With Bicarbonate Levels > ULN
Description
Participants had bicarbonate levels assessed throughout the 52-week treatment period. The percentage of participants who had any bicarbonate level that was > the ULN of 33 mEq/L during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With Consecutive Changes in Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) of >=3 x ULN
Description
Participants had AST and ALT levels assessed throughout the 52-week treatment period. The percentage of participants who had 2 consecutive assessments of either AST or ALT that were 3 x ULN or greater during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With Creatine Kinase (CK) Level >=10 x ULN
Description
Participants had CK levels assessed throughout the 52-week treatment period. The percentage of participants who had any CK level that was >=10 x ULN during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants With CK Level >=10 x ULN With Muscle Spasms
Description
Participants had CK levels assessed throughout the 52-week treatment period. The percentage of participants who had any CK level that was >=10 x ULN and had associated muscle spasms during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants Adjudicated Cardiovascular (CV) SAE
Description
An AE or suspected adverse reaction was considered an SAE if it resulted in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. All events were adjudicated by an expert committee independent of the Sponsor. The percentage of participants that experienced adjudicated SAEs of CV death, non-fatal stroke, non-fatal myocardial infarction, or unstable angina during the treatment phase is presented.
Time Frame
Up to 52 weeks
Title
Percentage of Participants Who Died From Any Cause - Treatment Phase
Description
The percentage of participants who died from any cause during the treatment phase is presented. All deaths were adjudicated by an expert committee independent of the Sponsor.
Time Frame
Up to 52 weeks
Secondary Outcome Measure Information:
Title
Percent Change From Baseline in High-Density Lipoprotein Cholesterol Levels
Description
The efficacy of adding anacetrapib 100 mg relative to placebo on plasma concentrations of high-density lipoprotein cholesterol (HDL-C) was evaluated at Week 0 (start of treatment phase) and Week 52 (end of treatment phase) or at discontinuation.
Time Frame
Baseline and Week 52
Title
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol Levels
Description
The efficacy of adding anacetrapib 100 mg was evaluated relative to placebo on plasma concentrations of non-high-density lipoprotein cholesterol (HDL-C) for the FAS population at Week 0 (start of treatment phase) and Week 52 (end of treatment phase) or at discontinuation.
Time Frame
Baseline and Week 52
Title
Percent Change From Baseline in Apolipoprotein (Apo) B Levels
Description
The efficacy of adding anacetrapib 100 mg was evaluated relative to placebo on plasma concentrations of apolipoprotein (Apo) B for the FAS population at Week 0 (start of treatment phase) and Week 52 (end of treatment phase) or at discontinuation.
Time Frame
Baseline and Week 52
Title
Percent Change From Baseline in Apolipoprotein (Apo) A-1 Levels
Description
The efficacy of adding anacetrapib 100 mg was evaluated relative to placebo on plasma concentrations of Apo A-1 for the FAS population at Week 0 (start of treatment phase) and Week 52 (end of treatment phase) or at discontinuation.
Time Frame
Baseline and Week 52
Title
Percent Change From Baseline in Lipoprotein(a) (Lp[a]) Levels
Description
The efficacy of adding anacetrapib 100 mg was evaluated relative to placebo on plasma concentrations of lipoprotein(a) (Lp[a]) for the FAS population at Week 0 (start of treatment phase) and Week 52 (end of treatment phase) or at discontinuation.
Time Frame
Baseline and Week 52
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
If of reproductive potential, must agree to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control for the duration of the study
Diagnosed with Heterozygous Familial Hypercholesterolemia (HeFH)
Have been treated with an optimal dose of statin for at least 6 weeks
Exclusion Criteria:
Received treatment with low-density lipoprotein (LDL) apheresis within 4 weeks of screening or expect to undergo treatment with LDL apheresis during the course of the study
Homozygous familial hypercholesterolemia
Severe chronic heart failure
Uncontrolled hypertension
Uncontrolled cardiac arrhythmias, myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), unstable angina, or stroke within 3 months
Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins
Active or chronic hepatobiliary, hepatic, or gall bladder disease
Pregnant or breast-feeding, or plans to become pregnant during the study or within 2 years after stopping study medication
History of ileal bypass, gastric bypass, or other significant condition associated with malabsorption
Human immunodeficiency virus (HIV) positive
History of malignancy ≤5 years
Donated blood products or has had phlebotomy of >300 mL within 8 weeks or intends to donate 250 mL of blood products or receive blood products within the projected duration of the study
Currently taking medications that are potent inhibitors or inducers of cytochrome P450 3A4 (CYP3A) (including but not limited to cyclosporine, systemic itraconazole or ketoconazole, erythromycin, clarithromycin, or telithromycin, nefazodone, protease inhibitors, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St John's wort) or has discontinued treatment <3 weeks prior
Consumes more than 2 alcoholic drinks per day
Currently participating or has participated in a study with an investigational compound or device within 3 months
Receiving treatment with systemic corticosteroids or taking systemic anabolic agents
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Merck Sharp & Dohme LLC
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php
Citations:
PubMed Identifier
25743173
Citation
Kastelein JJ, Besseling J, Shah S, Bergeron J, Langslet G, Hovingh GK, Al-Saady N, Koeijvoets M, Hunter J, Johnson-Levonas AO, Fable J, Sapre A, Mitchel Y. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet. 2015 May 30;385(9983):2153-61. doi: 10.1016/S0140-6736(14)62115-2. Epub 2015 Mar 3.
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Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
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