A Study of the Efficacy and Safety of MK-0653H in Japanese Participants With Hypercholesterolemia (MK-0653H-832)

A Phase III, Randomized, Active Comparator-controlled, Clinical Trial to Study the Efficacy and Safety of MK-0653H in Japanese Patients With Hypercholesterolemia.

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02741245

Enrollment

321

Registered

2016-04-18

Start date

2016-06-09

Completion date

2017-01-18

Last updated

2024-05-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypercholesterolemia

Brief summary

This study will evaluate the efficacy and safety and tolerability of 2 dose levels of MK-0653H in Japanese participants. The primary hypotheses are that the administration of MK-0653H is safe and tolerable and that MK-0653H is superior to single entity of Ezetimibe and Rosuvastatin in percent reduction from baseline in low-density lipoprotein-cholesterol (LDL-C) after 12 weeks of treatment.

Interventions

DRUGEzetimibe 10 mg

DRUGRosuvastatin 2.5 mg

DRUGPlacebo for Ezetimibe

DRUGPlacebo for Rosuvastatin

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

20 Years to 80 Years

Healthy volunteers

Inclusion criteria

* Japanese * Outpatient with hypercholesterolemia * Female participant who is of reproductive potential has to agree to remain abstinent or use (or partner use) two acceptable methods of birth control from date of signed informed consent to the 14 days after the last dose of study drug * Will maintain a stable diet that is consistent with the Japan Atherosclerosis Society Guideline 2012 (JAS 2012) for prevention of atherosclerotic cardiovascular diseases for the duration of the study

Exclusion criteria

* Uncontrolled hypertension (treated or untreated) * Uncontrolled type 1 or type 2 diabetes mellitus * History of coronary artery disease (CAD), CAD-equivalent disease * Familial hypercholesterolemia or has undergone LDL apheresis * Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins * Has had a gastrointestinal tract bypass, or other significant intestinal malabsorption * History of cancer within the past 5 years (except for successfully treated dermatological basal cell or squamous cell carcinoma or in situ cervical cancer) * Human Immunodeficiency Virus (HIV) positive * History of drug/ alcohol abuse within the past 5 years or psychiatric illness not adequately controlled and stable on pharmacotherapy * Consumes more than 25 g of alcohol per day * Currently following an excessive weight reduction diet * Currently engages in a vigorous exercise regimen (e.g.; marathon training, body building training etc.) or intends to start training during the study * Hypersensitivity or intolerance to Ezetimibe or Rosuvastatin * Myopathy or rhabdomyolysis with Ezetimibe or any statin * Pregnant or lactating * Taking any other investigational drugs and/or has taken any investigational drugs within 30 days

Design outcomes

Primary

Measure	Time frame	Description
Percentage Change From Baseline in Low-density Lipoprotein-cholesterol (LDL-C)	Baseline and Week 12	Participants had LDL-C levels assessed at baseline and after 12 weeks of study drug administration. The change from baseline was calculated. Results were reported as a M-estimate.
Percentage of Participants Who Experience at Least 1 Adverse Event (AE)	up to 14 weeks	An AE was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. The percentage of participants that reported at least 1 AE was summarized
Percentage of Participants Who Had Study Drug Discontinued Due to Adverse Event	up to 12 weeks	An AE was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. The percentage of participants that had study drug discontinued due to an AE was summarized.
Percentage of Participants Who Experience 1 or More Gastrointestinal-related AEs	up to 14 weeks	Gastrointestinal-related AEs included all preferred terms within system organ class of Gastrointestinal Disorders except Chapped Lips and Toothache.
Percentage of Participants Who Experience 1 or More Gallbladder-related AEs	up to 14 weeks	Gallbladder-related AEs included Bile Duct Obstruction, Bile Duct Stone, Bile Duct Stenosis, Biliary Colic, Cholangitis, Cholecystectomy, Cholecystitis, Cholelithiasis, Gallbladder Disorder, Gallbladder Perforation, Hepatic Pain, and Hydrocholecystis.
Percentage of Participants Who Experience 1 or More Allergic Reaction or Rash AEs	up to 14 weeks	Allergic Reaction or Rash AEs included Allergy to Arthropod Sting, Anaphylactoid Reaction, Anaphylactic Reaction, Anaphylatic Shock, Anaphylactoid Shock, Angioedema, Conjunctivitis Allergic, Contrast Media Reaction, Dermatitis, Dermatitis Allergic, Dermatitis Atopic, Dermatitis Bullous, Dermatitis Contact, Dermatitis Psoriasiform, Drug Hypersensitivity, Eczema, Eosinophila, Erythema, Eye Allergy, Face Oedema, Hypersensitivity, Mechanical Urticaria, Palmar Erythema, Periorbital Oedema, Photodermatosis, Photosensitivity Allergic reaction, Photosensitivity Reaction, Pigmentation Disorder, Pruritus, Pruritus Generalised, Rash, Rash Erythematous, Rash Follicular, Rash Generalised, Rash Maculo-Papular, Rash Papulosquamous, Rash Pruritic, Rash Pustular, Rash Vesicular, Rhinitis, Rhinitis Allergic, Rosacea, Skin Exfoliation, Skin Disorder, Skin Hyperpigmentation, Skin Lesion, Skin Mass, Skin Ulcer, Subcutaneous Nodule, Swelling Face, Systemic Lupus Erythematosus Rash, Urticaria.
Percentage of Participants Who Experience 1 or More Hepatitis-related AEs	up to 14 weeks	Hepatitis-related AEs included Cholestasis, Cytolytic Hepatitis, Hepatic Cyst, Hepatic Failure, Hepatic Lesion, Hepatic Necrosis, Hepatitis, Hepatitis Cholestatic, Hepatitis Fulminant, Hepatitis Infectious, Hepatocellular Injury, Hepatomegaly, Jaundice, Jaundice Cholestatic.
Percentage of Participants Who Experience Consecutive Elevations in Alanine Aminotransferase (ALT) ≥3 Times Upper Normal Limit (ULN)	up to 12 weeks	Participants had ALT levels assessed throughout the 12 week treatment period. Participants who had 2 consecutive assessments of ALT that were 3 x ULN or greater were recorded. The ALT ULN was 40 U/L.
Percentage of Participants Who Experience Consecutive Elevations in Aspartate Aminotransferase (AST) ≥3 Times Upper Normal Limit (ULN)	up to 12 weeks	Participants had AST levels assessed throughout the 12 week treatment period. Participants who had 2 consecutive assessments of AST that were 3 x ULN or greater were recorded. The AST ULN was 40 U/L..
Percentage of Participants Who Experience Consecutive Elevations in Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) ≥3 Times Upper Normal Limit (ULN)	up to 12 weeks	Participants had ALT and AST levels assessed throughout the 12 week treatment period. Participants who had 2 consecutive assessments of ALT and/or AST that were 3 x ULN or greater were recorded. The ALT and AST ULNs were 40 U/L.
Percentage of Participants Who Experience Elevation in Alanine Aminotransferase (ALT) ≥5 Times Upper Normal Limit (ULN)	up to 12 weeks	Participants had ALT levels assessed throughout the 12 week treatment period. Participants who had an assessments of ALT that was 5x ULN or greater were recorded. The ALT ULN was 40 U/L.
Percentage of Participants Who Experience Elevation in Aspartate Aminotransferase (AST) ≥5 Times Upper Normal Limit (ULN)	up to 12 weeks	Participants had AST levels assessed throughout the 12 week treatment period. Participants who had an assessments of AST that was 5x ULN or greater were recorded. The AST ULN was 40 U/L.
Percentage of Participants Who Experience Elevation in Alanine Aminotransferase (ALT) ≥10 Times Upper Normal Limit (ULN)	up to 12 weeks	Participants had ALT levels assessed throughout the 12 week treatment period. Participants who had an assessments of ALT that was 10x ULN or greater were recorded. The ALT ULN was 40 U/L.
Percentage of Participants Who Experience Elevation in Aspartate Aminotransferase (AST) ≥10 Times Upper Normal Limit (ULN)	up to 12 weeks	Participants had AST levels assessed throughout the 12 week treatment period. Participants who had an assessments of AST that was 10x ULN or greater were recorded. The AST ULN was 40 U/L.
Percentage of Participants Who Experience Consecutive Elevations in Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) ≥10 Times Upper Normal Limit (ULN)	up to 12 weeks	Participants had ALT and AST levels assessed throughout the 12 week treatment period. Participants who had 2 consecutive assessments of ALT and/or AST that were 10x ULN or greater were recorded. The ALT and AST ULNs were 40 U/L.
Percentage of Participants With Potential Hy's Law Condition	up to 12 weeks	Percentage of Participants with Potential Hy's Law Condition (defined as serum ALT or serum AST elevations \>3xULN, with serum alkalinephosphatase \<2xULN and total bilirubin (TBL) ≥2xULN) was summarized. The ALT and AST ULNs were 40 U/L. The ULN for alkaline phosphatase was 359 IU/L and the ULN for total bilirubin was 1.2 mg/dL.
Percentage of Participants Who Experience Elevations in Creatine Kinase (CK) ≥10 Times ULN	up to 12 weeks	Participants had creatine phosphokinase (CK) levels assessed throughout the 12 week treatment period. Participants who had any CK level that was ≥10 x ULN were recorded. The CK ULNs for males and females were 287 IU/L and 163 IU/L, respectively.
Percentage of Participants Who Experience Elevations in Creatine Kinase (CK) ≥10 Times ULN With Muscle Symptoms	up to 12 weeks	Participants had CK levels assessed throughout the 52 week treatment period. Participants who had any CK level that was ≥10 x ULN and had associated muscle symptoms present within +/- 7 days were recorded. The CK ULNs for males and females were 287 IU/L and 163 IU/L, respectively.
Percentage of Participants Who Experience Elevations in Creatine Kinase (CK) ≥10 Times ULN and Drug-Related Muscle Symptoms	up to 12 weeks	Participants had CK levels assessed throughout the 52 week treatment period. Participants who had any CK level that was ≥10 x ULN and had associated muscle symptoms present within +/- 7 days that were reported as at least possibly-related to study drug were recorded. The CK ULNs for males and females were 287 IU/L and 163 IU/L, respectively.

Participant flow

Participants by arm

Arm	Count
Ezetimibe 10 mg 1 Ezetimibe 10 mg tablet and 2 Rosuvastatin placebo capsules once daily for 12 weeks	35
Rosuvastatin 2.5 mg 1 Rosuvastatin 2.5 mg capsule, 1 Rosuvastatin placebo capsule and 1 Ezetimibe placebo tablet once daily for 12 weeks.	72
Rosuvastatin 5.0 mg 2 Rosuvastatin 2.5 mg capsules and Ezetimibe placebo tablet once daily for 12 weeks.	71
Ezetimibe 10 mg+ Rosuvastatin 2.5 mg 1 Ezetimbie 10 mg tablet, 1 Rosuvastatin 2.5 mg capsule and 1 Rosuvastatin placebo capsule once daily for 12 weeks.	71
Ezetimibe 10 mg+ Rosuvastatin 5.0 mg 1 Ezetimbie 10 mg tablet and 2 Rosuvastatin 2.5 mg capsules once daily for 12 weeks.	72
Total	321

Withdrawals & dropouts

Period	Reason	FG001	FG003	FG004
Overall Study	Adverse Event	0	2	2
Overall Study	Protocol Violation	1	1	0
Overall Study	Withdrawal by Subject	0	1	0

Baseline characteristics

Characteristic	Total	Ezetimibe 10 mg+ Rosuvastatin 5.0 mg	Ezetimibe 10 mg+ Rosuvastatin 2.5 mg	Rosuvastatin 5.0 mg	Rosuvastatin 2.5 mg	Ezetimibe 10 mg
Age, Continuous	57.0 Years STANDARD_DEVIATION 10.1	58.2 Years STANDARD_DEVIATION 10.6	56.0 Years STANDARD_DEVIATION 10.3	58.9 Years STANDARD_DEVIATION 9	55.7 Years STANDARD_DEVIATION 10.6	56.0 Years STANDARD_DEVIATION 8.9
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	321 Participants	72 Participants	71 Participants	71 Participants	72 Participants	35 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Sex: Female, Male Female	166 Participants	37 Participants	37 Participants	40 Participants	36 Participants	16 Participants
Sex: Female, Male Male	155 Participants	35 Participants	34 Participants	31 Participants	36 Participants	19 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 35	0 / 72	0 / 71	0 / 71	0 / 72
other Total, other adverse events	6 / 35	8 / 72	11 / 71	6 / 71	7 / 72
serious Total, serious adverse events	0 / 35	0 / 72	1 / 71	0 / 71	0 / 72

Outcome results

Primary

Percentage Change From Baseline in Low-density Lipoprotein-cholesterol (LDL-C)

Participants had LDL-C levels assessed at baseline and after 12 weeks of study drug administration. The change from baseline was calculated. Results were reported as a M-estimate.

Time frame: Baseline and Week 12

Population: All randomized participants who received at least 1 dose of study drug, had baseline or post-baseline data and had baseline data for those analyses that required baseline data.

Arm	Measure	Value (MEAN)
Ezetimibe 10 mg	Percentage Change From Baseline in Low-density Lipoprotein-cholesterol (LDL-C)	-18.7 Percentage Change
Rosuvastatin 2.5 mg	Percentage Change From Baseline in Low-density Lipoprotein-cholesterol (LDL-C)	-39.8 Percentage Change
Rosuvastatin 5.0 mg	Percentage Change From Baseline in Low-density Lipoprotein-cholesterol (LDL-C)	-47.2 Percentage Change
Ezetimibe 10 mg+ Rosuvastatin 2.5 mg	Percentage Change From Baseline in Low-density Lipoprotein-cholesterol (LDL-C)	-54.6 Percentage Change
Ezetimibe 10 mg+ Rosuvastatin 5.0 mg	Percentage Change From Baseline in Low-density Lipoprotein-cholesterol (LDL-C)	-60.5 Percentage Change

p-value: <0.00195% CI: [-39.9, -32]Shapiro-Wilk test

p-value: <0.00195% CI: [-18, -11.6]Shapiro-Wilk test

p-value: <0.00195% CI: [-45.8, -37.9]Shapiro-Wilk test

p-value: <0.00195% CI: [-16.6, -10.1]Shapiro-Wilk test

Primary

Percentage of Participants Who Experience 1 or More Allergic Reaction or Rash AEs

Allergic Reaction or Rash AEs included Allergy to Arthropod Sting, Anaphylactoid Reaction, Anaphylactic Reaction, Anaphylatic Shock, Anaphylactoid Shock, Angioedema, Conjunctivitis Allergic, Contrast Media Reaction, Dermatitis, Dermatitis Allergic, Dermatitis Atopic, Dermatitis Bullous, Dermatitis Contact, Dermatitis Psoriasiform, Drug Hypersensitivity, Eczema, Eosinophila, Erythema, Eye Allergy, Face Oedema, Hypersensitivity, Mechanical Urticaria, Palmar Erythema, Periorbital Oedema, Photodermatosis, Photosensitivity Allergic reaction, Photosensitivity Reaction, Pigmentation Disorder, Pruritus, Pruritus Generalised, Rash, Rash Erythematous, Rash Follicular, Rash Generalised, Rash Maculo-Papular, Rash Papulosquamous, Rash Pruritic, Rash Pustular, Rash Vesicular, Rhinitis, Rhinitis Allergic, Rosacea, Skin Exfoliation, Skin Disorder, Skin Hyperpigmentation, Skin Lesion, Skin Mass, Skin Ulcer, Subcutaneous Nodule, Swelling Face, Systemic Lupus Erythematosus Rash, Urticaria.

Time frame: up to 14 weeks