Study to Determine the Effect of Repeated Administration of Diltiazem on the Pharmacokinetics of Darapladib (Sb-480848).

An Open-Label, Three Period, Single Sequence Study To Determine The Effect Of Repeat Oral Dosing Of Diltiazem On The Pharmacokinetics Of Repeat Oral Dosing Of Darapladib (SB-480848).

Darapladib (SB-480848) is a novel, selective, orally active inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2) currently under clinical development by GlaxoSmithKline as a potential anti-atherosclerosis agent for reduction of major adverse cardiovascular (CV) events in patient populations with chronic coronary heart disease and after an acute coronary syndrome.

This study will determine the effect of repeated administration of diltiazem on the pharmacokinetics of a repeated administration of darapladib. A drug interaction study with a moderate CYP3A4 inhibitor is warranted to provide guidance to prescribing physicians.

Study Overview

• Status: Completed
• Conditions: Atherosclerosis
• Intervention / Treatment: Drug: Darapladib; Drug: Diltiazem

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21225
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female aged between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and ECG.
• A subject with an alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase or bilirubin laboratory result outside the reference range may be included only if both the Investigator and the GSK Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• BMI within the range 19-37 kilogram per square meter (kg/m2) (inclusive).
• A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy [for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 milli-international units per milliliter (MlU/ml) and estradiol < 40 picogram/milliliter [(pg/ml) (<147 pmol/L) is confirmatory].
• A female subject is eligible to participate if she is of Child-bearing potential and is abstinent or agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the final follow-up visit.
• A female subject is eligible to participate if she is of Child-bearing potential and has only same-sex partners, when this is her preferred and usual lifestyle.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
• Single QT duration corrected for heart rate by Fridericia's formula (QTcF) < 450 Millisecond (msec)

Exclusion Criteria:

• A subject will not be eligible for inclusion in this study if any of the following criteria apply:

Criteria Based Upon Medical Histories

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.
• History of sensitivity to heparin or heparin-induced thrombocytopenia.
• History of sensitivity to any of the study medications, including diltiazem, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
• Any contraindications for diltiazem administration.
• Any condition that, in the opinion of the investigator, presents undue risk from the study medications, including diltiazem, or procedures.
• Requiring the use of oral or injectable strong Cytochrome P450 (CYP3) A4 inhibitors or use of other CYP3A4 inhibitor/inducers within 14 days prior to dosing.
• History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions
• Clinical criteria for diagnosing anaphylaxis or severe allergic response. Criteria Based Upon Diagnostic Assessments
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• A positive pre-study drug/alcohol screen.
• A positive test for human immunodeficiency virus (HIV) antibody.
• Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at screening or prior to dosing.

Other Criteria

• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Lactating females.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
• Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
• Unwillingness or inability to follow the procedures outlines in the protocol.
• Subject is mentally or legally incapacitated.
• Consumption of grapefruit or grapefruit juice within 7 days prior to the first dose of study medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Darapladib+Diltizem Arm; Each subject will receive darapladib EC tablet 160 mg once daily for 10 days followed by darapladib EC tablet 160 mg once daily + diltiazem 240mg once daily for 14 days and then diltiazem 240mg once daily alone for three days	Drug: Darapladib; Enteric coated, free base (micronized) white round tablet, 160mg, Oral/repeat dose/10 days (Treatment Period 1), 14 days (Treatment Period 2); Drug: Diltiazem; Extended release, Blue capsule imprinted with cardizem CD and 240mg on one end, 240 mg, Oral/repeat dose/17 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC(0-24h) of darapladib	The area under the concentrations-time curve (AUC0-24) from the time of administration of darapladib up to 24 h after administration.	Up to 32 days. (PK samples will be collected on Days 8, 9, 26 and 27 at predose. Day 10 and Day 28 predose and at 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24, 32, 48, 72, and 96 hours post-dose)
Cmax of darapladib	The maximum concentration (Cmax) was obtained directly from the measured concentration-time curves.	Up to 32 days. (PK samples will be collected on Days 8, 9, 26 and 27 at predose. Day 10 and Day 28 predose and at 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24, 32, 48, 72, and 96 hours post-dose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with adverse event (AE).	AE's will be collected from the start of study treatment to the last follow up.	Up to 70 days.
12-Lead electrocardiogram (ECG) assessment as a measure of safety and tolerability	Single 12-lead ECGs will be obtained after the subject has been in a supine position for at least 10 minutes at each timepoint during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals.	Up to 42 days. (Screening Day 32 and Follow up [Day 38 to 42]).
Vital signs assessment as a measure of safety and tolerability	Systolic and diastolic blood pressure and pulse rate measurements will be recorded after the subject has been resting in a semi-supine or supine position for at least 10 minutes.	Up to 42 days (Screening, Day -1, 15, 16, 22, 28, 32 and Follow up [Day 38 to 42]).
Safety laboratory tests assessment as a measure of safety and tolerability	Hematology, clinical chemistry, urinalysis were assessed.	Up to 42 days (Screening, Day -1, 15, 32 and Follow up [Day 38 to 42]).
Tmax and t1/2 of darapladib.	Tmax is defined as the time required reaching the maximum concentration of the drug in the plasma after its administration. t1/2 is defined as the time taken to reach half the concentration of the drug after administration.	Up to 32 days (PK samples will be collected on Days 8, 9, 26 and 27 at predose. Day 10 and Day 28 predose and at 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24, 32, 48, 72, and 96 hours post-dose.

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 14, 2013
• Primary Completion (ACTUAL): September 30, 2013
• Study Completion (ACTUAL): September 30, 2013

Study Registration Dates

• First Submitted: May 9, 2013
• First Submitted That Met QC Criteria: May 9, 2013
• First Posted (ESTIMATE): May 13, 2013

Study Record Updates

• Last Update Posted (ACTUAL): July 13, 2017
• Last Update Submitted That Met QC Criteria: July 10, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Atherosclerosis; healthy volunteer; CYP3A4; Drug interaction; Lp-PLA2
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Phospholipase A2 Inhibitors; Darapladib; Diltiazem
• Other Study ID Numbers: 115679

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Clinical Study Report
   Information identifier: 115679
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Study Protocol
   Information identifier: 115679
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Annotated Case Report Form
   Information identifier: 115679
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Individual Participant Data Set
   Information identifier: 115679
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Statistical Analysis Plan
   Information identifier: 115679
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Informed Consent Form
   Information identifier: 115679
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Dataset Specification
   Information identifier: 115679
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register